Clinical trial NCT03932448: Fever After Tick Bite Study
Official title: Fever After Tick Bite (FATB) Study; Determining the Etiology of Tick-Borne Human Infections in Northern Europe
Study type: OBSERVATIONAL
Overall status: WITHDRAWN
Conditions: Tick-Bite; Fever
Tick Fever
Tick-Borne Diseases
Encephalitis, Tick-Borne
Tick Bites
Lead sponsor: Göteborg University
Sponsor class: OTHER
Collaborators: name: Sahlgrenska University Hospital
name: Vastra Gotaland Region
First posted: 2019-04-30
Enrollment: 0
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Men and women ≥18 years old with documented or a medical history of fever (≥38°C) within 2 weeks after a tick bite.

Brief summary: The proposed study is a collaboration between Microbiology, SU/Sahlgrenska and the Infectious Diseases clinic at SU/Östra as well as several Infectious Diseases clinics throughout Sweden aiming at improving microbiological diagnostic assays regarding the early identification of tick-borne microorganisms (including as of yet unidentified pathogens) capable of causing human disease using modern diagnostic tools.

At the initial study visit (day 0) plasma, serum, urine, saliva, and PBMCs (and tick, if available) will be collected from patients developing fever within two weeks after a tick bite. Additional follow-up samples will be obtained after 9 and 30 days as well as after 6 months. The initial samples will be analyzed using (a) directed multiplex PCR analysis for Tick-Borne Encephalitis (TBE), Borrelia, Anaplasma, Neoerlichia, Rickettsia, Coxiella, Tularemia, and Babesiosis in plasma, whole blood and urine, (b) conventional IgM and IgG serology for TBE, (c) "Next Generation Sequencing" (NGS) for the detection of bacterial 16s rRNA as well as unknown viruses, (d) potential biomarkers, and (e) host genetic factors. Among patients where initial sampling indicates the presence of a potential pathogen or in patients developing neurological symptoms, a lumbar puncture will be performed and CSF will be further analyzed. Samples will also be evaluated regarding potential microbiological factors predisposing for severity of infection.

The primary objective of the study is to improve diagnostic tools in the initial early phase of infections caused by tick-borne pathogens, especially TBE prior to the affliction of the central nervous system, and to attempt to identify which factors impact the course of infection as it is believed that approximately 75% of infected individuals resolve their infection in this first phase whereas others develop meningoencephalitis with significant subsequent neurological sequelae. Secondary objectives of the study include investigating for the presence of and treating other tick-borne pathogens, setting the stage for coming clinical trials evaluating novel anti-viral therapies for TBE.


Eligibility criteria: Inclusion Criteria:

* Written informed consent
* Male and female patients ≥18 years of age
* Medical history of tick bite within past 2 weeks
* Documented or medical history of fever (≥38°C) within past 2 weeks

Exclusion Criteria:

* Inability or unwillingness to provide informed consent or abide by the requirements of the study
* Presence of urinary tract symptoms
* Presence of non-tick related, infectious agent causing fever, e.g. a respiratory virus
* Presence of other medical, non-infectious cause of fever

Primary outcomes:
measure: Etiology of fever (≥38°C) developing within 2 weeks after a tick bite.
timeFrame: Up to two weeks after the tick bite.
measure: Proportion of subjects developing neurological symptoms after a tick bite.
timeFrame: Up to six months after the tick bite.
measure: Proportion of subjects developing other serious, non-neurological symptoms or disease after a tick bite.
timeFrame: Up to six months after the tick bite.
Secondary outcomes:
measure: Impact of body mass index (BMI) of subjects on the risk of development of neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Impact of waist circumference of subjects on the risk of development of neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Impact of gender of subjects on the risk of development of neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Impact of age of subjects on the risk of development of neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Impact of body mass index of subjects developing other serious, non-neurological symptoms or disease.
timeFrame: Up to six months after the tick bite.
measure: Impact of waist circumference of subjects developing other serious, non-neurological symptoms or disease.
timeFrame: Up to six months after the tick bite.
measure: Impact of gender of subjects developing other serious, non-neurological symptoms or disease.
timeFrame: Up to six months after the tick bite.
measure: Impact of age of subjects developing other serious, non-neurological symptoms or disease.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of the utility of Next Generation Sequencing (NGS) for the detection of unknown viruses and of bacterial 16s rRNA vs. directed Multiplex PCR
timeFrame: Up to 30 days after the tick bite.
measure: Prospective evaluation of the specificity and sensitivity of TBEV-RNA and TBE IgM serology in the early phase of infection, i.e. up to 30 days after the tick bite.
timeFrame: Up to 30 days after the tick bite.
measure: Prospective evaluation of the specificity and sensitivity of TBEV-RNA in urine vs. plasma/whole blood in the early phase of TBE infection, i.e. up to 30 days after the tick bite.
timeFrame: Up to 30 days after the tick bite.
measure: Prospective evaluation of the specificity and sensitivity of PCR for Borrelia DNA in plasma/serum as well as Borrelia IgM serology in the early phase of infection, i.e. up to 30 days after the tick bite.
timeFrame: Up to 30 days after the tick bite.
measure: Prospective evaluation of the specificity and sensitivity of early evaluation of plasma concentrations of the neurological markers NFL in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of the specificity and sensitivity of early evaluation of plasma concentrations of the neurological marker T-tau in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of the specificity and sensitivity of early evaluation of plasma concentrations of the neurological marker GFAp in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of the specificity and sensitivity of early evaluation of plasma concentrations of IP-10 (aka CXCL10) in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of the specificity and sensitivity of early evaluation of 25-hydroxy vitamin D (25(OH)D) concentrations in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of peripheral blood mononuclear cells (PBMCs) analyzed by FACS, in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of the impact of host genetic polymorphisms in the IFNL4 gene in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of the impact of host genetic polymorphisms in the ITPA gene in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
measure: Prospective evaluation of the impact of prior vaccination against TBE on frequency and outcome of TBEV infection.
timeFrame: From time of prior vaccination until six months after the tick bite.
measure: Prospective evaluation of the impact of prior vaccination against Yellow Fever on frequency and outcome of TBEV infection.
timeFrame: From time of prior vaccination until six months after the tick bite.
measure: Prospective evaluation of the impact of prior vaccination against Japanese Encephalitis on frequency and outcome of TBEV infection.
timeFrame: From time of prior vaccination until six months after the tick bite.
measure: Prospective evaluation of the association between presence or absence of immunosuppression in relation to the likelihood of developing neurological symptoms.
timeFrame: Up to six months after the tick bite.
Other outcomes:
Locations:
city: Gothenburg
country: Sweden
facility: Dept. of Infectious Diseases
Study officials:
affiliation: Göteborg University
name: Martin Lagging, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: