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6/1/15 Poughkeepsie Journal piece "Review of Lyme disease treatment leaves out patients"

Commentary: Mary Beth Pfeiffer from the Poughkeepsie Journal published an article on the upcoming IDSA guidelines for the diagnosis and treatment of Lyme disease, which focuses on panel members and conflicts of interest. "Raging controversy over Lyme treatment guidelines in large part led the federal Institute of Medicine in 2011 to publish standards for developing medical guidelines that were fair and unbiased. The 2006 Lyme guidelines had been questioned in 2008 by then-Connecticut Attorney General Richard Blumenthal, now a U.S. senator, who alleged panel members had "undisclosed financial interests .... in Lyme disease diagnostic tests, patents and consulting arrangements with insurance companies;" as a result, he said, the panel "improperly ignored or minimized consideration of alternative medical opinion" on chronic Lyme disease...The Institute of Medicine said the controversy was "illustrative" of the need for a uniform process across diseases, involving doctors, patients and scientists with diverse viewpoints. Its report made clear that conflicts of interest could lead to bias by, among others, "specialty societies, which might benefit or whose members might gain from guideline recommendations." The recent ILADS guidelines which were published in a peer reviewed medical journal, strictly followed IOM recommendations. 

There is concern that the new IDSA guidelines are not following IOM recommendations, since patient groups have pointed out that members of the existing panel are the same authors from the prior guidelines, who deny the existence of chronic Lyme, with ongoing conflicts on interest, including receiving government or private research grants for the development of Lyme testing. Lyme testing is known to be unreliable, and "because tests fail early on — which mainstream scientists acknowledge — and the rash does not always occur, such endorsements lead to undiagnosed cases".

The 2010 IDSA review panel was "split on whether to discourage clinical diagnosis", but missed diagnosis can not only lead to chronic disability, it can also result in fatal outcomes. This was illustrated in the recent demise of Joseph Elone, a local Poughkeepsie High School student, who had a negative ELISA test for Lyme disease, and died several weeks later from disseminated Lyme. The CDC themselves have said that Lyme is a clinical diagnosis. The CDC Surveillance Case Definition is a case with an EM rash or a case with at least one objective manifestation such as meningitis, cranial neuropathy, arthritis, or AV block, that is laboratory confirmed.  In the words of the CDC: “This surveillance case definition was developed for national reporting of Lyme disease; it is not intended to be used in clinical diagnosis.” Centers for Disease Control Prevention MMWR56(23);573-576, June 15, 2007. Even the FDA has stated“…a patient with active Lyme disease may have a negative test result…”Brown SL, Hansen SL, Langone JJ. (FDA Medical Bulletin) Role of serology in the diagnosis of Lyme disease. JAMA. 1999 Jul 7;282(1):62-6. The prior IDSA panel did not follow these CDC and FDA recommendations. Why? Is there compelling scientific evidence that the blood tests are reliable, or on the contrary, is there evidence that the blood tests are unreliable? Can Lyme disease persist? Here are some of the scientific references that need to be reviewed by the upcoming IDSA guidelines panel that show why the surveillance case definition was developed for national reporting of Lyme disease, and was not intended to be used in clinical diagnosis:

False seronegativity has been extensively reported in the peer review medical literature:

1.         Steere AC. Seronegative Lyme disease. JAMA. 1993 Sep 15;270(11):1369

2.         Kaiser R. False-negative serology in patients with neuroborreliosis and the value of employing of different borrelial strains in serological assays. J Med Microbiol. 2000

3.         Pikelj F, Strle F, Mozina M. Seronegative Lyme disease and transitory atrioventricular block. Ann Intern Med 1989 Jul 1;111(1):90. Oct;49(10):911-5.

4.         Dejmkova H, Hulinska D, Tegzova D, Pavelka K, Gatterova J, Vavrik P. Seronegative Lyme arthritis caused by Borrelia garinii. Clin Rheumatol. 2002 Aug;21(4):330-4.

5.         Brunner M. New method for detection of Borrelia burgdorferi antigen complexed to antibody in seronegative Lyme disease. J Immunol Methods. 2001 Mar 1;249(1-2):185-90.

6.         Breier F, Khanakah G, Stanek G, Kunz G, Aberer E, Schmidt B, Tappeiner G. Isolation and polymerase chain reaction typing of Borrelia afzelii from a skin lesion in a seronegative patient with generalized ulcerating bullous lichen sclerosus et atrophicus. Br J Dermatol. 2001 Feb;144(2):387-92.

7.         Schutzer SE, Coyle PK, Belman AL, Golightly MG, Drulle J. Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease. Lancet. 1990 Feb 10;335(8685):312-5

8.         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 Dec 1;319(22):1441-6

The effect of using the IDSA guidelines would be to miss roughly half of those suffering with Lyme disease:

•           Marangoni, A. et al. Comparative evaluation of three different ELISA methods for the diagnosis of early culture-confirmed Lyme disease in Italy. J. Med. Microbiol. 54, 361-367 (2005);

•           Ang, C.W.,et al. 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. 30, 1027-1032 (2011).

•           Wojciechowska-Koszko, et al. Serodiagnosis of borreliosis; Arch. Immunol. Ther. Exp. 59, 69-77 (2011).

John Hopkins University also found problems with the CDC two-tiered testing approach. In 2005, John’s Hopkins did a study and found that the CDC two tiered testing missed up to 55% of positive Lyme cases (Coulter,et al.,J Clin Microbiol  2005;43:5080-5084)

Understanding the role of laboratory testing in Lyme disease and other tick-borne diseases requires understanding that the 2 tiered protocol of using a Lyme ELISA followed by a Western Blot will miss approximately 1/2 of the patients secondary to the insensitivity of the ELISA test. The utility of the Western Blot is therefore based on understanding specific bands which reflect exposure to Borrelia: these include the 23kDa, 31kDa, 34kDa, 39kDa, 83-93kDa.

•           Ma et al, Serodiagnosis of Lyme Borreliosis by Western Immunoblot: Reactivity of Various Significant Antibodies against Borrelia burgdorferi. Journal of Clinical Microbiology, Feb. 1992, p. 370-376.

PCR testing is an important diagnostic tool for seronegative patients, but many require multiple sets over time using serum, urine, spinal fluid, etc from reliable laboratories, and we may fail to detect antibodies because of borrelia antibodies bound in circulating immune complexes:

•           Coyle, et al. Detection of Bb antigens in CSF. Neurology 1993;43:1093-1097;

•           Schutzer SE, Coyle PK, Belman AL, Golightly MG, Drulle J. Sequestration of antibody to Borrelia burgdorferi in immune complexes in seronegative Lyme disease. Lancet. 1990 Feb 10;335(8685):312-5;

We also have over 100 different strains of borrelia in the US, and over 300 strains worldwide, including the new relapsing fever borrelia, Borrelia miyamotoi, which cannot be found on standard two tiered testing. Standard testing for borrelia by most commercial laboratories only uses the B31 strain, and will therefore miss many borrelia species.

Regarding the rationale for long term treatment: According to the CDC, as many as 20% of patients remain ill after the short term treatment protocol recommended by the IDSA (http://www.cdc.gov/lyme/treatment/). Other studies suggest the treatment failure rate for early Lyme disease may be as high as 36%:

 •           Aucott JN, et al. Post-treatment Lyme disease syndrome symptomatology and the impact on life functioning: is there something here? Qual Life Res. 2013 Feb;22(1):75-84

In late Lyme disease, treatment failure rates may exceed 50%:

•           Cameron, D., Horowitz, R, et al: Treatment of Lyme disease: a medicolegal assessment. Expert review of anti-infective therapy. 2004 Aug;2(4):533-57

 

Why do patients fail short term therapy? The peer reviewed medical literature shows chronic persistent infection despite intensive antibiotics:

•           Bradley JF,et al, The Persistence of Spirochetal Nucleic Acids in Active Lyme Arthritis. Ann Int Med 1994;487-9

•           Bayer ME, Zhang L, Bayer MH. Borrelia burgdorferi DNA in the urine of treated patients with chronic Lyme Disease symptoms. A PCR study of 97 cases. Infection 1996. Sept-Oct;24(5):347-53

•           Diringer MN, et al, Lyme meningoencephalitis- report of a severe, penicillin resistant case. Arthritis & Rheum, 1987;30:705-708

•           Donta, ST, Tetracycline therapy in chronic Lyme disease. Chronic Infectious Diseases, 1997; 25 (Suppl 1): 552-56

•           Fitzpatrick JE, et al. Chronic septic arthritis caused by Borrelia burgdorferi. Clin Ortho 1993 Dec;(297):238-41

•           Georgilis K, Peacocke M, & Klempner MS. Fibroblasts protect the Lyme disease spirochete, Borrelia burgdorferi, from ceftriaxone in vitro. J Infect Dis 1992;166: 440-444

•           Fallon BA, et al. Repeated antibiotic treatment in chronic Lyme disease, Journal of Spirochetal and Tick-borne Diseases, 1999; 6 (Fall/Winter):94-101

•           Fraser DD, et al. Molecular detection of persistent Borrelia burgdorferi in a man with dermatomyositis. Clinical and Exper Rheum. 1992;10:387-390

•           Fried MD et al, Borrelia burdorferi persists in the gastrointestinal tract of children and adolescents with Lyme Disease, JNL of Spirochetal and Tick-borne Diseases, Spring/Summer 2002; 9:11-15

 •           Girschick HJ, et al. Intracellular persistence of Borrelia burgdorferi in human synovial cells. Rheumatol Int 1996;16(3):125-132

•           Hassler D, et al. Pulsed high-dose cefotaxime therapy in refractory Lyme Borreliosis (letter). Lancet 1991;338:193

•           Horowitz RI. Chronic Persistent Lyme Borreliosis: PCR evidence of chronic infection despite extended antibiotic therapy: A Retrospective Review. Abstract XIII Intl Sci Conf on Lyme Disease. Mar 24-26, 2000.

•           Haupl T, et al. Persistence of Borrelia burgdorferi in ligamentous tissue from a patient with chronic Lyme borreliosis. Arthritis Rheum 1993;36:1621-1626

•           Karma A, et al. Long term follow-up of chronic Lyme neuroretinitis. Retina 1996;16:505-509

•           Keller TL, et al. PCR detection of Borrelia burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology 1992;43:32-42

•           Masters EJ, et al. Spirochetemia after continuous high-dose oral amoxicillin therapy. Infect Dis Clin Practice 1994;3:207-208

•           Ma Y, et al. Intracellular localization of Borrelia burgdorferi within human endothelial cells. Infect Immun 1991;59:671-678

•           Meier P, et al. Pars plana vitrectomy in Borrelia burgdorferi endophthalmitis. Klin Monatsbl Augenheilkd 1998 Dec;213(6):351-4

•           Preac-Mursic V, et al. Survival of Borrelia burgdorferi in antibiotically treated patients with Lyme borreliosis. Infection 1989;17:355-359.

•           Preac-Mursic V, et al. Persistence of Borrelia burdorferi and Histopathological Alterations in Experimentally Infected Animals. A comparison with Histopathological Findings in Human Lyme Disease. Infection 1990;18(6):332-341

•           Straubinger RK, et al. Persistence of Borrelia burgdorferi in Experimentally Infected Dogs after Antibiotic Treatment. J Clin Microbiol 1997;35(1):111-116

•           Embers, M. et al. Persistence of Borrelia burgdorferi in Rhesus Macaques following Antibiotic treatment of Disseminated Infection. PLoS ONE 7(1): e29914. doi:10.1371/journal.pone

 

 Chronic persistent infection with Bb despite intensive antibiotics was also proven in two recent Xenodiagnostics studies. The first was in mice:

•           Hodzic E, Barthold SW (2014) Resurgence of Persisting Non-Cultivable Borrelia burgdorferi following Antibiotic Treatment in Mice. PLoS ONE 9(1): e86907.

Results confirmed previous studies: Bb could not be cultured from tissues, but low copy numbers of Bb flaB DNA were detectable in tissues up to 8 months after completion of treatment & RNA transcription of genes was seen with visualized spirochetes.

In humans, a recent NIH study by Dr Marques showed that among ten patients who had high levels of antibodies against B. burgdorferi after antibiotic treatment, two of those patients had “indeterminate results”, and one patient with Post Treatment Lyme disease syndrome (PTLDS) had a positive result, confirming evidence of ongoing Borrelia DNA in these patients:

•           Marques, A. et al. Xenodiagnosis to Detect Borrelia burgdorferi Infection: A First-in-Human Study. Clinical Infectious Diseases DOI: 10.1093/cid/cit939 (2014).

Despite this overwhelming research, some physicians feel that there is no evidence of prolonged antibiotics helping symptoms. We know that short term antibiotics fail in 25%-71% of patients with late stage disease:

•           Berglund J, Stjernberg L, Ornstein K, Tykesson-Joelsson K, Walter H. 5-y Follow-up study of patients with neuroborreliosis. Scand J Infec Dis. 2002;34(6):421-5.

•           Valesová H, Mailer J, Havlík J, Hulínská D, Hercogová J. Long-term results in patients with Lyme arthritis following treatment with ceftriaxone. Infection. 1996 Jan-Feb;24(1):98-102

These frequent treatment relapses and failures with short term therapy are documented by other authors:

•           Logigian (1990) : After 6 mo’s of therapy, 10/27 patients treated with IV AB’s relapsed or had treatment failure.

•           Pfister (1991): 33 patients with neuroborreliosis were treated with IV AB’s. After a mean of 8.1 months 10/27 were symptomatic and borrelia persisted in the CSF in 1 patient.

•           Shadick (1994) : 10/38 pts relapsed (5 with IV) within 1 year of treatment, and had repeated AB treatment.

•           Asch (1994) : 28% relapsed w/ major organ involvement 3.2 years after initial treatment

 Many doctors use IDSA guidelines to base their conclusions to not treat sick patients with long term antibiotics, and base it on double blind placebo controlled trials. However only three NIH-funded trials have been conducted on the treatment of chronic Lyme disease:

•           Klempner M, Hu L, Evans J, Schmid C, Johnson G, Trevino R, et al. Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. The New England journal of medicine. 2001 Jul 12:85-92

•           Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, et al. Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology. 2003 Jun 24;60(12):1923-30

•           Fallon BA, Keilp JG, Corbera KM, Petkova E, Britton CB, Dwyer E, et al. A randomized, placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology. 2008 Mar 25:992-1003

 These were inadequate treatment trials as sample sizes were extremely small, ranging from 37 to 78 patients. Critics have pointed out that studies this small lack sufficient statistical power to measure clinically relevant improvement:

•           Cameron DJ, Johnson LB, Maloney EL. Evidence assessments and guideline recommendations in Lyme disease: the clinical management of known tick bites, erythema migrans rashes and persistent disease. Expert Review Anti-Infective Therapy. 2014 Sep;12(9):1103-35.

•           Institute of Medicine. Clinical Practice Guidelines We Can Trust. Washington, DC: National Academies Press; 2011. Available from: http://books.nap.edu/openbook.php?record_id=1305

 Nevertheless, two of the three clinical trials demonstrated that re treatment improved some patients’ measures, such as fatigue and pain (Krupp, Fallon). Others have shown improvement in cognitive function, in those with Lyme encephalopathy (Fallon).

•           Fallon BA, Petkova E, Keilp J, Britton C. A reappraisal of the U.S. clinical trials of Post-Treatment Lyme Disease Syndrome. Open Neurology Journal. 2012;6(Supp. 1-M2):79-87.

 •           Delong et al. Antibiotic retreatment of Lyme disease in patients with persistent symptoms: A biostatistical review of randomized, placebo controlled, clinical trials. Contemporary Clinical Trials 33 (2012), 1132-1142

The medical literature does in fact show a benefit to using longer treatment regimens for disseminated Lyme Disease:

 1. Wahlberg,P. et al, Treatment of late Lyme borreliosis. J Infect, 1994. 29(3): p255-61 →31% improved w/ 14 days of Rocephin, 89% improved w/ Rocephin + 100d of Amoxicillin and Probenecid, 83% improved w/ Rocephin, then 100 days of cephadroxil

2. Donta, ST., Tetracycline therapy for chronic Lyme disease. Clin Infect Dis, 1997. 25 Suppl 1: p.S52-6. →277 pts with chronic LD treated between 1-11 months: 20% cured, 70% improved, 10% failed

 3. Oksi, J et al., Comparison of oral cefixime and intravenous ceftriaxone followed by oral amoxicillin in disseminated Lyme borreliosis. Eur J Clin Microbiol Infect Dis, 1998. 17(10)  :p 715-9→ 30 pts w/ chronic Lyme disease were treated for 100 days, and 90% had good or excellent response 

4. Oksi, J., et al. Borrelia burgdorferi detected by culture and PCR in clinical relapse of disseminated Lyme borreliosis. Ann Med, 1999. 31(3):p.225-32→32/165 patients with disseminated Lyme were treated for 1 or more months of antibiotics, and showed that even more than 3 months of treatment may not eradicate the spirochete, and that longer term therapy may be necessary. This last study detected chronic persistent Lyme by both PCR and culture, the “gold standard” for proving chronic infection.

The issue of persistence and "persister" bacteria has been proven in the scientific literature for both Lyme and other diseases. There are many potential mechanisms to explain persistence of borrelia after standard antibiotic therapies, including gene recombination, where borrelia can modify its surface antigen VlsE, and non-expressed vls, in gene cassettes, creating different outer surface antigens, helping to avoid immune recognition (Variable VlsE Is Critical for Host Reinfection by the Lyme Disease Spirochete. Rogovskyy AS, et al. PLoS ONE 8(4): e61226. http://dx.doi.org/10.1371/journal.pone.0061226) as well as recent studies that have identified a number of genes and pathways that shed light on the mechanisms of persister formation or survival. Persisters are a small fraction of quiescent bacterial cells that survive lethal antibiotics but can re grow leading to post-treatment relapse. Examples include TB, syphilis, endocarditis, brucellosis, and biofilm infections (including Lyme disease). Mechanisms of persistence also include toxin–antitoxin molecules, DNA repair or protection, phosphate metabolism, anti-oxidative defense and macromolecule degradation (Persisters, persistent infections and the Yin–Yang model, Ying Zhang; Emerging Microbes and Infections (2014) 3, e3; doi:10.1038/emi.2014.3). Some of the newer drug regimens identified by Dr Ying Zhang from John Hopkins University may also have greater efficacy in combination and in sequential treatments (Feng J, Auwaerter PG, Zhang Y (2015) Drug Combinations against Borrelia burgdorferi Persisters In Vitro: Eradication Achieved by Using Daptomycin, Cefoperazone and Doxycycline. PLoS ONE 10(3): e0117207. doi:10.1371/journal.pone.0117207). The recent article published in Antimicrobial Agents and Chemotherapy by Sharma, also discusses how borrelia can form  drug-tolerant persister cells, and how pulsing antibiotics may help improve clinical outcomes (Antimicrobial Agents And Chemotherapy, pii: AAC.00864-15. Online first, 2015 May 26.http://doi.org/10.1128/AAC.00864-15).

In conclusion, the scientific literature shows: unreliable blood tests, persistence of borrelia despite short term treatment, with peer reviewed clinical trials demonstrating the benefit of longer term antibiotic therapies. The science however is still not completely settled regarding how to best diagnose and treat complex patients who have failed classical therapies. For example, we don't know which pulse therapies with which antibiotics may have the greatest efficacy in eliminating the infection.  I have had success however treating the majority of chronic Lyme patients with the diagnostic and treatment recommendations discussed in my book "Why Can't I Get Better? Solving the Mystery of Lyme and Chronic Disease", using the 16 point MSIDS diagnostic model. There are hundreds of peer reviewed scientific studies in the reference section backing up the MSIDS approach, starting on page 487-514 of my book, and these should be reviewed by health care providers trying to understand how to best help their patients. I am presently doing studies in my office evaluating some of the newer treatment recommendations, to see if they will provide further benefit for those suffering with persistent illness. It is therefore incumbent on health care providers to review the past and present scientific research, and use their best clinical judgment in treating their patients. It is also incumbent on the IDSA panel to review up to date scientific literature, without conflicts of interest, so that we have guidelines that can be relied upon to help the millions suffering with diagnosed and undiagnosed tick-borne diseases. http://www.poughkeepsiejournal.com/story/news/local/2015/05/30/lyme-disease-panel-charged-biased/28218615/

6/1/15 Review of Lyme disease treatment leaves out patients, Mary Beth Pfeiffer, Poughkeepsie Journal

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