by Vincent RacanielloThursday, November 24, 2011 at 06:45 AM EST
Note: This account draws from interviews, a close reading of a fractionof the 4608 epidemiologic studies that pop up (as of today; yesterday it was4606) on a PubMed search for “chronic fatigue syndrome,” and a review of manypages of government documents–in particular the minutes and testimony frommeetings of the Chronic Fatigue Syndrome Advisory Committee to the U.S.Department of Health and Human Services, one of many such panels established toprovide guidance to federal health officials. not much here will be a surpriseto anyone who has read the better ME/CFS blogs, or Hillary Johnson’sauthoritative and prodigiously researched 1996 account, Osler’s Web: Inside the Labyrinth of theChronic Fatigue Syndrome Epidemic. some readers might know that I havewritten a number of articles on chronic fatigue syndrome as a freelancecontributor to The new YorkTimes, so I want to be clear: The Times has nothing to do with thispiece. I want to thank Professor Racaniello for letting me invade his space topost this very long story.
David Tuller is coordinator of a new concurrent masters degree in public health and journalism at UCBerkeley. he was a guest on TWiV119.
In the early 1990s, Mary Schweitzer, a history professor at VillanovaUniversity near Philadelphia, suffered through successive bouts ofsickness—mononucleosis associated with Epstein-Barr virus, a stomachparasite, repeated episodes of bronchitis. one day, while reviewing studentexams in her office, she slumped over and blacked out. not long after, shereceived a diagnosis of chronic fatigue syndrome.
In written testimony to a federal advisory committee a few years ago, Dr.Schweitzer described how disabled she eventually became: “On a bad day, I wouldnever get up at all, or would lie in bed curled up under the covers…Iexperienced pain behind my eyes and in the back of my neck. It felt as ifsomebody had hit me in the back of the head with a baseball bat, and someoneelse was trying to unscrew my eyeballs with a pair of pliers.”
Over the years, Dr. Schweitzer has tested positive for multiple viruses. Sheexperiences severe lapses in memory, concentration and other cognitive skills.She suffers from “neurally mediated hypotension,” a form of low blood pressurearising from nerve dysfunction, which causes nausea, loss of balance, andfainting. Her muscle and joint pain can be intense, and she frequently requiresa wheelchair. Her white blood cell counts have been way off; her immune systemis often out of whack. She left her position at Villanova because of disabilityand has been unable to work most of the years since.
Like others with chronic fatigue syndrome, Dr. Schweitzer is used to havingher illness ignored, mocked or treated as a manifestation of trauma, depressionor hypochondria—not only by doctors, colleagues and strangers but byfriends, family members and federal researchers, too. So when the U.S. Centersfor Disease Control and Prevention reported last year that people with chronicfatigue syndrome are more likely to suffer from “maladaptive personalityfeatures”—in particular from “higher scores on neuroticism” and higherrates of “paranoid, schizoid, avoidant, obsessive-compulsive and depressivepersonality disorders”—Dr. Schweitzer dismissed the research as”incredibly stupid” but “not surprising.” In another recent study, the CDC hadreported—also incredibly stupidly, from Dr. Schweitzer’sperspective–that childhood trauma, such as sexual or emotional abuse, was a”an important risk factor” for the illness.
For Dr. Schweitzer, other patients and advocates, and much if not all of thenon-CDC research community involved with the illness, those two studiessymbolize much of what has gone wrong with the agency’s research program onchronic fatigue syndrome. as the country’s leading public health organization,the CDC has enjoyed remarkable success in the fight against many diseases. Butits history with chronic fatigue syndrome, commonly called CFS, is a matter ofbitter–and ongoing—dispute.
“We’re talking about a million people who are really, really sick withsomething,” said Dr. Schweitzer, 61, in one of a series of recentconversations. “And we have been mistreated for years by people who areconvinced that it’s just personality disorders or stress or some behavior thatwe can change and miraculously be well. none of us want to be sick or are doingthis to ourselves.”
The CDC’s mandate is to investigate threats to the health and safety of thepopulation; develop ways to prevent, disable or mitigate those threats; anddisseminate key information to the public, policy-makers, health care providersand other audiences. given those varied responsibilities, the CDC’spronouncements about any topic—in this case, chronic fatiguesyndrome–exert an enormous impact on policy, clinical care, insurancereimbursement and public attitudes. Advocates say that when the agency reportsthat people with CFS suffer from paranoid personality disorder, the publicremembers the association, as do other scientists, government officials, healthcare providers, and insurance adjusters.
In fact, since the CDC first investigated an outbreak of a non-resolving,flu-like illness in the Lake Tahoe area in the mid-1980s, the agency’s CFSprogram has been marked by financial scandal, an epidemiologic strategyrejected as fatally flawed by the top researchers in the field, and the kind oftoxic relationship with much of the patient community that can undermine thetrust and cooperation needed for effective policy-making and public healthstrategies. on a more substantive level, over the past quarter-century, theCDC’s research program has yielded little or no actionable information aboutcauses, biomarkers, diagnostic tests, or pharmaceutical treatments. nor has theagency done much to track long-term outcomes–such as cancer rates, heartattacks and suicides–among people with the illness.
The reason for those failures, critics charge, is that the CDC has spentyears looking in the wrong places. Starting with its 1988 report on theillness, they say, the agency has downplayed or dismissed abundant evidencethat CFS is an organic disease, or cluster of diseases, characterized by severeimmune-system and neurological dysfunctions as well as the frequent presence ofmultiple viral infections. Instead, say the critics, the agency has focusedmajor resources on investigating proposed psychiatric and trauma-relatedfactors and associations–the personality disorder and trauma studies werepublished, respectively, in the journals Psychotherapy andPsychosomatics and Archives of General Psychiatry–even thoughstress and trauma make people more vulnerable to any number of healthconditions.
Moreover, they charge, the CDC’s website on the illness has long been a fontof misinformation and has been routinely used by insurance companies to denylegitimate claims for tests ordered by doctors. (After years of complaints frompatients and doctors, a paragraph that dismissed the usefulness of many tests,including those for various infectious agents, was finally changed this month.)Critics also note that the CDC website does not incorporate much clinicalexpertise from doctors who have treated patients for years, but it doeshighlight a behavioral form of treatment—a gradual increase in exercise,known as “graded exercise therapy”–that is widely discredited in the CFScommunity. Patient surveys and anecdotal testimony, as well as an increasinglyrobust body of research, suggest that the therapy might cause severe relapsesin CFS patients by encouraging over-exertion.
“The CDC has never taken chronic fatigue syndrome seriously,” said SanFrancisco writer and former psychotherapist Michael Allen, who suffered asevere flu in the early 1990s and has never recovered his health. “They pay lipservice to it being a serious physical illness, but in their hearts they thinkit’s just a form of mental illness.”
Much of the anger for the CDC’s perceived failings over the years hastargeted Dr. William Reeves, an epidemiologist and architect of the CFSresearch program from 1989 until his abrupt move last year to another divisionof the agency. With his gruff and sometimes dismissive manner, Dr. Reeves wasnever popular with the patient community, which came to view him as hostile tothe search for viral or other organic causes of the illness; many non-CDCresearchers echoed that complaint. when it emerged in the late 1990s that theagency had been diverting funds designated for CFS to other programs and thenlying to Congress about it, Dr. Reeves—who was in charge of the programwhile the financial irregularities were taking place–sought and receivedwhistle-blower protection.
Dr. Reeves also enraged the patient community by his refusal to considerchanging the much-hated name of the disease—a name endorsed by the CDC inits 1988 paper and aggressively promoted in a public awareness campaign theagency launched in the mid-2000s. Patients say the name, like the term‘yuppie flu,’ reinforces stereotypes that they are a bunch ofself-entitled whiners and malingerers and that the illness itself is a form ofhysteria, the latter-day version of the Victorian malady known as”neurasthenia.” That’s why many doctors, researchers and patients have longpromoted a less-stigmatizing clinical name for the illness that predated theselection of chronic fatigue syndrome: “myalgic encephalomyelitis,” or ME,which means “muscle pain with inflammation of the central nervous system.”
It is not possible to exaggerate how much patients despise the name andbelieve it has hindered public understanding—and how much they fault theCDC and Dr. Reeves for championing it. “If they’d hired a focus group to comeup with a name that screams ‘silly’ and ‘meaningless,’ theycouldn’t have done a better job than ‘chronic fatigue syndrome,’” saidDr. Schweitzer.
In an interview with The new York Times earlier this year,bestselling author Laura Hillenbrand (Seabiscuit, Unbroken),who has lived with CFS for decades, called the name of the illness”condescending” and “so grossly misleading.” She added: “The average person whohas this disease, before they got it, we were not lazy people; it’s verytypical that people were Type a and hard, hard workers… Fatigue is what weexperience, but it is what a match is to an atomic bomb. This disease leavespeople bedridden. I’ve gone through phases where I couldn’t roll over in bed. Icouldn’t speak. to have it called ‘fatigue’ is a gross misnomer.”
After Dr. Reeves unveiled a revised epidemiologic method for identifyingpeople with CFS, the CDC estimated in 2007 that there were 4 million people inthe U.S. with the illness—a remarkable ten-fold increase over theprevious CDC estimate in 2003. Other experts dismissed this dramatic rise as anartifact of the agency’s poor epidemiology. Subsequent research reported thatthe new CDC approach misclassified people with primary depression as havingchronic fatigue syndrome, when they did not; that kind of misclassificationcould easily lead to increased prevalence rates as well as false and possiblyharmful research results.
In the late 2000s, leading patient, advocacy and scientific organizationsengaged in an increasingly public revolt against Dr. Reeves’ leadership. InJanuary of 2010, the CDC abruptly appointed him as senior advisor for mentalhealth surveillance in another part of the agency. Dr. Elizabeth Unger, anexpert on human papillomavirus who had worked with Dr. Reeves for years, wasnamed to replace him—first temporarily, then permanently–as chief of theChronic Viral Diseases Branch, which currently houses the chronic fatiguesyndrome program.
Now, almost two years after Dr. Reeves’ departure, advocates and researcherssay they have seen a shift in tone—some believe it is genuine, othersnot–but so far little change in substance. (Requests to interview both Dr.Reeves and Dr. Unger, conveyed through the CDC media office, were declined;however, with a press officer acting as intermediary, Dr. Unger responded toquestions via e-mail.)
“I’m committed to continuing an aggressive program to address the needs ofCFS patients and families for quality medical care and to move CFS into themainstream of public health,” wrote Dr. Unger. She added that the agency isdeveloping new materials about CFS for medical and health care professionals,and has contracted for studies that will help clarify questions about how toidentify the illness.
Dr. Unger has made a point of meeting with patient, advocacy and scientificorganizations. In contrast to her predecessor, she has impressed some advocatesand researchers with her willingness to listen to their concerns and seek outjoint initiatives. But reflecting a widespread view, one activist (whopreferred to remain anonymous) said that “overall, I do not feel much haschanged under Dr. Unger…I do look forward to changing my mind, though, ifappropriate actions are taken.”
Another person with a long history of involvement in the CFS issue offered asimilar assessment, noting that Dr. Unger needs to do much more, and do it morequickly, to demonstrate that she’s pursuing a different approach. “I think shehas got a window of opportunity, but the patient community is only going togive her so long,” said this advocate. “She can throw off the Reeves mantle andmake a break with the past, or she can maintain the past. But there’s not amiddle ground here, and she’s got to make a decision.”
Kim McCleary, president and CEO of the CFIDS Association of America, theoldest organization on the illness, said she believes Dr. Unger “is trying torestore some credibility to the CDC’s program.” But, added McCleary, whoseorganization worked closely with Dr. Reeves for years but ultimately opposedhis leadership, “she’s not going to move quickly, she’s not going to doanything bold, she’s going to move pretty methodically along a linearpath.”
Although Dr. Reeves’ departure received little public notice, it was awatershed event for patients and advocates, many of whom blame the agency forthe prolonged lack of significant progress in CFS research. (They also blameyears of inadequate funding from the National Institutes of Health, but that’sanother long story; it is worth noting, however, that the NIH online databaseof spending by disease category indicates only $4 to $6 million allocatedannually for CFS in recent years, a small amount compared to other illnessesassociated with similar levels of morbidity. While the roles of the CDC and NIHcan overlap significantly, the NIH generally focuses more on basic researchinto disease processes than on epidemiology and the development of publichealth strategies and interventions.)
The personnel shift at the CDC also occurred during a volatile period in thescientific domain. In October 2009, the journal Science published aheadline-grabbing study that linked CFS to XMRV, a poorly understood mouseleukemia retrovirus. The finding thrilled the patient community because itappeared to offer a plausible explanation for the disease and to suggesttreatment possibilities. Although a second study found links between CFS and agroup of mouse leukemia retroviruses related to XMRV, other research has failedto support the proposed association. The Science report was partiallyretracted earlier this year, and most researchers now believe the initialfindings were an artifact of laboratory contamination. Results expected earlynext year from a large NIH-sponsored study should settle the XMRV issue,although not the issue of whether another retrovirus might eventually be linkedto cases of CFS.
(In the meantime, in a bizarre and unsettling turn of events, the seniorauthor of the original XMRV paper, Dr. Judy Mikovits, is engaged in a fiercelegal battle with her former employer, the Whittemore Peterson Institute forNeuro-Immune Disease, at the University of Nevada in Reno. The institutesponsored the XMRV research but has accused Dr. Mikovits, its erstwhile starscientist, of stealing laboratory notebooks and other materials—a chargeshe has denied. Public feuding between the institute and Dr. Mikovits ratchetedup as the hypothesis they jointly championed appeared to be falling apart. Theinstitute filed a lawsuit against her earlier this month; she has alsoapparently been charged with “possession of stolen property,” according to anews update in Science. last Friday, Dr. Mikovits was arrested inCalifornia as a “fugitive from justice” and spent the weekend in jail; she wasreleased on bail after a hearing on Tuesday.)
Nevertheless, the heightened focus on CFS during the past couple of yearshas brought the illness greater attention from a larger group of scientists,including many infectious disease experts who had not previously given it muchthought (e.g. the host of this blog, Columbia University virologist VincentRacaniello). Experts now believe that one or a combination of viral or otherinfections, or perhaps other physiologic insults such as environmental toxins,can trigger an immune response that never shuts itself off; the immune responseitself is likely the cause of many of the symptoms.
Dr. Racaniello said that when he used to question colleagues about chronicfatigue syndrome, they would argue that it was an imaginary illness. “Everytime I asked someone about it, they would say it doesn’t exist, it isn’t a realdisease, even as recently as the past year,” he said. “But once you startpaying attention and reading papers, this looks like a chronic or hyper-immuneactivation. These patients have a lot of signs that their immune systems arefiring almost constantly.”
According to this view, the revved up immune system is actually much lesseffective at controlling other infections, and studies have found associationsbetween CFS and a grab-bag of pathogens, including members of the herpesvirus,parvovirus, and enterovirus families. recent research from Norway has also lentsupport to the hypothesis that at least some people with CFS are suffering froma form of autoimmune disorder, perhaps triggered by one or multiple infections.Neurological impairments are also virtually always part of the complex; a studylast year in the journal PLoS one found that people with CFS and aform of Lyme disease have patterns of proteins in their cerebrospinal fluidthat clearly distinguish them from each other as well as from healthycontrols.
In many cases, additional research has failed to confirm associations fromprior studies. yet there is a reasonable epidemiologic explanation for suchdivergent results: Most experts believe that there are likely many sub-groupsor clusters of CFS patients, with a variety of infectious and possiblyenvironmental exposures; studies that don’t account for suchdistinctions—and most haven’t–are much less likely to reach consistentresults about causation or treatment. Moreover, different research groups haveused different methods of identifying people with chronic fatigue syndrome,making it even harder to compare findings across studies—a situation thatcan encourage speculation that the roots of the illness lie in patients’psyches.
“This ambiguity over definitions has made it difficult for researchers topinpoint a biological cause,” wrote Leonard Jason, a professor of communitypsychology at DePaul University in Chicago and an expert in CFS, in an essaypublished this year in The Wall Street Journal. “When investigatorscompare very different samples, it is difficult, if not impossible, toreplicate findings from one lab to another. and when consistent biologicalfindings do not emerge, investigators might inappropriately conclude that CFSis only a psychiatric problem.”
In any event, the most promising research into the disease has been takingplace not at the CDC or NIH but at academic medical centers; much of the newwork is being funded by private donors who have family members with CFS.Researchers from Stanford, Harvard, University of Miami, Columbia, and otherleading institutions are all engaged in innovative efforts focused onpathogenesis, diagnosis and treatment, and in particular on such issues asinfectious triggers, biological markers, and medical therapies.
Dr. Derek Enlander, a longtime CFS clinician in new York, recently helped tolaunch an ME/CFS research and treatment center at Mt. Sinai Hospital; hishighly regarded team hopes to explore genetic as well as other factors involvedin the illness. The center was founded with the aid of a $1 million privatedonation, said Dr. Enlander, adding that such outside funding allows the groupthe freedom to pursue promising avenues of investigation. “I believe that anindependent organization such as ours, which is not funded by the government oranswerable to the government, can be the leader in new research,” said Dr.Enlander.
The Role of Case Definitions
Chronic fatigue syndrome is estimated to afflict about one million people inthe U.S., although most remain undiagnosed. some patients improve over time orhave periods of better and worse health, but many remain disabled or evenhomebound for years. The symptoms include profound exhaustion, especiallyfollowing minimal exertion, as well as disordered sleep, cognitive impairment,sore throat, and swollen lymph nodes, among others. It is one of a number ofso-called “contested illnesses” that have emerged in recent decades to presentthorny dilemmas for public policy and medical care; others include chronic Lymedisease, Gulf War syndrome, fibromyalgia, and multiple chemicalsensitivity.
These conditions are characterized by shifting patterns of symptoms, a lackof agreed-upon biological markers and diagnostic tests, arguments over theinterpretation of evidence, and competing claims of scientific authority.Patients presenting with these illnesses can bedevil doctors, who want to helpbut have few proven tools at their disposal. They might or might not be willingto try unorthodox strategies; some doctors clearly take advantage of patientswho are desperate for relief. such contested illnesses impact millions ofpeople and their families, cost the U.S. billions in lost productivity, andconsume a significant chunk of health care resources—and yet remainpoorly understood. With so much at stake, they often emerge as societal andlegal battlegrounds, with patients, clinicians, researchers, insurers, healthofficials and government bureaucrats all seeking to influence and controldialogue, debate and policy.
This conflict often plays out in struggles over a critical epidemiologictool known as the “case definition”—a set of criteria for research orclinical use that ideally identifies all those who have a condition and screensout all those who don’t. Creating a case definition is easiest when adefinitive laboratory test exists, as with HIV or hepatitis C. With an illnesslike CFS that is identified through symptoms, devising a completely accuratecase definition is almost impossible; some people with the illness will alwaysfall outside the parameters of the case definition, and some who have someother condition, or nothing at all, will be misdiagnosed—or willself-diagnose–as having CFS. yet without a case definition that is as accurateas possible, researchers cannot achieve valid or reliable results.
“If you recognize something is happening, you need a case definition so youcan count it,” Andrew Moss, an emeritus professor of epidemiology at theUniversity of California, San Francisco, and an early AIDS investigator, toldme for an article I wrote about case definitions earlier this year. “You needto know whether the numbers are going up or down, or whether treatment andprevention work. and if you have a bad case definition, then it’s verydifficult to figure out what’s going on.”
Non-CDC researchers say the problem with the agency’s 2005 method foridentifying CFS cases is that it mistakenly classifies people with primarydepression as having chronic fatigue syndrome instead. Depression and CFS canresemble, overlap and interact with each other in multiple ways; patients withCFS may get very depressed about their situation, and depression often causesfatigue, as can many other ailments. So distinguishing chronic fatigue syndromefrom primary depression—in other words, depression that preceded andperhaps caused the fatigue—is important but tricky, and requires nuancedinstruments. In epidemiologic studies that conflate the two, treatments thatare known to be effective for depression could appear to be effective forchronic fatigue syndrome, even if they might not be.
A case in point is a treatment called “graded exercise therapy,” a slowincrease in exercise that has been promoted for CFS patients by the Britishpsychiatric, medical, and insurance establishments; it is also highlighted as atreatment option on the CDC’s website and educational materials.
There is no dispute that exercise can be a very effective treatment fordepression. But people with chronic fatigue syndrome generally suffer from adistinctive symptom known as “post-exertional malaise”—a disproportionatedepletion of energy following minimal activity that is not a typical feature ofdepression. (However, the word ‘malaise,’ like the word ‘fatigue,’is a complete misnomer; post-exertional malaise is much closer to a seriouscrash or relapse than a Victorian fainting spell.) an emerging field ofresearch—much of it taking place at the University of Utah and Universityof the Pacific in Stockton, California–indicates that people with CFS sufferfrom problems with oxygen consumption, energy production and muscle recovery.So it’s not surprising that increasing activity levels could lead in some ormany cases to a prolonged resurgence of their symptoms rather than theimprovement predicted by proponents of graded exercise therapy.
Patients with CFS are very familiar with post-exertional malaise. Manyreport having recovered for a period of time, then pushing themselves too hardand suffering a devastating set-back, repeating the cycle multiple times beforelearning to adjust their pace. when Mary Schweitzer experiences post-exertionalmalaise, she said, she loses her formidable communications skills.
“I get close to incoherent,” she wrote in a recent e-mail. “I can’t makesense, and nobody can make much sense out of what I say. I am used to it nowand try to make a joke out of it, but it’s sad.” as a result, she wrote, shehas learned what people with CFS call ‘envelope theory,’ based onpublished work from Dr. Jason’s research group at DePaul University: how toharness their energy by recognizing their limits, and not pushing beyond them.that approach is essentially the antithesis of graded exercise therapy.
“You learn what will bring on a crash–sitting upright at a restaurant, forexample–and you just don’t do it,” wrote Dr. Schweitzer. “You live in what wecall your ‘envelope.’ then if something special comes along like abirthday, you push the envelope, and if you get a push-back, you know you stillhave the same boundaries.”
Like Laura Hillenbrand, Mary Schweitzer is an author (although the book shewrote from her doctoral research at Johns Hopkins, Custom and Contract:Household, Government, and the Economy in Colonial Pennsylvania, hasundoubtedly never reached Seabiscuit-y heights in Amazon’s rankings).She grew up in Richmond, Virginia; boogied in the mud at Woodstock; wooed herfuture husband, Bob, with home-cooked lasagna (he was the teaching assistant inan economics course she as an undergraduate at Duke); and was teaching,conducting research, and raising two kids when CFS whacked her life upsidedown.
Dr. Schweitzer said she could never have managed through the years withoutthe support and devotion of her husband, a professor of finance and economicsat the University of Delaware. But she has also improved significantly onintermittent treatment with Ampligen, a drug that appears to be effective forsome people with CFS. The drug hasn’t been approved by the U.S. Food and DrugAdministration, but Dr. Schweitzer currently receives it as part of an ongoingclinical trial. She travels twice a week from her home in Delaware to herdoctor’s office in Manhattan for infusions of Ampligen; unlike in most clinicaltrials, she has to pay for the drug, which costs her $16,000 a year.
When off Ampligen, she has suffered major crashes; at one point severalyears ago, she tested positive for four herpesviruses—Epstein-Barr,cytomegalovirus, HHV-6A, and HHV-7—and Coxsackie B, an enterovirus.Whenever she can, she addresses public forums, in particular the twice-yearlymeetings of the Chronic Fatigue Syndrome Advisory Committee, one of manycommittees created to offer guidance to the U.S. Department of Health and HumanServices; she estimates that she has testified to date at thirty hearings,conferences or meetings. when she speaks, in a public forum or one-to-one, sheis articulate, passionate, loud, tender, demanding, funny and fierce. In one ofher many statements to the federal advisory committee, Dr. Schweitzer describedone of her severe relapses.
“I lost the ability to walk normally and we had to bring the wheelchair backup from the basement,” she wrote. “I dropped things, and when I tried to loadthe dishwasher I crashed one glass against another…It made no difference thatnow I knew the names of the various symptoms–ataxia, expressive aphasia,short-term memory loss, central auditory processing dysfunction, etc. my brainhad disappeared.”
The conflict over the nature and definition of CFS–between the CDC and thepatient community, as well as between the agency and other researchers–datesback to the initial investigations of an outbreak in Incline Village, Nevada,near Lake Tahoe, of a mysterious illness, possibly associated with Epstein-Barrvirus. The outbreak was one of many reports in the mid-80s of what was alreadybeing called “chronic Epstein-Barr syndrome” or “chronic mononucleosis.”(Epstein-Barr virus causes most cases of mononucleosis).
In its 1988 paper on the illness, a CDC-led team of researchers cast doubton the Epstein-Barr hypothesis and rechristened the phenomenon “chronic fatiguesyndrome” to discourage unproven assumptions about viral origins. (Ironically,because CFS began as a suspected viral illness, the research program hasremained housed in the agency’s viral section.) The paper proposed acomplicated case definition requiring six months of unexplained fatigue, pluseither six of eleven “symptom criteria” (mild fever, sore throat, painful lymphnodes, muscle weakness, muscle pain, prolonged fatigue post-exercise,headaches, joint pain, neuropsychological complaints, sleep disturbances, andsudden onset of the illness) and two of three “physical criteria” (fever, sorethroat, and palpable or tender lymph nodes, documented by a physician twice, atleast one month apart); or eight of the eleven symptom criteria, without thephysical criteria.
In retrospect, for many patients the CDC’s first big blunder was in notcalling the Tahoe illness myalgic encephalomyelitis in the first place. Benignmyalgic encephalomyelitis has long been recognized by the World HealthOrganization as a synonym for “postviral fatigue syndrome,” which is listed asa neurological illness. The term was coined to refer to a similar flu-likeoutbreak at a major London hospital in the 1950s (although “benign” has sincedropped out of common usage.) In practice, many patient and advocacy groups nowcombine the two terms as CFS/ME or ME/CFS, or use ME alone.
Dr. Reeves was not on hand for the original investigation, but joined theCDC in 1989 as chief of what was then called the Viral Exanthems andHerpesvirus Branch. Dr. Reeves received his B.a. in 1965 from the University ofCalifornia, Berkeley, where his father was a renowned expert in mosquito-borneillnesses and served as dean of Berkeley’s School of Public Health; he studiedmedicine at University of California, San Francisco, earned a masters inepidemiology at the University of Washington, and worked at a major medicalresearch center in Panama for a dozen years before joining the CDC in 1989.
A Harvard-led research team described the Tahoe outbreak in far more seriousterms than the 1988 CDC report: the patients, they reported in 1992 in theAnnals of Internal Medicine, had abnormal MRI brain scans, significantalterations in white blood cells counts and functioning, and signs of activeinfection with a recently discovered pathogen, HHV-6. The illness, they wrote,was likely a “chronic, immunologically mediated inflammatory process of thecentral nervous system.”
In a letter to the journal listing more than a dozen purportedmethodological flaws, the CDC—with Dr. Reeves as the leadauthor—dismissed the Harvard study and its findings in unusually bluntterms. “We conclude that the disease…described is not the chronic fatiguesyndrome or any other clinical entity and that they showed no association withactive HHV-6 replication,” wrote Dr. Reeves and his colleagues.
A pattern appeared to have been established. In a subsequent episode in theearly 1990s, chronicled in detail in Osler’s Web, the CDC failed toconfirm other researchers’ reports of a retroviral link to chronic fatiguesyndrome. These and other contradictory results gave rise on both sides toclaims and counter-claims and counter-counter-claims (etc.) of methodologicalflaws, unjustified assumptions, and other scientific sins of omission orcommission.
In the early 1990s, a CDC-led team reviewed the complex 1988 case definitionand published a revised and somewhat simplified version. according to these1994 guidelines, a diagnosis of CFS required the presence of six months ofdisabling, medically unexplained fatigue, along with at least four of eightother symptoms: impaired memory or concentration, disordered or unrestfulsleep, muscle pain, joint pain, headache, tender lymph nodes, sore throat, andpost-exertional malaise. Although the definition relied on self-reportedsymptoms rather than biological tests or standardized instruments to measurelevels of fatigue and disability, it soon became the most widely used set ofcriteria in both research and clinical settings.
The Financial Scandal
Two years after the CDC issued its 1994 case definition, Osler’sWeb was published to strong reviews. The book documented how the CDCroutinely diverted money slated for CFS research to other projects because oflack of concern about the illness. (The CDC did not officially comment on thebook at the time, according to a CDC spokeswoman.) Two years later, Dr. Reevesleveled similar charges against his superiors, noting that the CDC lied toCongress about how it spent CFS funding; he received whistleblowerprotection.
In his statement, he reported that, for example, in 1996 the agency spent$1.2 million for laboratory equipment and supplies for measles and polio andcharged it to the CFS account. In 1995, he reported, the agency charged the CFSprogram $2.6 million for funding spent on unrelated studies. he had, he stated”attempted to rectify this within CDC” before going public.
“I believe that CDC has intentionally misrepresented monies allocated to CFSresearch and I cannot ethically support this,” wrote Dr. Reeves in his publicstatement. “The misrepresentations involve systematically charging between$400,000 and $2 million incurred by unrelated activities to CFS between 1995-97and reporting to DHHS [Department of Health and Human Services], Congress andpatients that the monies were used for CFS research.”
A 1999 report from the inspector general of HHS found that of the $22.7million the CDC charged to its CFS program between 1995 and 1998, less thanhalf was clearly spent on the illness. The report noted: “CDC spent significantportions of CFS funds on the costs of other programs and activities unrelatedto CFS and failed to adequately document the relevance of other costs chargedto the CFS program…as a result of these inappropriate charges, CDC officialsprovided inaccurate information to Congress regarding the use of CFSfunds.”
The inspector general’s report found that $8.8 million was spent on non-CFSprojects and that the documentation on an additional $4.1 million was so poorthat it was impossible to determine whether they were used to support CFSresearch or not. even as the CDC shortchanged the CFS program, the reportnoted, it disregarded Congressional requests to support important researchinitiatives. as an example, the report noted that Congress had urged the CDC toexpand its surveillance of CFS among adolescents and to hire aneuroendocrinologist “to enable expansion of its research efforts and pursuepromising findings from other Federal agencies and the private sector.”
At the time of the inspector general’s report, however, the CDC had haltedan ongoing adolescent study and had not hired an endocrinologist—even asallocated money wasn’t being spent. The report noted: “Internalcorrespondence… indicated that delays were forced due to a ‘lack ofavailable funds.’ yet, we found that large portions of budgeted CFS funds hadbeen held in reserve by the Division Director during the year, and were notreleased until after the deadline for obligations had passed. Thus, whileimportant enhancements were not being implemented, more than $850,000 of FY1998 budgeted funds were never made available to the program.”
In the wake of the scandal, Dr. Reeves’ boss left his position; the agencyagreed to reform its accounting practices and restore more than $12 million tothe CFS program over the next several years. Although Dr. Reeves’ whistleblowerstatus effectively solidified his position at the CDC, his statement didn’tanswer all outstanding questions. given the revelations from Osler’sWeb in 1996, it seemed unlikely to many patients and advocates that keyofficials at the agency could have been unaware of accountingirregularities–especially since they apparently continued through 1998,according to the federal investigators.
A subsequent investigation in 2000 from the U.S. General Accounting Office(now called the Government Accountability Office) found that communicationbetween the CDC and the NIH about CFS research programs and priorities waspoor. The limited coordination, as well as the CDC misspending, had hamperedprogress in the search for answers to the illness, the investigatorsreported.
The financial scandal left many CFS advocates, patients and researchers witha lingering distrust toward the CDC. In the following years, however, some ofthe CDC’s work in chronic fatigue syndrome—funded by the millionsrestored to the budget–received praise.
In 2003, Dr. Reeves’ study of CFS in Wichita, Kansas, yielded a diseaseprevalence of 235 per 100,000 percent of the adult population, or about 400,000overall in the U.S. that figure was below the generally accepted estimate ofone million sufferers, derived from a community-based study in the Chicago areaby Dr. Jason’s research group at DePaul University. yet the new figure wasaccepted as far more accurate than the agency’s earlier estimates, fromresearch in the 1990s, that less than 20,000 people had the illness; thatresearch had been criticized for relying on doctors’ reports of patients withCFS, a far less effective epidemiologic method of assessing prevalence thancommunity-based surveys. The Wichita research also provided a sense of thesocietal burden of CFS; the CDC team reported that the illness cost the economy$9.1 billion a year in lost productivity, and people with CFS lost an average$20,000 annually in earnings.
Also praised was the CDC’s partnership with Australian researchers on astudy reporting that more than 10 percent of a cohort suffering from acuteviral illnesses went on to develop CFS–one of the agency’s few successfulefforts to document viral links. and in 2006, the CDC published—withgreat fanfare–a set of 14 studies in the journal Pharmacogenetics,which found significant variations in CFS patients of gene expression andactivity related to how the body handles and adapts to physical and emotionalchallenges and stress.
Much of the research focused on genes associated with thehypothalamic-pituitary-adrenal axis, which regulates the body’s stressresponses, among other functions. at a press conference introducing thestudies, Dr. Reeves outlined his understanding of the illness: “The workinghypothesis is that the HPA axis and the brain is a plastic organ which changesits actual physical architecture depending on stresses accumulated over thelifetime,” he explained. “So as people experience stress, and that can bechildhood abuse, it can be childhood infections, it can be multipleinjuries…to some extent the genetics determine how you are going to react tothem, they determine how your allostatic load [a stress-related indicator] mayaccumulate, and more importantly, they actually determine your subsequentreaction to stress applied at a later time during the lifespan.”
Dr. Reeves himself declared the illness to be a matter of great publichealth concern and expressed empathy for patients. “People with CFS are as sickand as functionally impaired as someone with AIDS, with breast cancer, withchronic obstructive pulmonary disease,” he told me in 2007, when I wrote myfirst story about the disease for The new York Times.
Some advocates welcomed the genetics studies for providing evidence that theillness had a biological basis and was not a figment of patients’ imaginations.But a news article in Science about the Pharmacogeneticspapers reported that other scientists had raised serious methodologicalquestions about the CDC’s approach, with one prominent researcher calling thenew findings “meaningless.” Others in the CFS community feared that the focuson stress and trauma as major factors left the door open for the CDC to focuson a wide range of psychologically and behaviorally oriented approaches in thesearch for both causes and treatments—and they note the recentpersonality disorder and childhood abuse studies as proof of theirconcerns.
The Rejected Empiric Criteria
Other CDC efforts, such as the multi-million-dollar public awarenesscampaign to brand the name “chronic fatigue syndrome,” dismayed much of thepatient and advocacy community, given ongoing and fervent attempts to have theillness officially renamed ME. and in a highly controversial move, Dr. Reevesspearheaded in 2005 the creation of the new, purportedly more precise method ofidentifying patients; critics feared the approach would wreak havoc withepidemiologic studies by mixing a lot of people with depression but not CFSinto samples of people all presumed to have chronic fatigue syndrome.
During the 2000s, researchers—including many clinicians who actuallytreated patients and understood how seriously ill they could be—hadcontinued to be dissatisfied with the 1994 case definition, which they feltimprecisely described the condition. for one thing, the definition allowed forbut did not require the presence of post-exertional malaise (reminder: read”relapse” or “crash,” rather than “malaise”). yet it was increasingly apparentthat post-exertional malaise, and not fatigue alone, was a cardinal symptom formany if not most patients, and one that clearly helped distinguish CFS fromprimary depression, as well as other chronic illnesses. The CDC definition alsoallowed for but did not require the presence of cognitive and neurologicalproblems, although these appeared to afflict almost everyone with thecondition.
Other research groups were using their own case definitions, making it hardto compare results. The “Oxford criteria” developed in great Britain requiredonly the presence of six months of disabling fatigue; that single-symptomcriterion was criticized as so broad that it was likely to identify many peoplewith primary depression rather than CFS. a more detailed 2003 case definitiondeveloped in Canada focused on post-exertional malaise as a cardinal symptom ofwhat it called ME/CFS. Required symptoms also included disordered sleep, pain,and neurologic symptoms, as well as signs of dysfunction in the immune,endocrine and autonomic nervous systems.
Earlier this year, a team of top researchers—not surprisingly, withoutany participation from the CDC–published a new “international consensus” casedefinition, which adopted the name myalgic encephalomyelitis and abandonedchronic fatigue syndrome altogether. Using the Canadian definition as ajumping-off point, the new international definition also dropped the constructof “fatigue” in favor of requiring post-exertional malaise, which they renamed”post-exertional neuroimmune exhaustion.” Other required symptoms includeneurological and energy production impairments.
In contrast, the 2005 effort by the CDC to “operationalize” the earlier 1994case definition–by introducing standardized questionnaires and measurementscales to assess levels of fatigue and functional impairment—has found nosupport outside the CDC itself. In suggesting specific instruments and scales,Dr. Reeves and his research team proposed cut-off points to representsufficient grounds for identifying CFS.
Yet when the CDC researchers applied these new “empiric” criteria, as theycalled them, to a population in Atlanta in 2007, they found a prevalence of2.54 percent of the adult population. Extrapolated nationwide, that meant thatfour million people—in other words, ten times the CDC estimate from itsWichita research just four years earlier, and four times the widely acceptedfigure of about one million—had the illness. Dr. Reeves and hisco-authors defended the new numbers, attributing the increased prevalenceestimates to a broad sampling strategy and “application of more sensitive andspecific measures of the CFS diagnostic parameters.”
Others outside the CDC dismissed the new numbers as absurdly inflated andargued that the empiric criteria, like the Oxford criteria but unlike the 2003Canadian case definition, blurred and expanded rather than clarified thedisease boundaries. While some advocates believed the increased estimates wouldfocus more attention on the illness and should therefore be embraced, manyothers—including leading epidemiologists–believed that the expandedcategory could make it harder to isolate physiological correlates; thatfailure, in turn, would make it more likely that others would continue toperceive it to be largely a psychiatric illness.
One study from Dr. Jason’s research group at DePaul University, frequentlycited by advocates, found that 38 percent of a group suffering from majordepression but not chronic fatigue syndrome were misdiagnosed as having CFSusing the new empiric case definition. The researchers reported that thescales, measurements and cut-off points indicated by the CDC group did notsufficiently distinguish between emotional and physiological sources of fatigueand disability; in other words, someone could be identified as having CFS underthe new method solely because of fatigue or disability arising largely frompsychological causes, such as depression.
“Given the CDC’s stature and respect in the scientific world, this newdefinition might be widely used by investigators and clinicians,” wrote Dr.Jason and his co-authors. “This might result in the erroneous inclusion ofpeople with primary psychiatric conditions in CFS samples, with detrimentalconsequences for the interpretation of epidemiologic, etiologic, and treatmentefficacy findings for people with CFS.” The authors also noted pointedly thatthe population prevalence for CFS calculated using the empiric definition wasclose to that for major depressive disorders.
Although the empiric case definition was published six years ago, it has notfound any favor outside the CDC, raising questions about the comparability ofCDC data derived from its use to results from other studies. Dr. Unger wrote inher e-mail response that she knew of no other researchers who had adopted theempiric criteria, although she noted that “others have started applying casedefinitions using instruments as tools, recognizing the improved ability to getconsistent results.” Three major ongoing CDC studies have samples selectedthrough use of the empiric criteria.
Dr. Unger appeared reluctant to whole-heartedly endorse the estimate, basedon the empiric criteria, that 4 million people in the U.S. have CFS, but shedid not back away from it either. “No single study or approach can beconsidered sufficient to determine the true population prevalence of an illnessas complex as CFS,” she wrote. “Like all studies, the 2007 prevalence estimatesof CFS based on the Georgia surveillance study are subject to the limitationsof the study design. however, the Georgia study, along with those from otherinvestigators, does demonstrate the public health importance of CFS and it isthe CDC’s most recent study on the prevalence.”
Dr. Unger indicated that the agency “is in dialogue with other investigatorsabout instruments and methods to best characterize and stratify CFS patients.”The agency is also launching studies with several investigators to enroll andcharacterize patients from seven clinical practices headed by leading CFSphysicians to help clarify issues involving the case definition as well as thename.
“We are planning to collect standardized data on all the domains of illnessincluded in the Canadian Consensus Criteria of CFS/ME, the 1994 CFS definitionand the newly proposed International ME definition,” she wrote. “We anticipatethat this data will assist researchers and clinicians in considering furtherrefinements of the case definition.” With regards to the name of the illness,she wrote: “Opinions of advocates, clinicians and researchers remain dividedabout whether CFS and ME are the same or different entities. however, we arefollowing the discussions with interest and would consider any consensus thatis reached by patient groups and the scientific community going forward.”
Another conflict that has dogged the agency involves its CFS website.Advocates and patients have long complained that it conveys seriousmisinformation, in particular on aspects of diagnosis, treatment and managementof the illness. for example, until this month the website included thefollowing language: “No diagnostic tests for infectious agents, such asEpstein-Barr virus, enteroviruses, retroviruses, human herpesvirus 6,Candida albicans, and Mycoplasma incognita, are diagnosticfor CFS and as such should not be used (except to identify an illness thatwould exclude a CFS diagnosis, such as mononucleosis). In addition, noimmunologic tests, including cell profiling tests such as measurements ofnatural killer cell (NK) number or function, cytokine tests (e.g.,interleukin-1, interleukin-6, or interferon), or cell marker tests (e.g., CD25or CD16), have ever been shown to have value for diagnosing CFS. Other teststhat must be regarded as experimental for making the diagnosis of CFS includethe tilt table test for NMH, and imaging techniques such as MRI, PET-scan, orSPECT-scan.”
Advocates and patients appealed to the CDC many times over the years toremove the language. They acknowledged that these and other tests were notdiagnostic for CFS but insisted that wasn’t the point; even though the testscouldn’t be used to confirm that a patient had CFS, they were important weaponsfor disease management. Experienced clinicians, like Dr. Enlander at Mt. Sinaiand Dr. Nancy Klimas, a top researcher at the University of Miami, have longused tests such as these to identify CFS sub-groups and individualize treatmentstrategies, given their patients’ histories of immune dysregulation and viralinfections. yet clinicians report that they have received letters frominsurance companies citing that paragraph in rejecting claims for tests theyhave ordered, in some cases as recently as last summer.
The agency finally removed that language this month, after an advisory groupreviewed the website and requested a host of changes. “They [the reviewers]provided useful feedback in early October and CDC is incorporating thisfeedback into our ongoing efforts to improve the CFS website,” wrote Dr. Unger.Replacing the old language is a new passage that suggests that some of the sametests once disallowed for diagnosis of CFS can be useful for diseasemanagement—as advocates have been saying all along. Patient groupswelcomed the change, but some advocates said it was minimal and long overdue,given that many insurance claims had been rejected unfairly in years past.
Another major complaint about the website has been the agency’s longstandingpromotion of two treatments developed and championed in the United Kingdom:graded exercise therapy and cognitive behavior therapy. In the U.K, mentalhealth professionals have dominated research into and treatment of chronicfatigue syndrome; they use the Oxford criteria, requiring only six months ofunexplained fatigue. a major British study using this case definition andpublished earlier this year indicated some improvement with graded exercisetherapy and cognitive behavior therapy. But U.S. experts on the illness, atleast those outside the CDC’s immediate orbit, generally believe that the U.K.case definition—like the CDC’s empiric definition–is likely to define acohort that includes a lot of people with depression, and not actual CFS, astheir primary complaint.
To those convinced that CFS is a condition of psychogenic and not organicorigin, it probably doesn’t matter if people with depression are mixed up in astudy sample. In the framework of chronic fatigue syndrome endorsed by theBritish medical establishment, the prolonged fatigue and associated illness arelargely considered to be caused by the patient’s inability or unwillingness tomaintain an active lifestyle—an avoidance triggered by some form ofstress, psychological issues or perhaps even an infectious illness. Thatavoidance of activity then leads to a physiological deconditioning that impactsmultiple body systems and organs.
“It’s a psychological model,” said Dr. Jason of DePaul University, of theBritish view of CFS. “It’s an illness that might be caused by some kind ofvirus or trauma, but what’s maintaining it is that you have some sort of phobicavoidance of activity. The idea is your bone and muscle mass decrease, youbecome weak. So if you can get a person to slowly increase the amount ofactivity that they do, they will break this phobic avoidance.”
In the U.K. framework, graded exercise therapy is often paired withcognitive behavior therapy in the treatment protocol for CFS. Cognitivebehavior therapy is a treatment modality with widespread application, and islikely to be useful to many people undergoing major stresses–whether fromcancer, a back injury, an existential crisis, fear of sex, migraines, a baddivorce, or cognitive fatigue syndrome. however, the kind of cognitive behaviortherapy prescribed in great Britain to treat people with CFS—as Dr. Jasonand other researchers have repeatedly noted–is largely geared towardconvincing patients to overcome their avoidance phobia and increase activitylevels; in other words, to encourage them to participate in something very muchlike graded exercise therapy.
But for people who experience post-exertional relapses of their symptoms,graded exercise therapy could be harmful, not helpful; in addition to theemerging research about post-exertional malaise, patient surveys in the U.K.have indicated a high degree of unhappiness and increased morbidity among thosewho have been through a course of graded exercise therapy. and, say critics,cognitive behavior therapy could also be harmful, if the goal is to convincepatients to engage in graded exercise therapy or otherwise ramp up activitylevels.
Dr. Unger wrote in her response that she was aware of patient concerns aboutincluding information on graded exercise therapy and cognitive behavior therapyon the website, and that the agency was reviewing those sections. The goal ofthe information, she wrote, was to let patients know about treatment optionsthey could discuss with their health care providers. “Though these approachesmay not work for everyone, the scientific literature shows that they providesome benefit to some patients,” she wrote.
However, Dr. Unger declined to comment specifically on the contestedscientific literature from the U.K. that actually reported the modest benefitsfrom these therapies, noting that “as a rule, CDC doesn’t comment on researchnot conducted by CDC.”
The View from the Chronic Fatigue Syndrome Advisory Committee
The growing dismay about Dr. Reeves’ leadership and the agency’s problematicCFS research program are evident in the minutes and testimony from thetwice-yearly meetings in the late 2000s of the Chronic Fatigue SyndromeAdvisory Committee of the Department of Health and Human Services. The mandateof the committee, with a rotating membership of clinicians, researchers,patients and advocates, is to offer guidance and recommendations to thedepartment. In 2007, the committee requested financial records from the CDC’sCFS program. Dr. Jason, a member of the CFSAC, and Dr. Reeves, an ex officiomember as the CDC’s representative, sparred publicly over access to therecords.
At that meeting, however, Kim McCleary, the head of the CFIDS Association ofAmerica, testified that the CFS program, based on a review of the CDC financialdocuments that the committee had sought, suffered from “shameful scientificleadership, zero accountability, invisible outcomes and millions and millionsof dollars stuck in suspended animation, if not wasted…only the governmentcontractors seem to be benefiting from millions spent for which there are noworthwhile outcomes for American taxpayers, or CFS patients.”
The largest chunk of the program’s funding, reported McCleary, went to asingle private research organization, Abt Associates in Cambridge,Massachusetts, in sole-source or no-bid contracts for the epidemiologicresearch that was being widely criticized by other scientists. at least $2.7million committed to Abt was “in limbo”–obligated to specific projects butremaining unspent—and work on other projects was proceeding slowly and atgreat cost, she testified. The financial mismanagement, testified McCleary,”has resulted in program management coming often to this committee and tellingother investigators that no funds are available for new projects orcollaborations.”
(The CFIDS Association of America had been criticized by some otheradvocates over the years for its previous close association with Dr. Reeves.The organization had provided essential public support for Dr. Reeves duringthe accounting scandal in the late 1990s; in the mid-to-late 2000s itimplemented the agency’s controversial multi-million-dollar CFS publicawareness campaign at a time when others were seeking to change the diseasename. McCleary’s public rebuke of Dr. Reeves’ leadership, therefore, was viewedas a significant blow to the CFS program and found a welcome audience.)
McCleary’s report further shredded support for Dr. Reeves among committeemembers; some were researchers struggling with their own funding issues. Thefinancial accounting appeared to confirm a frequently heard complaint about theCDC and Dr. Reeves—that they were not taking full advantage ofopportunities to collaborate with outside scientists at academic researchcenters.
Christopher Snell, a professor of sports sciences at the University of thePacific in Stockton, CA, and a committee member, stated, according to theminutes: “As somebody who works on a shoe string budget, when I start to lookat some of these numbers, I was somewhat appalled… It just does not seem tobe the best use of the funds. The thing that we asked for at a couple ofprevious meetings was for the CDC to consider more collaboration with outsideentities. we meant people who work a lot cheaper. It would seem that there arepeople out there with great ideas who would love to work with the CDC for muchless money.”
Dr. Klimas, also a committee member, noted that she had been collaboratingwith the CDC on a study comparing people with CFS and Gulf War illness, andthat the agency had failed to finish its testing on samples, citing fundingproblems. She also unleashed another common charge: that the CDC was simply notinterested in the role of pathogens. according to the minutes, “Dr. Klimas saidthat CDC has made it known that the agency has no intention of looking forinfectious agents. She added that other research organizations are pursuingidentification of pathogens and that CDC should be embarrassed not to belooking for them as well…despite the evidence, the CDC is still saying thatviruses don’t matter in the illness even though people are already beingtreated for them. She said that the science is there to provide options waybeyond the CDC’s recommended behavioral treatment and exercise.”
At itsThis article originally appeared on virology blog.