Intravenous immunoglobulin

Intravenous immunoglobulin (IVIG) is a proposed treatment for chronic fatigue syndrome.

Evidence
There has been inconsistent evidence for the use of IVIG in the treatment of ME or CFS. This may be due to the heterogeneity of triggers and immune system involvement in the ME/CFS population.

The American Journal of Medicine published two studies with different conclusions following each other in the November 1990 issue. The two studies were done in different countries and neither report the case definitions used to identify patients. The study with positive results used a dose twice that as the study with negative results. Following are the abstracts.

Positive results
"METHOD: Forty-nine patients (40 with abnormal cell-mediated immunity) participated in a randomized, double-blind, placebo-controlled trial to determine the effectiveness of high-dose intravenously administered immunoglobulin G. The patients received three intravenous infusions of a placebo solution or immunoglobulin at a dose of 2 g/kg/month. Assessment of the severity of symptoms and associated disability, both before and after treatment, was completed at detailed interviews by a physician and psychiatrist, who were unaware of the treatment status. In addition, any change in physical symptoms and functional capacity was recorded using visual analogue scales, while changes in psychologic morbidity were assessed using patient-rated indices of depression. Cell-mediated immunity was evaluated by T-cell subset analysis, delayed-type hypersensitivity skin testing, and lymphocyte transformation with phytohemagglutinin. 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."
 * 1990, A double-blind, placebo-controlled trial of intravenous immunoglobulin therapy in patients with chronic fatigue syndrome. Done by the Department of Infectious Diseases, Prince Henry Hospital, Sydney, Australia.

Negative results
"METHODS: Thirty patients with CFS were enrolled in a double-blind, placebo-controlled trial of IV IgG. The treatment regimen consisted of IV IgG (1 g/kg) or intravenous placebo (1% albumin solution) administered every 30 days for 6 months. Participants completed a self-assessment form prior to each of the six treatments, which was used to measure severity of symptoms, functional status, and health perceptions. Patients were also asked to report adverse experiences defined as worsening of symptoms occurring within 48 hours of each treatment. RESULTS: Twenty-eight patients completed the trial. At baseline, all 28 patients complained of moderate to severe fatigue, and measures of social functioning and health perceptions showed marked impairment. Low levels of IgG1 were found in 12 (42.9%), and 18 (64.3%) had low levels of IgG3. At the end of the study, no significant therapeutic benefit could be detected in terms of symptom amelioration or improvement in functional status, despite restoration of IgG1 levels to a normal range. Major adverse experiences were observed in 20% of both the IV IgG and placebo groups. CONCLUSION: The results of this study indicate that IV IgG is unlikely to be of clinical benefit in CFS.
 * 1990, A controlled trial of intravenous immunoglobulin G in chronic fatigue syndrome. Done by the Department of Medicine, Hennepin County Medical Center, Minneapolis, Minnesota.

Other Positive Studies

 * 2008, Tae Park, MD, presented his study about IVIG for ME/CFS patients at the 3rd Invest in ME International ME Conference. He checked the Glomerular filtration rate (GFR) in 125 ME/CFS patients who met the Fukuda criteria by measuring s-creatinine clearance with cockcroft-auld formula. "We found there were significant renal blood flow improvements in 60 patients (50%) with IVIG treatment...the improvement of renal blood flow is between 35% and 60% of previous GFR. These findings of improved renal blood flow may be evidence of improved cerebral blood flow...[and] may explain the improvement of cognitive function and other symptoms of ME/CFS patients with IVIG treatments."


 * 2003, "Successful Intravenous Immunoglobulin Therapy in 3 Cases of Parvovirus B19-Associated Chronic Fatigue Syndrome""'ABSTRACT: 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.'"


 * 1999, "Five-Year Follow-Up of Young People with Chronic Fatigue Syndrome Following the Double Blind Randomised Controlled Intravenous Gammaglobulin Trial."'Summary: Three and 5 year follow-up studies of eighty-nine young people with Chronic Fatigue Syndrome who completed a double blind randomised controlled trial of intravenous gammaglobulin has been conducted to determine whether the improvement following the intravenous gammaglobulin was sustained...Follow-up data were obtained on 86 of 89 after the study concluded...There was no persistent deterioration in function related to CFS in any young person. Four had reported recurrence of symptoms lasting 3-8 months and again improved. Others remained ‘improved’ or continued to improve...Seventeen per cent of those who responded were still moderately unwell with another 23% ‘not back to normal yet.’ Sixty per cent of participants considered they were ‘well’ at the last follow-up with 45% scoring 10/10...There was no deterioration in overall function over the 5 years following participation in the gammaglobulin trial, and young people continued to improve although a significant number were still disabled.'"


 * 1997, "Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents." Done at the Department of Paediatrics, University of Melbourne Royal Children's Hospital, Victoria, Australia. "'ABSTRACT: A double blind randomized controlled trial was conducted in 71 adolescents aged 11-18 years... [fulfilling] Fukuda et al., 1994...Three infusions of 1 gm/kg ... were given one month apart. The dummy solution was a 10% w/v maltose solution with 1% albumin of equivalent volume for weight. Efficacy was assessed by difference in a mean functional score including school attendance, school work, social activity and physical activity, between baseline, three months and six months after the final infusion. There was a significant mean functional improvement at the six month follow-up of 70 adolescents with Chronic Fatigue Syndrome of average duration 18 months. There was also a significant improvement for both groups from the beginning of the trial to the six month post infusion follow-up."


 * 1992, "Immunological and psychological dysfunction in patients receiving immunotherapy for chronic fatigue syndrome." Study done at Mood Disorders Unit, Prince Henry Hospital, Little Bay, Australia. "'ABSTRACT: Associations between immunological and psychological dysfunction in 33 patients with Chronic Fatigue Syndrome (CFS) were examined before and in response to treatment in a double blind, placebo-controlled trial of high dose intravenous immunoglobulin. Only those patients who received active immunotherapy demonstrated a consistent pattern of correlations between improvement in depressive symptoms and markers of cell-mediated immunity (CMI). This finding lends some support to the hypothesis that depressive symptoms in patients with CFS occur secondary to, or share a common pathophysiology with, immunological dysfunction. This pattern and the lack of strong associations between depression and immunological disturbance prior to treatment are less supportive of the view that CFS is primarily a form of depressive disorder or that immunological dysfunction in patients with CFS is secondary to concurrent depression."

Clinicians
Dr. Irving Spurr of the UK, "uses immunogloulin treatment extensively and has not done a RCT [randomized controlled trial] because he does not believe it is ethical to not offer it to clients. There are apparently problems with the use of IVIG in the UK and so he used IM."

Dr. John Chia of the US, uses IVIG in patients with both hypogammaglobulinemia and CFS.

Risks & safety
The risks of IGIV administration must be carefully weighed against potential benefits.

From 1-15% of people receiving IVIG infusions report mild self-limited symptoms, including: fever, chills, headache, myalgia, nausea and/or vomiting, low back pain, increased heart rate, blood pressure changes, shortness of breath and chest tightness. Onset of symptoms range from 30 minutes to several days post-infusion. The cause is thought to be from pathogen die-off and/or a mild allergic reaction. As with any blood product, severe and even fatal anaphylactoid reactions may occur. When using IVIG, the risk is in patients with anti-IgA antibodies of the IgG and IgE isotypes in the patient's serum, though this condition is extremely rare.

Reports of renal failure associated with IVIG occur in less than 1% of cases. Caution is urged for those patients with pre-existing renal insufficiency.

One case study recorded a paradoxical effect where IVIG administration increased the replication of Parvovirus B19, a pathogen associated with CFS.

Costs & availability
IVIG for ME/CFS is considered an off-use or non-FDA approved treatment. As a result, few physicians prescribe it and insurance companies will not cover it, unless a co-morbid condition that merits IVIG exists. The estimated out of pocket cost in the U.S. for a four dose course of IVIG for a 70 kg person at 2 g/kg could cost $25,000-$26,000.

List of studies

 * Paradoxical response to intravenous immunoglobulin in a case of Parvovirus B19-associated chronic fatigue syndrome, Attard, Luciano et al.Journal of Clinical Virology, Volume 62 , 54 - 57