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LETTERS: Raphael B Stricker and Lorraine Johnson Let's tackle the testing BMJ 2007; 335: 1008 [Full text]

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Lyme Wars: Critique misses mark

Richard B. Porwancher, Linda Bockenstedt, Raymond Dattwyler, John Halperin, Barbara J. B. Johnson, Peter Krause, Robert B. Nadelman, Eugene Shapiro, Gary P. Wormser   (30 November 2007)

Re: Lyme Wars: A view from an Enlisted

Elizabeth L Maloney   (3 December 2007)

Commercial Lyme Testing: Mathematical Gymnastics are Unconvincing.

Raphael B. Stricker, Lorraine Johnson   (3 December 2007)

Two-Tier Testing Delays the Diagnosis of Lyme Disease

Phyllis C Mervine   (10 December 2007)

Lyme disease debate: facts or fiction

Richard B. Porwancher, Linda Bockenstedt, Raymond Dattwyler, Peter J. Krause, Barbara J.B. Johnson, John Halperin, Robert B. Nadelman, Eugene Shapiro, and Gary P. Wormser   (23 April 2008)

Re: Lyme disease debate: facts or fiction

Raphael B. Stricker, Lorraine Johnson   (28 April 2008)

Lyme Wars: Critique misses mark 30 November 2007
Richard B. Porwancher, Infectious disease specialist 445 Prospect Avenue, Princeton, NJ, 08540, USA, Linda Bockenstedt, Raymond Dattwyler, John Halperin, Barbara J. B. Johnson, Peter Krause, Robert B. Nadelman, Eugene Shapiro, Gary P. Wormser Send response to journal: Re: Lyme Wars: Critique misses mark	A recent letter by Stricker and Johnson[1]claims that 2-tier testing advocated by the Centers for Disease Control and Prevention (CDC) is diagnostically useless (i.e. no better than a coin toss). Their critique illustrates the misuse of statistics and the omission of important data from their references. For each of six different studies, a single sensitivity and specificity for 2-tier testing was reported by Stricker and Johnson[1] without mention of the disease manifestations evaluated or the timing of samples. These six sets of sensitivities and specificities were then averaged, generating a composite sensitivity of 56% and specificity of 99%. Stricker and Johnson[1] arrive at these numbers by inappropriately combining data from study populations that are not homogeneous. They report the sensitivity of 2-tier testing in the convalescent sera of patients previously treated for erythema migrans in 2 instances[2,3], in the acute sera of patients with erythema migrans in another instance[4], in 2 studies of patients with multiple disease manifestations[5,6], and in one study where clinical manifestations were not reported[7] Even if the six study populations were homogeneous, one cannot average means from different studies to yield a proper aggregate value for either sensitivity or specificity; it is necessary to weight the calculation according to the size of the sample in each study. It is well known that serology is less sensitive in patients with erythema migrans, particularly during the first two weeks of illness[3] and that detecting serologic reactivity in patients with either cutaneous or early neurological disease may require a second (convalescent phase) serum sample. Testing of paired samples has been recommended by the CDC since 1994 if acute serology is negative in patients with early Lyme disease[8]. Stricker and Johnson[1] ignore the fact that the sensitivity of 2-tier testing in patients with extracutaneous manifestations of disease, such as arthritis, approaches 100%[9]; they cite the overall 2-tier sensitivity reported by Bacon et al.[6] as 190/280 (68%), but fail to note that 88/94 (94%) of those patients with extracutaneous manifestions of disease were also 2-tier positive, ranging from 9/11 patients (82%) with early neurological disease, to 55/57 patients (96.5%) with arthritis and 11/11 patients (100%) with late neurological disease. Stricker and Johnson[1] also cite the overall 2-tier sensitivity reported by Ledue et al.[5] as 27/54 (50%). Of the 41 Lyme disease patients contributed to the Ledue study [5] by the CDC, all 16 patients (100%) with extracutaneous manifestions (e.g. arthritis, facial palsy, peripheral neuropathy, meningitis, and heart block) had positive 2-tier tests by CDC (M. Schriefer, CDC, personal communication); when 2-tier testing was repeated on stored sera from these same patients by Ledue et al.[5], 13/16 (81%) were seropositive and two of the seronegative patients had early disease, including one with facial palsy and a second with heart block. All of the above data from the CDC is publicly available. Useless tests will generate a positive result just as often in those with disease as in those without disease. Using Stricker and Johnson's calculations[1], a positive 2-tier test is 56 times more likely in patients with Lyme disease than in uninfected controls, and a negative test is 2.25 times more likely in controls than in patients with Lyme disease. Thus, even if we accept their calculations as valid, Stricker and Johnson’s data[1] actually suggest that the 2-tier approach has significant diagnostic value. If a clinical evaluation for Lyme disease is conducted in a setting where Lyme disease is unlikely (e.g. absence of objective findings), then a highly specific test, like the 2-tier, is the most accurate; in this setting a negative 2-tier test is usually sufficient to rule out the condition[10]. Two-tier testing is also helpful for supporting the clinical diagnosis of extracutaneous Lyme disease[10]. When evaluating patients with erythema migrans, the pretest probability of Lyme disease is so high that even negative tests (2-tier included) cannot rule out the illness[10,11]. Therefore, serology is not recommended for diagnosis when the patient has typical erythema migrans. 1 Stricker RB, Johnson L. Let’s tackle the testing. BMJ 2007;335:1008 2 Trevejo RT, Krause PJ, Sikand,VK, Schriefer ME, Ryan R, Lepore T et al. Evaluation of Two-Test Serodiagnostic Method for Early Lyme Disease in Clinical Practice. J Infect Dis 1999;179:931-8. 3 Nowakowski J, Schwartz I, Liveris D, Wang G, Aguero-Rosenfeld ME, Girao G, et al. Laboratory diagnostic techniques for patients with early Lyme disease associated with erythema migrans: a comparison of different techniques. Clin Infect Dis 2001;33(12):2023-7. 4 Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease J Clin Microbiol 1995;33(2):419-27. 5 Ledue TB, Collins MF, Craig WY. New laboratory guidelines for serologic diagnosis of Lyme disease: evaluation of the two-test protocol. J Clin Microbiol 1996;34(10):2343-50. 6 Bacon RM, Biggerstaff BJ, Schriefer ME, Gilmore RD Jr., Philipp MT, Steere AC, et al. Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2-tiered testing using whole-cell lysates. J Infect Dis 2003;187:1187-99. 7 Schmitz JL, Powell CS, Folds JD. Comparison of seven commercial kits for detection of antibodies to Borrelia burgdorferi. Eur J Clin Microbiol Infect Dis 1993;12:419-24. 8 Proceedings of the second national conference on serologic diagnosis of Lyme disease, 1994. Association of State and Territorial Public Health Laboratory Directors, Washington, D.C., p.1. 9 Dressler F, Whalen JA, Reinhardt BN, Steere AC. Western blotting in the serodiagnosis of Lyme disease. J Infect Dis. 1993; 167:392-400. 10 Tugwell P, Dennis DT, Weinstein A, et al. Laboratory evaluation in the diagnosis of Lyme disease. Ann Intern Med 1997;127: 1109-23. 11 Seltzer EG and Shapiro ED. Misdiagnosis of Lyme disease: when not to order serologic tests. Pediatr Infect Dis J 1996;15: 762-3. Competing interests: This is a partial list of competing interests. If you are interested in this article, we will provide the remainder. None of the competing interests are significant since we are supporting an old method to diagnose Lyme disease and none of us hold any patents or see direct monies from sales of the method we are supporting in this letter. The patents we hold related to newer diagnostic methods, including recombinant antigens. Barbara Johnson holds two patents that concern laboratory diagnosis of Lyme disease. RP has two patents concerning bioinformatic diagnosis of Lyme disease and a grant to study bioinformatic diagnosis of Lyme disease from the National Institutes of Health (AI069564-01). 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. Editorial note The complete list of potential competing interests was added on 12 February 2008 by Sharon Davies with the authors' agreement: Dr. Bockenstedt reports no conflicts. 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. 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. Dr. Barbara Johnson holds two patents that concern laboratory diagnosis of Lyme disease. Dr. Peter J. Krause has a patent with McGill University and the University of Colorado on a diagnostic test for babesiosis. Dr. Robert B. Nadelman reports that he has been retained as an expert witness in medical malpractice cases related to Lyme disease. Dr. Richard Porwancher reports having received a NIH research grant (SBIR-AT-NIAID, 1R43AI069564). He holds two patents on bioinformatics algorithms to diagnose Lyme disease, but receives no royalties. He served as an expert witness for the New Jersey State Board Of Medical Examiners (USA) in 2004. 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. 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.
Re: Lyme Wars: A view from an Enlisted 3 December 2007
Elizabeth L Maloney, physician Wyoming, MN 55092 Send response to journal: Re: Re: Lyme Wars: A view from an Enlisted	As a clinician, my primary concern with regards to testing schemes is that they must be truly applicable to the clinical situation for which they are employed. Serologic testing in late neurologic Lyme disease can be quite useful, as Porwancher et al (1) point out, but the tests are frequently misunderstood and the results misused. Consider the two-tier testing protocol for Lyme adopted by the CDC (2). Missing Lyme may lead to significant morbidity. The goal of step 1 is to identify all potential Lyme patients from a group of patients with clinical characteristics suggestive of the illness; this requires a highly sensitive test. The inappropriate use of antibiotics may be harmful, thus, it is important to only treat patients who truly have Lyme. The goal of step 2 is to weed out the false positives amongst all the positives generated in step 1. Here, circumstances call for a very specific test. In this scheme, only those positive in step 1 require additional scrutiny; the negatives are done, Lyme has been “ruled out”. What looks good in theory falls apart in practice. In my Lyme- endemic locale, most labs use the C6 ELISA as the first step in the laboratory confirmation process. And, as Bacon et al (3) demonstrated, the C6 simply isn’t sensitive enough to be used in this way. The results of the other testing modalities are of no consequence to patients from my area; what matters to them is how the C6 performs. Table 1 reports that of the 11 patients with late neurologic Lyme, the C6 was negative in 3, yielding a sensitivity of only 73%. Unfortunately, 27% of late Lyme patients could easily be told by poorly informed physicians that Lyme has been ruled out when they indeed have the illness. The poor performance of the C6 is not limited to late neurologic Lyme patients; the overall sensitivity in the study was 66%. Even paired testing will not save patients from being misdiagnosed; C6 sensitivity in early convalescent samples only rose to 70%. How does a clinician correctly use the results of the two-tier algorithm if step 1 employs the C6 ELISA? By using laboratory testing only to confirm a clinical diagnosis of Lyme and not using it to rule Lyme out. Laboratory shortcuts to a diagnosis may be desired by clinicians but, in Lyme, such paths will lead many astray. Reference: 1. Porwancher R, Bockenstedt L, Dattwyler R, Halperin J, Johnson B, Krause P, Nadelman R, Shapiro E, Wormser G. Lyme Wars: Critique misses mark. bmj.com 30 Nov 2007 2. Centers for Disease Control and Prevention. Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 1995; 44:590–1. 3. Bacon RM, Biggerstaff BJ, Schriefer ME, Gilmore RD Jr., Philipp MT, Steere AC, et al. Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2- tiered testing using whole-cell lysates. J Infect Dis 2003;187:1187- 99. Competing interests: None declared
Commercial Lyme Testing: Mathematical Gymnastics are Unconvincing. 3 December 2007
Raphael B. Stricker, MD 450 Sutter Street, Suite 1504, San Francisco, CA 94108, Lorraine Johnson Send response to journal: Re: Commercial Lyme Testing: Mathematical Gymnastics are Unconvincing.	Porwancher and colleagues attempt to defend two-tier commercial Lyme testing with the kind of inaccuracies and misstatements that have fueled the “Lyme Wars” over the years. The authors criticize our analysis of commercial Lyme testing (1) by claiming that we included heterogeneous studies in our evaluation, specifically studies of patients with an erythema migrans rash whose acute samples should be less reactive on the commercial tests. This is not the case. The articles that we evaluated included “convalescent” sample testing, and in general our sensitivity and specificity results are based on these data points, not on the early testing. For example, the study by Engstrom et al. (2), which Porwancher and colleagues characterize as an evaluation of “acute sera”, includes six testing time points from the day treatment was initiated to one year post-treatment. We chose the “convalescent” time point for our evaluation. In the study by Ledue et al., we did include analysis of well-characterized early and late Lyme disease samples provided by the Centers for Disease Control and Prevention and the College of American Pathologists (3). However, 41 of the 54 serum samples were from patients with late Lyme disease, and the two-tier test sensitivity in this group was only 47%, worse than a coin toss. Ironically, both of these studies found that commercial two-tier testing in early Lyme disease was more sensitive than in late Lyme disease, which contradicts the contention of Porwancher and colleagues. Porwancher and colleagues also consider it inappropriate that our analysis includes studies of Lyme patients with “multiple disease manifestations”. They cite the study by Bacon et al. (4) showing that selected patients with arthritis or neurologic disease have better detection rates with the commercial testing. This type of slicing and dicing of limited data disregards the tremendous diagnostic difficulties in many Lyme patients whose symptoms are more diffuse. It is disingenuous to maintain that commercial two-tier testing is accurate for late Lyme disease because 11/11 patients with late neurologic disease had positive testing (too small a sample to give meaningful results), while ignoring the fact that overall two-tier testing in 280 Lyme patients yields an inadequate sensitivity of 68% and convalescent testing in 106 patients yields an inadequate sensitivity of 67% (4). In view of the often complex presentation of late Lyme disease, the broader numbers indicate that commercial two-tier testing fails as a diagnostic tool (5,6). A review of Lyme disease testing published in 2005 contains the following statement: “Relatively few studies using currently available commercial tests have evaluated the performance of the recommended two- tier testing on well-characterized sera from patients with extracutaneous manifestations of Lyme borreliosis” (7). The composite studies of 342 Lyme patients and 737 controls outlined in our communication (1) give an accurate and appropriately weighted view of the insensitivity of commercial Lyme testing. Although Porwancher and colleagues attempt to support this testing through mathematical gymnastics portraying Lyme patients as so-and-so many times more positive than controls or vice versa, their manipulations fail to overcome the diagnostic inaccuracy of the commercial two-tier test system in the real world of Lyme disease. Raphael B. Stricker, MD Past President, International Lyme & Associated Diseases Society San Francisco, CA 94108 Lorraine Johnson, JD, MBA Executive Director, California Lyme Disease Association Los Angeles, CA 90068 References 1. Stricker RB, Johnson L. Lyme Wars: Let’s tackle the testing. BMJ 2007;335:1008. 2. Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol 1995;33:419-27. 3. Ledue TB, Collins MF, Craig WY. New laboratory guidelines for serologic diagnosis of Lyme disease: evaluation of the two-test protocol. J Clin Microbiol 1996;34:2343-50. 4. Bacon RM, Biggerstaff BJ, Schriefer ME, et al. Serodiagnosis of Lyme disease by kinetic enzyme-linked immunosorbent assay using recombinant VlsE1 or peptide antigens of Borrelia burgdorferi compared with 2-tiered testing using whole-cell lysates. J Infect Dis 2003;187:1187 -99. 5. Johnson L, Stricker RB. Treatment of Lyme disease: A medicolegal assessment. Expert Rev Anti-Infect Ther 2004;2:533-57. 6. Stricker RB. Counterpoint: Long-term antibiotic therapy improves persistent symptoms associated with Lyme disease. Clin Infect Dis 2007;45:149-57. 7. Aguero-Rosenfeld ME, Wang G, Schwartz I, Wormser GP. Diagnosis of Lyme borreliosis. Clin Microbiol Rev 2005;18:464-509. Competing interests: RBS serves on the advisory panel for QMedRx.
Two-Tier Testing Delays the Diagnosis of Lyme Disease 10 December 2007
Phyllis C Mervine, President, California Lyme Disease Association Ukiah CA 95482 Send response to journal: Re: Two-Tier Testing Delays the Diagnosis of Lyme Disease	The California Lyme Disease Association (CALDA) is one of many patient education and advocacy groups for people with Lyme disease in the United States. CALDA was established to compensate for the abysmal failure of mainstream medicine to recognize the clinical features of Lyme disease. In 2004, because of our collective experience counseling thousands of patients, CALDA developed and distributed a questionnaire to patients with persistent Lyme disease throughout the nation. Seventy-three percent (73%) of 182 respondents were denied a Lyme diagnosis at least once due to a negative enzyme-linked immunosorbent assay (ELISA) according to Centers for Disease Control and Prevention (CDC) criteria. Of these, thirty-one percent (31%) were denied access to a Western blot (WB) by their physicians due to a negative ELISA. Sixty-one percent (61%) of respondents were denied a Lyme diagnosis at least once due to a negative WB by CDC surveillance criteria. The strict adherence to CDC surveillance criteria (either ELISA or WB) for diagnostic purposes resulted in a delay in diagnosis of one year or more for 49% of responding patients. The average period of delay in diagnosis was almost 4½ years. Physicians of 81% of patients failed to diagnose Lyme disease because of strict adherence to the CDC surveillance criteria, and many of these patients incurred treatment delays as well. Delayed diagnosis in Lyme disease can allow the disease to progress from generally treatable to more resistant or unresponsive to treatment, with devastating consequences to patients, many of them children. Thanks to doctors like Porwancher et al., who are more interested in promoting insensitive tests than in recognizing what goes on in the trenches,[1] there appears to be no end in sight for the heartbreaking work of CALDA's volunteer patient advocates. ___________________________________________________________________________________________________ _ 1 Porwancher R, Bockenstedt L, Dattwyler R, Halperin J, Johnson B, Krause P, Nadelman R, Shapiro E, Wormser G. Lyme Wars: Critique misses mark. bmj.com 30 Nov 2007 Competing interests: None declared
Lyme disease debate: facts or fiction 23 April 2008
Richard B. Porwancher, Infectious Disease Specialist 445 Prospect Avenue, Princeton, NJ 08540, USA, Linda Bockenstedt, Raymond Dattwyler, Peter J. Krause, Barbara J.B. Johnson, John Halperin, Robert B. Nadelman, Eugene Shapiro, and Gary P. Wormser Send response to journal: Re: Lyme disease debate: facts or fiction	In their letter to this journal (BMJ 2007;335:1008), Stricker and Johnson stated, “In simple terms, the chance of a patient with Lyme disease being diagnosed using the commercial tests approved by the Food and Drug Administration (FDA) and sanctioned by the Centers for Disease Control and Prevention (CDC) is about getting heads or tails when tossing a coin…” In subsequent correspondence we pointed out key analytical errors in their argument (http://www.bmj.com/cgi/eletters/335/7628/1008). We also wish to bring to your readers' attention that 2 of their 6 references evaluated tests that were neither FDA-approved nor CDC- recommended (1,2). In fact, the study by Schmitz et al.(1) was published in 1993, the year before the CDC endorsed using the 2-tier serologic method to assist with diagnosis (3). While Stricker and Johnson claim that Engstrom et al.(2) demonstrated the inadequacy of 2-tier testing for convalescent sera, the CDC does not recommend using 2-tier IgM serology for samples collected more than 30 days after onset of symptoms, and the IgG Western blot criteria used by Engstrom (2) were different from those advocated by the CDC. While we favor vigorous debate, it should be based on current scientific data that are accurately reported to the public. 1) Schmitz JL, Powell CS, Folds JD. Comparison of seven commercial kits for detection of antibodies to Borrelia burgdorferi. Eur J Clin Microbiol Infect Dis 1993;12:419-24. 2) Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease J Clin Microbiol 1995;33(2):419-27. 3) Proceedings of the Second National Conference on Serologic Diagnosis of Lyme Disease (October 27-29, 1994; Dearborn, Michigan). Washington, DC: Association of State and Territorial Public Health Laboratory Directors 1995:1-5. Competing interests: Competing interests were previously listed 12 February 2008.
Re: Lyme disease debate: facts or fiction 28 April 2008
Raphael B. Stricker, MD 450 Sutter Street, Suite 1504, San Francisco, CA 94108, Lorraine Johnson Send response to journal: Re: Re: Lyme disease debate: facts or fiction	Porwancher and colleagues choose fiction over fact in their latest attack on our publication describing the "coin toss" sensitivity of commercial Lyme testing (1). They argue that two of the studies cited in our article evaluated tests that were neither approved by the Food and Drug Administration (FDA) nor recommended by the Centers for Disease Control and Prevention (CDC). This statement is incorrect. The study by Schmitz et al. (2) examined the sensitivity and specificity of the Mardx(R) and Cambridge Biotech(R) commercial Western blots. These commercial test kits were both "FDA-approved and CDC- recommended" after the CDC established the two-tier test system to "assist in diagnosis" of Lyme disease (3). In fact, a subsequent evaluation of these two commercial tests reported that the kits had sensitivities of 47% and 44%, respectively - worse than a coin toss (3). The insensitive Mardx(R) Western blot remains the standard FDA-approved commercial Lyme test in the United States. The study by Engstrom et al. (4) did evaluate both IgG and IgM enzyme -linked immunosorbent assay (ELISA) serologies, as stated by Porwancher and colleagues. However, we focused on the CDC-recommended IgG ELISA results, as reported in Table 1. The maximum sensitivity of the screening IgG ELISA was 42%, noted when patients were 8-12 days into treatment. Since a confirmatory Western blot would only be performed following a positive screening ELISA (according to CDC guidelines), the maximum sensitivity of the two-tier test system is therefore limited to the sensitivity of the ELISA - again, worse than a coin toss. In view of the poor sensitivity of the CDC-recommended screening ELISA, the fact that Engstrom et al. used non-CDC criteria to interpret their confirmatory Western blot testing is irrelevant to the sensitivity discussion. Based on this updated evaluation, we must now conclude that the sensitivity of "FDA-approved and CDC-recommended" commercial Lyme testing is in fact worse than a coin toss. To paraphrase the old saying, you can't make a silk purse out of the sow's ear of commercial Lyme testing. References 1. Stricker RB, Johnson L. Lyme wars: let's tackle the testing. BMJ 2007;335:1008. 2. Schmitz JL, Powell CS, Folds JD. Comparison of seven commercial kits for detection of antibodies to Borrelia burgdorferi. Eur J Clin Microbiol Infect Dis 1993;12:419-24. 3. Tilton RC, Sand MN, Manak M. The Western immunoblot for Lyme disease: determination of sensitivity, specificity, and interpretive criteria with use of commercially available performance panels. Clin Infect Dis 1997;25(Suppl 1):S31-4. 4. Engstrom SM, Shoop E, Johnson RC. Immunoblot interpretation criteria for serodiagnosis of early Lyme disease. J Clin Microbiol 1995;33:419-27. Competing interests: RBS serves on the advisory panel for QMedRx.