Archive for the ‘research’ Category

Established Populations of Rickettsia Parkeri-Infected Amblyomma Maculatum Ticks in New York City, NY, USA

https://www.liebertpub.com/doi/abs/10.1089/vbz.2021.0085?journalCode=vbz

Established Populations of Rickettsia parkeri-Infected Amblyomma maculatum Ticks in New York City, New York, USA

Published Online:24 Dec 2021https://doi.org/10.1089/vbz.2021.0085

Abstract

Objectives: We sought to determine the habitat associations and pathogen status of Amblyomma maculatum (Gulf Coast tick) ticks in New York City (NYC), New York, USA, a newly expanded portion of their range.

Methods: We collected 88 ticks from two NYC parks on Staten Island, one of the five boroughs of NYC, and compared our findings with similar habitat in Brooklyn, New York during the same time period (April 30–September 1). We tested 76 for pathogens.

Results: We found adult and immature ticks in native and invasive grasses at Freshkills and Brookfield parks on Staten Island. No A. maculatum ticks were found in Brooklyn.

  • 52.6% of ticks tested were infected with Rickettsia parkeri—the etiological agent of R. parkeri rickettsiosis.

Conclusions: This high rate of R. parkeri in a dense urban center is of concern to the medical community, who should be aware of this species’ presence and the symptoms of R. parkeri rickettsiosis.

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research, Rickettsia, Ticks

Cats & Cars Helping Scientists Study Lyme Disease

https://mta.ca/about/news/cats-and-cars-help-scientists-study-lyme-disease-fri-01282022-0859

Cats and cars help scientists study Lyme disease

28 Jan 2022
Study from Mount Allison University researchers uses citizen science to find a new source of Lyme disease bacteria in New Brunswick mice

SACKVILLE, NB – A new study from Mount Allison University, aided by cats and cat owners, is shedding light on a new source of Lyme disease bacteria in the Maritimes and how the Lyme disease pathogen in transmitted in wildlife.

Mount Allison University biology professor Dr. Vett Lloyd and graduate student Chris Zinck recently published a paper, Borrelia burgdorferi and Borrelia miyamotoi in Atlantic Canadian wildlife, in the peer-reviewed journal PLOS ONE.

Lloyd and Zinck partnered with local veterinarians and cat owners to collect wildlife specimens and study them for zoonotic diseases – diseases such as Lyme disease that are transmitted from wildlife to humans. In this latest study, Lloyd, who heads Mount Allison’s Tick Lab, and Zinck have found a new wildlife species, the jumping mouse, that can carry Lyme disease in New Brunswick. The pair also discovered that one of the types of Lyme disease bacteria can be transmitted through the placenta to the young in that mouse species.

“We know that Lyme disease is abundant in New Brunswick wildlife,” says Lloyd. “But we didn’t know how abundant it was in wild animals in the province and these findings raise more concerns about the potential risks of Lyme disease in our region.”

To collect wildlife specimens, researchers used a Citizen Science approach, enlisting the assistance local cats and motorists in providing a large number of mice, voles, shrews, squirrels, porcupines, and other animals, to study.

Lloyd came up with the community-based approach at her home with her cat Entropy, a calico who hunts with surgical precision.

“As I looked at yet another one of Entropy’s ‘gifts’ on the front step, I wondered if there was a way for these little lives to contribute to science,” says Lloyd. “I had the same thought on my drive into work along the TransCanada highway each day, seeing animals on the side of the road.”
Zinck, who completed both his undergraduate and master’s degrees at Mount Allison and is currently completing his PhD at the University of Saskatchewan, also hit the road in the name of science. With a safety vest and permits in tow, he collected and dissected several hundred accidentally killed wild animals, finding both the known Lyme disease bacteria, Borrelia burgdorferi, and a different kind, Borrelia miyamotoi, in specimens.

“This work is important for the health of people and their pets as Borrelia miyamotoi infection would not be detected by the standard Lyme disease tests,” says Lloyd. “Even more surprisingly, we found that an infected jumping mouse mother had passed the infection on to her fetuses. This has implications for the health of wildlife and although few people would worry too much about the health of wild mice, it does have implications for a rapid increase in infected mice and the possibility that an infected human mother could pass on the infection to her child.”

Lloyd and Zinck hope that this work will help people realize how closely people and wildlife are connected and that the community can participate in advancing science.

The article, published on Jan. 22, is available to the public on journal’s website: PLOS ONE https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0262229

Category:

Borrelia Miyamotoi (Relapsing Fever Group), Lyme, research

BMJ Demands Immediate Vaccine Data

https://articles.mercola.com/sites/articles/archive/2022/02/01/bmj-demands-immediate-vaccine-data

BMJ Demands Immediate Vaccine Data

Analysis by Dr. Joseph Mercola
Feb. 1, 2022

Story at-a-glance –

  • BMJ editor Peter Doshi has publicly called for release of raw data from the clinical trials that led to the emergency use authorization of the COVID-19 shots. The FDA has a statutory obligation to publish the Pfizer data after drug approval, leaving Moderna, Johnson & Johnson and AstraZeneca to provide the raw data
  • The delay in releasing raw data is reminiscent of Roche’s handling of Tamiflu and Gilead’s determination to get authorization for remdesivir to treat COVID-19, despite clinical data demonstrating the drug showed little or no positive effect
  • At least one Pfizer testing facility had poor practices, including data that were falsified, patients who were unblinded and poorly trained people hired to administer the injections
  • In an opinion piece published coincidentally on the day the FDA announced full approval of the Pfizer injection, Doshi noted Pfizer’s August 2021 preprint paper held no new information since April 2021, and the shot demonstrated waning immunity in Israel, where it was used exclusively

While other Big Pharma manufacturers have developed and released a COVID-19 genetic therapy injection, only shots from Pfizer, Moderna and Johnson & Johnson have been approved in the U.S.1

The British Medical Journal (BMJ) editor Peter Doshi, an associate professor of pharmaceutical health services research at the University of Maryland School of Pharmacy, has called for the release of the clinical trial raw data on which the emergency use authorizations were based.2

As of December 2021, there were 12 countries with the capacity to produce the shots being distributed throughout the world, with approximately 200 vaccine candidates that are in preclinical development.3 According to OpenVAERS,4 there have been 1,053,828 adverse events reported as of January 14, 2022, and of those 593,078 (56.2%) are attributed to the Pfizer/BioNTech shot.

Of the three emergency use authorization approved shots in the U.S., Pfizer’s Comirnaty was the only one approved for full use by the FDA in August 2021.5 The thing is, Comirnaty is not available in the U.S., and won’t be made available as long as doses of the Emergency Use Authorized Pfizer shot, BNT162b2, remain.6

In other words, the shot that has triggered more than half of all adverse events is the one that is being touted as approved by the FDA — when in reality the shot that was actually approved isn’t even available yet. Dr. Peter Marks, FDA’s director of the Center for Biologics Evaluation and Research wrote this as justification for the approval to do this in the FDA press release:7

“Our scientific and medical experts conducted an incredibly thorough and thoughtful evaluation of this vaccine. We evaluated scientific data and information included in hundreds of thousands of pages, conducted our own analyses of Comirnaty’s safety and effectiveness, and performed a detailed assessment of the manufacturing processes, including inspections of the manufacturing facilities.”

It is the FDA’s statutory obligation8 to publish this “incredibly thorough” evaluation of the data and their own analysis within 30 days of a drug approval. Yet, after a Freedom of Information Act request and subsequent lawsuit by a nonprofit group to release the data,9 the FDA proposed to release documentation over many decades.

Ultimately, they asked a federal judge to give them 75 years to complete the process,10 but in January 2022 a federal judge ordered the FDA to accelerate this schedule to eight months.11

Pfizer Won’t Accept Requests for Trial Data Until 2025

According to Doshi,12 it will take Pfizer at least 24 months after the study completion date listed on ClinicalTrials.gov13 to even consider a request to release the primary data. Doshi calls this an “unacceptable delay,” and yet the lack of access to data is not unique to Pfizer.

Moderna and AstraZeneca14 have both indicated they will have similar delays in releasing their data.15 Since only the data from Pfizer can be released by the FDA, it falls to Moderna, Johnson & Johnson and AstraZeneca to provide the raw data. Doshi points out that raw data for other therapeutics tied to COVID-19 are also difficult to uncover.

For example, the published reports of the monoclonal antibody therapy produced by Regeneron state that any raw data will not be released to others.16 Only the methods and findings will be released, and the raw data will only be considered once the drug has been approved and if there’s legal authority to share it.

Likewise, Doshi notes the raw data from the National Institutes of Health for the drug promoted to treat COVID-19 — remdesivir — is limited, with the accompanying explanation: “The longitudinal data set only contains a small subset of the protocol and statistical analysis plan objectives.”17 Doshi argues the point, writing:

“We are left with publications but no access to the underlying data on reasonable request. This is worrying for trial participants, researchers, clinicians, journal editors, policy makers, and the public. The journals that have published these primary studies may argue that they faced an awkward dilemma, caught between making the summary findings available quickly and upholding the best ethical values that support timely access to underlying data.

In our view, there is no dilemma; the anonymized individual participant data from clinical trials must be made available for independent scrutiny.”

Access to the underlying data is necessary for transparent decision-making. Each of these are essential steps for public health safety. Doshi notes18 that had information been revealed as to why the vaccine trials were not used to test efficacy against the infection, countries would have learned earlier about how the vaccine allowed transmission in the pandemic and would have been able to plan public health strategies accordingly.

Pfizer has been a habitual offender in shady dealings, having been sued in multiple venues over unethical drug testing, illegal marketing practices,19 bribery in multiple countries,20 environmental violations,21 labor and worker safety violations and more.22,23

Doshi cites documentation24 that three of the companies have had past criminal and civil settlements costing them billions of dollars, one pleaded guilty to fraud and other drug companies have jumped into developing a genetic injection with no track record before the pandemic. These actions create doubt that the raw data will adequately support the manufacturers claims.

Lack of Raw Data After Drug Release Reminiscent of Tamiflu

Doshi recalls that 12 years ago the scientific community called for the release of raw data from clinical trials from another drug that was stockpiled by governments around the world in the middle of a different pandemic.25

In this case, most of the trials that formed the foundation of the government approval and stockpiling of Tamiflu were sponsored by the manufacturer and ghost written by writers paid by the manufacturer. Ironically, those who were listed as principal authors did not have access to the raw data.

The history of Tamiflu also parallels remdesivir, a drug that has little or no positive effect on treatment of COVID.26 Dr. Tom Jefferson is an epidemiologist who works for the Cochrane Collaboration, an organization that collects and reviews medical research findings.

In his presentation at the Symposium about Scientific Freedom in Copenhagen,27 Jefferson described the intricate and complex journey he and his team took to publish the only Cochrane review that was based solely on raw unpublished regulatory data for Tamiflu.

Ultimately, his review demonstrated that the drug shortened the duration of symptoms from flu by less than one day. However, the struggle to obtain the data was nearly as eye-opening as the results.

It took four years for Roche to deliver 150,000 pages of clinical data to Jefferson’s team.28 After getting the data, Jefferson found that although the drug was used worldwide, the WHO had never vetted the raw data, nor had the European Medicines Agency, nor had the CDC.

The FDA had seen the data, however, which prompted them to request a published statement on the label “saying serious bacterial infections may begin with influenza-like symptoms or may coexist with or without complications … but Tamiflu has not been shown to prevent such complications.”29 Jefferson commented: “The FDA was saying, this business about complications, no evidence of that.”

Jefferson also notes that even a decade after the Tamiflu Phase 3 trials were completed, they remained unpublished. From an analysis the team determined:

“there was no convincing trial evidence that Tamiflu affected influenza complications and treatment or influenza infections in prophylaxis.”30

At Least One Pfizer Shot Testing Facility Had Poor Practices

Paul Thacker, investigative journalist from the BMJ, reported on evidence presented by researchers in a Texas privately-owned clinical research lab that the data integrity in Pfizer’s vaccine trial was suspect.31 While this should have been front-page news in 2021, the mainstream media completely ignored it.

According to Brook Jackson, a veteran clinical research coordinator with 20 years of experience, the Pfizer Phase 3 COVID jab trial included data that were falsified, patients who were unblinded and poorly trained people hired to administer the injections. Additionally, follow up on any adverse side effects reported by the participants lagged significantly.

Thacker led the article with the statement: “Revelations of poor practices at a contract research company helping to carry out Pfizer’s pivotal COVID-19 vaccine trial raise questions about data integrity and regulatory oversight.”32

Jackson attempted to inform her superiors multiple times. When her concerns were ignored, she called the FDA and filed an email complaint. Hours later she was fired after working just two weeks. According to her separation letter the management had decided she was “not a good fit” for the company. According to Jackson, this was the first time she’d ever been fired in her 20-year career as a clinical research coordinator.

While the briefing document that Pfizer submitted to the FDA in the application for an emergency use authorization contained no indication of any problems at the lab, Jackson has since provided The BMJ with “dozens of internal company documents, photos, audio recordings and emails”33 proving her concerns were valid.

The BMJ also learned that Jackson’s allegations were supported by others. Months later, Jackson reconnected with employees who were either fired from the lab or who left. One official sent a text message to Jackson saying, “everything that you complained about was spot on.”34

Two other former employees spoke to The BMJ anonymously confirming the broad allegations made in Jackson’s complaint, with one person saying she had worked on more than four dozen trials during her career, but had never experienced the type of work environment at Ventavia on the Pfizer trial.

For example, in several cases there weren’t enough employees to swab the trial participants who were reporting symptoms, even though the trial required lab confirmation of symptomatic COVID-19 as a primary endpoint. The employee called the data produced by the Ventavia lab for the Pfizer trial “a crazy mess.”35

Preprint Data Demonstrate Waning Immunity by March 2021

Doshi also addressed the need for adequate and controlled studies with long-term follow-up before granting approval for vaccinations, most notably the COVID-19 genetic therapy injection.36 In an opinion piece published August 23, 2021, he discussed the updated results that Pfizer had posted for their ongoing Phase 3 COVID-19 vaccine trial.37

Months before, the company had announced the vaccine efficacy was estimated to be “up to six months” after injection.38 While updated results were published one year after the trial began,39 there were not 10 months of data in the follow-up. The paper appeared to be based on the same data included in the April 1, 2021, news release from Pfizer.40

The efficacy results were identical, claiming 91.3% efficacy against symptomatic disease “up to six months of follow-up.” Doshi points out that this matters because it is thus far the most information Pfizer had offered to the public as they were pursuing full approval from the FDA. Both Pfizer41 and the CDC42 have claimed the shot is 95% effective.

Without addressing whether that 95% is absolute or relative risk reduction, or how Pfizer arrived at those claims, it’s also important to note that little can be said about how long vaccine-induced immunity could last when researchers had only measured two months of data.

“Waning immunity” is a known issue for some vaccines, such as the influenza shot.43 Doshi notes44 there have been some studies that found near zero effectiveness only three months after the flu vaccine was administered. The crucial question is the level of effectiveness of the vaccine after an individual is exposed to the virus.

In early July 2021, Israel’s Ministry of Health reported that efficacy against asymptomatic disease fell dramatically in the months following vaccinations. Israel exclusively uses the Pfizer vaccine, which Pfizer’s chief scientific officer, Philip Dormitzer, told a Zoom meeting:45

“Early in the pandemic we established a relationship with the Israeli Ministry of Health where they used exclusively the Pfizer vaccine and then monitored it very closely, so we had a sort of laboratory where we could see the effect.”

Only 7% of Trial Participants Reached 6 Months of Data

Data released from Israel show the efficacy fell to 64% over one month from June 6, 2021, to July 5, 2021.46 By late July, the efficacy had dropped dramatically again to 39%.47 While these numbers are low, the FDA’s expectation is that any approved vaccine should be at least 50% effective.48

Starting in December 2020, Pfizer unblinded the majority of the participants in the trial and allowed the placebo group to get vaccinated. By March 13, 2021, 93% of those participating in the Pfizer trial had been unblinded. This means the reference to six months of safety and efficacy in the preprint paper reports on only the 7% of trial participants that reached six months of the blinded follow up.

While the paper was published one year after the trial began, the data reported do not go past the first six months, which is the time period in which Israel reports efficacy dropped to 39%. Doshi goes on to say:49

“It is hard to imagine that the <10% of trial participants who remained blinded at six months (which presumably further dwindled after 13 March 2021) could constitute a reliable or valid sample to produce further findings. And the preprint does not report any demographic comparisons to justify future analyses.”

Although claims have been made that the vaccine prevents severe disease, the trials were not designed to study severe disease, which Doshi details in another paper published in The BMJ.50 In the opinion piece published in The BMJ, Doshi writes:51

“But here we are, with FDA reportedly on the verge of granting a marketing license 13 months into the still ongoing, two-year pivotal trial, with no reported data past 13 March 2021, unclear efficacy after six months due to unblinding, evidence of waning protection irrespective of the Delta variant, and limited reporting of safety data.”

Coincidentally, the very day Doshi’s paper was published in The BMJ, the FDA announced approval for the Pfizer COVID-19 shot being marketed as Comirnaty.52

Yet, without adequate data analysis, and with mounting numbers of adverse events reported to VAERS,53 the FDA still expanded eligibility for the jab to include children 12 years and older to receive a single booster dose and approved emergency use authorization for children 5 years old and older.54 Doshi ends with a reasoned and logical call to action to the FDA:55

“FDA should be demanding that the companies complete the two-year follow-up, as originally planned (even without a placebo group, much can still be learned about safety). They should demand adequate, controlled studies using patient outcomes in the now substantial population of people who have recovered from covid. And regulators should bolster public trust by helping ensure that everyone can access the underlying data.”

Sources and References

Category:

research, vaccines, Viruses

Points of View: Lyme Disease & Patients

https://danielcameronmd.com/points-of-view-lyme-disease-patients-and-physicians/

Points of view: Lyme disease patients and physicians

frustration in lyme disease patient as he talks to doctor

Raffetin and colleagues explore the perceptions and experiences of Lyme disease patients in an article entitled “Perceptions, Representations, and Experiences of Patients Presenting Nonspecific Symptoms in the Context of Suspected Lyme Borreliosis.” [1]

By

The authors looked at the perceptions, representations, and experiences of patients who had Lyme disease with nonspecific symptoms and no objective manifestations of the disease. This small study included 12 patients with confirmed and non-confirmed Lyme disease or unexplained symptoms.

“Our study highlights that some physicians may also experience a lack of knowledge and information about [Lyme Borreliosis], increasing the difficulty to answer the patient’s needs,” wrote Raffetin et al. 1

The investigators described several themes from their interviews with patients, along with patient statements expressing their frustrations.

Painful Experience with the Disease, Leading to Confusion and Fear

  • “Nothing could bring me relief …, the pain was almost unbearable.”
  • “Always tired, tired … tired, tired.”

Incomprehension, Fear, and Doubt when Faced with the Lack of Explanation for the Symptoms

  • “We kept doing the analyses, we didn’t understand.”
  • “The patients expressed a feeling of fear of unpredictable flare-ups, of not being cured, etc.”
  • “I was afraid of not knowing how I would end up.”

Long and Difficult Treatment Path, Experienced as an Obstacle Course

Fight against the Medical World

  • “My GP, I am reluctant to ask him, he doesn’t want to believe me.”
  • “They don’t listen, … they look at everything medical, and as long as the tests are negative, they say that you have nothing.”
  • “The absence of consensus on recommendations at the time of the study has reinforced the feeling of abandonment by the scientific community.”

Disease Taking a Serious Toll on the Patient’s Health

Multiple and Negative Repercussions, Experienced as an Injustice

  • “At the professional level, the patients reported absences linked to multiple medical consultations, repeated leave from work, etc.”
  • “Activities were impacted by the unpredictability of the symptoms, leading to the feeling of being overwhelmed by the disease.”
  • “The patients described either a lack of understanding from their relatives, or unconditional support, sometimes with the family adapting to their condition.”

Frustration expressed by doctors

The authors also described the frustration among doctors treating Lyme disease patients. “According to a survey, one-third of general practitioners experience difficulty when faced with the ‘insistent’ demands of ‘hyper-informed’ patients.”

“The major challenge for the doctor is to determine on one hand the limits of his own knowledge and his capacity to answer the patient, and on the other hand the quality of the patient’s information sources.”

Some of the problems lie in the lack of education. “The patients highlighted the poor training of physicians regarding persistent symptoms, as has also been shown in several studies on somatic symptom disorders.”

“These results are consistent with the views of the [general practitioners] interviewed in a study by Lisowski et al., 87% of whom said they were uncomfortable following up with patients who had symptoms after a full course of antibiotics due to having failed to provide codified management.”

The authors emphasized the need for a “coordinated care pathway and careful listening and recognition.” They also suggested that specialized reference centers might help meet these expectations.

Related Articles:
Lyme disease myths lead to frustrations for doctors
References:
  1. Raffetin A, Barquin A, Nguala S, et al. Perceptions, Representations, and Experiences of Patients Presenting Nonspecific Symptoms in the Context of Suspected Lyme Borreliosis. Microorganisms. Jul 15 2021;9(7)doi:10.3390/microorganisms9071515

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Category:

Lyme, research

What We Know & Don’t Know About Lyme Disease

https://www.frontiersin.org/articles/10.3389/fpubh.2021.819541

MINI REVIEW article

Front. Public Health, 21 January 2022 | https://doi.org/10.3389/fpubh.2021.819541

What We Know and Don’t Know About Lyme Disease

Sam T. Donta*

Consultant, Infectious Diseases, Falmouth Hospital, Falmouth, MA, United States

We know the cause of Lyme disease. We know that the bacteria can be found in the initial rash, and occasionally in the blood in the subsequent 2–3 months, but after then, its subsequent location is unknown. Whereas diagnosis and treatment of early Lyme disease is generally straightforward, the etiology of relapsing or persisting symptoms is yet to be defined, and presents clinical challenges. There are no current tests to determine if the infection is still present or absent, thus complicating diagnosis and treatment. Presented here are approaches to the diagnosis and treatment of persisting Lyme disease, based on available published information, and the experience of the author.

Introduction

It has been more than 40 years since the discovery of the causative agent of Lyme disease. Much has been learned, but several key questions remain:

  1. how do we know if the infection has been eradicated
  2. can it become dormant
  3. can it reactivate in patients with persistent symptoms, are these due to continuing infection or to non-infectious sequelae, and 4-are there treatments that can resolve the infection

Pathogenesis

We know that Lyme disease is caused by the bacterium Borrelia burgdorferi, transmitted by the bite of an Ixodes tick. We know that the bacteria may be isolated from the typical erythema migrans rash, and can be occasionally recovered from the circulating blood in the subsequent 2–3 months (1). After that time, it has not been possible to consistently isolate the bacteria from any body fluids or tissues.

So, where are they? Under the skin, as demonstrated in studies with macaque primates (2), and similarly in preliminary studies in humans (3)? Intracellularly, as is the case of most, if not all pathogens that can become latent, then recur? Or both? Hence, the central question at the heart of the controversy surrounding the diagnosis and treatment of Lyme disease; i.e., whether persisting or relapsing symptoms are due to continuing infection or due to post-infectious phenomena.

Accumulating evidence regarding the persistence of biologically active, albeit non-replicating bacteria derives from several studies in various animal models. Hodzic et al. demonstrated that B. burgdorferi can persist in mice following antibiotic treatment but were non-cultivatable (4). Casselli et al. demonstrated that B. burgdorferi can colonize the dura mater in mice, are biologically active, and induce host gene inflammatory responses (5). Embers et al. demonstrated post-antibiotic treatment persistence in a non-human primate naturally tick infected model (6) and recovery of the spirochete by xenodiagnosis (2). Similarly, there was recovery of non-cultivatable B. burgdorferi by xenodiagnosis in a few human patients who had had an erythema migrans rash and had had prior antibiotic treatment (3). These results, plus observations by us and others that retreatment of patients with recurring or persisting symptoms following initial antibiotic treatment using specific antibiotic regimens (7), lend strong support to the hypothesis that it is persistent infection by B. burgdorferi that is the likely cause of persisting symptomatology. In contrast, attribution of post-infectious symptoms to some post-infectious phenomena has only been speculative without any supporting evidence.

Diagnostic Issues

Currently, in the absence of any currently available means to directly detect the bacteria or its products, the diagnosis is dependent on the clinical history and any associated manifestations, along with the results of serologic studies. A major clinical problem is, that with the exception of patients with Lyme arthritis, most patients with continuing symptoms have no objective signs for Lyme disease, making the diagnosis dependent on the clinical picture that overlaps with that of chronic fatigue syndrome and fibromyalgia. Making it more difficult is the fact that many such patients do not have robust serologic responses to the causative organisms (8). And, despite claims that once one is treated with 4 weeks of antibiotics, one no longer has Lyme disease, or, if Lyme test results revert to negative, it means one no longer has Lyme disease, these claims being unsupportable in the absence of any means to prove the bacteria’s absence (9).

It also appears illogical, when patients have persisting or relapsing symptoms identical to those at the initial presentation, to opine that the infection is no longer present and that the remaining symptoms are post-Lyme disease of yet to be defined cause. It would seem more logical to assume that the infection has not been eradicated. It may be that ongoing symptoms are due to post-infectious factors, e.g., autoimmunity without provocation from persistent infection, but that has yet to be demonstrated as an obvious cause of the ongoing clinical picture. It seems much more likely that the cause of symptoms are due to some bacterial product, be it an exotoxin or endotoxin, similar to that that is at the root of most, if not all other bacterial infections, accompanied with host-responses to that virulence product or products, including inflammatory and autoimmune responses (10).

Serologic Issues

A similar lack of logic is present in analyzing the results of Lyme Western blot reactions, specifically IgM responses. How logical is it to use positive IgM responses to support the diagnosis of early Lyme disease, but deem that those same responses in patients with ongoing or relapsing symptoms are false-positive responses? Is it not more logical to assume that continued IgM reactivity, in the presence of ongoing symptoms, might be an indicator of unresolved infection in the absence of any available test to determine the continuing presence or absence of the causative organisms? In support of that conjecture, the results of several studies in various animal models, indicate that the causative borrelia are able to modulate humoral antibody responses such that the normal conversion of IgM to IgG antibody responses is abrogated (11).

Treatment Issues

As if confirming the diagnosis isn’t sufficiently difficult, the treatment of relapsing or persisting symptoms has presented its own challenges. There are many antibiotics that are active in vitro against the Lyme bacteria, but have not been clinically very effective. In early Lyme disease, treatment with doxycycline, amoxicillin, or cefuroxime over a period of a few weeks is generally effective. It is in patients with relapsing or persisting symptoms, including those previously treated, inadequately treated, or untreated, that the question arises as to whether any further antibiotic treatment is effective. The answer appears to be yes, if one looks at the pharmacology of specific antibiotics.

Doxycycline appears to have limited efficacy in patients with persisting or relapsing symptoms, especially in patients with symptoms present for greater than a few months. Doxycycline is highly protein-bound in the circulation, and it is unlikely that sufficient antibiotic can diffuse into tissues and cells to affect the borrelia. In contrast, tetracycline, which is not highly protein bound, appears to be clinically effective (10). Our observational results in several thousands of patients since our initial publication attests to both the greater efficacy of tetracycline vs. doxycycline in terms of both dosing and duration of treatment (12).

Beta-lactam antibiotics, including intravenous ceftriaxone, appear to be of limited clinical efficacy, perhaps because (a) that class of antibiotic has its effects on multiplying organisms, and there is no evidence that the Lyme borrelia are multiplying in persistent or relapsing disease, and (b) they are incapable of intracellular penetration. These antibiotics may offer temporary symptom relief, which might be due to their effects on glutamate accumulation during neurotransmission (13), without resolving the underlying infection.

Of particular interest are the effects of macrolide antibiotics (e.g., erythromycin, clarithromycin, azithromycin) on Lyme disease. They are highly active in vitro, and are capable of intracellular penetration, but appear to be of limited clinical value in patients with persistent symptoms. In analyzing the possible reasons, if the borrelia reside intracellularly in an acidic endosome, as is the case for numerous other microbes capable of intracellular persistence, macrolide antibiotics are not very active at an acidic pH. The use of a lysosomotropic agent (e.g., hydroxychloroquine, amantadine) to alkalinize the acidic endosome appears to result in clinical efficacy (14).

There have been two clinical trials using differing antibiotic regimens over a 3 month period of time in patients with persisting symptoms of Lyme disease. In the first trial, patients were given a month of ceftriaxone followed by 2 months of doxycycline vs. placebo treatment, and positive PCR reactivity to Borrelia burgdorferi was an exclusionary criterim for this study (15). In the other trial, patients with persisting symptoms were given an initial week of IV ceftriaxone, then randomized to being given the combination of clarithromycin and hydroxychloroquine vs. placebo for 3 months (16). In neither trial was there any reported greater improvement between the antibiotic treatment arms and placebo arms. The results of these studies have been reviewed with several reservations being expressed about study design, the instruments used to measure changes in symptoms, and interpretation of the results (17). In the former trial, neither ceftriaxone nor doxycycline were given for 3 months, and the assumption that both antibiotics are of equal efficacy is not supportable according to differing mechanisms of action. In the case of ceftriaxone, its antibiotic activity is based on its interference with replicating organisms, and given that there is no evidence to indicate that, once B. burgdorferi has established itself, there is any multiplication of note, it would not be expected to be effective in patients with persistent symptoms. And in the author’s observational experience, even the use of ceftriaxone over periods of time up to 6 months or more was without much if any benefit, with any possible benefit in a few patients due to ceftriaxone’s interference with the glutamate receptor system. In the case of doxycycline, whether a longer duration of treatment or increased dosing would have been effective remains unanswered. Observations by numerous clinicians suggest that higher doses of doxycycline, i.e., 300–400 mg/day might be more effective than the commonly used dosing of 200 mg/day.

In the trial utilizing the combination of clarithromycin and hydroxychloroquine, based on our initial published report, the trial was contaminated by the use of ceftriaxone in all patients prior to randomization to the active or placebo groups. Of greater importance is the failure to consider both the duration of prior symptomatology and the duration of treatment itself. As indicated in our published observations (12, 14), patients with persistent or relapsing symptoms for less than a year appeared to be cured, ie no recurring symptoms for greater than a year, by a treatment course of 3–6 months. In patients with persisting symptoms for >2 or more years, however, treatment success required a treatment duration of 6 or more months, and up to 18 months in patients with persisting symptoms for >5 or more years. Another likely flaw in that trial was not controlling for the use of adjunctive vitamin C. Supplemental vitamin C can be a strong acidifying agent, counteracting the effects of hydroxychloroquine (7, 14), and thus possibly accounting for some of the trial’s failure to show any benefit of this treatment.

Future Directions

The key remaining questions are whether there can be found a better, more direct detection test to indicate the presence or absence of active B. burgdorferi, and whether additional controlled treatment trials using longer durations of treatment with the tetracycline or clarithromycin/hydroxychloroquine regimen, or regimens utilizing different antibiotics or combination of certain antibiotics that might prove effective. The results of recent in vitro and early animal model experiments by Zhang (18) and by Lewis (19) might hold promise of other potentially effective approaches to the management of patients with persistent symptoms of Lyme disease.

Of additional likely importance is the potential role of antibiotic tolerance as a mechanism of persistence and “resistance” of B.burgdoferi to treatment in patients with persisting symptoms. Recent results of experiments with other bacterial organisms that can persist demonstrate the likely role of antibiotic-tolerance as the mechanism by which they persist (20). This mechanism apparently relies on a ribonuclease produced by the organisms. If our preliminary results with BB0755, an annotated ribonuclease, that demonstrated cytotoxic activity with tissue-cultured cells of neural origin (21), is due to its ribonuclease activity, then this possibility might offer an explanation to B.burgdorferi’s antibiotic tolerance.

There are additional questions that a better understanding of the pathophysiology of Lyme disease might lead to better approaches to the diagnosis and treatment of Lyme disease, especially in its persistent form. These include the possible role of antibiotic-tolerant persisters.

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s Note

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Keywords: Lyme disease, Lyme diagnosis, Lyme pathogenesis, Lyme treatment, Lyme serology

Citation: Donta ST (2022) What We Know and Don’t Know About Lyme Disease. Front. Public Health 9:819541. doi: 10.3389/fpubh.2021.819541

Received: 21 November 2021; Accepted: 20 December 2021;
Published: 21 January 2022.

Edited by:  Christian Perronne, Assistance Publique Hopitaux De Paris, France

Reviewed by:  Robert Carroll Bransfield, Rutgers, The State University of New Jersey, United States

Copyright © 2022 Donta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Category:

Lyme, research, Testing, Treatment