Issues
There are numerous issues with testing and diagnosis.
According to a recent review “a major obstacle is that only 30% of the patients report a history of tick bite and only 70–80% present with a primary erythema migrans, the pathognomonic (diagnostic) initial lesion. This lesion may go unrecognized, or be mistaken for an ‘insect bite’ or an ‘allergic rash’. Mini-erythema migrans are less likely to be diagnosed”. The situation is more complex in Scotland as in a recent study, “the low number of patients with EM (48%) was surprising and is much lower than that documented in other studies (69.1 to 89.3%).” and “only 61% of patients could recall having a tick bite”. A recent study in monkeys found that only 10% infected by a tick bite “produced a bona fide erythema migrans rash”.
Diagnostic tests are therefore relied on. However, these are unreliable. According to Lyme Disease Action (certified by the Information Standard run by NHS England), “there are no conclusive tests for Lyme disease currently in routine use in the UK that will accurately diagnose Lyme disease or distinguish active from past infection.”
According to Scottish doctors, “traditional two-tier (enzyme immunoassay [EIA] screening and Western blot confirmation) testing for the laboratory diagnosis of Lyme borreliosis (LB) is expensive, lacks sensitivity in the diagnosis of early LB, cannot distinguish between current and past infection and cannot be used as a marker for treatment response”.
According to Trinity Biotech, one manufacturer of tests for borrelia, “patients in the early stage of disease and a portion of patients with late manifestations may not have detectable antibodies.”
It has been known since 1988 that some patients with chronic Lyme disease do not develop antibodies, when a study in the New England Journal of Medicine concluded that although chronically ill “patients had clinically active disease, none had diagnostic levels of antibodies to B. burgdorferi on either a standard enzyme-linked immunosorbent assay or immunofluorescence assay. On Western blot analysis, the level of immunoglobulin reactivity against B. burgdorferi in serum from these patients was no greater than that in serum from normal controls”. Findings of a recent study “disprove that all patients with LNB develop positive serum Borrelia antibodies within 6 weeks after infection”. It has recently been stated by Dr. Steven Phillips (Facebook) that “there are now over 50 medical journal articles documenting Lyme disease despite negative antibody tests. This research spans all stages of illness, including late stage disease”. In addition, immune response in European patients has been found to be undulatory and so test results can be intermittently negative during infection. In a recent study in monkeys, antibodies did not develop in one monkey, waned with antibiotic treatment, and waned without treatment in some.
A recent study demonstrated that round body forms induced “distinct immune responses compared to spirochetes in vitro” and concluded that “these results suggest that round bodies have a role in Lyme disease pathogenesis”.
In a recent meta-analysis, it was found that “sensitivity of an individual test was as low as 7.4%. The mean sensitivity of all test kits with all samples was 59.5%, and ranged from 30.6% to 86.2%”. In a related study, it was found that “using clinically representative LD test sensitivities, the two-tier test generated over 500 times more false-negative results than two-stage HIV testing”. Another study concluded that “In the serology of EM in Europe, C6 ELISA does not seem to cover all cases”.
Doctors therefore need to be able to recognise a collection of symptoms of Lyme disease, many of which mimic other illnesses, with or without an erythema migrans rash and with or without positive serology.
Recent research on a Lyme antigen test which uses urine instead of blood and which does not depend on the presence of antibodies has shown great promise. A commercial Lyme antigen test, described as “a game changing tool for Lyme disease diagnosis”, is now available in Europe but is not yet available to Scottish patients. One study concluded that “a sensitive and reliable DNA-based test is needed to support the diagnosis of Lyme disease and Lyme disease-like borreliosis”. “A novel lymphocyte transformation test (LTT-MELISA) for Lyme borreliosis” has been suggested. Another article describes “An Enhanced ELISPOT Assay for Sensitive Detection of Antigen-Specific T Cell Responses to Borrelia burgdorferi” which has “has a significantly higher specificity and sensitivity compared with the Western Blot assay that is currently used as a diagnostic measure”. Some biomarkers have been found useful in monitoring the course of treatment. These include CXCL13 and CD57.
In a very useful review of the European situation, it has been stated that “Development of new diagnostic methods is badly needed. New PCR methods and new genomic techniques, such as high throughput sequencing, could prove promising in identifying the complex mix of microbial agents that are probably involved”.
Next generation Lyme disease tests that use recombinant proteins or specific synthetic peptides, and alternative testing protocols, are now ready for clinical use. IGeneX offer Immunoblot tests which are more reliable than current tests.
In the meantime, combining band 41 of the Western Blot with a high CD4/CD8 ratio has been found to be more accurate than current diagnostic methods and could be easily implemented.
Scottish Testing was More Limited in the Past
The Scottish Lyme Reference Laboratory at Raigmore has put much effort into improving testing in Scotland. However, according to a recent Scottish paper, “initially, an in-house Western blot incorporating reference strain B. burgdorferi sensu stricto was used, followed by a local B. burgdorferi sensu stricto and B. afzelii antigen (50:50) mix in June 2007. … There was a significant change in testing protocols in July 2012. The in-house Western blot was replaced with CE marked commercial assays (EU Lyme IgG Western blot, Trinity Biotech or Recomline Lyme IgG, Mikrogen)”.
Tests are not Available for all Species of Borrelia
The Chief Medical Officer (personal letter from November 2016) advised that, “in a study, 8% of ticks from 25 sites across Scotland were identified as being infected with B. valaisiana, however, the majority of genospecies were B. afzelii (48%) and B. garinii (36%)”. It is not known how prevalent the more recently identified borrelia miyamotoi is but it has been identified to exist in Scotland.
However, a study of local Highland isolates identified 6 strains which differed from the reference strains. There may therefore be other unidentified strains in Scotland which are not being tested for. A study in England also found other isolates different from foreign ones.
The Chief Medical Officer also stated that “Raigmore Hospital … carried out an internal audit by comparing five commercial and one in-house immunoblot method which identified the Mikrogen assay as the most effective and accurate immunoblot. This is the assay which is currently being used and can detect antibodies to B. burgdorferi sensu stricto, B. afzelii, B.garinii, B.speilmanii and B.bavariensis.”
So, testing in Scotland was initially limited to only borrelia Burgdorferi and borrelia afzelii. Although the recent tests used includes borrelia garinii, current testing does not include borrelia valaisiana or borrelia miyamotoi. As borrelai valaisiana has a prevalance of 8% in ticks in Scotland, and the prevalence of borrelai miyamotoi is unknown, at least 8% of infections and possibly much higher could be missed. There are issues with tests which could possibly be used for Borrelia miyamotoi. Borrelia valaisiana is often stated as not being pathogenic to humans but there has been at least one report of human disease. As testing does not include Borrelia valaisiana, there is no way of knowing if there is a greater level of human illness caused by this strain. As of October 2018, testing for borrelia miyamotoi is planned for 2019. This is much appreciated, but more is needed.
Tests are not Available for all Tick-Borne Co-infections
The situation is complicated because ticks can transmit multiple infections, which many patients have. There are no tests which cover all species of bartonella, babesia, and other tick-borne co-infections. A recent study in cats showed multiple species of borrelia and babesia in attatched ticks. A recent European study found many pathogens in ticks and suggested that transmission could be facilitated by interactions between pathogens. A further study “suggests a role for ticks in the transmission of and as a reservoir for … emerging pathogenic Chlamydia-related bacteria”. Many emerging chlamydia species are considered zoonotic. A recent review stated that “many Bartonella bacteraemic human patients do not have antibodies against the infecting Bartonella sp. found in their blood or tissues”. Viruses are also transmitted by ticks and the full spectrum of tick-borne pathogens has not yet been identified.
As of October 2018, testing for anaplasma is planned for 2019. This is much appreciated but more infections need to be tested for and clinical diagnosis needs to be accepted prior to tests being available. It is possible to be infected with anaplasma and for tests to be negative.
A study in Australia, a country previously thought to be free of Lyme disease, found “considerable presence of borreliosis in Australia, and a highly significant burden of coinfections accompanying borreliosis transmission”, including babesia, bartonella, anaplasma, etc. We believe that if a similar study was done in Scotland it would show the same.
In a US study, patients were found to be infected with up to 16 infections, with 64% being infected with 5-8 infections. Much more focus needs to be placed on identifying all co-infections.
Lyme Disease can be Misdiagnosed
Given the unreliability of testing and the undulatory nature of immune response, it is very easy for Lyme Disease to be misdiagnosed. The Lyme Disease Action charity provides a long list of differential diagnoses. A validated questionnaire is available to help clinicians with diagnosis.
Lyme Disease has also been controversially linked as a potential cause for numerous diseases, including Alzheimer’s Disease (AD), Motor Neuron Disease (also known as Amyotrophic Lateral Sclerosis), Multiple Sclerosis, and others.
A number of studies have shown that “Borrelia burgdorferi persists in the brain in chronic lyme neuroborreliosis and may be associated with Alzheimer disease.” In another recent study, researchers duplicated previous findings that demonstrate “that the plaques, which are characteristically found in AD brains, reveal the presence of biofilms. These biofilms are undoubtedly made by the spirochetes present there; further, we have also found that the biofilms co-localize with the β amyloid that is a signature finding in the disease”. A recent meta-analysis showed “a strongly positive association between bacterial infection and AD”. There have been case reports of initial misdiagnosis of dementia.
A recent paper is one of a number which link Amyotrophic Lateral Sclerosis to borrelia infection, reporting on “Lyme disease -induced polyradiculopathy mimicking amyotrophic lateral sclerosis.”
It has been hypothesised that “Chronic Lyme borreliosis [is] at the root of multiple sclerosis – is a cure with antibiotics attainable?”
A recent article found “association between infectious burden and Parkinson’s disease”, including Borrelia burgdorferi amongst other infections. Subacute parkinsonism has recently been found as a complication of Lyme Disease.
Diagnostic Codes Were Missing
On June 18, 2018 the World Health Organization (WHO) issued the 11th revision of the International Classification of Diseases or ICD11. The Ad Hoc Committee for Health Equity in ICD11 Borreliosis Codes executed a comprehensive approach that successfully established new codes for life-threatening complications from Lyme. This is a major achievement for the global Lyme community because it is the first time in over 25 years that these serious complications have been officially recognized by the WHO. However, patients have, until now, had complications from their illnesses denied in part because of lack of these diagnostic codes.