Primary objective: To assess microbiological, immunological, genetic, clinical, cognitive-behavioral, and epidemiological determinants for development of persisting symptoms in both adult and juvenile Lyme patients, and establish prediction rules *…
ID
Source
Brief title
Condition
- Bacterial infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study endpoint is whom of the confirmed Lyme patients develop
persisting symptoms, based upon the validated symptom and disability
questionnaires.
The main study parameters are all microbiological, immunological, genetic,
clinical, cognitive-behavioral, and epidemiological parameters measured during
follow-up of these confirmed Lyme patients, that possibly predict development
of such persisting symptoms, i.e.:
-Quantitative PCRs for Borrelia on skin and blood samples
-typed Borrelia cultures from skin samples, and minimal inhibitory
concentrations (MICs) for relevant antibiotics, as well as molecular typing of
cultivated Borrelia burgdorferi subspecies
-PCRs for other tick-borne pathogens on skin and blood samples
-Antibiotic trough levels in blood samples collected during standard antibiotic
treatment in all clinical Lyme center patients
-Borrelia C6 ELISA (IgM/IgG; Immunetics) and both a IgM and IgG immunoblot
(Mikrogen) and serology for other tick-borne pathogens in blood samples.
-Cellular immune responses: ex-vivo stimulation of whole blood and (fresh)
PBMCs - collected before and after antibiotic treatment with Borrelia and other
stimuli.
- Four cellular tests (Spirofind® (Oxford Immunotec), QuantiFERON Lyme®
(QIAGEN), the EliSpot assay developed by AID (Autoimmun Diagnostika GmbH) in
Strassberg, Germany) and the LTT-MELISA (developed by Invitalabs in Neuss,
Germany) before and after antibiotic treatment. The tests are based on the ex
vivo stimulation of blood (whole blood or PBMCs) with Borrelia according to the
manufacturers protocol to examine the specific cellular immune reactivity to B.
burgdorferi s.l and to assess whether test results are related to clinical
outcome.
-Gene expression arrays: we will perform micro-arrays (Illumina) using RNA from
frozen peripheral blood mononuclear cells (PBMCs) * collected before and after
antibiotic treatment * that are ex-vivo stimulated with Borrelia and other
stimuli.
-Humoral immune response: IgG2/IgG1 ratios in patients before and after
treatment in search of an activity marker.
-Complement cascade: Mannose Binding Lectin (MBL) levels before and after
treatment
-All relevant outcomes of the questionnaires that possibly predict development
of persisting symptoms.
Secondary outcome
Secondary study parameters are all microbiological, immunological, genetic,
clinical, cognitive-behavioral, and epidemiological parameters as described
above * but now in the unconfirmed Lyme patients with existing persisting
symptoms * that are possibly similar to the determinants of such persisting
symptoms that were identified in the confirmed Lyme patients.
Background summary
In the past 15 years, a three-fold increase in the number of tick bites and
cases of Lyme borreliosis has been observed in the Netherlands, with currently
more than one million tick bites and 20.000-30.000 Lyme borreliosis cases per
year. 20-30% of all tick bites and Lyme borreliosis is attributed to children.
The majority of Lyme borreliosis patients respond well to antibiotic treatment
but around 5-20% of patients report persisting symptoms such as musculoskeletal
pain, neurocognitive symptoms and fatigue. These persisting and sometimes
disabling symptoms can have great impact on the quality of life.
Currently it is not known to what extent long-term persisting symptoms are
related to persistence of Borrelia infection, auto-inflammation or
auto-immunity, co-infection with other tick-borne pathogens, or other
mechanisms. In the proposed study, we will prospectively investigate the
clinical course of antibiotic-treated Lyme borreliosis and assess the actual
risk of developing persisting symptoms. To assess specific determinants for
development of such symptoms, we will include microbiological, immunological,
genetic, clinical, cognitive-behavioral, and epidemiological explanations for
these symptoms in the measurements during patient follow-up.
Children may well have different risks and/or determinants to develop
persisting symptoms than adults. Since such differences would call for specific
diagnostic and treatment strategies for children, the risk and determinants of
persisting symptoms with Lyme borreliosis should be assessed specific for
children and for adults.
Furthermore, no other prospective studies have been performed to persisting
symptoms after Lyme borreliosis in children. Several differences between
children and adults for acute Lyme manifestations that may well be related to
different risk and determinants of persisting symptoms have been described. The
inclusion and prospective follow-up of children in this study allows us to look
specifically for determinants that predict for development of persisting
symptoms for individual children.
Our study is unique and innovative by its prospective and holistic approach.
The prospective follow-up of patients allows us to identify determinants that
predict the development of persisting symptoms for individual patients, both
for children and for adults. The results of this study will thus contribute to
future treatment strategies that prevent or resolve persisting symptoms in
individual Lyme borreliosis patients.
Study objective
Primary objective: To assess microbiological, immunological, genetic, clinical,
cognitive-behavioral, and epidemiological determinants for development of
persisting symptoms in both adult and juvenile Lyme patients, and establish
prediction rules * for the occurrence and intensity of persisting symptoms *
for individual patients.
Secondary objective(s):
1- To assess the outcome and long-term effects of early localized, early
disseminated and late disseminated Lyme borreliosis, both in children and in
adults.
2- To assess what determinants of persisting symptoms in confirmed patients are
existent in unconfirmed patients with existing persisting symptoms, and thus
suggestive of similar mechanisms leading to persistence of symptoms, both in
children and in adults.
3- To propose more personalized treatment and diagnostic strategies for both
adult and juvenile Lyme borreliosis patients, which can be validated in further
studies to asses to what extent they actually prevent and resolve long-term
persisting symptoms in children and in adults.
Study design
This is a prospective observational cohort study without intervention but with
invasive measurements.
We will prospectively investigate the long-term effects of Lyme borreliosis by
a one year follow-up of 2000 adult and 300 juvenile patients with early
localized, early disseminated or late disseminated Lyme borreliosis. Patients
will be included before or just after start of treatment. In addition we will
also include 300 adult and 50 juvenile patients with suspected but unconfirmed
Lyme disease that have already developed persisting symptoms.
Study burden and risks
Participation in the study has no direct benefits for the subject. There is the
possibility for the treating physician to contact the investigators for
assistance in the diagnosis and (further) treatment, if during or after the
study symptoms develop or persist. Participation contributes to enhanced
insight in the development of persisting symptoms of Lyme borreliosis, and thus
to the possible improvement of the diagnosis and/or treatment of people
suffering from Lyme disease in the future. The burden of participation consists
of blood sampling, filling in questionnaires, and for some of the adult
participants also taking skin biopsies and skin swabs. We also include minors,
who constitute 20-30% of all Lyme patients. Their specific risk to develop
persisting symptoms after treatment should be assessed, as well as possible
determinants/mechanisms for development of such symptoms. Based on the study
results, treatment strategies specific for minors and/or adults can be
proposed, in order to prevent or resolve persisting Lyme-related symptoms. For
all study participants, upon request by a patient*s GP or medical specialist,
the project team can support diagnosis of possible Lyme-related disease or
symptoms, facilitated by the study measurements if applicable.
Antonie van Leeuwenhoeklaan 9
Bilthoven 3721 MA
NL
Antonie van Leeuwenhoeklaan 9
Bilthoven 3721 MA
NL
Listed location countries
Age
Inclusion criteria
Inclusion criteria are partly dependent on the patient group and the route of inclusion.
Patients included through Tekenradar.nl:
- are 5 yrs and older.
(there are no age restrictions for patients included through clinical Lyme centers)
EM patients included through Tekenradar.nl:
- report an EM at Tekenradar.nl with a diameter larger than 5 cm and that has been present for less than 3 months;
- have a confirmed (typical or atypical) EM diagnosed by their GP;
- have not yet started treatment for the EM or started maximum 4 days earlier at the moment of inclusion;
Confirmed Lyme patients:
- have a confirmed diagnosis of early or late Lyme borreliosis;
- have not yet started treatment at the moment of inclusion, or, if included via Tekenradar.nl at most 4 days before inclusion, or, if included via Clinical Lyme Centers, at most 1 week before inclusion.
Unconfirmed Lyme patients included through the Clinical Lyme Centers:
- symptoms that are present at the time of inclusion and have persisted for more than 6 months, such as myalgia and arthralgia, neuralgia, concentration disorders and cognitive disturbances, with or without fatigue.
- have a history of an unconfirmed suspicion for Lyme disease based on a positive result of a non-recommended diagnostic test OR onset of disease symptoms (as described above) that have started within one month after a documented tick bite;
-have a negative serological test for Borrelia spp.
Exclusion criteria
Exclusion criteria are partly dependent on patient group and route of inclusion.
All patients (and/or their parents/guardians):
- are unable to give informed consent or do not have a thorough command of the Dutch language.
Confirmed Lyme patients included through Tekenradar.nl:
-started treatment more than 4 days before inclusion.
Confirmed Lyme patients included through the Clinical Lyme Centers:
- started treatment more than one week before inclusion.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
In other registers
| Register | ID |
|---|---|
| CCMO | NL50227.094.14 |
| OMON | NL-OMON27509 |