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Internet-based cognitive behavior therapy (I-CBT) for adolescents with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has been shown to be effective in a randomized controlled trial (RCT; Fatigue in Teenagers on the Internet [FITNET]). FITNET can cause a significant reduction in fatigue and disability.
We aimed to investigate whether FITNET treatment implemented in routine clinical care (IMP-FITNET) was as effective, using the outcomes of the FITNET RCT as the benchmark.
Outcomes of CFS/ME adolescents who started IMP-FITNET between October 2012 and March 2018 as part of routine clinical care were compared to the outcomes in the FITNET RCT. The primary outcome was fatigue severity assessed posttreatment. The secondary outcomes were self-reported physical functioning, school attendance, and recovery rates. Clinically relevant deterioration was assessed posttreatment, and for this outcome, a face-to-face CBT trial was used as the benchmark. The attitude of therapists toward the usability of IMP-FITNET was assessed through semistructured interviews. The number of face-to-face consultations during IMP-FITNET was registered.
Of the 384 referred adolescents with CFS/ME, 244 (63.5%) started IMP-FITNET, 84 (21.9%) started face-to-face CBT, and 56 (14.6%) were not eligible for CBT. Posttreatment scores for fatigue severity (mean 26.0, SD 13.8), physical functioning (mean 88.2, SD 15.0), and full school attendance (mean 84.3, SD 26.5) fell within the 95% CIs of the FITNET RCT. Deterioration of fatigue and physical functioning after IMP-FITNET was observed at rates of 1.2% (n=3) and 4.1% (n=10), respectively, which is comparable to a waiting list condition (fatigue: 1.2% vs 5.7%, χ21=3.5,
IMP-FITNET is an effective and safe treatment for adolescents with CFS/ME in routine clinical care.
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling condition in which patients have severe, medically unexplained, and persistent (>6 months) fatigue, resulting in impairment of functioning [
The etiology of CFS/ME is unknown. The context of the biopsychosocial model defines individual predisposing, precipitating, and perpetuating factors that provoke and maintain severe fatigue and disability [
The primary aim of this study was to determine whether FITNET implemented in RCC (IMP-FITNET) is as effective as in a research context with respect to the outcomes of fatigue severity, physical functioning, school attendance, and recovery rates, using the outcomes of the previous RCT as the benchmark [
This was an observational study of RCC. Data were collected retrospectively from adolescents who finished treatment in RCC after implementation.
All patients were referred to the Expert Centre for Chronic Fatigue (ECCF), a national referral center for IMP-FITNET and face-to-face CBT for adolescents with CFS/ME, and were retrospectively included in the study between October 2012 and March 2018.
The inclusion criteria were as follows: (1) CFS according to the US Centers for Disease Control (CDC) criteria revised in 2003 [
Posttreatment effectiveness in terms of fatigue severity, physical functioning, school attendance, and recovery rates were compared with results derived from the previously published RCT on FITNET [
The Dutch Medical Research Involving Human Subjects Act did not apply to our study, as the collected data were part of RCC. Therefore, no formal ethical approval from the medical ethics committee was needed for this study.
CBT for CFS/ME is developed on the basis of a cognitive behavioral model of CFS, assuming that behavior and beliefs can perpetuate symptoms [
Eleven trained cognitive behavioral therapists who received weekly supervision from experienced clinical psychologists delivered face-to-face CBT and IMP-FITNET.
All outcome variables were self-reported. The primary outcome was fatigue severity assessed with the subscale fatigue severity of the CIS-20. This subscale consists of eight items scored on a 7-point Likert scale, resulting in a fatigue severity score ranging from 8 to 56. A score ≥40 indicates the presence of severe fatigue [
Physical functioning was measured with the subscale physical functioning (nine items, range 0%-100%) of the Child Health Questionnaire-87 (CHQ-87). The questionnaire is validated and has good internal consistency [
School presence was assessed using a diary and reported as the percentage of classes attended over the past 2 weeks divided by the scheduled number of classes for peers [
Recovery was defined in relation to healthy peers by having a CIS-fatigue score <40 [
Deterioration of fatigue was defined as an increase of more than six points in CIS-fatigue, and deterioration of physical functioning was defined as a decrease of more than 10 points in CHQ-physical [
The benchmark for deterioration, as a proxy for safety, was the waiting list condition in a prior RCT on the efficacy of face-to-face CBT [
Using a semistructured telephone interview, 11 therapists were asked which criteria they used to propose to start with either IMP-FITNET or face-to-face CBT for the individual adolescent or face-to-face consultations during IMP-FITNET. Nine therapists participated. Interviews with the therapist were recorded and transcribed by one researcher (EA). The themes were independently synthesized by two researchers (EA and LNN) based on the interviews [
After referral, adolescents had two diagnostic face-to-face sessions with a psychologist. The results of the baseline assessment were discussed with the adolescent and parents, and this was followed by a shared decision for either IMP-FITNET or face-to-face CBT. Following treatment, adolescents completed an online posttreatment assessment, which was discussed in a face-to-face session.
The demographic characteristics of the adolescents and baseline scores were compared using a benchmark strategy, in which the baseline scores of RCC were compared with the 95% CIs of corresponding values in the FITNET RCT. If the mean value in RCC was outside the 95% CI of the RCT, it was considered divergent. The same procedure was used to compare the post-treatment outcomes of RCC with the RCT. Baseline characteristics of patients lost to follow-up were compared with those who were assessed posttreatment using a
Analyses were based on intention to treat, using the summary estimate of five imputations for 15 missing observations in the primary outcome, with the assumption that data were missing at random [
SPSS version 25 (IBM Corp) was used for statistical analyses, and significance was set at
Of the 384 referred adolescents, 371 were eligible for treatment, of which 328 (88.4%) started treatment. Of the 328 patients, 244 (74.4%) received IMP-FITNET and 84 (25.6%) received face-to-face CBT. All 328 adolescents filled out the baseline assessment, 229 of the 244 patients (93.8%) who received IMP-FITNET completed the posttreatment assessment, and 71 of the 84 patients (84.5%) who received face-to-face CBT completed the posttreatment assessment (
Study flow of the patients in routine clinical care. CBT: cognitive behavioral therapy; CFS: chronic fatigue syndrome; IMP-FITNET: implemented Fatigue in Teenagers on the Internet.
Adolescents lost to follow-up differed significantly in physical functioning at baseline (mean score 64.7, SD 16.4 vs mean score [lost to follow-up] 73.0, SD 19.4;
The percentage of adolescents lost to follow-up was significantly higher in IMP-FITNET than in the FITNET RCT (8.5% [n=28] vs 3.0% [n=4], N=463, χ21=3.3,
Baseline characteristics of the patients in routine clinical care and the 95% CIs of the benchmark Fatigue in Teenagers on the Internet randomized controlled trial scores.
Variable | IMP-FITNETa (N=244) | F2F-CBTb (N=84) | 95% CI benchmark FITNET RCTc (N=135)d |
Age at entry (years), mean (SD) | 16.1 (1.4) | 15.4 (1.8) | 15.6-16.1e |
Gender (female), n (%) | 202 (82.8%) | 62 (73.8%) | 76%-89%e |
Duration of symptoms at entry (months), median (range) | 18 (3-96) | 30 (6-96) | 20-27 monthse |
Fatigue severity (CISf), mean (SD) | 49.8 (5.0) | 48.7 (6.3) | 50.6-52.2e |
School attendance, mean % (SD) | 60.5 (34.2) | 61.1 (33.4) | 37.0-47.6e |
Number of children with >85% school attendance, n/N (%) | 70/244 (31.3%) | 22/84 (28.9%) | 5%-15%e |
Physical functioning (CHQ-87g), mean (SD) | 64.7 (16.4) | 63.2 (19.3) | 55.7-61.8e |
Anxiety score (STAICh), mean (SD) | 31.9 (7.4) | 34.7 (8.0) | 31.9-34.4e |
aIMP-FITNET: implemented Fatigue in Teenagers on the Internet.
bF2F-CBT: face-to-face cognitive behavior therapy.
cRCT: randomized controlled trial.
dBenchmark FITNET RCT: the study by Nijhof et al [
e95% CIs of the values of the benchmark FITNET RCT.
fCIS: Checklist Individual Strength.
gCHQ-87: Child Health Questionnaire-87.
hSTAIC: State-Trait Anxiety Inventory for Children.
The CIS-fatigue severity score after IMP-FITNET and face-to-face CBT in RCC fell within the 95% CI of the benchmark FITNET study. Additionally, 173 of the 229 adolescents (75.5%) with a posttreatment fatigue score had a reliable change index score greater than +1.96 and a score lower than 40 on the CIS. All secondary outcomes (
In RCC, 3 of the 244 patients (1.2%) reported a clinically significant deterioration of fatigue severity after IMP-FITNET. In the waiting list condition of a face-to-face CBT benchmark study, 2 out of 35 patients (5.7%) showed clinically significant deterioration in fatigue severity [
In RCC, 10 of the 244 patients (4.1%) reported clinically significant deterioration of physical functioning after IMP-FITNET. In the benchmark study [
The within-treatment group effect size of FITNET in the RCT was large (Cohen
Posttreatment scores of patients in routine clinical care and the 95% CIs of the benchmark Fatigue in Teenagers on the Internet randomized controlled trial scores.
Variable | IMP-FITNETa (N=229) | F2F-CBTb (N=71) | 95% CI benchmark FITNET RCTc (N=67)d |
Fatigue severity (CISe), mean (SD) | 26.0 (13.8) | 25.8 (12.3) | 20.7-27.3f |
Physical functioning (CHQ-87g), mean (SD) | 88.2 (15.0) | 89.3 (12.8) | 85.2-91.9f |
School attendance, mean % (SD) | 84.3 (26.5) | 87.1 (23.6) | 77.1-91.5f |
Recoveryh, % | 58% | 60% | 54-77%f |
aIMP-FITNET: implemented Fatigue in Teenagers on the Internet.
bF2F-CBT: face-to-face cognitive behavior therapy.
cRCT: randomized controlled trial.
dBenchmark FITNET RCT: the study by Nijhof et al [
eCIS: Checklist Individual Strength.
f95% CIs of the values of the benchmark FITNET RCT.
gCHQ-87: Child Health Questionnaire-87.
hCutoff scores for recovery are as follows: fatigue severity of <40 on the CIS-20 subscale fatigue; school absence of ≤10%, and a physical functioning score of ≥85% on the CHQ-87 subscale physical functioning.
Number of patients with symptom deterioration between preassessment and postassessment.
Variable | IMP-FITNETa (N=244) | F2F-CBTb (N=71) | Waiting list conditionc (N=35) |
Deterioration of fatigue severityd, n (%) | 3 (1.2%) | 2 (2.8%) | 2 (5.7%) |
Deterioration of physical functioninge,f, n (%) | 10 (4.1%) | 2 (2.8%) | 4 (11.4%) |
aIMP-FITNET: implemented Fatigue in Teenagers on the Internet.
bF2F-CBT: face-to-face cognitive behavior therapy.
cData from adolescents on a waiting list condition in a study by Stulemeijer et al [
dIncrease of >6 points on the Checklist Individual Strength (CIS).
eDecrease of >10 points on the Child Health Questionnaire-87 (CHQ-87) for patients following IMP-FITNET or F2F-CBT.
fDecrease of >10 points on the Short Form-36 (SF-36).
Nine of the 11 therapists were interviewed. Face-to-face CBT was preferred to IMP-FITNET when there were interaction problems in the family or when the patient had psychiatric or somatic comorbidities. Therapists decided to make use of face-to-face consultations during IMP-FITNET treatment in the case of perceived inability of the patient to benefit from solely IMP-FITNET or anticipated problems with adherence and motivation. In general, therapists preferred blended therapy with combinations of IMP-FITNET.
Of the 244 adolescents who started IMP-FITNET, 116 (47.5%) followed only IMP-FITNET without face-to-face consultations and 102 (41.8%) had at least one face-to-face consultation with their therapist, and of these, 41 adolescents (16.8%) had over 3 face-to-face consultations. Adolescents who used face-to-face consultations had on average about three face-to-face consultations (mean 3.2, SD 3.81, modus 1). Moreover, videoconferencing became an additional feature during IMP-FITNET treatment for 50 patients, of which 23 patients (46.0%) used videoconferencing, with an average of 5.1 conferences (SD 3.48) lasting on average 24.3 minutes (SD 20.7).
The posttreatment outcomes of adolescents with CFS/ME treated with I-CBT implemented in RCC (IMP-FITNET) were within the CIs of the outcomes from the benchmark with respect to levels of fatigue severity, physical functioning, school attendance, and recovery rates at posttreatment. Additionally, 133 of the 229 (58.1%) adolescents treated with IMP-FITNET met the recovery criteria posttreatment. The within-treatment group effect size of the decrease in fatigue severity with IMP-FITNET was also within the CI of the benchmark. At baseline, patients had an average fatigue severity score of 49.8 (SD 5.0), and after treatment, their fatigue severity score reduced on average by 23.8 points to 26.0 (SD 13.8). We conclude from this that IMP-FITNET applied in RCC is an effective intervention. Our findings are in line with the results of studies in adult patients with CFS/ME, in which blended CBT implemented in RCC was as effective as in a research context [
The primary and secondary outcomes of adolescents following face-to-face CBT were also within the CIs of the FITNET RCT. A quarter of the referred patients eligible for IMP-FITNET started with face-to-face CBT after a shared decision process. This was more often the case when patients were young, were male, had a long symptom duration, and were anxious. Therapists indicated preferring face-to-face CBT in case of family interaction problems, psychiatric or somatic comorbidities, and problems with motivation.
The prevalence of a clinically significant deterioration following IMP-FITNET was low in general and comparable with a waiting list condition of a prior CBT study [
At baseline, differences existed between adolescents who received IMP-FITNET and those in the benchmark FITNET RCT. Adolescents in RCC were less severely fatigued, were less physically impaired, had less school absence, and had a shorter symptom duration compared with patients from the benchmark RCT. This may be the result of the increased availability of an evidence-based and internet-based treatment for this patient group after nationwide implementation of I-CBT that followed the publication of the FITNET RCT results. Moreover, for these less severely affected adolescents with CFS/ME, IMP-FITNET is effective. IMP-FITNET has the advantage that adolescents do not need to travel for treatment. The nationwide availability of an effective intervention favors earlier referral.
This clinical observational study was not designed to investigate the difference in effectiveness of IMP-FITNET versus face-to-face CBT in relation to specific patient populations. Nevertheless, we found that even with a less strict treatment protocol and a more blended form of treatment, IMP-FITNET is effective. Although CBT for adolescents with CFS/ME (FITNET, face-to-face CBT, or IMP-FITNET) is considered effective, one-third of patients do not recover. To further improve the treatment and prognosis of adolescent CFS/ME, it is important to identify the factors that contribute to treatment effectiveness and assess which factors are associated with nonrecovery. Some issues need further consideration. First, in this observational study design, the choice of the treatment form (face to face vs IMP-FITNET) was determined by health care providers taking into account the patient’s preference. For this reason, there are methodological limitations, and the most important one is the risk of confounding by indication [
IMP-FITNET in RCC was adapted according to therapist and patient preferences for video or face-to-face consultations. A substantial number of adolescents who followed IMP-FITNET had one or more face-to-face consultations. A blended form of IMP-FITNET, in which different modalities of communication can be used, may have advantages and is in line with the current practice to combine internet interventions with face-to-face interaction with a therapist. One limitation is that during implementation of the FITNET treatment, technical options were expanded, for example, video consultations were integrated in the portal. The increasingly rapid development within software systems makes it more difficult to compare treatments designed at different time points. More research is necessary to inform when blended CBT is more effective than internet-based treatment alone. Further research also has to show whether blended care, with video consultations, is as cost-effective as FITNET with only email contact.
In conclusion, this study showed that IMP-FITNET is an effective and safe treatment for adolescents with CFS/ME in RCC. In RCC, the therapist can tailor the mode of delivery of the intervention to the needs of the individual patient.
Posttreatment scores of the 226 patients in routine clinical care who fulfilled all the inclusion criteria of the Fatigue in Teenagers on the Internet randomized controlled trial.
cognitive behavior therapy
chronic fatigue syndrome
Child Health Questionnaire-87
Checklist Individual Strength-20
Fatigue in Teenagers on the Internet
internet-based cognitive behavior therapy
implemented Fatigue in Teenagers on the Internet
myalgic encephalomyelitis
routine clinical care
randomized controlled trial
HK was the principal investigator of this study. EA and LNN were responsible for data gathering. EA, LNN, EEBVDS, and HK were responsible for the data analysis and for drafting the report. HK, SLN, and EMVDP designed and supervised the study, and revised the manuscript critically. All authors have read and approved the final submitted manuscript.
None declared.