Karl McManus Foundation’s reply to the RCPA position statement on Lyme disease and ways of reducing inappropriate pathology testing in AustraliaKarl McManus Foundation (KMF) regards the RCPA’s position statement on Lyme disease in Australia and the document ‘RCPA’s top ten targets aims to beat inappropriate pathology requesting’ incongruous given that the findings of the Clinical advisory committee (2013-2014) into Lyme Disease concluded that “Further research is required to determine if Borrelia bacteria are present in Australian ticks”.
Australians do travel to other countries in addition to the USA, where Borrelia genospecies have not been identified (B.burgdorferi sensu lato and relapsing fever Borrelia). KMF considers the position statement being premature with research outcomes pending and not supportive of clinicians diagnosing patients with potential exposure to Borrelia species, regardless of whether the infection was acquired overseas or not.
The scoping study on Lyme disease in Australia compiled by Prof. John McKenzie in Australia indicated that there is a pathogen(s) causing Lyme-like disease in Australian ticks. The causative agent(s) is yet to be identified. The scoping study also concluded that the “jury is out” so we can’t say whether Lyme disease is present or not in Australia. This uncertain status of Lyme disease classifies Australia as an indeterminate region, not non-endemic.
RCPA document assumes that Australian testing is able to detect all Borrelia burgdorferi senso lato group bacteria. This is not the case, the first tier test ELISA or EIA is based on B.burgdorferi sensu stricto, B31 lab strain. Borrelia genome has high genetic variation due to the presence of more than 21 plasmids and horizontal DNA transfer1. Therefore an ELISA based upon one genospecies is not likely to detect an immune response to all Borrelia.
Furthermore, there is no concordance amongst NATA accredited labs which ELISA or immunoblot kits are used. Some used Mardix kits (manufactured for the USA market, Borrelia burgdorferi sensu stricto, B31 strain based). Recently some have changed to NovaLisa and Diasorin for ELISA. For the immunoblots, some use in house tests others have recently switched to Euroimmune Immunoblots IgG (recombinant B31 and B garinii and B afzeli proteins). Even in the USA these tests are not able to detect all the genospecies of the B.Burgdorferi sensu lato group. CDC admitted that reported cases (36,000) of Lyme disease represent only10% of total cases that contract Lyme disease in the USA, by correcting the statistics, realistically 360,000 people contract Lyme disease in the USA2. Hinckley et al3 report that in 2008, 244,000-440,000 people contracted Lyme disease in the USA.
The ELISA tests in the USA have 29-68% detection rate4,5. This big variation in detection rate reaffirms the inadequacy of the two tier diagnostic approach. The CDC criteria used in the USA is a surveillance criteria and the CDC advice clinicians against using the surveillance criteria6 criteria6. The American tests are not able to detect all of the European Borrelia genospecies, so if an American gets bitten in Europe they may not get the appropriate diagnosis7. B.burgdorferi sensu stricto is more antigenic then the other common genospecies of the B.burgdorferi sensu lato group1. ELISA kits designed for the USA market would not be sufficiently sensitive for Australian patients, who have travelled to Europe or Asia or Africa.
The C6 antigen assay relies on the 26 amino acid sequence within the VlsE protein which is supposed to be constant but has only 66% rate of detection rate for B. Burgdorferi sensu stricto, a 33% failure rate in the USA8. The C6 antigen assay in Europe has a higher failure rate9 and in Australia the failure rate may be even higher. As an assay that only detects IgG it is likely to have a high failure rate in stage III and beyond if patients have different genospecies and/or are immunodysregulated.
Testing in Australia is not able to detect Borrelia species from Asia, common destinations for Australians is South East Asia (China, India, Japan). These countries are endemic for relapsing fever Borrelia10 and may also be endemic for B.burgdorferi sensu lato. The RCPA manual does not provide a test for relapsing fever this is despite increasing number of Australians traveling to Asia, Middle East and Africa. In addition these countries do not have the resources to investigate and determine their prevalent genospecies of Borrelia. RCPA manual lists only tests based upon Borrelia burgdorferi sensu stricto. Can we afford to ignore overseas acquired relapsing fever and assume that Borrelia infection only “occur occasionally”? Without appropriate testing we risk having many Australians being misdiagnosed with chronic disorders of no cause or cure such as CFS/ME, fibromyalgia, dementia, paralysis, atypical neurodegenerative diseases. Narrow scope in tests combined with clinical unfamiliarity has an increased likelihood not only of leading to misdiagnosis, treatment failure and persistent symptoms but the unnecessary ill health and cost to society as chronically ill Australians need ongoing care. Restriction on testing may save funds in the short term but in long term can cause increase of healthcare costs.
The two tier testing is disputed in the USA and many countries globally are rejecting the 2 tier system with 5/10 immunoblot bands as a positive standard. These countries include, Scotland, Germany and Russia11,12,13 . Therefore, the confidence of RCPA in proclaiming that Australian labs can comfortably detect infections by Borrelia species may be unfounded.
Lyme Borreliosis due to the non-specificity of symptoms is difficult to diagnose and there is an overreliance on pathology tests. If RCPA further curtails tests as per “top 10 targets Aims to beat inappropriate pathology requesting”, which include “Lyme disease testing in the absence of travel to endemic areas” it will cause even greater number of misdiagnoses. Travel to indeterminate areas that may have Borrelia burgdorferi sensu lato genospecies in their fauna need to be considered in the diagnosis process. If people with Borreliosis symptoms from these non- endemic areas are not tested they will be unfairly misdiagnosed when there is already an added difficulty in diagnosis due to clinical symptom unfamiliarity and non-specificity.
It is important to note that many patients with Lyme Borreliosis from Europe do not present with an EM (erythema migrans) rash and have significant neurological involvement of polyneuropathy and meningoencephalitis especially when symptoms become evident after a prolonged delay post tick bite14. In order to improve diagnosis there is a need to broaden the range of genospecies tested so that travellers to USA and Europe and Asia and Africa can be diagnosed appropriately.
Another important point is indirect testing assumes immuno-competence, yet there is growing evidence,15,16 which show Borreliosis, especially in stage III can cause substantial immune dysfunction which can impact the outcome of Lyme disease serology tests-ELISA and the immuno-blot. Direct method of detecting of DNA (PCR) has narrow specificity due to the high variation in the Borrelia genome. So a testing system that uses both methods can have better outcomes.
It is difficult for overseas labs to be NATA accredited as they don’t have an outlet in Australia. NATA accreditation is based upon an international standard ISO 15189. ISO 15189 is made up of ISO 17025 and ISO 900017. The labs referred to being in the USA and Germany, are accredited according to their country’s requirements. The labs in Germany comply with EU standards which are on par with international standards and the labs in the USA comply with the State of New York and California standards. There is a mutual recognition arrangement by signatories to ILAC (International. Laboratory Accreditation Corporation)18 . All the accreditation bodies in the USA and the accreditation body in Germany and NATA aresignatories. Hence we can’t ignore or overlook the results of these labs. Routine labs in the USA use only B31 strain for the source of their immunoblots. The labs in question include other strains of Borrelia in their immunoblot to broaden the range of the Borrelia genospecies proteins patients’ sera can react to and get a better correlation with clinical symptoms. Does this invalidate those labs? As the accreditation of the inferred overseas labs is equal to NATA, non- acceptance of these labs testing by RCPA is unethical/contravenes ILAC’s principles. This is detrimental to the appropriate diagnosis of Australian patients who are ill and who otherwise would not get the correct diagnosis and treatment as they usually fit into the “atypical” diagnosis classification.
Inappropriate testing in Australia is likely to contribute to the increasing number of patients being misdiagnosed regardless of whether they have travelled overseas or not. Furthermore, overseas labs results have a better correlation with the clinical symptoms of the patients and the diagnosis is usually further supported by a Herxheimer reaction when antibiotics are prescribed which adds to the evidence of spirochaetal infection and the lessening of patients symptoms validates the diagnoses.
There are significant diagnostic and management challenges following an arthropod bite, overseas or local. At present there is no specific referral pathway to establish the diagnosis of a local Lyme-like disease in Australia. Surveillance reporting and publishing the data can play a vital role in contributing to characterizing this disease. A broader approach is more informative for an indeterminate region like Australia as it contributes to antigenic data for different Borrelia species and more validated diagnoses, when considered with other supportive clinical information for spirochaetal infections, such as a Herxheimer reaction when antibiotics are prescribed.
It is hoped that RCPA take into account the comments made above regarding the testing for Borrelia in Australia and edit the RCPA position statement and remove the Lyme disease testing from the” Top ten aims to beat inappropriate testing” list, accordingly in the best interest of the patients who do have Borreliosis symptoms regardless of where they contracted the infection(s).
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Growing evidence of an emerging tick-borne disease that causes a Lyme like illness for many Australian patients
On 12 November 2015, the Senate referred the following matter to the Senate Community Affairs References Committee for inquiry and report:
The growing evidence of an emerging tick-borne disease that causes a Lyme‑like illness for many Australian patients.