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Rapid Responses: Rapid Responses published:
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On what basis was it decided that Immunoglobulin was not suitable for CFS?
- Tom Kindlon (24 October 2008)
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Successful intravenous immunoglobulin treatment for parvovirus B19-associated chronic fatigue syndrome (CFS)
- Charles Bernard Shepherd (26 October 2008)
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Important exclusion in the Department of Health guidelines for intravenous immunoglobulin
- A K Saha (1 November 2008)
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The systemic vasculitides and urgent prescribing of immunoglobulin
- Drew Provan, Helen M Chapel, W A Carrock Sewell, and Denise O’Shaughnessy (23 December 2008)
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Department of Health immunoglobulin guidelines are evidence-based and provide a framework for all treatment decisions
- Drew Provan, Helen M Chapel, W A Carrock Sewell, and Denise O’Shaughnessy (23 December 2008)
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CFS is increasingly recognised as a heterogeneous condition
- Tom Kindlon (7 October 2009)
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Tom Kindlon, Information Officer (voluntary position) Irish ME/CFS Association
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Chronic Fatigue Syndrome (CFS) is included in this document in the relatively short list of conditions for which Immunoglobulin is not recommended. How was this decision reached? Was it because of NICE recommendations? By the criteria they used for their guidance on "CFS/ME", there would be a lot more conditions in the same category as CFS as, in CFS as in many other conditions, there have not been many studies involving Immunoglobulin (although some doctors in the UK and in other countries, who haven't published on the subject, do use it). How was the positive study by Kerr[1] viewed? Its abstract is short so, rather than try to summarise it, here it is: "Three cases of chronic fatigue syndrome (CFS) that followed acute parvovirus B19 infection were treated with a 5-day course of intravenous immunoglobulin (IVIG; 400 mg/kg per day), the only specific treatment for parvovirus B19 infection. We examined the influence of IVIG treatment on the production of cytokines and chemokines in individuals with CFS due to parvovirus B19. IVIG therapy led to clearance of parvovirus B19 viremia, resolution of symptoms, and improvement in physical and functional ability in all patients, as well as resolution of cytokine dysregulation." These patients had been ill for over 2 years. Was the decision influenced as it was felt that CBT was "effective" for CFS? The decision makers may be interested to know that a meta- analysis of the efficacy of CBT for CFS was recently published[2]. The studies involved a total of 1371 patients. This involved calculating the size of an effect measure, the Cohen's d value. They calculated d using the following method: "Separate mean effect sizes were calculated for each category of outcome variable (e.g., fatigue self- rating) and for each type of outcome variable (mental, physical, and mixed mental and physical). Studies generally included multiple outcome measures. For all analyses except those that compared different categories or types of outcome variables, we used the mean effect size of all the relevant outcome variables of the study." d was calculated to be 0.48. For anyone unfamiliar with Cohen's d values, they are not bounded by 1; also, the higher the score, the bigger the "effect size" i.e. the more "effective" a treatment was found to be. Cohen's d values are considered to be a small effect size at 0.2, a moderate effect size at 0.5, and a large effect size at 0.8[3]. [1] Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19 -associated chronic fatigue syndrome. Clin Infect Dis. 2003 May 1;36(9):e100-6 [2] Malouff, J. M., et al., Efficacy of cognitive behavioral therapy for chronic fatigue syndrome: A meta-analysis. Clinical Psychology Review (2007), doi:10.1016/j.cpr.2007.10.004 [3] Cohen J: Statistical power analysis for the behavioural sciences. Edited by: 2. New Jersey: Lawrence Erlbaum; 1988. Competing interests: None declared |
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Charles Bernard Shepherd, Medical Adviser, ME Association ME Association, 7 Apollo Office Court, Radclive Road, Gawcott, Buckinghamshire MK18 4DF
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Whilst accepting that the overall evidence base from randomised clinical trials for supporting the use of intravenous immunoglobulin in the case of CFS is weak, this is a very heterogeneous condition in both clinical presentation and possible pathogenesis. So like Tom Kindlon (rapid responses) I would query whether the study by Kerr et al (1) into the use of immunoglobulin in parvovirus B-19 associated chronic fatigue syndrome has been taken into account and whether the authors would specifically advise against the use of this form of treatment in a very specific sub-group of CFS patients? Dr Charles Shepherd Hon Medical Adviser, ME Association 1 Kerr JR et al. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B-19 associated chronic fatigue syndrome. Clinical Infectious Diseases 2003; 36: 100 - 106. Competing interests: None declared |
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A K Saha, Specialist Registrar Department of Rheumatology,North Middlesex University Hospital , Sterlling Way, London. N18 1QX
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I am disheartened to read the recent Department of Health guidelines for the prescribing of intravenous immunoglobulin. The vasculitides have been put into the so called grey box of unlisted conditions where the evidence base is weak. The full guidelines state that in the above conditions, immunosuppression is the preferred treatment of choice but does not take co-existing sepsis into consideration- a common scenario encountered in these diseases where immunosuppression is contraindicated. If intravenous immunoglobulin is to be given in this situation, one that is commonly encountered, it requires two panels to sanction the prescription. Time is of the essence here and the requirement for two groups to review these cases will lead to unnecessarily and possible fatal delays. With the worldwide shortage of intravenous immunoglobulin and the ethical and practical issues in enrolling this subgroup of patients in trials, the vasculitides will never have a strong evidence base and unlikely on this basis to be put into the so called red/blue box. Thus, without more flexibility in these guidelines to allow for this scenario, unnecessary morbidity and mortality will result. Competing interests: None declared |
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Drew Provan, Consultant Haematologist Department of Haematology, Barts and the London NHS Trust, The Royal London Hospital, London E1 2ES, Helen M Chapel, W A Carrock Sewell, and Denise O’Shaughnessy
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We thank Dr Saha for his interest in these Department of Health guidelines. The systemic vasculitides are a large group of multisystem disorders characterised by a very heterogeneous clinical presentation, course, and prognosis. The guidelines address the management of Kawasaki disease, which is given the highest priority for immunoglobulin treatment because of clear evidence of benefit, which can be life-saving; but for other vasculitides, the evidence of benefit of immunoglobulin is weak and it is correct that these disorders are given low priority. It is important to realize that the introduction of this prioritization was essential to maintain supply for those in whom the provision of immunoglobulin is life- saving. But it is equally important to realize that, although the prescribing of immunoglobulin in an emergency case will require sanctioning by the local Immunoglobulin Assessment Panel, all Trusts are expected to have an urgent panel request process in place, with a point of contact for clinicians who will coordinate this emergency requesting process. Immunoglobulin is a scarce product and it is reasonable to insist that before prescribing, even in an emergency situation, local discussions take place and the prescribing decision is taken in the context of local availability and weighed against local priorities. There continues to be a national shortage, with three occasions recorded in the past year when patients receiving ongoing treatment with immunoglobulin were forced to wait for further treatment because of specific brand shortages. There is no ‘slack’ in the system of supply and little capacity to react in an unplanned situation, for example failure of a supplier to fulfill an order because of an unforeseen problem. Developing the evidence base, particularly for grey indications, is a key priority for health commissioners. It is acknowledged that there is a pressing need to shrink the grey indications list, moving conditions from there to either the blue or black indications. The health commissioners have attached great importance to ensuring that there is compliance regarding data input to the national database, as well as participation in trials. The possibility of establishing an ‘n of 1’ trial unit is currently being explored. Competing interests: All authors were members of the Department of Health’s IVIg Expert Working Group: guideline development group (DP, DO’S), demand management plan group (HMC, DO’S), and database development group (WACS, DO’S). |
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Drew Provan, Consultant Haematologist 1Department of Haematology, Barts and the London NHS Trust, The Royal London Hospital, London E1 2ES, Helen M Chapel, W A Carrock Sewell, and Denise O’Shaughnessy
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We thank the ME/CFS associations for their interest in these Department of Health (DH) guidelines. Clearly, some form of treatment prioritisation had to be introduced to ensure that, for those considered the highest priority because of risk to life without treatment, immunoglobulin is available. It is not the intention to deny patients effective treatment, but rather to introduce a prioritisation that ensures availability of life-saving treatment for those groups of patients in whom benefit is proven. The process by which treatment recommendations were made is set out in detail in the guidelines and was not related to NICE recommendations. In the case of ME/CFS, the decision to recommend against immunoglobulin was made by eminent neurologists, and was evidence-based. The principal study reviewed (a randomized, double-blind, placebo-controlled trial) showed no significant benefit of intravenous immunoglobulin [1]; the evidence provided by this study was not outweighed by the small case- report study cited by Tom Kindlon [2]. The findings of the randomized study raise another important consideration before immunoglobulin is prescribed – the potential for adverse reactions. The use of immunoglobulin should be carefully considered because of potential and sometimes fatal individual risks associated with treatment with a blood product, such as transmitted infections. Finally, it is important to understand that the guidelines and the demand management plan provide a framework for all treatment decisions. There is a process of ‘exceptionality’ that offers the opportunity for treatment in cases that fall outside the broad definition of a disease state. In the case of parvovirus B19-associated CFS, the treating physician may request immunoglobulin treatment on the basis that parvovirus B19-associated CFS is different from the reference population of CFS patients. The physician would be expected to present evidence to the local immunoglobulin assessment panel that an individual patient is likely to gain significantly more benefit from the intervention than might be expected for the average patient with that condition. In such exceptional cases, health commissioners would be asked to sanction funding of the treatment following approval by the local panel. As for all cases of immunoglobulin treatment, the national immunoglobulin database entry must be fully completed, and this will become a requirement for funding in the near future. 1.Vollmer-Conna U, Hickie I, Hadzi-Pavlovic D, Tymms K, Wakefield D, Dwyer J, et al. Intravenous immunoglobulin is ineffective in the treatment of patients with chronic fatigue syndrome. Am J Med 1997;103:38-43. 2.Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19–associated chronic fatigue syndrome. Clin Infect Dis 2003;36:100-106. Competing interests: All authors were members of the Department of Health’s IVIg Expert Working Group: guideline development group (DP, DO’S), demand management plan group (HMC, DO’S), and database development group (WACS, DO’S). |
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Tom Kindlon, Information Officer (voluntary position) Irish ME/CFS Association, Dublin, Ireland
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Following on from my last e-letter[1]: I have now located the first edition of these guidelines[2]. This edition by Provan et al[2], when putting Chronic Fatigue Syndrome (CFS) in the "black indications" group, explicitly recommends CBT for CFS. This seems to ignore the fact that CFS is increasingly recognised as being a heterogeneous condition[3]. Also, Price et al. [4] reviewed 15 studies of CBT with a total of 1043 ME/CFS participants. At treatment end, 40% of people in the CBT group showed clinical improvement in contrast to only 26% in usual care, but changes were not maintained at a 1-7-month follow-up when including people who had dropped out, which hardly suggests CBT is a solution for all. Roberts et al[5] recently found that the subgroup of CFS with hypocortisolism had a poor response to CBT. How many of the "eminent neurologists" that Provan et al. refer to had actually used on IVIg on CFS patients? If any have used it, did it help none of their patients? If none were helped, this would seem to be an unusual group from patients I've heard from. Did the "eminent neurologists" make any attempt to sub-group the patients? From what I have heard, most neurologists in the UK are not that interested in CFS so I feel these are valid points to raise. At the main international conference for CFS, a poster demonstrated that in South Korean CFS patients IVIg improved kidney function[6]. The same researcher also reported a positive outcome for cognitive function. These are outcome measures that have not generally been used in trials of CBT for CFS. Was the following study[7] looked at: "Antibodies against Epstein- Barr virus, associated with antibody dependent cytotoxic cell activity, were found to be present in diminished titer in 20 of 22 patients tested with chronic mononucleosis syndrome (CMS). Gamma globulin was shown to improve symptoms in 53% of the patients treated, compared with 32% of placebo injections. 89.5% of 57 patients treated with a gamma globulin treatment program remained in the treatment program because of relief of symptoms, and only four patients dropped out because there was no relief of symptoms or side effects. Four patients experienced complete relief of symptoms following a variable length treatment program. It would appear that intramuscular gamma globulin treatment is efficacious in the treatment of CMS and that the average interval between treatments is three weeks." "Chronic mononucleosis syndrome" would generally be called CFS these days. I have just been reading the minutes of the last (US) Chronic Fatigue Syndrome Advisory Committee (CFSAC) meeting[8]. The CFSAC is a federal US committee which advises the Health and Human Services Secretary on matters relating to CFS. Dr. James Oleske, chairman of the committee mentioned his experiences of IVIg: "I got involved with CFS mainly because I was studying very severe EBV patients and post-EBV people who were having some clear and defined immunodeficiencies. I was involved in a clinical trial to see if IV gammoglobulin helped them. The data I have is on a much more infectious disease-driven group than Dr. Jason's." [..] "There are a number of investigational therapies that I don't think we've done much with because we haven't had a clinical trial program where we can enroll patients from multiple sites. The numbers game becomes very important. I can tell you that immunoglobulin helps patients who have subclass deficiency and recurring pulmonary infections" [..] "I also had analyzed the kids on gammaglobulin. I can't publish this data because when I submitted it, most of the people said, "What are your criteria for diagnosis?" I thought I would also mention this successful double-blind, placebo- controlled trial[9] which had the following results and conclusions: "RESULTS: At the interview conducted by the physician 3 months after the final infusion, 10 of 23 (43%) immunoglobulin recipients and three of the 26 (12%) placebo recipients were assessed as having responded with a substantial reduction in their symptoms and recommencement of work, leisure, and social activities. The patients designated as having responded had improvement in physical, psychologic, and immunologic measures (p less than 0.01 for each). CONCLUSION: Immunomodulatory treatment with immunoglobulin is effective in a significant number of patients with CFS, a finding that supports the concept that an immunologic disturbance may be important in the pathogenesis of this disorder." In my last reply[1], I included information on the successful trial by Kerr and colleagues[10] on the CFS subgroup associated with Parvovirus B-19. A case-study[11] also found IVIg to be successful for a case of CFS associated with Parvovirus B19. Given this information, I hope for the next edition of the guidelines, serious consideration will be given as to whether it would be better to put CFS in the grey indications group, rather than the black indications group. ["Grey indications are those for which the evidence base is weak, in many cases because the disease is rare; IVIg treatment should be considered on a case-by-case basis, prioritised against other competing demands." Black indications: "Indications for which IVIg is not recommended - The prescription of IVIg is not appropriate for the following conditions."] References: [1] Kindlon T. On what basis was it decided that Immunoglobulin was not suitable for CFS? http://www.bmj.com/cgi/eletters/337/oct20_2/a1831#203678 [2] Provan D et al. Clinical guidelines for the use of intravenous immunoglobulin. (1st edition) http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_080787.pdf [Last accessed: 2 Oct 2009] [3] Jason LA, Corradi K, Torres-Harding S, Taylor RR, King C. Chronic fatigue syndrome: the need for subtypes. Neuropsychol Rev. 2005 Mar;15(1):29-58. Review. PMID: 15929497 [4] Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue syndrome in adults. Cochrane Database of Systematic Reviews Issue 2. Art No.: CD001027. doi:10.1002/14651858. CD001027.pub2. [5] Roberts AD, Charler ML, Papadopoulos A, Wessely S, Chalder T, Cleare AJ. Does hypocortisolism predict a poor response to cognitive behavioural therapy in chronic fatigue syndrome? Psychol Med. 2009 Jul 17:1-8. [Epub ahead of print] PMID: 19607750 [6] Park T. Improved renal function in CFS patients with IV immunoglobulin treatment. Poster Presentation, 9th International IACFS/ME Research and Clinical Conference, March 2009. [7] Dubois RE. Gamma globulin therapy for chronic mononucleosis syndrome. AIDS Research 1986; 2(1): 191-5. [8] Minutes of the CFSAC Meeting, May 2009. US Dept of Health & Human Services website: http://www.hhs.gov/advcomcfs/meetings/minutes/cfsac052709min.pdf [Last accessed: 2 Oct 2009] [9] Lloyd A, Hickie I, Wakefield D, Boughton CR. A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. American Journal of Medicine 1990; 89: 561-68. [10] Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous immunoglobulin therapy in 3 cases of parvovirus B19 -associated chronic fatigue syndrome. Clin Infect Dis. 2003 May 1;36(9):e100-6 [11] Jacobson SK, Daly JS, Thorne GM, McIntosh K. Chronic parvovirus B19 infection resulting in chronic fatigue syndrome: case history and review. Clin Infect Dis. 1997 Jun;24(6):1048-51. Competing interests: None declared |
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