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czwartek, 17 października 2019

The Long-Term Persistence of Borrelia burgdorferi Antigens and DNA in the Tissues of a Patient with Lyme Disease

 https://www.mdpi.com/2079-6382/8/4/183/htm?fbclid=IwAR31zncs0VpYET06UT_HTaIinPjJAOCDjxcFJ9e_XKRSN_NoxAwM5X2bwL0

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 Dr.Horowitz - Facebook 

Dr Sapi i jej grupa właśnie opublikowali artykuł na temat przetrwania boreliozy i roli przetrwałych i stacjonarnych form biofilmu u pacjenta poddanego długotrwałej antybiotykoterapii.

Oto przegląd nauki:
Przeglądana literatura medyczna pokazuje przewlekłe i uporczywe zakażenie Borrelia pomimo intensywnych antybiotyków:


• 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, R.I.; Freeman, P.R. Precision Medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1. International Journal of General Medicine 2019:12 101–119
https://www.dovepress.com/articles.php?article_id=44148
• 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 Au-genheilkd 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 Dis-ease. 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
• Embers ME, Hasenkampf NR, et al. (2017) Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS ONE 12(12): e0189071. https://doi.org/10.1371/journal.pone.0189071
Chronic persistent infection with Bb despite intensive antibiotics was also proven in three recent Xenodiagnostics studies. The first and second was in mice and macaques:
• 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
• Embers ME, Hasenkampf NR, et al. (2017) Variable manifestations, diverse seroreactivity and post-treatment persistence in non-human primates exposed to Borrelia burgdorferi by tick feeding. PLoS ONE 12(12): e0189071. https://doi.org/10.1371/journal.pone.0189071
In this study, “Persistence of B. burgdorferi was evaluated using xenodiagnosis, bioassays in mice, multiple methods of molecular detection, immunostaining with polyclonal and monoclonal antibodies and an in vivo culture system. Our results demonstrate host-dependent signs of infection and variation in antibody responses. In addition, we observed evidence of persistent, intact, metabolically-active B. burgdorferi after antibiotic treatment of disseminated infection and showed that persistence may not be reflected by maintenance of specific antibody production by the host”.
In humans, a recent NIH xenodiagnostic 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).
A recent study published by Middelveen et al also proved persistence of borrelia by culture, pathology and molecular testing after standard antibiotic therapy in patients with ongoing symptoms of Lyme disease:
• Persistent Borrelia Infection in Patients with Ongoing Symptoms of Lyme Disease. Marianne J. Middelveen, Eva Sapi ID , Jennie Burke, Katherine R. Filush, Agustin Franco,
Melissa C. Fesler and Raphael B. Stricker. Healthcare 2018, 6, 33; doi:10.3390/healthcare6020033
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. 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 Eng-land 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 clini-cally 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
These trials also did not address the multifactorial causes of chronic illness, including the role of associated co-infections and abnormalities on the 16-point MSIDS map, published in the peer-reviewed literature to have an effect on the outcome of patients suffering with chronic Lyme disease/PTLDS:
Conclusion from Horowitz, R.I., Freeman, PR. Precision medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1. https://www.ncbi.nlm.nih.gov/pubmed/30863136
https://www.dovepress.com/precision-medicine-retrospective-…
“Many of our patients infected with Lyme disease and associated coinfections had severe symptoms, often relapsed with commonly used therapies, and did not present with an EM rash nor meet the CDC two-tiered surveillance criteria. Almost two-thirds of patients had been exposed to between five and eight infections/coinfections and 14.5% of patients were PCR positive for B. burgdorferi despite seem-ingly
“adequate” antibiotic therapy for months or years prior to DDS therapy (N=29, 14.5%). Evidence of persistent infection with HHV6, Bartonella, and/or Mycoplasma was also confirmed by PCR in several patients, although many in our study had evidence of other medical problems accounting for ongoing symptoms. These included associated immune dysfunction/immune deficiency, inflammation, environ-mental
toxins with detoxification problems, GI problems, allergies, nutritional deficiencies, hormone, and autonomic nervous system dysregulation as well as sleep and psychiatric disorders in those suffering with post treatment Lyme symptoms. None of these factors had been addressed in the three prior NIH randomized controlled Lyme trials, nor the European PLEASE trial and could explain in part why patients remained ill. Many patients with late Lyme disease in those trials failed conventional beta lactam, tetracycline, macrolide, or other antibiotic therapies even if given for 4–6 weeks.
International Journal of General Medicine downloaded from https://www.dovepress.com/ by 148.74.180.43 on 19-Feb-2019. Dovepress 115 Horowitz and Freeman, 2019.
Nevertheless, two of the three clinical trials demonstrated that retreatment improved some patients’ measures, such as fatigue and pain (Krupp, Fallon) using older antibiotic protocols that did not address the role of biofilm microcolonies/persister forms. Other studies 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)  715-9→ 30 pts w/ chronic Lyme disease were treated for 100 days, and 90% had good or excellent responses
• 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 treat-ment 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.
During the past several years, newer peer-reviewed scientific publications by Dr Horowitz and other researchers have shown that borrelia can act as a “persister” bacteria, like TB and leprosy, due in part to biofilms protecting the organism, as well as dormant forms not killed by standard antibiotic protocols. In 2016, Dr Horowitz published the first statistically validated oral “persister” protocol for Lyme disease, based on scientific research from Johns Hopkins University and Dr Kim Lewis’s lab at Northeastern University. The list below references some of the most recent scientific articles on the ability of Borrelia burgdorferi to persist in biofilms and stationary ‘persister forms’:
• Persisters, persistent infections and the Yin–Yang model, Ying Zhang; Emerging Microbes and Infections (2014) 3, e3;
• Feng, J, Zhang, Y. et al. Stationary Phase Persister/Biofilm Microcolony of Borrelia burgdorferi Causes More Severe Disease in a Mouse Model of Lyme Arthritis: Implications for Understand-ing Persistence, Post-Treatment Lyme Disease Syndrome (PTLDS), and Treatment Failure. Pub-lished in Discovery Medicine on March 28, 2019. http://www.discoverymedicine.com/…/persister-biofilm-micro…/
• Rudenko, N. et al. Metamorphoses of Lyme disease spirochetes: phenomenon of Borrelia persisters. Parasites Vectors (2019) 12:237. https://doi.org/10.1186/s13071-019-3495-7
• Zhang, Y (2015) Drug Combinations against Borrelia burgdorferi Persisters In Vitro: Eradication Achieved by Using Daptomycin, Cefoperazone and Doxycycline. PLoS ONE 10(3): e0117207
• Identification of new compounds with high activity against stationary phase Borrelia burgdorferi from the NCI compound collection. Zhang, Y. Emerging Microbes and Infections (2015) 4, e31
• Lewis K. Persister cells, dormancy and infectious disease. Nature Rev Microbiol. 2007; 5 (1): 48–56. doi:10.1038/nrmicro1557. PMID 17143318.
• Horowitz RI, Freeman PR. The use of dapsone as a novel “persister” drug in the treatment of chronic Lyme disease/post treatment Lyme disease syndrome. J Clin Exp Dermatol Res. 2016;7:345.
• Horowitz, R.I.; Freeman, P.R. Precision Medicine: retrospective chart review and data analysis of 200 patients on dapsone combination therapy for chronic Lyme disease/post-treatment Lyme disease syndrome: part 1. International Journal of General Medicine 2019:12 101–119
• https://www.dovepress.com/articles.php?article_id=44148
• Horowitz RI, Freeman PR Are Mycobacterium Drugs Effective for Treatment Resistant Lyme Disease, Tick-Borne Co-Infections, and Autoimmune Disease? JSM Arthritis(2016) 1(2): 1008.
The complexity and effectiveness of treating Lyme disease with a broad-based treatment model and using persister drug regimens was also highlighted in the journal Healthcare in 2018:
• Horowitz, R.I.; Freeman, P.R. Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2. Healthcare 2018, 6, 129. https://www.ncbi.nlm.nih.gov/pubmed/30400667
PDF Version: http://www.mdpi.com/2227-9032/6/4/129/pdf
In conclusion, the scientific literature shows persistence of borrelia despite short term treatment, and peer reviewed clinical trials showing benefit of using longer term antibiotic therapies. It is therefore incumbent on the physician to use their best clinical judgment in treating their patients. Lyme and associated tick-borne diseases are spreading in the United States and worldwide, increasing health care costs, causing disability and widespread suffering. It is essential to update treatment guidelines based on the above referenced peer-reviewed science, especially as we now have 2 peer reviewed publications involving 300 patients who have undergone dapsone combination therapy successfully for treatment resistant illness.
I will be speaking at the Mt. Sinai LymeMind conference on Oct 19th in NYC and discuss brand new in vivo research (paper in peer review) showing the efficacy of dapsone combination therapy in culture against the resistant forms of Borrelia burgdorferi. This work helps confirm the clinical success that we have been seeing in our patients. My wife is almost 2 years out from the protocol and still in remission, and I saw another young man in our medical office a few days ago who just finished the double dose dapsone protocol and was well for the first time in years.
We are getting close to a durable solution for those who have been chronically ill, and biofilm and persister forms are definitely playing a role based on the research and outcomes of our clinical studies and those of other researchers.
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