Lots of patient explanations, and then reality

A California Lyme disease organization is advertising the contents of their latest newsletter, which includes topics such as, “how Lyme persists despite treatment,” and “10 reasons Lyme patients don’t get better.”  I’d love to read these interesting bits of fantasy, but I don’t have to.  As luck would have it, there’s a nice new summary of such issues:

Nervous System Lyme Disease: Diagnosis and Treatment. Halperin JJ. Curr Treat Options Neurol. 2013 May 12.

Here follows a few highlights from his review.

As with much else in medicine, the diagnosis of Lyme disease is ultimately clinical. This does not mean that any clinician can freely create an arbitrary definition. Rather Lyme disease is associated with a range of clinical and laboratory findings, each of which carries varying positive and negative predictive values, all of which must be considered in arriving at the diagnosis.

Early serologic testing was far from perfect, spawning the often-repeated opinion that it is generally unreliable. However with the development of two-tier testing (screening ELISA followed by confirmatory Western blot for positive or borderline screening tests) and subsequent technical improvements, overall accuracy has increased from the mid 80 % range to the high 90 % range—correctly interpreted and used in the appropriate setting. Several limitations are inherent in all serologic testing. Since, in any infection, it takes several weeks for the humoral response to generate detectable specific antibody, serologic results are predictably negative in the first 3–6 weeks of infection. In other infections diagnosed serologically, acute and convalescent sera are routinely tested to address this — something not normally done in Lyme disease perhaps because of incorrect inferences from reaginic testing in syphilis. About 50 % of patients with EM will be seronegative; patients with this characteristic rash should be treated without even obtaining blood tests.

Finally, and again peculiar to Lyme disease, is the notion that the administration of antibiotics — either at the time of serologic testing, or in a subcurative dose after infection but prior to testing — could render serologic testing falsely negative. The first notion is neither biologically plausible nor supported by any empiric evidence. The second was hypothesized in the 1980’s. This has not been supported by subsequent work and was almost certainly an artifact of the technology in use 25 years ago.

In vitro, B. burgdorferi remains highly sensitive to many common oral antibiotics including tetracyclines, penicillins, and various second and third generation cephalosporins. Although sensitive in vitro to macrolides such as erythromycin and azithromycin, these agents are less effective clinically. Among parenteral antibiotics ceftriaxone and cefotaxime have equivalentefficacy, although the once a day dosing of ceftriaxone makes it easier—and more economical—to administer. Meningeal dose penicillin is effective but may be inferior, based on a small number of Class 3 and 4 studies.

Guidelines generally recommend 3–4 weeks of antibiotic therapy, although there is a paucity of evidence indicating that treatment beyond 2 weeks provides additional benefit.

Most of the controversy regarding treatment of Lyme disease stems from the observation that many patients, particularly those with neuroborreliosis, remain symptomatic following completion of recommended treatment. Persisting symptoms fall into one of several categories. Individuals with focal neurologic damage, such as facial nerve palsy, may have a residual deficit that will slowly recover. This is the natural history of virtually any nervous system insult, and should not lead to confusion. More problematic has been the observation that many patients continue to have non-neurologic systemic symptoms at the completion of treatment. Patients with active Lyme disease often experience the same nonspecific symptoms—malaise, fatigue, aches and pains, cognitive slowness, etc.—seen in those with other active infections and inflammatory states ranging from pneumonia to viral meningitis to active ulcerative colitis. These symptoms often persist after recommended treatment, both in Lyme disease and other disorders. Just as pneumonia treatment would not be extended for such symptoms, or for a persistent infiltrate on chest X-ray, these symptoms do not provide a rationale for continuing treatment in Lyme disease. Similarly, since laboratory testing measures infection-specific antibody and not bacteria, persisting test positivity does not require continued treatment.

The patient population that has drawn the most attention consists of individuals in whom these systemic symptoms occur or persist for more than 6 months after appropriate treatment. Such individuals, referred to as having post-Lyme disease syndrome or, by some, chronic Lyme disease, lack any of the usual objective markers of active disease such as clinically evident new inflammatory involvement of joints, nervous system or other organs. Treatment trials lead to two clear conclusions. First, despite the tremendous amount of attention focused on this disorder, it is quite uncommon. Trials have generally had great difficulty recruiting appropriate subjects, despite screening thousands of individuals who believe they meet criteria for the diagnosis. Second, prolonged treatment with up to 10 weeks of parenteral ceftriaxone confers no lasting benefit, and may entail significant risk, inconvenience, and cost.

A number of novel mechanisms has been suggested to explain this purported state, most of which are based on the assumption of persisting infection. The most common suggestion is that B. burgdorferi adopts a form—intracellular, cyst-like or in a biofilm—that hides it from the host immune response and from antimicrobials. The biggest challenge to this hypothesis (other than the absence of credible evidence that it occurs in humans) is logical. First, there are numerous examples of other infections, tuberculosis being the most common, where individuals harbor more immunogenic microorganisms for years with no symptoms whatever.

The second challenge relates to pathophysiology. There are just 2 potential mechanisms by which a micro-organism can affect its host—directly by secreting exotoxins, molecules that migrate away from the site of infection, and then trigger physiologic effects, or indirectly by triggering a host immune response that then becomes misdirected or overly amplified, causing symptoms. B. burgdorferi does not secrete an exotoxin, excluding the first mechanism. Although it is thought that much of the symptomatology of B. burgdorferi relates to the host immune response, if the pathophysiology of this purported chronic infection requires that the organism remains hidden from the immune response, it becomes implausible to argue that an accentuated immune response is responsible for symptoms.

If this patient population is not suffering from persistent infection, what then is responsible for their ongoing, highly troubling symptoms? Perhaps the best answer comes from a series of epidemiologic studies. First, controlled studies do not generally show these symptoms to be more common in patients treated for Lyme disease than in controls; however, patients treated for Lyme disease are more likely to attribute symptoms to the infection that they had, demonstrating the common human tendency to try to identify associations to explain the otherwise unexplained.

It seems plausible that this syndrome reflects nothing more than the coincidental occurrence of this poorly understood clinical syndrome in individuals who happen to have had Lyme disease. This is not to minimize these symptoms or their impact on the lives of patients with them; however, the evidence seems compelling that they are not evidence of ongoing infection and do not benefit from antimicrobial therapy.

Depression and Infection

Antidepressants Linked to Doubling of C difficile Risk

Fran Lowry

May 07, 2013

Two antidepressants — mirtazapine and fluoxetine — have been linked to a significantly increased risk for Clostridium difficile infection (CDI), new research shows.

Investigators at the University of Michigan in Ann Arbor found that the drugs were associated with a 2-fold increased risk for the infection, particularly in older individuals who live alone.

"Clinicians prescribing antimicrobials to patients with depression should be aware of the possible increased risk of CDI in this patient population," lead author Mary A. M. Rogers, PhD, told Medscape Medical News.

The study was published online May 7 in BMC Medicine.

[snip]

"One of the possible underlying reasons for the link between depression and C difficile infection comes from studies of the bacterial makeup of the gut," Dr. Rogers said.

"This is important because C difficile infection tends to occur when there is less diversity in gut bacterial communities, such as after receiving antibiotics, and we know from previous studies that patients with depression have different bacterial communities in their gut than individuals without depression. We don't know exactly why this is, but inflammation may play a role, or changes in the diet," she said.

Colonization vs. Infection

Excerpts from: MicrobiologyBytes

May 16th, 2013

Asymptomatic carriage of Mycoplasma pneumoniae common in children

Remember Koch’s Postulates? 

These are the four criteria designed to establish a causal relationship between a causative microbe and a disease:

1. The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms.
2. The microorganism must be isolated from a diseased organism and grown in pure culture.
3. The cultured microorganism should cause disease when introduced into a healthy organism.
4. The microorganism must be reisolated from the inoculated, diseased experimental host and identified as being identical to the original specific causative agent.

Simply finding a potentially-disease causing organism does not necessarily mean it’s up to no good!

The bacterium Mycoplasma  pneumoniae is carried at high rates in the upper respiratory tracts of healthy children and usual diagnostic tests cannot differentiate between such asymptomatic carriage and actual respiratory tract infection, according to a new study. These findings are important as they suggest that clinicians may need to reconsider the clinical significance of a positive test result for the presence of this bacterium.

The researchers compared upper respiratory tract swabs and blood culture results taken from 321 children (aged 3 months to 16 years) admitted to hospital with a respiratory tract infection with those from 405 healthy children undergoing an elective surgical procedure. They found that the prevalence of M. pneumoniae (as measured using PCR tests) did not differ significantly between the asymptomatic group and the symptomatic group. There was also no difference in prevalence when diagnosed using blood tests. In addition, a high rate of other bacteria and viruses was found in both asymptomatic and symptomatic children.

This data indicates that the presence of M. pneumoniae in the upper respiratory tract is common in asymptomatic children. Current diagnostic tests for M. pneumoniae are unable to differentiate between asymptomatic carriage and symptomatic infection. Cinicians may need to readdress the clinical significance of a positive test result.

More Lyme Protests

What if Lyme activists held a rally (again) and the same people showed up (again) saying the same old things (again)?  Case in point:

NEWS: “Sometimes a little rebellion is necessary” 14th May 2013.  Dr. Kenneth Leigner, speaking at New York City's Lyme protest rally May 10, called on Lyme patients to be "pro-active, militant and resolute" in demanding the care they need and deserve.  The following is the text of Dr. Leigner’s remarks at the World Wide Lyme Rally & Protest Friday, May 10, 2013 Union Square, New York City.  [Name misspelled]

“Chronic Lyme disease does not exist”.

There are four possibilities to explain why a person might hold this view:

They can be ‘dumb as bags of rocks’.

They can be character-disordered, with excessively rigid thinking, and perfect, impenetrable circular logic.

They can be corrupt.

They can be sociopaths.

One thing is for damn sure: they are truly lousy clinicians.

Isn’t that 5 reasons?  How about a 6^th reason: there’s no convincing evidence—after some 30 years of clinical practice and research—for B. burgdorferi surviving an adequate dose of common antibiotics.

Liegner has been at this for a couple of decades now.  He’s a private practice physician with lots of patients who think they have a permanent Lyme infection, and, who knows, given his locale and statistical probability, at some point a real patient with Lyme disease has probably walked into his waiting room.  He attends these patient rallies, I suspect, for reasons of ego stroking and patient hunting.  He often shows up at real science conferences and then notes his attendance on a resume padded with such events* and with a listing of published letters-to-the-editor, which most lay people might mistake for actual research publications.  It’s a resume that would embarrass a real scientist or physician scientist.

So he’s back in the “Lyme” light talking about an anecdotal patient from 1991, a rhesus monkey as the appropriate model for human infections and treatments, and how managed health care is keeping Lyme patients from getting treated.  “An infection that can be chronic and require a long-term treatment approach does not fit the ‘business model’ of managed care: predictable premiums, predictable costs, predictable profit.  With managed care it became feasible to control costs by defining away the chronic infectious aspects of Lyme disease.”  Oddly, the “business model” doesn’t seem to have a problem with paying for long-term treatments of HIV, HepC, or detectable bacterial infectious such as TB and Q Fever.  I guess the magic word here is “detectable,” which is not the case with so-called chronic Lyme disease.  

Liegner again: “Health plans and insurers and hospitals red flag physicians not conforming to IDSA guidelines for sanctioning and often report them to State Boards of Medical Practice** to ‘break their knees’.  This cowardly and despicable ‘modus operandi’ is an assault on physicians’ most prized possession: professional autonomy and independent medical judgment.”  So, he’s likely to be a cash-only doc, wanting to avoid the queries of state medical boards and insurance standards.  As he said above, he wants to be able to do whatever the hell he wants without anyone questioning his professional competence or motives.  And who wouldn’t want that?  Still, I think it’s a good idea for physicians to maintain some ethics and some degree of competence…even in the privacy of their own offices.  

The rest of Liegner’s very long speech (7 pages)—and heard previously on many occasions—is the requisite condemnation of various actual infectious disease experts (e.g., Dattwyler, Steere, Wormser), complaints about the IDSA and false statements about the actual conclusions of the 2009 re-review of the IDSA guidelines, comparisons of the current treatment of so-called chronic Lyme patients to Tuskegee, and the re-litigation of a case involving one his patients and her medical insurance company in 1998.  The judge concluded: “The appellants' claim is without merit. The evidence established that Empire periodically amended and revised its policy with respect to the treatment of Lyme disease "in response to published, peer-reviewed studies". While such amendments and revisions of its policy may have resulted in stricter standards that made it more difficult for policyholders to establish that intravenous antibiotic therapy was "medically necessary" to treat Lyme disease, it cannot be concluded that such conduct was intended to defeat the contract. To do so would essentially require Empire to ignore the latest research and findings within the medical community concerning what is appropriate treatment for a given medical condition. Taken to its extreme, this would lead to the absurd result that an insurer could be forced to cover treatment which is no longer considered medically effective, while at the same time denying coverage for treatment which has recently been proven to be effective in treating a given disease or medical condition.” (The opinion of the court was delivered by: Friedmann, J.)   I guess Leigner got stiffed, and he’s still miffed.

Liegner, who is a technician, not a scientist, also noted, “Honest science does not need to suppress opposing views.” That’s correct; all it requires is reproducible evidence from those seeking to overturn current theories and practices.  

We’re waiting….

*For example, public events open to all:

Member, Treatment Panel, N.I.H. State-of-the-Art Conference on Lyme Disease, March 1991, Bethesda, MD. 

Co-Chair, Treatment Poster Discussion Section, Fifth International Conference on lyme Borreliosis, May/June 1992, Arlington, VA.

Participant, N.I.A.I.D. Consultations on Chronic Lyme Disease, February & October, 1994, Rockville, MD. 

Member, Program Committee, 7th International Conference on Lyme Borreliosis, San Francisco, CA., Spring 1996. 

Presenter to Infectious Diseases Society of America Lyme Disease Review Panel, July 30, 2009, Washington, D.C. 

** Here’s a curious item: “Douglas Nadjari, Esq. – NY, who successfully counseled Dr. Liegner through the OPMC process.” Anyone know what specifically brought Liegner and his attorney before the New York State Office of Professional Medical Conduct?

Bottom of Form

Top of Form

Vaccines and Public Confidence

Measuring vaccine confidence: analysis of data obtained by a media surveillance system used to analyse public concerns about vaccines, 13 May 2013. Heidi J Larson, David MD Smith, Pauline Paterson, Melissa Cumming, Elisabeth Eckersberger, Clark C Freifeld, Isaac Ghinai, Caitlin Jarrett, Louisa Paushter, John S Brownstein, Lawrence C Madoff

Background

The intensity, spread, and effects of public opinion about vaccines are growing as new modes of communication speed up information sharing, contributing to vaccine hesitancy, refusals, and disease outbreaks. We aimed to develop a new application of existing surveillance systems to detect and characterise early signs of vaccine issues. We also aimed to develop a typology of concerns and a way to assess the priority of each concern.

Methods

Following preliminary research by The Vaccine Confidence Project, media reports (eg, online articles, blogs, government reports) were obtained using the HealthMap automated data collection system, adapted to monitor online reports about vaccines, vaccination programmes, and vaccine-preventable diseases. Any reports that did not meet the inclusion criteria—any reference to a human vaccine or vaccination campaign or programme that was accessible online—were removed from analysis. Reports were manually analysed for content and categorised by concerns, vaccine, disease, location, and source of report, and overall positive or negative sentiment towards vaccines. They were then given a priority level depending on the seriousness of the reported event and time of event occurrence. We used descriptive statistics to analyse the data collected during a period of 1 year, after refinements to the search terms and processes had been made.

Findings

We analysed data from 10 380 reports (from 144 countries) obtained between May 1, 2011, and April 30, 2012. 7171 (69%) contained positive or neutral content and 3209 (31%) contained negative content. Of the negative reports, 1977 (24%) were associated with impacts on vaccine programmes and disease outbreaks; 1726 (21%) with beliefs, awareness, and perceptions; 1371 (16%) with vaccine safety; and 1336 (16%) with vaccine delivery programmes. We were able to disaggregate the data by country and vaccine type, and monitor evolution of events over time and location in specific regions where vaccine concerns were high.

Interpretation

Real-time monitoring and analysis of vaccine concerns over time and location could help immunization programmes to tailor more effective and timely strategies to address specific public concerns.

We now have a growing body of evidence of the potential risks of the spread of unchecked rumours, and of failing to address legitimate questions and concerns. Even if concerns driven by misinformation or reported adverse events are investigated and confirmed as not being caused by vaccines, concerns and reputations in the public mind need to be addressed. Although 69% of the global reports were positive about vaccines, 31% were not. And, of these 31%, a large proportion of concerns are related to belief systems. The public health community should not underestimate the implications of the global burden of belief.

There's no helping some people

Girl With Tics Bucks Doctors, Blames Lyme Disease

ABC News, by SYDNEY LUPKIN

May 13, 2013

On Dec. 19, 2011, Lori Brownell, who was 17 at the time, shot a YouTube video of herself as she talked about the tics she'd developed weeks earlier. She twitched her body, fluttered her fingers and made noises in her throat as she described her fainting and seizing episodes.

Within a few months, 18 high school girls and one boy in western New York came down with the same Tourette's syndrome-like symptoms as Lori's, sparking a national media frenzy and a medical mystery. Although Lori lives in Corinth, N.Y., she became lumped in with the majority of the tic-ing girls 250 miles away in Le Roy, because she'd driven through the town with a friend on her way to a softball game in Ohio.

Fourteen of the 19 tic-ing patients sought treatment at Dent Neurologic Institute, where they were eventually diagnosed with mass psychogenic illness, a rare form of conversion disorder in which an emotional response to stress can manifest in physical symptoms, such as tics. They have all since recovered, their doctor, Dr. Jennifer McVige, told ABCNews.com.

But not Lori. Lori's mother did not want to send her to Dent because it had diagnosed the other girls with conversion disorder – a diagnosis experts said patients often greet with denial.

Instead, Lori and her mother say they believe "chronic" Lyme disease, a controversial diagnosis, caused Lori's tics and may even have caused the Le Roy girls' tics, too. But most doctors -- and insurance providers -- say there's no such thing as "chronic" Lyme disease, and that Lyme disease doesn't cause Tourette's syndrome-like tics.

"The short answer is you won't find that in medical texts," said Dr. William Schaffner, a former president of the National Foundation for Infectious Diseases. "Since Lyme disease has been studied with enormous care and thoroughness, the literature on Lyme first described 35 or 40 years ago now fills half a room. Its clinical manifestations are extremely well known. I think this is an unlikely cause of this single girl's illness."

Still, Lori has been on intravenous antibiotics to treat Lyme disease for nearly a year.

Although Lori was honored with the Tick-Borne Disease Alliance's Courage Award this month, Schaffner said groups often peg symptoms to the wrong illness in an attempt to explain them.

"Then, when science doesn't bear out, it's very difficult for people to accept that," he said, adding that "chronic" Lyme disease was an example of this.

Schaffner, who heads Vanderbilt University's department of preventive medicine, said doctors at the Infectious Disease Association of America concluded that the bacterium that causes Lyme is killed off after a week or two of antibiotics. It doesn't linger and cause recurring or worsening symptoms. "That syndrome doesn't exist," Schaffner said of "chronic" Lyme disease.

Although Lori's doctor prescribed long-term intravenous antibiotics to be delivered through a semi-permanent opening in her arm called a PICC line, the CDC said studies have found that long-term antibiotics don't work any better than placebos.

As 14 of the 19 tic-ing teenagers went to Dent Neurologic Institute for further testing, with help from experts at the New York Department of Health and the National Institutes of Health, Brownell refused to send Lori there.

"No, Lori did not go to Dent, would never go to Dent, nor would I ever want to have them see her," Brownell said. "They're the ones saying it's mass hysteria for those other girls like in Le Roy."

McVige, a pediatric neurologist at Dent Institute, treated the other Le Roy teenagers, looking for infectious or environmental causes for their tics. She found none.  McVige also tested them for Lyme disease. None of her patients tested positive for that either.

Lori…has made 38 YouTube videos and participated in three documentaries. She said she wants to let the medical community, including the CDC, know that it's wrong about Lyme disease. 

Lori learned about Lyme disease because a woman saw her story and wrote her a letter, complete with pamphlets and Lyme information.

But finding a doctor to diagnose her wasn't easy. Ultimately, Lori's mom had to drive her three hours to Mount Kisco, N.Y. "I realized it's hard to get people to listen to and believe in it," Lori said. "I found out not many people or doctors do."

Although Lori had tested negative for Lyme disease in 2009, two years before her tics started, Dr. Daniel Cameron said he diagnosed her with it in 2012 based on her medical history, which included a swollen knee the year she was tested for Lyme. Cameron said Lori probably had a false negative test in 2009, and that the bacterium had smoldered and gotten worse over time, causing neurological symptoms.  He prescribed long-term intravenous antibiotics….

Because chronic Lyme disease and long-term intravenous antibiotic treatments aren't accepted as a diagnosis or treatment by the general medical community, Lori's mother said most of her insurance claims have been turned down. She said her insurance company denied her $1,531.60 a week, and she owed tens of thousands of dollars in medical expenses.

One clinic stopped giving Lori medicine because it said its infectious disease specialist had to examine Lori for it to continue treatment, Brownell said. The clinic, according to Brownell, said Cameron's diagnosis wasn't sufficient.

A surprising use for antibiotics

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Hanne B. Albert, Joan S. Sorensen, Berit Schiott Christensen, Claus Manniche. Antibiotic treatment in patients with chronic low back pain and vertebral bone edema (Modic type 1 changes): a double-blind randomized clinical controlled trial of efficacy. Eur Spine J (2013) 22:697–707.

Modic type 1 changes are bone edema in vertebrae and have been shown to be both commonly observed in and tightly associated with, low back pain. A recent systematic review showed that the prevalence for any type of Modic change in patients with non-specific low back pain (LBP) was 46 % as opposed to 6 % in the general population.

Infection is one of the hypothetical causes of the bone edema underlying Modic type 1 changes. Stirling found nuclear tissue removed under strict sterile conditions during surgery for lumbar herniated discs, to be infected with low virulent anaerobic organisms (Proprionibacteriumacnes and Corynebacterium propinquum) in 53 % of the patients. To investigate if skin contamination was the cause of this surprising result, Stirling et al. conducted another study with 207 patients with lumbar disc herniation and 27 patients with other spinal disorders such as scoliosis, fracture and tumors, all patients had nucleus material removed. In 37 % of the patients with lumbar disc herniation bacteria were identified, mainly P. acnes. Conversely, no (0 %) bacteria were found in the extracted nuclear material in the group with other spinal disorders.

The aim of this study was to test the efficacy of Modic antibiotic spine therapy (MAST) in patients with chronic low back pain, new Modic type 1 changes in the vertebrae adjacent to a previously herniated disc. Additionally, we investigated whether a dose–response relationship could be identified.

Three independent experts in infectious diseases were presented with the bacterial culture results of Stirling’s study and all three recommended amoxicillin–clavulanate. This drug is known to be able to penetrate into the discs. Therefore, treatment consisted of amoxicillin–clavulanate (500 mg/ 125 mg) (Bioclavid) tablets three times a day, at 8 h intervals, for 100 days. This long duration of antibiotic treatment is commonly prescribed for post-operative discitis.

Perhaps most encouraging for further work in this area has been the finding that the improvements obtained with the current MAST protocol, in this group of traditionally resistant chronic low back pain patients, has been substantially greater than those described with all other

established conservative treatments.

Proprionibacterium acnes bacteria secrete propionic acid, which has the capacity to dissolve fatty bone marrow and bone. We hypothesize that diffusion of propionic acid from the disc into the vertebrae causes the Modic changes. Similarly, as increased TNF-alfa and the growth of PGP-5 unmyelinated nerve fibers have been reported in Type 1 Modic changes, with the inherent slowness of these pathological processes perhaps explaining the delayed onset of improvement observed in this study.

Many antibiotics have an anti-inflammatory effect, via TNFa-inhibition. However, amoxicillin–clavulanate (Bioclavid) has been shown to have a very small anti-inflammatory effect comparable to other antibiotics and only an inhibitory effect on IL-1 and IL-8, not TNFa which is present in the Modic changes. This was an additional reason for the selection of amoxicillin–clavulanate (Bioclavid) in this study. Normally, anti-inflammatory effects are rapid quite fast-acting, whereas in this study the effect took 6–8 weeks to manifest, more consistent with the clinical course of resolving infection in poorly vascularized infected tissue, i.e., an antibiotic effect.

A New LD Vaccine? Probably Not in the US

Notes from:

Lyme disease vaccination: are we ready to try again? Paul Lantos. Lancet Infectious Diseases, May 2013.

Research in the 1990s ultimately confirmed the suitability of OspA vaccination for prevention of human Lyme disease. Two commercial OspA vaccines, LYMErix (SmithKline Beecham) and ImuLyme (Connaught) were registered with the US Food and Drug Administration (FDA), and LYMErix was ultimately licensed in December, 1998. Three doses of this vaccine had 76% protective efficacy against definite Lyme disease and 100% against asymptomatic infection. According to several models, the vaccine was cost effective for individuals at high risk of infection. However, in early 2002, LYMErix was voluntarily withdrawn from the market, merely 38 months after its approval. The withdrawal was not because of any substantiated concerns about safety—the vaccine was not a commercial success.

In The Lancet InfectiousDiseases, Nina Wressnigg and colleagues address this issue in a phase 1/2 trial of a novel multivalent OspA vaccine. The vaccine contains epitopes from six distinct OspA serotypes. In addition to B burgdorferi sensu stricto, the vaccine extends coverage to Borrelia garinii, Borrelia afzelii, and Borrelia bavariensis. Wressnigg and colleagues showed that 30ug, 60ug, and 90ug doses of adjuvanted or non-adjuvanted vaccine induced substantial mean IgG antibody titres against six OspA serotypes after three initial vaccinations, and again after a booster given 9–12 months after the first vaccination.

If this new OspA vaccine comes into clinical use, it could prevent Lyme disease throughout Asia, Europe, and North America….

However, our past experience with Lyme disease vaccination should prompt some circumspection about whether a new vaccine can ever overcome the factors that caused the commercial failure of LYMErix. First, Lyme disease is geographically confined, and the risk of Lyme disease is related to activities in tick habitat, so not all individuals in regions where the disease is endemic are at equal risk. Second, the disease is not lethal and does not cause permanent morbidity, and outcomes of antibiotic treatment are excellent in most cases. Finally, small rodents are the natural reservoir for B burgdorferi, and transmission between people does not occur, so even 100% vaccine uptake would not result in so-called herd immunity.

It could be too early to judge how Lyme disease vaccination would fare in a European market, but the tick-borne encephalitis vaccine should offer some perspective. Tick-borne encephalitis is transmitted by the same Ixodes spp ticks as Eurasian Lyme disease and largely shares its geographical range. The disease is potentially lethal, leaves many survivors with permanent neurological impairment, and is untreatable. Its vaccine is highly effective and produces sustained immunity. Yet—except in the setting of mass vaccination campaigns, such as in Austria—vaccination frequency in endemic areas of Europe is appallingly low: less than 15% in much of Europe and less than 5% in Slovenia, where the disease is highly endemic.

Another Shot at a Lyme Vaccine

Some highlights from the recent Lyme/OspA vaccine trial in Europe. 

Safety and immunogenicity of a novel multivalent OspA vaccine against Lyme borreliosis in healthy adults: a double-blind, randomised, dose-escalation phase 1/2 trial. 

Nina Wressnigg, Eva-Maria Pöllabauer, Gerald Aichinger, Daniel Portsmouth, Alexandra Löw-Baselli, Sandor Fritsch, Ian Livey, Brian A Crowe,Michael Schwendinger, Peter Brühl, Andreas Pilz, Thomas Dvorak, Julia Singer, Clair Firth, Benjamin Luft, Bernhard Schmitt, Markus Zeitlinger,Markus Müller, Herwig Kollaritsch, Maria Paulke-Korinek, Meral Esen, Peter G Kremsner, Hartmut J Ehrlich, P Noel Barrett.

Lancet Inf. Dis., May 2013.

Background

Lyme borreliosis is caused by Borrelia burgdorferi sensu stricto in the USA and by several Borrelia species in Europe and Asia, but no human vaccine is available. We investigated the safety and immunogenicity of adjuvanted and non-adjuvanted vaccines containing protective epitopes from Borrelia species outer surface protein A (OspA) serotypes in healthy adults.

Methods

Between March 1, 2011, and May 8, 2012, we did a double-blind, randomised, dose-escalation phase 1/2 study at four sites in Austria and Germany. Healthy adults aged 18–70 years who were seronegative for B burgdorferi sensu lato were eligible for inclusion. Participants were recruited sequentially and randomly assigned to one of six study groups in equal ratios via an electronic data capture system. Participants and investigators were masked to group allocation. Participants received three vaccinations containing 30 μg, 60 μg, or 90 μg OspA* antigen with or without an adjuvant, with intervals of 28 days, and a booster 9–12 months after the first immunisation. The coprimary endpoints were the frequency and severity of injection-site and systemic reactions within 7 days of each vaccination, and the antibody responses to OspA serotypes 1–6, as established by ELISA. This study is registered with ClinicalTrials.gov, number NCT01504347.

Findings

300 participants were randomly assigned: 151 to adjuvanted vaccines (50 to 30 μg, 51 to 60 μg, and 50 to 90 μg doses), and 149 to non-adjuvanted vaccines (50 to 30 μg, 49 to 60 μg, and 50 to 90 μg doses). Adverse reactions were predominantly mild, and no vaccine-related serious adverse events were reported. The risk of systemic reactions and of moderate or severe systemic reactions was significantly lower for adjuvanted than non-adjuvanted formulations. The 30 μg adjuvanted formulation had the best tolerability profile; only headache, injection site pain, and tenderness affected more than 6% of patients. All doses and formulations induced substantial mean IgG antibody titres against OspA serotypes 1–6 after the first three vaccinations (range 6944–17 321) and booster (19 056–32 824) immunisations. The 30 μg adjuvanted formulation induced the highest antibody titres after the booster: range 26 143 to 42 381.

Interpretation

The novel multivalent OspA vaccine could be an effective intervention for prevention of Lyme

borreliosis in Europe and the USA, and possibly worldwide. Larger confirmatory formulation studies will need to be done that include individuals seropositive for Borrelia burgdorferi sensu lato before placebo-controlled phase 3 efficacy studies can begin.

Funding

Baxter.

*We have used knowledge of OspA structure and function to develop a new vaccine, which comprises three recombinant OspA antigens. Each recombinant OspA antigen contains protective epitopes from two different OspA serotypes: OspA-1 and OspA-2 (B burgdorferi sensu stricto and Borrelia afzelii); OspA-5 and OspA-3 (both Borrelia garinii); and OspA-6 and OspA-4 (B garinii and Borrelia bavariensis). In a proof-of-concept study, one chimeric molecule (OspA-1 and OspA-2) elicited antibody responses that protected mice against infection with either B burgdorferi sensu stricto (OspA-1) or B afzelii (OspA-2). The new multivalent vaccine is designed to protect against all major disease-causing Borrelia species in the USA (OspA-1) and Europe (OspA serotypes 1–6), and potentially throughout the world. The hypothetical risk of T-cell cross-reactivity has been eliminated with the replacement of the putative cross-reactive OspA-1 epitope with the corresponding OspA-2 sequence. We did a dose-finding study to investigate the safety and immunogenicity of adjuvanted and non-adjuvanted vaccine formulations in healthy adults.

Our primary ELISA-based immunogenicity data are supported by the finding that vaccine-induced antibodies can also bind to and promote the killing of B burgdorferi, B afzelii, B bavariensis, and B garinii. OspA antibodies could prevent tick-to-host transmission by various mechanisms, such as aggregation or interference with one of the many specific functions attributed to OspA…. Importantly, the results of the surface-binding assay show that antibodies induced by the multivalent OspA vaccine can bind to strains expressing OspA serotypes 1–6, which are representative of all major human pathogenic Borrelia species. These data, together with the preclinical evidence for protection against challenge in mouse infection models, suggest that the vaccine has the potential to induce protective antibody responses.

When it’s not Lyme disease

This is a handy cheat sheet for clinicians trying to sort through the various tick-borne pathogens common to the U.S. and their clinical manifestations.

Shah RG, Sood SK. Clinical approach to known and emerging tick-borne infections other than Lyme disease. Curr Opin Pediatr. 2013 Jun;25(3):407-18.

It is evident from the recent literature reviewed that the scope of tick-borne illnesses has been broadening. Because of the diverse clinical manifestations and multiple clinical complications of tick-borne infections, it is important for pediatricians to consider tick-borne infections in the differential diagnosis of patients with common infectious presentations. Familiarity with different tick vectors will aid the clinician in recognition of specific tick-borne infections. In the past few years, several new pathogens have emerged as tick-borne causes of human disease. The prevalence of pathogens such as DTV [deer tick virus] and novel spotted fever rickettsiae in ticks, and the availability of genetic sequencing to aid in their diagnosis, augurs for increased detection of novel diseases in the future.

See color images and distribution maps of various ticks found in the U.S.

Note: In 2012, McMullan et al. reported two cases of a disease caused by a phlebovirus in Missouri. The phlebovirus, named the Heartland virus, was presumed to be the causative pathogen in two men who had a severe febrile illness, with various nonspecific clinical manifestations that included fever, severe fatigue, headache, gastrointestinal symptoms, myalgia, and a dry cough. Phleboviruses, which may be transmitted by sand flies, mosquitoes or ticks, were not previously known to cause tick-borne disease in the United States.

Open Access Journals

U.S. Government Accuses Open Access Publisher of Trademark Infringement

by Jocelyn Kaiser on 9 May 2013

Misleading? A federal lawyer alleges that OMICS Publishing Group has used NIH's name in erroneous ways.

Submitting a paper to a new open access journal can be a risky venture: More and more companies are popping up with an offer to publish a report for a fee but deliver less than expected—sometimes they skip peer review or use editors who do no work—according to critics such as Jeffrey Beall, a University of Colorado, Denver, librarian who keeps a list of so-called predatory publishers. Now, the U.S. government has jumped in as an enforcer, warning one open access publisher to stop misusing the names of the National Institutes of Health (NIH) and the agency's employees in promotional material.

Read the article here.

It's all in your head

Nocebo Mass Delusion

Published by Steven Novella

Expectation bias cuts both ways, for positive and negative expectations. Expectation bias, the tendency to perceive and accept data that reinforces your expectation, is one of the m any contributors to placebo effects (the illusion of a positive benefit that derive from something other than an active treatment). It is also, however, part of nocebo effects  (the illusion of negative side effects from something other than active treatment).

Expectation bias can be powerful enough in some people to lead not only to the perception of a benefit or side effect but to a frank delusion. When this happens on a large scale, that can lead to a mass delusion. There are many episode that demonstrate this effect, but now there is also a controlled experiment that also confirms it.

A recent study looked at sham exposure to wifi signals in 147 subjects. They were first exposed to either a documentary about the dangers of wifi, or to a documentary about internet security. A total of 54% of the subjects experienced

“…agitation and anxiety, loss of concentration or tingling in their fingers, arms, legs, and feet. Two participants left the study prematurely because their symptoms were so severe that they no longer wanted to be exposed to the assumed radiation.”

Further, the group exposed to the wifi documentary experience significantly more symptoms.  This is a small study but it matches prior research showing that those who believe they have electromagnetic sensitivity will experience symptoms when exposed to sham EMF. The difference with the current study is that it used healthy volunteers and controlled for media exposure.

Read the entire post here.

Maybe You Should Move

Lane RS, Fedorova N, Kleinjan JE, Maxwell M. Eco-epidemiological factors contributing to the low risk of human exposure to ixodid tick-borne borreliae in southern California, USA. Ticks Tick Borne Dis. 2013 May 2

In northwestern California, the nymph of I. pacificus is the primary vector of LD-group spirochetes, Borrelia burgdorferi sensu lato (Bb sl), with the average infection prevalence usually ranging from about 2 to 15% versus only 1–4% in adult. In southern California, the primary microhabitats of the nymphs have not been identified. Furthermore, culture or DNA isolates of B. burgdorferi from this region are rare suggesting that some, if not most, of the LD cases may be caused by borreliae related to, but genetically distinct from, B. burgdorferi.

Three state parks were selected for investigation because they are located near Malibu, an affluent coastal community where LD cases anecdotally have been physician-diagnosed. Our specific objectives were 3-fold: to discover the previously unknown primary microhabitats of I. pacificus nymphs in chaparral and oak-woodland litter areas; to determine the abundance, seasonality, and prevalence of borrelial infection in host-seeking nymphs and adults of I. pacificus and another important human-biter, the Pacific Coast tick (Dermacentor occidentalis); and to identify to genospecies any DNA isolates detected in either nymphs or adult ticks.

None of the questing (n = 27) or lizard-attached I. pacificus nymphs (n = 118) tested by PCR was positive, but B. burgdorferi was detected in very low percentages of the I. pacificus and D. occidentalis adults. Although D. occidentalis cannot transmit B. burgdorferi during feeding, the larvae and nymphs infrequently acquire and trans-stadially pass spirochetes after having fed on infected reservoir hosts, such as the western gray squirrel. Most importantly, only one of 7 infected I. pacificus adults collected from fall 2009 to early spring 2010 contained the human pathogen B. burgdorferi, so the infection prevalence in this tick (0.04%) was less than that (0.22%) in D. occidentalis, an in efficient vector.

Despite the very low Bbsl infection prevalence in I. pacificus ticks, a mixed infection of 2 distinctive, uncharacterized Bbsl strains of unknown pathogenic significance was detected in DNA isolate LAC 1935. Statewide, mixed infections of B. burgdorferi strains (genotypes) were not detected in 15 Borrelia-infected I. pacificus nymphs or adults out of 948 ticks tested using a multilocus PCR electrospray mass spectrometry assay. We did not detect B. miyamotoi infection in any of the I. pacificus nymphs or adults. In northern California, B. miyamotoi was detected previously in 1.7% of 234 I. pacificus nymphs and 0.7% of 282 adults from dense woodland, ecotonal grass, or chaparral habitats in foothill rangeland, or in 0.5% of 814 adult ticks from a heavily used recreational area. Borrelia miyamotoi infects certain Ixodes spp. ticks in Asia, Europe, and North America, but it was not discovered to be a zoonotic pathogen until recently.

LD is an uncommon disease in California with an average annual incidence of 0.21 confirmed cases per 100,000 person-years from 2001 to 2010. In Los Angeles County, where the present study was conducted, the incidence for the same period was much lower than the statewide average, i.e., 0.07 cases per 100,000 person-years. Paradoxically, LD is a highly focal disease with incidence rates at the zip-code level within some northern counties (>20 cases/100,000 person-years) approaching those reported from some highly endemic states in the northeastern United States.

Conclusions

The risk of a person being bitten by a B. burgdorferi-infected I. pacificus nymph or adult in the Santa Monica Mountain habitats studied is very low. This region was selected for surveillance because its nearby parklands are a mecca for outdoor enthusiasts and, anecdotally, LD cases were being physician-diagnosed there. Our acarologic findings underscore the need for follow-up studies throughout southern California to ascertain if they are representative of a broad regional phenomenon or, contrariwise, if isolated areas of elevated risk exist in a vast sea of low risk.

Timing is everything.  Here’s a bit of commentary just posted on the California Lyme group’s web site:

“One of the first TOUCHED BY LYME blogs I ever wrote back in January 2009 was called “No Lyme in (your zip code here).” I recounted the widespread experience of Lyme patients—in diverse locations—who are informed by medical practitioners that they couldn’t have Lyme disease because it “doesn’t exist” in their city or county or state.”

“Of course there are deer in southern California, but that’s beside the point. Ticks can be spread by birds, rodents, and other mammals. Lyme-infected ticks have been found throughout the state, including Orange County.”

Gotta love these people.  They have great faith in their own opinions but not much in epidemiology or surveillance.  Check those zip codes.

Microbiome spawns a fake disease

GAPS stands for Gut and Psychology Syndrome.

It is the invention of Dr. Natasha Campbell-McBride. According to her, a wide variety of health problems can be traced to a single cause: an imbalance of gut microbes.  She cites ancient wisdom: Hippocrates said all diseases begin in the gut. She says science confirmed that wisdom when it discovered that 90% of all cells and all genetic material in the human body belongs to the gut flora. She says the modern world poses many dangers for the gut flora, and once it is damaged, the health of the whole body enters a downward slide towards disease. She claims that autism and ADD, OCD, schizophrenia, epilepsy, depression, and numerous other ailments are all digestive disorders.

Read more at Science-Based Medicine.

Where are all the science writers?

Johns Hopkins Graduate Science Writing Program to Close

Science, May 01, 2013

For 30 years, the Writing Seminars Department at Johns Hopkins University in Baltimore, Maryland, has offered scientists and science-minded journalists the opportunity to hone their writing and communication skills through its master's degree in science writing. The program was one of the big five graduate science-writing programs in the United States. (The others are the UCSC; the MIT; NYU; and BU.) Graduates of John Hopkins University's program have gone on to staff positions with Scientific American, Science News, New Scientist, Time, USA Today, NPR, Radiolab, NASA, Science, and many others—including Science Careers. On Monday, the science writing program's director, Ann Finkbeiner, e-mailed alumni of the program to announce that there would be no 2013–2014 class. The program is shuttering.

Read more here.

Paging Dr. Congress

N.J. Congressman urges action on Lyme Disease legislation, says more research needed

Christopher Robbins, NJ.com  

May 01, 2013

U.S. Rep. Chris Smith has been struggling for 15 years to increase the nation's awareness and improve scientists' understanding of Lyme Disease and other tick-borne illnesses. But it remains an uphill battle. Smith (R-4th) used a Tuesday press conference to promote Lyme Disease Awareness Month and two bills in the U.S. House of Representatives – both of which would establish a blue-ribbon commission to study the crippling illness.

[snip]

[Just what Washington needs, another commission.  The only people who want such a bureaucratic creation are Lyme activists who are constantly looking for ways to gain control, or at least some degree of oversight, over the research activities of the CDC and NIH.]

[snip]

Smith says his continuing work on Lyme Disease has been frustrated by apathy among his colleagues and a lack of understanding among the general public.  “With Lyme… we have been met at every turn with gross ignorance, vexing indifference or overt hostility,” Smith said.

[Well, its’ hard to get worked up about a common bacterial infection that is non-fatal, non-communicable, antibiotic responsive, and seasonally- and regionally-limited.]

Currently, scientists use a test that detects antibodies, the immune system’s response to the organism causing Lyme Disease, but do not detect the organism itself. The problem is that some people don’t create antibodies to fight the disease soon enough to prevent its spread to the brain and nervous system, others do not create antibodies at all. “H.R. 611 will promote development of new and improved diagnostic tests, boost surveillance and reporting, push clinical outcomes research and expand efforts to combat this dreaded disease

[That’s not true.  There is plenty of time between initial infection and the detection of IgM or IgG antibodies.  Moreover, there are a number other diagnostics indicators (e.g., an attached tick, an EM rash) to suggest the likelihood of a nascent Lyme infection.  Even with such a delay, this “dreaded disease” is hardly that given the above mentioned characteristics.]

Smith said he hopes the panel’s work would help doctors and public health officials educate families about the illness, boosting prevention and early treatment. “If we get the science right, we’ll get more researchers,” he said.

[No, if you “get the science right” there will be less need for researchers.  In the U.S. these days, we don’t need too many polio or yellow fever researchers because the problems have been solved.]

Smith said the medical community currently does not recognize Lyme Disease as a chronic illness, which conflicts with patient experiences. “I believe evidence is overwhelming that chronic Lyme is a terrible, overwhelming disease and we need to find ways to treat this. To say otherwise is an inaccurate and unscientific opinion,” he said.

[The medical community certainly recognizes the long-term damaged caused by an untreated infection, Lyme or otherwise.  What they don’t recognize is an Andromeda Strain infection that is permanent and undetectable, but made manageable with expensive antibiotics paid for by other people.]

Read the entire article here.