TICK-BORNE ILLNESS SYMPTOMS, TESTING, AND DIAGNOSIS

Lyme borreliosis

Steere AC, Strle F, Wormser GP, Hu LT, Branda JA, Hovius JW, Li X, Mead PS.
Nature Reviews Disease Primers. 2016 Dec 15;2:16090 https://www.ncbi.nlm.nih.gov/pubmed/27976670
Lyme borreliosis is a tick-borne disease that predominantly occurs in temperate regions of the northern hemisphere and is primarily caused by the bacterium Borrelia burgdorferi in North America and Borrelia afzelii or Borrelia garinii in Europe and Asia. Infection usually begins with an expanding skin lesion, known as erythema migrans (referred to as stage 1), which, if untreated, can be followed by early disseminated infection, particularly neurological abnormalities (stage 2), and by late infection, especially arthritis in North America or acrodermatitis chronica atrophicans in Europe (stage 3).
However, the disease can present with any of these manifestations.

Chronic Lyme Disease: A Working Case Definition
Stricker RB and Fesler MC
International Lyme & Associated Diseases Society, Bethesda, MD; Union Square Medical Associates, San Francisco, CA, USA
http://austinpublishinggroup.com/chronic-diseases/online-first.php
Although Lyme disease is the most common tickborne illness in the USA and Eurasia, the pathophysiology and clinical course of chronic Lyme disease (CLD) have not been formally defined. The purpose of this paper is to present a working case definition of CLD based on analysis of more than 700 peerreviewed publications. According to this definition, CLD is a multisystem illness with diverse musculoskeletal, neuropsychiatric and/or cardiovascular manifestations that result from ongoing infection with pathogenic members of the Borrelia spirochete complex often associated with other tickborne disease (TBD) pathogens. To qualify for the diagnosis of CLD, patients must have Lymecompatible symptoms and signs that are either consistently or variably present for six or more months. Two subcategories of CLD include untreated chronic Lyme disease (CLD-U) and chronic Lyme disease following a limited course of antibiotic treatment (CLD-T). The symptom patterns and optimal therapy of CLD require further study.

Diagnostic challenges of early Lyme disease: Lessons from a community case series
John Aucott, Candis Morrison, Beatriz Munoz, Peter C Rowe, Alison Schwarzwalder and Sheila K West
BMC Infectious Diseases20099:79 Published: 01 June 2009
https://doi.org/10.1186/1471-2334-9-79©
The majority (61%) of patients in this case series were diagnosed with early Lyme disease. Of those diagnosed with early Lyme disease, 13% did not present with erythema migrans; of those not presenting with a rash, 54% had been previously misdiagnosed. Among those with a rash, the diagnosis of erythema migrans was initially missed in 23% of patients whose rash was subsequently confirmed. Of all patients previously misdiagnosed, 41% had received initial antibiotics likely to be ineffective against Lyme disease.

“Proof That Chronic Lyme Disease Exists,”
Interdisciplinary Perspectives on Infectious Diseases, vol. 2010 Article ID 876450, 4 pages, 2010. doi:10.1155/2010/876450
Daniel J. Cameron
http://www.hindawi.com/journals/ipid/2010/876450.html
The evidence continues to mount that Chronic Lyme Disease (CLD) exists and must be addressed by the medical community if solutions are to be found. Four National Institutes of Health (NIH) trials validated the existence and severity of CLD. Despite the evidence, there are physicians who continue to deny the existence and severity of CLD, which can hinder efforts to find a solution. Recognizing CLD could facilitate efforts to avoid diagnostic delays of two years and durations of illness of 4.7 to 9 years described in the NIH trials.The risk to society of emerging antibiotic-resistant organisms should be weighed against the societal risks associated with failing to treat an emerging population saddled with CLD. The mixed long-term outcome in children could also be examined. Once we accept the evidence that CLD exists, the medical community should be able to find solutions. Medical professionals should be encouraged to examine whether: (1) innovative treatments for early LD might prevent CLD, (2) early diagnosis of CLD might result in better treatment outcomes, and (3) more effective treatment regimens can be developed for CLD patients who have had prolonged illness and an associated poor quality of life.

Severity of chronic Lyme disease compared to other chronic conditions: a quality of life survey.
Johnson L, Wilcox S, Mankoff J, Stricker RB. (2014) PeerJ 2:e322.
http://dx.doi.org/10.7717/peerj.322
Compared to the general population and patients with other chronic diseases reviewed here, patients with CLD reported significantly lower health quality status, more bad mental and physical health days, a significant symptom disease burden, and greater activity limitations. They also reported impairment in their ability to work, increased utilization of healthcare services, and greater out of pocket medical costs.

The Clinical, Symptom, and Quality-of-Life Characterization of a Well-Defined Group of Patients with Posttreatment Lyme Disease Syndrome
Rebman AW, Bechtold KT, Yang T, Mihm EA, Soloski MJ, Novak CB, Aucott JN.
Frontiers in Medicine (Lausanne). 2017 Dec 14;4:224.
https://doi.org/10.3389/fmed.2017.00224
Although physical exam and clinical laboratory tests showed few objective abnormalities, standardized symptom questionnaires revealed that patients with PTLDS are highly and clinically significantly symptomatic, with poor health-related quality of life. PTLDS patients exhibited levels of fatigue, musculoskeletal pain, sleep disturbance, and depression which were both clinically relevant and statistically significantly higher than controls. Our study shows that PTLDS can be successfully identified using a systematic approach to diagnosis and symptom measurement. As the prevalence of PTLDS continues to rise, there will be an increased need for physician education to more effectively identify and manage PTLDS as part of integrated patient care.

Lyme Disease (Borrelia burgdorferi) 2017 Case Definition
Centers for Disease Control and Prevention, Council of State and Territorial Epidemiologists (CSTE) Position Statement(s)
Source: https://wwwn.cdc.gov/nndss/conditions/lyme-disease/case-definition/2017/ Clinical Description
A systemic, tick-borne disease with protean manifestations, including dermatologic, rheumatologic, neurologic, and cardiac abnormalities. The most common clinical marker for the disease is erythema migrans (EM), the initial skin lesion that occurs in 60%-80% of patients.

Lyme disease and post-treatment Lyme disease syndrome: the neglected disease in our own backyard
L.A. Crowder, V.A. Yedlin, E.R. Weinstein, K.B. Kortte, J.N. Aucott
Public Health, online before print Septtember 9, 2014.
http://doi.org/10.1016/j.puhe.2014.06.016
A 15% response rate was seen for the survey. 50% of respondents were from Lyme endemic states. Less than 5% of faculty members consider themselves expert in Lyme or PTLDS. Many faculty members had known someone with Lyme disease or PTLDS, but few had been diagnosed themselves. Most believe that PTLDS can be severe and chronic, is not easy to treat, and does not resolve on its own, but were uncertain about its aetiology. Most respondents also felt that the incidence of Lyme disease will increase and that more education is needed.

Evaluating polymicrobial immune responses in patients suffering from tick-borne diseases
Kunal Garg, Leena Meriläinen, Ole Franz, Heidi Pirttinen, Marco Quevedo-Diaz, Stephen Croucher & Leona Gilbert
Scientific Reportsvolume 8, Article number: 15932 (2018)
https://www.nature.com/articles/s41598-018-34393-9
Four hundred and thirty-two human serum samples organized into seven categories followed Centers for Disease Control and Prevention two-tier Lyme disease (LD) diagnosis guidelines and Infectious Disease Society of America guidelines for post-treatment Lyme disease syndrome. All patient categories were tested for their immunoglobulin M (IgM) and G (IgG) responses against 20 microbes associated with TBD. Our findings recognize that microbial infections in patients suffering from TBDs do not follow the one microbe, one disease Germ Theory as 65% of the TBD patients produce immune responses to various microbes. We have established a causal association between TBD patients and TBD associated co-infections and essential opportunistic microbes following Bradford Hill’s criteria. This study indicated an 85% probability that a randomly selected TBD patient will respond to Borrelia and other related TBD microbes rather than to Borrelia alone. A paradigm shift is required in current healthcare policies to diagnose TBD so that patients can get tested and treated even for opportunistic infections.

New Insights Into Stages of Lyme Disease Symptoms From a Novel Hospital-Based Registry
Jessika Lobraico, Amber Butler, Joann Petrini, Ramin Ahmadi
Journal of Primary Care and Community Health, October 2014, vol. 5, no. 4, 284-287. http://doi.org/10.1177/2150131914540693
The Lyme Disease Registry has enrolled 256 participants, 24% are acute cases, 45% are persistently symptomatic cases, and 31% are recovered cases. The symptoms experienced by the group of patients with persistent symptoms had unexpectedly strong overlap with those experienced by acutely infected patients.The difference between symptoms in the acutely infected patients and those experiencing persistent symptoms is not as large as initially thought.

Accuracy of Clinician Suspicion of Lyme Disease in the Emergency Department
Nigrovic LE, Bennett JE, Balamuth F, Levas MN, Chenard RL, Maulden AB, Garro AC; for Pedi Lyme Net.
Pediatrics, online first 2017 Nov 24. pii: e20171975.
https://doi.org/10.1542/peds.2017-1975
We enrolled 1021 children with a median age of 9 years (interquartile range, 5–13 years). Of these, 238 (23%) had Lyme disease. Clinician suspicion had a minimal ability to discriminate between children with and without Lyme disease: area under the curve, 0.75 (95% confidence interval, 0.71–0.79). Of the 554 children who the treating clinicians thought were unlikely to have Lyme disease (score 1–3), 65 (12%) had Lyme disease, and of the 127 children who the treating clinicians thought were very likely to have Lyme disease (score 8–10), 39 (31%) did not have Lyme disease.

The Accuracy of Diagnostic Tests for Lyme Disease in Humans, A Systematic Review and Meta-Analysis of North American Research.
Waddell LA, Greig J, Mascarenhas M, Harding S, Lindsay R, Ogden N.
PLoS One. 2016 Dec 21;11(12):e0168613.
http://doi.org/10.1371/journal.pone.0168613
There has been an increasing incidence of Lyme disease (LD) in Canada and the United States corresponding to the expanding range of the Ixodes tick vector and Lyme disease agent (Borrelia burgdorferi sensu stricto). There are many diagnostic tests for LD available in North America, all of which have some performance issues, and physicians are concerned about the appropriate use and interpretation of these tests. The objective of this systematic review is to summarize the North American evidence on the accuracy of diagnostic tests and test regimes at various stages of LD.

To test or not to test? Laboratory support for the diagnosis of Lyme borreliosis
Horowitz R, Lacout A, Marcy PY, Perronne C.
Clinical Microbiology and Infection, online first, 2017 Oct 10.
https://doi.org/10.1016/j.cmi.2017.09.015
Formal serology in patients presenting with presumptive Lyme disease symptoms is not sufficient to definitively rule out Lyme disease. A broader laboratory panel approach such as including a polymerase chain reaction (PCR) or ELISPOT test can be more sensitive and specific. The search for an antibody intrathecal production may not be essential to the diagnosis in some neuroboreliosis cases (peripheral neuropathy).

Erythema Migrans: A Spectrum of Histopathologic Changes
Wilson, Thomas C.; Legler, Allison; Madison, Kathi C.; Fairley, Janet A.; Swick, Brian L.
American Journal of Dermatopathology, online before print, 20 June 2012
http://dx.doi.org/10.1097/DAD.0b013e31825879be
Herein, we describe 4 cases of erythema migrans, all biopsied at the periphery of the lesion and confirmed by serologic studies, demonstrating a variety of unconventional histopathologic patterns.

Atypical erythema migrans in Patients with PCR-positive Lyme disease
Schutzer SE, Berger BW, Krueger JG, Eshoo MW, Ecker DJ, Aucott JN.
Emerging Infectious Diseases, Volume 19, No. 5, May 2013.
http://dx.doi.org/10.3201/eid1905.120796
The best diagnostic sign in patients with early Lyme disease is a skin lesion, erythema migrans (EM). However this sign may not occur or be recognized in 30% of cases. Furthermore, the EM rash may not display a classic bull’s-eye (ring-within-a-ring) appearance, a fact that may be underappreciated. Some studies noted uncharacteristic variants of EM in 25% – 30% of cases. One study reported the rash to be uniformly red in 60% of cases. Other atypical variants of EM are a blue-red appearance and, occasionally, a vesicular central region. We describe the occurrence of atypical EM in patients with microbiologically proven Borrelia burgdorferi infection.

Vesicular erythema migrans: an atypical and easily misdiagnosed form of Lyme disease
Mazori, Daniel R; Orme, Charisse M; Mir, Adnan; Meehan, Shane A; & Neimann, Andrea L. (2015).
Dermatology Online Journal, 21(8). doj_28428.
http://escholarship.org/uc/item/9cs1x7r5
Erythema migrans is the initial sign in the majority of patients infected with Borrelia, the genus of spirochetes that causes Lyme disease. Early identification and treatment decrease the risk of progression to later stages of disease. Although a “bull’s eye” appearance owing to lesional clearing is considered classic for erythema migrans, this feature is surprisingly often lacking among patients in the United States.

The Many Masks of Cutaneous Lyme Disease
Miraflor AP, Seidel GD, Perry AE, Castanedo-Tardan MP, Guill MA, Yan S.
Journal of Cutaneous Pathology, online first, 2015 Sep 8.
http://doi.org/10.1111/cup.12620
Early cutaneous Lyme disease, erythema migrans, may show different histopathologic patterns. The intent of this case series is to raise awareness of these findings to prevent misdiagnosis and keep this entity in the differential.

Early Lyme disease: a flu-like illness without erythema migrans.
Feder HM Jr, Gerber MA, Krause PJ, Ryan R, Shapiro ED.
http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=8424027&ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum
The existence of a form of early Lyme disease characterized by a flu-like illness without erythema migrans is controversial. To confirm the existence and define the clinical characteristics of the flu-like illness without erythema migrans of localized Lyme disease, the authors studied patients from a Lyme disease endemic area of Connecticut who visited their primary care physicians with an undefined flu-like illness. Patients kept a diary of their symptoms. Acute and convalescent sera were obtained. The diagnosis of Lyme disease was based on the appearance of IgM or IgG antibodies to Borrelia burgdorferi as demonstrated by both enzyme-linked immunosorbent assay and immunoblot assay. Twenty-four untreated patients were studied. In five patients acute serologic evidence of Lyme disease developed. The flu-like illness in these five patients was characterized by fever and fatigue and resolved spontaneously in 5 to 21 days. Symptoms recurred in three of these five patients. The existence of a flu-like illness without erythema migrans of early Lyme disease has been clearly established. Prospective, controlled studies are needed to better define its incidence, characteristics, and prognosis so that appropriate diagnostic and therapeutic strategies can be developed.

Lyme Disease: Beyond Erythema Migrans
Allen HB, Vin H, Warner C, Joshi S.
Journal of Clinical & Experimental Dermatology Research, 7:2; Online first, February 22, 2016.
http://dx.doi.org/10.4172/2155-9554.1000330
Background: With the recent discoveries of Borrelia burgdorferi and other spirochetes in the brains of Alzheimer’s patients and with a recent analysis showing the very same pathology in both syphilitic and Alzheimer’s dementia it seems both rational and urgent to consider all aspects of Lyme disease in a new light, especially the concept of “overdiagnosis”. The very presence of the organisms in the brains following supposedly effective treatment for Lyme disease is contradictory and should be the starting point for diagnosis and treatment. Also for consideration is the reliance on erythema migrans and serologies in the diagnosis of Lyme disease inasmuch as they occur in less than half the patients.

Gender Disparity between Cutaneous and Non-Cutaneous Manifestations of Lyme Borreliosis.
Strle F, Wormser GP, Mead P, Dhaduvai K, Longo MV,Adenikinju O, Soman S, Tefera Y, Maraspin V, Lotric-Furlan S, Ogrinc K, Cimperman J, Ruzic-Sabljic E, Stupica D.
PLoS One. 2013 May 30;8(5):e64110.
http://dx.doi.org/10.1371/journal.pone.0064110
In conclusion, patients with cutaneous manifestations of Lyme borreliosis were predominantly female, whereas those with non-cutaneous manifestations were predominantly male. This provocative finding is unexplained but may have direct relevance to the pathogenesis of Lyme borreliosis.

Differential Diagnosis and the Suspension of Judgment
Ashley Graham Kennedy
Journal of Medicine and Philosophy, online before print 29 August 2013.
http://doi.org/10.1093/jmp/jht043
In this paper I argue that ethics and evidence are intricately intertwined within the clinical practice of differential diagnosis. Too often, when a disease is difficult to diagnose, a physician will dismiss it as being “not real” or “all in the patient’s head.” This is both an ethical and an evidential problem. In the paper my aim is two-fold. First, via the examination of two case studies (late-stage Lyme disease and Addison’s disease), I try to elucidate why this kind of dismissal takes place. Then, I propose a potential solution to the problem. I argue that instead of dismissing a patient’s illness as “not real,” physicians ought to exercise a compassionate suspension of judgment when a diagnosis cannot be immediately made. I argue that suspending judgment has methodological, epistemic, and ethical virtues and therefore should always be preferred to patient dismissal in the clinical setting.

Empirical validation of the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire for suspected Lyme disease
Citera M, Freeman PR, Horowitz RI
International Journal of General Medicine, online first 4 September 2017.
https://doi.org/10.2147/IJGM.S140224
Lyme disease is spreading worldwide, with multiple Borrelia species causing a broad range of clinical symptoms that mimic other illnesses. A validated Lyme disease screening questionnaire would be clinically useful for both providers and patients. Three studies evaluated such a screening tool, namely the Horowitz Multiple Systemic Infectious Disease Syndrome (MSIDS) Questionnaire. The purpose was to see if the questionnaire could accurately distinguish between Lyme patients and healthy individuals. The results consistently demonstrated that the HMQ accurately differentiated those with Lyme disease from healthy individuals. Three migratory pain survey items (persistent muscular pain, arthritic pain, and nerve pain/paresthesias) robustly identified individuals with verified Lyme disease. The results support the use of the HMQ as a valid, efficient, and low-cost screening tool for medical practitioners to decide if additional testing is warranted to distinguish between Lyme disease and other illnesses.

Borrelia burgdorferi tissue morphologies and imaging methodologies.
Macdonald AB.
European Journal of Clinical Microbiology and Infectious
Diseases, online before print, 2013 Mar 12
http://dx.doi.org/10.1007/s10096-013-1853-5
This manuscript offers an image presentation of diverse forms of Borrelia burgdorferi spirochetes which are not spiral or corkscrew shaped. Explanations are offered to justify the legitimacy of tissue forms of Borrelia which may confuse the inexperienced microscopic examiner and which may lead to the misdiagnosis of non-spiral forms as artifacts.

A Borrelia burgdorferi surface-exposed transmembrane protein lacking detectable immune responses supports pathogen persistence and constitutes a vaccine target.
Kung F, Kaur S, Smith AA, Yang X, Wilder CN, Sharma K, Buyuktanir O, Pal U.
The Journal of Infectious Diseases, online first 2016 Jan 7.
http://doi.org/10.1093/infdis/jiw013
Borrelia burgdorferi harbors a limited set of transmembrane surface proteins, most of which constitute key targets of humoral immune responses. Taken together, these studies highlight the essential role of an apparently immune-invisible borrelial transmembrane protein in facilitating infection and its usefulness as a target of protective host immunity blocking the transmission of B. burgdorferi.

Evidence of in vivo existence of Borrelia biofilm in borrelial lymphocytomas
E. Sapi, K. Balasubramanian, A. Poruri, J. S. Maghsoudlou, K. M. Socarras, A. V. Timmaraju, K. R. Filush, K. Gupta, S. Shaikh, P. A. S. Theophilus, D. F. Luecke, A. MacDonald, B. Zelger
European Journal of Microbiology and Immunology, online before print, February 9, 2016.
http://dx.doi.org/10.1556/1886.2015.00049
Lyme borreliosis, caused by the spirochete Borrelia burgdorferi sensu lato, has grown into a major public health problem. We recently identified a novel morphological form of B. burgdorferi, called biofilm, a structure that is well known to be highly resistant to antibiotics. In summary, this is the first study that demonstrates the presence of Borrelia biofilm in human infected skin tissues.

A short-term Borrelia burgdorferi infection model identifies tissue tropisms and bloodstream survival conferred by adhesion proteins.
Ritchie JA, Coburn J.
Infection and Immunity, pii: IAI.00349-15. Online first, 2015 May 26.
http://doi.org/10.1128/IAI.00349-15
We have developed an in vivo model of vascular interaction of B. burgdorferi in which the bacteria are injected intravenously and allowed to circulate for 1 hour. This model has shown that the fibronectin binding protein BB0347 has a tropism for joint tissue. We have also shown an importance of the integrin binding protein, P66, in binding to vasculature of the ear and heart.

Characteristics of seroconversion and implications for diagnosis of post-treatment Lyme disease syndrome: acute and convalescent serology among a prospective cohort of early Lyme disease patients
Alison W. Rebman, Lauren A. Crowder, Allison Kirkpatrick, John N. Aucott
Clinical Rheumatology, March 2015, Volume 34, Issue 3, pp 585-589.
http://doi.org/10.1007/s10067-014-2706-z
Two-tier serology is often used to confirm a diagnosis of Lyme disease. One hundred and four patients with physician diagnosed erythema migrans rashes had blood samples taken before and after 3 weeks of doxycycline treatment for early Lyme disease. Acute and convalescent serologies for Borrelia burgdorferi were interpreted according to the 2-tier antibody testing criteria proposed by the Centers for Disease Control and Prevention. Among the baseline variables included in the analysis, disseminated lesions (p?<?0.0001), a longer duration of illness (p?<?0.0001), and a higher number of reported symptoms (p?=?0.004) were highly significantly associated with positive final serostatus, while male sex (p? =?0.05) was borderline significant. This variability, and the lack of seroconversion in a subset of patients, highlights the limitations of using serology alone in identifying early Lyme disease.

Borrelia burgdorferi Manipulates Innate and Adaptive Immunity to Establish Persistence in Rodent Reservoir Hosts
Karen E. Tracy, Nicole Baumgarth
Front Immunol. 2017; 8: 116. Published online 2017 Feb 20.
doi: 10.3389/fimmu.2017.00116
Although B. burgdorferi infection induces both innate and adaptive immune responses, they are ultimately ineffective in clearing the infection from reservoir hosts, leading to bacterial persistence.

CD4+ T cells promote antibody production but not sustained affinity maturation during Borrelia burgdorferi infection
Elsner RA, Hastey CJ, Baumgarth N.
Infection and Immunity, online before print, 2014 Oct 13. pii: IAI.02471-14.
http://doi.org/10.1128/IAI.02471-14
The data further suggest that Bb-infection drives humoral response away from protective, high-affinity and long-lived antibody responses and towards rapid induction of strongly induced, short-lived antibodies, of limited efficacy.

Serodiagnosis of Borreliosis: Indirect Immunofluorescence Assay, Enzyme-Linked Immunosorbent Assay and Immunoblotting
Iwona Wojciechowska-Koszko, Iwona Maczynska, Zbigniew Szych and Stefania Giedrys-Kalemba
Archivum Immunologiae et Therapiae Experimentalis, published onlinebefore print, 22 January 2011.
http://dx.doi.org/10.1007/s00005-010-0111-0
The IIFA screening test used for diagnosing Lyme borreliosis produced the highest percentage of positive results, which were then confirmed by immunoblot, but not by ELISA. Therefore using only ELISA as a screening test or for diagnosing Lyme borreliosis seems debatable.

A comparison of Lyme disease serologic test results from four laboratories in patients with persistent symptoms after antibiotic treatment
Brian A. Fallon, Martina Pavlicova, Samantha W. Coffino, and Carl Brenner
Clinical Infectious Diseases, online before print September 2, 2014
http://doi.org/10.1093/cid/ciu703
In general there was little difference among the labs in the percentage of positive test results on the ELISAs and IgG WBs, although the number of discordant results was often high. The IgM WB performed poorly in our patient population of individuals with later stage illness, a result consistent with previous studies. While there was surprisingly little difference among the labs in percentage of positive results on most assays using CDC criteria, interlaboratory variability was considerable and remains a problem in LD testing.

Biofilms busters to improve the detection of Borrelia using PCR
Lacout A, Dacher V, El Hajjam M, Marcy PY, Perronne C.
Medical Hypotheses. 2018 Mar; 112:4-6.
https://doi.org/10.1016/j.mehy.2018.01.005
The serology tests commonly used for diagnosis of Lyme Disease show a wide sensitivity varying from 34% to 70,5%, leaving many infected patients with false negative tests.
Alternative techniques such as polymerase chain reaction (PCR) could be helpful but not conclusive enough. Using biofilm busters, such as stevia and serratiopeptidase, could lead to bacterial blood release, thus increasing the spirochete load, making PCR test more sensitive, thus improving the patient’s diagnosis and management.

Development of a sensitive PCR-dot blot assay to supplement serological tests for diagnosing Lyme disease
Shah, J.S., D’ Cruz, I., Ward, S. et al.
European Journal of Clinical Microbiology & Infectious Diseases, online first December 27, 2017.
https://doi.org/10.1007/s10096-017-3162-x
Results of the assay on 107 and 402 clinical samples from patients with suspected Lyme disease from Houston, Texas or received at the IGeneX laboratory in Palo Alto, California, respectively, were analyzed together with WB findings. The LM-PCR assay was highly specific for B. burgdorferi. In the Texas samples, 23 (21.5%) patients antibody-negative in WB assays by current US Centers for Disease Control (CDC) recommended criteria were positive by LM-PCR performed on urine, serum or whole blood samples. With IGeneX samples, of the 402 LM-PCR positive blood samples, only 70 met the CDC criteria for positive WBs, while 236 met IGeneX criteria for positive WB.
Use of the LM-PCR assay and optimization of current CDC serological criteria can improve the diagnosis of Lyme disease.

Antigens of Borrella burgdorferi Recognized during Lyme Disease – Appearance of a New Immunoglobulin M Response and Expansion of the Immunoglobulin G Response Late in the Illness
Joseph E. Craft, Duncan K. Fischer, Grant T. Shimamoto, and Allen C. Steere Departments of Internal Medicine and Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, Connecticut 06510
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC423723/pdf/jcinvest00109-0086.pdf
Using immunoblots, we identified proteins of Borrelia burgdorferi bound by IgM and IgG antibodies during Lyme disease. In 12 patients with early disease alone, both the IgM and IgG responses were restricted primarily to a 41-kD antigen. This limited response disappeared within several months. In contrast, among six patients with prolonged illness, the IgM response to the 41-kD protein sometimes persisted for months to years, and late in the illness during arthritis, a new IgM response sometimes developed to a 34-kD component of the organism. The IgG response in these patients appeared in a characteristic sequential pattern over months to years to as many as 11 spirochetal antigens. The appearance of a new IgM response and the expansion of the IgG response late in the illness, and the lack of such responses in patients with early disease alone,suggest that B. burgdorferi remains alive throughout illness.

Improved Sensitivity of Lyme disease Western Blots Prepared with a Mixture of Borrelia Burgdorferi Strains 297 and B31
Shah JS, Du Cruz I, Narciso W, Lo W and Harris NS
Chronic Diseases – International, published online, December 10, 2014.
http://tinyurl.com/mn5cxdr
A total of 364 control and patient sera (including 88 from treated patients with confirmed Lyme disease) were tested. The sensitivity of the combined IgG and IgM commercial WB using CDC criteria was 77.1%. When the in-house IgG and IgM WB and CDC criteria were used, the combined sensitivity improved to 88.6%, while use of the in-house IgG and IgM WB and in-house interpretation criteria resulted in a combined sensitivity that increased to 97.1%. Using CDC criteria, the specificity of the in-house IgG and IgM WB was 100% and 97.1%, respectively; using in-house criteria; the specificity was 95.3% and 93.1% respectively. By removal of patients who reacted to band 31kDa but tested negative for antibodies to recombinant OspA antigen, in-house IgG and IgM WB specificity increased to >97%.

Local Borrelia burgdorferi sensu stricto and Borrelia afzelii strains in a single mixed antigen improves Western blot sensitivity
Sally Mavin, Roger Evans, Rachel M Milner, Jean MW Chatterton and Darrel O Ho-Yen
J Clin Pathol. Published Online First: 23 February 2009.
http://dx.doi.org/10.1136/jcp.2008.063461
The mixed antigen and revised interpretation criteria has successfully been incorporated into the routine diagnostic testing service, increasing the sensitivity of the in-house IgG Western blot test for Scottish patients.

Interpretation criteria in Western blot diagnosis of Lyme borreliosis.
Mavin S, McDonagh S, Evans R, Milner RM, Chatterton JM, Ho-Yen DO.
British Journal of Biomedical Science 2011; 68(1); 5-10.
http://www.ncbi.nlm.nih.gov/pubmed/21473255
In total, 76 patients who were negative/equivocal became positive, which may have led to a change in their management. Conversely, 33 patients who were weak-positive became equivocal but their management may not have been affected.

More specific bands in the IgG western blot in sera from Scottish patients with suspected Lyme borreliosis.
Evans R, Mavin S, McDonagh S, Chatterton JM, Milner R, Ho-Yen DO.
Journal of Clinical Pathology, published online before print, June 30, 2010.
http://dx.doi.org/10.1136/jcp.2010.076307
Results suggest that the 20, 28 and 48 kDa bands should be regarded as specific.

Improving the Yield of Blood Cultures in Early Lyme Disease.
Liveris D, Schwartz I, Bittker S, Cooper D, Iyer R, Cox ME, Wormser GP.
Journal of Clinical Microbiology, online before print on 13 April 2011.
http://dx.doi.org/10.1128/JCM.00350-11
Approximately 45% of untreated United States patients with early Lyme disease associated with erythema migrans have a positive blood culture based on microscopic detection of Borrelia burgdorferi in Barbour-Stoenner-Kelly medium after 2-12 weeks of incubation.

Commercial test kits for detection of Lyme borreliosis: a meta-analysis of test accuracy
Cook MJ, Puri BK
International Journal of General Medicine, Volume 2016:9, Pages 427-440 (Online first, 18 November 2016).
https://doi.org/10.2147/IJGM.S122313
The clinical diagnosis of Lyme borreliosis can be supported by various test methodologies; test kits are available from many manufacturers. Literature searches were carried out to identify studies that reported characteristics of the test kits.
Of 50 searched studies, 18 were included where the tests were commercially available and samples were proven to be positive using serology testing, evidence of an erythema migrans rash, and/or culture. Additional requirements were a test specificity of =85% and publication in the last 20 years.The weighted mean sensitivity for all tests and for all samples was 59.5%. Individual study means varied from 30.6% to 86.2%. Sensitivity for each test technology varied from 62.4% for Western blot kits, and 62.3% for enzyme-linked immunosorbent assay tests, to 53.9% for synthetic C6 peptide ELISA tests and 53.7% when the two-tier methodology was used.

Cerebrospinal fluid findings in adults with acute Lyme neuroborreliosis
Marija Djukic, Carsten Schmidt-Samoa, Peter Lange, Annette Spreer, Katja Neubieser, Helmut Eiffert, Roland Nau and Holger Schmidt
Journal of Neurology, Volume 259, Number 4 (2012), 630-63.
http://dx.doi.org/10.1007/s00415-011-6221-8
Presence of BB-specific antibodies in the cerebrospinal fluid (CSF) with evidence of their intrathecal production in conjunction with the white cell count in the CSF and typical clinical symptoms is the traditional diagnostic gold standard of Lyme neuroborreliosis (LNB). In the Reiber nomograms, intrathecal immunoglobulin synthesis was found for IgM in 70.2% followed by IgG in 19.5%. Isoelectric focussing detected an intrathecal IgG synthesis in 83 patients (70.3%). Elevated BB AIs in the CSF were found in 97 patients (82.2%). Patients with VM showed lower CSF protein concentration and CSF/serum quotients of albumin than LNB patients. In acute LNB, all patients had elevated cerebrospinal fluid (CSF) leukocyte counts.

Neuroimmunomodulators in neuroborreliosis and Lyme encephalopathy
Eckman EA, Pacheco-Quinto J, Herdt AR, Halperin JJ.
Clinical Infectious Diseases, online first 2018 Jan 11.
https://doi.org/10.1093/cid/ciy019
Patients with mild cognitive symptoms occurring during acute Lyme disease, and/or following appropriate treatment, have normal CSF but elevated serum levels of T-helper 17 markers and T-cell growth factors. These markers are also elevated in non-Lyme disease patients experiencing similar symptoms. Our results support that in the absence of CSF abnormalities, neurobehavioral symptoms are associated with systemic inflammation, not CNS infection or inflammation, and are not specific to Lyme disease.

Suppression of Long-Lived Humoral Immunity Following Borrelia burgdorferi Infection
Rebecca A. Elsner, Christine J. Hastey, Kimberly J. Olsen, Nicole Baumgarth
Published: July 2, 2015
http://dx.plos.org/10.1371/journal.ppat.1004976
Infections with the Lyme Disease agent, Borrelia burgdorferi, often fail to generate long-term protective immunity. We show here that this is because the immune system of the Borrelia-infected host generates only short-lived, structurally abnormal and non-functional germinal centers. These germinal centers fail to induce memory B cells and long-lived antibody-producing plasma cells, leaving the host susceptible to reinfection with Bb. This inability to induce long-term immunity was not due to the nature of Borrelia antigens, as even T-dependent antigens of Borrelia were unable to induce such responses. Moreover, influenza vaccine antigens, when applied during Borrelia-infection, failed to induce strong antibody responses and immune-protection from influenza challenge.

Delayed diagnosis of lyme neuroborreliosis presenting with abducens neuropathy without intrathecal synthesis of Borrelia antibodies.
Radzišauskiene D, Ambrozaitis A, Marciuškiene E.
Medicina (Kaunas). 2013;49(2):89-94.
http://www.ncbi.nlm.nih.gov/pubmed/23888345
The intrathecal synthesis of Borrelia burgdorferi antibodies is of diagnostic importance, but in rare cases, immunoglobulins against the Borrelia burgdorferi antigen may not be detected. We report a case of possible Lyme neuroborreliosis presenting with sixth cranial nerve neuropathy at the onset of the disease further developing into typical meningoradiculitis and multiple mononeuropathy. Surprisingly, Borrelia burgdorferi antibodies were not detected in the cerebrospinal fluid.

Lyme Disease May Be Sexually Transmitted, Study Suggests
Online PR News, 20-January-2014
www.onlineprnews.com/news/454866-1390261507-lyme-disease-may-be-sexually-transmitted-study-suggests.html
As expected, all of the control subjects tested negative for Borrelia burgdorferi in semen samples or vaginal secretions. In contrast, all women with Lyme disease tested positive for Borrelia burgdorferi in vaginal secretions, while about half of the men with Lyme disease tested positive for the Lyme spirochete in semen samples. Furthermore, one of the heterosexual couples with Lyme disease showed identical strains of the Lyme spirochete in their genital secretions. “The presence of the Lyme spirochete in genital secretions and identical strains in married couples strongly suggests that sexual transmission of the disease occurs,” said Dr. Mayne.

Culture and identification of Borrelia spirochetes in human vaginal and seminal secretions
Marianne J. Middelveen, Jennie Burke, Eva Sapi, Cheryl Bandoski, Katherine R. Filush, Yean Wang, Agustin Franco, Arun Timmaraju, Hilary A. Schlinger, Peter J. Mayne, Raphael B. Stricker
https://f1000research.com/articles/3-309/v3
The culture of viable Borrelia spirochetes in genital secretions suggests that Lyme disease could be transmitted by intimate contact from person to person.

Changes in antibody reactivity to Borrelia burgdorferi three months after a tick bite. A cohort of 1,886 persons.
Dessau RB, Fryland L, Wilhelmsson P, Ekerfelt C, Nyman D, Forsberg P, Lindgren PE
Clinical and Vaccine Immunology, pii: CVI.00026-15. Online first, 2015 May 20.
http://doi.org/10.1128/CVI.00026-15
In conclusion, 5.4% of people with tick bites developed a rise in borrelia-specific antibodies above the 2.5% percentile in either ELISA assay, but only 40 (2.1%) developed clinical Lyme borreliosis.

Synovial fluid findings in children with knee monoarthritis in lyme disease endemic areas.
Deanehan JK, Nigrovic PA, Milewski MD, Tan Tanny SP, Kimia AA, Smith BG, Nigrovic LE.
Pediatric Emergency Care. 2014 Jan;30(1):16-9.
http://doi.org/10.1097/PEC.0000000000000028
There were no significant differences in the synovial fluid WBC, absolute neutrophil count, and percent neutrophils for children with Lyme and septic arthritis. In Lyme endemic areas, synovial fluid results alone do not differentiate septic from Lyme arthritis. Therefore, other clinical or laboratory indicators are needed to direct the care of patients with knee monoarthritis.

Burden and viability of Borrelia burgdorferi in skin or joints, of patients with erythema migrans or lyme arthritis
Xin Li, Gail McHugh, Nitin Damle, Vijay K. Sikand, Lisa Glickstein and Allen C. Steere
Arthritis & Rheumatism, online before print May 17, 2011.
http://dx.doi.org/10.1002/art.30384
B. burgdorferi in EM lesions were active and viable, whereas those in SF were moribund or dead at any time point. Thus, detection of B. burgdorferi DNA in SF is not a reliable test of active joint infection in Lyme disease.

Serum Inflammatory Mediators as Markers of Human Lyme Disease Activity.
Soloski MJ, Crowder LA, Lahey LJ, Wagner CA, Robinson WH, et al. (2014)
PLoS ONE 9(4): e93243.
http://doi.org/10.1371/journal.pone.0093243
Collectively these results indicate that the levels of serum chemokines and the levels of expression of their respective chemokine receptors on T cell subsets may prove to be informative biomarkers for Lyme disease and related to specific disease manifestations.

SPECT Brain Imaging in Chronic Lyme Disease
Donta, Sam T. MD, Noto, Richard B. MD, Vento, John A. MD
Clinical Nuclear Medicine, September 2012, Volume 37, Issue 9, e219-e222.
http://dx.doi.org/10.1097/RLU.0b013e318262ad9b
Of all patients, 75% demonstrated abnormalities in perfusion to various areas of the brain, most notably the frontal, temporal, and parietal lobes. Patients considered to be seropositive and those considered seronegative had similar rates, types, and severity of perfusion defects. Abnormalities of MRI of the brain were seen in 14% of patients. Treatment with antibiotics, especially those with intracellular-penetrating activity, resulted in resolution or improvement of abnormalities in 70% of patients over a 1- to 2-year period.

Regional Cerebral Blood Flow and Metabolic Rate in Persistent Lyme Encephalopathy
Brian A. Fallon, MD; Richard B. Lipkin, BA; Kathy M. Corbera, MD; Shan Yu, PhD; Mitchell S. Nobler, MD; John G. Keilp, PhD; Eva Petkova, PhD; Sarah H. Lisanby, MD; James R. Moeller, PhD; Iordan Slavov, PhD; Ronald Van Heertum, MD; Brett D. Mensh, MD, PhD; Harold A. Sackeim, PhD
Archives of General Psychiatry, May 2009, Volume 66, No. 5, p.554-563.
http://archpsyc.ama-assn.org/cgi/content/abstract/66/5/554
There is controversy regarding whether objective neurobiological abnormalities exist after intensive antibiotic treatment for Lyme disease. To determine whether patients with a history of well-characterized Lyme disease and persistent cognitive deficit show abnormalities in global or topographic distributions of regional cerebral blood flow (rCBF) or cerebral metabolic rate (rCMR). Statistical parametric mapping analyses revealed regional abnormalities in all rCBF and rCMR measurements that were consistent in location across imaging methods and primarily reflected hypoactivity. Deficits were noted in bilateral gray and white matter regions, primarily in the temporal, parietal, and limbic areas. Although diminished global hypercapnic CBF reactivity (P < .02) was suggestive of a component of vascular compromise, the close coupling between CBF and CMR suggests that the regional abnormalities are primarily metabolically driven. Patients did not differ from controls on global resting CBF and CMR measurements.Patients with persistent Lyme encephalopathy have objectively quantifiable topographic abnormalities in functional brain activity. These CBF and CMR reductions were observed in all measurement conditions. Future research should address whether this pattern is also seen in acute neurologic Lyme disease.

Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome.
Schutzer SE, Angel TE, Liu T, Schepmoes AA, Clauss TR, Adkins JN, et al.
(2011) PLoS ONE 6(2): e17287.
https://doi.org/10.1371/journal.pone.0017287
Pooled cerebrospinal fluid (CSF) samples from nPTLS patients, CFS patients, and healthy volunteers were comprehensively analyzed using high-resolution mass spectrometry (MS), coupled with immunoaffinity depletion methods to reduce protein-masking by abundant proteins. Individual patient and healthy control CSF samples were analyzed directly employing a MS-based label-free quantitative proteomics approach. We found that both groups, and individuals within the groups, could be distinguished from each other and normals based on their specific CSF proteins (p<0.01). CFS (n = 43) had 2,783 non-redundant proteins, nPTLS (n = 25) contained 2,768 proteins, and healthy normals had 2,630 proteins.

Lyme Disease Presents Differently in Men and Women
By Sharon Worcester, Family Practice News Digital Network, Rockville, Maryland
March 22, 2012
http://www.familypracticenews.com/news/more-top-news/single-view/lyme-disease-presents-differently-in-men-and-women/1bf48578d5.html
Women with Lyme disease display more clinical symptoms than do men with the disease and also are less likely to seroconvert following treatment, according to findings from a prospective cohort study involving 77 patients. Numerous symptoms were reported more often by the 37 women in the study than by the 40 men. For example, significantly more women than men reported joint pain, muscle pain, headache, back pain, heart palpitations, nausea, vomiting, anxiety, numbness and tingling, and changes in vision during at least one of six preplanned study visits with a physician.

Tickborne diseases other than Lyme in the United States
Eickhoff C, Blaylock J.
Cleveland Clinic Journal of Medicine. 2017 Jul;84(7):555-567.
https://doi.org/10.3949/ccjm.84a.16110
Tickborne diseases are increasing in the United States, and the geographic range of tick vectors is expanding. Tickborne diseases are challenging to diagnose, as they present with vague symptoms such as fever, constitutional symptoms, and nonspecific laboratory abnormalities. A high degree of clinical suspicion is required to make a diagnosis, as patients often do not recall a tick bite. The availability of laboratory testing for tickborne diseases is limited, especially in the acute setting. Therefore, if a tickborne disease is suspected, empiric therapy should often be initiated before laboratory confirmation of the disease is available.

Role of Chronic Bacterial and Viral Infections in Neurodegenerative, Neurobehavioural, Psychiatric, Autoimmune and Fatiguing Illnesses: Part 2
Garth L. Nicolson and Jorg Haier, British Journal of Medical Practitioners, 2010;3(1):301.
http://tinyurl.com/yg2fdmk
Chronically ill patients with neurodegenerative and neurobehavioural and psychiatric diseases commonly have systemic and central nervous system bacterial and viral infections. In addition, other chronic illnesses where neurological manifestations are routinely found, such as fatiguing and autoimmune diseases, Lyme disease and Gulf War illnesses, also show systemic bacterial and viral infections that could be important in disease inception, progression or increasing the types/severities of signs and symptoms. Evidence of Mycoplasma species, Chlamydia pneumoniae, Borrelia burgdorferi, human herpesvirus-1, -6 and -7 and other bacterial and viral infections revealed high infection rates in the above illnesses that were not found in controls. Although the specific roles of chronic infections in various diseases and their pathogeneses have not been carefully determined, the data suggest that chronic bacterial and/or viral infections are common features of progressive chronic diseases.

Severe Symptomatic Babesiosis Co-infection with Lyme Disease
Zaiem F, Alkawam H, Lee S, Fabisevich M.
QJM. pii: hcv168. Online first, 2015 Sep 14.
http://dx.doi.org/10.1093/qjmed/hcv168
When patients presented with malaria-like illness in the areas endemic for Babesia infection, physicians should keep Babesiosis high on their differential list. Co-infection with Borrelia should be considered in patients with atypical presentation or with a poor response to proper therapy.

Seroprevalence of Babesia microti in Individuals with Lyme Disease
Curcio Sabino R., Tria Laurel P., and Gucwa Azad L.
Vector-Borne and Zoonotic Diseases, Online Ahead of Print: October 24, 2016.
http://doi.org/10.1089/vbz.2016.2020
Babesiosis is an emerging tick-borne disease (TBD) caused by Babesia microti, an intracellular parasite of red blood cells. Overall, 26.9% of the serum samples tested were positive for IgM and IgG antibodies against B. microti, suggesting exposure to TBD. Individuals who tested positive for Lyme disease as determined by two-tiered serological testing and the presence of both IgM and IgG antibodies directed against B. burgdorferi, were significantly increased for antibodies directed against B. microti (28.6%; p?<?0.05), suggesting the possibility of coinfection with both TBDs.

Risk Factors for Severe Infection, Hospitalization, and Prolonged Antimicrobial Therapy in Patients with Babesiosis
Mareedu N, Schotthoefer AM, Tompkins J, Hall MC, Fritsche TR, Frost HM.
The American Journal of Tropical Medicine and Hygiene, online first 2017 Jul 10.
https://doi.org/10.4269/ajtmh.17-0146
Babesiosis is an emerging tick-borne disease transmitted by the hard tick Ixodes scapularis, which also transmits Lyme disease. Better gradation of prognostic indicators are needed to determine which patients may develop serious complications requiring hospitalization, and to provide early guidance on appropriate therapy. In this study, we evaluated 128 patients with smear or real time polymerase chain reaction-confirmed Babesia microti infections over a period of 16 years. Patients with asplenia or immunocompromising conditions were more likely to have severe infection (P < 0.01), require hospitalization (P < 0.01), or receive prolonged courses of antimicrobials (P < 0.01). Nausea or vomiting (P < 0.01) and diarrhea (P < 0.01) along with hyperbilirubinemia (P < 0.01) were predictive of severe infection, hospitalization, and prolonged antimicrobial therapy.

Vector Competence of the Tick Ixodes ricinus for Transmission of Bartonella birtlesii.
PLoS Neglected Tropical Diseases. 2011;5(5):e1186. Epub 2011 May 31.
Reis C, Cote M, Le Rhun D, Lecuelle B, Levin ML, Vayssier-Taussat M, Bonnet SI.
http://dx.doi.org/10.1371/journal.pntd.0001186
Histochemical staining showed the presence of bacteria in salivary glands and muscle tissues of partially engorged adult ticks, which had molted from the infected nymphs. These results confirm the vector competence of I. ricinus for B. birtlesii and represent the first in vivo demonstration of a Bartonella sp. transmission by ticks. Consequently, bartonelloses should be now included in the differential diagnosis for patients exposed to tick bites.

Cat Scratch Neuroretinitis: The Role of Acute and Convalescent Titers for Diagnosis
Gulati, Archit; Yalamanchili, Sushma; Golnik, Karl C.; Lee, Andrew G. MD
Journal of Neuro-Ophthalmology, online before print, 21 September 2011.
http://www.ncbi.nlm.nih.gov/pubmed/21941214
Cat scratch neuroretinitis (CSN) is a clinical diagnosis supported by serological testing. We present 2 cases of CSN in which initial acute titers were negative or equivocal for Bartonella henselae while convalescent titers were shown to be positive. We report these cases to emphasize that a single acute negative titer is insufficient to exclude the diagnosis of CSN and that convalescent titers should be obtained in patients for whom there is a high clinical suspicion of the disease.

Status Epilepticus Due to Cat Scratch Disease: Recognition, Diagnosis, and Thoughts on Pathogenesis
Schuster AL, Honeycutt TC, Hamrick HJ.
Pediatric Emergency Care. 2016 Nov;32(11):789-791.
http://doi.org/10.1097/PEC.0000000000000367
Despite the publication of a number of case reports since the 1950s, physician awareness of the unique relationship between cat scratch disease (CSD) and acute encephalopathy remains limited. This report alerts emergency medicine physicians to include CSD encephalopathy (CSDE) in the differential diagnosis when a previously healthy child presents with status epilepticus. Prompt recognition of this relationship impacts the selection of initial diagnostic studies and antibiotic choices and permits reliable insight into prognosis.

Bartonella spp. bacteremia and rheumatic symptoms in patients from Lyme disease-endemic region.
Maggi RG, Mozayeni BR, Pultorak EL, Hegarty BC, Bradley JM, Correa M, et al.
Emerging Infectious Disease, Volume 18, Number 5, May 2012.
http://dx.doi.org/10.3201/eid1805.111366
Bartonella spp. infection has been reported in association with an expanding spectrum of symptoms and lesions. Among 296 patients examined by a rheumatologist, prevalence of antibodies against Bartonella henselae, B. koehlerae, or B. vinsonii subsp. berkhoffii (185 [62%]) and Bartonella spp. bacteremia (122 [41.1%]) was high. Conditions diagnosed before referral included Lyme disease (46.6%), arthralgia/arthritis (20.6%), chronic fatigue (19.6%), and fibromyalgia (6.1%). B. henselae bacteremia was significantly associated with prior referral to a neurologist, most often for blurred vision, subcortical neurologic deficits, or numbness in the extremities.

Clinical Findings and Diagnosis in Human Granulocytic Anaplasmosis: A Case Series From Massachusetts
Mayo Clinic Proceedings, Volume 87, Issue 3 , Pages 233-239, March 2012.
Ana A. Weil, Elinor L. Baron, Catherine M. Brown, and Mark S. Drapkin
http://www.mayoclinicproceedings.org/article/S0025-6196%2812%2900125-5/abstract
Thirty-three cases were confirmed during the 2009 transmission season, and 14 of these patients (42%) required hospitalization. Thrombocytopenia and/or leukopenia were observed at the time of presentation in 25 of 30 patients (86%) in whom both white blood cell and platelet counts were determined, and 28 of 33 patients (85%) reported fever. Rash occurred in only 2 of the 33 patients (6%), and 25 (76%) reported one or more respiratory or gastrointestinal symptom.

Comparison of a Real-time PCR Method with Serology and Blood Smear Analysis for Diagnosis of Human Anaplasmosis: Importance of Infection Time Course for Optimal Test Utilization.
Schotthoefer AM, Meece JK, Ivacic LC, Bertz PD, Zhang K,
Weiler T, Uphoff TS, Fritsche TR.
Journal of Clinical Microbiology, online before print, 2013 May 1.
http://dx.doi.org/10.1128/JCM.00347-13
There was poor agreement between the real-time PCR assay and serologic test results: 19.8% (19/96) and 13.7% (29/212) of seropositive and -negative patients, respectively, were PCR positive. Seropositivity increased with days of illness, demonstrating that serologic detection methods are best utilized during presumed convalescence. Our results indicated that optimal performance and utilization of laboratory tests for diagnosis of anaplasmosis requires knowledge regarding symptom onset or days of illness.

Infection with hemotropic Mycoplasma sp. in people with and without extensive arthropod and animal contact.
Maggi RG, Compton SM, Trull CL, Mascarelli PE, Mozayeni BR, Breitschwerdt EB.
Journal of Clinical Microbiolog, online before print 2013 Jul 17.
http://doi.org/10.1128/JCM.01125-13
PCR amplification targeting the 16S rRNA gene was used to test individuals with and without extensive arthropod and animal contact for the possibility of hemotropic mycoplasma infection. The prevalence of hemotropic mycoplasma infection (4.7%) was significantly greater in previously reported cohorts of veterinarians, veterinary technicians, spouses of veterinary professionals, and others with extensive arthropod exposure and/or frequent animal contact, as compared to a previously reported cohort of patients examined by a rheumatologist because of chronic joint pain or evidence of small vessel disease (0.7%). Historical exposure to animals and arthropod vectors that can harbor hemotropic mycoplasma spp. should be considered during epidemiological investigations and when evaluating individual patients.

Expression of C-Reactive Protein and Serum Amyloid A in Early to Late Manifestations of Lyme Disease
Uhde M, Ajamian M, Li X, Wormser GP, Marques A, Alaedini A.
Clinical Infectious Diseases, online first, 2016 September 1.
http://doi.org/10.1093/cid/ciw599
These findings indicate that circulating CRP and SAA levels are highest when the concentration of spirochetes is greatest in skin and/or blood and that levels decline after the dissemination of the organism to extracutaneous sites in subsequent stages of infection. The data also suggest that antibiotic-refractory Lyme arthritis and post-treatment Lyme disease syndrome are associated with elevated CRP responses that are driven by inflammatory mechanisms distinct from those in active infection.

Effects of Borrelia on host immune system: Possible consequences for diagnostics
Mualla McManus, Ann Cincotta
Advances in Integrative Medicine, online before print, January 12, 2015.
http://dx.doi.org/10.1016/j.aimed.2014.11.002
Diagnosis is difficult not only due to multi-systemic and nonspecific nature of symptoms but also due to the indirect diagnostics assuming immuno-competence in all three stages of Borreliosis. Indirect diagnostics are the most common method of testing for Borreliosis as they are cheap and convenient. However due to wide variation in antigenicity of genospecies, the sensitivity and specificity of diagnostics can be questioned. Evidence is accumulating which suggests that immune dysregulation induced by Borrelia (and other tick borne infections) can impact the indirect diagnostics, especially in Stage 3. The immune status of the borreliosis patient needs to be considered, especially in Stage 3 in conjunction with clinical symptoms in the diagnosis. Borrelia has the ability to manipulate both the innate and active immunity and alter the cytokines secreted hence alter the path of the immune response. Immune parameters such as IFN-gamma/IL-10, lymphocyte markers, complement C3a, C4a, and total immunoglobulin levels may help to discriminate between stages and monitor treatment outcomes. The level of immune dysfunction in Stage 3 may depend on the number of co-infections delivered by a tick bite, such as Babesia, and Rickettsia, the genospecies of Borrelia, other pathogens, the patients’ biome and immunogenetics.

Lyme borreliosis: a review of data on transmission time after tick attachment.
Cook MJ.
International Journal of General Medicine. 2014 Dec 19;8:1-8. eCollection 2015.
http://dx.doi.org/10.2147/IJGM.S73791
A literature review has determined that in animal models, transmission can occur in <16 hours, and the minimum attachment time for transmission of infection has never been established. Mechanisms for early transmission of spirochetes have been proposed based on their presence in different organs of the tick. Studies have found systemic infection and the presence of spirochetes in the tick salivary glands prior to feeding, which could result in cases of rapid transmission. Also, there is evidence that spirochete transmission times and virulence depend upon the tick and Borrelia species.

Do Tick Attachment Times Vary between Different Tick-Pathogen Systems?
Stephanie L. Richards, Ricky Langley, Charles S. Apperson and Elizabeth Watson
Environments 2017, 4(2), 37; Online first, May 9, 2017.
http://dx.doi.org/10.3390/environments4020037
Improvements to risk assessments are needed to enhance our understanding of tick-borne disease epidemiology. We review tick vectors and duration of tick attachment required for pathogen transmission for the following pathogens/toxins and diseases: (1) Anaplasma phagocytophilum (anaplasmosis); (2) Babesia microti (babesiosis); (3) Borrelia burgdorferi (Lyme disease); (4) Southern tick-associated rash illness; (5) Borrelia hermsii (tick-borne relapsing fever); (6) Borrelia parkeri (tick-borne relapsing fever); (7) Borrelia turicatae (tick-borne relapsing fever); (8) Borrelia mayonii; (9) Borrelia miyamotoi; (10) Coxiella burnetii (Query fever); (11) Ehrlichia chaffeensis (ehrlichiosis); (12) Ehrlichia ewingii (ehrlichiosis); (13) Ehrlichia muris; (14) Francisella tularensis (tularemia); (15) Rickettsia 364D; (16) Rickettsia montanensis; (17) Rickettsia parkeri (American boutonneuse fever, American tick bite fever); (18) Rickettsia ricketsii (Rocky Mountain spotted fever); (19) Colorado tick fever virus (Colorado tick fever); (20) Heartland virus; (21) Powassan virus (Powassan disease); (22) tick paralysis neurotoxin; and (23) Galactose-a-1,3-galactose (Mammalian Meat Allergy-alpha-gal syndrome). Published studies for 12 of the 23 pathogens/diseases showed tick attachment times. Reported tick attachment times varied (<1 h to seven days) between pathogen/toxin type and tick vector. Not all studies were designed to detect the duration of attachment required for transmission. Knowledge of this important aspect of vector competence is lacking and impairs risk assessment for some tick-borne pathogens.

Pathogen transmission in relation to duration of attachment by Ixodes scapularis ticks
Lars Eisen
Ticks and Tick-borne Diseases, online first, January 31, 2018.
https://doi.org/10.1016/j.ttbdis.2018.01.002
The blacklegged tick, Ixodes scapularis, is the primary vector to humans in the eastern United States of the deer tick virus lineage of Powassan virus (Powassan virus disease); the protozoan parasite Babesia microti (babesiosis); and multiple bacterial disease agents including Anaplasma phagocytophilum (anaplasmosis), Borrelia burgdorferi and Borrelia mayonii (Lyme disease), Borrelia miyamotoi (relapsing fever-like illness, named Borrelia miyamotoi disease), and Ehrlichia muris eauclairensis (a minor causative agent of ehrlichiosis). With the notable exception of Powassan virus, which can be transmitted within minutes after attachment by an infected tick, there is no doubt that the risk of transmission of other I. scapularis-borne pathogens, including Lyme disease spirochetes, increases with the length of time (number of days) infected ticks are allowed to remain attached. This review summarizes data from experimental transmission studies to reinforce the important disease-prevention message that regular (at least daily) tick checks and prompt tick removal has strong potential to reduce the risk of transmission of I. scapularis-borne bacterial and parasitic pathogens from infected attached ticks.

Transmission of Borrelia miyamotoi sensu lato relapsing fever group spirochetes in relation to duration of attachment by Ixodes scapularis nymphs
Nicole E.Breuner, Marc C.Dolan, Adam J.Replogle, Christopher Sexton, Andrias Hojgaard, Karen A.Boegler, Rebecca J.Clark, Lars Eisen
Ticks and Tick-borne Diseases, Volume 8, Issue 5, August 2017, Pages 677-681.
https://doi.org/10.1016/j.ttbdis.2017.03.008
We conclude that (i) single I. scapularis nymphs effectively transmit B. miyamotoi relapsing fever group spirochetes while feeding,(ii) transmission can occur within the first 24 h of nymphal attachment, and (iii) the probability of transmission increases with the duration of nymphal attachment.

Topical azithromycin for the prevention of Lyme borreliosis: a randomised, placebo-controlled, phase 3 efficacy trial
Schwameis M, Kündig T, Huber G, et al.
The Lancet Infectious Diseases, available online 20 December 2016.
http://dx.doi.org/10.1016/S1473-3099(16)30529-1
Lyme borreliosis develops in 1–5% of individuals bitten by ticks, but with a diagnostic gap affecting up to 30% of patients, a broadly applicable pharmacological prevention strategy is needed. Topical azithromycin effectively eradicated Borrelia burgdorferi sensu lato from the skin in preclinical studies. We assessed its efficacy in human beings. Topical azithromycin was well tolerated and had a good safety profile. Inclusion of asymptomatic seroconversion into the primary efficacy analysis led to no prevention effect with topical azithromycin. Adequately powered studies assessing only erythema migrans should be considered. A subgroup analysis in this study suggested that topical azithromycin reduces erythema migrans after bites of infected ticks.

Single dose prophylactic treatment of a tick bite only prevents a Lyme rash

danielcameronmd.com/importance-second-opinion-prophylactic-treatment-tick-bite/

Blog: All Things Lyme, by Daniel Cameron, MD, MPH, a nationally recognized leader for his expertise in the diagnosis and treatment of Lyme disease and other tick-borne illnesses. March 19, 2017

In a recent review entitled “Lyme Disease: Emergency Department Considerations,” the authors recommend using a one-time, single dose of doxycycline for the prophylactic treatment of a tick bite, despite the fact that there has been only one study exploring the effectiveness of such a limited dosage. The article also neglects to mention that there are doctors who take a different approach and advise against a one-time, single dose

Tick Bite Prophylaxis: Results From a 2012 Survey of Healthcare Providers

Perea, A. E., Hinckley, A. F. and Mead, P. S.
Zoonoses and Public Health, online before print, September 22, 2014.
http://doi.org/10.1111/zph.12159
In a recent national survey, over 30% of healthcare providers (HCPs) reported prescribing tick bite prophylaxis in the previous year.

Efficacy of antibiotic prophylaxis for the prevention of Lyme disease: an updated systematic review and meta-analysis
Journal of Antimicrobial Chemotherapy 2010 65(6):1137-1144.
Warshafsky S, Lee DH, Francois LK, Nowakowski J, Nadelman RB, Wormser GP.
Published online before print on April 9, 2010.
http://dx.doi.org/10.1093/jac/dkq097
Conclusions: The available evidence to date supports the use of antibiotic prophylaxis for the prevention of Lyme disease in endemic areas following an Ixodes tick bite. Pooled data from four placebo-controlled trials suggests that one case of Lyme disease is prevented for about every 50 patients who are treated with antibiotics.

Human Coinfection with Borrelia burgdorferi and Babesia microti in the United States
Knapp KL, Rice NA.
Journal of Parasitology Research, online first November 30, 2015.
http://dx.doi.org/10.1155/2015/587131
Borrelia burgdorferi, the causative agent of Lyme disease, and Babesia microti, a causative agent of babesiosis, are increasingly implicated in the growing tick-borne disease burden in the northeastern United States. These pathogens are transmitted via the bite of an infected tick vector, Ixodes scapularis, which is capable of harboring and inoculating a host with multiple pathogens simultaneously.

A prospective evaluation of chronic Babesia microti infection in seroreactive blood donors
Bloch, E. M., Levin, A. E., Williamson, P. C., Cyrus, S., Shaz, B. H., Kessler, D., Gorlin, J., Bruhn, R., Lee, T.-H., Montalvo, L., Kamel, H. and Busch, M. P.
Transfusion, online first May 17, 2016.
http://doi.org/10.1111/trf.13617
Thirty-seven (61.67%; 24 NY, seven MN, six NM) of 60 eligible RR donors enrolled in the study; 20 of 37 (54%) completed the 12-month follow-up visit of which 15 (75%) were still seroreactive. Nine PCR-positive donors were identified during index screening; five participated in the follow-up study, three were PCR positive at 6 months, and two remained positive at final follow-up (378 and 404 days).

Distribution and survival of Borrelia miyamotoi in human blood components
Thorp AM, Tonnetti L.
Transfusion, online first, 2015 Dec 21.
http://doi.org/10.1111/trf.13398
Borrelia miyamotoi, the agent of relapsing fever, is a tick-borne spirochete first isolated in Japan in 1994. Since then, the spirochete has been detected in ticks globally, generally in the same vectors as the Lyme disease agent. This study demonstrated that B. miyamotoi can survive standard storage conditions of most human blood components, suggesting the possibility of transmission by blood transfusion.

Gender Bias in Chronic Lyme Disease
Raphael B. Stricker and Lorraine Johnson.
Journal of Women’s Health.
http://doi.org/10.1089/jwh.2009.1657
Published in Volume: 18 Issue 10: October 26, 2009
Findings that among patients with confirmed early Lyme disease, just one-third of the women, compared to half of the men, had a positive result on the CDC-approved tests. This explanation is reinforced by the fact that men are overrepresented (by as much as 2-to-1) in studies of patients with late Lyme, a diagnosis that is even stricter than PTLDS, requiring not only a positive test result but an objective clinical sign like arthritis.

Implications of Gender in Chronic Lyme Disease
Journal of Women’s Health. June 2009, 18(6): 831-834.
http://dx.doi.org/10.1089/jwh.2008.1193
Gary P. Wormser, Eugene D. Shapiro
Patients with chronic Lyme disease were significantly more likely to be female than were patients diagnosed with either Lyme disease (odds ratio [OR] 2.42, 95% confidence interval [CI] 1.98 – 2.94, p<0.0001) or with post-Lyme disease syndrome (OR 2.32, 95% CI 1.62 – 3.34, p<0.0001).

Sex differences in the clinical and serologic presentation of early lyme disease: Results from a retrospective review
Schwarzwalder A, Schneider MF, Lydecker A, Aucott JN.
Gender Medicine, 2010 Aug;7(4):320-9.
http://dx.doi.org/10.1016/j.genm.2010.08.002
Results: In a total of 125 patients, there were no significant differences in clinical presentation by sex. The initial self-misdiagnosis rates for men and women were 10% and 18%, respectively (P = NS). Among the 62 patients with a serologic test as part of their clinical evaluation, 50% of men had a positive, 2-tier result compared with 32% of women (P = NS). Among the 41 patients with a positive ELISA, median ELISA values (3.4 vs 2.0; P = 0.03) and median number of immunoglobulin G (IgG) bands (4 vs 2; P = 0.03) were significantly higher among men. In this small, retrospective sample, we found evidence for sex-based differences in the magnitude of ELISA and IgG serologic response to early Lyme disease. Such differences could have implications for appropriate diagnosis, treatment, and disease classification. Larger, prospective studies are needed to replicate the results found in this study and to examine their relationship to sex-based immunologic variability.

Tickborne Relapsing Fever in a Mother and Newborn Child
Morbidity and Mortality Weekly Report (MMWR) 61(10);174-176. March 16, 2012
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6110a3.htm?s_cid=mm6110a3_w
Reported by: Elisabeth W. Lawaczeck, DVM, Colorado Dept of Public Health and Environment. Paul S. Mead, MD, Martin E. Schriefer, PhD, Div of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases; Meghan E. Brett, MD, Jeffrey T. McCollum, DVM, EIS officers, CDC.
Tickborne relapsing fever (TBRF) is a bacterial infection caused by certain species of Borrelia spirochetes and transmitted through the bite of Ornithodoros ticks. Clinical illness is characterized by relapsing fever, myalgias, and malaise. On May 10, 2011, CDC and the Colorado Department of Public Health and Environment were notified of two patients with TBRF: a young woman and her newborn child. This report summarizes the clinical course of these patients and emphasizes the importance of considering a diagnosis of TBRF among patients with compatible clinical symptoms and residence or travel in a TBRF-endemic area. Pregnant women and neonates are at increased risk for TBRF-associated complications and require prompt diagnosis and treatment for optimal clinical outcomes. Public health follow-up of reported TBRF cases should include a search for persons sharing an exposure with the patient and environmental investigation with remediation measures to prevent additional infections. Blood and serum samples from the mother and her newborn were tested by CDC’s Bacterial Diseases Branch, Fort Collins, Colorado. Presence of spirochetes was visually confirmed from the newborn’s blood smear prepared May 7; a whole blood sample collected the same day yielded evidence of relapsing fever Borrelia species by polymerase chain reaction. Sequencing of polymerase chain reaction targets revealed 100% match to Borrelia hermsii.

Tick secret revealed: Westchester researchers first to prove baby got babesiosis before birth
By Jane Lerner, The Journal News, White Plains, New York
July 6, 2012
http://www.lohud.com/article/20120706/NEWS02/307060050
Westchester County researchers have confirmed for the first time a case of a pregnant woman passing on babesiosis, an increasingly common tick-borne illness, to her unborn baby.

Disease Caused By Insect Bites Can Be Transmitted To Children At Birth, NC State Researcher Finds
North Carolina State University, Raleigh, North Carolina 919.515.6142
May 5, 2010
http://news.ncsu.edu/uncategorized/bartonella/
Cat scratch disease was thought to be a self-limiting, or “one-time” infection; however, Breitschwerdt’s previous work discovered cases of children and adults with chronic, blood-borne Bartonella infections – from strains of the bacteria that are most often transmitted to cats (B. henselae) and dogs (B. vinsonii subsp. berkhoffii) by fleas and other insects. In his most recent case study, Breitschwerdt’s research group tested blood and tissue samples taken over a period of years from a mother, father and son who had suffered chronic illnesses for over a decade. Autopsy samples from their daughter – the son’s twin who died shortly after birth – contained DNA evidence of B. henselae and B. vinsonii subsp. berkhoffi infection, which was also found in the other members of the family.

Bartonella henselae infection in a family experiencing neurological and neurocognitive abnormalities after woodlouse hunter spider bites.
Mascarelli PE, Maggi RG, Hopkins S, Mozayeni BR, L Trull C, Bradley JM, Hegarty BC, Breitschwerdt EB.
Parasites and Vectors, 6:98. Online before print, April 15,2013.
http://dx.doi.org/10.1186/1756-3305-6-98
Antibody titers to B. vinsonii subsp. berkhoffii (Bvb) genotypes I-III, B. henselae (Bh) and B. koehlerae (Bk) were determined using an IFA test. Management of the medical problems reported by these patiens was provided by their respective physicians. In this investigation, immediately prior to the onset of symptoms two children in a family experienced puncture-like skin lesions after exposure to and presumptive bites from woodlouse hunter spiders. Shortly thereafter, the mother and both children developed hive-like lesions. Over the ensuing months, the youngest son was diagnosed with Guillain-Barre (GBS) syndrome followed by Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP). The older son developed intermittent disorientation and irritability, and the mother experienced fatigue, headaches, joint pain and memory loss. When tested approximately three years after the woodlouse hunter spider infestation, all three family members were Bartonella henselae seroreactive and B. henselae DNA was amplified and sequenced from blood, serum or Bartonella alpha-proteobacteria (BAPGM) enrichment blood cultures from the mother and oldest son.

Vasculitis, cerebral infarction and persistent Bartonella henselae infection in a child
Balakrishnan N, Ericson M, Maggi R, Breitschwerdt EB.
Parasites & Vectors. 2016 May 10; 9(1):254.
http://doi.org/10.1186/s13071-016-1547-9
The genus Bartonella is comprised of a rapidly increasing number of pathogenic species that induce a seemingly diverse spectrum of neurological symptoms. During the 12 year period that followed the initial onset of neurological and gastrointestinal symptoms, an 11 year-old girl experienced a spectrum of neurological complaints including frequent headaches, visual and auditory hallucinations, anxiety, vision loss involving the lower left quadrant of both eyes, episodic bouts of generalized paralysis, facial palsy, chronic insomnia, seizures, dizziness, cognitive dysfunction, and memory loss.

Bartonella henselae bacteremia in a mother and son potentially associated with tick exposure.
Maggi RG, Ericson M, Mascarelli PE, Bradley JM, Breitschwerdt EB.
Parasit Vectors. 2013 Apr 15;6:101. doi: 10.1186/1756-3305-6-101.
https://www.ncbi.nlm.nih.gov/pubmed/23587194
The mother and son were exhibiting symptoms including fatigue, headaches, memory loss, disorientation, peripheral neuropathic pain, striae (son only), and loss of coordination, whereas the father and daughter were healthy. The mother was seroreactive to multiple Bartonella spp. antigens and bacteremia was confirmed by PCR amplification of B. henselae DNA from blood, and from a BAPGM blood agar plate subculture isolate. The son was not seroreactive to any Bartonella sp. antigen, but B. henselae DNA was amplified from several blood and serum samples, from BAPGM enrichment blood culture, and from a cutaneous striae biopsy. The father and daughter were seronegative to all Bartonella spp. antigens, and negative for Bartonella DNA amplification.

In the Crucible of Chronic Lyme Disease
Physician, Dr. Kenneth B. Liegner, takes on Centers for Disease Control and Prevention (CDC) & Infectious Diseases Society of America (IDSA) dogma in new scientific book
April 20, 2016
http://www.prweb.com/releases/2016/04/prweb13354473.htm
Poughkeepsie, New York – Despite scientific studies, the CDC and IDSA dismiss any existence of chronic Lyme disease. Kenneth B. Liegner, M.D. has compiled into a single volume a compelling argument that the disease does exist in his book, “In the Crucible of Chronic Lyme Disease.” This body of work includes scientific articles, speeches and presentations, correspondence with legislators and principals in the field, and photographs of persons important in the history of the disease. It illustrates a rational, ethical and scientifically based approach to care of persons suffering from this still incompletely understood illness. “We are in the midst of paradigm change,” Dr. Liegner said. “Improved methods of diagnosis, treatment and prevention are urgently needed.” Dr. Liegner has spent more than 25 years working with Lyme and tick-borne diseases and has personally cared for many patients suffering from chronic Lyme disease. He calls for a “Manhattan Project” for better diagnosis, treatment and prevention of Lyme and other tick-borne diseases, and advocates for physician autonomy and patient rights. “It took medical science roughly 500 years to gain a good understanding of syphilis,” Dr. Liegner said. “We are but 40 years in to Lyme disease, caused by a spirochete considerably more genetically complex than Treponema pallidum, the organism causing syphilis.”

Tick-Borne Disease Preventive Practices and Perceptions in an Endemic Area
Amber D. Butlera, Tannaz Sedghib, Joann R. Petrinia, Ramin Ahmadia
Ticks and Tick-borne Diseases, Available online 7 December 2015.
http://dx.doi.org/10.1016/j.ttbdis.2015.12.003
Lyme disease is the most commonly reported vector-borne illness in the United States. Since the institution of Nationally Notifiable surveillance efforts for Lyme disease in the United States in 1991, there has been a consistent increase in the number of reported cases. Thus, the need for targeted prevention strategies is underscored. Overall, participants’ knowledge of tick-borne diseases was poor; the average knowledge score was only 57% (SD 22.6%). The reported frequency of performing preventive behaviors was variable. The most commonly reported behavior was performing a tick check (68%); use of tick repellent was the least commonly reported behavior (38%). Those who were more knowledgeable about Lyme disease were more likely to perform tick checks but knowledge score was not significantly associated with any of the other three behaviors studied.

Ability of Three General-Use Pesticides To Suppress Nymphal Ixodes scapularis and Amblyomma americanum (Acari: Ixodidae)
Jordan RA, Schulze TL, Eisen L, Dolan MC.
Journal of the American Mosquito Control Association. 2017 Mar;33(1):50-55.
https://doi.org/10.2987/16-6610.1
We evaluated 3 over-the-counter pesticides for their ability to suppress host-seeking Ixodes scapularis and Amblyomma americanum nymphs. We applied liquid concentrate and granular formulations of Bayer Advanced Complete Insect Killer, Spectracide Triazicide Insect Killer, and Ortho Bug-B-Gon to forest plots using equipment available for purchase at retail home improvement outlets. Granular formulations provided less consistent results, including lower 1-day knockdown rates for both species, due to very dry conditions, which prevented adequate release of the active ingredient from the carrier materials. After it rained in the study area, 7 and 14 days after application, we observed =99% suppression of both species. At 28 days posttreatment, control ranged between 87.5% and 95.6% for I. scapularis and between 89.3% and 94.4% for A. americanum. We show that these over-the-counter acaricides effectively suppressed 2 medically important tick vectors for at least 4 wk, and they provide a cost-effective tick control option for homeowners. In general, liquid formulations provided more rapid and greater and more consistent suppression than granular formulations.

Pilot study assessing the effectiveness of factory-treated, long-lasting permethrin-impregnated clothing for the prevention of tick bites during occupational tick exposure in highly infested military training areas, Germany.
Faulde MK, Rutenfranz M, Keth A, Hepke J, Rogge M, Görner A.
Parasitology Research, online before print, 2014 Nov 22.
http://doi.org/10.1007/s00436-014-4232-y
Neither the tick density means from 2009 to 2011 nor associated B. burgdorferi s.l. prevalences differed significantly among the military locations investigated. The documented tick bite reductions clearly demonstrate the powerful protective effectiveness of properly worn PTBDUs against tick bites. Nevertheless, all apparel worn over PTBDUs should also be impregnated with permethrin in order to prevent tick infestation and subsequent bites.

Variable clinical presentations of babesiosis
Paparone P, Paparone PW.
The Nurse Practitioner, 2018 Oct;43(10):48-54.
https://doi.org/10.1097/01.NPR.0000545000.07640.11
Human babesiosis continues to spread in multiple regions of the US. It is transmitted by Ixodes species ticks, as are Lyme disease and anaplasmosis. Its variable clinical presentations, together with serologic detection limitations, require that a high index of clinical suspicion be present for prompt diagnosis. This article discusses case examples showing the wide range of symptoms and presentations that are possible with babesiosis.

Multidisciplinary management of patients presenting with Lyme disease suspicion
Jacquet C, Goehringer F, Baux E, et. al.
Médecine et Maladies Infectieuses, online first, 2018 Sep 3.
https://doi.org/10.1016/j.medmal.2018.06.002
The teaching hospital of Nancy, France, implemented a specific multidisciplinary care pathway (French acronym AMDPL) to improve the management of patients presenting with Lyme borreliosis (LB) suspicion. We aimed to assess the first year of activity of this care pathway.
We included all patients managed in the AMDPL pathway from November 1, 2016 to October 31, 2017. The first step was a dedicated Lyme disease consultation with an infectious disease specialist. Following this consultation, the LB diagnosis was either confirmed and adequate treatment was prescribed, or a differential diagnosis was established and patients received adequate management, or further investigations were required and patients were offered multidisciplinary management as part of a day hospitalization.
A total of 468 patients were included. LB diagnosis was confirmed in 15% of patients (69/468), 49% of patients received a differential diagnosis, and 26% (122/468) of patients had the LB diagnosis ruled out without receiving any other diagnosis.
This is to our knowledge the first multidisciplinary center implemented in France for the management of patients presenting with LB suspicion related to polymorphous signs and symptoms. Several diagnoses could be confirmed or corrected, although some symptoms and complaints could not be explained. This cohort could improve our knowledge of LB and its differential diagnoses.

Pilot Study of Immunoblots with Recombinant Borrelia burgdorferi Antigens for Laboratory Diagnosis of Lyme Disease.
Liu S, Cruz ID, Ramos CC, Taleon P, Ramasamy R, Shah J.
Healthcare. 2018 Aug 14;6(3). pii: E99.
https://doi.org/10.3390/healthcare6030099
Accurate laboratory diagnosis of Lyme disease (Lyme borreliosis), caused by the spirochete Borrelia burgdorferi (BB), is difficult and yet important to prevent serious disease. The US Centers for Disease Control and Prevention (CDC) presently recommends a screening test for serum antibodies followed by confirmation with a more specific Western blot (WB) test to detect IgG and IgM antibodies against antigens in whole cell lysates of BB.
Borrelia species related to BB cause tick-borne relapsing fever (TBRF). TBRF is increasingly recognized as a health problem in the US and occurs in areas where Lyme disease is prevalent. The two groups of Borrelia share related antigens.
We have developed a modified WB procedure termed the Lyme immunoblots (IBs) using recombinant antigens from common strains and species of the BB sensu lato complex for serological diagnosis of Lyme disease. A reference collection of 178 sera from 26 patients with and 152 patients without Lyme disease were assessed by WB and IB in a blinded manner using either criteria for positive antibody reactions recommended by the CDC or criteria developed in-house.
The sensitivity, specificity, positive and negative predictive values obtained with the reference sera suggest that the Lyme IB is superior to the Lyme WB for detection of specific antibodies in Lyme disease. The Lyme IB showed no significant reaction with rabbit antisera produced against two Borrelia species causing TBRF in the US, suggesting that the Lyme IB may be also useful for excluding TBRF.

Identification of Urine Metabolites as Biomarkers of Early Lyme Disease
Pegalajar-Jurado A, Fitzgerald BL, Islam MN, Belisle JT, Wormser GP, Waller KS, Ashton LV, Webb KJ, Delorey MJ, Clark RJ, Molins CR.
Scientific Reports, 2018 Aug 15; 8(1):12204.
https://doi.org/10.1038/s41598-018-29713-y
Metabolites detectible in human biofluids are attractive biomarkers for the diagnosis of early Lyme disease (ELD), a vector-borne infectious disease. Urine represents an easily obtained clinical sample that can be applied for diagnostic purposes. However, few studies have explored urine for biomarkers of ELD.
In this study, metabolomics approaches were applied to evaluate small molecule metabolites in urine from patients with ELD (n?=?14), infectious mononucleosis (n?=?14) and healthy controls (n?=?14). Metabolic biosignatures for ELD versus healthy controls and ELD versus infectious mononucleosis were generated using untargeted metabolomics.
Pathway analyses and metabolite identification revealed the dysregulation of several metabolic processes in ELD as compared to healthy controls or mononucleosis, including metabolism of tryptophan. Linear discriminant analyses demonstrated that individual metabolic biosignatures can correctly discriminate ELD from the other patient groups with accuracies of 71 to 100%.
These data provide proof-of-concept for use of urine metabolites as biomarkers for diagnostic classification of ELD.

Infection Kinetics and Tropism of Borrelia burgdorferi sensu lato in Mouse After Natural (via Ticks) or Artificial (Needle) Infection Depends on the Bacterial Strain.
Sertour N, Cotté V, Garnier M, Malandrin L, Ferquel E, Choumet V.
Frontiers in Microbiology. 2018 Jul 31;9:1722. eCollection 2018.
https://doi.org/10.3389/fmicb.2018.01722
Borrelia burgdorferi sl is a complex of pathogen bacteria transmitted to the host by Ixodes ticks. European Ixodes ricinus ticks transmit different B. burgdorferi species, pathogenic to human. Bacteria are principally present in unfed tick midgut, then migrate to salivary glands during blood meal and infect a new host via saliva. In this study, efficiency of transmission in a mouse model of three pathogen species belonging to the B. burgdorferi sl complex, B. burgdorferi sensu stricto (B31, N40, and BRE-13), B. afzelii (IBS-5), and B. bavariensis (PBi) is examined in order to evaluate infection risk after tick bite.
We compared the dissemination of the Borrelia species in mice after tick bite and needle injection. Location in the ticks and transmission to mice were also determined for the three species by following infection kinetics. After inoculation, we found a significant prevalence in the brain for PBi and BRE-13, in the heart, for PBi, in the skin where B31 was more prevalent than PBi and in the ankle where both B31 and N40 were more present than PBi. After tick bite, statistical analyses showed that BRE-13 was more prevalent than N40 in the brain, in the bladder and in the inguinal lymph node.
When Borrelia dissemination was compared after inoculation and tick bite, we observed heart infection only after tick inoculation of BRE-13, and PBi was only detected after tick bite in the skin. For N40, a higher number of positive organs was found after inoculation compared to tick bite. All European B. burgdorferi sl strains studied were detected in female salivary glands before blood meal and infected mice within 24 h of tick bite. Moreover, Borrelia-infected nymphs were able to infect mice as early as 12 h of tick attachment.
Our study shows the need to remove ticks as early as possible after attachment. Moreover, Borrelia tropism varied according to the strain as well as between ticks bite and needle inoculation, confirming the association between some strains and clinical manifestation of Lyme borreliosis, as well as the role played by tick saliva in the efficiency of Borrelia infection and dissemination in vertebrates.

Congenital Babesiosis After Maternal Infection With Borrelia burgdorferi and Babesia microti
Saetre K, Godhwani N, Maria M, Patel D, Wang G, Li KI, Wormser GP, Nolan SM.
Journal of the Pediatric Infectious Diseases Society, 2018 Feb 19;7(1):e1-e5.
https://doi.org/10.1093/jpids/pix074
We describe the cases of 2 infants with congenital babesiosis born to mothers with prepartum Lyme disease and subclinical Babesia microti infection.
The infants both developed anemia, neutropenia, and thrombocytopenia, and 1 infant required red blood cell transfusion. Both infants recovered with treatment.
Additional studies are warranted to define the optimal management strategy for pregnant women with early Lyme disease in geographic areas in which B microti infection is endemic.

Obstacles to diagnosis and treatment of Lyme disease in the USA: a qualitative study
Hirsch AG, Herman RJ, Rebman A, Moon KA, Aucott J, Heaney C, Schwartz BS.
BMJ Open. 2018 Jun 11;8(6):e021367.
https://doi.org/10.1136/bmjopen-2017-021367
Objective
For many individuals with Lyme disease, prompt treatment leads to rapid resolution of infection. However, severe complications can occur if treatment is delayed. Our objective was to identify themes around belated diagnosis or treatment of Lyme disease using the General Model of Total Patient Delay (GMTPD).
Results
Appraisal delay themes included symptom misattribution, intermittent symptoms and misperceptions about the necessity of a bull’s-eye rash. Health insurance status was a driver of illness and behavioural delays. Scheduling delay was not noted by participants, in part, because 10 of the 26 patients went to urgent care or emergency department settings. Misdiagnoses were more common in these settings, contributing to treatment delay.
Conclusion
Our study identified potentially modifiable risk factors for belated treatment. Targeting these risk factors may minimise time to treatment and reduce the occurrence of preventable complications.

Blood cell disruption to significantly improve the Borrelia PCR detection sensitivity in borreliosis in humans
Lacout A, Mone Y, Franck M, Marcy PY, Mas M, Veas F, Perronne C.
Medical Hypotheses. 2018 Jul;116:1-3.
https://doi.org/10.1016/j.mehy.2018.04.012
Lyme disease is the most frequently reported zoonotic tick-borne disease worldwide, and the number of infected humans is increasing. Lyme disease (or Lyme borreliosis) is an affection caused by the spirochete Borrelia burgdorferi, sensu lato. Lyme disease is also reported as a variety of misleading clinical symptomatologies. Infected patient’s blood serology is the most currently test used for its diagnosis. However, serology has a low sensitivity, which ranges from 34% to 70%.
Thus, there are numerous subsequent false-negative diagnoses despite an active clinical infection profile. Therefore, alternative and more sensitive techniques are required to detect the antigens or nucleic acids of Borrelia. Actually, the most appropriate methodological approach seems to be the polymerase chain reaction (PCR). However, PCR will detect the only “visible” part available of the targeted DNA presence in the blood of the infected patients. Consequently PCR alone will not be conclusive enough to reach the final diagnosis. Considering the ability of Borrelia to invade host cells, we hypothesize that a selective lysis of all blood cells should improve the diagnostic sensitivity of the detection of Borrelia by PCR in whole blood, and subsequently reduce the false-negative diagnostic rate, thus improving the patient’s diagnosis and therapeutic management.

Dynamics of Spirochetemia and Early PCR Detection of Borrelia miyamotoi
Karan L, Makenov M, Kolyasnikova N, Stukolova O, Toporkova M, Olenkova O.
Emerging Infectious Diseases 2018 May;24(5):860-867.
https://doi.org/10.3201/eid2405.170829
We investigated whether Borrelia miyamotoi disease can be detected in its early stage by using PCR for borrelial 16S rRNA, which molecule (DNA or RNA) is the best choice for this test, and whether spirochetes are present in blood during the acute phase of B. miyamotoi disease.
A total of 473 patients with a suspected tickborne infection in Yekaterinburg, Russia, in 2009, 2010, and 2015 were enrolled in this study. Blood samples were analyzed by using quantitative PCR or ELISA, and a diagnosis of borreliosis was confirmed for 310 patients.
For patients with erythema migrans, 5 (3%) of 167 were positive for B. miyamotoi by PCR; for patients without erythema migrans, 65 (45%) of 143 were positive for B. miyamotoi by PCR. The median concentration for RNA was 3.8 times that for DNA. Median time for detection of B. miyamotoi in blood was 4 days.

Evaluating polymicrobial immune responses in patients suffering from tick-borne diseases
Garg K, Meriläinen L, Franz O, Pirttinen H, Quevedo-Diaz M, Croucher S, Gilbert L.
Scientific Reports 2018 Oct 29;8(1):15932.
https://doi.org/10.1038/s41598-018-34393-9
This study indicated an 85% probability that a randomly selected TBD patient will respond to Borrelia and other related TBD microbes rather than to Borrelia alone. A paradigm shift is required in current healthcare policies to diagnose TBD so that patients can get tested and treated even for opportunistic infections.

Detection of tick-borne infection in Morgellons disease patients by serological and molecular techniques
Middelveen MJ, Cruz ID, Fesler MC, Stricker RB, Shah JS.
Clinical, Cosmetic and Investigational Dermatology 2018 Nov 9;11:561-569. eCollection 2018.
https://doi.org/10.2147/CCID.S184521
Seroreactivity to Bb, RFB or both was detected in 63% of the cohort, while positive PCR testing for Bb, RFB or both was detected in 53% of the cohort. Overall, 90% of patients tested positive for exposure and/or infection with Borrelia spirochetes. B. henselae infection was detected by PCR in skin sections or body fluids from 20% of the subjects, and B. henselae FISH testing was positive in 30% of the dermatological specimens submitted for study.
The study demonstrates an association between MD and positive tests for both Bb and RFB spirochetes. In conjunction with previous studies, our study provides corroborative evidence linking MD to Borrelia infection and tick-borne illness.

Age-Related Differential Stimulation of Immune Response by Babesia microti and Borrelia burgdorferi During Acute Phase of Infection Affects Disease Severity
Vitomir Djokic, Shekerah Primus, Lavoisier Akoolo, Monideep Chakraborti and Nikhat Parveen
Frontiers in Immunology, online first 07 December 2018.
https://doi.org/10.3389/fimmu.2018.02891
At 3 weeks post-infection, diminished pathogen-specific antibody production in coinfected young, but not older mice, as compared to mice infected with each pathogen individually may also contribute to increased inflammation observed due to B. burgdorferiinfection, thus causing persistent Lyme disease observed in coinfected mice and reported in patients.
Thus, higher combined proinflammatory response to B. burgdorferi due to Th1 and Th17 cells likely reduced B. microti parasitemia significantly only in young mice later in infection, while the presence of B. microti reduced humoral immunity later in infection and enhanced tissue colonization by Lyme spirochetes in these mice even at the acute stage, thereby increasing inflammatory arthritis.

The Underdiagnosis of Neuropsychiatric Lyme Disease in Children and Adults
Fallon, Brian & M. Kochevar, Janice & Gaito, Andrea & Nields, Jenifer. (1998).
The Psychiatric clinics of North America.
https://www.researchgate.net/publication/13511010_The_underdiagnosis_of_neuropsychiatric_Lyme_Disease_in_children_and_adults
Lyme Disease has been called “The New Great Imitator,” a replacement for that old “great imitator” neurosyphilis. This article reviews the numerous psychiatric and neurologic presentations found in adults and children. It then reviews the features of Lyme Disease, which makes it almost uniquely hard to diagnose, including the complexity and unreliability of serologic tests. Clinical examples follow that illustrate those presentations of this disease that mimic attention deficit hyperactivity disorder (ADHD), depression, and multiple sclerosis.

The Association Between Tick-borne Infections, Lyme Borreliosis and Autism Spectrum Disorders
Bransfield, Robert & S Wulfman, Jeffrey & T Harvey, William & I Usman, Anju. (2008)
https://www.researchgate.net/publication/5865632_The_association_between_tick-borne_infections_Lyme_borreliosis_and_autism_spectrum_disorders
Chronic infectious diseases, including tick-borne infections such as Borrelia burgdorferi may have direct effects, promote other infections and create a weakened, sensitized and immunologically vulnerable state during fetal development and infancy leading to increased vulnerability for developing autism spectrum disorders. A dysfunctional synergism with other predisposing and contributing factors may contribute to autism spectrum disorders by provoking innate and adaptive immune reactions to cause and perpetuate effects in susceptible individuals that result in inflammation, molecular mimicry, kynurenine pathway changes, increased quinolinic acid and decreased serotonin, oxidative stress, mitochondrial dysfunction and excitotoxicity that impair the development of the amygdala and other neural structures and neural networks resulting in a partial Klüver-Bucy Syndrome and other deficits resulting in autism spectrum disorders and/or exacerbating autism spectrum disorders from other causes throughout life. Support for this hypothesis includes multiple cases of mothers with Lyme disease and children with autism spectrum disorders; fetal neurological abnormalities associated with tick-borne diseases; similarities between tick-borne diseases and autism spectrum disorder regarding symptoms, pathophysiology, immune reactivity, temporal lobe pathology, and brain imaging data.

A Systematic Review on the Impact of Gestational Lyme Disease in Humans on the Fetus and Newborn
Waddell LA, Greig J, Lindsay LR, Hinckley AF, Ogden NH. PLoS One. (2018)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231644/
Lyme disease (LD), caused by bacteria of the Borrelia burgdorferi sensu lato species complex, is the most common vector-borne disease in North America and Europe. A systematic review (SR) was conducted to summarize the global literature on adverse birth outcomes associated with gestational LD in humans. Adverse birth outcomes included spontaneous miscarriage or fetal death (n = 12), newborn death (n = 8), and newborns with an abnormal outcome (e.g. hyperbilirubinemia, respiratory distress and syndactyly) at birth (n = 16). This SR summarizes evidence from case studies that provide some limited evidence for transplacental transmission of Bburgdorferi. There was inconsistent evidence for adverse birth outcomes of gestational LD in the epidemiological research, and uncommon adverse outcomes for the fetus may occur as a consequence of gestational LD. The global evidence does not fully characterize the potential impact of gestational LD, and future research that addresses the knowledge gaps may change the findings in this SR. Given the current evidence; prompt diagnosis and treatment of LD during pregnancy is recommended.

Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi. Antimicrobial agents and chemotherapy. Kersten, A & Poitschek, C & Rauch, S & Aberer, Elisabeth. (1995)
https://www.researchgate.net/publication/15572947_Effects_of_penicillin_ceftriaxone_and_doxycycline_on_morphology_of_Borrelia_burgdorferi
Antibiotic therapy with penicillin, doxycycline, and ceftriaxone has proven to be effective for the treatment of Lyme borreliosis.
In some patients, however, it was noticed that borreliae can survival in the tissues in spite of seemingly adequate therapy.
For a better understanding of this phenomenon, we investigated the different modes of degeneration of Borrelia burgdorferi
suspensions during a 96-h exposure to various antibiotics. By dark-field microscopy and ultrastructural investigations, increasing
blebbing and the gradual formation of granular and cystic structures could be followed during the exposure time. Although
antibiotic concentrations at the MIC at which 90% of organisms are inhibited after 72 h were 80% or even greater, motile organisms
were still present after incubation with penicillin and doxycycline but not after incubation with ceftriaxone. By transmission
electron microscopy, intact spirochetal parts, mostly situated in cysts, were seen up to 96 h after exposure with all three
antibiotics tested. According to experiences from studies with other spirochetes it is suggested that encysted borreliae,
granules, and the remaining blebs might be responsible for the ongoing antigenic stimulus leading to complaints of chronic
Lyme borreliosis.

Effects of penicillin, ceftriaxone, and doxycycline on morphology of Borrelia burgdorferi. Antimicrobial agents and chemotherapy
Kersten, A & Poitschek, C & Rauch, S & Aberer, Elisabeth. (1995).
https://www.researchgate.net/publication/277412544_Borrelia_burgdorferi_the_Causative_Agent_of_Lyme_Disease_Forms_Drug-Tolerant_Persister_Cells
Antibiotic therapy with penicillin, doxycycline, and ceftriaxone has proven to be effective for the treatment of Lyme borreliosis.In some patients, however, it was noticed that borreliae can survival in the tissues in spite of seemingly adequate therapy.
For a better understanding of this phenomenon, we investigated the different modes of degeneration of Borrelia burgdorferi suspensions during a 96-h exposure to various antibiotics. By dark-field microscopy and ultrastructural investigations, increasing
blebbing and the gradual formation of granular and cystic structures could be followed during the exposure time. Although antibiotic concentrations at the MIC at which 90% of organisms are inhibited after 72 h were 80% or even greater, motile organisms
were still present after incubation with penicillin and doxycycline but not after incubation with ceftriaxone. By transmission electron microscopy, intact spirochetal parts, mostly situated in cysts, were seen up to 96 h after exposure with all three
antibiotics tested. According to experiences from studies with other spirochetes it is suggested that encysted borreliae, granules, and the remaining blebs might be responsible for the ongoing antigenic stimulus leading to complaints of chronic
Lyme borreliosis.

Two-Tier Lyme Disease Serology Test Results Can Vary According to the Specific First-Tier Test Used
Alexandra B Maulden, Aris C Garro, Fran Balamuth, Michael N Levas, Jonathan E Bennett, Desiree N Neville, John A Branda, Lise E Nigrovic
Journal of the Pediatric Infectious Diseases Society, online first February 22, 2019.
https://doi.org/10.1093/jpids/piy133
Two-tier Lyme disease test results differed for a substantial number of children on the basis of the specific first-tier test used. In children for whom there is a high clinical suspicion for Lyme disease and who have an initially negative test result, clinicians should consider retesting for Lyme disease.

Blood smear not reliable in diagnosing Borrelia miyamotoi disease
Lyme Science Blog, by Daniel Cameron, MD, MPH, Mt. Kisco, New York
January 29, 2019
http://danielcameronmd.com/blood-smear-not-reliable-in-diagnosing-borrelia-miyamotoi-disease
Some doctors have suggested that a blood smear should be used to confirm the diagnosis of Borrelia miyamotoi disease (BMD). But as Telford and colleagues demonstrate, a blood smear may not be so reliable.

A minority of children diagnosed with Lyme disease recall a preceding tick bite
Lise E. Nigrovic, Desiree N. Neville, Fran Balamuth, Jonathan E. Bennett, Michael N.Levas, Aris C. Garro, for Pedi Lyme Net
Ticks and Tick-borne Diseases, online first February 26, 2019.
https://doi.org/10.1016/j.ttbdis.2019.02.015
Of 1,770 children undergoing emergency department evaluation for Lyme disease, 362 (20.5%) children had Lyme disease. Of those with an available tick bite history, only a minority of those with Lyme disease had a recognized tick bite (60/325; 18.5%, 95% confidence interval 14.6 – 23.0%). Lack of a tick bite history does not reliably exclude Lyme disease.

Bartonella spp. Bloodstream Infection
Edward B. Breitschwerdt, Ricardo G. Maggi, Caroline Quach, and Julie M. Bradley
Vector-Borne and Zoonotic Diseases. Online first, 27 Mar 2019.
https://doi.org/10.1089/vbz.2018.2353
Recently, bloodstream infections with various Bartonella spp. have been documented in nonimmunocompromised individuals in association with a spectrum of cardiovascular, neurologic, and rheumatologic symptoms. As documented in this family, symptoms for which the medical implications remain unclear can occur in multiple family members infected with one or more Bartonella spp. Serial serologic and molecular microbiological findings supported exposure to or infection with Bartonella spp. in all seven family members.  Either antibiotics failed to eliminate bacteremic infection, resulted in partial resolution of symptoms, or potentially reinfection occurred during the 19-month study period.

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