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Lyme Culture Test Causes Uproar Per News

Posted by Phillipa on January 31, 2013, at 20:30:58

Interesting Phillipa. Western Blots are the ones I had.

Medscape Medical News

Lyme Culture Test Causes Uproar

Janis C. Kelly
Jan 30, 2013

Lyme Disease

A new chapter in the Lyme disease controversy opened in September 2011 when Advanced Laboratory Services, Inc, announced the commercial availability of a new culture test for Borrelia burgdorferi. Some Lyme patient advocacy groups and physicians began encouraging patients to have the $595 test, but others are concerned about the early commercialization of the still-unvalidated test. This concern may result in changes to how the US Food and Drug Administration (FDA) regulates so-called "homebrew" or laboratory-developed tests (LDTs).

Physicians on all sides of the Lyme disease arena agree that a reliable culture test for active Borrelia infection would be a breakthrough. They differ on whether it is a good idea to market a blood test to consumers before it has been validated, peer-reviewed, published, reviewed by the FDA, or widely vetted by infectious disease experts with experience in Borrelia infections.

Joseph J. Burrascano Jr, MD, senior vice president of medical affairs and medical director for Advanced Research Corporation, voiced the complaint of many in the field that the 2-tier Lyme disease test approved and used by Centers for Disease Control and Prevention (CDC) relies on a serologic assay that can only indicate possible past exposure.

"What is very much needed is a direct test that can indicate whether living Borrelia are present in a patient," Dr. Burrascano said.

No Published Data

Soon after Advanced Laboratory Services' initial public announcements about the new culture test, emails and public statements attributed to Dr. Burrascano began appearing on Lyme-related Internet sites, including comments that the culture test was approximately 94% sensitive and 100% specific.

Dr. Burrascano told Medscape Medical News that the validity of the culture test was established using blood samples provided by physicians and that the identity of Borrelia was confirmed by its ability to grow in Borrelia-specific media, by its characteristic appearance on darkfield microscopy, by reacting to published Borrelia-specific polyclonal and monoclonal immunostains, by DNA polymerase chain reaction (PCR) at 2 different loci, and by direct DNA sequencing. These data are so far unpublished.

According to Dr. Burrascano, "All clinical samples turned out to be B burgdorferi sensu stricto, which would be expected, as the clinical samples all came from patients who met the strict CDC surveillance case definition as having Lyme.... In addition, when a large number of normal controls were tested (well people), none of them had any positive cultures, meaning that there were no false-positives."

Dr. Burrascano said that a paper reporting the data has been submitted for publication and that "2 university-based research labs are each separately well on their way in validating the results of Advanced Labs."

Paul Mead, MD, MPH, chief of epidemiology and surveillance activity in the CDC's Bacterial Diseases Branch, Fort Collins, Colorado, told Medscape Medical News, "There is a long history of alternative, poorly validated tests being used to diagnose Lyme disease. Recently, we've been hearing about new blood culture techniques in which patient blood samples are incubated with an unspecified media for up to several months and then tested by polyclonal immunostaining and, in some cases, PCR assays.... We are very concerned about the accuracy of these sorts of tests. The methods are not well-described, and their validity and accuracy have not been documented either in the peer-reviewed literature or through the process of FDA clearance. We are concerned that potentially bogus tests are being marketed directly and at great expense to patients."

One of the healthcare providers experiencing a surge in patient requests for the Advanced Laboratory Services test is Gary Green, MD, infectious diseases chief and clinical director of the HIV Team & Travel Clinic at Kaiser Permanente in Santa Rosa, California. Dr. Green told Medscape Medical News that many patients who request the Lyme blood culture test have symptoms they are convinced are a result of chronic Lyme disease even though they test negative on all other standard tests.

Dr. Green said, "The problem with a test that has not been validated and not been tested outside the source of invention is that we don't know whether it is at all accurate. Using an unvalidated test in modern medicine is dangerous and unethical."

Marketed Without FDA Approval

FDA spokesperson Michelle Bolek told Medscape Medical News that the Advanced Laboratory Services, Inc, Lyme test has not been cleared by FDA but can be marketed without approval because it is considered to be an LDT.

Bolek said, "LDTs refer to in vitro diagnostics that are manufactured by and offered in the same laboratory." The Advanced Laboratory Services Lyme culture is in this category because, although patient blood samples may come from other states, all analysis is done at the Advanced Laboratory Services facility in Pennsylvania.

Bolek added, "Since the implementation of the 1976 Medical Device Amendments, the FDA has generally exercised its enforcement discretion and not enforced regulations that apply to LDTs. Initially, the FDA viewed LDTs as relatively simple, well-understood tests that diagnosed rare diseases and conditions and that were intended to be used by physicians and pathologists in a single institution, where they were actively involved in patient care.... These tests are [now] often performed in commercial laboratory settings that are geographically separate from the patient's primary healthcare professionals and their healthcare setting. These tests, which are becoming more complex and high risk, are playing an increasingly important role in clinical decision-making. As a result, LDTs that have not been properly validated put patients at risk, such as for missed diagnosis, wrong diagnosis, and failure to receive appropriate treatment."

Bolek told Medscape Medical News that the FDA believes that a risk-based approach to regulating LDTs is appropriate and that the agency is currently working on new guidance for regulating such tests.

New York State already has in place additional regulatory requirements, which is why the Advanced Laboratory Services Lyme culture is not available in that state. Basically, the New York State Department of Health has regulatory authority to examine the accuracy of any laboratory test being ordered by a New York State physician, regardless of where the laboratory work is done.

An example of why independent validation studies matter is the outcome of proficiency studies the New York State Department of Health conducted in 2000 on a Lyme disease test marketed by IGeneX, Inc. Results of these studies showed that the laboratory failed to identify as positive 2 samples (of 20) that had been spiked with B burgdorferi and incorrectly identified as positive 4 of 14 negative samples. The manufacturer subsequently satisfied New York State requirements for that test.

Millions of Tests Annually

Each year, more than 3.4 million tests for Lyme disease are done in the United States, and about 38,000 cases of confirmed or probable Lyme disease are reported to the CDC via the standard US surveillance system for notifiable diseases.

Advanced Laboratory Services marketing materials state, "The CDC estimates that in the USA there are more than 300,000 new cases each year and there may be as many as 4 million people currently infected." Dr. Mead said that this is incorrect: The CDC expects about 30,000 new cases of Lyme disease per year, and the agency is currently developing updated estimates for nation-wide prevalence.

The methodology behind the Advanced Laboratory Services Lyme culture test has yet to be presented at relevant scientific meetings, reported in peer-reviewed journals, or validated by other laboratories. The company references its marketing claims with 2 studies by Eva Sapi, PhD, from the University of New Haven, Connecticut, and colleagues. In both studies, low-passage isolates of B31 and 297 strains of B burgdorferi obtained from the American Type Tissue Collection were cultured in Barbour-Stoner Kelly H complete medium with 6% rabbit serum and incubated at 33C with 5% CO2 in a shaking incubator at 250 rotations per minute.

The first study was an in vitro evaluation of B burgdorferi antibiotic susceptibility. It was Infection and Drug Resistance a journal published by Dove Press. Dove Press was included in a recent comparative review of " 'Predatory' Open-Access Scholarly Publishers." In addition, the senior author, Raphael B. Stricker, MD, was previously involved in AIDS research at the University of California, San Francisco, and was the subject of a finding of scientific misconduct by the university and the Office of Research Integrity at the National Institutes of Health, which concluded that Dr. Stricker "falsified data for a manuscript and a [US Public Health Service]-supported publication reporting research on AIDS. In the manuscript...[he] selectively suppressed data that did not support his hypothesis, and reported consistently positive data whereas only one of four experiments had produced positive results."

The second paper by Dr. Sapi, published in PLoS One in 2012, reported an in vitro study of biofilm formation by B burgdorferi.

In neither study was the culture method used as a diagnostic test for Lyme disease in human participants, and neither study includes data that would support or validate such use. Dr. Burrascano told Medscape Medical News that a paper or papers reporting diagnostic use of the culture method had been submitted for publication.

Dr. Burrascano said, "Dr. Sapi's work on biofilms was very helpful, but her lab used [the B31 strain of B burgdorferi] while her work is very important, what Advanced Labs came up with is still more advanced. The initial research at Advanced Labs was done with B31, but when some basic questions were answered, then 2 sets of clinical patient samples were used: to further the basic research, and then to ultimately do the clinical trial. Both of these are being reported in the one article which has been submitted."

Meanwhile, however, the company moved ahead with vigorous commercialization of the Lyme disease culture test.

The cost for the Advanced Laboratory Services "basic culture with polyclonal staining" is listed as $595.00 on the company's Web site. "PCR with DNA sequencing, monoclonal immunostaining, and extended culture are options that are provided at an additional cost.... Because Advanced Laboratory Services does not participate in insurance plans, the sample must be sent with credit card information or check." Thousands of patients seeking Lyme culture tests at $595.00 per test would represent millions of dollars per year in sales for the company.

What Clinicians Need to Know

Although many Lyme patient advocates believe that serology becomes falsely negative during and because of antibiotic treatment, infectious disease specialists tell Medscape Medical News that this is unlikely and does not happen in any other infectious disease.

Most cases of acute B burgdorferi resolve after a few weeks of standard antibiotic treatment. Other patients struggle with prolonged nonspecific symptoms such as aches, malaise, and cognitive deficits.

The predictive value of laboratory tests is a function of the sensitivity and specificity of the test and of the population being tested. Tests used in a population with low likelihood of Lyme disease may produce more false-positive than true-positive results, leading to expensive, unnecessary, and potentially harmful overtreatment. The American College of Physicians has recommended that laboratory testing be ordered only for patients with an estimated pretest probability of Lyme disease between 20% and 80%. Patients with only nonspecific symptoms such as headache, fatigue, and muscle or joint pains and no history of erythema migrans have a pretest Lyme probability of less than 20%, regardless of where they live.

"Unfortunately," Dr. Green said, "many people truly struggling with symptoms they think may be related to chronic Lyme disease understandably lose objectivity about a test like this to discern whether it is credible or valid. The medical community needs to be critical of itself and of the tests that we use."

Dr. Green added, "What I would say to a patient concerned about Lyme disease, struggling with a myriad of symptoms, is that we don't know if this test is valid. Until it is validated, it is irresponsible to use this in clinical medicine for the fear that you might be wrong in diagnosis. The harm is that perhaps there is a different and accurate etiology we are missing, and we get misled with a misdiagnosis from this unreliable test result. The patient may have objective disease or infection from another etiology that would not be identified if we hang our hat on this misinformation. It will derail diagnosis and treatment."

Dr. Mead concluded, "These situations call for both empathy and education. Patients with chronic unexplained symptoms are understandably desperate to find out what is wrong with them and often do not appreciate the limitations of these unvalidated, alternative tests. Clinicians need to encourage them to keep an open mind about the cause of their symptoms and to work with the patient to find answers using validated testing methods."

Medscape Medical News attempted unsuccessfully to reach Advanced Laboratory Services, Inc, and Dr. Sapi for comment.

Dr. Burrascano has disclosed no financial interest in the laboratory, in the Borrelia culture, or in any intellectual property and receives no commissions from the tests. Dr. Burrascano is senior vice president of medical affairs and medical director for Advanced Research Corporation, a contract research organization with the same president and corporate address as Advanced Laboratory Services, Inc. Dr. Mead And Dr. Green have disclosed no relevant financial relationships.




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