Biochemical and vascular aspects of pediatric chronic fatigue syndrome

Authors

Kennedy G, Khan F, Hill A, Underwood C, Belch JJF

Institution

Vascular and Inflammatory Diseases Research Unit, The Institute of Cardiovascular Research, Centre for Cardiovascular and Lung Biology, Division of Medical Sciences, Ninewells Hospital and Medical School, Dundee, UK

Objective

To evaluate biochemical and vascular aspects of pediatric chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

Design

Cross-sectional clinical study.

Setting

Tayside, Scotland, United Kingdom.

Participants

Twenty-five children with CFS/ME and 23 healthy children recruited from throughout the UK.

Interventions

Participants were given a full clinical examination to establish a diagnosis of CFS/ME and were asked to describe and score their CFS/ME symptoms. Biochemical markers were measured. Arterial wave reflection was estimated to assess systemic arterial stiffness.

Main outcome measures

Markers of oxidative stress and free radicals; C-reactive protein level; white blood cell apoptosis; and arterial wave reflection.

Results

Children with CFS/ME had increased oxidative stress compared with control individuals (isoprostanes: 252.30 vs 215.60 pg/mL, P=.007; vitamin C, mean [SD]: 0.84 [0.26] vs 1.15 [0.28] mg/dL, P<.001; vitamin E, 8.72 [2.39] vs 10.94 [3.46] µg/mL, P=.01) and increased white blood cell apoptosis (neutrophils: 53.7% vs 35.7%, P=.005; lymphocytes: 40.1% vs 24.6%, P=.009). Arterial stiffness variables did not differ significantly between the groups (mean augmentation index, -0.57% vs -0.47%, P=.09); however, the derived variables significantly correlated with total (r=0.543, P=.02) and low-density lipoprotein (r=0.631, P=.004) cholesterol in patients with CFS/ME but not in controls.

Conclusions

Biomedical anomalies seen in adults with CFS/ME — increased oxidative stress and increased white blood cell apoptosis — can also be observed in children with clinically diagnosed CFS/ME compared with matched controls. Unlike their adult counterparts, however, arterial stiffness remained within the reference range in these pediatric patients.

Publication

Archives of Pediatrics and Adolescent Medicine, 2010 Sep; 164(9): 817–23.

Funding Acknowledgements

We thank ME Research UK, Tenovus Scotland, the Young ME Sufferers Trust (Tymes Trust), and Search ME for providing funding for this study. Prof. Belch also receives funding from the Sir John Fisher Foundation, and this help is gratefully acknowledged.

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Comment by ME Research UK

Illness in youngsters has a particular poignancy; the transformation of a bright, active child into one who is unable to go to school or play with friends is something that touches us all.

There are few, if any, good estimates of the numbers of children affected by ME/CFS. Assuming rough prevalence figures of 60 to 70 cases per 100,000, however, it is likely that around 9,000 people under the age of 16 in the UK have this diagnosis. As the report to the Chief Medical Officer in 2002 made clear, this illness “represents a substantial problem in the young” and “potentially threatens physical, emotional, and intellectual development of children and young people, and can disrupt education and social and family life, at a particularly vulnerable time of life”.

The results of a previous study on quality of life in children with ME/CFS were recently published in Pediatrics by Dr Gwen Kennedy at the Vascular and Inflammatory Diseases Research Unit in the University of Dundee. In parallel with this work, Dr Kennedy and her colleague Dr Faisel Khan have been investigating biochemical and vascular abnormalities in children with the disease, and their results have just appeared in the US journal Archives of Pediatrics and Adolescent Medicine.

The Dundee group had previously reported a number of biochemical and vascular abnormalities in adults with ME/CFS. These mainly involve the immune and cardiovascular systems, and include an increase in the programmed death (apoptosis) of white blood cells, raised levels of oxidative stress which can damage blood vessels and other organs, increased markers of inflammation, and abnormalities in blood vessel function. All of these are potentially associated with a future risk for cardiovascular problems such as heart disease and stroke.

Drs Kennedy and Khan wanted to investigate whether these abnormalities were also present in children with ME/CFS, given the potential long-term consequences for cardiovascular risk. Risk factors such as high cholesterol and increased blood pressure, which are usually associated with adult diseases, have also been found in children and can progress into adulthood as hypercholesterolaemia and hypertension, so it is important that risks are identified as early in life as possible.

Twenty-five children with ME/CFS (all between the ages of 10 and 18 years) and 23 healthy children matched for age, gender and stage of puberty were recruited from throughout the UK. The diagnosis of ME/CFS had been made according to a revised version of the CDC-1994 case definition, and was confirmed by the researchers from a clinical examination.

A blood sample was taken from each child (using an anaesthetic cream to minimise their discomfort), and this was then subjected to a battery of tests in Dr Kennedy’s laboratory. The child’s blood pressure was measured, and then the pulse at their wrist was detected using a special pen-like probe applied lightly to the skin. This records the fluctuations in pressure as each pulse travels along the artery, and is exactly what you feel with your finger when you take your own pulse. This recording of the pulse is then analysed on a computer to give information on how flexible the artery is, which gives an indication of its health and function.

Overall, compared with healthy control children, the young people with ME/CFS had:

  1. Higher levels of oxidative stress, manifested as elevated levels of isoprostanes
  2. Reduced levels of vitamins C and E
  3. A greater percentage of white blood cells undergoing apoptosis (see graph below)
  4. A trend towards increased arterial stiffness, although this was not statistically significant
Neutrophil apoptosis
 
As Dr Kennedy points out, the increased oxidative stress may be due to a deficiency of antioxidants in the diet (such as vitamins C and E, found to be reduced in this study). However, she feels it is more likely to have been caused by white blood cells releasing an excessive amount of highly reactive free radicals, possibly from exercising muscle. This would tie in with the finding of increased white cell apoptosis, and Dr Kennedy has previously reported increased oxidative stress following exercise in adults with ME/CFS. She does emphasise, however, that more studies, perhaps including an assessment of diet, are needed to determine this mechanism.

The increased apoptosis (or programmed cell death) may be caused by a number of factors, including a persistent viral infection or toxic agent, or an abnormal immunological response. This finding is particularly intriguing given that many patients, including most children in this study, report that their disease started following a viral infection of some kind. At present, however, there is insufficient evidence to make a causal link between infection and increased apoptosis, though the finding is tantalising.

Although there were no other statistically significant changes in the children with ME/CFS, there was a clustering of markers such as arterial stiffness and cholesterol that showed small changes which may indicate the possibility of future cardiovascular risk. This type of clustering has been shown before in healthy children and in young people with diabetes. Although it should be stressed that children with ME/CFS are at no immediate risk of developing cardiovascular problems, we might expect these changes to become greater (closer to the adult pattern) as the children grow older and have been ill for longer.

Dr Kennedy and her team conclude their report by saying that the findings show that many children with ME/CFS “have an underlying, detectable abnormality in the behaviour of their immune cells, consistent with an activated inflammatory process”, and provide evidence of “a persistent or reactivating viral infection triggering apoptosis of white blood cells with an increased production of free radicals”.

It is important that these abnormalities have now been recognised in children with ME/CFS. To date, aside from symptomatic treatments, no specific therapy is available for children or adults with ME/CFS. Based on these and other biomedical findings in the disease, putative therapies could perhaps include both pharmacological and non-pharmacological strategies (to treat dysautonomia, for example), or antioxidant or antiviral interventions.

This essay is an extract from our article (pdf 941 KB) in the Autumn 2010 issue of Breakthrough.

Co-funders of the study

ME Research UK funds biomedical research into ME/CFS with the aim of finding the cause of the illness and developing effective treatments. It funds the work of a growing number of scientists in the UK and worldwide, and to date has invested over £600,000 to support biomedical research. We are particularly grateful to the ME organisations which have provided larger donations to help us fund specific projects, details of which including some of the resulting scientific papers can be found on our research pages.

The Young ME Sufferers (Tymes) Trust, one of the major co-funders of the study at the University of Dundee, is the longest established national UK service for children and young people with ME and their families. A well-respected national charity, which recently won the Queen’s Award for Voluntary Service, its entire professional team give their time free of charge. It runs an Advice Line, provides access to ME experts for doctors, teachers and social workers, and produces a magazine for children, families and professionals. The Trust played a major role in producing the children’s section of the Department of Health Report on CFS/ME (2002). It promotes interactive virtual education for children with ME, and provides the Tymes Trustcard — a pass card for children in school, endorsed by the Association of School and College Leaders. More information on the Tymes Trust and its work can be obtained at its website.

Search ME, based in Rosyth, Fife, was founded in 2002. Its aims are to improve the lives of people with ME and to provide them with a voice on the Cross Party Group for ME in the Scottish Parliament. The charity has raised the bulk of its donations through organising Rock and Pop Concerts. Search ME became an early supporter of the study at the University of Dundee and helped fund the work carried out there. Members of the charity are very proud of the work carried out at Dundee and of all the people involved. Further information can be found on their website.

Tenovus Scotland has funded world class cancer research across the UK for over 40 years, providing a vital link by funding pilot studies which can attract further support from major funding bodies such as the Wellcome Trust, the MRC, Cancer Research UK, the British Heart Foundation and many others. Further information can be found at its website.

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