Tuesday, 22 November 2016

ARE LYME DISEASE TESTS ACCURATE?

Commercial test kits for detection of Lyme borreliosis: a meta-analysis of test accuracy

Michael J Cook,Basant K Puri2

1Independent researcher, Dorset, UK; 2Department of Medicine, Hammersmith Hospital, Imperial College London, London, UK

Abstract: The clinical diagnosis of Lyme borreliosis can be supported by various test methodologies; test kits are available from many manufacturers. Literature searches were carried out to identify studies that reported characteristics of the test kits. Of 50 searched studies, 18 were included where the tests were commercially available and samples were proven to be positive using serology testing, evidence of an erythema migrans rash, and/or culture. Additional requirements were a test specificity of ≥85% and publication in the last 20 years. The weighted mean sensitivity for all tests and for all samples was 59.5%. Individual study means varied from 30.6% to 86.2%. Sensitivity for each test technology varied from 62.4% for Western blot kits, and 62.3% for enzyme-linked immunosorbent assay tests, to 53.9% for synthetic C6 peptide ELISA tests and 53.7% when the two-tier methodology was used. Test sensitivity increased as dissemination of the pathogen affected different organs; however, the absence of data on the time from infection to serological testing and the lack of standard definitions for “early” and “late” disease prevented analysis of test sensitivity versus time of infection. The lack of standardization of the definitions of disease stage and the possibility of retrospective selection bias prevented clear evaluation of test sensitivity by “stage”. The sensitivity for samples classified as acute disease was 35.4%, with a corresponding sensitivity of 64.5% for samples from patients defined as convalescent. Regression analysis demonstrated an improvement of 4% in test sensitivity over the 20-year study period. The studies did not provide data to indicate the sensitivity of tests used in a clinical setting since the effect of recent use of antibiotics or steroids or other factors affecting antibody response was not factored in. The tests were developed for only specific Borrelia species; sensitivities for other species could not be calculated.

Just published by Dover Press with links to full article:-

Thursday, 27 October 2016

LIVING WITH LYME DISEASE - IRISH DOCUMENTARY



Published on Oct 27, 2016
This documentary is the compelling story of people affected by Lyme disease in Ireland.
Lyme disease, also known as Lyme Borreliosis, is an infectious disease caused by bacteria of the Borrelia type.
Lyme disease is a bacterial infection typically transmitted through the bite of an infected tick. It is one of the fastest growing infectious diseases in the world.

Wednesday, 26 October 2016

STIFF PERSON SYNDROME AND LYME DISEASE

Stiff Person Syndrome or Stiff Man Syndrome as it was previously called.

From the National Organization of Rare Disorder NORD :-

'Stiff-person syndrome (SPS) is a rare acquired neurological disorder characterized by progressive muscle stiffness (rigidity) and repeated episodes of painful muscle spasms. Muscular rigidity often fluctuates (i.e., grows worse and then improves) and usually occurs along with the muscle spasms. Spasms may occur randomly or be triggered by a variety of different events including a sudden noise or light physical contact. In most cases, other neurological signs or symptoms do not occur. The severity and progression of SPS varies from one person to another. If left untreated, SPS can potentially progress to cause difficulty walking and significantly impact a person's ability to perform routine, daily tasks. Although the exact cause of SPS is unknown, it is believed to be an autoimmune disorder and sometimes occurs along with other autoimmune disorders.
Stiff-person syndrome has been described in the medical literature under many different, confusing names. Originally described as stiff-man syndrome, the name was changed to reflect that the disorder can affect individuals of any age and of either gender. In fact, most individuals with the condition are women. Stiff-person syndrome is considered by many researchers to be a spectrum of disease ranging from the involvement of just one area of the body to a widespread, rapidly progressive form that also includes involvement of the brain stem and spinal cord (progressive encephalomyelitis with rigidity and myoclonus).' 


An all body stiffness was one of my many symptoms which lasted years. The worst was that of rigidity on waking with a reduction in symptoms when painfully flexing every joint large and small. Once diagnosed with Lyme Disease and given long term antibiotics this stiffness gradually went away. I had always assumed it was something vascular maybe inflammation but was interested to read information on SPS and see the two studies published which associated Stiff Man Syndrome with Neuroborreliosis,  Lyme Disease. 


[Syndromes of continuous muscular activity: report of a central case (stiff-man) and a peripheral case (neuromyotonia) associated with neuroborreliosis].

[Article in Spanish]

Abstract

We describe two cases of continuous muscular activity: one which is central (the stiff-man syndrome), and another which is peripheral (neuromiotony), the latter in a patient suffering from diabetic neuropathy and with positive Borrellia burgdorferi serology in the bloodstream, as well as CSF. Both cases reacted favourably to medical treatment. In the first case botulinic toxin was used as a simultaneous treatment for focal pseudodystonia in one foot. Response was good. 
  

 1990 Feb;237(1):51-4.

Borrelia burgdorferi myelitis presenting as a partial stiff man syndrome.

Abstract

Eight weeks after a tick bite, a 33-year-old male patient presented with stiffness of one leg together with spasmodic painful jerks resembling stiff man syndrome. Isolated myelitis of lumbosacral segments of the spinal cord, apparently confined to the grey matter, was diagnosed and its spirochaetal aetiology confirmed by serology and CSF findings. Oligoclonal IgG bands in CSF specific for Borrelia burgdorferi were found. Thus, there is evidence that B. burgdorferi ist able to cause a localized myelitis, probably of spinal interneurons, presenting as a partial stiff man syndrome. 

Saturday, 22 October 2016

NOT ALL ANTIBIOTICS PULSED DOSED ERADICATE BIOFILM LIKE BORRELIA

Ceftriaxone Pulse Dosing Fails to Eradicate Biofilm-like Microcolony B. burgdorferi Persisters Which Are Sterilized by Daptomycin/Doxycycline/Cefuroxime Drug Combination without Pulse Dosing

Jie Feng1Shuo Zhang1Wanliang Shi1 and Ying Zhang1*
  • 1Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, USA
Although the majority of Lyme disease patients can be cured, at least 10-20% of the patients continue to suffer from persisting symptoms such as fatigue, muscular and joint pain, and neurologic impairment after standard 2-4 week antibiotic treatment. While the causes for this post-treatment Lyme disease symptoms are unclear, one possibility is due to B. burgdorferi persisters that are not effectively killed by current antibiotics such as doxycycline or amoxicillin used to treat Lyme disease. A previous study showed that four rounds of ceftriaxone pulse dosing treatment eradicated B. burgdorferi persisters in vitro using a relatively young late log phase culture (5 day old). In this study, we investigated if ceftriaxone pulse dosing could also eradicate B. burgdorferi persisters in older stationary phase cultures (10 day old) enriched with more resistant microcolony form of persisters. We found that ceftriaxone pulse dosing could only eradicate planktonic log phase B. burgdorferi spirochetal forms and round body forms but not more resistant aggregated biofilm-like microcolony persisters enriched in stationary phase cultures. Moreover, we found that not all drugs are suitable for pulse dosing, with bactericidal drugs ceftriaxone and cefuroxime being more appropriate for pulse dosing than bacteriostatic drug doxycycline and persister drug daptomycin. We also showed that drug combination pulse dosing treatment was more effective than single drug pulse dosing. Importantly, we demonstrate that pulse dosing treatment impaired the activity of the persister drug daptomycin and its drug combination against B. burgdorferi persisters and that the most effective way to kill the more resistant biofilm-like microcolonies is the daptomycin/doxycycline/ceftriaxone triple drug combination without pulse dosing. Our findings indicate pulse dosing may not always work as a general principle but rather depends on the specific drugs used, with cidal drugs being more appropriate for pulse dosing than static or persister drugs, and that drug combination approach with persister drugs is more effective at killing the more resistant microcolony form of persisters than pulse dosing. These observations may have implications for more effective treatment of Lyme disease. Future studies are required to validate these findings in animal models of B. burgdorferi persistence.

http://journal.frontiersin.org/article/10.3389/fmicb.2016.01744/abstract

Tuesday, 18 October 2016

'LIVING WITH LYME DISEASE' DOCUMENTARY FROM IRELAND

An excellent documentary shown on IrishTV recently on Lyme disease


Published on Aug 31, 2016
Nicci St.George Smith met James and Brian at the 2016 Irish Lyme Disease Conference organised by Ann Maher in conjunction with Tick Talk Ireland

Here they tell her about their journey toward completing their documentary LIVING WITH LYME




Further information from Tick Talk Ireland http://www.ticktalkireland.org/


Saturday, 15 October 2016

SWISS AGENT - RICKETTSIA HELVETICA FOUND IN UK TICKS

The Internet has been a buzz recently with the news that Willy Burgdorfer found patients with Lyme disease their blood showed a strong reaction for the Swiss Agent ( Rickettsia Helvetica)


The ‘Swiss Agent’: Long-forgotten research unearths new mystery about Lyme disease

'At a government lab in Montana, Willy Burgdorfer typed a letter to a colleague, reporting that blood from Lyme patients showed “very strong reactions” on a test for an obscure, tick-borne bacterium. He called it the “Swiss Agent.”
Now STAT has obtained those documents, including some discovered in boxes of Burgdorfer’s personal papers found in his garage after his death in 2014. The papers — including letters to collaborators, lab records, and blood test results — indicate that the Swiss Agent was infecting people in Connecticut and Long Island in the late 1970s.'
'On the top of a stack of documents in his garage was a mysterious note, penned boldly in red ink in the scientist’s unmistakable handwriting. “I wondered why somebody didn’t do something,” it said. “Then I realized that I am somebody.”'
The STAT article can be read at this link:-
'The STAT article reports that both Jorge Benach and Allen Steere now say it is time to take a closer look at Rickettsia helvetica’s role in Lyme disease. Benach says the research “should be done” because public health concerns warrant a closer look.
For patients, looking into pathogenic factors related to persistence in tick-borne disease is long overdue. The failure to note the existence of the Swiss agent along with Borrelia burgdorferi is bacteria in the initial publication about Lyme disease may have set back progress in understanding the pathogenicity of Lyme disease decades.' From Lyme Policy Wonk :-

An interesting angle is that from Lyme MD 
http://lymemd.blogspot.co.uk/2016/10/the-swiss-agent.html?spref=fb&m=1

In 2011 this was published:-

First detection of spotted fever group rickettsiae in Ixodes ricinus and Dermacentor reticulatus ticks in the UK. 

Tijsse-Klasen EJameson LJFonville MLeach SSprong HMedlock JM.


Abstract

A preliminary study was conducted to determine the presence of spotted fever rickettsiae in two species of British tick (Ixodes ricinus and Dermacentor reticulatus). The 16S rRNA gene of Rickettsia spp. was detected in 39/401 (9·7%) of ticks tested, including 22/338 (6·5%) I. ricinus and 17/63 (27%) D. reticulatus. Some positive I. ricinus samples showed 100% homology with Rickettsia helvetica (10/22), and most positive D. reticulatus showed 100% homology with R. raoultii (13/17). Five other Rickettsia spp. were detected exhibiting 96-99% homology. Ticks positive for rickettsiae were collected from various hosts and from vegetation from eight counties across Great Britain. The distribution of R. helvetica in various engorged and unfed stages of I. ricinus suggests that R. helvetica is widespread. R. raoultii was found in questing adult D. reticulatus in Wales and England. This is the first evidence of potentially pathogenic spotted fever rickettsiae in British ticks.

This study suggests the Swiss Agent ( Rickettsia Helvetica ) is widespread in the UK. More research is required to find out what role this infection is having on people sick in the UK following a tick bite. 


Monday, 12 September 2016

LYME DISEASE TESTING - SENSITIVITY?

Testing for Lyme Disease is problematic for several reasons

'Scientifically, sensitivity (% of definite positive patients who test positive by the test in question) and specificity (% of well patients who test negative by the test in question) are measured against another test, such as CDC surveillance pos WB, which is how the patients are determined to be positive in the first place.  As ALL tests for Borrelia lack sensitivity to some extent this makes the sensitivity and specificity of the test in question highly suspect, or limited.  This, of course, means sensitivity and specificity are not really related to % of patients who ACTUALLY have the disease, but % who have been determined by a particular test of limited sensitivity to have the disease, a subset.  As patients who have been definitely determined to have Borreliosis by the CDC criteria for surveillance, and the CDC are measuring the sensitivity of a new test against that, of course the sensitivity of that new test will be inflated, a great advantage if you are the holder of the patent of that new test.  This would be especially so if the new test is measuring some parameter which is related in some way to the baseline test (such as both measuring antibodies to something).
In reality any of the various tests available if positive is a likely indication the patient has Borreliosis, but any one of them will have some false positives.  The false positive rate is not scientifically possible to accurately determine from evidence.  In Borreliosis the sceptics commonly cry "false positive" for any one test which shows positive, but they have no evidential basis on which to ground their claims.  It is certainly helpful to the patient's cause to have 2 separate tests positive, making a false positive far less likely.  In areas of medicine other than Lyme it is usually clinical suspicion plus one suggestive, not necessarily strong positive, test which would be taken as diagnostic evidence.
However, IF the judges (the CDC) are actively trying to protect the health insurance industry (which would appear to be the case, based on the evidence of their judgements), of course their current stance would make a lot of sense.  If they applied the same level of criteria for all other infectious diseases, only a small fraction of patients with infections of all kinds would be diagnosable or treatable.'

I read the above explanation recently and have permission to share, it explains very clearly one aspect of the problems we have with Lyme serology.


Prof Perronne discusses other aspects of Serolgy in this publication 

Calibration of serology

When Lyme serology was developed, no reliable method was available to be used as a gold standard for comparison. As most of the signs and symptoms are non-specific, no reliable clinical diagnostic score could be established. The low yield of culture and the difficulty involved in using the technique routinely were another major obstacle. A pragmatic cut-off level for the serologic tests had to be determined arbitrarily on blood donors (EUCALB, ; Assous, ). In the late seventies, when Lyme disease was first discovered, it was understandably thought to be a rare and regional phenomenon. Therefore, a low prevalence was set as experts were afraid the serologies would produce too many false positive diagnoses (EUCALB, ; Assous, ). Patients and control populations are ill-defined with a high variability in predictive positive and negative values from one test to another. Culture of B. burgdorferi or detection of its genome by polymerase chain reaction (PCR) may occasionally confirm the clinical diagnosis in seronegative patients, however none of these methods are sensitive enough to be considered reliable diagnostic methods, especially in routine practice (Schutzer et al., ; Nields and Kveton, ; Chmielewska-Badora et al.,; Brunner, ; Assous, ; Holl-Wieden et al., ; Aguero-Rosenfeld, ; Dietrich et al.,; Wallet et al., ). As a result, many patients suffering signs and symptoms compatible with Lyme disease, but whose test is negative, are falling by the wayside.

Possible causes of seronegativity

Several factors leading to seronegativity have been identified in confirmed cases of Lyme disease: (i) the arbitrary cut-off level of tests, (ii) the sequestration of antibodies in immune complexes, (iii) the wide variety of species and subspecies of Borrelia that co-exist in different parts of the world, and (iv) coinfections with other pathogens which may be responsible for some or all of the symptoms or which may alter the immune response (Schutzer et al., ; Brunner, ). The complex B. burgdorferi sensu lato includes (Table (Table1):1): B. burgdorferi sensu stricto (including genetic diversity), B. afzelii, B. garinii (several serotypes) and additional species isolated in different parts of the world (Rudenko et al., ; Ogden et al., ). Some of these species have been isolated in symptomatic patients (Varela et al., ; Lopes de Carvalho et al., ; Rudenko et al., ; Stanek and Reiter, ; Branda and Rosenberg, ; Clark et al., ; Lee et al.,; Margos et al., ). B. spielmanii may cause early skin disease (Stanek and Reiter, ). B. bavariensis, B. bisettii, B. valaisiana, B. americana, B. andersonii, B. lonestari and more recently B. kurtenbachii have been isolated from patients with Lyme-like diseases (Varela et al., ; Rudenko et al.,; Rizzoli et al., ; Stanek and Reiter, ; Clark et al., ). The pathogenic role of B. lusitaniae, isolated in a case of vasculitis, remains to be substantiated (Rudenko et al., ). Despite such diversity in strains, most of the commercially available tests still rely on the original 1982 Massachusetts B31 isolate of B. burgdorferi. No diagnostic tool is available for routine detection of B. miyamotoi (Branda and Rosenberg,; Lee et al., ). Coinfections with other microbes add to the complexity of these illnesses (Table (Table1).1). Among patients with early Lyme disease in the USA, 2–12% were found to also have human granulocytic anaplasmosis, and 2–40% babesiosis (Wormser et al., ). In Brazil, a Lyme-like syndrome, due to the tickAmblyomma, has been described and mobile non cultivable spirochetes could be visualized in patients' blood using a dark field microscope (Mantovani et al., ). A new tick-borne bacterial pathogen, CandidatusNeoehrlichia mikurensis, was reported in Switzerland (Fehr et al., ). An illustration of the limits of serology is the Scottish example: the sensitivity of the immunoblot was improved by using local Scottish strains of Borrelia (Mavin et al., ).

Conclusion and perspectives

The numerous complexities of Lyme disease make it an extremely difficult illness to fully comprehend. It remains a diagnostic challenge even for the best informed of clinicians. The lack of a gold standard for diagnosis renders the management of patients difficult and seriously hinders our ability to produce accurate statistics, especially as very similar syndromes could be due to other species of Borrelia. In some patients suffering from syndromes of unclear origin, following tick bite, other microbial agents could also be playing a role.
To read Prof Perronne full paper