Autism and Lyme Disease

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Jul 30, 2013 - Ezekiel J. Emanuel, MD, PhD. Author Affiliation: Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia.
Letters

1. Emanuel EJ. The future of biomedical research. JAMA. 2013;309(15):1589-1590. 2. DiMasi JA, Hansen RW, Grabowski HG. The price of innovation: new estimates of drug development costs. J Health Econ. 2003;22(2):151-185.

medical research has been good in fueling economic growth is simply wrong. Ezekiel J. Emanuel, MD, PhD

In Reply I agree with Dr Moyé’s point that it is important that the business of research be a smaller proportion of the NIH dollars. But it cannot simply be that research institutions absorb more costs. The NIH too must try to streamline the paperwork and bureaucracy of actually receiving a grant and complying with all of its requirements. This would be consistent with President Obama’s executive order to reduce the burden of regulations.1 Mr Ma asserts NIH funding is such a small proportion of biomedical research funding that it is not responsible for much of the costly technology that drives up health care costs. If true, this claim would undermine the very argument to increase NIH funding. Assuming Ma’s viewpoint, opponents of NIH funding could argue that because the NIH covers such a minor part of biomedical research funding overall, cutting it will not hinder the important progress of medicine. In other words, NIH funding could be cut without worrying that new discoveries will be foregone. This seems a terrible defense of NIH funding. In addition, I did not argue that the NIH should focus only on funding research into cost-lowering advances. Instead I argued that cost-lowering advances should be part of the NIH focus in a way that it has never been. It currently plays no role in deciding what research projects to fund. My view is that it ought to be a criterion in evaluating grants for funding moving forward. Dr Arbiser seems to think that I argued against bevacizumab because it is a noncurative drug. But that is wrong. The problem with bevacizumab is that it has minimal effectiveness. It is not its noncurative properties that worry me. Imatinib does not cure chronic myeloid leukemia, but it is nevertheless a valuable addition to the anticancer armamentarium.2 If bevacizumab prolonged the life of cancer patients an average of 5 years, but cured no person of cancer, it would still be worthwhile. But unlike antiretroviral drugs for human immunodeficiency virus or imatinib, bevacizumab gives patients with metastatic colorectal cancer about an extra 4 months of life at costs of more than $100 000 per quality-adjusted life-year.3 And for other cancers (such as lung) bevacizumab adds even fewer months, and costs can exceed $500 000 per quality-adjusted life-year.4 Unlike Arbiser, I would not advocate strongly that on average NIH funding creates jobs and thriving small businesses. Doubtless there have been several successful startup biotechnology companies such as Amgen and Genentech that have generated large profits and good jobs. However, taken as a whole, the biotechnology industry is still a net financial loser.5 That is, more capital has been poured into the failing companies than the economic returns generated by the surviving successful companies. Furthermore, the current evaluations suggest that growth in health care costs have been an economic drag, not an economic boon.6 The more high technology used in medicine, such as bevacizumab, the higher health care costs, and the slower the US economy grows. The argument that bio856

Author Affiliation: Department of Medical Ethics and Health Policy, University of Pennsylvania, Philadelphia. Corresponding Author: Ezekiel J. Emanuel, MD, PhD, Department of Medical Ethics and Health Policy, University of Pennsylvania, 22 College Hall, Philadelphia, PA 19104 ([email protected]). Conflict of Interest Disclosures: The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Obama B. Executive Order 13563: improving regulation and regulatory review. Fed Regist. 2011;76:3821. 2. Reed SD, Anstrom KJ, Li Y, Schulman KA. Updated estimates of survival and cost effectiveness for imatinib versus interferon-alpha plus low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukaemia. Pharmacoeconomics. 2008;26(5):435-446. 3. Tappenden P, Jones R, Paisley S, Carroll C. Systematic review and economic evaluation of bevacizumab and cetuximab for the treatment of metastatic colorectal cancer. Health Technol Assess. 2007;11(12):1-128; iii-iv. 4. Goulart B, Ramsey S. A trial-based assessment of the cost-utility of bevacizumab and chemotherapy versus chemotherapy alone for advanced non-small cell lung cancer. Value Health. 2011;14(6):836-845. 5. FierceBiotech.com website. Biotech industry turns a profit for the first time, but milestone overshadowed as companies struggle for survival, report finds. http://www.fiercebiotech.com/press-releases/biotech-industry-turns-profit -first-time-milestone-overshadowed-companies-struggle-su. Accessibility verified July 30, 2013. 6. Executive Office of the President, Council of Economic Advisors. The economic case for health care reform. http://www.whitehouse.gov/assets /documents/CEA_Health_Care_Report.pdf. Accessibility verified July 30, 2013.

Autism and Lyme Disease To the Editor Ms Ajamian and colleagues1 quoted our work2,3 that found an association between autism spectrum disorder (ASD) and Lyme disease in their research letter on serological markers of Lyme disease in children with autism. Their study used the Centers for Disease Control and Prevention (CDC) testing criteria with enzyme-linked immunosorbent assays (ELISAs) followed by Western blotting. These assays, provided by Euroimmun, have only a 45% to 49% sensitivity.4 In addition, the patients were aged 2 to 18 years and developed autism as much as 18 years before the blood samples were drawn. A low sensitivity ELISA performed years later does not prove these patients were not exposed to an immune process triggered by Borrelia burgdorferi at the time the pathological process began. Only 5 of the 70 children with autism were tested with the more sensitive Western blot. In contrast, we cited studies that collectively included 130 children with ASDs and 62 controls tested by either Western blot without the full complement of specific bands or forensic polymerase chain reaction and Southern blot confirmation.3,5 Reactivity of B burgdorferi–specific bands on Western blot without the full number of bands meeting the CDC surveillance criteria is a more reliable indicator of prior exposure to B burgdorferi. Robert C. Bransfield, MD Mason Kuhn, MS

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Letters

Author Affiliations: Department of Psychiatry, Rutgers–Robert Wood Johnson Medical School, Piscataway, New Jersey (Bransfield); University of North Dakota, Grand Forks (Kuhn). Corresponding Author: Robert C. Bransfield, MD, Department of Psychiatry, Rutgers–Robert Wood Johnson Medical School, 225 Hwy 35, Red Bank, NJ 07701 ([email protected]). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Bransfield reported providing expert testimony on Lyme disease and receiving payment for grand rounds at medical schools on Lyme disease. No other disclosures were reported. 1. Ajamian M, Kosofsky BE, Wormser GP, Rajadhyaksha AM, Alaedini A. Serologic markers of Lyme disease in children with autism. JAMA. 2013;309(17):1771-1773. 2. Kuhn M, Grave S, Bransfield R, Harris S. Long term antibiotic therapy may be an effective treatment for children co-morbid with Lyme disease and autism spectrum disorder. Med Hypotheses. 2012;78(5):606-615. 3. Bransfield RC, Wulfman JS, Harvey WT, Usman AI. The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders. Med Hypotheses. 2008;70(5):967-974. 4. Ang CW, Notermans DW, Hommes M, Simoons-Smit AM, Herremans T. Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. Eur J Clin Microbiol Infect Dis. 2011;30(8):1027-1032. 5. Bransfield RC. Preventable cases of autism: relationship between chronic infectious diseases and neurological outcome. Pediatric Health. 2009;3(2):125-140.

In Reply We evaluated the hypothesis that the rate of Lyme disease or associated seroprevalence is increased in children with autism as has been put forward by Dr Bransfield and others.1,2 A key assertion previously made in their Medical Hypotheses articles is that a substantial number of children with autism have active Lyme disease, with associated symptoms presumably resolving through antibiotic treatment.1,2 However, Bransfield and Kuhn now instead suggest that Lyme disease triggered autism in the affected children’s distant past (ie, B burgdorferi infection was no longer present), citing that as a reason why seropositivity could not be detected in any of the autistic children that we studied. Such a claim is contradictory to their previous argument for the association of autism with ongoing and antibiotic-responsive B burgdorferi infection. We used the 2-tier testing system recommended by the CDC because it is the most widely accepted algorithm for serological assessment of Lyme disease in the United States. The suggestion that the immunoblot reactivity patterns for autistic children, even though not meeting criteria for seropositivity, nevertheless show more B burgdorferi–specific bands than would be found for children without autism is not supported by any published data and is doubtful. Furthermore, Bransfield and Kuhn try to rationalize away our negative serologi-

cal findings by suggesting that the assays we used have low sensitivity, citing an article from the Netherlands.3 However, the cited study was performed in individuals who were only suspected of Borrelia infection.3 As such, that particular study cannot be used for reporting assay diagnostic performances. Bransfield and Kuhn indicate that the studies they cited included 130 children with ASDs, but do not mention that those studies have not been published. It should be noted that our findings and conclusions were recently confirmed in an independent study that used the CDC-recommended 2-tier testing algorithm in addition to other diagnostic assays for Lyme disease.4 Mary Ajamian, MS Anjali M. Rajadhyaksha, PhD Armin Alaedini, PhD Author Affiliations: Department of Medicine, Columbia University Medical Center, New York, New York (Ajamian, Alaedini); Department of Pediatrics, Weill Cornell Medical College, New York, New York (Rajadhyaksha). Corresponding Author: Armin Alaedini, PhD, Columbia University Medical Center, 1130 St Nicholas Ave, Ninth Floor, New York, NY 10032 (aa819@columbia .edu). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Rajadhyaksha reported receiving a grant from the Hartwell Foundation for research related to autism. Dr Alaedini reported receiving grants from the National Institutes of Health, the Department of Defense, and the Lyme Research Alliance for research related to Lyme disease or autism. No other disclosures were reported. 1. Bransfield RC, Wulfman JS, Harvey WT, Usman AI. The association between tick-borne infections, Lyme borreliosis and autism spectrum disorders. Med Hypotheses. 2008;70(5):967-974. 2. Kuhn M, Grave S, Bransfield R, Harris S. Long term antibiotic therapy may be an effective treatment for children co-morbid with Lyme disease and autism spectrum disorder. Med Hypotheses. 2012;78(5):606-615. 3. Ang CW, Notermans DW, Hommes M, Simoons-Smit AM, Herremans T. Large differences between test strategies for the detection of anti-Borrelia antibodies are revealed by comparing eight ELISAs and five immunoblots. Eur J Clin Microbiol Infect Dis. 2011;30(8):1027-1032. 4. Burbelo PD, Swedo SE, Thurm A, et al. Lack of serum antibodies against Borrelia burgdorferi in children with autism. Clin Vaccine Immunol. 2013;20(7):1092-1093.

CORRECTION Addition of Disclaimer: In the Original Investigation entitled “Views of US Physicians About Controlling Health Care Costs” published in the July 24/31, 2013, issue of JAMA (2013;310[4]:380-388. doi:10.1001/jama.2013.8278), a disclaimer should have appeared. At the end of the article the following paragraph has been added: “Disclaimer: The views expressed in this article are those of the authors and do not reflect the official position of the National Institutes of Health, Department of Health and Human Services, or the US government.” This article has been corrected online.

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