Bad Blood, Bad Writing

After watching the episode of Grey's Anatomy called 'Bad Blood', it is time to call out the writer, Jeannine Renshaw. Usually, ‘Grey's’ will leave well enough alone when it comes to laboratory medicine, but this episode crossed the line in so many ways. Basically it was about a trauma victim who was a Jehovah Witness with a living will that explicitly stated no blood products to be transfused. Of course one of the self righteous characters had to try and smuggle a unit of blood into ICU to transfuse to the patient, and was caught by the wise and all seeing Christine Yang. How many transfusion medicine practitioners were appalled at this scene? Does the general public still accept the notion that blood and blood products float through the hospital setting to be used at the Doctor's whim? One couldn't help but notice that the unit in the scene had been pierced, so it was basically useless. Couldn't the scene had been a bit more realistic, or at least a disclaimer at the bottom stating that in an actual hospital blood and blood products are diligently monitored? After all is television the medium that has those disclaimers in car commercials "driven by professional driver in a closed course"? What is most frustrating is that after all the work that has been done to regain the public’s trust in transfusion medicine; one episode can blow it back into the Stone Age.

Twenty eight percent

It has been a while since the last posting. The goal this year was to have 52 posts (one/week) starting Sept. 19th. So far, 15 have been posted, a completion rate of 28.8%, a little of a quarter of a way done. The last one posted was on Dec. 28th,2011.
So why the delay?
Credit goes to Dave Crenshaw, author of “The Myth of Multitasking.” After reading this small, yet very informative book, one will look at multitasking as the fallacy it is. Explaining why would do the book and Mr. Crenshaw a disservice, break down and buy the book.
How does this affect the Labvocate?
Currently, the Labvocate is in the middle of a project that has to be done. The Labvocate was under the illusion that this project and writing posts at the same time could be accomplished. The reality is that neither occurred.
Multitasking is a myth.
Long live dedication to a single project till it is completed!

RFID in Transfusion Medicine

Radio Frequency Identification (RFID), or as it is also known as, Dedicated Short Range Communication (DSRC), is a technology that helps track an animal, person, or object. It does this by using a radio signal to locate what it is searching for. Unlike a barcode, it does not require direct contact or light-of-sign scanning.
There are three components in a RFID system; an antenna, transceiver and a transponder. The antenna sends out a radio frequency wave that is picked up by the transponder which sends back a signal. An example could a warehouse that wants to keep track of how boxes are in it. Each box will have a tag on it that has a transponder on it. An antenna will send out a radio wave that will activate the transponder on the tag to send a signal back. The transceiver will then receive this signal, and then a computer will not only count how many boxes respond, but where each box is in the warehouse.
This technology is being used in Transfusion Medicine. Of all the disciplines in Medical Laboratory Science, Transfusion Medicine is the only one where the end result (a blood product) will be given to the patient. Sometimes a transfusion reaction can occur from the blood product can cause a reaction to the patient, some of the most serious as a result of improper collection, processing or administration.
In any laboratory procedure, it is broken up into three main stages, pre-analytical, analytical, and post analytical.
In the pre-analytical stage, it is the proper collection of the specimen. This stage relies on properly identifying the patient and collecting the right specimens. If a three unit crossmatch is ordered for Mr. John Smith in Room 309, collecting a specimen from Mr. Jon Smythe of Room 903 will cause more harm then good. If Mr. Smythe in Room 903 needs a CBC, collecting a throat swab would be useless.
How RFID helps in the pre-analytical stage is that the person collecting the specimen receives a Transfusion Request Form (TRF) which then produces a label with a tag on it. At the patient’s bedside, the phlebotomist uses an RFID reader that confirms their ID from a tag on their ID bracelet. After the sample is collected and the label is put on it, it will then be scanned generating an electronic signature and updating the status of the specimen collection. The specimen will then be brought to the lab for testing.
At the analytical stage, the specimens will be processed, and RFID will signal whether or not the blood products are compatible with the patient.
In the post analytical stage, when the RN transports the blood product, one of two things can happen once it is transported to the ward. One, it can be transfused immediately, or something occurs that postpone transfusion. What happens to that blood product, for example a unit of blood? Packed red cells cannot stay out of a fridge longer than 30 minutes before transfusion. If the RN can document that the unit is put in a suitable fridge on the ward within 30 minutes, the unit does not have to be returned to the lab, and it can be used later. RFID allows the RN this option. While RFID cannot measure temperature, it can measure that the unit is put in the fridge, and for how long.
If there is no delay, RFID can be used to confirm that the blood product is the correct one the patient is to receive. This is done by using the RFID reader to read the tag on the patient’s armband and the tag on the unit. A mismatch will sound an alarm and prevent a mistake.
RFID has potential cost savings, especially those associated with Risk Management. Each hospital will have to determine if their organization would benefit from this technology. Currently, this system is not being used by the Canadian Blood Services, although some hospitals in the U.S. are. There is the argument that common sense and following standard operating procedures negate any reason for using RFID.
But then again that was what they said about computers and barcodes 15 years ago.

The Lowly Tape Measure-Newest Diagnostic Tool for Heart Disease

It has long been know that cardiovascular disease is the major cause of death in the developed world. Since 1948 with the groundbreaking study of the population of Framingham, Massachusetts, the risk factors of hypertension, elevated cholesterol and stress were identified.
A recent study, the Interheart study (http://www.medscape.com/viewarticle/489738) took the study of risk factors to an international level, including lower and middle income countries. Nine common factors were determined to contribute to heart disease; increased ApoB/apoA1 ratio, smoking, diabetes, hypertension, abdominal obesity, psychological factors, daily consumption of vegetables and fruit, exercise and alcohol intake.
So what’s the difference between obesity and abdominal obesity?
Abdominal obesity is defined as the accumulation of abdominal fat resulting in an increased waist size. For men it is defined as having a waist of more than 40 inches, 35 inches for women.
There you have it. Two diagnostic tests are required to determine your cardiovascular risk. One is a blood test that requires a blood specimen. The other involves a tape measure. Simply take the tape measure, wrap it around your waist at belly button limit and see what your risk factor is. Both are necessary, and will affect the other.

MDR/XDT TB and Carbapenem

The ‘White Plague’, or as it is commonly known Tuberculosis (TB) is making a comeback in not only the rest of the world, but in North America as well. HIV is helping the spread, an immuno-compromised patient be more susceptible than a healthy person.
In 2009, it was estimated by WHO that there were 9.4 new cases of TB. 3.3 % of these new cases (approximately 250,000 patients) had Multi Drug Resistant (MDR) TB. The criteria for a TB strain to be classified as MDR is to be resistant to the traditional treatment of isoniazid and rimfampin. In 2008, MDR was estimated to have killed 150,000.
To make matters worse, an even more strain strain has emerged, Extensively Drug-Resistant (XDR) TB. This strain is not only resistant to isoniazid and rimfampin, it is also immune to a fluoroquinolone and resistant to injectable amikacin, kanamycin or capreomycin.
With the exception of fluoroquinolones, there hasn’t been any new anti-TB antibiotics introduced for treatment.
TB was one of the first organisms that penicillin was not able to treat. The causative organism of TB, Mycobacterium tuberculosis, naturally produces a chemical called beta-lactamase which inhibits the active ingredient of penicillin, beta lactam, from working.
Recently though, researchers (http://www.einstein.yu.edu/home/news.asp?id=305 ) found that by combing two different drugs together, XDR TB could be killed in a laboratory setting. These two drugs were Clavulanic acid and meropenem ( a Carbapenem) .
Clavulanic acid by itself has no therapeutic effect. What it does do is neutralize beta-lactamases produced by bacteria. Unable to destroy the beta-lactam of the antibiotic, drugs such as penicillin can destroy the bacteria.
When Clavulanic acid is combined with a meropenem (a beta-lactam antibiotic), they can effectively destroy TB in a lab setting, but can they be used in a clinically setting?
In 2010, Belgium doctors treating a 14-year-old girl from Chechnya with XDR-TB with answered that question. With no other options to treat the acutely ill and malnourished patient, Clavulanic acid and meropenem produced positive results in eleven weeks. (http://www.stoptb.org/news/stories/2011/ns11_035.asp)
This is indeed positive news, but some cold realities have to be faced.
First of all, these drugs have to be administered intravenously. That not only requires an infrastructure to be put into place to provide patients this service, there is also the risks associated with long-term I.V. therapy (ie infection).
Secondly, there is the cost of these drugs.
Thirdly, clinical studies will have to be done to prove it’s effectiveness.
Finally, there is the possibility that resistance may develop to this combination. After all meropenem has recently been found to b useless against New Delhi metallo-beta-lactamase-1 (NDM-1) an enzyme at produces undetectable resistance to Beta-lactam drugs.
But hopefully this will prove to help with the global fight against TB.

Genotyping and Coronary Heart Disease

The quest for screening for heart disease is now gone to the genetic level. While it is still beneficial to screen using the traditional tests of cholesterol and triglyceride, the trend is to find more sensitive markers of heart disease.
One possibility was the discovery of the Trp719 Arg Polymorphism in Kinesin-Like Protein-6. Found in 30% of the population in Caucasians, African-Americans and Asians, it held promise as not only as a marker of heart disease, but by identifying patients with this variant it was found they were more responsive to Statin therapy (http://content.onlinejacc.org/cgi/content/short/51/4/449).
A new test was developed to test for this genotype to identify patients and put them on statin therapy.
Unfortunately, recent studies (http://www.medpagetoday.com/Cardiology/Dyslipidemia/25643) have indicated that testing for this genotype has no clinical value.
There is one genetic marker that has been found to be a reliable marker for cardiac disease, the Chromosome 9p21 region. In fact one study (http://www.ncbi.nlm.nih.gov/pubmed/22022235) found that the risk of MI and CVD conferred by Chromosome 9p21 SNPs appears to be modified by a prudent diet high in raw vegetables and fruits.
Could screening for this genotype be used to identify patients needing a dietary change to prevent heart disease?
If Chromosome 9p21 SNPs are a marker for heart disease that can be prevented by switching to a diet of raw fruit and vegetables, lipid testing will be just as important to make sure that the diet is reversing dyslipidaemia and heart disease risk.
On Oct.3, 2011, Warnex medical laboratories announced that they have “an exclusive distribution agreement in Canada for 10 of deCODE Genetics' DNA-based tests for assessing the risk of developing certain common diseases.” This will include the “deCODE MITM - Assesses the risk of myocardial infarction (heart attack). The test detects 8 SNPs in the sequence of the genome associated with risk of heart attack. These include the chromosome 9p21 variants discovered by deCODE, the highest impact and best validated genetic risk factors for heart attack yet found. The test provides a novel means of detecting the substantial genetic component to overall susceptibility to heart attack, risk that appears to be independent of well known risk factors such as elevated cholesterol and hypertension.”
It will be interesting if testing for chromosome 9p21 variants will supplement or replace lipd testing. As for KIF6, for now it seems that researchers agree to disagree about it’s clinical usefulness..for now.

Sensitivity vs. Specificity

Sensitivity vs. Specificity
When it comes to medicine, nothing is carved in stone, which is one issue this blog takes with medical dramas in the mainstream media; one test a diagnosis does not always make. In these dramas, a test is ordered, i.e. HIV, the result comes back, and the audience is lead to believe that it is infallible and the storyline continues.
Unfortunately, in the real three dimensional world of flesh and blood, this is not the case. Every diagnostic procedure has its limitations. In the medical laboratory, two terms are used to define them; specificity and sensitivity.
One can ask, aren’t these two of the same thing?
Specificity is the quality or condition of being specific and being specific is sharing or being those properties of something that allow it to be referred to a particular category.
Sensitivity is the quality of being sensitive, sensitive being capable of indicating minute differences.
(Thanks to http://www.merriam-webster.com/dictionary/specific for providing the definitions of these two terms).
So how does this relate to a diagnostic test? Every diagnostic procedure has one of two outcomes; it’s either positive or negative. The question that has to be asked though is it a true positive or a true negative? And on the other side of the coin, is it a false positive or a false negative?
This is always a little earth shattering in medicine when this simple truth is blurted out, sort of like being told that Santa Claus was actually your uncle, and that there’s no Easter Bunny. Unfortunately its reality and it goes back to the observation made in the first paragraph, one test a diagnosis does not always make.
Fortunately specificity and sensitivity help bring some stability to this shaky ground. When any diagnostic procedure is developed, it has to be tested against something referred to as the ‘Gold Standard’, the diagnostic test in use that is as close to being infallible as possible.
Thanks to examples found in other Web articles, the process of how this is done can be briefly explained.
The article is from http://en.wikipedia.org/wiki/Sensitivity_and_specificity, and the example used is a screening test for colon cancer, fecal occult blood (FOB). Now when screening for colon cancer, endoscopy is the preferred test, the ‘Gold Standard’. However, because it is more expensive and time consuming, it’s not practical or realistic to do it on every patient. Testing for hidden, or occult, blood in stool specimens is an easier screening tool for colon cancer. But how good is it compared to endoscopy?
From the example in this Wikipedia article, when FOB results are compared to endoscopy, there’s some good news and some bad news.
The good news was that as far as predicting whether a patient did not have colon cancer, FOB is quite reliable. True, it’s not 100%, but its rate of 91% can give the patient and physician confidence that there is no colon cancer present. The ability of FOB to show true negatives is high. The ability of a test to confirm true false negative results is its specificity, and FOB has good specificity.
However, the bad news is that when it comes to having true positive results, FOB’s track record isn’t as stellar. Bottom line, if the FOB is positive, a endoscopy would be highly recommended? Why? Because compared to endoscopy, FOB positive results are only truly positive 67% of the time. That means that a positive result can be wrong 33% of the time. That means on average, in every 100 patients with a positive FOB , 33 of them actually don’t have colon cancer, and will need an endoscopy to confirm it. When it comes to screening for colon cancer positives, FOB is not as sensitive as endoscopy.
Sensitivity is how well a test is at determining true positives from false positives. In this example endoscopy is the more sensitive diagnostic procedure as close as possible to but never attaining 100%.
On the other side of the coin, you want that diagnostic procedure to be specific as well. An example of this can be found at http://www.bmj.com/content/308/6943/1552.full. The disease in question being liver disease, the gold standard a liver biopsy examined by a pathologist, and the test evaluated a liver scan interpreted by a radiologist.
The good news was that a liver scan was just as reliable for diagnosing liver disease as a biopsy, catching 90% of true positives. Unfortunately, it wasn’t as good at identifying patients who didn’t have liver disease. It could only accurately report 63% of patients as true negatives. That meant that if 100 patients who had normal livers were given a liver scan, 63 of them would be correctly diagnosed of having normal livers. Good for them, but the other 37 normal patients would be misdiagnosed of having liver disease.
There’s one more observation to further muddy the waters. The specificity and sensitivity of the above tests mentioned are not absolute. One day a FOB may be more sensitive, a liver scan more specific. But no matter what no diagnostic test will have both 100% sensitivity and specificity.

Tricorder® Watch Update

(Note ; this posting was e-mailed to Oxford Diagnostics for comment on Dec.13th for comment. To date none has been received)
The Oct.3rd posting discussed what characteristics a diagnostic piece of equipment would need to be a Tricorder ®. They were:
- To be non invasive
- Portable
- Not harm the patient
While current glucose meters are portable, they will harm the patient and are invasive, requiring a drop of blood.
A new tool for diagnosing diabetes mellitus has been developed that could be the first Tricorder ®.
The new analyzer developed by Oxford Medical Diagnostics, identifies patients with diabetes by a totally radical approach. First, the specimen required is not blood but the breath of the patient, and the metabolite measured is not glucose but acetone.
Why acetone? Because that is the pathology of diabetes mellitus, the body is unable to utilize carbohydrates for energy, so it has to burn fat. One of the by-products of this process is ketone bodies, acetone being one of them. The presence of acetone in the breath could be indicative of diabetes, measuring the amount of acetone in the breath could determine how severe the diabetes is out of control.
Diabetes is not the only disease that Oxford Medical Diagnostics is using this new breath technology to diagnose. Going to their website, it can be seen that many pathological conditions may be diagnosed and treated using breath technology.
The basis of the technology is spectrometry, taking a vapour, vaporizing it and then measuring the spectra released to determine the chemical makeup of that vapour. This is actually ironic, since this use to be the technology used to measure serum sodium and potassium, until it was replaced with ion selective electrodes (ISE).
It will be interested to see where this technology will lead in the field of diagnostics. Quality control and proficiency testing will be challenging. Can this technology be used in Tight Glycemic control (see Dec.9th, 2009 posting).
This is definitely an exciting breakthrough, medicine may be closer to McCoy’s Tricorder ® then we realize.

CRP- Infection vs. Inflammation

(Before continue reading it has to be stressed that this blog is only to be used as a reference. If the reader has any questions regarding this test for their health, they must consult a licensed physician. The reference range of <5mg/L is being used only as an example as different analyzers and populations will have different reference ranges. The Labvocate’s purpose is for education and starting a dialogue about issues affecting the medical laboratory)

What exactly is CRP, or as it is also known as C - reactive protein and what role does it have as a diagnostic tool?
To start, what’s with the name? The C that this protein reacts with is the C-polysaccharide cell wall of Streptococcus pneumoniae, the bacteria that causes pneumonia. In 1930, two researchers, Tillet and Francis, discovered that when serum from patients with pneumonia was added to the C-polysaccharide cell wall of Streptococcus pneumoniae, a precipitate formed. That led to the discovery of C-Reactive protein, a protein synthesized by the liver that has been found to be increased in both infections and inflammation. It works to help remove pathogenic bacteria and/or dead damaged cells.
That’s the good news. An elevated CRP in a patient is a strong indicator of a pathological process occurring in the patient. The bad news is that it won’t tell you what the problem is. It’s like the body is calling ‘911’, and just as the operator answers and says, ‘This is 911, what is the state of your emergency?’ the caller hangs up, and the operator has to send someone in to investigate.
The first step is to be aware of the difference between ‘inflammation’ and ‘infection’.
Inflammation is the body’s response to repairing dead tissue. It can be acute or chronic. Symptoms include redness, heat, pain and swelling. Infection is a pathogenic condition where the body has been invaded by an organism.
Let’s illustrate this by a patient coming in with a sore knee. Upon examination it is noted that the joint in question has some of the hallmarks of inflammation and infection. Besides being sore, it is also swollen and red.
One of the tests done is a CRP and as expected it is elevated, answering the question that yes, a pathogenic process is occurring, probable due to the patient’s sore knee. The question is the elevated CRP due to an inflammation, an infection or both?
A CBC would also be needed and careful attention paid to the WBC and differential, doe it indicates an acute infection? Does the patient have a fever? Or is the patient a jogger who is developing early the early stages of osteoarthritis?
How about throwing this monkey wrench into the mix, maybe the patient just has is a sprained knee and the CRP is actually elevated due an increased risk of coronary artery disease? So instead of answering questions, the CRP has made more.
So how can the CRP be used as a useful diagnostic tool?
First of all, compare the value to the reference range. The reference range is dependent on the analyzer, but for arguments sake we’ll use a reference range of up to 5 mg/L. Values less then the reference range mean that the level of inflammation is non pathogenic. Levels over 5 mg/L mean that there the level of inflammation is pathogenic. If the CRP has spiked two to four times greater than the upper level of the reference range, there is acute inflammation occurring.
Going back to our patient with the sore knee a CRP is ordered and has a result of 6 mg/L. Compared to 5mg/L as a reference point, it can be stated that the patient probable has a significant amount of inflammation probable due to a chronic condition.
But what if the result is higher, 20 mg/L? This is indicative of a more acute inflammation. Did the patient do more than sprain the knee? Are imaging studies (ie MRI for soft tissue damage) indicated? Is the WBC elevated accompanied by fever, indicating a possible septic joint infection?
One advantage of the CRP is that it does not require special collection like other tests used to investigate sepsis. Lactic acid is a useful marker for sepsis, but it requires specialized collection. CRP testing can be added to routine testing.
CRP has been found to be a good marker of neonatal sepsis. In one study (The Role of C-Reactive Protein in the Evaluation and Management of Infants With Suspected Sepsis,Joan M. Hengst, RN,MSN, Posted 04/16/2003; Adv Neonatal Care), an increase of CRP levels taken 24 hrs apart could be an indicator of neonatal sepsis.
So even if CRP can be a vague test, it is still valuable as an indication of inflammation. The challenge is to determine and treat the source of the inflammation.

Stagnation vs. Incubation

Sometimes inspiration can come from the most unlikely sources; say for instance from a discarded book at a library sale. The novel in questions is an autobiography of Michelangelo called the ” The Agony and the Ecstasy”, by Irving Stone. Currently it is ranked #29147 on the Amazon bestseller list, not bad for being published in 1961. In 1965 it was made into an Academy Award nominated movie starring Charlton Heston and Rex Harris.
So what does the forty year biography of a Renaissance artist have to do with Medical Laboratory Science?
How about the story of how Michelangelo Buonarroti began his career as an artist?
We automatically assume that one day he picked up a paintbrush, started painting, and the rest is history. After all, back then things were simpler, less government bureaucracy, more individual freedom, right?
Imagine the reader’s surprise to find out the opposite to be true. First of all, the profession of a painter was highly regulated in Medieval Florence. Before Michelangelo could even start, he needed a master to apprentice under. Luckily for Michelangelo a friend was able to get him into the studio of Domenico Ghirlandaio.
But that was the first hurdle for Michelangelo. The second hurdle was to convince his father, Ludovico, to enter the profession. Ludovico regarded the career of an artist below his son since it would provide an income. Ghirlandaio was so impressed with Michelangelo’s talent, that he made the unheard offer to pay his apprentice.
The rest is history, right? Later comes the ceiling of the Sistine Chapel and Michelangelo lives happily ever after.
True, eventually Michelangelo would later on paint that masterpiece. But here’s the truly ironic part. Michelangelo did not become an apprentice in Ghirlandaio’s studio to become a painter. Michelangelo became Ghirlandaio’s apprentice to become a sculptor.
But becoming a sculptor was not an option at the time. Sculptures were not in vogue at the time, and Michelangelo was told not to waste his time. So what did Michelangelo do? Did he complain about being in a dead end job that was wasting his talents? Did Michelangelo..stagnate?
Anyone who loves art will tell you that eventually he did become a sculptor as well, one of the history’s best to be exact. Maybe that time spent as a painter helped his talent as a sculptor incubate.
How many of us go to our jobs to stagnate? Do any of us look at our jobs as an incubator instead of a prison? Certainly we make choices that we wish we hadn’t, but maybe if you take a second look at that decision’s merits, you can try a different approach to make it the right one.
Incubation is about growth, stagnation is not. That is the choice of how you want to spend your career.

New Perspective on Smudge Cells

What exactly are smudge cells (also known as basket cells)? In patients with Chronic Lymphocytic Leukemia (CLL), it is a comment used to describe cells that look exactly like that, a cell that has been run over by a steam roller and flattened out. They are formed as a result of the action of the blood being spread out over the glass slide used to make the differential. There are apoptotic lymphocytes , more fragile than regular lymphocytes.
Conventional wisdom was that they were an artefact and only the presence of them was all that was needed to be reported. Some labs went even further by adding a drop of bovine albumin to the blood before making a smear, since this additive preventing the lymphocytes from becoming damaged while the smear was made. Since it is possible for smudge cells to be present in a normal blood smear, the presence of smudge cells by itself do not indicate a pathological condition. Before CLL can be diagnosed, flow cytometry is required.
For patients with diagnosed CLL, the presence of smudge cells was noted, but no measurement of them was done.
Two recent articles may change that:

Johansson P. Et al , ‘Percentage of smudge cells determined on routine blood smears is a novel prognostic factor in Chronic Lymphocytic Leukemia, Leuk Res 2010:34:892-8.

Nowakovski, GS et al, Percentage of smudge cells on routine blood smears predicts survival in chronid lymphocytic leukemia.

Basically a smudge cell is a lymphocyte lacking a protein called vimentin in its cytoskeleton. Vimentin is responsible for the rigidity and integrity of cells, as well as playing a role in activation and transduction. Leukemic cells that are ZAP70/CD38 positive will have vimentin and be resistant to becoming smudge cells and be virulent . Leukemic cells that lack vimentin will become smudge cells and be less virulent.
Therefore a smear from a patient with a high percentage of smudge cells will have less virulent cells and a better outcome than a patient with few smudge cells.
The challenge will be twofold, determining how to consistently identify smudge cells, and how to present the data in a consistent form.

The Medical Laboratory’s role in Systemic Inflammatory Response Syndrome

In 1992, a new syndrome was introduced by the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM), called Systemic Inflammatory Response Syndrome (SIRS). It is defined as 2 or more of the following variables:
- Temperature of more than 38° C or less than 36° C
- Heart rate of more than 90 beats per minute
- Respiratory rate of more than 20 breaths per minute or a PaCO2 level of less than 32 mm HG
- WBC count of >12,000/μL or < 4,000/μL or > 10% bands.
So what happens in SIRS?
Basically some insult occurs to the body which responds by having the basic inflammatory response. Part of that response is the release of cytokines that have the goal of returning the body back to a healthy state. However, if whatever caused the inflammatory response is not treated, or worsens, the amount of cytokines released cause destruction, not healing. This is known as a ‘cytokine storm’, resulting in hypotension leading to end organ dysfunction.
So what can the lab do to help diagnose SIRS?
Measuring cytokines such as Interleukin 6 would help, but this is not practical in most labs.
Being aware of the WBC count is the first step. As noted above, that is one of the criteria that has to be filled in the diagnosis of SIRS. While an elevated WBC is usually indicative of infection, the haematologist must also beware that other causes can cause an increase in the WBC count, such as leukemia and stress. A decrease in WBC isn’t usually associated with sepsis, but because infection can cause the increased transfer (or pooling) of neutrophils to the infection before the bone marrow can respond by releasing more into circulation.
Then there’s the subject of bands. Immature neutrophils, referred to as bands because that’s what the nuclear material in the cell looks like, a band. Under the eye of an experienced haematologist, bands can be identified when a manual differential is done.
Unfortunately, when it comes to the topic of band identification, sometimes it’s easier for theologians to discuss how many angels can stand on the head of a pin than it is for experience haematologist to agree to what a band cell is. Some labs avoid this minefield altogether by lumping in the neutrophil and band count together and leaving it up to a pathologist to comment if there are an increased number of bands present. Trivial point here, the term ‘shift to the left’, was used to indicate an increased number of bands present.
An arterial blood gas can be used to measure the PaCO2 level. If the level is <32 mmHG, that can be indicative of SIRS as well.
One of the cytokines released, Interleukin 6, will stimulate the release of C-Reactive Protein (CRP). An increase of CRP could also help diagnose SIRS.
A positive blood culture could also be a warning sign that SIRS is happening. Sepsis is one of the causes of SIRS.
Not the only cause though, and that is something the lab has to be aware of. Other causes of SIRS include ischemia, trauma or a combination of other insults, such as serious burns.
The important thing to remember is this, SIRS can become a serious threat to the well being of the patient. It is the laboratory’s job to be aware of it, and to help diagnose it.

D-Dimer and DIC

The D-Dimer Test is an important tool for the diagnosis of pathological thrombosis such as Deep Vein Thrombosis (DVT) and Pulmonary Embolism(PE). Being able to identify patients at risk of these cardiovascular diseases can lead to prompt intervention with anticoagulant therapy preventing long term damage or death.
However the D-Dimer can also be used to help diagnose another coagulaopathy, Dessiminated Intravscular Coagulation. Basically something (ie trauma, septicaemia) triggers the coagulation system to initiate clotting. Tiny thrombi are then formed, blocking off the microcirculation and causing red blood cells to fragment, leading to organ dysfunction and anemia.
Unlike DVT and PE though, DIC is not a single entity, but a complex syndrome that has many different causes.
To help determine if a patient has DIC, The Subcommittee on DIC of the International Society on Thrombosis and Haemostasis (ISTH) developed a point system to help determine if "overt" DIC is present:

1. platelet count (more than 100 = 0; less than 100 = 1; less than 50 = 2)

2. elevated fibrin degradation products (FDP) (no increase = 0; moderate increase= 2; strong increase= 3)

3. Prothrombin Time (PT) upper limit of ref. range ( less than 3 secs = 0; more than 3 secs = 1; more than 6 sec. = 2)

4. fibrinogen level ( more than 100 mg/dl = 0; less than 100 mg/dl = 1)

Score of 5: compatible with overt DIC
(Taylor FB Jr, Toh CH, Hoots WK, et al, and the Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost. 2001;86:1327-1330.)
Notably absent from this list is the presence of schistocytes, red cells fragmented from circulating through the microthrombi blocking capillaries.
Platelet counts and PT are standard lab tests. Fibrinogen testing is not. As for elevated FDP, this too was, and still is, not a standard lab test, especially in smaller labs. The FDP test is used to measure the amount of fibrinolysis (breakdown of fibrin) present. It makes sense that in DIC there will be an abnormal amount of fibrin being formed, and at the same time an abnormal amount of fibrinolysis taking place. But one test that can be used to measure fibrinolaysis is the D-Dimer test. An increased D-Dimer test may be used to determine if there is an increased level of elevated fibrin degradation products. However, other conditions can cause an increased D-Dimer, and it is up to the lab to determine what level of D-Dimer will be used as the cutoff to be used in the ISTH grading system mentioned above.
For further information refer to :
Wada H, Gabazza EC, Asakura H, et al. Comparison of diagnostic criteria for disseminated intravascular coagulation (DIC): diagnostic criteria of the International Society of Thrombosis and Hemostasis (ISTH) and of the Japanese Ministry of Health and Welfare for overt DIC. Am J Hematol. 2003;74:17-22.
So in conclusion; the ISTH has a score to determine if DIC is present, the D-dimer can be used once a cutoff level has been determined for the method used, and the presence of schistocytes cannot be used to diagnose DIC.

Tricorder Watch

So what could be the Holy Grail of diagnostic equipment? The Tricorder®, that workhorse of the Star Trek TV series would be an obvious choice. With it’s flashing lights and whirring noises, it could measure three different parameters, weather patterns, geology and biology.
In the hands of Dr. Leonard ‘Bones’ McCoy the Tricorder® could diagnose any medical mystery. All it took was a few brief waves of his hand and the Chief Medical Officer of the Starship Enterprise was able to tell a dramatic Kirk and a calm Spock what the creature of the week was.
Point of Care (POC) instruments claim to be Tricorder®, but are they? What makes a good Tricorder®?
First of all it has to be portable. POC instruments are certainly that.
Second of all, they have to non invasive. Unfortunately, POC still need to penetrate skin to get a drop of blood in order to provide a result.
Finally, a Tricorder® will not harm the patient. No one ever gets sick because of McCoy placing it over them.
But despite all the promise that this futuristic diagnostic instrument offers, there are still some modern day realities that would have to be considered if tomorrow one was developed.
You still need to train someone how to interpret the data produced. To be effective, it would have to be in the hands of a healer, not a technologist.
Which brings me to the second point; you would still need a technologist to do the QC and maintenance of the Tricorder®. You couldn’t send one on the away team if it wasn’t working properly.
The Labvocate is constantly on Tricorder® watch, and there are a few developments in progress. This will be discussed in the future.

COPD vs. Global Warming

One more thought about COPD. Previously I wrote that there will be a rise in the number of cases of this condition, as well as becoming the third cause of death worldwide.
Why the increase? Air pollution is targeted as the main cause, especially in developing countries that don't have strict emission standards fro automobiles and industry.
So while there is much debate about whether or not climate change is due to air pollution. Has that caused the wild climate changes lately? At the risk of being called a heretic I'll say the jury is still out on that.
However, the rise of COPD is a definite indicator that air pollution needs to be decreased.
Then maybe we can all start breathing alittle bit easier.

COPD- Future Diagnostic Challenge

If you were to have a group of 100 Canadians in a room, four of them would have heart disease, one of them would be newly diagnosed with cancer, eight would have kidney disease and three of them would have type one diabetes. You would need to have a room holding a thousand Canadians before you would find one with AIDS.
But back to that original room of one hundred, there would a significant amount coughing and hacking from COPD (Chronic Obstructive Pulmonary Disease), twenty five percent to be exact. Currently, COPD is the fourth cause of death in the world, behind heart disease, CVA and lower respiratory infections.
Yet this is a condition that goes largely undiagnosed and treated until it is too late.
Why?
One reason could be that COPD is a broad based term for a number of different diseases. It also doesn't have a set criteria of classification. When does that annoying cough you've had for a month actually become defined as COPD?
But one reason it may go undiagnosed is because the test used to test for COPD is not found in the traditional medical disciplines of Medical Laboratory Science or Diagnostic Imaging. COPD is diagnosed by a test called spirometry.
This procedure measures airflow from lungs and determines if there are any obstructions present which could be causing COPD.
In 2000, it was estimated that 13 million Americans were undiagnosed with COPD. An office version of spirometry would be used the measure the forced expiratory volume at 6 seconds (VEV6) to screen for COPD.
Whatever version of spirometry used, this a test diagnostic facilities should investigate the feasibility of implementing. Accreditation agencies should also be involved to make sure that all spirometry testing is standardized. Finally, clinicians and patients should be educated about this test and the impact COPD will have on Canada's healthcare system.
If anything, it will help those 1 in 4 Canadians breathe a little bit more easier.

Apologies

First of my apologises for neglecting this blog. The last year has been an exciting one, 'thriving on chaos' as Tom Peters would put it. Hopefully I will be able to soon expand on that.
It is gratifying to see that there are people who read this blog and I thank them.
So what will I be trying to achieve with this blog in the following year?
First of all, I'm going to shoot for at least one posting per week.
Second of all, I'm going to still focus on matters concerning laboratory medicine.
But I'm going to add reflections on what I've been doing for the last year. I will be referring to Tom Peters and William Demings more this year. I might even throw in some references to the Book of Job as well, since I think that should be required reading for anyone working in Health Care.
Finally, I will be adding some posts about how lab medicine is affecting my own personal health.
Thank you for taking the time to read my posting. I look forward to your thoughts and comments.
Regards,
Mark Hawkins

Pathology of the Throat and HPV

It has been well documented that the human papillomavirus (HPV) can cause cervical cancer. There is now evidence that HPV main play a role in throat cancer. Does the unsafe sexual behavior presently done mean that there may be an epidemic of oropharyngeal cancer in the future? The or pharynx consists of the middle part of throat behind the mouth including the back one-third of the tongue, the soft palate, the side and back walls of the throat, and the tonsils. Cancer in this area can be difficult to diagnose and treat.
Maybe it’s time to treat this like cervical cancer. Pap smears on women at high risk of developing cervical cancer using Pap smears and HPV testing have helped to drastically reduce the death rate from cervical cancer in the industrialized world. Earlier detection has led to early treatment and better outcomes.
Would performing Pap smears on specimens from the oropharyngeal area be an effective screening test for throat cancer? Or what about gargling with mouth wash, and then centrfiuging the washings down to look for suspicious cells?
Hopefully, someone is reading this blog and it will get them asking the same question. Screening for an illness is the first step to treating an illness.

Explaing the 'e' in eGFR

What’s with this GFR test? For years there we were, medical professionals, just doing our jobs when out of nowhere comes a ‘new’ test we suddenly have to become knowledgeable of. It’s like we’re the only child whose parents have come home with a brand new baby sibling that we’re suddenly suppose to instantly love and accept. We didn’t ask for it, and things were fine until it came along to cause a lot of uncomfortable questions.
Hopefully this entry will answer questions about this newest diagnostic test.
First of all, GFR stands for Glomerular Filtration Rate. The glomerulus is the structure in the kidney responsible for filtering blood, so determine how well it is working can be used to measure kidney function.
Second of all, it’s not a new test. It’s actually a number calculated from a formula using four variables; plasma creatinine, age, gender and race.
Thirdly, the GFR derived from this formula is actually an estimated GFR . That’s why some labs report it as eGFR. Performing an actual GFR requires injecting a patient with a nuclear isotope (125I-iothalamate) and determining how long it takes for the kidneys to filter it out of the body. This is a procedure that cannot be performed on a large scale to screen patients who are at risk of developing chronic Kidney Disease (CKD).
In 1989 the National Institute of Diabetes and Digestion and Kidney Disease in the U.S. performed a study to see what affect diet could have on CKD and two of the tests used were plasma creatinine and 125I-iothalamate GFR.
As a result, a lot of useful data was produced, allowing researchers to develop a formula to quickly estimate GFR. The result was a magic number of 60 ml/minute/1.73 m^2. As long as the eGFR was 61 or greater, than the risk of CKD was decreased. A eGFR of 60 or less indicated further investigation.
Actually then, all the eGFR does is take the plasma creatinine and present is as a number to indicate kidney function.
But here are some ground rules for using the eGFR.
It cannot be used for paediatric patients eighteen years and under cannot have an eGFR performed on them. The test is gender specific. African Americans have a higher content of muscle, requiring a different formula than non African Americans.
Plasma creatinine must be used. Values from Point of care analyzers measuring creatinine using whole blood cannot use this formula.
In fact, any analyzer that measures plasma creatinine to calculate eGFR has to be standardized. What does that mean?
Finally, any analyzer that measures plasma creatinine has to be standardized. What does that mean?
The purpose of the eGFR is to screen patients at risk of developing CKD. However, if the analyzer being used has a high degree of variability , there is the potential for the patient having a wide range of results. One day your patient could have kidney disease with a eGFR of 58, the next day they could be a healthy 62.
An example of a successful standardization program is the one launched by the province of B.C. in 2003. It provided labs with specimens of known creatinine values for them to analyze. These labs then sent the results to the province, which calculated a correction factor for the analyzer.
The results speak for themselves.
Before the standardization program labs on average were reporting eGFR values 16.5% lower than they actually were. This meant that 535,000 British Columbians had been falsely diagnosed being at risk of developing kidney disease. By having labs use the correction factor in their formula for calculating eGFR, 449,000 patients were prevented from being misdiagnosed. Needless anxiety for the patient was avoided as well as the cost savings. The standardization program cost $335,000 to launch, and has a yearly budget of $135,000. Part of that goes towards educating physicians, patients and allied health professionals on the strengths and weaknesses of the eGFR as a diagnostic tool.
So the eGFR has become a useful diagnostic tool. The important thing is to be aware of its limitations, and not to obsess about its numbers.

Genetic Strip Mining

My first lesson on neonatal screening made a dramatic impression on me. I was a student at BCIT in 1985 and it was during a lecture in clinical chemistry the PKU test was explained to me. Before this test had been developed, thousands of newborns each year were destined to be warehoused in state run facilities for the mentally impaired with no hope of any sort of normal life. The lecturer had worked in that time frame to see firsthand these patients.
So what happened to change this?
In 1934 Dr. Asbjorn Folling of Norway observed that certain mentally retarded patients smelt strange. Giving in to his curiosity, he discovered the source of the odour was phenylacetic acid present in the patient’s urine. From his observations, Folling concluded that the mental retardation resulted from genetics and diet. Since the source of the phenylacetic acid was from a chemical called phenylketone, and it was present in the urine, the disease was called phenylketonuria (PKU).
So the next step in treating the disease was to determine how this all caused mental retardation in what appeared to be healthy newborns. The answer was that these infants were lacking an enzyme called phenylalanine hydroxylase which breaks down an essential amino acid called phenylanine . Without this enzyme, there is a build up phenylanine levels in the blood, resulting in elevated levels of phenylanine which are harmful to the central nervous system and if left untreated, lead to brain damage. Unable to properly break down the phenylanine, it is then converted to phenylacetic acid, which is then excreted into the urine.
In 1951 Horst Bickel, a German professor, developed a protein drink without any phenylanine in it, allowing for a infant with PKU to receive proper nutrition. Then in 1958, Robert Guthrie developed a way for testing for PKU that was simple and inexpensive. All it involved was placing a few drops of blood on a piece of filter paper. Eight years later in 1966, hospitals began screening for PKU.
In 1986, that was a very powerful message. Laboratory technologists could improve a patient’s outcome with a very simple test. Families were spared the bitter burden of institutionalizing a child.
Since this first neonatal screening, other tests have been included, such as genetic screening for cystic fibrosis and sickle cell anemia.
Unfortunately now events have occurred that have challenged just not PKU testing be done, but all neonatal screening.
In the four decades since the first PKU screening, genetic testing has grown exponentially. A person’s entire genome can be determined from a single drop of blood. Parents are concerned that blood stored on a PKU card can be used to determine that child’s genetic information, and be kept in a private data base. There is an expectation of privacy that blood samples from the millions of PKU cards collected is not turned into some huge ‘genetic strip mine,’ as researchers and private companies take advantage of this huge pool of DNA.
Parents cannot let fear prevent them from having their infants screened for disease. At the same time researcher’s have to be allowed to do research at a molecular level to help with disease diagnosis and treatment. The millions of PKU cards stored in hospitals world wide make a tempting target.
It is for the good of the newborn that government makes newborn screening mandatory, and it is also good that researchers try to find a treatments and cures for disease. In a historical perspective, did the doctor mentioned earlier, Dr. Folling, have to get permission to begin those groundbreaking experiments that led to the discovery of PKU? What if he had been denied that opportunity to find out why those patients had strange smelling urine, how many millions of patients would have had negative outcomes?
True, there has to be a limit to who has access to stored genetic material, whether it be dried blood on filter paper to tissue biopsies from a cancer patient. It is time for politicians to become not only involved, but informed.
What would my solution be? Earlier I used the term ‘genetic strip mining.’ Treat all stored genetic material as a public resource, and any company that develops that resource pay a royalty to the government for that material. Respect of patient’s privacy is paramount
These are interesting times. But we can’t let fear prevent us from making sure children of every generation have a chance to overcome the challenges they face in this business we call life, including the DNA they are born with.