Monday, 11 December 2017 15:26

Should the Lyme Patients’ RICO lawsuit include Yale?

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Recently, a group of Lyme disease patients in the United States filed a lawsuit against several major health insurance companies and a group of Lyme disease specialists seeking treble damages for RICO Act (Racketeer Influenced and Corrupt Organizations Act) and Sherman Act antitrust violations. Four months earlier, Dr. Sin Hang Lee also initiated a legal action against the CDC for anti-competitive campaign to stifle the use and availability of his DNA-based direct test to diagnose Lyme disease. More recently, court materials surfaced which show credible reasons to believe that the role of Yale University in suppressing development and use of direct detection methods in the diagnosis of Lyme disease at the early stage of infection for patient care should also be scrutinized by the media and the lawyers of the RICO suit.

“The medical profession has been transformed into a “healthcare industry”. In this world of free market economy, the healthcare providers in the pain management business may arguably have the rights to create public need for their services, just like Apple creating demand for its iPhone.” Dr. Lee

[Disclaimer: The following text does not necessarily reflect my personal opinions and views or those of the On Lyme Foundation. However, it does faithfully present my questions and Dr. Lee’s answers, informed by his five decades of outstanding professional achievements.]

Dr. Sin Hang Lee has - at the age of 85 - a unique perspective on the developments of the policies and politics of Lyme Disease. When Dr. Allen Steere, then a first-year fellow in rheumatology at Yale University, named the mysterious outbreak of Borreliose in Connecticut ‘juvenile Lyme arthritis’ in 1975, Lee was already an associate professor of pathology at Yale. An exclusive interview.

Q. Can you introduce yourself and tell how you got involved in Lyme disease?


Dr. Lee: I graduated in 1956 from Wuhan Medical College in China, an old medical school originally established by the Germans in Shanghai. Then I became a microbiologist and pathologist while teaching in different universities in China and Hong Kong. 

After a residency-fellowship training at Cornell Medical School-New York Hospital and Memorial Hospital for Cancer in New York City, I was certified by the American Board of Pathology and obtained the F.R.C.P. (C) degree by examination in 1966. After that I was on the faculty of McGill University - then Yale University - from 1968-2004. I was practicing pathology in the affiliated teaching hospitals and doing research on the side, including DNA sequencing at the later stage.

In 2004, I was employed as a pathologist in Connecticut at Milford Hospital where I began to develop routine molecular diagnostic methods using the PCR and DNA sequencing technologies to test patient samples to increase the accuracy of DNA-based tests. 

Researchers like myself could not develop or use PCR technologies without paying heavy licensing fees to Roche until the PCR patent owned by Hoffmann La Roche expired in 2006. Therefore, my research work in this field officially began in 2006. 

As a pathologist reading Papanicolaou smears for cervical cancer prevention, HPV detection and genotyping by DNA sequencing was my first priority among all the tests I needed to develop. The then chairman of the department of pathology of Milford Hospital and I published the first paper titled “Routine human papillomavirus genotyping by DNA sequencing in community hospital laboratories.” in June 2007. 

Commercial test kits for sexually transmitted infections were developed based on clinical trials conducted in the “red-light” districts worldwide often using sex workers as the test subjects. When these test kits are used in populations with low disease prevalence, the ‘false-positive’ test rates may become unacceptably high. Therefore, we added Chlamydia trachomatis and Neisseria gonorrhoeae to the test list because the middle-class women in Milford needed an accurate ‘no-false positive’ test for these sexually transmitted infections. We use nested PCR routinely to increase the sensitivity and Sanger sequencing to maintain the specificity on all positive test results.  

As a pathologist, accurate gynecology DNA tests are my major interest.  My laboratory currently has CLIA-approved test methods for HPV, Chlamydia trachomatis, Neisseria gonorrhoeae as well as Ashkenazi Jewish BRCA1 and BRCA2 founder mutations screen all on one Pap smear sample; these methods are implementable in community hospitals. 

Lyme surfacing

I was first appointed as an associate professor of pathology at Yale University in 1971. I have witnessed how Lyme arthritis was first described and reported in the world literature, and how patients have been diagnosed and treated in southern Connecticut in the past 40 years. 

Furthermore, since Milford Hospital was serving a population in southern Connecticut with a high rate of Lyme disease, the hospital administration and the medical staff - including the former chairman of the department of pathology in 2008 - saw a need to expand the nested PCR/DNA sequencing technologies to include Lyme disease. This was done to test patient blood samples for reliable diagnosis of Lyme disease at the early stage of infection for timely appropriate treatment. 

The staff of the department of pathology and the doctors of the emergency room (ER) of Milford Hospital started a research project to test the blood samples of the patients who presented to the ER with possible Lyme disease in 2008. 

The technical paper was published in April 2010 and the clinical paper in November 2010. It was the first direct blood test with DNA sequencing accuracy and a new DNA test that was useful for patient care. This development was widely reported in the news media. 

Q. What have you personally witnessed about the controversies on laboratory tests for the diagnosis of Lyme disease? 

Dr. Lee: Lyme borreliosis is a systemic bacterial infectious disease. According to the established principle in medical practice, all infectious diseases should be diagnosed by culture or detection of the nucleic acid of the causative agents in patient samples. If Lyme disease were first described after 2006 when the world-wide PCR patent expired, I am sure we would not have any diagnostic controversies today. 

Historically, Lyme arthritis was first described in the mid 1970’s by a group of rheumatologists at Yale medical school. It appears their business is pain management and not detection of infectious etiologies. When a spiral-form bacterium, now known as Borrelia burgdorferi, was found to be the causative agent, the only way to diagnose the infection in the early 1980’s was by measuring the antibodies against the bacteria in convalescent serum samples of the infected patients.

This is because the borrelia is difficult to culture in artificial media. Nucleic acid-based testing technologies, such as DNA sequencing and PCR were not available then. 

PCR patented

When the Nobel Prize for discovering the PCR technology was awarded to Kary Mullis in 1993, the PCR patent was already purchased by Hoffmann La Roche from Cetus. The world-wide PCR patent rights did not expire until 2006. Before 2006, no one could develop any PCR diagnostics without paying Roche a heavy fee. Roche representatives told me the upfront, plus fees for each distinct PCR, was $250,000.  

From the 1970s until 2006, heavy investments of money were made in the patented antibody-based technologies for diagnostic tests and in developing vaccines related to Lyme disease; these investments also helped to sponsor careers. 

However, diagnostic antibody titers are not measurable in Lyme disease patients until 4-6 weeks after infection. By then, the borrelial spirochetes have already invaded deep tissues, and may not be eradicated as easily as in the early spirochetemic stage of the infection.

Early diagnosis

Early diagnosis and timely treatment may cure most Lyme disease patients and these early interventions would reduce the need for pain management and immunosuppressive therapies. For this reason, we at Milford Hospital developed the first nested PCR/DNA sequencing-based test to diagnose Lyme disease infections before the antibodies are measurable. 

The test was approved by the Connecticut State Department of Public Health under CLIA in 2009 for patient care. But when I tried to publish our clinical data and to spread the DNA-based test technology, I found there is a national concerted resistance to even consider any direct DNA test approach for Lyme Disease. 

Q. Can you specify the kinds of resistance you have encountered? 

Dr. Lee: Except for the first technical paper, all my manuscripts based on studies of Lyme patient materials were rejected by mainstream American medical journals, including the American Journal of Clinical Pathology, the Journal of Clinical Microbiology and the Clinical Chemistry.

The reasons for rejection alleged ‘lack of readership interest at the editorial screening stage’, or a low priority score. This was quite a ‘coincidental’ message to come from all these journals and it meant the manuscripts were rejected by editorial censorship and had to be published in foreign journals. 

Although I had never met him in person, I knew Dr. Allen Steere was a pioneer in Lyme disease starting in Connecticut. Therefore, after my first technical paper on Lyme disease was accepted for publication in 2009, I sent the accepted manuscript to Dr. Steere at the Massachusetts General Hospital and informed him that there is an emerging reliable DNA method for diagnosis of early Lyme infection.

To my surprise, Steere wrote back in an email that he had no interest in reading the manuscript, because he was working on the C6 Lyme antibody test.  

Diagnostics Conference 2014

On November 8, 2014, there was a national meeting entitled “Lyme Borreliosis and Tick Borne Illnesses: Diagnostics, Emerging Pathogens and Avenues for New Research” held in Massachusetts General Hospital (MGH). The organizers of the meeting initially asked me if I would consider speaking on my experience of using nested PCR/Sanger sequencing for the diagnosis of Lyme borreliosis, in particular Borrelia miyamotoi in blood samples.

After I warned the initial organizer, a fellow pathologist, that he might need to check with his group at MGH first before sending me an official invitation because I knew Dr. Steere was in charge of approving the speakers’ list in the name of continued medical education. I did not want the organizer of the meeting to make a wrong political move at MGH for himself. 

As predicted, the invitation was aborted. Instead, I was advised to present a few Powerpoint slides at the Round Table Discussion and to distribute a Handout to the audience at the Round Table Discussion. However, in the end I was not allowed to present any Powerpoint slides and only allowed to distribute the Handout at the social event after the scientific meeting and after the Round Table Discussion. 

In the same year, without any explanation the CDC negated a previously agreed project titled “An open label, multi-site evaluation to assess the accuracy of current diagnostic laboratory testing methods in comparison to nested PCR and DNA sequencing for the detection of Lyme disease and related borreliosis”. This unfounded negation by the CDC of this planned project is the basis of my complaint and pending lawsuit against the CDC.  

Based on my personal experience and that of an increasing number of reputable scientists and medical professionals, there appears to be an orchestrated censorship campaign against free flow of scientific information on Lyme disease research, in particular against development of direct detection tests for the diagnosis of early infections.   

Q. On the internet, I found some people attacking you because you were fired by Milford Hospital in 2010 and you had filed a lawsuit against the Hospital. Then there was a Businesswire press release in August 2013, announcing resumption of your DNA sequencing-based testing for early Lyme disease by you at Milford Hospital. Can you comment on that?

Dr. Lee: Yes. The press release is titled “Milford Hospital Pathologist to Resume DNA Sequencing – Based Testing for Early Lyme Disease”. It was merely issued to settle a lawsuit. Milford Hospital has stopped offering direct DNA testing for Lyme disease since the end of 2010 after the Yale medical group took over the management. 


Q. Can you confirm that you filed a lawsuit against Milford Hospital after the Hospital terminated your appointment allegedly for cause in December 2010? 

Dr. Lee: Yes. But this lawsuit was settled in Court and the termination order was rescinded. My lawyer told me that I may not talk about the litigation, except to say that the lawsuit has been resolved. 

Q. I have obtained a copy of the formal complaint your lawyer filed on your behalf with the Superior Court in Connecticut. In this document, you state that Yale had you fired because their serology-based Lyme diagnostic tests could not compete with your nested PCR/DNA sequencing test to diagnose Lyme disease at early stage of infection. As I understand your complaint, a Yale medical group doctor became the new chairperson at Milford Hospital and then told the human resources director to fire you.  Can you confirm if I have read the document correctly? 

Dr. Lee: Yes. Your summary is correct. It is common knowledge that the Yale medical group has focused on serology-based tests in order to diagnose Lyme disease at convalescent stage of the infection and I want to diagnose Lyme disease at the early stage of infection before Lyme antibodies become measurable. 

These are two different approaches to diagnosing Lyme disease, from the rheumatologists’ point of view or from a pathologist’s point of view. This is a healthy scientific dispute that has nothing to do with the litigation.  

Q. In the pending lawsuit against the CDC, you claim that certain CDC officers engaged in an anti-competitive campaign to stifle development of direct DNA testing for Lyme disease. Did you consider filing the same complaint against the Yale medical group? 

Dr. Lee: No. In my view, the medical profession has been transformed into a “healthcare industry”. In this world of free market economy, the healthcare providers in the pain management business may arguably have the rights to create public need for their services, just like Apple creating demand for its iPhone. 

I cannot challenge a private group for conducting their normal business, but I can bring litigation against a competitor for anti-competitive activity and tortious interference with my business expectancies or on other grounds. 

However, the CDC is different from the private sector, because the CDC employees are government officials and public servants. Their salaries are paid by tax money and their job is to protect the public health and well-being and this includes any pain and suffering caused by unnecessarily delayed diagnosis and treatment of disease. 

As U.S. federal government employees, the CDC employees believe they enjoy a protective shroud against liability.  However, there are those who have made personal financial gains -in addition to their full salaries and benefits-through the relationships with the industry they forged when securing patents. These public servants have also been active in the reviewing, judging, preventing and stifling of the products, devices or methods set forth by their competitors against public interest.  

In the case of maintaining a dysfunctional Lyme disease policy, these public servants who knowingly work against public interest for a personal agenda and personal gain should be held accountable.  In contrast, Yale employees can do whatever they want to advance their employer’s business interest… as long as it is lawful.

Prescribing pain killers and immunosuppressants for patients with post-treatment Lyme disease syndrome (PTLDS) is a major business for the rheumatologists in Lyme disease-endemic areas. Delaying diagnosis of Lyme disease infection until the patients are in convalescence is an effective way to maintain a high number of customers with PTLDS for the pain management industry, a practice considered to be acceptable for more than 30 years.

Q. What do you think about the value of serology-based tests for Lyme disease diagnosis? What do you consider to be the right approach to diagnose Lyme disease?

Dr. Lee: Lyme disease is, in reality, primarily chronic Lyme disease, because all acute Lyme infections are not being diagnosed and timely treated in most endemic states. Unless the patient presents with a classic bull’s eye skin lesion to the treating physician in the acute phase of infection, the possibility will not even be considered. 

The problem of Lyme disease will probably disappear like that of rheumatic fever and rheumatic heart disease when an accurate direct detection test is used to detect all acute infections at the spirochetemic stage and treated properly like for group A strep throat infections in eliminating rheumatic diseases.  

Now we have realized that clinical Lyme borreliosis can be caused by many species and strains of borreliae, including some species from the heterogenous relapsing fever group, notably Borrelia miyamotoi. 

Just as we cannot use a Widal test to diagnose all Salmonella bacteremia cases, it is not possible to use one serology test kit to diagnose all borrelial infections. All antibody tests can generate false positive results, because antigen/antibody cross reactions are well known phenomena among different bacterial species. 

The only accurate non-cultural method for the detection of a suspected bacteremia beyond a reasonable doubt is to perform Sanger sequencing of a signature segment of the genomic DNA isolated from the bacteria in the patient’s blood sample. Laboratory diagnosis of bacteremia caused by difficult-to-culture microorganisms is technically challenging. To this day, “there is not a readily available, effective direct-detection method for Treponema pallidum“ in blood samples. 

To answer your question, I would say that the right approach to diagnose Lyme disease is to perform a highly sensitive nested PCR with a pair of comprehensive borrelial general primers followed by Sanger sequencing to validate the PCR amplicon.  


Q. What is your motivation to sue the CDC now? 

Dr. Lee: My motivation is to bring the facts to the public and demonstrate how the CDC’ is violating their own principle for diagnosis of bacterial infectious diseases. The Agency has allowed some officers of the CDC to intentionally suppress development and discourage the use of scientifically established direct DNA tests for reliable diagnosis of Lyme disease infections.

By winning this lawsuit, I would receive $57 million and these monies can be used to establish a global system for accurate direct DNA tests to diagnose Lyme disease at the early stage of infection and for diagnosis of the chronic Lyme disease patients still presenting with spirochetemia. 

Based on three decades of CDC history and current Lyme policy, there is no indication the current CDC bureaucracy would willingly fund such a project. We hope members of Congress who are truly looking out for their constituents will support an investigation into the CDC and bring about the necessary changes for the benefit of tax payers and consumers.

In order to perpetuate the dogma created before the era of DNA sequencing, government agencies and the mainstream healthcare industry, including those in the academic centers, have no interest in developing direct testing methods. Their modus operandi is to maintain the status quo of a dysfunctional system, while paying lip service to the need for more research on better testing. 

I must emphasize that my lawsuit is only against a few managers at the CDC. Over the years, I have known some very great and ethical CDC scientists. I have visited their labs and they have taught me a lot of molecular biology. 

In fact, one senior scientist from the CDC came to Milford to help me design the molecular diagnostic laboratory according to the CDC standard. Another senior CDC scientist went out his way to get me a sample of Ebola virus RNA for me to develop a field reverse transcriptase PCR/sequencing method - which I presented at an international meeting on Ebola research held in the Pasteur Institute in Paris in 2015. 


Q. What are your biggest concerns surrounding Lyme disease and public health care?

Dr. Lee: Lyme borreliosis is an emerging infectious disease transmitted by tick bites and is caused by numerous strains of Borrelia burgdorferi species and relapsing fever borreliae. The best way to prevent Lyme borreliosis is to avoid tick bites. 

However, ticks are going to be around with us for a long time. I just pulled out an engorged deer tick heavily infected with Borrelia burgdorferi from the skin of my left arm on this past Thanksgiving Day, the first tick bite in my life. About 30% of the ticks, all Ixodes scapularis, in my backyard are positive for borreliae with a Borrelia burgdorferi to Borrelia miyamotoi ratio being ~10/1.

Since we cannot prevent tick bites and borrelial infections altogether, we must try to prevent or to stop the invasion of the deep tissues by the borrelia after infection, namely to prevent chronic Lyme disease. That means timely appropriate antibiotic treatment after a reliable diagnosis at the early spirochetemic stage of infection. That means widely spread use of direct detection tests for borrelia in blood samples in endemic areas in the local hospital laboratories. Sending blood samples across the country for the diagnosis of bacteremia is not an established practice for good patient care.

To answer your question, I think my biggest concerns are how to convince the healthcare industry and public health authorities that Lyme borreliosis is a potentially serious infectious disease and the diagnosis cannot be based on serology tests for timely appropriate patient management.

Then, we need to convince the hospitals at the Lyme endemic areas to handle Lyme disease patients like other cases of bacteremia as they occur. The workup for the diagnosis of bacteremia is traditionally carried out in the local hospital laboratory, not in an out-of-State commercial laboratory.

It is not easy to change the status quo established in the past 40 years. But it is doable if there is a strong public demand.    

Dr. Sin Hang Lee

Interviewer / author: Huib Kraaijeveld

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Read 15405 times Last modified on Monday, 26 March 2018 11:46
Huib

Huib Kraaijeveld

Initiator On Lyme Foundation