Monday, November 3, 2008

Cost effective testing

The first question is whether testing should be done at all. Some might think of Lyme disease as a multi system disorder causing at least moderate disability. Others might think of it as a wide spectrum disorder with symptoms ranging from very mild to severe. In a way it is philosophical question. Many persons suffer with varying manifestations of chronic Lyme infection. Many patients are "colonized" with Lyme spirochetes but not necessarily ill, or very subtly ill. One should not test at all unless treatment is desired based on an assessment of symptoms. Treating patients with minimal symptoms can still be a daunting process. In many such cases watchful waiting may be the best course.

Given that TBD (tick borne disease) is suspected, also called LBC (Lyme Boreliosis complex), (Note these terms are replacing the term chronic Lyme disease because of the increasing assumption of a poly-microbial syndrome), one must give careful consideration regarding the use of ancillary laboratory testing.

The first phase of testing is of course the history and physical exam.
As we move into the realm of lab tests the first priority is to document exposure to Borrelia burdorferi, the Lyme spirochete. Most patients have insurance. This means that tests at "mill labs" like Labcorp and Quest are covered. This is usually the starting place. These labs do a mediocre job with serological(antibody) tests, but appear to do a poor job with PCR testing. Don't order the standard Lyme antibody test. This means an ELISA test will be done. We know this is a poor screening test. Order a direct Lyme Western Blot test. This is a better, yet still poor test. It only reports 13/28 bands. Despite this, sometimes we get lucky. Labcorp and Quest will do serological tests for Ehrlichia, Bartonella and Babesia. Labcorp does a PCR for Anaplasmosis which is poor, while Quest does a serology test for Anaplasmosis which is better. The Ehrlychia test is the best of this group. The other tests cannot be relied upon for varying reasons. Positive results for Babesia, Bartonella and Ehrlichia when they do appear, not only provide evidence regarding these co-infections, but also provide good, indirect evidence of Borrelia infection as well.

The CD57 test is frequently ordered. This is available only through Labcorp. It's value remains controversial. Low levels tend to suggest immune suppression and possible chronic infection. The C3a and C4a complement tests are available also only from Labcorp. They provide clues of inflammation and therefore infection.

Sed rate and CRP are markers of inflammation. They are frequently elevated. When positive they are helpful.

ANA and RF indicate autoimmune issues. These are also frequently elevated and offer further evidence regarding secondary autoimmune effects.

B12 and folic acid are important. Low levels are common and may be associated with co-infections within red blood cells.

Vitamin D levels: OH 25, and Dihydroxy 1,25 levels may indicate evidence of L-form disease and are useful markers.

CBC is important. Low WBC counts may correlate with Ehrlichia and other tick borne infections. Routine chemistries are important to screen for liver function abnormalities and other metabolic issues.

We have been cost effective so far, assuming third party coverage.

If we want better data we must use speciality labs. These labs generally do not participate with insurance plans.

Lyme Western Blots from reference labs like IgeneX and Clongen are very helpful. The yield can be improved by first giving antibiotics and then performing the assays, especially after a Herx response.

Routine Blood PCRs for Lyme have a very low yield and are not cost effective.

Some physicians assume that co-infections are present and treat empirically, especially if serological evidence of Lyme has been obtained.

The next cost effective test is a blood smear. The presence of gram negative rods or cocco-bacillis suggests Bartonella. if confirmation is desired, a DNA extraction with a 16S DNA fingerprint can be obtained. A finding of Babesia on a blood smear would be great, but this is a low yield procedure.

A new 15 species PCR for Babesia and a 20 species PCR for Bartonella is available from Clongen and should be cost effective. The mill labs do serology for B. microti and IgeneX does serology for B. duncani. This gives a decent yield but misses many pathogenic strains. The FISH test for B. microti from IgeneX is a good test, but it adds extra expense and it only tests for one species.

Let me say a word about the C6 Bb ELISA test. Most LLMDS don't do it because of a low yield. First, it is highly specific. A positive result is better evidence than a positive Western Blot. Second, I view numeric index results differently. The 0.9 cutoff is conservative and was calibrated for acute Lyme, not chronic Lyme disease. Levels over 0.3 are very suggestive and levels over 0.4 correlate highly with the Lyme diagnosis. This test is always worth doing. Because it is quantitative it can be monitored over time during the course of therapy. It frequently "seroconverts" after antibiotics have been administered.

In summary, there are many diagnostic lab options. Many co-infections can be diagnosed empirically. You can work with you LLMD to determine which tests are most appropriate and which fit into your budget. It is OK to discus the cost and benefits of the various tests. I think a good physician who trusts his clinical abilities will often be comfortable working with less lab data. The problem remains that even the best tests frequently miss clinically significant infections; so negative results should not be used as a justification to not treat.

Many LLMDS seem to order large panels from specialty labs which cost thousands of dollars. I think a thoutful approach can save patients a lot of out of pocket expense.


lymie said...

Why would the D levels reflect L form existence?

If you are low on 25 hydroxy and at the upper end of normal on 1,25 dihydroxy, does this mean that Vitamin D3 should be supplemented? What is the effect of such supplementation on the 1,25 form? I have heard of some lyme patients who feel better when supplementing vitamin D. Not sure which kind that are using.

dogdoc said...

Few quick ?'s

What do you think of multiplex Lyme PCR of blood from quality lab like Clongen? Do you think sampling handling like being able to walk the blood over to the lab could make a difference on PCR sensitivity (ie no lysis of cells and degradation in the blood due to storage and shipping)? I wonder if we could figure out where the borrelia are in a positive blood pcr- are they free in blood or intracellular?
Do you think the gram negative free bacteria on smears could be something in addition to Bartonella? I thought only B bacilliformis could be seen on standard wright, ect stains and the other Bartonellas you needed a silver stain to see. Do we culture? I'm guessing Labcore probably can't do the tougher ones there either- lot of these things need some pretty specialized media.
Cost effective testing is very important in the real world. We appreciate it very much, esp when you have many family members involved. It shouldn't be that the docs have to use inferior quality labs to get insurance coverage. You would think someone would think of the costs of misdiagnosis- and all of the tests, treatments, hospitalizations, ect for continually barking up the wrong tree and having patients get sicker and sicker.

dogdoc said...

One last quick ?- what about other measures of immunosupression instead of Cd57? Nk function perhaps or even lymphocyte and Ig profiles? NK function is decreased in CFS as frequently as HHV6, CMV. CPN, Coxack. ect titers are elevated. It would seem useful to come up with a reliable way to follow immunity. By the way, did you ever notice a correlation with CD57 and measures of inflammation and autoimmunity? Ie Like some are immunosupressed and some are hyperimmune?

Lyme report: Montgomery County, MD said...

Vitamin D- again. Vit D is not a vitamin. It is a hormone. It has anti-inflammatory steroid like effects. Receptors (VDRs) are found in white blood cells. Activation of the receptors causing a shift in immune function which favors survival of L-form bacteria living inside cells. This may be an evolved mechanism to enhance survival of the bacteria. Vit D supplements make you feel better in the short run, like steroids. In the long run they are counterproductive. That's the theory. No D supplements are recommended.

Lyme report: Montgomery County, MD said...

Lyme is rarely in blood. I don't think PCR testing of blood is cost effective. If someone is acutely ill the yield would be higher. The nuances are beyond me. Ask Clongen.

I don't know what the bacteria are. DNA fingerprints should ultimately be done. Various theories are bandied about without proof: Bartonella, BLOs, Hemobartonella and so on. Lots of different bacteria show up with a variety of stains. If they don't gram stain think Mycoplasma type organisms (no cell wall).

You can misdiagnosis with a million dollars of testing if you don't know what you are doing.

Immune system dysfunction: No well established tests/markers. Hi viral titers may be useful? CD57 doesn't seem to correlate with much.

dogdoc said...

High viral titers make sense for reactivation markers- CMV, HHV-6, coxack., ect. PCR's on the viruses would be nice to see if titers correlate with viremia. I wish there was a testing fund out there so we could collect some data with clinical studies. It would be nice to be able to find peices to the puzzle. I wonder why we don't seem to have studies on NK function and CD4-8 ratios, and Ig's by class? Have we done them and they just weren't useful or have we not investigated them yet? Do free Mycoplasma show up in the blood? I thought they would be obligately intracellular. I would really love to see what the bacteria are if they are common. That would seem to be another peice of the puzzle- bacteria don't usually float free in the blood like that. I wonder if we have other gram neg opportunists taking advantage of the immunosuppression?

sloborabas said...

I have read some very confusing advice with regards to blood testing, and I have no idea what is true or false:

* Blood to be tested for Babesia should be drawn during a full moon. I am not sure if that's someone's imagination running wild, or if there is a scientific reason for it, but I can see parasites following a lunar life cycle.
* Blood drawn in the late afternoon generally yields more positives for Lyme than "morning blood"
* The best time to test for Lyme is immediately after a monthy Herx reaction.
* It's best to test for Lyme after doing an "antibiotics challenge" where the patient is on antibiotics for a while, and then draw blood a couple of weeks after going off the abx.

DrSamM said...

I have a 3 year old who was found with an adult female deer tick in him. Where is best to have the tick tested for co-infections? what is best treatment for so young?