David J. Volkman

Amoxycillin plus probenecid versus doxycycline for treatment of erythema migrans borreliosis

72 adults with erythema migrans (early Lyme borreliosis) were enrolled in a randomised prospective trial comparing amoxycillin 500 mg plus probenecid 500 mg three times a day with doxycycline 100 mg twice a day for 21 days. These antibiotic regimens were chosen because of the known in-vitro sensitivity of Borrelia burgdorferi, the antibiotic tissue penetration, the pharmacokinetics of the drugs, and because the organism can disseminate early in the course of infection. 72 patients were evaluable (35 in the doxycycline group and 37 in the amoxycillin/probenecid group). The two regimens were equally effective for treatment of erythema migrans. Mild fatigue or arthralgia were the only post-treatment complaints, which resolved within 6 months. None of the patients needed further antibiotic treatment for Lyme borreliosis.

New chemotherapeutic approaches in the treatment of Lyme borreliosis.

1. It was demonstrated that while B. burgdorferi may be sensitive to relatively small concentrations of penicillin and ceftriaxone, the organism is killed slowly. This implies that, as in syphilis, prolonged blood levels of these drugs may be necessary in order to ensure cure. In contrast, the activity of tetracycline is more rapid in its action but is more dependent on drug concentration achieved. Unfortunately, the MIC and MBC for some strains are at or above the peak level achieved under optimal conditions. 2. Increasing the concentrations of penicillin or ceftriaxone above the MIC for the organism has little effect on the rate of killing. In contrast, the killing by tetracycline can be augmented by increasing concentrations of the drug. 3. Ceftriaxone is more active than penicillin, as measured by MIC, against the five strains of B. burgdorferi tested. 4. Ceftriaxone was efficacious in the treatment of Lyme borreliosis, which was recalcitrant to penicillin therapy. In a randomized trial comparing ceftriaxone to high-dose penicillin therapy, ceftriaxone was significantly more efficacious than penicillin in the treatment of the late complications of Lyme borreliosis.

Modulation of Natural Killer Cell Activity by Borrelia burgdorferi

Natural killer (NK) cells are a heterogenous subpopulation of peripheral blood lymphocytes (PBL) that have the ability to kill various tumors and tumor cell lines in the absence of prior sensitization. These cells have generated considerable interest and have been implicated in natural resistance to tumors,-5 resistance to viral infection:-7 transplantation rejection,** and immunoregulation of both T and B cells.e Recently, there has been evidence that NK cells or large granular lymphocytes (LGLs) are also involved in host resistance against bacterial infections. This has been demonstrated by the bactericidal activity of NK-like cells against certain bacteria such as Shigella and Salrn~nel la . ~~ In addition to these interactions, there are several reports that demonstrate bacterial activation and/or recruitment of NK and NK-like cells presumably through the production or action of interferon, interleukin-2, and/or lipopolysaccharide (LPS).z*68 Under certain conditions this augmentation may be inhibited by LPS,I7 which attests to the complex nature of the microorganism-host interactions. Furthermore, the NK cell killing of infected host cellsI5 or local inflammation secondary to the killing of extracellular microorganisms may be responsible for the tissue destruction seen in various bacterial infections. The humoral and cellular responses in Lyme borreliosis have recently been under active investigation. While the humoral antibody response to Borrelia burgdorferi is well characterized, the cellular immune response is not well defined. However, it is known that a strong specific T cell response to B. burgdorferi occurs early in the course of the disease. This response may even precede the development of a measurable antibody response in some cases.I9 Once established, this response is long lasting. In this report, the cellular immune response to B. burgdorferi is further investigated. Specifically, the modulation of NK cells and N K cell activity by B. burgdorferi both in vivo and in vitro is characterized and discussed.

Comment on: Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis

Sir, The recent article by Warshafsky et al. may encourage the use of single-oral-dose doxycycline for tick-bite prophylaxis, which in my opinion and in the light of other evidence, is likely to be ineffective. The recommendation for single-dose prophylaxis was first made by Nadelman et al. in 2001 as a result of a randomized controlled trial in 482 patients and was included in the Infectious Diseases Society of America’s (IDSA’s) guidelines for the treatment of Lyme disease. Three of the authors of the Nadelman et al. article were also authors of the IDSA guidelines. In their original article, Nadelman et al. showed that their single-dose regimen was 87% effective in blocking both the erythema migrans (EM) and the appearance of anti-Borrelia antibodies expected with borreliosis, but they did not show that it blocked actual infection in the antibiotic recipients. This is analogous to observations made in the 1950s that low-dose penicillin blocked cutaneous lesions of syphilis in rabbits but not the infection. The study by Nadelman et al. did not comment on complaints of fever and flu-like illness and limited its follow-up to 6 weeks instead of the 1–2 years used in other studies and no normal control group was used to compare the incidence of fever and flu-like illness with that of the treated/placebo groups. However, investigators at the CDC in Fort Collins, Colorado, showed that 80% of newly infected mice treated with a comparable single oral dose of doxycycline developed persistent borreliosis, which was found by grinding up tissues and using culture and PCR for bacterial detection. The sera from these mice were discarded without testing for anti-Borrelia antibodies so we do not know if they remained seronegative despite proven infection. Not surprisingly when the same criteria are used in the recent meta-analysis a similar result is obtained, i.e. a single oral dose blocks both EM and antibodies. By promoting this potentially flawed recommendation, the authors and the IDSA may actually promote persistent borreliosis that will be seronegative, and therefore difficult to diagnose. Transparency declarations

Seronegative disease after inadequate therapy in lyme arthritis: Comment on the article by Kannian et al

associated vasculitis, the title is misleading. This highlights one of the many problems with the terminology “ANCA-associated vasculitis” and the advantages of considering these as separate diseases, particularly within therapeutic trials. We do not think that these data lend any additional support for the use of IVIGs in WG and MPA. Although randomized, double-blind, controlled studies would be needed to determine effectiveness, the available data raise questions as to whether IVIG treatment warrants additional investigation in place of emerging therapies.

Production of phagocytosis-inducing factor and expression of 4B4 antigen by cloned human T cells before and after transformation with HTLV-I

The characteristics of 4 T-cell clones, each capable of producing phagocytosis-inducing factor (PIF), were compared before and after transformation with human T-lymphotropic virus Type 1 (HTLV-I). Before transformation, the four clones produced PIF transiently after stimulation with antigen or mitogen and expressed the phenotype T3(CD3)+, T4(CD4)+, T8(CD8)-, 4B4+, and 2H4-; the three clones that could be studied also expressed the OKT17 marker. After transformation, the cells expressed the same phenotypic markers, except for two clones that lost the CD3 antigen. The clones that were available for study before and after transformation also expressed the antigen detected by the monoclonal antibody 5/9. In addition, all clones secreted PIF constitutively after transformation. These characteristics of the four transformed T-cell clones closely resembled those of three long-term HTLV-I-transformed T-cell lines, HUT-102, C5/MJ, and MT-2, which also produced PIF constitutively and expressed the CD4 and 4B4, but not 2H4, markers. In addition, two other HTLV-I-transformed lines generated in the present study produced PIF constitutively. Since all nine HTLV-I transformed cell lines and all four untransformed clones secreted PIF, and since our previous studies have shown that only approximately 20% of CD4+ peripheral blood lymphocytes secrete PIF, these results suggest that HTLV-I may preferentially transform PIF-secreting CD4+ lymphocytes. The predominant 4B4+, 5/9+, 2H4- phenotype (characteristic of antigen-responsive T cells) of the untransformed and transformed clones as well as the long-term HTLV-I-transformed lines also suggests that the subset of CD4+ lymphocytes that proliferates in response to soluble antigen may be especially susceptible to transformation with this virus.

Letter to the Editor re “Anti-neural antibody reactivity in patients with a history of Lyme borreliosis and persistent symptoms” by Chandra et al.

To the Editor Chandra’s article Chandra et al., in press is an elegant demonstration of similar immunologic phenomena that have been previously observed in humans, i.e., auto-antibodies are produced in response to tissue damage De Scheerder et al., 1985. Borrelia invades the central nervous system (CNS), stimulates the CNS immune system Halperin et al., 1989, and elicits intrathecal antiborrelia antibodies. However, claiming that the post Lyme Syndrome (PLS) is caused by these antibodies is far from proven in a time when we emphasis ‘‘evidence based medicine”. Borrelia DNA has been isolated from the CNS of PLS patients Keller et al., 1992 and persistent borrelia infection is a well established possibility Barthold et al., 2010. After extensive antibiotic therapy borrelia becomes difficult to isolate Barthold et al., 2010. The mere presence of cross-reactive anti-borrelia antibodies in PLS patients does not establish these antibodies as the etiologic agents of PLS. Nor can a potential role of persistent borrelia infection be dismissed ex cathedra as ‘‘currently not thought to account for the symptoms”. The failure to isolate ‘‘live spirochetes” in PLS patients does not exclude their presence. Barthold et al. (2010) was forced to use several arduous techniques including xeno-transplants to visualize borrelia in antibiotic treated mice. Since the recommendation that a CDC five band Western Blot (WB) serologic criteria be used for the diagnosis Lyme Disease (LD). LD has been under reported and under recognized. In Georgia there were 714 CDC cases reported in 1989 but only 11 in 2007. Untreated borrelia infection in the spring may lead to frank arthritis in the fall.