Tag: comment

Commentary: Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients

Introduction: Studies to ascertain a possible relationship between herpesviruses and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have relied heavily on classical approaches, specifically, serological examination for antibodies against virus proteins, primarily structural, and/or increases in viral load (1–21). These data have been conflicting due in part to several features: the heterogeneity of the disease, high prevalence of the herpesviruses in the population since they can establish lifelong infections, and differences between laboratories. Two additional problems lead to conflicting data in serological studies: which viral antigens are to be used for detection, and what is the possible relationship, if any, of these viral antigens to ME/CFS? These are important questions that must be addressed for any data to provide meaningful insight into the possible contribution of a virus to the pathophysiology of ME/CFS. Although the experimental techniques used in Blomberg’s serological study were appropriate, the selection of specific herpesviruses and viral antigens studied gives a limited view of the humoral response in ME/CFS.

Discussion: Blomberg et al. (22) used a suspension multiplex immunoassay to detect antibodies against various herpesviruses’ antigens, derived from proteins expressed during latency or late lytic replication (Figure 1), with the goal of determining differences in antibody titers against these antigens between ME/CFS patients and controls. However, no rationale was given as to why these particular antigens were chosen and what association, if any, they may have with ME/CFS. This is important because the antigenic properties of the different virus proteins are not the same. As demonstrated in an eloquent study by Vaider-Shalt et al. (23), over the course of their evolution, herpes simplex virus 1 (HSV-1), Epstein-Barr virus (EBV), human herpesvirus 8 (HHV-8), and human cytomegalovirus have decreased the number of epitopes present in virus proteins in order to help them avoid immune detection. Thus, the ability of a virus protein to generate an antibody response is dependent upon the amount of protein present in the host and its antigenicity. It is also not clear why Blomberg et al. (22) included HSV-1/2, human cytomegalovirus, HHV-7, and varicella zoster virus (VZV) in their study since there are no up-to-date literature reports establishing a serological relationship between these viruses and ME/CFS.

Source: Ariza ME. Commentary: Antibodies to Human Herpesviruses in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients. Front Immunol. 2020;11:1400. Published 2020 Jul 23. doi:10.3389/fimmu.2020.01400 https://www.frontiersin.org/articles/10.3389/fimmu.2020.01400/full (Full text)

Reply to Comment on Detection of Mycotoxin in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605-617″ by Mark J. Mendell

The authors of [1] have received further correspondence from Mark J. Mendell [2] concerning the above paper. We strongly disagree that the case series, which is reported by Brewer, et al., has flawed methodologies and is unsuitable for publication in a peer-reviewed journal. We also disagree that the control group selected was inappropriate and thus results invalidate comparison and findings.

Mendell emphasizes throughout his document that this is in essence a case-control study. This is simply not true. In reviewing his comments, we must emphasize that he is reviewing this paper as an epidemiologist and not as a M.D. As many, if not all, epidemiologists are aware, the purpose of epidemiology is to establish associations, which may be causative or may reveal clues to causation [3]. Wang and Attia (2010) stated: “to study causes or exposures known to be harmful, it is not ethical nor feasible to use an experimental design; for example, one cannot ask one group to start smoking and another to abstain from smoking to study if smoking causes age-related macular degeneration. Observational studies do not interfere in human subjects’ choice of exposure and assess outcomes in subjects who were exposed or not exposed to the factors of interest; these are surveys, case-control, cohort studies (all with controls) or case series (without controls)” [3]. Kempen, in 2011, stated the uncontrolled case series may suffer from a fundamental defect of lacking a contemporaneous comparison group which then leaves authors and readers to resort to historical controls [4]. He continues to state that observational case series make up a substantial proportion of publications submitted to journals (in his case, ophthalmic journals), which aspire to promulgate generalizable knowledge. When these studies are appropriately used, they serve an important and legitimate purpose in furthering medical knowledge, particularly when a question of importance cannot be addressed by other methods because of ethical or logistical constraints.

The Brewer paper reports a case series from a clinician who treats patients. Thus, reporting of a case series, such as the Brewer paper, adds to generalizable knowledge. Brewer et al. made no causal inferences from this case series.

Kempen states that observational case series receive very little attention among epidemiologists because of the limitations of no control [4]. This does not mean in any way that the observations reported are not meaningful and potentially helpful to care givers and their patients.

Kooistra et al. furthermore stated that case reports and case series that lack comparison groups might present data that is biased and incomplete [5]. Despite that, studies like this one are useful for generating hypotheses for future studies.

We understand the issues that Mendell cites but strongly disagree with his assessment. Mendell gives his points as an epidemiologist, the authors of Brewer, et al., point out the medical interpretation of such data and do not emphasize that this is an epidemiology study. To not publish these data or other case series would be limiting further future hypotheses and future studies in the area of chronic fatigue and mycotoxins.

 

Source: Brewer J, Thrasher JD, Hooper D. Reply to Comment on Detection of Mycotoxin in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605-617″ by Mark J. Mendell. Toxins (Basel). 2016 Nov 7;8(11). pii: E325. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127122/ (Full article)

 

Reply to Comment on Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome Toxins 2013, 5, 605-617 by John W. Osterman, M.D.

This paper [1] was an observational case study. It was not intended to be, nor have we ever indicated that it was, an epidemiologic study [2]. One of the authors (Dr. Brewer) is an infectious disease specialist, who treats a number of patients with chronic fatigue syndrome (CFS). Dr. Brewer’s primary responsibility is to properly diagnose and treat these patients and ensure their wellbeing. In 2012, Dr. Brewer began to test patients for the presence of mycotoxins using the RealTime Lab’s mycotoxin panel. As he saw and treated more and more chronic fatigue patients, he began to see an association between the presence of mycotoxins and the symptoms of CFS. As this association became more apparent, Dr. Brewer discussed these findings with other experts in the field of mycotoxins. It was decided that these observations had potentially important clinical implications and the group decided to proceed with publication of this collection of clinical cases. The patients reported in our study were included based on their diagnosis (CFS) and not their exposure history.

These observations did lead to a hypothesis that perhaps the patients had internal fungal growth leading to both the symptoms of CFS and the presence of the mycotoxins produced by the fungi. Subsequently, this resulted in a treatment regimen for fungal colonization/infection in the sinuses, the results of which improved both the patient’s health and reduced the concentration of mycotoxins.

Never did the authors state or imply that mycotoxins caused CFS and never did we undertake a controlled study to look at CFS in a mycotoxin positive and a mycotoxin negative population. The major finding was the association between mycotoxins and CFS. In the paper (discussion section) several ideas were addressed (e.g., mitochondrial toxicity) as to possible pathophysiologic mechanisms.

The reference to the negative controls of another study, where the individuals were not exposed to a water damaged and potentially mold infested environment, was only meant to point out that the entire general population does not harbor elevated levels of mycotoxins, and/or the molds that produce them (despite low levels of exposure in the environment and potential mycotoxin-exposure in foods).

Much work would be and is needed to link mycotoxins and or mold as the causative agent of CFS and the authors understand that this would necessitate a clinical study with the appropriate mycotoxin negative controls. While this may be a future project, the focus now is on patient treatment and presentation of case histories such as the ones in this paper.

In summary, this was a clinical observation, not an epidemiological study. The findings are provocative and may have important implications for these types of illnesses. The results will hopefully stimulate and promote further investigation by our group and others.

 

Source: Brewer J, Thrasher JD, Hooper D. Reply to Comment on Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome Toxins 2013, 5, 605-617 by John W. Osterman, M.D. Toxins (Basel). 2016 Nov 7;8(11). pii: E323. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127120/ (Full article)

 

Comment on Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605-617

Abstract:

The paper by Brewer et al. entitled “Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605–617” is so methodologically flawed that it should never have been published in the scientific literature [1].

In this paper, the authors measure the presence of mycotoxins in the urine of 112 patients suffering from chronic fatigue syndrome (CFS). These finding are then compared to urine samples from 55 healthy control subjects “… with no history of exposure to WDB (water damaged buildings) or moldy environment…” (sic). Not surprisingly, there were more people from the CFS group with mold exposure than in the comparison group. These results are not surprising because, BY DEFINITION, the control group had no history of exposure to mold. By purposely choosing a control group with no history of mold exposure, the authors have statistically rigged their results in such a way that only a positive relationship will be found when compared to the CFS group.

Using the same approach, the authors could test urine from their CFS patients for the presence of caffeine metabolites and compare the results to urine from a group not exposed to caffeinated beverages; they would find more caffeine metabolites in the CFS group for the same methodological reasons, the control group having been purposely selected to be not exposed. The same would be true for nicotine metabolites in the CFS patients’ urine using urine from non-smokers as a comparison group or comparing urinary animal protein metabolites from the CFS group to animal protein metabolites in urine from vegetarians. The results from these studies would show a positive but erroneous association between CFS and caffeine, nicotine and animal protein. The same is true for the relationship that Brewer et al. purportedly found in this study of CFS and mold. The findings from this study are misleading and meaningless.

This study is an example of extreme selection bias and is akin to showing that men are shorter than women by comparing the height of an average group of men to that of women on the national basketball team!

Given the mountain of “junk” science on the Internet, I feel that a credible on-line scientific journal must ensure rigorous methodological standards for the papers it publishes. Such was not the case for this paper.

 

Source: Osterman JW. Comment on Detection of Mycotoxins in Patients with Chronic Fatigue Syndrome. Toxins 2013, 5, 605-617. Toxins (Basel). 2016 Nov 7;8(11). pii: E322. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5127119/ (Full article)

 

Suicide risk in people with chronic fatigue syndrome

The risk of dying is increased in many illnesses, but the mortality associated with chronic fatigue syndrome is relatively unexplored. In The Lancet, Emmert Roberts and colleagues1 report results from a case register study that linked the clinical details of more than 2000 people with chronic fatigue syndrome presenting to a specialist clinic (in London and the south of England) with mortality outcomes over 7 years. This is the largest study of its type so far, and used a robust case definition. The researchers noted that the overall risk of death in patients with chronic fatigue syndrome seemed no different from the risk in the general population. Cancer mortality was also similar. However, the findings for suicide deaths were striking—five people died during the 7-year period. Based on the suicide rate in the general population of England and Wales, the expected number would have been less than one death by suicide. In other words, suicide risk was increased almost seven-fold. A previous US study2 reported an increase in suicide mortality in people with fatigue symptoms, but was too small to show an increased suicide risk in those who met the criteria for chronic fatigue syndrome.

The results of the current study are potentially very important but need to be interpreted with caution. The study was quite small for an investigation of mortality (n=2147 patients of whom 17 died). This small sample meant that the stratified analyses in particular (investigation of the risk of death in sex, age, diagnostic, and deprivation subgroups) lacked statistical power. The increased suicide mortality (sex-standardised mortality ratio 6·85, 95% CI 2·22–15·98; p=0·002) was based on just a few deaths and the confidence intervals were wide. Two fewer suicide deaths would have meant that the findings were no longer significant.

The cohort itself was well defined but consisted of people who attended a national specialist centre run jointly by general medical and mental health service providers. This could mean that participants were representative of people with more severe or complex chronic fatigue syndrome, and the mortality findings might not be applicable to people with the disorder in primary care.

Read the rest of this comment here: http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00270-1/fulltext

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Source: Kapur N, Webb R. Suicide risk in people with chronic fatigue syndrome. Lancet. 2016 Apr 16;387(10028):1596-7. doi: 10.1016/S0140-6736(16)00270-1. Epub 2016 Feb 10. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00270-1/fulltext (Full article)

 

 

A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures

Abstract:

INTRODUCTION: Adamowicz and colleagues recently proposed to use “a consistent definition of recovery that captures a broad-based return to health with assessments of both fatigue and function as well as the patients’ perceptions of his/her recovery status” for patients with chronic fatigue syndrome (CFS).

METHODS: A qualitative analysis of case definitions for Myalgic encephalomyelitis (ME) and CFS and methods to assess the symptoms and clinical status of ME and CFS patients objectively.

RESULTS: The criteria of CFS define a heterogeneous disorder. ME, often used interchangeably with CFS, is principally defined by muscle weakness, cognitive impairment etc., but above all post-exertional “malaise”: a long-lasting increase in symptoms, e.g. muscle pain and cognitive deficits, after a minor exertion. The principle symptom of CFS however is “chronic fatigue”. Since post-exertional “malaise” is not obligatory for CFS, only part of the CFS patients meet the diagnostic criteria for ME, while not all ME patients qualify as CFS patients. There are several accepted methods to assess characteristic symptoms and the clinical status of ME and CFS patients using objective measures, e.g. (repeated) cardiopulmonary exercise tests.

CONCLUSION: To resolve the debate about the clinical status, proposed effectiveness of therapies and recovery in ME and CFS, it is crucial to accurately diagnose patients using well-defined criteria for ME and CFS and an objective assessment of various typical symptoms, since subjective measures such as “fatigue” will perpetuate the debate.

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Source: Twisk FN. A definition of recovery in myalgic encephalomyelitis and chronic fatigue syndrome should be based upon objective measures. Qual Life Res. 2014 Nov;23(9):2417-8. doi: 10.1007/s11136-014-0737-1. Epub 2014 Jun 17. https://www.ncbi.nlm.nih.gov/pubmed/24935018

 

Rebuttal to Ickmans et al. association between cognitive performance, physical fitness, and physical activity level in women with chronic fatigue syndrome

Dear Editor:

In a study recently published in Journal of Rehabilitation Research and Development, Ickmans et al. [1] found a substantially deteriorated physical exercise capacity in myalgic encephalopathy/chronic fatigue syndrome (ME/CFS), as established by a cardiopulmonary exercise test (peak oxygen uptake [VO2max]: 19.1 ± 4.6 mL/min/kg, peak heart rate: 145.1 ± 22.4 beats per minute [bpm], peak workload: 114.2 ± 31.3 W, compared with 27.2 ± 5.6 mL/min/ kg, 170.0 ± 36.2 bpm, and 114.2 ± 31.3 W, respectively, in sedentary controls). Ickmans et al. Also observed various cognitive deficits in ME/CFS, e.g., prolonged choice and simple reaction times in various Stroop subtests and the psychomotor vigilance task test (PVT), more errors of omission in the PVT, and worse letter recall scores on the operation span task test, indicative for working memory impairment and reduced psychomotor speed.

You can read the rest of this letter here:  http://www.rehab.research.va.gov/jour/2013/509/pdf/pagevii.pdf 

Comment on: Association between cognitive performance, physical fitness, and physical activity level in women with chronic fatigue syndrome. [J Rehabil Res Dev. 2013]

 

Source: Twisk F. Rebuttal to Ickmans et al. association between cognitive performance, physical fitness, and physical activity level in women with chronic fatigue syndrome. J Rehabil Res Dev. 2013;50(9):vii-viii. http://www.rehab.research.va.gov/jour/2013/509/pdf/pagevii.pdf (Full article)

 

Response to Derek Enlander

Sir,

Derek Enlander’s comments refer to Table 4 in our paper1 which describes the association of baseline characteristics with change in physical function at follow-up. It does not describe the outcome which can be found in Table 2. This shows an improvement in fatigue (−6.8; 95% CI −7.4 to −6.2; P < 0.001), physical function (4.4, 95% CI 3.0 to 5.8; P < 0.001), anxiety, depression and pain at follow-up.

In addition, as we state in the methods, the scores from the different inventories were re-scaled, so that a regression coefficient of 1 represents a 10% change in the score. Hence, the coefficient of −0.47 (95% CI −0.58 to −0.36) for the mean change in (re-scaled) SF-36 physical function per unit (re-scaled) Chalder Fatigue score at baseline, indicates that each 10% increment in baseline Chalder Fatigue (i.e. 3.3 points on the original 0 to 33 scale) is associated with a mean change of −4.7 points (95% CI −5.8 to −3.6 points) on the original 0 to 100 SF-36 scale at follow-up. Similarly, the coefficient of 0.81 (95% CI 0.75 to 0.87) for the mean change in (re-scaled) SF-36 physical function per unit (re-scaled) SF-36 score at baseline, indicates that each 10% increment in baseline physical function (i.e. 10 points on the original 0 to 100 SF-36 scale) is associated with a mean change of 8.1 points (95% CI 7.5 to 8.7 points) on the original 0 to 100 SF-36 scale at follow-up.

In summary, our paper shows that patients showed improvements in fatigue, physical disability, anxiety, depression and pain. Table 4 referred to by Derek Enlander show that worse fatigue and disability at assessment predict a worse outcome for disability at follow-up.

You can read the rest of this comment here: https://academic.oup.com/qjmed/article/107/3/247/1569245/Response-to-Derek-Enlander

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Source: Crawley E. Response to Derek Enlander. QJM. 2014 Mar;107(3):247. doi: 10.1093/qjmed/hct171. Epub 2013 Aug 22. https://academic.oup.com/qjmed/article/107/3/247/1569245/Response-to-Derek-Enlander (Full article)

 

 

RE: ‘Treatment outcome in adults with chronic fatigue syndrome: a prospective study

Sir,

In a very impressive paper1 embracing a large cohort (834) of ME CFS (myalgic encephalomyelitis, Chronic fatigue syndrome) patients selected by the Fukuda criteria, we can see in Table 4 the associations and changes of baseline characteristics with physical function at follow-up in the Chalder Fatigue scale −0.47 (−0.58 to −0.36) and in the SF-36 (physical function phase) 0.81 (0.75 to 0.87). This perhaps represents approximately an 8% change after the PACE recommended GET/CBT therapy after a variable number of months of therapy. This shows a relatively insignificant improvement. Do we presume that the authors therefore are not emphatically encouraging the PACE recommendation of GET/CBT as a means of primary treatment of ME CFS?

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Source: Enlander D. RE: ‘Treatment outcome in adults with chronic fatigue syndrome: a prospective study. QJM. 2014 Jan;107(1):87. doi: 10.1093/qjmed/hct169. Epub 2013 Aug 22. https://academic.oup.com/qjmed/article/107/1/87/1513843/RE-Treatment-outcome-in-adults-with-chronic

 

Apology

Dear Sir,

In our commentary [1] on paper by Broderick et al. regarding diagnostic criteria for CFS [2], Professor van Der Meer and I inadvertently cited a letter by Stouten et al. in a section of our correspondence suggesting that their response to the publication of the PACE [3] trial for patients with CFS was unscientific and included personal attacks on the authors of that study, as it was interspersed with a series of letters that met those descriptors. However, it is clear that the letter by Stouten et al. raised valid scientific concerns about the trial. We wish to note that this letter should not have been included as an example in our correspondence and apologize to the authors for any distress caused.

Comment on: A controversial consensus–comment on article by Broderick et al. [J Intern Med. 2012]

 

Source: Lloyd AR. Apology. J Intern Med. 2013 Jun;273(6):628. doi: 10.1111/joim.12074. Epub 2013 May 6. http://onlinelibrary.wiley.com/doi/10.1111/joim.12074/full (Full article)