On 2016 Jun 25, John D. Scott commented:

Response to Moore et al.

John D. Scott, B.Sc. (Agr.), M.Sc.

June 23, 2016

Re: Moore A, Nelson C, Molins C, Mead P, Schriefer M (2016) Current guidelines, common clinical pitfalls, and future direction for laboratory diagnosis of Lyme disease, United States. Emerg Infect Dis 22. doi 10.3201/eid2207.151694

The two-tiered Lyme disease serology test has failed countless patients, including my wife and me. We both have definitive proof of Lyme disease, and yet we have never tested positive using conventional two-tiered Lyme serology testing. We are culture-positive, PCR-positive, and show positivity for anti-Borrelia burgdorferi fluorescent stain on body fluids.

Using circular reasoning to tout the two-tiered Lyme disease serology test is unscientific. This spurious methodology is nothing more than stacking the deck before the experiment begins. Using only seropositive patients to show seropositivity is anti-science and highly flawed. In reality, the two-tiered system fails Lyme disease patients time and time again. When researchers flaunt a screening test that seldom works, it puts the populace at risk.

On 2016 Jun 18, Raphael Stricker commented:

Circular Reasoning in CDC Lyme Disease Test Review

Raphael B. Stricker, MD; Lorraine Johnson, JD, MBA

Previous studies have shown that commercial two-tier serological testing has a sensitivity of about 46% in later-stage Lyme disease in the USA [1]. Commercial two-tier Lyme testing in Europe demonstrates the same poor test sensitivity [2]. The Table in the latest Centers for Disease Control and Prevention (CDC) review by Moore et al. cites three studies allegedly showing that two-tier Lyme testing in later-stage (“non-cutaneous”) Lyme disease has a sensitivity of 87-96% [3]. These numbers will undoubtedly be used to support two-tier testing as a valid diagnostic tool for Lyme disease. Therefore it is important to understand the circular reasoning that produced these inflated and misleading numbers.

Analysis of the three studies cited in the CDC review reveals the following:

+1. Branda et al [4]: Two-tier Lyme test sensitivity 87% (55 patients). The Methods section of this article contains the following language: "All patients categorized as having Lyme disease met the CDC surveillance criteria for the diagnosis.” The reference for this statement [5] contains the CDC surveillance criteria for the diagnosis of Lyme disease. The portion of the CDC surveillance criteria relevant for later Lyme disease is set forth below.

Clinical case definition:

1. Erythema migrans, or
2. At least one late manifestation, as defined below, and laboratory confirmation of infection (emphasis added).

Laboratory criteria for diagnosis:

1. Isolation of Borrelia burgdorferi from clinical specimen, or
2. Demonstration of diagnostic levels of IgM and IgG antibodies to the spirochete in serum or CSF, or
3. Significant change in IgM or IgG antibody response to B. burgdorferi in paired acute- and convalescent-phase serum samples.

This surveillance case definition was developed for national reporting of Lyme disease; it is NOT appropriate for clinical diagnosis (emphasis added).

Comment: Although the Branda et al. study does not say how many later-stage Lyme patients were culture-positive, presumably most were included based on positive serology. Patients who had positive serology as part of the study entry criteria would be expected to have positive serology on the same outcome measure. Circular reasoning.

+2. Molins et al [6]: Two-tier Lyme test sensitivity 96% (46 patients). The Methods section of this article contains the following language: "Lyme disease serology or results from two-tiered testing did not play a role in patient enrollment except for inclusion of late-stage Lyme arthritis patients (emphasis added).”

Comment: Once again, patients with later-stage Lyme disease had to have positive serology in order to be included in the study, and then they had positive serology. Circular reasoning.

+3. Wormser et al [7]: Two-tier Lyme test sensitivity 94% (142 patients). This study was a cost analysis article based on another study [8] that contains the following language: "Lyme arthritis was defined as the presence of joint swelling that was clinically compatible with Lyme arthritis in conjunction with serologic evidence of borrelial infection demonstrated by at least a positive WCS ELISA (emphasis added).”

Comment: Once again, patients with later-stage Lyme disease had to have positive serology in order to be included in the study, and then they had positive serology. Circular reasoning.

Conclusions: Based on circular reasoning, the latest CDC analysis perpetuates the myth that two-tier testing is sensitive for later-stage Lyme disease. The comment in the CDC surveillance guidelines that this testing is NOT appropriate for clinical diagnosis is being ignored by the CDC.

References

[1] Stricker RB, Johnson L. Lyme disease diagnosis and treatment: Lessons from the AIDS epidemic. Minerva Med. 2010;101:419–25.

[2] 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;30:1027-32.

[3] Moore A, Nelson C, Molins C, Mead P, Schriefer M. Current guidelines, common clinical pitfalls, and future directions for laboratory diagnosis of Lyme disease, United States. Emerg Infect Dis. 2016 Jul;22(7). doi: 10.3201/eid2207.151694.

[4] Branda JA, Linskey K, Kim YA, Steere AC, Ferraro MJ. Two-tiered antibody testing for Lyme disease with use of 2 enzyme immunoassays, a whole-cell sonicate enzyme immunoassay fol¬lowed by a VlsE C6 peptide enzyme immunoassay. Clin Infect Dis. 2011;53:541–7.

[5] Wharton M, Chorba TL, Vogt RL, Morse DL, Buehler JW. Case definitions for public health surveillance. MMWR Recomm Rep 1990; 39:1–43.

[6] Molins CR, Sexton C, Young JW, Ashton LV, Pappert R, Beard CB, et al. Collection and characterization of samples for establishment of a serum repository for Lyme disease diagnostic test development and evaluation. J Clin Microbiol. 2014;52:3755–62.

[7] Wormser GP, Levin A, Soman S, Adenikinju O, Longo MV, Branda JA. Comparative cost-effectiveness of two-tiered testing strategies for serodiagnosis of Lyme disease with noncutaneous manifestations. J Clin Microbiol. 2013;51:4045–9.

[8] Wormser GP, Schriefer M, Aguero-Rosenfeld ME, Levin A, Steere AC, Nadelman RB, et al. Single-tier testing with the C6 peptide ELISA kit compared with two-tier testing for Lyme disease. Diagn Microbiol Infect Dis. 2013;75:9–15.

Disclosure: RBS and LJ are members of the International Lyme and Associated Diseases Society (ILADS) and directors of LymeDisease.org. They have no financial or other conflicts to declare.

On 2016 Jun 18, Raphael Stricker commented:

Circular Reasoning in CDC Lyme Disease Test Review

Raphael B. Stricker, MD; Lorraine Johnson, JD, MBA

Previous studies have shown that commercial two-tier serological testing has a sensitivity of about 46% in later-stage Lyme disease in the USA [1]. Commercial two-tier Lyme testing in Europe demonstrates the same poor test sensitivity [2]. The Table in the latest Centers for Disease Control and Prevention (CDC) review by Moore et al. cites three studies allegedly showing that two-tier Lyme testing in later-stage (“non-cutaneous”) Lyme disease has a sensitivity of 87-96% [3]. These numbers will undoubtedly be used to support two-tier testing as a valid diagnostic tool for Lyme disease. Therefore it is important to understand the circular reasoning that produced these inflated and misleading numbers.

Analysis of the three studies cited in the CDC review reveals the following:

+1. Branda et al [4]: Two-tier Lyme test sensitivity 87% (55 patients). The Methods section of this article contains the following language: "All patients categorized as having Lyme disease met the CDC surveillance criteria for the diagnosis.” The reference for this statement [5] contains the CDC surveillance criteria for the diagnosis of Lyme disease. The portion of the CDC surveillance criteria relevant for later Lyme disease is set forth below.

Clinical case definition:

1. Erythema migrans, or
2. At least one late manifestation, as defined below, and laboratory confirmation of infection (emphasis added).

Laboratory criteria for diagnosis:

1. Isolation of Borrelia burgdorferi from clinical specimen, or
2. Demonstration of diagnostic levels of IgM and IgG antibodies to the spirochete in serum or CSF, or
3. Significant change in IgM or IgG antibody response to B. burgdorferi in paired acute- and convalescent-phase serum samples.

This surveillance case definition was developed for national reporting of Lyme disease; it is NOT appropriate for clinical diagnosis (emphasis added).

Comment: Although the Branda et al. study does not say how many later-stage Lyme patients were culture-positive, presumably most were included based on positive serology. Patients who had positive serology as part of the study entry criteria would be expected to have positive serology on the same outcome measure. Circular reasoning.

+2. Molins et al [6]: Two-tier Lyme test sensitivity 96% (46 patients). The Methods section of this article contains the following language: "Lyme disease serology or results from two-tiered testing did not play a role in patient enrollment except for inclusion of late-stage Lyme arthritis patients (emphasis added).”

Comment: Once again, patients with later-stage Lyme disease had to have positive serology in order to be included in the study, and then they had positive serology. Circular reasoning.

+3. Wormser et al [7]: Two-tier Lyme test sensitivity 94% (142 patients). This study was a cost analysis article based on another study [8] that contains the following language: "Lyme arthritis was defined as the presence of joint swelling that was clinically compatible with Lyme arthritis in conjunction with serologic evidence of borrelial infection demonstrated by at least a positive WCS ELISA (emphasis added).”

Comment: Once again, patients with later-stage Lyme disease had to have positive serology in order to be included in the study, and then they had positive serology. Circular reasoning.

Conclusions: Based on circular reasoning, the latest CDC analysis perpetuates the myth that two-tier testing is sensitive for later-stage Lyme disease. The comment in the CDC surveillance guidelines that this testing is NOT appropriate for clinical diagnosis is being ignored by the CDC.

References

[1] Stricker RB, Johnson L. Lyme disease diagnosis and treatment: Lessons from the AIDS epidemic. Minerva Med. 2010;101:419–25.

[2] 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;30:1027-32.

[3] Moore A, Nelson C, Molins C, Mead P, Schriefer M. Current guidelines, common clinical pitfalls, and future directions for laboratory diagnosis of Lyme disease, United States. Emerg Infect Dis. 2016 Jul;22(7). doi: 10.3201/eid2207.151694.

[4] Branda JA, Linskey K, Kim YA, Steere AC, Ferraro MJ. Two-tiered antibody testing for Lyme disease with use of 2 enzyme immunoassays, a whole-cell sonicate enzyme immunoassay fol¬lowed by a VlsE C6 peptide enzyme immunoassay. Clin Infect Dis. 2011;53:541–7.

[5] Wharton M, Chorba TL, Vogt RL, Morse DL, Buehler JW. Case definitions for public health surveillance. MMWR Recomm Rep 1990; 39:1–43.

[6] Molins CR, Sexton C, Young JW, Ashton LV, Pappert R, Beard CB, et al. Collection and characterization of samples for establishment of a serum repository for Lyme disease diagnostic test development and evaluation. J Clin Microbiol. 2014;52:3755–62.

[7] Wormser GP, Levin A, Soman S, Adenikinju O, Longo MV, Branda JA. Comparative cost-effectiveness of two-tiered testing strategies for serodiagnosis of Lyme disease with noncutaneous manifestations. J Clin Microbiol. 2013;51:4045–9.

[8] Wormser GP, Schriefer M, Aguero-Rosenfeld ME, Levin A, Steere AC, Nadelman RB, et al. Single-tier testing with the C6 peptide ELISA kit compared with two-tier testing for Lyme disease. Diagn Microbiol Infect Dis. 2013;75:9–15.

Disclosure: RBS and LJ are members of the International Lyme and Associated Diseases Society (ILADS) and directors of LymeDisease.org. They have no financial or other conflicts to declare.

On 2016 Jun 25, John D. Scott commented:

Response to Moore et al.

John D. Scott, B.Sc. (Agr.), M.Sc.

June 23, 2016

Re: Moore A, Nelson C, Molins C, Mead P, Schriefer M (2016) Current guidelines, common clinical pitfalls, and future direction for laboratory diagnosis of Lyme disease, United States. Emerg Infect Dis 22. doi 10.3201/eid2207.151694

The two-tiered Lyme disease serology test has failed countless patients, including my wife and me. We both have definitive proof of Lyme disease, and yet we have never tested positive using conventional two-tiered Lyme serology testing. We are culture-positive, PCR-positive, and show positivity for anti-Borrelia burgdorferi fluorescent stain on body fluids.

Using circular reasoning to tout the two-tiered Lyme disease serology test is unscientific. This spurious methodology is nothing more than stacking the deck before the experiment begins. Using only seropositive patients to show seropositivity is anti-science and highly flawed. In reality, the two-tiered system fails Lyme disease patients time and time again. When researchers flaunt a screening test that seldom works, it puts the populace at risk.