A study focused at identifying disrupted biological factors and
patient-tailored interventions for adolescents with Q-Fever
Fatigue Syndrome

Severe debilitating fatigue is the dominant symptom of Q-fever fatigue syndrome
(QFS). However, little research on QFS has been done in adolescents on
pathogenesis or therapy. QFS bears resemblance to the fatigue observed in
chronic disorders such as Juvenile Idiopathic Arthritis (JIA) and Chronic
Fatigue Syndrome (CFS/ME). In recent literature, chronic fatigue is regarded as
a generic instead of a disease-specific symptom. Fatigue is considered the
result of a patient-specific complex interplay of psychosocial, lifestyle and
biological factors. This calls for a comparable approach for the various
fatigue syndromes. The proposed study integrates biology and a psychosocial
approach to create an in-depth understanding of QFS. Its treatment is
investigated by combining two interventions aimed at direct benefit for QFS
adolescent patients.

The first objective is to explore the biological profile (e.g. the
immunological profile, hypothalamic- pituitary-adrenal (HPA) axis,
mitochondrial dysfunctioning, the gut microbiome) of adolescents with QFS and
related fatigue disorders (CFS/ME, fatigued JIA patients) at baseline as
compared to controls.

The second objective is to evaluate across the three patient groups (QFS,
CFS/ME and fatigued JIA patients) the effectiveness of two interventions on
fatigue severity (primary outcome), quality of life and self-efficacy
(secondary outcomes): (1) patient-tailored PROfeel lifestyle advices, which are
partly based on an individual dynamic network of fatigue associated factors
that are assessed with the Ecological Momentary Assessments (EMA) methodology,
and (2) generic dietary advices based on the Dutch Voedingscentrum. In
addition, differences in effectiveness will be explored between the three
patient groups.

The third objective is to explore on the individual patient level the
effectiveness of the two interventions on fatigue severity (primary outcome)
and to explore the effectiveness on quality of life and self-efficacy
(secondary outcomes).

The fourth objective is to explore individual effects on pre-post intervention
change in the dynamic networks for the patient-tailored PROfeel lifestyle
advices-first group.

The fifth objective is to explore the relationship between individual
differences in the improvement on fatigue and change in the biological profile
in the interval T0, T2, T4 (pre-post interventions).

Objective 1: case-control comparison design.
Objective 2: randomized controlled trial (RCT) with two intervention arms.
Objective 3: multiple single subject experimental case series design.
Objective 4: multiple single subject pre-post DSEM network-estimates comparison
design.
Objective 5: multiple single subject experimental case series design.

All recruited patients (subgroups) and control groups start with a baseline
assessments (T0):
• The biological material (blood, saliva, faeces) is collected at study start
(please see below for more details). Children/ adolescents (12-29 yr) with QFS
are compared with a healthy control group of siblings/friends with positive
Q-fever serology but without fatigue and with Q-fever serological negative
controls.
• Questionnaires (outcome and possible predictors/ mediators, both participants
and parents). Patients and parents are invited to fill in digitalized
questionnaires. Participants were asked to fill out these questionnaires
without assistance from their parent(s) or the researcher.

Only the patient groups :
• Four weeks of intensive EMA at T0 (and T2): All patients will be invited to
discuss with the trial coordinator which personal factors may be relevant in
relation to the fatigue such as pain, dizziness, sleep, activity, school, work,
anger, isolation, fear. This will result in a short list of maximal 12 items
classified in symptoms, feelings, behavior, activities, cognitions which will
be measured 4-6 times a day during 4 weeks using the EMA technology.
• At T0, T2 and T4 all patients will be asked to fill in the outcome
questionnaires and to collect biological samples (for storage in biobank). At
T2 all patients will have another 4 weeks of intensive EMA.
• Will be followed during the study with weekly outcome measurements on the
smartphone. In case patients self-report sufficient improvement in fatigue
and/or show clinical significant improvement after the first intervention, they
will be asked to complete the weekly smartphone measurements for 12 more weeks
after the first intervention. In case patients self-report and/or show clinical
significant improvement after the second intervention, they will be asked to
complete the weekly smartphone measurements for 12 more weeks after the second
intervention. In case patients do not self-report and/or show clinical
significant improvement after the second intervention, they will be offered
alternative therapy and will be asked to complete weekly smartphone measurement
until T5.
• At T5 there is follow-up measurement.

patients:
4 weeks intensive questionnaires (EMA) twice
3 vists a 45-60 min combined with regular visit if possible
2x 12 weeks intervention.

In case patients self-report sufficient improvement in fatigue severity and/or
show clinically significant improvement in fatigue severity after the first
intervention, they are not obliged to participate in the second intervention.
If they choose not to enroll in the second intervention, they will be asked to
complete the weekly smartphone questionnaire for only 12 more weeks (i.e. until
week 28 of the study). In case patients self-report sufficient improvement
and/or show clinical significant improvement in fatigue severity after the
second intervention, they are also asked to complete the weekly smartphone
questionnaire for 12 more weeks (i.e. until week 44 of the study).

Throughout the study, we aim to combine patients research participation as much
as possible with regular visits and care in order to minimize participation
burden.


healthy controls:
1 visit to the hospital 45 min.