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.