On 2013 Dec 19, Raphael Stricker commented:

Clinical Evidence for Rapid Transmission of Lyme Disease Following a Tickbite: Response to Binnicker et al.

Raphael B. Stricker, MD,* Eleanor D. Hynote, MD,* and Phyllis C. Mervine, EdM.*

*International Lyme and Associated Diseases Society, P.O. Box 341461, Bethesda, MD 20827-1461. www.ILADS.org

Binnicker et al. dispute the clinical diagnosis of Lyme disease in our patients based on three factors: (1) a “physician-diagnosed target lesion” was not present at the site of the tickbite; (2) although an IgM antibody response was present, conversion to an IgG response was not documented; and (3) recovery of Borrelia burgdorferi, the spirochetal agent of Lyme disease, was not demonstrated by culture or molecular techniques.

First, it is important to recall that Lyme disease is a clinical diagnosis according to the Centers for Disease Control and Prevention (CDC), which states that “general symptoms” such as fatigue, chills, fever, headache, muscle and joint aches, and swollen lymph nodes “may be the only evidence of infection” in early Lyme disease (CDC, 2012). In addition, the erythema migrans (EM) rash manifests as a “target lesion” in only 9% of cases (Stonehouse et al, 2010), may take up to 30 days to develop (CDC, 2012) and may be completely absent in up to 50% of patients with Lyme disease, as it was in our three patients (Steinberg et al, 1996; Stricker et al, 2006; Kudish et al, 2007). Second, in the setting of a tickbite and clinical symptoms of acute Lyme disease, the prompt administration of antibiotics may abort the typical serological response, as acknowledged by Binnicker et al. and others (Dattwyler et al. 1988; Aguero-Rosenfeld et al, 1996). Few studies have evaluated the serological evolution in Lyme disease patients treated as promptly as ours were (see below). Third, culture and molecular testing is highly insensitive in blood samples and even in tissue or synovial fluid from Lyme disease patients (Coulter et al, 2005; Stricker, 2007; Babady et al, 2008). Thus from a symptom-based and serological perspective, our patients met the CDC case definition of acute Lyme disease even in the absence of a target-shaped EM rash and insensitive laboratory procedures.

Binnicker et al. also mention the CDC “recommendation” that Lyme serology should be performed using a two-tier algorithm. This serological analysis involves a screening enzyme immunoassay or immunofluorescence assay and confirmatory Western blot performed with kits approved by the Food and Drug Administration (FDA) for commercial sale. However the CDC states that this algorithm was developed “for the purposes of surveillance” and was not intended for diagnosis of Lyme disease (CDC, 2011). Furthermore, the FDA-approved commercial two-tier test system has a sensitivity of only 46% and yields results that appear to be biased against women (Binnicker et al, 2008; Stricker and Johnson, 2011). Our patients were tested using a “gender neutral” system that has a sensitivity and specificity of >90% (Shah et al, 2010). Thus our patients had laboratory evaluation that was appropriate for the diagnosis of Lyme disease.

Our report confirms studies in both animals and humans that document transmission of Lyme disease within 24 hours of a tickbite (Piesman et al, 1987; Patmas and Remorca, 1994; Strle et al, 1996a, 1996b; Angelov, 1996; Sood et al, 1997). When animal and human studies produce apparently conflicting results, the contradictory findings should be given serious consideration, even if they contravene existing clinical dogma.

References

1. Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB, Wormser GP. Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol. 1996;34:1-9.
2. Angelov L. Unusual features in the epidemiology of Lyme borreliosis. Eur J Epidemiol. 1996;12:9-11.
3. Babady NE, Sloan LM, Vetter EA, Patel R, Binnicker MJ. Percent positive rate of Lyme real-time polymerase chain reaction in blood, cerebrospinal fluid, synovial fluid, and tissue. Diagn Microbiol Infect Dis. 2008 ;62:464-6.
4. Binnicker MJ, Jespersen DJ, Harring JA, Rollins LO, Bryant SC, Beito EM. Evaluation of two commercial systems for automated processing, reading, and interpretation of Lyme borreliosis Western blots. J Clin Microbiol. 2008;46:2216-21.
5. Binnicker MJ, Theel ES, Pritt BS. Lack of evidence for rapid transmission of Lyme disease following a tick bite. Diagn Microbiol Infect Dis. 2012;73:102-3.
6. Centers for Disease Control and Prevention (CDC, 2011). Lyme disease (Borrelia burgdorferi) 2011 case definition. Available at http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=752&DatePub=1/1/2011 12:00:00 AM. Accessed December 4, 2013.
7. Centers for Disease Control and Prevention (CDC, 2012). Signs and symptoms of Lyme disease. Available at http://www.cdc.gov/lyme/signs_symptoms/index.html. Accessed December 4, 2013.
8. Coulter P, Lema C, Flayhart D, Linhardt AS, Aucott JN, Auwaerter PG, Dumler JS. Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease. J Clin Microbiol. 2005;43:5080-4.
9. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med. 1988;319:1441-6.
10. Hynote ED, Mervine PC, Stricker RB. Clinical evidence for rapid transmission of Lyme disease following a tickbite. Diagn Microbiol Infect Dis. 2012;72:188-92.
11. Kudish K, Sleavin W, Hathcock L. Lyme disease trends: Delaware, 2000 - 2004. Del Med J. 2007;79:51-8.
12. Patmas MA, Remorca C. Disseminated Lyme disease after short-duration tick bite. J Spiro Tick Dis. 1994;1:77-78.
13. Piesman J, Mather TN, Sinsky RJ, Spielman A. Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol. 1987;25:557-8.
14. Shah JS, Du Cruz I., Narciso W, Lo W, Harris NS. Improved clinical sensitivity for detection of antibodies to Borrelia burgdorferi by Western blots prepared from a mixture of two strains of B. burgdorferi, 297 and B31, and interpreted by in-house criteria. European Infect Dis. 2010;4:56–60.
15. Sood SK, Salzman MB, Johnson BJ, Happ CM, Feig K, Carmody L, Rubin LG, Hilton E, Piesman J. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis. 1997;175:996-9.
16. Steinberg SH, Strickland GT, Pena C, Israel E. Lyme disease surveillance in Maryland, 1992. Ann Epidemiol. 1996;6:24-9.
17. Stonehouse A, Studdiford JS, Henry CA. An update on the diagnosis and treatment of early Lyme disease: "focusing on the bull's eye, you may miss the mark". J Emerg Med. 2010;39:e147-51.
18. Stricker RB, Lautin A, Burrascano JJ. Lyme disease: the quest for magic bullets. Chemotherapy. 2006;52:53-9.
19. Stricker RB. Counterpoint: long-term antibiotic therapy improves persistent symptoms associated with lyme disease. Clin Infect Dis. 2007;45:149-57.
20. Stricker RB, Johnson L. The pain of chronic Lyme disease: moving the discourse backward? FASEB J. 2011;25:4085-7.
21. Stricker RB, Hynote ED, Mervine PC. Clinical evidence for rapid transmission of Lyme disease following a tickbite: response to Piesman and Gray. Diagn Microbiol Infect Dis. 2012;73:104-5.
22. Strle F, Nelson JA, Ruzic-Sabljic E, Cimperman J, Maraspin V, Lotric-Furlan S, Cheng Y, Picken MM, Trenholme GM, Picken RN. European Lyme borreliosis: 231 culture-confirmed cases involving patients with erythema migrans. Clin Infect Dis. 1996a;23:61-5.
23. Strle F, Maraspin V, Furlan-Lotric S, Cimperman J. Epidemiological study of a cohort of adult patients with Erythema migrans registered in Slovenia in 1993. Eur J Epidemiol. 1996b ;12:503-7.

On 2013 Dec 19, Raphael Stricker commented:

Clinical Evidence for Rapid Transmission of Lyme Disease Following a Tickbite: Response to Binnicker et al.

Raphael B. Stricker, MD,* Eleanor D. Hynote, MD,* and Phyllis C. Mervine, EdM.*

*International Lyme and Associated Diseases Society, P.O. Box 341461, Bethesda, MD 20827-1461. www.ILADS.org

Binnicker et al. dispute the clinical diagnosis of Lyme disease in our patients based on three factors: (1) a “physician-diagnosed target lesion” was not present at the site of the tickbite; (2) although an IgM antibody response was present, conversion to an IgG response was not documented; and (3) recovery of Borrelia burgdorferi, the spirochetal agent of Lyme disease, was not demonstrated by culture or molecular techniques.

First, it is important to recall that Lyme disease is a clinical diagnosis according to the Centers for Disease Control and Prevention (CDC), which states that “general symptoms” such as fatigue, chills, fever, headache, muscle and joint aches, and swollen lymph nodes “may be the only evidence of infection” in early Lyme disease (CDC, 2012). In addition, the erythema migrans (EM) rash manifests as a “target lesion” in only 9% of cases (Stonehouse et al, 2010), may take up to 30 days to develop (CDC, 2012) and may be completely absent in up to 50% of patients with Lyme disease, as it was in our three patients (Steinberg et al, 1996; Stricker et al, 2006; Kudish et al, 2007). Second, in the setting of a tickbite and clinical symptoms of acute Lyme disease, the prompt administration of antibiotics may abort the typical serological response, as acknowledged by Binnicker et al. and others (Dattwyler et al. 1988; Aguero-Rosenfeld et al, 1996). Few studies have evaluated the serological evolution in Lyme disease patients treated as promptly as ours were (see below). Third, culture and molecular testing is highly insensitive in blood samples and even in tissue or synovial fluid from Lyme disease patients (Coulter et al, 2005; Stricker, 2007; Babady et al, 2008). Thus from a symptom-based and serological perspective, our patients met the CDC case definition of acute Lyme disease even in the absence of a target-shaped EM rash and insensitive laboratory procedures.

Binnicker et al. also mention the CDC “recommendation” that Lyme serology should be performed using a two-tier algorithm. This serological analysis involves a screening enzyme immunoassay or immunofluorescence assay and confirmatory Western blot performed with kits approved by the Food and Drug Administration (FDA) for commercial sale. However the CDC states that this algorithm was developed “for the purposes of surveillance” and was not intended for diagnosis of Lyme disease (CDC, 2011). Furthermore, the FDA-approved commercial two-tier test system has a sensitivity of only 46% and yields results that appear to be biased against women (Binnicker et al, 2008; Stricker and Johnson, 2011). Our patients were tested using a “gender neutral” system that has a sensitivity and specificity of >90% (Shah et al, 2010). Thus our patients had laboratory evaluation that was appropriate for the diagnosis of Lyme disease.

Our report confirms studies in both animals and humans that document transmission of Lyme disease within 24 hours of a tickbite (Piesman et al, 1987; Patmas and Remorca, 1994; Strle et al, 1996a, 1996b; Angelov, 1996; Sood et al, 1997). When animal and human studies produce apparently conflicting results, the contradictory findings should be given serious consideration, even if they contravene existing clinical dogma.

References

1. Aguero-Rosenfeld ME, Nowakowski J, Bittker S, Cooper D, Nadelman RB, Wormser GP. Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol. 1996;34:1-9.
2. Angelov L. Unusual features in the epidemiology of Lyme borreliosis. Eur J Epidemiol. 1996;12:9-11.
3. Babady NE, Sloan LM, Vetter EA, Patel R, Binnicker MJ. Percent positive rate of Lyme real-time polymerase chain reaction in blood, cerebrospinal fluid, synovial fluid, and tissue. Diagn Microbiol Infect Dis. 2008 ;62:464-6.
4. Binnicker MJ, Jespersen DJ, Harring JA, Rollins LO, Bryant SC, Beito EM. Evaluation of two commercial systems for automated processing, reading, and interpretation of Lyme borreliosis Western blots. J Clin Microbiol. 2008;46:2216-21.
5. Binnicker MJ, Theel ES, Pritt BS. Lack of evidence for rapid transmission of Lyme disease following a tick bite. Diagn Microbiol Infect Dis. 2012;73:102-3.
6. Centers for Disease Control and Prevention (CDC, 2011). Lyme disease (Borrelia burgdorferi) 2011 case definition. Available at http://wwwn.cdc.gov/NNDSS/script/casedef.aspx?CondYrID=752&DatePub=1/1/2011 12:00:00 AM. Accessed December 4, 2013.
7. Centers for Disease Control and Prevention (CDC, 2012). Signs and symptoms of Lyme disease. Available at http://www.cdc.gov/lyme/signs_symptoms/index.html. Accessed December 4, 2013.
8. Coulter P, Lema C, Flayhart D, Linhardt AS, Aucott JN, Auwaerter PG, Dumler JS. Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease. J Clin Microbiol. 2005;43:5080-4.
9. Dattwyler RJ, Volkman DJ, Luft BJ, Halperin JJ, Thomas J, Golightly MG. Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med. 1988;319:1441-6.
10. Hynote ED, Mervine PC, Stricker RB. Clinical evidence for rapid transmission of Lyme disease following a tickbite. Diagn Microbiol Infect Dis. 2012;72:188-92.
11. Kudish K, Sleavin W, Hathcock L. Lyme disease trends: Delaware, 2000 - 2004. Del Med J. 2007;79:51-8.
12. Patmas MA, Remorca C. Disseminated Lyme disease after short-duration tick bite. J Spiro Tick Dis. 1994;1:77-78.
13. Piesman J, Mather TN, Sinsky RJ, Spielman A. Duration of tick attachment and Borrelia burgdorferi transmission. J Clin Microbiol. 1987;25:557-8.
14. Shah JS, Du Cruz I., Narciso W, Lo W, Harris NS. Improved clinical sensitivity for detection of antibodies to Borrelia burgdorferi by Western blots prepared from a mixture of two strains of B. burgdorferi, 297 and B31, and interpreted by in-house criteria. European Infect Dis. 2010;4:56–60.
15. Sood SK, Salzman MB, Johnson BJ, Happ CM, Feig K, Carmody L, Rubin LG, Hilton E, Piesman J. Duration of tick attachment as a predictor of the risk of Lyme disease in an area in which Lyme disease is endemic. J Infect Dis. 1997;175:996-9.
16. Steinberg SH, Strickland GT, Pena C, Israel E. Lyme disease surveillance in Maryland, 1992. Ann Epidemiol. 1996;6:24-9.
17. Stonehouse A, Studdiford JS, Henry CA. An update on the diagnosis and treatment of early Lyme disease: "focusing on the bull's eye, you may miss the mark". J Emerg Med. 2010;39:e147-51.
18. Stricker RB, Lautin A, Burrascano JJ. Lyme disease: the quest for magic bullets. Chemotherapy. 2006;52:53-9.
19. Stricker RB. Counterpoint: long-term antibiotic therapy improves persistent symptoms associated with lyme disease. Clin Infect Dis. 2007;45:149-57.
20. Stricker RB, Johnson L. The pain of chronic Lyme disease: moving the discourse backward? FASEB J. 2011;25:4085-7.
21. Stricker RB, Hynote ED, Mervine PC. Clinical evidence for rapid transmission of Lyme disease following a tickbite: response to Piesman and Gray. Diagn Microbiol Infect Dis. 2012;73:104-5.
22. Strle F, Nelson JA, Ruzic-Sabljic E, Cimperman J, Maraspin V, Lotric-Furlan S, Cheng Y, Picken MM, Trenholme GM, Picken RN. European Lyme borreliosis: 231 culture-confirmed cases involving patients with erythema migrans. Clin Infect Dis. 1996a;23:61-5.
23. Strle F, Maraspin V, Furlan-Lotric S, Cimperman J. Epidemiological study of a cohort of adult patients with Erythema migrans registered in Slovenia in 1993. Eur J Epidemiol. 1996b ;12:503-7.