Welkom bij het Lymeforum

Projectomschrijving

Lymeziekte wordt veroorzaakt door de Borrelia bacterie, welke wordt overgedragen door teken. Per jaar krijgen in Nederland circa 25.000 mensen Lymeziekte. Veel mensen ontwikkelen een rode huidafwijking, maar die wordt niet altijd herkend of gezien. Ook treedt deze niet altijd op en presenteren patiënten zich met verder gevorderde klachten.

De huidige diagnostische tests kennen twee belangrijke beperkingen, 1) ze zijn vaak negatief vroeg in het beloop van de ziekte, en 2) bij langdurige klachten maken ze niet goed onderscheid tussen een oude of actieve Borrelia infectie. Van zogeheten cellulaire tests wordt gezegd dat ze mogelijkerwijs gevoeliger zijn vroeg in het beloop van de ziekte en dat ze wel onderscheid kunnen maken tussen een oude (al dan niet behandelde) of actieve Borrelia infectie. Dit is echter nog niet goed genoeg onderzocht.

Het doel van onze studie is daarom het bepalen of enkele cellulaire tests van aanvullende waarden zijn in het stellen van de diagnose Lymeziekte.

Projectgegevens
Projectnummer: 522050001
Status: Lopend
Looptijd: 2017 - 2021
Projectleider en penvoerder:
Dr. J.W.R. Hovius
Academisch Medisch Centrum

Project
Victory: Validation of Cellular tests for Lyme borreliosis

Samenvatting van de aanvraag

Lyme borreliosis is caused by spirochetes belonging to the B. burgdorferi sensu lato group, which are transmitted by ticks. The incidence of Lyme borreliosis in the Netherlands has increased and currently 25.000 new cases are diagnosed each year. The diagnosis of the first manifestation of Lyme borreliosis - erythema migrans - is based on the clinical presentation; no additional testing is required. Nonetheless, it can be difficult to discriminate an (atypical) erythema migrans from other skin disorders.

The diagnosis of disseminated Lyme borreliosis requires additional testing, but the current serological tests are insensitive in the early phase of disease and have difficulties distinguishing between an old and active B. burgdorferi sl infection. Therefore, diagnostic tests with a higher sensitivity early in the course of Lyme borreliosis and with the ability to discriminate between a past and active B. burgdorferi sl infection would add to the existing diagnostic repertoire. It has been postulated that cellular tests have such capacities. Such tests, although used for clinical purposes and popular among different groups of patients and physicians, are not well validated.

Hence, we aim to validate cellular tests to determine their additional value in the diagnosis of Lyme borreliosis. As part of the proposed project, we will test two pre-market tests, i.e. the revised Spirofind (Oxford Immunotec) and the QuantiFERON Lyme (QIAGEN) test.

In addition, as part of the current proposal we will organize a meeting together with the Dutch Lyme borreliosis Patient Organization (NVLP) to select additional cellular tests that are currently used by Dutch patients. In that regard we have had fruitful discussions with BCA (Augsburg, Germany), Invitalabs (Neuss, Germany) and Arminlabs (Augsburg, Germany), and we also contacted IMD (Berlin, Germany). From these and potentially other test suppliers we will, together with the NVLP, select one or two additional tests. The selected tests will be investigated in two independent and complementary cohorts.

The first group consists of Lyme borreliosis patients, diagnosed according to established European case definitions. These patients, mainly patients with an erythema migrans, but also patients with disseminated Lyme borreliosis manifestations, are recruited as part of the on-going national LymeProspect study.

All of these patients will receive antibiotic therapy. As part of the LymeProspect study, enrolled patients are subjected to two blood draws (t=0 and t=6 weeks) and the follow-up, by visits and multiple online questionnaires, is one year. As part of the current proposal, we will draw extra blood at t=0 and t=6 in all study objects. In addition, but only from patients that do not have objection, blood will be drawn at t=12 weeks.

In the two remaining years of the LymeProspect study we expect to enroll 600-800 patients. In addition, we will test 250 controls (200 healthy controls, 40 patients with auto-immune diseases and 10 patients with secondary Syphilis). By this clinical validation, we are able to determine the sensitivity and specificity of these tests in Dutch patients, derived from primary and secondary care populations. Since we will perform these tests before and after antibiotic treatment, we will also assess whether such tests have the potential to be used as point of cure tests.

In parallel, at the two Lyme referral centers at the Academic Medical Center (Amsterdam) and the Radboudumc (Nijmegen), we will use these tests in adjunction to routine B. burgdorferi sl serology. Patients will be classified as having definite, probable or questionable Lyme borreliosis, post-treatment Lyme borreliosis syndrome, persisting B. burgdorferi sl infection or no Lyme borreliosis, according to published criteria.

All patients will receive standard care, but will also be subjected to two (t=0 and t=12 weeks) blood draws and follow-up is one year. Two subgroups - definite and probable Lyme borreliosis, and definite and probable persisting B. burgdorferi sl infection – will also be subjected to a blood draw at t=6 weeks. Although data from the cellular tests or questionnaires will not determine clinical management of these patients, investigating the different tests in this tertiary care population provides additional information on the sensitivity, specificity, and importantly also the positive and negative predictive value of the different tests in a clinical cohort study. We will enroll a total of 600-800 patients through the AMC and Radboudumc in approximately three years.

Our hybrid - premarket tests and tests used by Dutch patients suspected of Lyme borreliosis - and parallel - two different patient cohorts - approach will expedite knowledge on the usefulness of cellular tests, answer pressing scientific and societal questions on the value of such tests in the diagnosis of Lyme borreliosis, and allows for swift translation or implementation of our findings into daily practice.

A positive result from the LTT for Borrelia is suspicious, but not evidential of an active Borrelia infection.

Certain laboratories offer different methods for the detection of Borrelia-specific activation of T lymphocytes, such as the EliSpot-Test-Borrelia®, for example, to answer these questions. In these methods, the induction of cytokine synthesis is measured at the cellular level. Al- though the EliSpot is well-established in the diagnosis of infectious diseases (TB), its impor- tance in the diagnosis of borreliosis has yet to be tested by appropriate techniques.

Eus schreef:Ik ben een enorme fan van de richtlijn van de DBG. Zojuist zocht ik er even iets in op en vond het volgende;

A positive result from the LTT for Borrelia is suspicious, but not evidential of an active Borrelia infection.

Certain laboratories offer different methods for the detection of Borrelia-specific activation of T lymphocytes, such as the EliSpot-Test-Borrelia®, for example, to answer these questions. In these methods, the induction of cytokine synthesis is measured at the cellular level. Al- though the EliSpot is well-established in the diagnosis of infectious diseases (TB), its impor- tance in the diagnosis of borreliosis has yet to be tested by appropriate techniques.

The following arguments support the use of cellular immunological methods in the laboratory diagnosis of Lyme borreliosis:

1. The direct identification of the causative agent is proof of Lyme borreliosis. The sensitivity of the methods for the direct identification of Borrelia is technically inadequate at present for daily practice.

Sproetje schreef:
Verder valt het me op dat DBG ook dit zegt:

The following arguments support the use of cellular immunological methods in the laboratory diagnosis of Lyme borreliosis:

1. The direct identification of the causative agent is proof of Lyme borreliosis. The sensitivity of the methods for the direct identification of Borrelia is technically inadequate at present for daily practice.

Hoe wil men die "direct identification of the causative agent" dan aantonen?

Verder vind ik dat zinnetje ook wel een beetje dubbel, want als "direct identification of the causative agent proof is of Lyme borreliosis", dan is zo'n LTT toch helemaal niet meer nodig?

Maar zelf zeggen ze ook dat deze "direct identification" technisch inadequaat is.
Waarschijnlijk wordt daar de DNA dan mee bedoelt?