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Winter 2004 

Big Picture of CFIDS Emerges
Wichita study's breadth alters government and scientific view of illness
By Vicki Walker

Even after more than 20 years of study, the "big picture" of chronic fatigue and immune dysfunction syndrome (CFIDS) has been absent from research, as scientists have narrowly focused on one or two hypotheses at a time.

The main reason is financial: research dollars for CFIDS have been paltry and comprehensive studies are extremely expensive. Ironically, the 1999 federal inquiry into misspending of CFIDS funds at the U.S. Centers for Disease Control and Prevention (CDC), and the subsequent restoration of $12.9 million to the agency's CFIDS program, made it possible for CDC to launch the most expansive study yet.

In 1997, CDC began calling 56,154 residents of Wichita, Kan. , asking if any household member was experiencing fatigue or tiredness lasting more than one month. Those who responded affirmatively underwent an extensive screening questionnaire. People who seemed likely to have CFIDS (and a group of healthy controls) saw a study doctor for an extensive medical workup. Those who met the case definition for chronic fatigue syndrome (CFS) and a sample of healthy controls were invited back to the clinic annually to provide data on the course of CFIDS.

This study has produced a vast amount of information that has improved understanding of CFIDS. Most important, it involves people who are not generally part of CFIDS research. Since most had not been previously diagnosed with CFIDS, they would never have been studied otherwise. Most prior research has used patients in CFIDS specialty clinics, who are likely sicker and more affluent than people with CFIDS in the general population.

CDC's previously published results from the Wichita study include improved estimates of the prevalence of CFIDS ¡ª which rose from early guesses of four to eight per 100,000 to CDC's current 235 per 100,000 (nearly half a million American adults) - and the disturbing fact that only 16 percent of people who have CFIDS are diagnosed. In the past four months, CDC has published four papers presenting findings from the Wichita study. All of the articles summarized below are available in "open access" journals, meaning that anyone can read the entire paper on the Web. URLs for each article are provided at the end of each summary. CDC researchers chose to publish in these journals to expedite the release of this data; conventional journals often take a year or more to publish findings.

Relapses and remissions are common
While CFIDS has long been considered a fluctuating illness, little hard data to back this up has been available. At each annual follow-up visit the CDC researchers classified each subject as having: a) CFS (meets all 1994 CFS criteria); b) partial remission (absence of fatigue, rest improves fatigue, fatigue doesn't interfere with activities, or fewer than four of eight case-defining symptoms; c) total remission (none of the case-defining criteria); or d) an exclusionary condition (permanent or temporary condition that precludes a CFS diagnosis).

Of the 65 CFS subjects who participated, 56.9 percent were classified in the total or partial remission categories at one or more follow-up visits, but only 22.5 percent sustained partial and 10 percent total remission over two or more study periods. At any follow-up visit only 20¨C33 percent remained in the CFS state and only 7.5 percent remained in the CFS state at two consecutive evaluation visits. Those who had been ill fewer than two years or who had fewer symptoms at the initial evaluation were slightly more likely to have remissions.

These data clearly show that people with CFS cycle in and out of the "CFS state" (as outlined in the 1994 case definition) at irregular intervals. More than half of those who said they had a reduction in fatigue since their last evaluation stated they had at least six periods of remission in the last year. No particular treatment seemed to be associated with remission.

One weakness of the study is that the only people who were included were those who met research definition criteria at the initial clinical evaluation; people who were in a temporary remission at the first clinic visit were not part of the study. The investigators also point out that clinicians likely wouldn't use such conservative criteria to diagnose CFS; most of the people probably would have continued to have a CFS diagnosis through their periods of remission.

Other interesting findings were that 31 percent had been previously diagnosed with depression, but only 17 percent tested positive for a lifetime major depressive disorder. Twenty-three percent were later diagnosed with exclusionary conditions - mainly sleep disorders, major depression with melancholia and inflammatory bowel disease. The most common symptoms were sleep-related (unrefreshing sleep and problems falling asleep). More than 60 percent were unemployed, but only 17 percent attributed unemployment to their fatiguing illness.

Reference: Nisenbaum R, Jones JF, Unger ER, Reyes M, Reeves WC. A population-based study of the clinical course of chronic fatigue syndrome. Health and Quality of Life Outcomes 2003,1:49. www.hqlo.com/content/1/1/49

CFS as serious as other medical conditions
People with CFS are as impaired as people with medical conditions such as cancer, multiple sclerosis and AIDS.

Fatigued people in Wichita were classified into various categories, based upon their symptoms and medical history. One of the categories - "explained syndromic fatigue" - included people who would have met the full CFS criteria, except they had a medical or psychiatric condition which precluded the diagnosis. These included cancer within five years, emphysema, AIDS, lupus, multiple sclerosis, cardiovascular disease within two years, chronic hepatitis, major surgery within the past year, schizophrenia and substance abuse within five years of onset.

People with CFS and explained syndromic fatigue had similar levels of impairment in physical, social and recreational functioning, underscoring the fact that people with CFS are as impaired as people with better-known and -accepted conditions.

One difference between these groups was in employment: 40 percent of explained syndromic fatigue subjects reported being unemployed due to their illness, while only 15 percent of CFS subjects reported the same. (The 15 percent figure differs from the 17 percent in the previous study because only 43 CFS subjects data were included in this paper, compared to 65 in the previous one.) The investigators believe this difference may be due to the relative difficulty of securing disability benefits for CFS compared to better-accepted conditions. The CFS subjects may continue working because they do not believe there is an alternative. Also, since most of the CFS subjects had not been previously diagnosed, they likely did not have a basis for applying for disability benefits.

Reference: Solomon L, Nisenbaum R, Reyes M, Papanicolaou DA, Reeves WC. Functional status of persons with chronic fatigue syndrome in the Wichita, Kansas, population. Health and Quality of Life Outcomes 2003;1:48. www.hqlo.com/content/1/1/48

PWCs use more medications
People with CFS (PWCs) use more medications and nutritional supplements than healthy people. Pain relievers and vitamins/ supplements were the most common types of drugs used by both groups, but the CFS subjects used more of them. The 90 CFS subjects (the majority of whom were not diagnosed before they were contacted for the study) used a median of five drugs each, while the 63 healthy controls used a median of two drugs each.

The CFS subjects were more likely than the healthy controls to use pain relievers, supplements/ vitamins, hormones, antidepressants, gastrointestinal agents, central nervous system drugs and benzodiazepines.

The researchers did not ask why each product was used, so they could not explain the reasons for increased medication and supplement use. However, it does underscore CFS patients' greater need for symptom relief.

Reference: Jones JF, Nisenbaum R, Reeves WC. Medication use by persons with chronic fatigue syndrome: results of a randomized telephone survey in Wichita, Kansas. Health and Quality of Life Outcomes 2003,1:74 www.hqlo.com/content/1/1/74

Genes differ in sudden and gradual onset PWCs
Female CFS subjects with sudden onset (developing within one week) have a different genetic profile than those with gradual onset (developing over more than a month). The CDC researchers examined 3,800 genes in 23 female CFS patients and found that the sudden onset group had 117 genes that were expressed differently from those with gradual onset. The main differences were in metabolism and RNA processing genes.

The researchers did not compare the CFS subjects with healthy controls, so it is unknown which group most differs from normal.

This study supports prior research suggesting that onset type may be an important clue to the heterogeneity of the CFS population. DeLuca, et al, reported that sudden onset CFS was more likely to develop following a viral or bacterial infection and Mawle, et al, reported that gradual onset CFS was associated with a greater number of stressful life events in the year prior to onset.

Reference: Whistler T, Unger ER, Nisenbaum R, Vernon SD. Integration of gene expression, clinical and epidemiologic data to characterize chronic fatigue syndrome. Journal of Translational Medicine 2003,1:10. www.translational-medicine.com/content/1/1/10

Tip of the iceberg
The information CDC has published to date is only a small portion of the data collected from the multiyear study. CDC is starting to analyze data from the most intensive segment of the study: a two-day hospital stay which included neuroendocrine, immune and autonomic nervous system tests; sleep studies; memory and information processing tests; and stress and psychological tests.

Approximately 400 people with CFS, severe chronic fatigue, explained syndromic fatigue or no fatigue were invited to participate in this comprehensive testing battery. Once analysis is completed, this portion of the study should provide a wealth of information about the biology of CFS. (For more on the CDC research, see the Winter 2003 Chronicle article on the subject at  http://www.cfids.org/archives/2003/2003-1-article01.asp