Increased neutrophil apoptosis in chronic fatigue syndrome

G Kennedy; V Spence; C Underwood; J J F Belch

doi:10.1136/jcp.2003.015511

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Increased neutrophil apoptosis in chronic fatigue syndrome

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Re: Chronic fatigue syndrome and immune dysfunction : cause or effect?
Gwen Kennedy
Published on: 5 October 2004
Re: Chronic fatigue syndrome and immune dysfunction : cause or effect?
Angela D Flack
Published on: 21 September 2004
More Immunological profiling needed
Nicholas J McAdden
Published on: 10 September 2004
Re: Chronic fatigue syndrome and immune dysfunction : cause or effect?
Paul Schaafsma
Published on: 23 August 2004
Chronic fatigue syndrome and immune dysfunction : cause or effect?
IAN P CHANDLER
Published on: 18 August 2004

Published on: 5 October 2004
Re: Chronic fatigue syndrome and immune dysfunction : cause or effect?
- Gwen Kennedy, Postdoctoral Research Assistant
- Other Contributors:
  Vance A. Spence, Christine Underwood, and Jill J.F. Belch
Dear Editor
In his letter of the letter 18th August 2004, Dr Chandler makes some interesting comments on our paper “Increased neutrophil apoptosis in chronic fatigue syndrome” [1]. He states that “a more likely explanation for the group's findings are that CFS patients have a primary psychological disorder with the secondary expected immune dysfunction”. We strongly disagree with this statement.
It is n...
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Dear Editor
In his letter of the letter 18th August 2004, Dr Chandler makes some interesting comments on our paper “Increased neutrophil apoptosis in chronic fatigue syndrome” [1]. He states that “a more likely explanation for the group's findings are that CFS patients have a primary psychological disorder with the secondary expected immune dysfunction”. We strongly disagree with this statement.
It is noteworthy that many research findings that support a physical basis to CFS are constantly under attack and are commonly reduced to the lowest common denominator i.e. that CFS is “psychological in origin”. Dr Chandler comments that, “there is a wealth of data suggesting that primary depressive illnesses are associated with immune function defects”. That may be true, however, we are not aware of a study which shows that neutrophils are significantly apoptotic in depressed patients and that this is associated with an increase in the pro-inflammatory cytokine, transforming growth factor â-1. Furthermore, the CFS patients in our study were not depressed or excessively anxious and we have already reported on their psychological status in a separate report [2]. Indeed, three groups of CFS patients are mentioned in that report [2]: those with self-reported symptoms which developed sporadically (CFS, n =48); after Gulf War service (GW, n =24); and following exposure to organophosphate insecticides (OP, n =25). All of these patients underwent a clinical examination which included psychiatric status, they all completed the MOS SF-36 quality of life and Hospital Anxiety and Depression scales, and fulfilled major and minor criteria for CDC-1994 CFS. The GW and OP cohorts had significant impairments to both emotional and mental health measures (GW > OP) when compared to their own controls and to the sporadic CFS patients. We have not yet reported on the neutrophil apoptosis data on the GW and OP patients (or in other studies of their lymphocyte function) but neither cohort had any difference in the percentage of neutrophils undergoing apoptosis when compared with their respective controls. We additionally found that the GW and OP cohorts had no difference in the percentages of tumour necrosis factor receptor-1 death receptor molecules expressed on their neutrophils or levels of platelet poor plasma activated transforming growth factor â-1. This data is at variance with Dr Chandlers comment that “a more likely explanation for the group's findings are that CFS patients have a primary psychological disorder”.
What is clear is that the term CFS is heterogeneous and lacks specificity as others have reported [3, 4]. The CFS patients in our study should more accurately be described as those having myalgic encephalomyelitis (ME) as defined by Ramsay [5] which has recently been reported to be operationally distinct from those with chronic fatigue and chronic fatigue syndrome [6] especially in the neurological and neuropsychiatric areas reported in our recent study [2]. Fatigue is a symptom and not a disease and, ultimately, “an operational CFS case definition will need to be based on empirical studies designed to delineate the possibly distinct biological pathways that result in illness” [3]: such a case definition already exists [7]. Our paper on increased neutrophil apoptosis in a specific subset of patients within the CFS construct goes some way to assisting in this process of classification.
References
(1) Kennedy G, Spence V, Underwood C. Increased neutrophil apoptosis in chronic fatigue syndrome. J Clinical Pathology 2004; 57: 891-3
(2) Kennedy G, Abbot NC, Spence V, Underwood C, Belch JJF. The specificity of the CDC-1994 criteria for chronic fatigue syndrome: a comparison of health status in three groups of patients who fulfill the criteria. Annals of Epidemiology 2004; 14: 95-100
(3) Reeves WC, Lloyd A, Vernon SD et al. Identification of ambiguities in the 1994 chronic fatigue syndrome research case definition and recommendations for resolution. BMC Health Services Research 2003, 3:25
(4) Jason LA, King CP, Richman JA, et al. US case definition of Chronic Fatigue Syndrome: Diagnostic and theoretical issues. J Chronic Fatigue Syndrome 1999; 5: 3–33.
(5) Ramsay, M. A. (1988). Myalgic encephalomyelitis and post-viral fatigue states: The saga of Royal Free disease (2nd ed.). Hampshire, UK: Gower.
(6) Jason LA, Helgerson J, Torres-Harding SR et al. Variability in diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns of symptoms and disability. Evaluation & the Health Professions 2003; 26: 3-22
(7) Carruthers BM, Jain AK, De Meirleir KL, Peterson DL, Klimas NG, Lerner AM, et al. Myalgic encephalomyelitis/chronic fatigue syndrome: Clinical working case definition, diagnostic and treatment protocols. J Chronic Fatigue Syndrome 2003; 11: 7–116.
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Conflict of Interest:
None declared.
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Published on: 21 September 2004
Re: Chronic fatigue syndrome and immune dysfunction : cause or effect?
- Angela D Flack, Early retired as a result of M.E.
Dear Editor
I welcome the latest research on neutrophil apoptosis from a educated, experienced, and motivated M.E. expert.
I am very concerned, and thoroughly disappointed again, that, despite the concerns raised, by hundreds of well educated people, involved with M.E. worldwide, for many years, someone who ha...
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Dear Editor
I welcome the latest research on neutrophil apoptosis from a educated, experienced, and motivated M.E. expert.
I am very concerned, and thoroughly disappointed again, that, despite the concerns raised, by hundreds of well educated people, involved with M.E. worldwide, for many years, someone who has admitted to being "quite new" to a SHO post, on a Chronic Fatigue ward, has assumed, that he has the authority and education, to criticise the outcome of this research, at this stage, when most people admit they are not 100% sure about the aetiology M.E.
This seems to be a pre-determined blinkered attitude, that screams out "l know all there is to know". I will not tolerate, on behalf of the members of the M.E.Association, the approach perpetrated by information solely provided by the Psychiatrists, who have continually reported, that M.E. is an illness belief, that one has a real illness that must not be encouraged, by validating, or providing medical testing, for a non-illness.
The Department of Health have on many occasions, declared that they are duty bound, to take account of all national and international information and evidence, from all sources so as to provide as broad a spectrum of ideas and treatment plans as is reasonable. And to provide the least damaging and most helpful, practical treatment or advice for all. The Canadian Guidelines have the potential to be adapted for world wide use, but l have been told the government appears to use international advice only, when it suits them, and ignore it when it suits patients.
Has the DOH considered fully, the possible financial implications, for us all, if there is no research into the physical, epidemiological and biological cause of M.E.? This has resulted in many cases of long term physical damage,<see 25% Report 2002-2004> which has resulted in the death of hundreds of people every year.
A high proportion are those have been young adults, who have been constantly, denied referrals, to the independent, M.E. specialists that we have in our files.
Angela Dorothy Flack
Declared interest: Trustee MEA. APPG/DLA Rep
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Conflict of Interest:
None declared.
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Published on: 10 September 2004
More Immunological profiling needed
- Nicholas J McAdden, Company Director
Dear Editor
It is disappointing to read Ian Chandler's comments on this work. Dr Chandler's rather simplified logic seems to work like this:
- Depression is a psychiatric illness.
- Immunological abnormalities can be found in depression.
- CFS is also a psychiatric disorder and so there is no point in measuring immunological parameters because any findings will be redundant.
...
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Dear Editor
It is disappointing to read Ian Chandler's comments on this work. Dr Chandler's rather simplified logic seems to work like this:
- Depression is a psychiatric illness.
- Immunological abnormalities can be found in depression.
- CFS is also a psychiatric disorder and so there is no point in measuring immunological parameters because any findings will be redundant.
CFS remains a debilitating condition for which more pathological data is desperately needed. Psychiatric studies, whilst having been of value in the past, are failing to provide new insight into disease aetiology, nor are they providing effective treatments, particularly for those patients who are most seriously affected by the condition.
Immunological profiling will undoubtedly lead to immunomodulatory interventions for a number of medical conditions. Perhaps one of these will be CFS, perhaps not. It may even be the case for certain subgroups with clinical depression. The point is, we'll never know unless we encourage this type of research.
I hope that medical professionals like Dr Chandler are prepared to adjust their views on CFS if and when further findings are published.
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Conflict of Interest:
None declared.
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Published on: 23 August 2004
Re: Chronic fatigue syndrome and immune dysfunction : cause or effect?
- Paul Schaafsma
Dear Editor
Ian Chandler's response to this study, insisting that any immune abnormality is secondary to depression is without scientific merit.
Several studies comparing ME/CFIDS patients with patients suffering from clinical depression have found important physical differences. SPECT brain imaging studies sh...
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Dear Editor
Ian Chandler's response to this study, insisting that any immune abnormality is secondary to depression is without scientific merit.
Several studies comparing ME/CFIDS patients with patients suffering from clinical depression have found important physical differences. SPECT brain imaging studies show ME/CFIDS patients suffer from hypoperfusion that gets worse, rather than better, after exercise, a pattern not found in depressed patients.
Studies have also show a reduced pain threshold in ME/CFIDS patients, which again responds to exercise in a manner opposite to that found in healthy and depressed control groups - pain thresholds get lower, instead of higher.
These studies amount to clinical confirmation of a simple but often- ignored distinction. When people suffering from depression exercise they feel better, when people suffering from ME/CFIDS exercise they feel much worse, often for days afterwards.
As an adult male diagnosed with ME/CFIDS, I can tell you that few things are more 'depressing' than encountering medical professionals like Mr. Chandler, who discount all evidence of organic illness in ME/CFIDS patients because of a willful, even perverse attachment to the belief that our symptoms are 'all in our heads'.
To hold to that position despite all evidence to the contrary demonstrates a mindset in which empathy and scientific curiosity are markedly absent - in other words, a mindset uniquely unsuited for responsible diagnosis and treatment of complex illnesses like this one.
Mr. Chandler's position is one which cannot be altered by encounters with contrary facts. If presented with undisputable evidence of, say, chronic bacterial infection in a patient with ME/CFIDS, Mr. Chandler will acknowledge the infection but deny that it has anything at all to do with ME/CFIDS itself.
Do depressed people experience symptom remission when treated with Ampligen, an immune-modulating drug? Do depressed people regain their health and vitality after long-courses of antibiotics? The answer, of course, is no. Patients with ME/CFIDS, however, do.
Mr. Chandler would no doubt object that the studies demonstrating this improvement are not large enough to be considered definitive. The point, of course, is that views such as his are the primary reason that adequate research budgets for these illnesses are not forthcoming.
Sincerely,
Paul Schaafsma
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Conflict of Interest:
None declared.
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Published on: 18 August 2004
Chronic fatigue syndrome and immune dysfunction : cause or effect?
- IAN P CHANDLER, SpR Cellular Pathology
Dear Editor
Having read Kennedy et al's short report on finding increased neutrophil apoptosis in patients with chronic fatigue syndrome, I am unable to agree with their conclusion that "these findings provide new evidence that patients with CFS have an underlying abnormality in their immune cells" [1]. They provide no evidence that the immune defect is causative, and, on the contrary, there is a wealth of...
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Dear Editor
Having read Kennedy et al's short report on finding increased neutrophil apoptosis in patients with chronic fatigue syndrome, I am unable to agree with their conclusion that "these findings provide new evidence that patients with CFS have an underlying abnormality in their immune cells" [1]. They provide no evidence that the immune defect is causative, and, on the contrary, there is a wealth of data suggesting that primary depressive illnesses are associated with immune function defects. Research papers in neuropsychology journals over the last year have described abnormalities of natural killer cell function, T cell function, and neutrophil function in psychological stress, depression, and associated loneliness [2-5]. As somebody who has spent an albeit relatively short time working as an SHO in a CFS specialist ward, I would suggest that a more likely explanation for the group's findings are that CFS patients have a primary psychological disorder with the secondary expected immune dysfunction predicted by the referenced papers above.
References
(1) Kennedy G, Spence V, Underwood C. Increased neutrophil apoptosis in chronic fatigue syndrome. J Clin Pathol 2004;57:891-3.
(2) Frank MG, Hendricks SE, Burke WJ et al. Clinical response augments NK cell activity independent of treatment modality. Psychol Med 2004 Apr; 34(3)491-8.
(3) Steptoe S, Owen N, Kunz-Ebrecht SR et al. Loneliness and neuroendocrine, cardiovascular and inflammatory stress response in middle- aged men and women. Psychoneuroendocrinology 2004 Jun 29(5)593-611.
(4) Silberman DM, Ayelli-Edgar V, Zorilla-Zubilete M et al. Impaired T cell dependent humoral response and its relationship with T lymphocyte sensitivity to stress hormones in a chronic mild stress model of depression. Brain Behav Immuno 2004 Jan 18(1)81-90.
(5) Irie M, Asami S, Ikeda M et al. Depressive state relates to female oxidative DNA damage via neutrophil activation. Biochem Biophys Res Commun 2003 Nov 28;311(4)1014-18.
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Conflict of Interest:
None declared.
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