Long-term Effects of COVID-19 in Adolescents
Conditions: Covid19
Sponsor: University Hospital, Akershus

 
 
Long-Term Effects of COVID-19 in Adolescents (LoTECA) 
 
 
 
Study protocol  
NCT 04686734 
Date: 4th of January, 2021. 
Revised #1: 26th of January 2021 (addition of control group). 
Revised #2: 20th of March 2021 (addition of cardiology 
substudy) 
Revised #3: 20th of June 2021 (addition of qualitative 
substudy) 
Revised #4: 13th of August 2021 (addition of 12 months 
follow-up appointment for fatigue cases at 6 months follow-
up) 
Revised #5: 17th of August 2021 (addition of brain fMRI 
substudy) 
Revised #6: 23th of September 2021 (increase number of 
participants in cardiology substudy) 
Revised #7: 31th of January 2022 (addition of post-COVID-
19 syndrome (WHO definition) as endpoint) 
 

 
2 
 
Project description 
 
1. State of the art, knowledge needs and project objectives 
The Coronavirus Disease 2019 pandemic has high mortality; in general, children are mildly affected 
The Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome 
Coronavirus 2 (SARS-CoV-2), is a tremendous threat to human health and welfare worldwide.55 The clinical 
presentation varies from asymptomatic infection over mild upper respiratory tract illness to severe viral 
pneumonia causing Acute Respiratory Distress Syndrome (ARDS) and respiratory failure; old age and chronic 
cardiovascular morbidity are important risk factors for severe outcome.56   
Evidence suggests that previously healthy children are usually mildly affected by SARS-CoV-2 in the 
acute phase. A nation-wide retrospective study in China including 2143 children with COVID-19 reported 
“severe” or “critical” disease among 6 % only; age < 1 year was a risk factor.13 Two other Chinese studies of 
hospitalized children during the height of the pandemic in the city of Wuhan showed excellent recovery in the 
great majority, and only one death.29,32 Corroborating these results, statistics from the outbreak in Italy report 
only 1.2% COVID-19 cases and no deaths < 18 years of age.30  
 
Long-lasting complications to COVID-19 in children might be development of post-infectious chronic 
fatigue and chronic fatigue syndrome  
Despite the relatively mild clinical presentation of COVID-19 in children, the long-lasting medical effects of 
is unknown at the moment. However, as fatigue seems to be a prominent symptom of COVID-19 infection,13 
it is conceivable – and in line with preliminary reports - that post-infectious chronic fatigue (PICF) might 
develop in vulnerable individuals, of which a subgroup may fulfill diagnostic criteria for the Chronic Fatigue 
Syndrome (CFS). PICF/CFS is a well-known sequel of several other infections, such as Epstein-Barr virus 
(EBV).17,22 Normally, increased load of the infectious agent is not reported in PICF/CFS.5,25 The underlying 
causes remain elusive; however, autoimmunity is a possible mechanism. The most consistent immune 
alteration is a tendency towards low-grade systemic inflammation, as reflected in significantly elevated serum 
C-reactive protein (CRP),25,53 elevated pro-inflammatory cytokines,24,39 and increased levels of innate 
immunity gene products in whole blood gene expression analyses.41 Alternatively, immune disturbances might 
be a side-effect which is not causally involved in PICF/CFS symptoms and disabilities. Recent neurobiological 
studies suggest that PICF/CFS is related to misguided automatic and unconscious predictions.26,54 This 
alternative model is supported by evidence of psychosocial factors (such as negative life events and trait 
negative affectivity) being risk factors for long-lasting post-infectious conditions.  
PIFC/CFS is a significant health problem among adolescents: Disability is often severe, treatment 
options are limited, and there is a strong negative impact upon academic development, social security systems, 
and family networks.19 The societal costs are correspondingly large.47 The present pandemic provides a unique 
opportunity to further scrutinize the disease mechanisms underlying PIFC/CFS in children.  
 
COVID-19 is associated with inflammatory enhancement; a “cytokine storm” might contribute to 
development of respiratory failure 
At a gross level, the immunological host response to SARS-CoV-2 is characterised by increased levels of 
circulating proinflammatory cytokines; this inflammatory enhancement, which might escalate towards a 
“cytokine-storm”, is thought to contribute significantly to tissue damage and clinical deterioration, including 
severe pulmonary pathology and ARDS.8,46,58 
Interestingly, SARS-CoV infection is also associated with a delayed expression of type I interferon 
(IFN) signaling, which is a crucial part of the innate defense against viral infections.36 Type I IFN signaling is 
initiated by pattern recognition receptors (such as the Toll-like receptors) in responses to viral nucleic acid; the 
subsequent intracellular cascade promotes the synthesis of type I interferons (IFNs), which in turn activate the 
JAK-STAT signal pathway promoting the expression of IFN-stimulated genes (ISGs).40 One effect of this 
signaling cascade is increased transcription of the APOBEC3-family of deoxycytidine deaminases that 
counteract a broad range of retroviruses, including coronaviridae.2,38 The net result is a limitation of virus 
spread. The N protein of SARS-CoV seems to antagonize the type I interferon (IFN) signaling by interacting 
with the pattern recognition receptors, thereby enabling the virus to escape this host response;33 other viral 
mechanisms might contribute as well.8 

 
3 
 
This “escape capability” might explain important features of COVID-19 infection as well, such as the 
rapid viral replication rate in infected individuals, which in turn might contribute to tissue pathology.28 In 
addition, it has been hypothesized that this viral IFN antagonism plays a crucial part in promoting the “cytokine 
storm” in SARS-CoV infection:7 The delayed type I IFN signaling promotes the accumulation of pathogenic 
inflammatory monocyte-macrophages (IMMs), which in turn are responsible for increased cytokine levels as 
well as direct lung tissue damage and inhibition of virus-specific T cell responses. Thus, a detailed mapping 
of the initial innate responses to SARS-CoV-2 might provide a clue towards better understanding of two 
separate causes of tissue damage, which over time might amplify each other in a vicious circle: The direct 
cytotoxic effect of the virus as well as the immunopathologies resulting from uncontrolled inflammatory 
enhancement.  
 
This study aims to study long-term effects in adolescent COVID-19, in particular development of 
chronic fatigue 
The overarching objective for this prospective cohort study on COVID-19 in adolescents is to study the long-
term effects, with particular emphasis on post-infectious chronic fatigue. We hypothesise that children having 
undergone COVID-19 has a higher prevalence of PICF/CFS long after the acute infectious event; furthermore, 
that risk factors for PICF/CFS encompass a complex mixture of genetic vulnerability and psychosocial factors. 
 
2. Material and methods 
The design allows prospective as well as cross-sectional analyses 
Adolescents (12-25 years) with confirmed SARS-CoV-2-infection (cases) are eligible for the present study 
(Table 1, Fig. 2). In addition, a group of adolescents with suspected COVID-19, but negative SARS-CoV-2 
test (controls), will be included from the same population and during the same time period. Inclusion will be 
based on informed consent from patients/next-of-kin. We assume a total number of 500 included cases and 
100 included controls. A follow-up appointment is scheduled 6 months after inclusion. Those who report 
fatigue at this time point (a sum score ≥ 4 at Chalder Fatigue Questionnaire, each item scored 0-0-1-1) will be 
summoned for a second follow-up appointment 12 months after inclusion.  
 
Risk factors for long-term complications will be analysed using regression modelling. This study has two 
primary endpoints:  
1. Chalder Fatigue Questionnaire (CFQ) total sum score at 6 months is the first primary endpoint.6 The CFQ 
is known to have good validity and reliability in children.  
2. Post-COVID-19 syndrome caseness at 6 months is the second primary endpoint. A case definition of post-
COVID-19 syndrome was published by the World Health Organization in September 2021 (cf.  
https://www.who.int/publications/i/item/WHO-2019-nCoV-Surveillance_Case_Definition-2020.2). 
Hence, this endpoint was added to the protocol during the course of the study, but before database lock. 
Relevant independent (explanatory) variables include (but are not restricted to):  
 
Background: Sex, age, ethnicity, previous medical history, smoking habits in family, presence of 
allergy/atopy, etc. 
 
Initial clinical findings: Symptom load/intensity, fever, routine blood haematology and biochemistry, etc. 
 
Infectious load: SARS-CoV-2 viral counts.  
 
Immune function: Increased general inflammation 
 
Genetic predisposition: Cf. below (Tab. 2) for a comprehensive list of candidate genetic markers 
 
Questionnaire results: Emotionality (depression/anxiety, emotional awareness), personality factors 
(neuroticism, worrying), perceived loneliness, and negative life events. 
Table 1. Criteria for inclusion and exclusion  
 
Inclusion criteria – cases 
Inclusion criteria – controls 
Positive SARS-CoV-2 test 
Suspected SARS-CoV-2 infection 
Age 12-25 years 
Negative SARS-CoV-2 test 
≤ 28 days since onset of first symptom 
Age 12-25 years 
 
≤ 28 days since onset of first symptom 
 
 
Exclusion criteria – cases 
Exclusion criteria – controls 
Hospitalised because of COVID-19 
Pregnancy 
Pregnancy 
Lack of consent from patient/next-of-kin 
Lack of consent from patient/next-of-kin 
 

 
4 
 
Autonomic cardiovascular control: Increased sympathetic nervous activity, decreased parasympathetic 
nervous activity 
 
Cognitive functions: Increased verbal memory, attention bias towards disease-related words, reduced 
working memory  
 
 
 
 
 
 
 
 
 
 
Investigations 
encompass 
clinical 
and 
microbiological 
assessments, 
a 
questionnaire, 
pressure pain threshold, biobanking and assessment 
of autonomic and cognitive functions.  
At baseline as well as at 6 months follow-up, included 
individuals will be exposed to a standardised 
investigational program, lasting about 1,5 hours. All 
participants will be instructed to fast overnight and 
abstain from tobacco products and caffeine at least 48 
hours. Participants will bring morning spot urine in a 
sterile container as well as a fecal sample (Bio-Me, Oslo, 
Norway), and are to apply a local anesthetic ointment 
(EMLA®, AstraZeneca) on both antecubital areas one 
hour before arriving. Then, the following investigations 
are to be carried out in a fixed sequence:  
 Clinical assessment: A comprehensive recording of 
exposure, previous medical history, symptoms and 
findings, and routine blood tests.  
 Biobanking: Biobanking of blood samples (whole 
blood, plasma, serum, RNA, viable Peripheral Blood 
Mononuclear Cells (PBMC)) as well as urine, hair and 
fecal samples, for subsequent analyses (cf. below). 
Blood sampling will be obtained in a fixed sequence 
from antecubital venous puncture. 
 Questionnnaire: A composite questionnaire will chart 
clinical symptoms, as well as background, psychological 
and social variables, and will be used for diagnostic 
categorization according to different case definitions of 
CFS/ME. The Chalder Fatigue Questionnaire (CFQ) 
charts subjective experience of physical and mental 
fatigue, and has been extensively used in CFS research. 
In this study, the CFQ total linear score (i.e. the sum 
across all 11 items, each item scored on a zero to three 
Likert scale) is applied as the primary endpoint in 
prediction modelling. Furthermore, fatigue caseness is 
defined as a CFQ total dichotomous score of 4 or higher 
(each item scored 0-0-1-1). The Hospital Anxiety and Depression Scale (HADS) is a validated 
Table 2. Candidate genes for gene sequencing 
Gene 
Protein 
ACE 
Angiotensine converting enzyme 
ADRA1A 
α1A adrenergic receptor 
ADRA2A 
α2A adrenergic receptor 
ADRB2 
β2 adrenergic receptor 
BDNF 
Brain-derived neurotrophic factor 
CCL27 
Chemokine (C-C motif) ligand 27  
CCR4 
C-C chemokine receptor type 4 
COMT 
Catechol-O-methyltransferase 
CXCL16 
Chemokine (C-X-C motif) ligand 16  
DRD2 
Dopamine receptor D2 
DRD4 
Dopamine receptor D4  
HTR1A 
5-HT1b receptor  
HTR1B 
5-HT1a receptor  
HTR2A 
5-HT receptor 2A 
IFNG 
Interferon gamma 
IL10 
Interleukin 10 
IL12B 
Subunit beta of interleukin 12 
IL17B 
Interleukin 17 B 
IL17F 
IL-17F 
IL18 
Interleukin-18 
IL1A 
Interleukin 1 alpha 
IL1B 
Interleukin 1 beta 
IL1RN 
Interleukin 1 receptor antagonist 
IL2RB 
Interleukin-2 receptor subunit beta 
IL4 
Interleukin 4 
IL6 
Interleukin 6 
IL8 
Interleukin 8 
IRAK4 
Interleukin-1 receptor-associated kinase 4 
IRF7 
Interferon regulatory factor 7 
MAOA 
Monoamine oxidase A 
MAOB 
Monoamine oxidase B 
NR3C1 
Glucocorticoid receptor 
NRAMP1 
Natural resistance-associated macrophage protein 1 
SLC6A2 
Norepinephrine transporter 
SLC6A3 
Dopamine active transporter 
SLC6A4 
5-HT transporter 
TH 
Tyrosine hydroxylase 
TIRAP 
Adapter molecule associated with toll-like receptors 
TLR4 
Toll-like receptor 4 
TNF 
TNF 
TPH2 
Tryptophan hydroxylase 2 
Figure 2. Design overview of the 
present project.  

 
5 
questionnaire for charting symptoms of depression and anxiety. It consists of 14 items rated zero to three 
on Likert scales, allowing computation of sub-scores for depression and anxiety symptoms. In the present 
study, these sub-scores as well as total sum score will be applied. The Life Event Checklist (LEC) is a 
validated questionnaire for assessing both positive and negative life events. The inventory lists 45 events; 
the respondents are asked to mark each of them as positive or negative, and grade their impact on four-
point Likert scales. The Brief Pain Inventory (BPI) is a validated questionnaire for assessing pain. In this 
study, the four BPI items assessing pain severity on ten-point Likert scales will be used to compute a total 
sum score; in addition, scores on a single item (average pain) will be reported. Cf. supplement for further 
information on questionnaire instruments.  
 
Autonomic cardiovascular control: A 5-minute ECG recording will be performed applying The Bittium 
Faro 360®  device (Bittium Corporation, Oulu, Finland), enabling later heart rate variability analyses. In 
the frequency-domain, vagal (parasympathetic) activity is the main contributor to high-frequency (HF) 
variability of heart rate, whereas both vagal and sympathetic activity contributes to low-frequency (LF) 
variability. The LF/HF ratio is considered an index of sympathovagal balance. 
 
Spirometry: The EasyOne Air® spirometer device (NDD Medical Technologies, Andover, Massachusetts, 
USA) is used to obtain standard ventilation variables.  
 
Cognitive functions. Participants are exposed to the Hopkins Verbal Learning Test-Revised (HVLT-R), 
assessing verbal learning, delayed recall, and recognition; the Digit Span forward and backward test, 
assessing working memory; an Attention Bias test of automatic biases towards disease-associated words; 
and the Function Acquisition Speed Test assessing cognitive fusion.  
Ahus will host the biobank and database for the present study. 
 
Detailed echocardiography will be performed in a subgroup of patients and controls for a cardiology 
sub-study 
In addition to these routine investigations, a total of appr. 40 cases and 20 controls will be consecutively 
included in a cardiology sub-study featuring detailed echocardiographic examination. The aim of this substudy 
is to assess the impact on heart function from COVID-19 in the acute phase of the infection (ie .2-3 weeks 
after symptom onset) as well as on a long-term basis. Examinations will be carried out by an experienced 
cardiologist using GE Vingmed E95 scanner (GE Vingmed Ultrasound, Horten, Norway) with adult 2D and 
3D probes. In addition to the ~60 participants included at baseline and followed prospectively, we will also 
perform echocardiography in a total of 90 individuals (cases and controls) at 6 months follow-up only, in order 
to increase statistical powert for cross-sectional analyses.  
 
Semi-structured interviews will be performed at 6 months follow-up in a group adolescents suffering 
from persistent symptoms 
At 6 months follow-up, a total of 25 individual who are 12-18 years of age and suffer from persistent symptoms 
after COVID-19 will be invited to a qualitative study addressing coping, coping beliefs and hope. The 
participants are recruited based on purposive sampling, and invited to a semi-structured interview lasting about 
one hour  
 
Brain fMRI during resting state and a fatigue-provoking tast will be performed in a subgroup of 
participants at 6 months follow-up 
At 6 months follow-up, study participants will be invited to a brain fMRI substudy. This substudy is integrated 
in the BRAINMINT project (cf. https://www.sv.uio.no/psi/english/research/projects/brainmint/index.html), 
and includes a resting state recording as well as a fatigue inducing task applying the multiple object tracking 
(MOT) paradigm. The total number of included participants in this substudy depends on MRI scanner 
availability, but we aim for at least 300.  
 
Considerations on power estimation and statistical analyses 
The novelty of COVID-19 and the lack of comparable studies among adolescents precludes a formal power 
analyses. However, it should be noted that a prospective cohort of 500 patients is comparable to similar cohort 
studies in the field. Based upon previous post-infective studies, about 10 % of included patients will adhere to 
diagnostic definitions of CFS after 6 months; in the present study, that will leave about 50 cases for cross-
sectional analyses, which is also considered sufficient to detect at least medium effect sizes. 

 
6 
 
All statistical analyses are carried out with SPSS statistical software, and a p < 0.05 are considered 
statistically significant. Missing values are to be handled by multiple imputation techniques.  
 
Ethics 
Participation is based upon informed consent, and thorough information will be provided orally as well as in 
writing to the participants and (if younger than 16 years) to their parents/next-of-kin. All data will be treated 
and stored without personal identifying information, and in accordance with national directives. Generally, 
investigational methods are neither harmful nor painful (local anaesthetic ointment will be given prior to 
venous puncture).  
 
Gender perspectives 
Severe COVID-19 appears to be more common in males than in females.56 Post-infectious complications, 
however, such as PICF/CFS, are more common among females than males, the ratio being about 3:1. Thus, 
such complications strongly impact on women’s health, but have traditionally received low attention. In this 
project, possible gender differences will be scrutinized in the analyses.  
 
The projects benefits from a strong relationship to well-established research networks 
The projects builds upon two collaborating networks that have been firmly established through previous 
research project: a) An international consortium of researchers on post-infectious complications (Collaborative 
of Fatigue Following Infection, COFFI), encompassing highly reputed research groups from six countries (US, 
UK, Australia, New Zealand, The Netherlands and Norway), and with the lead co-PI of this proposal as the 
chair of the consortium; b) An in-house collaborative with the EpiGen Molecular Research Laboratory and the 
Dept. of Microbiology, which are equipped with state of the art technology and manages the local biobank 
facilities. There are several co-publications within all these networks already. 
 
The present project will guide clinical care and priorities in acute disease, contribute to development 
of therapeutics and prophylaxis, and help understand mechanisms behind long-term complications 
The on-going COVID-19 pandemic represents a global threat towards health and welfare. The present project 
aims to mitigate some of the detrimental consequences. First and foremost, it will provide increased knowledge 
on long-term effects including a better understanding of PICF/CFS and other sequels, and might guide clinical 
services and development of prophylactic measures. To the best of our knowledge, no similar study on 
adolescents has been performed – or is ongoing – at present.  
 
Primary and secondary stakeholders 
Given the seriousness of COVID-19 infections and the urgent need for scientific knowledge, rapid and 
continuous dissemination or project results will receive high attention. The target for dissemination is not 
restricted to the scientific community, but includes a wide range of health-care workers, politicians, policy 
makers, health care administrators, and the general public.  
 
Results will be disseminated widely; scientific dissemination is prioritized 
Several means of dissemination will be exploited, including scientific papers; popular science newspaper 
articles; giving interviews; meetings with politicians, public health providers and other stakeholders; social 
media. Dissemination to researchers and the scientific community includes publications in international, peer-
reviewed medical journals. The main results will be offered to journals of high impact. Negative findings will 
also be reported.  
 
 
3. Implementation 
Research group, project managers, and in-house resources 
The present project is hosted by the PAEDIA research group at Akershus University Hospital (Ahus), which 
has extensive experience in translational immunology as well as clinical research, and a strong track record of 
result dissemination and implementation. The group has established a well-working infrastructure for patient 
flow and data acquisition, and a large collaborative network with national and international experts on various 
methodological aspects.  

 
7 
The PAEDIA research group is headed by Prof. Vegard Wyller, who is also the PI of the present 
project, and Chair of the COFFI collaboration. Prof. Wyller is the most published and cited PICF/CFS 
researcher in Norway. Other members of PAEDIA include two postdoctoral fellows, six PhD fellows, two 
master students, and three clinical consultants. The local research support staff consists of one laboratory 
engineer, two research nurses and two research secretaries. An internal learning program for PhD fellows has 
been established, encompassing a) one-to-one supervision sessions; b) regular in-group discussions; c) invited 
lecturers; d) oral presentation training and practice; e) seminars on selected topics (statistics, ethics). A total 
of five PhD fellows have successfully graduated over the past four years.  
PAEDIA’s primary collaborating unit at Ahus is the EpiGen Molecular Research Laboratory, headed 
by prof. Hilde Nilsen, which is equipped with state of the art technology and manages the local biobank 
facilities. Profs. Nilsen and Wyller have collaborated closely for several years, enjoying complementary 
expertise and ensuring a translational perspective. 
 
National collaborative network and the COFFI collaborative 
Over the last decade, Prof. Wyller has established a multidisciplinary national scientific collaborative network, 
covering a large area of expertise. Several co-publications exist. For the present project, the collaboration with 
Profs. B. Fevang and T.E. Mollnes at Oslo University hospital provides expertise in basic and applied 
immunology, the collaboration with Prof. H.L. Nilsen provides expertise in molecular immunology.  
The COFFI consortium was founded by principle investigators following 12 post-infection cohorts in 
six countries.21 As of March 2019, the consortium is chaired by Prof. Wyller; basic infrastructure (data 
managing, biobanking, statistical support) has been established, and will be made available for the present 
project.  
Important measures to ensure integration between all collaborators encompass a) Shared responsibility 
for PhD supervision, b) Regular meetings (video link for international partners) to discuss scientific and 
strategic challenges; c) Hosting of seminars; and d) Face-to-face meetings.  
 
Infrastructure and activities 
Necessary research infrastructure is primarily related to a) immunological and molecular laboratory facilities, 
b) biobanking facilities, and c) data management facilities. All these facilities are available through the 
established collaborative networks, in particular the COFFI collaborative which is already hosted at Ahus.  
 
Personnel and funding 
Study personnel (paediatrician, research nurse and research secretary) necessary for initiation of the study and 
primary data acquisition is available within the PAEDIA research group. For data analyses, writing of papers, 
etc. a full-time PhD fellow will be needed, and funding will be sought from relevant funding institutions during 
the coming months. Other running costs in the project will be covered by the Section for Research and 
Development at Dept. of Pediatrics, Ahus.  
 
An advisory board of two user representatives is the most important user involvement 
For the present project, an advisory board of users will formally established, consisting of a) One representative 
from the “Youth council” at Ahus, consisting of adolescents suffering from chronic disorders; and b) One 
representative from the organization Recovery Norway, consisting of individuals having recovered from post-
infectious chronic fatigue and similar conditions. The advisory board will meet quarterly with the PI; important 
themes for discussions are results’ interpretation and practical impact, ethical issues, considerations regarding 
further research, and dissemination/implementation strategies. 
 
 
4. References 
 
1. 
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Cameron B, et al. J Med Virol 2010;82:1684-8 
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Chalder T, at el. J Psychosom Res 1993;37:147-53 
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Channappanavar R, et al. Cell Host Microbe 2016;19:181-93. 
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Channappanavar R, et al. Semin Immunopathol 2017;39:529-39. 

 
8 
9. 
Chen D, et al. Emerg Microbes Infect 2019;8:1511-23.’ 
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14. Edwards K, et al. Biologicals 2019;60:1-7. 
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16. Heimdal I, et al. J Infect Dis 2019;219:1198-1206 
17. Hickie I, et al. BMJ 2006;333:575-81 
18. Huang C, et al. Lancet 2020;395:497-506. 
19. Institute of Medicine. Beyond myalgic encephalomyelitis/chronic fatigue syndrome. Washington: The National Academies 
Press, 2015. 
20. Ivashkiv LB, et al. Nat Rev Immunol 2014;14:36-49. 
21. Katz B, et al. Fatigue 2018;6:106-21. 
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Long-Term Effects of COVID-19 in Adolescents (LoTECA) 
 
Supplement 
 
Late effects after COVID-19 in adolescents – overview of inventories  
Category 
Inventory 
Characteristics 
References 
No. in 
questionnaire 
BACKGROUND/DEMOGRAPHICS 
 
 
 
 
Household, socioeconomic level 
Self-invented 
Household members; parents work/education; 
chronic disease in family 
 
1-6 
Smoking, alcohol, drugs 
Self-invented 
Alcoholic beverages, illicit drugs, smoking; 5-
point Likert scale (never to each day) 
 
7-12 
SYMPTOMS AND FUNCTIONS 
 
 
 
 
Fatigue  
Chalder Fatigue Scale 
11 items; 4-point Likert scale; each item scored 
0-3; total sum score range 0 to 33.  
Chalder T, Berelowitz G, 
Pawlikowska T, et al. J 
Psychosom Res 
1993;37:147-53. 
14 
Chronic Fatigue Syndrome diagnosis 
and related symptoms 
CDC symptom inventory for CFS 
Self-invented 
28 items addressing frequency of symptoms on 
5-point Likert scale; each item scored 1-5 (never 
to each day/always).  
Wagner D, et al. Popul 
Health Metr 2005;3:8 
13 
Post-exertional malaise (PEM) 
PEM items from DePaul Symptom Questionnaire 
5 items addressing frequency of symptoms on 5 
point Likert scale; each item scored 0-4 (never to 
each day/always). Average, then multiply with 
25 to get a 100 point scoring scale.  
Bedree H, et al. Fatigue 
2019; 7: 166-79 
13 
Sleep disturbances 
Karolinska sleep questionnaire (KSQ) 
12 items addressing frequency of sleep related 
problems; 6-point Likert scale scored 1 – 6; 
lower score means more symptoms. Indexes for 
insomnia, awakening problems, and sleepiness 
Akerstedt T, Ingre M, 
Broman JE, Kecklund G. 
Chronobiol Int 2008;25:333-
48 
16 

 
10 
Pain 
Brief Pain Inventory (BPI) 
4 items; 10 point Likert scale score 1 - 10 (no 
pain to worst pain possible) 
Klepstad P, et al. J Pain 
Symptom Manage 
2002;24:517-25. 
15 
Depression/Anxiety symptoms 
Hospital Anxiety and Depression Symptoms 
(HADS) 
14 items; 4 point Likert scale scored 0 – 3 (8 
items with reversed scoring). Indexes for anxiety 
symptoms and depressive symptoms, also total 
sum score range 0 to 42. 
Zigmond AS, Snaith RP. 
Acta Psychiatr Scand 
1983;67:361-70. 
17 
Negative affect 
Positive and Negative Affect Schedule (PANAS-
SF) 
5 items addressing negative affects (ashamed, 
anxious, nervous, hostile, upset); 5-point Likert 
scale scored 1-5. Total sum score range 5-25 
Thompson ER. J of Cross-
Cultural Psychology 2016; 
38: 227-42. 
18 
Illness perception 
Brief Illness Perception Questionnaire  
8 items; 10 point Likert scale, scoring 1 – 10. 
Broadbent E, et al. J 
Psychosom Res 
2006;60:631-7 
20 
Quality of life  
Pediatric Quality of Life (PedsQL) 
23 items; 5 point Likert scale scored 0 – 4, and 
then multiplied with 25 to get a 100 point scale; 
average score reported. Four subdomains: health 
related, emotional, social, school.  
Varni JW, et al. Health and 
quality of life outcomes 
2007;5:9. 
19 
Interoception 
Body Vigilance Scale (BVS) 
4 items; 11 point Likert scales 0 – 10. Score on 
item 3 should be devided by 10. Scores on item 
4: average among 15 sensations. Total sum score 
range 0 to 40. 
Schmidt NB, et al. J Consult 
Clin Psychol 1997; 65: 214-
20. 
21 
Miscellaneous/hypotheses generating 
Self-invented 
a) 1 item addressing avoidance behavior: “To 
what degree do you avoid everything that may 
worsen your symptoms”?  
b) 1 item addressing school absenteeism. 
 
20/22 
CONSTITUTIONAL 
 
 
 
 
Neuroticism 
NEO-FFI-30 
6 items making up the neuroticism axis; 5-point 
Likert scale scored 0 – 4. Total sum score range 
0 – 24. 
Körner A, et al. Psychother 
Psychosom Med Psych. 
2008; 58: 238-245 
24 

 
11 
Worrying tendencies 
Penn State Worry Questionnaire (PSWQ) 
16 items; 5-point Likert scale scored 1 – 5 
(reversed scoring of item1,3,8,10,11). Total sum 
score range 16 to 80 
Pallesen, S, et al. 
Scandinavian Journal of 
Psychology 2006, 47, 281–
291 
25 
Emotional awareness 
Toronto Alexithymia Scale (TAS-20) 
7 items making up the index of Difficult 
identifying feelings. 5-point Likert scale scored 
1-5, total sum score range 7 to 49. 
Bagby RM, et al.. J 
Psychosom Res 1994;38:33-
40. 
23 
Loneliness 
UCLA loneliness scale 
20 items; 4-point Likert scale scored 1 – 4 
(reverse scoring of item 1,5,6,9,10,15,16,19,20). 
Total sum score from 20 to 80. 
Russell, D., et al. Journal of 
Personality and Social 
Psychology 1980, 39(3), 
472–480 
26 
Self-efficacy 
General Self-Efficacy Scale, short form 
6 items; 4-point Likert scale scored 1 – 4. Total 
sum score from 6 to 24.  
Romppel M, et al. 
Psychosoc Med 2013; 10: 
Doc01.  
27 
Adverse life events 
Life Events Checklist (LEC) 
48 prespecified life events (good and bad). 4-
point Likert scale addressing subjective impact.  
Johnson JH, McCutcheon, 
S.M. Assessing life stress in 
older children and 
adolescents. In I.G. Sarason 
& C.C. Spielberger (Eds), 
Stress and anxiety 
1980;7:111-25. 
30/31 
Miscellaneous/hypotheses generating 
Child-Adolscent Perfectionism Scale (CAPS); 
Highly Sensitive Person Scale (HSP); Parentign 
Dimension Inventory (PDI); self-invented 
a) 1 item addressing socially prescribed 
perfectionism (from CAPS): “Others always 
expect me to be perfect”, 1-5 Likert scale 
b) 2 items from HSP: Startling tendencies and 
affected by other people’s feeling tendencies 
c) 2 items from the PDI, both addressering 
parental control.  
d) 4 items self-invented (interoceptive awareness 
and positive expectancies): “The intensity of 
symptoms tells how dangerous a disease is”; “if 
you have a bodily complaint, every effort should 
be taken not to make it worse”; “it is important 
 
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12 
to be attentive to bodily signals in order to 
discover early signs of disease”; “things often 
turns out to be more easy than I anticipated”.