Lyme disease is an infection that is transmitted through
the bite of a tick infected with a bacterium called
Borrelia burgdorferi. Ticks typically get the bacterium
by biting infected animals, like deer, mice and bandicoots. 

 

Lyme Disease – One Of The Most Controversial 
Illnesses In The History Of Medicine.

Attorney General forces Infectious Diseases Society of America
to redo Lyme guidelines due to flawed development process
L Johnson,1 R B Stricker2 1 California Lyme Disease Association,
Ukiah, California, USA;


2 International Lyme and Associated Diseases Society, Bethesda, Maryland, USA Correspondence to:
Dr R B Stricker, 450 Sutter Street,
Suite 1504,
 San Francisco,
California 94108, USA;
rstricker@usmamed.com
Received 30 June 2008 Accepted 25 February 2009

 

ABSTRACT
Lyme disease is one of the most controversial illnesses in the history of medicine.

In 2006 the Connecticut Attorney General launched an antitrust investigation into the Lyme guidelines development process of the Infectious Diseases Society of America (IDSA). In a recent settlement with IDSA, the Attorney General noted important commercial conflicts of interest and suppression of scientific evidence that had tainted the guidelines process. This paper explores two broad ethical themes that influenced the IDSA investigation. The first is the growing problem of conflicts of interest among guidelines developers, and the second is the increasing centralisation of medical decisions by insurance companies, which use treatment guidelines as a means of controlling the practices of individual doctors and denying treatment for patients. The implications of the first-ever antitrust investigation of medical guidelines and the proposed model to remediate the tainted IDSA guidelines process are also discussed. The diagnosis and treatment of Lyme disease is highly controversial, and most patients are aware that obtaining a diagnosis and treatment for this tick-borne illness can be difficult. One group of doctors, the Infectious Diseases Society of America (IDSA), issued Lyme treatment guidelines in 2000 that promoted a narrow definition of the disease.1 These guidelines excluded most Lyme patients and denied them treatment for their illness. The IDSA viewpoint has been adopted without question by government agencies, insurers, medical boards and hospitals. As a result, the diagnosis and treatment of Lyme disease has been suppressed, with profound healthcare implications for patients, their families and their communities. The level of disability of patients with Lyme disease is equal to that of patients with congestive heart failure and there are at least 21 studies documenting death in patients with this potentially devastating tickborne illness.1 AN INVESTIGATION AGAINST THE IDSA When the IDSA sought to revise its Lyme treatment guidelines in 2006, patients and their treating doctors tried to obtain a voice in the guidelines process. The IDSA denied their requests for participation and limited the guidelines panel to researchers known to have a bias against the diagnosis and treatment of Lyme disease. The IDSA panel then selectively ignored evidence of persistent infection or clinical improvement with antibiotic treatment in patients with persistent symptoms of the disease. From the perspective of antitrust law, the behaviour of IDSA drew attention to its monopoly power, the fact that its guidelines were treated as mandatory and that members of the guidelines panel had commercial conflicts of interest and intentionally excluded divergent viewpoints and evidence. These facts dovetailed with IDSA’s power to control the playing field and enforce its guidelines by providing insurers with second opinions while instigating and testifying at unprofessional conduct actions against doctors who did not comply with the IDSA guidelines. In addition, the IDSA’s ability to further suppress the debate through its role as the gatekeepers (on editorial boards and as peer reviewers) for medical journals, medical conferences and grand rounds supported the antitrust argument when patients started complaining that they were being denied care for their disease. The California Lyme Disease Association (CALDA), the national Lyme Disease Association, Connecticut-based Time for Lyme and other groups affected by the guidelines approached the Connecticut Attorney General, Richard Blumenthal, and expressed their concerns about patients being denied care. In late 2006, the Attorney General launched an antitrust investigation into IDSA and its Lyme guidelines panel for misuse of monopoly power and exclusionary conduct in the development of the guidelines. The antitrust theory is that when a medical society has monopoly power such that its guidelines can take on the force of law, as the IDSA guidelines do, it has an obligation to ensure that the development process is fair, does not exclude competing points of view, and that its panel is not driven by commercial conflicts of interest. To our knowledge, this is the first-ever antitrust investigation into the development process for medical guidelines. In May 2008, after an extensive investigation, the Attorney General announced a settlement of the antitrust investigation into the IDSA guidelines development process. The settlement stipulates that the IDSA must put together a new panel free from conflicts of interest, permit the introduction of evidence opposing its viewpoints, and hold a public hearing (aired live on the Internet) on controversial recommendations of the guidelines panel. While this is an important victory for the Lyme community, the settlement has broader implications for medical guidelines generally because it represents the first time that conflicts of interest in the guidelines development process have been addressed using antitrust theories. Clinical ethics J Med Ethics 2009;35:283–288. doi:10.1136/jme.2008.026526 283 There are two broad themes that set the stage for the investigation by the Attorney General. The first is the growing problem of conflicts of interest among guidelines developers, and the second is the increasing centralisation of medical decisions by insurance companies, who use treatment guidelines as a means of controlling the practices of individual doctors.

 

CONFLICTS OF INTEREST MEAN THAT THE QUALITY OF PATIENT CARE MAY TAKE A BACK SEAT TO OTHER COMMERCIAL INTERESTS HELD BY GUIDELINE PANEL MEMBERS
A survey of medical experts who write guidelines for treating conditions such as heart disease, depression and diabetes has found that nearly nine out of 10 have financial ties to the pharmaceutical industry, and the ties are almost never disclosed.2 Drug companies foster relationships with key opinion leaders among academic researchers who can help develop, obtain Food and Drug Administration (FDA) approval and create a market for drugs, diagnostic tests or vaccines. Panel members may also have consulting relationships with insurers. Before this case, there had been no effective remedy for guidelines developed by panels with conflicts of interest. While researchers argue that ‘‘all is well’’ provided conflicts are disclosed, other commentators have pointed out that disclosure is not a sufficient remedy when commercial interests drive the process (including selection and interpretation of evidence) and conclusions of a guidelines panel. Merrill Goozner, director of the Integrity in Science Project at the Center for Science in the Public Interest, testified before the Institute of Medicine3 : ‘‘The system for reviewing the body of evidence in a field; deriving best practices through systematic reviews; writing clinical practice guidelines; conducting and evaluating comparative research; and, vitally important, evaluating evidence for regulatory purposes should be entirely free from conflicts of interest.’’ Goozner emphasises the need to maintain strong boundaries between those who determine how medicine is practised and researchers who conduct industry-funded research. The most influential members of the IDSA guidelines panel had commercial interests related to Lyme vaccines, diagnostic tests, and insurance consulting (table 1 and appendix A). Some of the panellists had been involved in the development of the first Lyme vaccine and had run clinical trials for the vaccine, which was withdrawn from the market after patients reported serious arthritic and neurological side effects.4 Several panellists had been sued as part of a class action lawsuit or served as expert witnesses for the vaccine manufacturer, and some are working on the second generation of Lyme vaccines, which are still under development. Some panellists acknowledged that they owned or had interests in Lyme diagnostic tests or consulted for insurers. The panel was composed of researchers who supported each other’s work and who controlled enormous amounts of government funding for research. These conflicts are disclosed by key panel members themselves in their own publications or statements to the press (table 1 and appendix 1). Commercial conflicts of interest on guidelines panels is a growing problem in healthcare because panellists may no longer hold the interests of the patient paramount, and the guidelines may determine the medical standard of care for patient treatment. When commercial interests drive the train, patient concerns take a backseat. The New York Times reported on a guidelines panel for blood pressure that reduced the threshold level at which patients should receive medication.11 It turned out that many of the panellists on the hypertension panel had links to the drug companies that produced antihypertensive medications. These manufacturers stood to gain from disease definitions that expanded the size of their commercial market and increased sales. Many doctors believe that they can rise above commercial conflicts of interest, but common sense tells us otherwise. Put a little bit of money in the game and the nature of the debate simply changes. The IDSA has said that it was not exclusionary in its panel selection and that it listened to competing points of view. This is not true. The association rejected out of hand requests for a seat at the table by patient groups, doctors’ organisations and individual treating doctors—even those who were IDSA members. In its previous guidelines panel, IDSA summarily tossed off the panel one researcher who disagreed with the panel chair on the best approach for treatment of chronic Lyme disease. Dr Gary Wormser, who chaired the Lyme guidelines panel, scoffs at the notion that commercial interests could have played a role in the development process12: Table 1 Summary of disclosed conflicts of interest by five key guideline panel members Author Conflict Source G Wormser Lyme diagnostic tests (Immunetics, Bio-Rad, Biopeptides, Diaspex, Abbott Laboratories) Self-disclosure, IDSA Guidelines 20065 Self-disclosure, New England Journal of Medicine 20076 Lyme vaccines (Baxter, AstraZeneca, Biopeptides) Expert witness for medical malpractice involving Lyme disease R Dattwyler Lyme diagnostic tests (Biopeptides and Baxter) Self-disclosure, IDSA Guidelines 2006 Lyme vaccines (Baxter, Biopeptides) Self-disclosure, BMJ Lyme Wars 20077 US patent 7008625 Recombinant Constructs of Bb Self-disclosure, see individual patents listed in conflict column Provisional patent 60/812,595 on a live ‘‘bacterial vaccine’’, PCT/US2005/023106 ‘‘oral vaccine for Borrelia’’, a wildlife vaccine Brook Technologies Release8 Provisional patent 60/799,016, ‘‘Peptide Diagnostic Agent for Lyme’’ Expert witness for medical malpractice involving Lyme disease E Shapiro Vaccines: Sanofi-Aventis, NIH Grants K24RR022477, KL2RR024138, and UL1RR024139. Self-disclosure, IDSA Guidelines 2006 Self-disclosure, New England Journal of Medicine 2007 Expert testimony: medical malpractice and unprofessional conduct actions Self-disclosure, American Academy of Neurology 20079 Insurance: reviews Lyme disease disability claims for Metropolitan Life Insurance A Steere Lyme vaccines (Baxter, GlaxoSmithKline) Self-disclosure, IDSA Guidelines 2006 Lyme diagnostic tests (Viramed) Self-disclosure, Nature 200610 J Halperin Vaccines: serves as an expert witness on behalf of Lymerix (GlaxoSmithKline) in litigation regarding adverse effects from first generation vaccines (ongoing) Self-disclosure, IDSA Guidelines 2006 Clinical ethics 284 J Med Ethics 2009;35:283–288. doi:10.1136/jme.2008.026526 ‘‘There’s no potential financial gain for generic drugs that are recommended for short courses. It’s inconceivable that anyone would think so. To me it seems disingenuous to make these allegations when they are so absurd.’’ In Wormser’s view, because the panel members were not promoting drugs for treatment there could be no conflict of interest. People are used to thinking about conflicts of interest in terms of drugs used for treatment, but the arena is much broader than that. There is tremendous financial gain in Lyme disease through vaccines, diagnostic tests and consulting with insurance companies. The IDSA guidelines restrict the definition of the disease and mandate laboratory testing. Guidelines that restrict the disease definition are favourable to vaccine manufacturers because they increase the effective rate for the vaccines so that fewer people taking the vaccine ‘‘get’’ the disease. Guidelines that mandate testing for disease diagnosis promote the interests of those who develop and manufacture diagnostic tests. Guidelines that deny treatment to patients are favourable to insurance companies and those who are paid to consult with them. The IDSA Lyme guidelines panel members had commercial interests in each of these areas.

 

CENTRALISED MEDICINE REDUCES CHOICE FOR PATIENTS AND LIMITS THE DOCTOR’S ABILITY TO USE CLINICAL JUDGEMENT
The increased concentration and centralisation of power in medicine was also an important factor leading up to the antitrust investigation. Twenty years ago, individual doctors had more autonomy than they do today in deciding whether to comply with medical guidelines. Medical malpractice and unprofessional conduct actions were always rooted in the standard of care, which was determined by the consensus of practising doctors, but guidelines became a vehicle for driving the standard of care. This transformed a very fluid environment where opinions in medical practice changed as individual doctors’ viewpoints changed based on new information from the latest medical conference or grand rounds, the success or failure in treating patients or the latest study read by the doctors. The opinions of individual panel members on guidelines panels of powerful medical societies became a proxy for the opinions of doctors in the broader community. With ‘‘evidencebased’’ guidelines, someone other than the treating doctors selects, interprets and makes recommendations regarding treatment. The problem arises when the ability of a doctor to select, interpret and exercise clinical judgement is replaced by an obligation to comply with guidelines that do not work or that are not appropriate for the individual patient. Population-based treatment approaches using average results leave individual patients who are not the ‘‘norm’’ out of the equation. This is why it is important to treat the patient rather than the disease, and why displacing the treating doctor’s judgement is risky business. Commercial interests, particularly those of insurers and drug manufacturers, see guidelines as a means of controlling medical costs or furthering vaccines, drugs or diagnostic tests. As a result, guidelines became part of the ‘‘one-stop shopping’’ marketing strategy of pharmaceutical companies and part of the cost-containment strategy of insurers. In addition to the role of commercial interests and conflicts of interest discussed above, an equally important issue is the shift of guidelines from a ‘‘suggestion’’ to a ‘‘mandated standard of care’’ that is intended to displace doctors’ autonomy with centralised medical decisions. Guidelines permit insurers to shift the emphasis from clinical judgement to a centralised, largely administrative function, with an emphasis on actuarially predictable population-based care. Dr David Eddy, senior adviser to Kaiser Permanente, notes that ‘‘if the fight to control health care costs is to be successful, it will have to address [the decisions physicians make about treatments].’’13 Guidelines are the mechanism for doing this. Specialty societies embrace treatment guidelines because these official protocols expand their sphere of influence in an insurance-driven environment. Specialty societies such as the IDSA are extremely insurance-conscious because the livelihood of their members hinges on the acceptability of their guidelines and the role their members play as ambassadors and enforcers of second opinion of those guidelines. According to Eddy, ‘‘[I]t would not be stretching things too far to say that whoever controls practice policies controls medicine.’’14 What this means is that if one can control the development of treatment guidelines and can obtain compliance from doctors, one can effectively control the way doctors practise medicine and also control costs. This is why insurers are driven by guidelines. Insurers control doctors’ practices through economic profiling that compels doctors within the insurer’s network to conform to guidelines or cost parameters on threat of termination from the network. Insurers control out-ofnetwork costs by refusing to reimburse claims for services that do not conform to guidelines. The government is the USA’s largest insurer through Medicare and this fact, plus the drive towards universal healthcare, has placed more emphasis on cost control through guidelines. The health insurance industry relies heavily on third party guidelines (such as the IDSA Lyme guidelines) to provide a shield against potential litigation as well as to control costs. Historically, health insurers have been held accountable for violations of the standard of care (just as doctors can be). However, when powerful third parties develop the guidelines, they can drive the standard of care. When large specialty societies drive the standard of care, no one is accountable for malpractice if these standards are ‘‘wrong’’. The specialty society does not have the individual physician–patient relationship that would create the duty of care necessary for malpractice, and the insurer is shielded because it is relying on an acceptable standard of care. In this case, the IDSA promulgates guidelines that the insurers rely on to justify denials of care, thereby reducing costs. When patients seek out a doctor who does not follow the IDSA guidelines, the insurers require a second opinion from an ‘‘infectious disease’’ expert, thereby creating a highly effective enforcement cycle for insurers using third party guideline developers. Guidelines by specialty societies provide a particularly effective means of controlling general medical practice. The same control issues apply to appeals of insurance denials through the ‘‘independent medical review’’ process sanctioned by most states. This review process assists insurers by having a third party review their claims. Some insurers who are not required by law to use the review process nevertheless elect to use this approach because it is an inexpensive way of disposing of claims as a practical matter without litigation or arbitration. There are only a handful of ‘‘independent review organisations’’ (IROs) used by the states that have adopted independent review processes. These organisations represent insurers as their bread and butter work and perform independent reviews on the side. While the internal processes of IROs are a black box (there is no transparency in their procedures), the general concept is that these organisations also rely on guidelines by third parties, Clinical ethics J Med Ethics 2009;35:283–288. doi:10.1136/jme.2008.026526 285 particularly the guidelines of a specialty society. As a result, specialty society guidelines have a large role in determining the care that may be provided, not only by members of their society but also by family doctors and internists. Insurers can also rely on these guidelines to police doctors within their networks, terminating the contracts of those who are not complying. Hospitals (which can operate like insurance providers these days) can use these guidelines to determine the care provided within the hospital and whether hospital privileges will be extended or revoked for doctors who do not follow the guidelines.

 

RESTRICTIVE GUIDELINES ARE VIEWED AS MANDATORY BY THE MEDICAL COMMUNITY
The guidelines published by the IDSA in November of 2006 were extremely restrictive and denied the use of clinical judgement in the diagnosis and treatment of Lyme disease. This is a critical point because when patients fail treatment under the IDSA guidelines (which restrict Lyme treatment to 30 days), they are given no alternative treatment. Doctors are essentially told to sit on their hands and let the patients experience a disability that is equivalent to that of congestive heart failure—with no treatment offered. Doctors are told that they must ignore their clinical experience and ignore the patient’s history, course of treatment and past responsiveness to medication. It is the exclusion of treatment options and denial of the doctor’s right to use clinical judgement that makes the guidelines so restrictive. Add the fact that IDSA is so powerful in the medical community and that its opinions are given the force of law by medical boards and insurers and one has all of the ingredients necessary to deny patients with chronic Lyme disease any treatment whatsoever. The IDSA’s role in instigating and testifying at unprofessional conduct hearings and in supporting insurance denials of care makes compliance with its guidelines mandatory. This enforcement deters doctors who might otherwise treat patients with chronic Lyme disease from doing so.

 

THE ATTORNEY GENERAL’S INVESTIGATION
Findings of the investigation The Attorney General found that the IDSA Lyme guidelines panel, which was hand-picked by Dr G Wormser, had important conflicts of interest, intentionally blocked the appointment of panel members with divergent viewpoints, and intentionally excluded evidence that was not in conformity with the bias of the panel15: ‘‘The IDSA’s guideline panel improperly ignored or minimized consideration of alternative medical opinion and evidence regarding chronic Lyme disease, potentially raising serious questions about whether the recommendations reflected all relevant science’’. Some of the specific findings were: c Dr Wormser, the panel chair was selected inappropriately, ‘‘held a bias regarding the existence of chronic Lyme’’ and ‘‘handpick[ed] a likeminded panel without scrutiny by or formal approval of the IDSA’s oversight committee’’. c The IDSA panel members had financial interests—‘‘in drug companies, Lyme disease diagnostic tests, patents and consulting arrangements with insurance companies’’ The IDSA failed to conduct a conflicts of interest review for any of the panellists, several of whom had conflicts of interests. c The IDSA’s 2000 and 2006 Lyme disease panels refused to accept or meaningfully consider information regarding the existence of chronic Lyme disease. c The IDSA blocked appointment of scientists and doctors with divergent views on chronic Lyme who sought to serve on the 2006 guidelines panel by informing them that the panel was fully staffed, even though it was later expanded. c The IDSA portrayed the American Association of Neurology copycat guidelines as corroborating its own when it knew that the two panels shared several authors, including the chairmen of both groups, and were working on guidelines at the same time.16 The settlement The settlement is a process—essentially a reassessment of the guidelines by a panel free of conflicts—with safeguards to ensure that evidence and opinions are not suppressed The Attorney General has always been clear that his role is not to make medical judgements or to trump science. Instead, his role is to make sure that the development process is fair, non-exclusionary, and not tainted by conflicts of interest. According to the Attorney General’s findings,15 the IDSA panel members had important conflicts: ‘‘The IDSA’s 2006 Lyme disease guideline panel undercut its credibility by allowing individuals with financial interests—in drug companies, Lyme disease diagnostic tests, patents and consulting arrangements with insurance companies—to exclude divergent medical evidence and opinion.’’ The IDSA settlement establishes a model to redress these conflicts of interest and the consequent suppression of scientific evidence and patient treatment options. The settlement requires the IDSA to reconvene a new Lyme treatment guidelines panel made up of conflict-free panellists under the auspices of an ethicist, to hold a public hearing and to review all recommendations of the guidelines. Panellists from the original guidelines panel are precluded from sitting on this new panel. The Attorney General’s press release concerning the settlement highlights important findings of impropriety on the part of IDSA and forces the organisation to re-examine its guidelines in a public forum (aired live over the Internet) using an open scientific hearing that will consider evidence from a broad spectrum of science. All panelists will be screened for potential conflicts of interest by Dr Howard Brody, a medical ethicist specialising in such conflicts.

 

SETTLEMENT PROCESS PHASES
While no overall timetable is specified, it seems likely that the settlement process will take 6–12 months. The settlement has three phases: c the selection of the chair and the panel; c the internal collection of scientific evidence and call for submissions of scientific evidence from the public; c the public hearing of the evidence, which will be aired live on the Internet. The settlement stipulates that IDSA must set up a panel of 8– 12 members (including the chair) ‘‘who, as a group, reflect a balanced variety of perspectives and experience across a broad range of relevant disciplines, ranging from clinical experience in treating patients with Lyme disease to experience in investigating the best methods to diagnose and treat Lyme disease or other infectious diseases’’ to review the recommendations in its guidelines.15 Clinical ethics 286 J Med Ethics 2009;35:283–288. doi:10.1136/jme.2008.026526 Selection of the chair The chair of the panel is critically important because this person and the IDSA Standards and Practice Guidelines Committee will select the panel members from the pool of applicants. The chair will be selected in an open process—meaning any qualified individual can apply—by the IDSA Standards and Practice Guidelines Committee. The IDSA will post an announcement on its website encouraging qualified doctors or researchers to apply. Those who apply for the chair may also be considered for panel member positions. In addition to the requirements to be on the panel, the chair must: c be trained in infectious disease; c not have published a point of view on Lyme disease; c be knowledgeable on Lyme disease but not necessarily an expert; c have experience in the review and interpretation of the medical scientific literature; c have known abilities to: – complete a task in a timely manner; – consider varying points of view; – bring groups of individuals to consensus. Selection of the panel The panel will be selected by the chair and the Standards and Practice Guidelines Committee. This too will be through an open process with IDSA posting an announcement on its website soliciting applicants. IDSA is required to give ‘‘fair consideration to all reasonable applicants’’. A prospective panel member cannot have previously served on a Lyme guidelines panel, must be free of conflicts of interest, must be a doctor or a researcher, and need not be a member of the IDSA. All panellists will be screened for potential conflicts of interest by Dr Brody, the independent medical ethicist. The panel members selected must as a group15: ‘‘reflect a balanced variety of perspectives and experience across a broad range of relevant disciplines, ranging from clinical experience in treating patients with Lyme disease to experience in investigating the best methods to diagnose and treat Lyme disease or other infectious diseases.’’ Evidence selection The settlement agreement provides for an internal collection of evidence by the IDSA staff and provides a 60-day window for people who are not on the panel to submit scientific studies for review by the panel. The IDSA must post an announcement calling for submissions of evidence by individuals and organisations. The evidence submitted must be distributed to and considered by the guidelines panel. Public presentations and hearing Following the collection and review of scientific evidence, those who want to present evidence to the panel are invited to apply. Any stakeholder may apply to make a presentation, although preference will be given to researchers and doctors. The panel will work with the medical ethicist and the Connecticut Attorney General’s office to finalise the list of presenters and must reserve time for divergent opinions. Presenters must disclose conflicts of interest, but the conflicts will not preclude the presenter from participating. Once the presenters have been selected, there will be a public hearing of the presentations that will be aired live over the Internet. The presenters will identify specific recommendations of the IDSA guidelines that they take issue with and will present the scientific evidence opposing the recommendation. Panel determinations The panel will make a determination whether each recommendation contested ‘‘is medically sound in light of all of the evidence and information provided’’.15 Each determination will require a 75% supermajority vote of the panel members (9/12, if the panel comprises 12 members). So, if the recommendation that a tick bite not be treated is contested, for example, a supermajority of the panel would need to vote in favour of the original recommendation for it to stand. Once each of the contested recommendations has been reviewed, the panel will determine whether the guidelines need to be revised in whole, in part, or not at all. If the guidelines need to be revised, then the new treatment recommendations will also be subject to the 75% voting requirement. The notion here is that a ‘‘consensus’’ of the panel is 75%, and all determinations require a consensus.

 

THE ATTORNEY GENERAL INTENDS TO ENFORCE THE TERMS OF THE SETTLEMENT AGREEMENT A number of comments by the IDSA president, Dr Donald Poretz, imply that the IDSA views its obligations under the Connecticut Attorney General’s settlement agreement as being a process of merely ‘‘going through the motions’’ and that the guidelines will remain unchanged.17 This type of dismissive attitude by the IDSA is shocking to patients. The Attorney General found important conflicts of interest for guidelines panel members, bias in the selection of participants, suppression of scientific evidence, blocking of divergent viewpoints and foreclosure of treatment options for patients. These are the types of findings that a responsible medical society would take seriously by launching an internal investigation into the guidelines panel. Restrictive guidelines constrain doctors from using clinical judgement and prevent them from using more effective treatments and individualised care. The notion of ‘‘going through the motions’’ on an issue of such enormous social, economic and medical importance is morally wrong. Moreover, it is likely to backfire politically. Attorney General Blumenthal has demonstrated that he is a man of courage, resolve and persistence—a man who intends to enforce the terms of the settlement agreement and expects the IDSA to comply with its terms. Acknowledgements: The authors thank R Wolfram, K Newby, M Perez-Lizano and B Blossom for helpful discussion. Competing interests: RBS serves without compensation on the medical advisory panel for QMedRx Inc. He has no financial ties to the company. Provenance and peer review: Not commissioned; externally peer reviewed. REFERENCES 1. Johnson LB, Stricker RB. Treatment of Lyme disease—a medicolegal assessment. Expert Rev Anti-infect Ther 2004;2:533–57. 2. Stolberg S. Study says clinical guides often hide ties of doctors. New York Times. 6 Feb 2002; National Desk. www.nytimes.com/2002/02/06/health/06DRUG.html (accessed 9 Mar 2009). 3. Integrity in Science. Integrity in Science Watch Week of 03/10/2008. IOM urged to recommend conflict-free zone for medicine. www.cspinet.org/integrity/watch/ 200803101.html (accessed 9 Mar 2009). 4. Stricker RB. LymerixH risks revisited. Microbe 2008;3:1–2. 5. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The clinical assessment, treatment, and prevention of Lyme disease, human granulocytic anaplasmosis, and babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1089–134. (See appendix A for details of competing interests.) 6. Feder HM, Johnson BJB, O’Connell S, et al, the Ad Hoc International Lyme Disease Group. A critical appraisal of ‘‘chronic Lyme disease’’. N Engl J Med 2007;357:1422– Clinical ethics J Med Ethics 2009;35:283–288. doi:10.1136/jme.2008.026526 287 30. Erratum in: N Engl J Med 2008;358:1084. (See appendix A for details of competing interests.) 7. Porwancher RB, Bockenstedt L, Dattwyler R, et al. Lyme Wars: Critique misses mark. BMJ rapid response 30 Nov 2007. www.bmj.com/cgi/eletters/335/7628/1008 (accessed 9 Mar 2009). (See appendix A for details of competing interests.) 8. Center for Biotechnology. Companies developed. Brook Biotechnologies. http:// www.biotech.sunysb.edu/industDev/comp-dev.html (accessed 9 Mar 2009). (See appendix A for details of competing interests.) 9. Halperin JJ, Shapiro ED, Logigian E, et al. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology, Neurology 2007;69:91–102. (See appendix A for details of competing interests.) 10. Abbott A. Uphill struggle. Nature 2006;439:524–5. (See appendix A for details of competing interests). 11. Saul S. Unease on industry’s role in hypertension debate. New York Times. 20 May 2006. www.nytimes.com/2006/05/20/business/20hyper.html?ex= 1148788800&en=c743a665286103ef&ei=5070&emc=eta1 (accessed 9 Mar 2009). 12. Ferrette C. Lyme disease expert defends research. Journal News. 6 May 2008. http://m.lohud.com/news.jsp?key=76504 (accessed 14 Mar 2009). 13. Eddy DM. Three battles to watch in the 1990s. JAMA 1993;270:520–6. 14. Eddy DM. Clinical decision making: from theory to practice, practice policies—what are they? JAMA 2000;263:877–8. 15. Connecticut Attorney General’s Office. Attorney General’s investigation reveals flawed Lyme disease guideline process, IDSA agrees to reassess guidelines, install independent arbiter. 1 May 2008. http://www.ct.gov/ag/cwp/view.asp?a=2795&q= 414284 (accessed 9 Mar 2009). 16. Stricker RB, Johnson LB. Practice parameter: treatment of nervous system Lyme disease (an evidence-based review). Neurology 2008;70:1719. 17. Landers SJ. Lyme treatment accord ends antitrust probe. American Medical News 9 June 2008. http://www.ama-assn.org/amednews/2008/06/09/hlsa0609.htm (accessed 9 Mar 2009). APPENDIX A Conflicts of interests reported in references 5–10 Reference 5: IDSA Guidelines 2006. Potential conflicts of interest. c G.P.W. has received consulting fees from Baxter and research support from Immunetics, and he is a founder of Diaspex, a company that does not offer products or services. c R.J.D. has served as a speaker for Pfizer and is part owner of Biopeptides, a biotech company that develops vaccines and laboratory diagnostics, including products for Borrelia burgdorferi. c J.J.H. has served as an expert witness on behalf of Lymerix (GlaxoSmithKline). c A.C.S. has received consulting fees from Baxter. Reference 6: Feder et al, N Engl J Med 2007 c Dr. Shapiro reports serving as an expert witness in medical-malpractice cases related to Lyme disease, reviewing claims of disability related to Lyme disease for Metropolitan Life Insurance Company, and receiving speaker’s fees from Merck and Sanofi-Aventis. c Dr. Steere reports receiving a research grant from Viramed and fees from Novartis. c Dr. Wormser reports receiving research grants related to Lyme disease from Immunetics, Bio-Rad, and Biopeptides and education grants from Merck and AstraZeneca to New York Medical College for visiting lecturers for infectiousdisease grand rounds, being part owner of Diaspex (a company that is now inactive with no products or services), owning equity in Abbott, serving as an expert witness in a medical-malpractice case, and being retained in other medical-malpractice cases involving Lyme disease. He may become a consultant to Biopeptides. Reference 7: Porwancher et al, BMJ 2007 c Dr. Raymond Dattwyler reports that he is the principal owner of Biopeptides Corporation. He has a United States provisional patent 60/812,595 on a live ‘‘bacterial vaccine,’’ an oral vaccine platform technology; PCT/US2005/023106 ‘‘oral vaccine for Borrelia,’’ a wildlife vaccine; United States provisional patent 60/ 799,016, ‘‘Peptide Diagnostic Agent for Lyme.’’ He has served as an expert witness in medical malpractice cases involving Lyme disease. c Dr. John Halperin reports having served as an expert witness in malpractice cases involving Lyme disease. He was an expert witness for GlaxoSmithKline which made LYMErix. c Dr. Robert B. Nadelman reports that he has been retained as an expert witness in medical malpractice cases related to Lyme disease. c Dr. Eugene Shapiro reports having served as an expert witness in medical malpractice cases related to Lyme disease. He has reviewed claims of disability related to Lyme disease for Metropolitan Life Insurance Company. c Dr. Gary P. Wormser reports that he has had research grants from Immunetics, Inc., BioRad, and may receive one from Biopeptides’ He reports educational grants to NYMC to support ID grand rounds from Merck and AstraZeneca, and possibly Pfizer in the future. He has equity in Abbott and has been an expert witness in malpractice cases involving Lyme disease. Reference 8 Brook Biotechnologies was created in 1994 to develop and commercialize the first FDA-approved diagnostic test kit for Lyme Disease. Brook Biotechnologies has recently ceased operations and the technology has been licensed to Baxter Diagnostics. Reference 9: Halperin et al, Neurology 2007 c Dr. Halperin holds equity in Abbott, Bristol Myers Squibb, Johnson & Johnson, Schering Plough, and Vasogen. He has served as an expert witness in medical malpractice actions. c Dr. Shapiro has received funds for reviewing disability claims from Metropolitan Life Insurance Company and has served as an expert witness in malpractice actions. He has also received honoraria from Merck, Inc. and Aventis for speaking engagements. Dr. Shapiro receives funding from NIH grants K24RR022477, KL2RR024138, and UL1RR024139. c Dr. Wormser reports having received research grants related to Lyme disease from the Centers for Disease Control and Prevention, the National Institutes of Health, Immunetics, Inc., and BioRad. He was part owner of Diaspex, LLC, a company with no products or services. He has been an expert witness for the United States in a medical malpractice case and has been retained in other medical practice cases involving Lyme disease. Dr. Wormser has overseen educational grants to New York Medical College to support Infectious Diseases grand rounds from Merck and AstraZeneca, and one from Pfizer is expected in 2008. Reference 10: Abbott, Nature 2006 c Steere, who has worked as a consultant for Baxter vaccines, says ‘‘There is no proof that autoimmunity ever developed in anyone, but it could be a very rare side effect.’’ Clinical ethics 288 J Med Ethics 2009;35:283–288. doi:10.1136/jme.2008.026526 http://jme.bmj.com/cgi/content/abstract/35/5/283?eletter Electronic Letters to: L Johnson and R B Stricker Attorney General forces Infectious Diseases Society of America to redo Lyme guidelines due to flawed development process J Med Ethics 2009; 35: 283-288

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21 May 2009 Lyme Article Was Riddled with Inaccuracies–Putting Patients at Risk Anne Gershon, President Infectious Diseases Society of America The article entitled “Attorney General Forces Infectious Disease Society of America to redo Lyme guidelines due to flawed development process” that appeared in the Journal of Medical Ethics purporting to explain the agreement between the Connecticut Attorney General and the Infectious Diseases Society of America (IDSA) regarding its Lyme disease guideline was extremely disturbing. This article is riddled with inaccuracies and misleading information. The article is the latest salvo from a small but vocal group of physicians and patients who attribute a wide range of vague symptoms to what they call “chronic” Lyme disease. To treat “chronic” Lyme infection, this self-described “Lymeliterate” group promotes the use of long-term antibiotics – often delivered intravenously for months or even years. The cost of this treatment must be borne by patients themselves, leading a discerning person to question the authors’ interest in the real reason why they want the treatment guidelines changed. Blinded, randomized controlled trials show that long-term antibiotic treatment is not effective for any condition described as “chronic Lyme” – a condition that currently has no consistent diagnostic markers. Far worse, this treatment has been shown to be extremely risky, potentially leading to fatal infections, serious drug reactions and fostering development of life-threatening drug-resistant superbugs. That this group continues to use its assaults on the IDSA and its Lyme disease guidelines as a platform to promote a not only unproven but expensive and potentially dangerous therapy is, we believe, clearly unethical. Among the many inaccuracies in this article, the most egregious charge is that the IDSA’s Lyme disease guidelines “excluded most Lyme patients and denied them treatment for their illness.” It is difficult to find an accurate sentiment in that statement. To start with, the guidelines are simply that, guidelines, and by their very nature do not “exclude” patients, nor “deny” them treatment. Further, the authors seem intentionally to confuse Lyme disease – a proven and highly treatable illness – with “chronic” Lyme infection, an unproven condition that a small group of doctors may provide as a “diagnosis” for patients with vague but often serious symptoms. There is no solid evidence of the existence of “chronic” Lyme infection. Although we do not doubt that there are patients who initially were treated for Lyme disease infection and subsequently have ongoing, vague symptoms, we are concerned these patients likely are suffering from a different or new illness and are receiving potentially dangerous “treatment” rather than being evaluated, properly diagnosed, and treated appropriately. Although a comprehensive response to the remaining charges would require an entire article, following are our comments regarding several of the most salient. • Regarding the agreement (not “settlement”) between the IDSA and the Connecticut Attorney General, the IDSA was not forced to “redo” the Lyme guidelines and no “antitrust laws” were broken. The Lyme disease guidelines remain in effect. IDSA voluntarily agreed to a special one-time review of the Lyme disease guidelines. IDSA paid no fines or penalties and is not restricted from promulgating guidelines of Lyme disease or other conditions. • The statement “at least 21 studies documenting death in patients with this potentially devastating tick-borne illness” is patently wrong. Lyme disease is not a life-threatening disease. This statement is reminiscent of a tabloid headline – the patients may have had Lyme disease, and may have died, but not of Lyme disease. • The IDSA Lyme disease guideline panel spent months scouring all of the Lyme disease research. Specific studies were not “selectively ignored,” but in fact stringently reviewed along with all of the other research. Based on widely accepted principles of evidencebased medicine, some studies were determined to lack scientific rigor, and were therefore not used as a basis for treatment guidelines. • The comment that the guidelines are “treated as mandatory” and end up “denying” treatment to patients is inaccurate. The purpose of the guidelines is to attempt to guide physicians in providing the highest- quality treatment that is not harmful to patients. However, they are guidelines, not mandates. • IDSA does not have nor seek monopoly power. We do not work with insurers on any guidelines, nor do we develop our guidelines for the sake of insurers. We develop guidelines to provide guidance to our members, with the ultimate goal of ensuring the best quality in patient care and to protect the public’s health. • Regarding the makeup of the guidelines panel, the IDSA chose the panel of experts that we believe is the most knowledgeable for the job. Further, the panel was not limited to “researchers known to have a bias against the diagnosis and treatment of Lyme disease.” In fact, the point of the panel was to guide physicians in treating Lyme disease, a known and highly treatable disease. • The remark that some of the panel members were working on the development of vaccines is irrelevant. There are no Lyme disease vaccines approved for use in humans and the IDSA has made no recommendations in that regard. The vaccine mentioned in the article was previously in development, but the decision not to manufacture it was made before the guidelines were published. • Regarding conflicts of interest among panel members, physicians with expertise in a specialty of medicine are often called upon to serve as expert witnesses, just as lawyers are often asked to do. This is a professional activity, and compensation is relatively modest. The same is true of consultation fees with commercial organizations, as long as specific guidelines are followed. The physicians on our panel followed those guidelines. The implication that physicians on the guidelines panel stand to monetarily gain from their recommendations seems particularly hypocritical coming from a group of practitioners who stand to gain financially from treating vulnerable patients with an unproven condition using an unproven, expensive, invasive and risky long-term therapy. The IDSA is widely recognized as the pre-eminent authority on the treatment of infectious disease. We are in good company in our lack of support of the therapy advocated by the authors of this article, including the American Academy of Pediatrics, the American College of Physicians, the Medical Letter, the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and even review articles in major medical journals such as the New England Journal of Medicine. We take our responsibility as protectors of the public health seriously, and as physicians who stand by our Hippocratic Oath to “above all, do no harm,” we wish there were more evidence that these authors and the groups they represent did the same. Sincerely, Anne Gershon President, IDSA 5 June 2009 IDSA Lyme Guidelines: Response to Dr. Gershon Raphael B. Stricker, MD, ILADS, Lorraine Johnson, CALDA IDSA Lyme Guidelines: Response to Dr. Gershon It is not surprising that Anne Gershon, the current president of the Infectious Diseases Society of America (IDSA), would come to the defense of her society’s beleaguered Lyme guidelines. What is disturbing is that Dr. Gershon relies on the same specious arguments that were debunked by the Connecticut Attorney General’s investigation of the IDSA Lyme guidelines process () and refuted in our article. Here is a rebuttal to her views. As stated in our article, the IDSA Lyme guidelines are not “simply guidelines”, as Dr. Gershon meekly maintains. They are a highly restrictive set of directives published by the largest group of infectious disease specialists in the world, and they allow a monopolistic medical society to set a standard of care that forecloses treatment options for patients. The IDSA guidelines trivialize Lyme disease, ignoring the growing number of patients with persistent symptoms of tick-borne illness leading to significant disability. The guidelines also discount the importance of clinical judgment and fail to provide treatment options for Lyme patients. As Dr. Gershon knows, the IDSA Lyme guidelines are treated as the mandatory standard of care by insurers, government agencies and medical boards, and they are used to deny patients access to the only viable treatment option for chronic Lyme disease. Readers can easily refer to the findings of the Attorney General to dispel Dr. Gershon’s protestations regarding suppression of evidence and the use of a hand-picked panel with known biases and substantial conflicts of interest, as the findings on these points are clear. Basically, IDSA researchers selected their own papers based on their own research bias, found no faults with their own studies, discounted the studies of others, and excluded opposing viewpoints in reaching their conclusions. Even the strongest proponents of evidence-based medicine would cringe at the amount of bias the panel members brought to the table. As noted in our article, their conclusions support the interests of vaccine patent holders who favor a narrow disease definition that increases the efficacy and odds of approval of a vaccine. Their conclusions also favor diagnostic test patent holders by mandating a positive test for diagnosis. Their conclusions put money in the pocket of consultants who help to deny patient care and reduce costs for insurers. The Attorney General found that IDSA panel members had conflicts of interest in each of these areas. Did anyone on this panel represent the interests of patients to gain access to the only medical option that might improve their quality of life? The answer is no. Nor can IDSA shore up its guidelines by asserting that other medical societies independently corroborate them. First, most of the groups listed by Dr. Gershon do not endorse IDSA’s 2006 guidelines. Second, as pointed out by the Attorney General in his findings, corroboration of the IDSA guidelines was anything but independent. Hence, the Attorney General found that “The IDSA portrayed another medical association’s [American Academy of Neurology] Lyme disease guidelines as corroborating its own when it knew that the two [guidelines] panels shared several authors, including the chairmen of both groups, and were working on guidelines at the same time”. The New England Journal of Medicine article cited by Dr. Gershon also shared authors with the IDSA panel. Both publications appeared after the Attorney General’s investigation was launched, and there was no disclosure of the rather glaring conflict of interest of panel members who authored these “independent” attempts to exonerate themselves in the face of an ongoing investigation. Dr. Gershon implies that “Lyme-literate” physicians prey upon misinformed and misguided patients. Nothing could be further from the truth. In reality, patients by the thousands seek care from “Lyme- literate” physicians because the IDSA guidelines have failed them and the IDSA physicians who rely on those guidelines have abandoned them. Dr. Gershon also derides treating physicians for being paid fees for their services. However, there is a big difference between being paid to care for patients and profiting from third-party industry ties that should have no place in determining patient care. If patients are unhappy with their treatment, they have the power to leave a treating physician and seek another, and they also have the ability to express their concerns and ensure that those concerns are addressed. In short, their physicians are accountable for their care. Patients have no similar recourse with the guidelines panel of a dominant medical society that has the authority to set the rules for patient care but is not accountable to those patients when care fails. It is all too easy to turn a blind eye on treatment failures and patient suffering when one never sees or treats the patient, is not responsible for the consequences of failure and neglect, and has no obligation to the individual. IDSA’s assertion that this medical abandonment is necessary to honor its hypocratic oath to “first, do no harm” could be used to justify the denial of any medical treatment, as all treatments have the potential to do harm. While this may appeal to insurers, Lyme patients who are suffering a disability equivalent to congestive heart failure certainly deserve better. Lorraine Johnson, JD, MBA, Chief Executive Officer, California Lyme Disease Association Raphael B. Stricker, MD, Past President, International Lyme & Associated Diseases Society

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9 June 2009 Dr. Gershon is Off Base Elizabeth L Maloney, Physician It is ironic that Dr. Gershon, president of the IDSA, would decree the article by Johnson and Stricker to be full of “inaccuracies and misleading information” only to mislead readers using inaccurate information. A look at the science may be enlightening. The IDSA holds that Lyme disease is easily cured, yet data from treatment trials cited in the 2006 IDSA guidelines suggests otherwise. The issue of persistent symptoms following treatment for Lyme disease is a particularly vexing one, and the etiology of these symptoms remains unproven. Animal studies and human case reports suggest that persistent infection with the Lyme spirochete does occur. To investigate this further, four separate trials studied the use of additional antibiotics in patients with persistent symptoms following standard IDSA-sanctioned therapy for Lyme disease. The patients in the retreatment trials had been ill for extended periods of time. For example, in one study, patients, on average, had been symptomatic for roughly 4.5 years despite previous antibiotic therapy. The response to treatment in these trials was mixed. While one investigator found no improvement with treatment, two others found a significant and sustained treatment-related reduction in fatigue. Debilitating fatigue is a prominent complaint in patients with persistent symptoms following standard antibiotic therapy for Lyme disease. Thus the statement by Dr. Gershon, “(b)linded, randomized controlled trials show that long-term antibiotic treatment is not effective for any condition described as ‘chronic Lyme’ ” is inaccurate and misleading. The semantics involved in identifying patients who remain symptomatic after treatment is important. Dr. Gershon notes that there are no consistent markers for chronic Lyme disease, implying that there is no evidence for its existence. Yet the IDSA guidelines create a new diagnostic category, “post-Lyme syndrome”, with a similar problem: “PostLyme syndrome” implies the existence of definitive evidence that the initial bacterial infection has been cleared. However, available testing modalities cannot provide such evidence, nor is there a specific biologic marker for “post-Lyme syndrome”. Rather, the syndrome seems to be defined by failure of a restricted course of antibiotics to eliminate Lyme disease -related symptoms in a given individual. It is more likely that “post-Lyme syndrome” represents a failure of restricted antibiotic therapy to clear the infection, as outlined in the animal and human studies mentioned above, rather than a nebulous entity with no clear definition and no available treatment. Dr. Gershon contends that Lyme disease is not a fatal illness. This statement is incorrect. Lyme disease has been associated with fatal myocarditis and encephalomyelitis (1,2), as well as intrauterine fetal death (3). Furthermore, tick-borne coinfections with the agents of Babesiosis, Anaplasmosis, Ehrlichiosis, Rickettsiosis and Tularemia are well-known direct causes of mortality, and these coinfections can be transmitted together with the Lyme spirochete (4-7). Because of clinical ignorance about these diseases and poor laboratory test sensitivity, it is likely that fatal cases of tick-borne diseases may go unrecognized and consequently are under-reported (7,8). Politicians, including the Attorney General of Connecticut, are drawn into the Lyme disease arena because IDSA has allowed politics to enter into the discussion of this illness through its restrictive guidelines process. Generalizable studies that address the many variables affecting patients with Lyme disease are desperately needed to improve our understanding of the illness in order to better guide treatment. Until that work is completed, minds and options need to remain open. The 2006 IDSA guidelines take the opposite approach, which is why they need to be substantially revised. 1: Tavora F, Burke A, Li L, Franks TJ, Virmani R. Postmortem confirmation of Lyme carditis with polymerase chain reaction. Cardiovasc Pathol. 2008; Mar-Apr;17(2):103-7. 2: van Assen S, Bosma F, Staals LM, Kullberg BJ, Melchers WJ, Lammens M, Kornips FH, Vos PE, Fikkers BG. Acute disseminated encephalomyelitis associated with Borrelia burgdorferi. J Neurol. 2004 May;251(5):626-9. 3: Markowitz LE, Steere AC, Benach JL, Slade JD, Broome CV. Lyme disease during pregnancy. JAMA. 1986 Jun 27;255(24):3394-6. 4: Javed MZ, Srivastava M, Zhang S, Kandathil M. Concurrent babesiosis and ehrlichiosis in an elderly host. Mayo Clin Proc. 2001 May;76(5):563-5. 5: Bakken JS, Dumler JS. Clinical diagnosis and treatment of human granulocytotropic anaplasmosis. Ann N Y Acad Sci. 2006 Oct;1078:236-47. 6: Penn RL, Kinasewitz GT. Factors associated with a poor outcome in tularemia. Arch Intern Med. 1987 Feb;147(2):265-8. 7: Paddock CD, Holman RC, Krebs JW, Childs JE. Assessing the magnitude of fatal Rocky Mountain spotted fever in the United States: comparison of two national data sources. Am J Trop Med Hyg. 2002 Oct;67(4):349-54. 8: Millar BC, Xu J, Moore JE. Molecular diagnostics of medically important bacterial infections. Curr Issues Mol Biol. 2007 Jan;9(1):21-39.

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9 June 2009
Three cheers Amelia M Withington MD,
Physician Crozer-Chester Medical Center, Upland, PA

I am wholeheartedly in agreement with Dr. Stricker’s and Ms. Johnson’s
response to Dr. Gershon’s letter.

Lyme Disease and its associated conditions are extremely complex illnesses, and patients who are suffering from them have their suffering exacerbated by misguided attempts to “treat ideologically”. Just last week, a new patient gave me the history that her clotted ‘pic’ line was ignored for hours by an ER physician who said he didn’t “believe” in treating Lyme Disease IV, and who had his working diagnosis as psychiatric, until the infection became fulminant in the ER! Such needless risk and suffering would be best avoided if we can at least “agree to diagree” and carry on with supporting the treatment plan of the specialist who began the treatment. I find the collaboration of my local colleagues invaluable, as we cope with the increase in severity and number of cases of tick-borne illnesses of all types in this area. Many thanks to Dr. Stricker and his colleagues from around the world for sharing their experiences in treating these conditions, which appear to have some regional variations in the types of illnesses presenting, as well as their frequency and severity. I would encourage all who are interested in these conditions to attend the excellent LDA/IDSA conferences which will be held in Bethesda, MD in October this year. Sincerely, Amelia Withington MD The author has requested enhancement of the downloaded file. All in-text references underlined in blue are linked
to publications on ResearchGate.

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