Assessing severity of illness and outcomes of treatment in children with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME): a systematic review of patient-reported outcome measures (PROMs).

Chronic Fatigue Syndrome or Myalgic Encephalomyelitis (CFS/ME) in children is characterized by persistent or recurrent debilitating fatigue which results in a substantial reduction in activity. There is a growing interest in the use of questionnaires, or patient-reported outcome measures (PROMs), to assess how patients function and feel in relation to their health and associated healthcare. However, guidance for PROM selection for children with CFS/ME does not exist. We reviewed the quality and acceptability of PROMs used with children with CFS/ME to inform recommendations for practice. We conducted a systematic review of PROMs completed by children with CFS/ME. The quality of the evaluative studies and the reviewed measures were assessed against recommended criteria using an appraisal framework and the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. We sought evidence of measurement (reliability, validity, responsiveness, interpretability, data quality) and practical properties (acceptability, relevance, feasibility). Sixteen articles were included in the review, providing evidence of reliability and/or validity for 13 PROMs. Of these, five were child-specific (one health-related quality-of-life; four emotional well-being) and eight were not (four emotional well-being, three fatigue-specific; and one generic). All measures had limited evidence of measurement properties and no evidence of practical properties. Recommendations for patient-reported assessment are difficult to make because of limited evidence of the quality and acceptability of PROMs for children with CFS/ME. The appraisal method highlighted significant methodological and quality issues which must be addressed in future research. There is a lack of qualitative evidence describing the outcomes of healthcare that are important to children with CFS/ME, and the relevance or appropriateness of available measures. Future PROM development and evaluation in this group must seek to involve children collaboratively to ensure that the outcomes that children care about are assessed in an acceptable way.

The financial and psychological impacts on mothers of children with chronic fatigue syndrome (CFS/ME).

BACKGROUND: Paediatric chronic fatigue syndrome or myalgic encephalopathy (CFS/ME) is relatively common and children can be severely affected attending little or no school for extended periods. There are no studies quantifying the financial impact of having a child with CFS/ME and there is little information of the impact on parental mood. METHODS: Forty mothers of children with CFS/ME from a regional specialist CFS/ME service completed inventories to assess their psychological well-being (Hospital Anxiety and Depression Scale, General Health Questionnaire-12) loss of earnings and increased expenditure. In addition, eight mothers took part in a semi-structured qualitative interview. RESULTS: Most parents of children with CFS/ME experience loss of monthly income (mean = £247) and increase in monthly expenditure (mean = £206). Twenty-eight (72%) mothers were above the cut-off for the General Health Questionnaire-12 compared with 20% in the healthy population (95% CI 55, 85, P < 0.001) suggesting they probably have a mental health problem. This may be explained by the qualitative interviews where mothers described five areas contributing to poor parental health: lack of understanding from others; marital tension; concern about their child's distress; concern about the impact on siblings and emotional distress causing physical symptoms. CONCLUSIONS: The majority of families of children with CFS/ME experience decreased income and increased expenditure with a marked impact on maternal psychological health. Clinicians need to be aware of this to provide appropriate support to families who care for children with CFS/ME.

Cost-effectiveness of Interventions for Chronic Fatigue Syndrome or Myalgic Encephalomyelitis: A Systematic Review of Economic Evaluations.

INTRODUCTION: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has profound quality of life and economic consequences for individuals, their family, formal services and wider society. Little is known about which therapeutic interventions are more cost-effective. OBJECTIVE: A systematic review was carried out to identify and critically appraise the evidence on the cost-effectiveness of CFS/ME interventions. METHODS: The review protocol was prespecified (PROSPERO: CRD42018118731). Searches were carried out across two databases-MEDLINE (1946-2020) and EMBASE (1974-2020). Additional studies were identified by searching reference lists. Only peer-reviewed journal articles of full economic evaluations examining CFS/ME interventions were included. Trial- and/or model-based economic evaluations were eligible. Data extraction and screening were carried out independently by two reviewers. The methodological quality of the economic evaluation and trial were assessed using the Consensus Health Economic Criteria checklist (CHEC-list) and Risk of Bias-2 (RoB-2) tool, respectively. A narrative synthesis was used to summarise the economic evidence for interventions for adults and children in primary and secondary care settings. RESULTS: Ten economic evaluations, all based on data derived from randomised controlled trials, met our eligibility criteria. Cognitive behavioural therapy (CBT) was evaluated across five studies, making it the most commonly evaluated intervention. There was evidence from three trials to support CBT as a cost-effective treatment option for adults; however, findings on CBT were not uniform, suggesting that cost-effectiveness may be context-specific. A wide array of other interventions were evaluated in adults, including limited evidence from two trials supporting the cost effectiveness of graded exercise therapy (GET). Just one study assessed intervention options for children. Our review highlighted the importance of informal care costs and productivity losses in the evaluation of CFS/ME interventions. CONCLUSIONS: We identified a limited patchwork of evidence on the cost-effectiveness of interventions for CFS/ME. Evidence supports CBT as a cost-effective treatment option for adults; however, cost-effectiveness may depend on the duration and frequency of sessions. Limited evidence supports the cost effectiveness of GET. Key weaknesses in the literature included small sample sizes and short duration of follow-up. Further research is needed on pharmacological interventions and therapies for children.

Treatment preference and recruitment to pediatric RCTs: A systematic review.

BACKGROUND: Recruitment to pediatric randomised controlled trials (RCTs) can be a challenge, with ethical issues surrounding assent and consent. Pediatric RCTs frequently recruit from a smaller pool of patients making adequate recruitment difficult. One factor which influences recruitment and retention in pediatric trials is patient and parent preferences for treatment. PURPOSE: To systematically review pediatric RCTs reporting treatment preference. METHODS: Database searches included: MEDLINE, CINAHL, EMBASE, and COCHRANE.Qualitative or quantitative papers were eligible if they reported: pediatric population, (0-17 years) recruited to an RCT and reported treatment preference for all or some of the participants/parents in any clinical area. Data extraction included: Number of eligible participants consenting to randomisation arms, number of eligible patients not randomised because of treatment preference, and any further information reported on preferences (e.g., if parent preference was different from child). RESULTS: Fifty-two studies were included. The number of eligible families declining participation in an RCT because of preference for treatment varied widely (between 2 and 70%) in feasibility, conventional and preference trial designs. Some families consented to trial involvement despite having preferences for a specific treatment. Data relating to 'participant flow and recruitment' was not always reported consistently, therefore numbers who were lost to follow-up or withdrew due to preference could not be extracted. CONCLUSIONS: Families often have treatment preferences which may affect trial recruitment. Whilst children appear to hold treatment preferences, this is rarely reported. Further investigation is needed to understand the reasons for preference and the impact preference has on RCT recruitment, retention and outcome.

Obesity in adolescents with chronic fatigue syndrome: an observational study.

OBJECTIVE: Identify the prevalence of obesity in patients with chronic fatigue syndrome (CFS) compared with healthy adolescents, and those identified with CFS in a population cohort. DESIGN: Cross-sectional analysis of multiple imputed data. SETTING: Data from UK paediatric CFS/myalgic encephalomyelitis (CFS/ME) services compared with data collected at two time points in the Avon Longitudinal Study of Parents and Children (ALSPAC). PATIENTS: 1685 adolescents who attended a CFS/ME specialist service between 2004 and 2014 and 13 978 adolescents aged approximately 13 years and 16 years participating in the ALSPAC study. MAIN OUTCOME MEASURES: Body mass index (BMI) (kg/m2), sex-specific and age-specific BMI Z-scores (relative to the International Obesity Task Force cut-offs) and prevalence of obesity (%). RESULTS: Adolescents who had attended specialist CFS/ME services had a higher prevalence of obesity (age 13 years: 9.28%; age 16 years: 16.43%) compared with both adolescents classified as CFS/ME in ALSPAC (age 13 years: 3.72%; age 16 years: 5.46%) and those non-CFS in ALSPAC (age 13 years: 4.18%; age 16 years: 4.46%). The increased odds of obesity in those who attended specialist services (relative to non-CFS in ALSPAC) was apparent at both 13 years (OR: 2.31 (1.54 to 3.48)) and 16 years, with a greater likelihood observed at 16 years (OR: 4.07 (2.04 to 8.11)). CONCLUSIONS: We observed an increased prevalence of obesity in adolescents who were affected severely enough to be referred to a specialist CFS/ME service. Further longitudinal research is required in order to identify the temporal relationship between the two conditions.

Spontaneous partial expectoration of an endobronchial carcinoid.

Typical pulmonary carcinoid tumors often present as proximal endobronchial masses discovered during the evaluation of cough and/or hemoptysis. We present a case of a carcinoid tumor that presented with spontaneous partial expectoration. A review of the literature revealed 16 cases of expectoration of fragments from various primary and metastatic tumors. Our case appears to be the first report of the expectoration of a carcinoid tumor.

A theoretical analysis of the accuracy of single-energy CT bone-mineral measurements.

A relationship has been derived between the in vivo concentration of calcium hydroxyapatite and the in vitro concentration of K2HPO4 solution in a single-energy quantitative computed tomography (QCT) bone-mineral determination. Under certain simplifying assumptions this relationship is linear. The gradient term has been calculated as a function of scanner effective energy using the measured variation of solvent water density with K2HPO4 concentration; it ranges from 1.17 at 60 keV to 1.21 at 80 keV. The intercept term has been calculated as a function of effective energy, patient age and trabecular bone volume (TBV) by modelling the constituents of whole trabecular bone and using published normal composition data. It varies from about 15 to 25 mg cm-3 at an effective energy of 70 keV and within a TBV range of 5 to 20%. This intercept term may be used as an additive correction which improves the accuracy of single-energy QCT results without significant loss of precision. However, the method is limited by the uncertainties of tissue composition in an individual patient.

Bone mineral content in normal UK subjects.

Bone mineral content in the lumbar vertebrae and in the shaft of the left radius has been measured in 129 normal British subjects using quantitative computed tomography and single-photon absorptiometry. Significant negative correlations between bone mineral content and age were found at both sites in males and females (p less than 0.001 in all cases). When expressed in g/cm the bone mineral content in the radial shaft showed significant positive correlations with body height and weight in both sexes, but after correction for bone size only a weak correlation with body height in males was found. Spinal trabecular bone mineral content showed no significant correlations with body height or weight in either sex. Comparison of the values obtained with normal data from centres in the USA revealed lower mean values for both radial and spinal bone mineral content in the British subjects. These differences emphasize the importance of using locally derived normal data for comparison with values obtained from patients.

A test of an interruption/temporal-uncertainty theory of auditory backward recognition masking of target duration.

The present study examined auditory backward masking in a task requiring subjects to label a target sound as having a long or short duration. Perception of target duration was influenced by the interaction of the effects of (1) the similarity of the target/mask duration, (2) the acoustic similarity of the target and mask (tone vs. white noise), and (3) the interstimulus interval (ISI) between the target and mask. Specifically, relative to the long duration (100 ms) mask, the short duration (40 ms) mask helped performance for the target having a similar short duration (55 ms) but hurt performance for the target having a dissimilar long duration (85 ms). This effect of the similarity of target/mask duration was greater for acoustically similar targets and masks than for acoustically dissimilar targets and masks, and particularly so at the intermediate (45, 105, 165, 205 ms) ISIs. These results can be explained within the framework of Massaro and Idson's (1976) two-stage model by assuming that masking of perceived auditory duration is the result of two processes: (a) the mask's interruption of target processing in a peripheral auditory processing stage, and (b) a confusion of which item is the target vs. the mask, due to temporal uncertainty in the transfer of the target and mask into a central auditory processing stage.

In vivo tissue characterization using quantitative computed tomography: a review.

Over the past 15 years many attempts have been made to make use of the quantitative information contained within computed tomography (CT) scanner images. A survey of the various approaches to quantitative computed tomography (QCT) is reported. The technical limitations of QCT are discussed. It is concluded that the measurement of bone mineral content is currently the only clinically well-established QCT technique.

Acute confusion among hospitalized elders in a rural hospital.

The NEECHAM Confusion Scale was used to study the incidence and severity of acute confusion among elders in a rural community hospital. Thirty-eight patients over the age of 64 were assessed for confusion within 48 hours of admission. The NEECHAM Confusion Scale was readministered to a sub-sample of 17 elders within 24 hours of pending discharge. The incidence of acute confusion was 81.5% at admission with a prevalence of 52.9% at discharge. Staff identified signs of acute confusion in 34.2% of the elders confused upon admission as indicated by the NEECHAM Confusion Scale. These findings have major implications for adult health nursing practice.

Treatment outcome in adults with chronic fatigue syndrome: a prospective study in England based on the CFS/ME National Outcomes Database.

BACKGROUND: Chronic fatigue syndrome (CFS) is relatively common and disabling. Over 8000 patients attend adult services each year, yet little is known about the outcome of patients attending NHS services. AIM: Investigate the outcome of patients with CFS and what factors predict outcome. DESIGN: Longitudinal patient cohort. METHODS: We used data from six CFS/ME (myalgic encephalomyelitis) specialist services to measure changes in fatigue (Chalder Fatigue Scale), physical function (SF-36), anxiety and depression (Hospital Anxiety and Depression Scale) and pain (visual analogue pain rating scale) between clinical assessment and 8-20 months of follow-up. We used multivariable linear regression to investigate baseline factors associated with outcomes at follow-up. RESULTS: Baseline data obtained at clinical assessment were available for 1643 patients, of whom 834 (51%) had complete follow-up data. There were improvements in fatigue [mean difference from assessment to outcome: -6.8; 95% confidence interval (CI) -7.4 to -6.2; P < 0.001]; physical function (4.4; 95% CI 3.0-5.8; P < 0.001), anxiety (-0.6; 95% CI -0.9 to -0.3; P < 0.001), depression (-1.6; 95% CI -1.9 to -1.4; P < 0.001) and pain (-5.3; 95% CI -7.0 to -3.6; P < 0.001). Worse fatigue, physical function and pain at clinical assessment predicted a worse outcome for fatigue at follow-up. Older age, increased pain and physical function at assessment were associated with poorer physical function at follow-up. CONCLUSION: Patients who attend NHS specialist CFS/ME services can expect similar improvements in fatigue, anxiety and depression to participants receiving cognitive behavioural therapy and graded exercise therapy in a recent trial, but are likely to experience less improvement in physical function. Outcomes were predicted by fatigue, disability and pain at assessment.

Association between school absence and physical function in paediatric chronic fatigue syndrome/myalgic encephalopathy.

OBJECTIVE: To investigate factors associated with school attendance and physical function in paediatric chronic fatigue syndrome/myalgic encephalopathy (CFS/ME). DESIGN: Cross-sectional study. SETTING: Regional specialist CFS/ME service. PATIENTS: Children and young people aged under 18 years. OUTCOME MEASURES: Self-reported school attendance and physical function measured using the physical function subscale of the Short Form 36. METHODS: Linear and logistic regression analysis of data from self-completed assessment forms on children attending a regional specialist service between 2004 and 2007. Analyses were done in two groups of children: with a completed Spence Children's Anxiety Scale (SCAS) and with a completed Hospital Anxiety and Depression Scale (HADS). RESULTS: Of 211 children with CFS/ME, 62% attended 40% of school or less. In children with completed SCAS, those with better physical function were more likely to attend school (adjusted odds ratio (OR) 1.70; 95% CI 1.36 to 2.13). This was also true for those with completed HADS (adjusted OR 2.05; 95% CI 1.4 to 3.01). Increasing fatigue and pain and low mood were associated with worse physical function. There was no evidence that anxiety, gender, age at assessment, family history of CFS/ME or time from onset of symptoms to assessment in clinic were associated with school attendance or physical function. IMPLICATIONS: Paediatricians should recognise that reduced school attendance is associated with reduced physical function rather than anxiety. Improving school attendance in children with CFS/ME should focus on evidence-based interventions to improve physical function, particularly concentrating on interventions that are likely to reduce pain and fatigue.

Memory and attention problems in children with chronic fatigue syndrome or myalgic encephalopathy.

OBJECTIVE: To understand more about the problems children with chronic fatigue syndrome (CFS) or myalgic encephalopathy (ME) experience with memory and attention, and to test the feasibility of quantitative measurement of both memory and attention. DESIGN: Four-item semistructured questionnaire and neuropsychological test battery with 10 psychometric subtests. SETTING: Family home of the child taking part. PATIENTS: 20 children with a diagnosis of CFS/ME experiencing memory and/or concentration problems were recruited between April and October 2007 from a regional CFS/ME clinical service (female 13; average age 13.5 years; range 8-16). METHODS: Each child, parent and teacher was asked to describe the child's memory and attention problems. Responses were subject to thematic analysis by two independent researchers. In addition, each child completed a battery of 10 tests to measure: processing speed; attention; immediate and delayed memory; working memory; executive function. Raw scores were converted into age-scaled scores and the children's psychometric scores on the 10 tests taken were compared with normative data using t tests. RESULTS: Children with CFS/ME, their parents and teachers described problems with focussed attention, sustained attention, recall and stress. Scores for sustained attention (mean 8.1, 95% CI 6.3 to 9.9), switching attention (7.5, 5.5 to 9.4), divided attention (6.9, 5.5 to 8.2), auditory learning (8.2, 6.8 to 9.6) and immediate recall (8.7, 7.3 to 10.0) appeared lower than the normative mean of 10. CONCLUSIONS: Children with CFS/ME appear to experience problems with attention, which may have adverse implications for verbal memory. These cognitive problems may explain some of the educational difficulties associated with CFS.

Chronic fatigue syndrome in children aged 11 years old and younger.

UNLABELLED: Children in primary school can be very disabled by chronic fatigue syndrome or ME (CFS/ME). The clinical presentation in this age group (under 12 years old) is almost identical to that in older children. AIM: To describe children who presented to the Bath paediatric CFS/ME service under the age of 12 years. METHOD: Inventories measuring fatigue, pain, functional disability, anxiety, family history and symptoms were collected prospectively for all children presenting to the Bath CFS/ME service between September 2004 and April 2007. Data from children who presented to the service under the age of 12 are described and compared to those who presented at age 12 or older. RESULTS: 178 children (under the age of 18) were diagnosed as having CFS/ME using the RCPCH criteria out of 216 children assessed. The mean age at assessment for children with CFS/ME was 14.5 years old (SD 2.9). Thirty-two (16%) children were under 12 years at the time of assessment, four children were under 5 years and the youngest child was 2 years old. Children under 12 were very disabled with mean school attendance of just over 40% (average 2 days a week), Chalder fatigue score of 8.29 (CI 7.14 to 9.43 maximum possible score = 11) and pain visual analogue score of 39.7 (possible range 0-100). Comparison with children aged 12 or older showed that both groups were remarkably similar at assessment. Twenty-four out of the 26 children with complete symptom lists would have been diagnosed as having CFS/ME using the stricter adult Centers of Disease Control and prevention (CDC) criteria. CONCLUSION: Disability in the under-12 age group was high, with low levels of school attendance, high levels of fatigue, anxiety, functional disability and pain. The clinical pattern seen is almost identical to that seen in older children, and the majority of children would also be diagnosed as having CFS/ME using the stricter adult definition.

Hereditary predisposition to low interleukin-10 production in children with extended oligoarticular juvenile idiopathic arthritis.

OBJECTIVE: To determine whether children with extended oligoarticular juvenile idiopathic arthritis (JIA) produce less of the anti-inflammatory cytokine interleukin-10 (IL-10) than those with persistent oligoarticular JIA. METHODS: We measured IL-10 production in the parents of children with oligoarticular or extended oligoarticular JIA, from whole-blood cultures stimulated with lipopolysaccharide. RESULTS: IL-10 production was lower in the parents of children with extended oligoarticular JIA compared with those of children with oligoarticular JIA (P=0.034). There was an increase in the percentage of ATA-containing genotypes (i.e. genotypes ATA/ATA, ATA/ACC or ATA/GCC) in the parents of children with extended oligoarticular JIA compared with healthy controls (P<0.02) but not in the parents of children with oligoarticular JIA. CONCLUSIONS: As approximately 84% of the variation in IL-10 production is thought to be genetically regulated, these results suggest that stimulated IL-10 production would be lower in children with extended oligoarticular JIA. Because IL-10 is an anti-inflammatory cytokine, this may partly explain why this group of children has more severe disease.

Increased rate of spinal trabecular bone loss in patients with inflammatory bowel disease.

The rate of spinal trabecular bone loss during one year was measured in 54 patients with inflammatory bowel disease. The mean change in spinal bone mineral content was -5.1 mg/ml K2HPO4, representing 3% of the initial bone mineral content. The rate of bone loss showed a significant negative correlation with body mass index (r = -0.276, p less than 0.05) but no other significant correlations were found with other clinical or biochemical indices, including the total amount of prednisolone taken during the course of the study. Eleven patients had bone loss greater than 15 mg/ml/year; these included four non-steroid treated patients, two of whom had disease confined to the large bowel. The results indicate rapid rates of bone loss in some patients with inflammatory bowel disease over the course of one year. Although steroid therapy and malnutrition are likely to be contributory factors in some patients, other, as yet unidentified, risk factors also operate. The rapid bone loss observed in some patients emphasises the need for effective prophylactic regimes.

Spinal trabecular bone mineral content in patients with non-steroid treated rheumatoid arthritis.

Spinal trabecular bone mineral content was measured in the first, second, and third lumbar vertebrae by quantitative computed tomography in 88 patients with non-steroid treated rheumatoid arthritis. Results were compared with those obtained in 105 healthy control subjects. The mean bone mineral content in the patient group, 135.8 (SD 32.8) mg/ml K2HOP4, was significantly lower than that in the controls (151.9 (32.1) mg/ml, p less than 0.01). Division of patients and controls into three age groups showed that the reduction in bone mineral content was most marked in the youngest age group (21-40 years), the mean value in male patients being significantly lower than in controls (149.6 (51.3) v 171.7 (23.9) mg/ml K2HPO4, p less than 0.05); in female patients in this age group the corresponding values were 160 (26.1) v 178.4 (22.0) mg/ml, 0.05 less than p less than 0.1). No significant difference in mean values between patients and controls was found in the other age groups. Of the 88 patients, six (7%) had abnormally low values, defined as a bone mineral content greater than 2 SD below the normal mean. One vertebral crush fracture was found in one patient but not in any of the controls. No correlation was found between bone mineral content and body weight, duration of disease, or disability as assessed by the London and Steinbroker methods. These results demonstrate a lower spinal trabecular bone mineral content in non-steroid treated patients with rheumatoid arthritis than in age and sex matched controls, the difference being most marked in younger patients. The finding of abnormally low values in 7% of the patients indicates a slightly increased prevalence of spinal osteoporosis in these patients.

Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis.

OBJECTIVE: To determine the distribution of the interleukin-10 (IL-10) 5' flanking region haplotypes in children with arthritis and in controls, and to investigate the functional significance of each haplotype. METHODS: Sequence-specific oligonucleotide probing was used to determine haplotype frequency. Transient transfection studies were used to investigate the transcription of reporter genes driven by each haplotype. Whole blood cultures were performed to assess IL-10 production by each genotype. RESULTS: Patients with arthritis involving >4 joints were more likely to have a genotype with an ATA haplotype than those whose arthritis remained restricted to <4 joints. This ATA haplotype was associated with lower transcriptional activity than the GCC haplotype (P = 0.02), and the ATA/ATA genotype was associated with lower IL-10 production under lipopolysaccharide stimulation than other genotypes (P < 0.02). CONCLUSION: The results of this study demonstrate the functional significance of the ATA haplotype and reveal a significant association of genotypes containing this haplotype with extended oligoarthritis.