welcome. i'm dr. john iskander. on behalf of cdc i'dlike to welcome you to public health grandrounds for february 2016. continuing education credits for public health grand roundsare available for physicians, nurses, pharmacists,health educators and other health professionals. please see more on thegrand rounds website. our speaker disclosure forthis session is noted here.
grand rounds is availableon all of your favorite web and social media sites, weare also live tweeting today. use hash tag cdcgrandrounds. here is a preview of upcominggrand rounds sessions, please join us live on orthe web at your convenience. i'd also like to thanktoday's featured speakers and the many people listedon this slide who helped to make this session possible. we have a featuredvideo segment on youtube
and our website calledbeyond the data which is posted shortlyafter the session. this month's segmentfeatures my interview with dr. anthony komaroff. we also have partnered withcdc public health library and information center to feature scientific articlesrelevant to the session, the full listing is availableat the science clips website. it's now my pleasure
to introduce cdc'sassociate director for science dr. harold jaffe. thank you, john, and thanks tomy speakers for coming and all of you for being here. chronic fatigue syndrome is animportant public health problem. i think that's the onemessage we are going to get across today. although many questionsabout the syndrome remain to be answered, we knowthat the disease is real
and that affectedpatients suffer greatly. furthermore, the economic impact of the disease is feltacross the country. chronic fatigue syndrome isa biologically based illness that affects individualsin nearly all aspects of their lives, significantlyaffecting their ability to work and support their families. sadly, studies show manypatients experience significant barriers in terms of receivingappropriate healthcare.
this needs to change, we needto enable healthcare providers to better recognize andoffer better treatments for this condition. today we will learn that whilethere's currently no cure, there are managementand therapeutic advances that can help patientsand their families. we do need bio markers tomake the disease more clearly diagnosable, but you will hearsome about those collaborations and studies that areunder way with a goal
of improving our diagnosticabilities and our treatments, but in the meantime dedicatedscientists, clinicians and patients are helpingus incrementally build our knowledge base aboutthe disease. we are aware that just the namechronic fatigue syndrome is imperfect in many waysand can be unhelpful to clinicians and patients. however, we shouldnot let legitimate and heartfelt disagreements
about the nomenclature impedeour scientific progress. cdc's public health approach to reducing cfs morbidityincludes working partnerships with clinical researchexperts, patient advocacy groups and other governmental agencies. at a time of unprecedentedattention to this profoundly disturbingcondition cdc is committed to the broad outreach andclinical education efforts. this session is just one part.
again, the message is cdcis in this for the long run, we are not going away. we encourage our viewers to use and widely sharetoday's information. thank you. applause . thank you, dr. jaffe. our first speakeris dr. charles lapp. thank you, dr. iskander, iappreciate the introduction
and i can't tellyou how delighted and honored i am to be here. thanks to the cdc forinviting me to speak today. i can't wait to tell you aboutchronic fatigue syndrome. let me start by saying thatin 1991 one of my colleagues, david bell, wrote a bookentitled "the disease of a thousand names"and that title sort of exemplifies the sort of confusion we havehad about this illness.
the signs and the symptomsare so general and diverse that chronic fatigue syndromemimics many other disorders and has earned numerous monikers over the years including royalfree disease, iceland disease, tapanui flu, theyuppie flu, by the way, that came from the eminentmedical journal rolling stone magazine. it's also been calledmyaligic encephalopathy, chronic fatigue immunedysfunction syndrome,
and more recentlyseid which stands for systemic exertionintolerance disease. for this presentation, howeverwe will be using the more common name chronic fatiguesyndrome which was chosen because 100 percent of the study's subjectsexperienced an unusually severe and persistent type of fatigue. now, there's no explanation whyindividuals contract chronic fatigue syndrome, but wedo know that the majority
of cases occur acutelyover hours to days and typically follow abacterial or viral-like illness. so let me introduce youto a typical clinical case and this is an actualcase from my practice. jane was a 37-year-oldinternet technologist for a community bank, she hadbeen physically active in sports and working out and had beenmaintaining her own household when she contracted aflu-like illness in 2011. she was bed bound at firstand very slow to recover.
within days she noticedan unusual fatigue after minimal activities,then insomnia, then achiness in the joints then generalizedmuscle pain and weakness. she soon found it difficult to recall recentconversations and events. reading concentrationwas limited and she had troublecomprehending what she had read or even tv showsthat she had watched. she would search for words,lose her train of thought
and friends would sometime haveto finish sentences for her. sleep had always been good butnow she was restless at night and she would awakenunrefreshed, even after many hoursof bed rest. she felt stiff and sore andfoggy and for an hour or two after the awakening she noticeddizziness or light headedness on getting up quicklyand on a couple of occasions she saw stars, butno tunnel vision, no syncope. now she was unable to keep upthe house and she had to rely
on friends and family tohelp her with the cleaning, the laundry and the shopping. she would attempt to keepup at home and at work, but exertion would inevitablymake the symptoms worse and if she exerted toomuch she would end up sick and chair bound for oneor two days afterward. evaluation by her primary carephysician revealed rather low blood pressure, but there wasno immediate orthostatic blood pressure drop and otherwise theexamination was unremarkable.
blood work was unremarkable. having no explanationfor her symptoms, despite the profound reductionin her physical abilities, jane became anxious abouther future and frustrated and discouraged as well. so our clinical casedemonstrates all the key features of chronicfatigue syndrome. exertion intolerance andthat debilitating fatigue, post exertion relapseand malaise,
new onset of sleep problems,cognitive difficulties, orthostatic intolerance,symptoms that wax and wane and these whole body flu-likemyalgias or arthralgias, or widespread body pain. now, the cause ofexertion intolerance, pain, sleep disruption,cognitive dysfunction and other cfs symptomsis unknown, but there is an identifiabletrigger in a majority of the cases that we see.
a large majority of patientsreport a precipitating factor hours to days beforetheir symptoms begin. the largest category ispreceding infections although a variety of other medical and surgical events canoccur before the onset of chronic fatigue syndrome. cfs is triggered by viralor bacterial infection in about 75 percent ofthe cases that we see and noninfectious causes such astrauma, surgery or childbirth,
allergic reaction, stressor emotional trauma occur in much smaller numbers. there is some evidencethat high levels of concurrent stress maycontribute to the precipitation now, the typical course is aroller coaster ride of flares, alternating withrelative improvements. while overexertion,sleep deprivation and emotional stress are wellknown to trigger the flares, many relapses occurspontaneously and they last
for an indefiniteperiod of time. the unpredictableonset and the severity of such relapses make itdifficult for a person with cfs to plan ahead or to function on a regular predictableor sustained basis. clinical management contributesto some functional improvement, but total recovery is uncommonand most adults do not return to their pre-illnesslevel of function. now, individuals with chronicfatigue syndrome are also more
likely than the generalpopulation to suffer comorbidities such asfibromyalgia, irritable bowel and bladder, sjogren's syndrome,joint hyper extensibility or ehlers-danlos syndrome and several othermedical conditions. sadly, however, it'san invisible illness and to the casual observerpatients appear entirely normal and healthy, but thegravity of the disease is such that it totally changesone lifestyle and the lives
around that patient as well. one of my patientspointed out to me -- and i make this a quote - "this illness can take awayeverything, your dignity, your livelihood, yourfamily, your marriage and even all of your money." so as you can imagine,the symptoms of chronic fatiguesyndrome overlap with many disorders includingdepression, ms, systemic lupus,
endocrine disorders, hepatitisand many other illnesses. so in order to confirma diagnosis of chronic fatigue syndrome,one needs to exclude disorders that could plausibly explainthe exertion intolerance and the other symptoms. the essentials of evaluationinclude, as you see here, a thorough medical history, athorough psychosocial history such as a history ofdysfunctional childhood, prior verbal or physicalabuse, substance abuse.
complete physical examination,a mental health examination, perhaps using validated screenssuch as the hospital anxiety and depression scale or the patient healthquestionnaire, the phq 8. such an evaluationtypically takes about 30 to 60 minutes in my office. lastly, it's recommended to obtain basic screeninglaboratory tests. they may include a cbc with awhite blood cell differential,
blood chemistry such as thecomprehensive metabolic panel, thyroid functioningtests such as the tsh and especially the free t4, asedimentation rate and/or a crp, which of course aremarkers of inflammation, and a routine urinalysis. now, sometimes additionallab work is obtained, if clinically indicatedof course, to rule out otherpossible causes of fatigue such as infection,autoimmune disorders, endocrine
or hormonal problems,celiac disease, et cetera. the results of such testingis usually unremarkable but it does help rule outthose other conditions that could plausibly explain thefatigue and the other symptoms. dr. komaroff will soon bedescribing the institute of medicine recommendations, butsuffice it to say at this point that the iom recommendsmaking the diagnosis actively, and that means it's importantto make the diagnosis promptly, even before one excludesother plausible causes.
so the institute ofmedicine criteria for systemic exertionintolerance disease, or seid, provides a brief and simplemethod for diagnosing cfs, but many clinicians includingmyself corroborate the diagnosis with established instrumentssuch as the fukuda criteria of 1994 or the canadianconsensus criteria. making a diagnosis promptlyreduces anxiety and uncertainty for the patient andreduces medical costs because numerousexclusionary lab studies
and procedures wouldnot be needed. so let's consider theprognosis for these patients. in a systemic review of thenatural course of cfs a median of 39.5 percent of adultswith cfs improved and a median of 5 percent experiencedcomplete recovery. the likelihood ofrecovery decreases with baseline illness severity,the duration of the illness, and the presence of comorbidpsychiatric conditions. children and adolescentsfair somewhat better
with one paper reporting 60percent recovery at five years and 88 percent at 12 years afterthe onset of their illness. in another longitudinal study of25 adolescents with cfs compared to 25 healthy controls, 80 percent of the patientshad remitted over a course of 25 years, but many stillreported more impairment than the controls. now, the management of chronicfatigue syndrome can be briefly summed up by these fourpillars, if you will.
education, behavioralchange, medication and nonmedication-basedtreatments. first, reliable educationmaterials should be provided to the patients and anexcellent source is online at the cdc website, cdc.gov/cfs. behavioral modification has beeneffective to limit depression, anxiety and abnormalcoping mechanisms such as denial andescape avoidance. pharmacologically,sleep disruption
and pain are usuallyaddressed first and may require consultationwith a sleep specialist or a pain management group. we generally avoidnarcotic pain medications but helpful therapies includetricyclics such as amitriptyline and cyclobenzaprine, thensri such as duloxetine and milnacipran, anti-epilepticmedications like pregabalin. the next step in managementis to address severe symptoms and to address thosecomorbidities
that the patients suffer. nonpharmacological therapymight include epsom soaks, hot and cold packs,liniments, massage, osteopathic manipulation,acupuncture and the like. another form of nonpharmacologicaltherapy is staying active but not too active. we recommend starting withvery low levels of activity and proceeding slowly.
brief intervals ofactivity should be followed by adequate rest in orderto avoid a flare of symptoms or to avoid the postexertional malaise. consider beginning withactive stretching and range of motion exercisesagainst gravity, then follow with lightresistance training with light weights, forexample, or elastic bands. we then advance to certaintypes of aerobic activities such as tai chi, yoga, walking,bicycling or aqua therapy.
to avoid flares patientsshould limit activity by time, say less than fiveminutes per day to start, and limit the numberof repetitions, and if they experienceany excessive fatigue, reduce the amount of time orthe number of repetitions. so the summary fromthe clinical aspect is that we can find chronicfatigue syndrome present in both pediatricand adult groups, it typically has a precedingmedical event, often infection,
patients benefit from earliercomprehensive evaluation and diagnosis. the disease can have severeimpact on quality of life, but improvement and recoveryare certainly possible, and there is no curativetherapy, but graded exercise and some types of pharmacotherapy canbe of great benefit. thank you very much and inow relinquish the podium to dr. beth unger who is going
to discuss the publichealth approach to chronic fatigue syndrome. thank you very much. when designing a publichealth approach to illness, one of the first steps is to understand theepidemiology of the condition. for cfs answering thisquestion is difficult because there is no simpletest to make the diagnosis, and findings willdiffer depending
on how the patientsare identified. for example, self-reportcompared with clinical assessment, as well as where the studyis conducted, for example, in clinics compared withthe population as a whole. population-based studies that include clinicalassessments are generally considered to give themost accurate estimates, but these are complexand expensive.
extrapolating estimates fromthe three u.s. population-based surveys to the country asa whole, we can estimate that at least 1 millionamericans suffer from cfs. most patients identified in the population surveys havebeen ill longer than five years and only about half ofthose affected continue to seek medical care. in addition, only about 20percent of those identified as cfs have been actuallydiagnosed by a physician.
this emphasizes the need for more physicianeducation about this illness. these studies indicatethat cfs is three to four more times commonin women than in men, persons of all race and ethnicbackgrounds are affected, and there is a disproportionateburden of cfs in minority and socioeconomicallydisadvantaged groups. the highest prevalenceof illness is in 40 to 50 year olds, butthe age range is broad
and includes childrenand adolescents. it's important to understand theeconomic impact of the illness and barriers to healthcareutilization. patients, their families and society all bear significantcosts associated with cfs. these include direct medicalcosts of provider visits and medications, and indirectcosts of lost productivity. in the u.s. the estimated annualdirect medical cost is between 9 and 14 billion dollars.
in nearly one quarter of theseexpenses are paid directly by the patient and their family. the estimated annual cost oflost productivity is between 9 and 37 billion dollars. when cfs occurs before age25, the ability of patients to complete their educationis significantly impaired. inability to achieve their fulleducation potential can have a lifelong impact onearning potential. cfs patients facesignificant barriers
to receiving appropriatehealthcare. a population-based study ingeorgia found that 55 percent of persons with cfs reported atleast one barrier to healthcare. finances prevented10% from seeking care. this is twofold higher thanthe population average found in the 2005 nationalhealth interview survey. while the cause or causesof cfs are not known, studies have identifiedsome factors that are associatedwith the illness.
risk factors may suggest avenuesto explore to discover causes or to develop interventions. infections have beenlinked to cfs because patients oftenreport an acute onset after a flu-like illnessthat does not go away, and some patients have a history of frequent infectionsprior to their illness. epidemiologic studies donot support association with any single pathogen.
post infectious fatigue,that is failure to recover from a documented infection,occurs in about 10% of patients with a variety of viraland nonviral pathogens, such as epstein-barr virus,ross river virus, q fever, that is coxiellaburnetii, or giardia. the severity of the acuteinfection is most predictive of subsequent illnessand there is no evidence of an unusual persistenceof infections in those who remain ill.
compared to healthycontrols persons with cfs have had exposure tosignificantly more stressors and are more likely to havea higher allostatic load, that is a measure of thephysiologic consequences of chronic neuroendocrineresponse to stress. they are also more likelyto have metabolic syndrome. these associations areunlikely to be specific to cfs as stress is a factor inmany chronic illnesses. twin and family studies supportthe contribution of both genetic
and environmentalfactors in cfs. no specific geneshave been identified and a polygenetic explanation for increased susceptibilityis most likely. cdc recently shifted its focusfrom population-based surveys to studying cfs patientsbeing cared for by clinicians with specializedexpertise in cfs. population-basedsurveys are helpful to identify the fullspectrum of those affected
and include a broad rangeof illness severity. patients identifiedfrom clinics tend to have more severe illness. most studies of cfs have beenconducted in patients enrolled from single clinics and includesmall numbers of patients. many intriguing findingshave not been replicated, leading to the suggestionthat heterogeneity of patients may contributeto this difficulty. our study is designed todocument a comprehensive picture
of cfs patients identifiedin multiple clinics and to describe the approachthat experts use to diagnose and manage their patients. we use standardizedquestionnaires to measure the major domains orcharacteristics of the illness. these questionnaires measurethe level of function, pain, fatigue, type and severityof symptoms, and sleep. we also collected medicalhistory, family history, physical examinationresults, medications
and results of laboratory tests. we included the promisinstruments that were designed and validated by nih tomeasure symptoms experienced in many different illnesses to allow comparisonbetween illnesses. the sf 36 measures of function and multi-dimension fatigueinventory have also been widely used in a variety of conditions. seven clinical sites haveparticipated in this study
which was initiated in 2011. five participate underthe umbrella organization of the open medicineinstitute consortium. the clinicians participating areall well known respected experts in cfs and include one ofour speakers today, dr. lapp. their expertise is what givescredibility to the study. we are very grateful to theirpatients who have agreed to be part of this study and have acceptedthe additional burden
of completing the manyquestionnaires required. we collected completedata on 471 patients in the baseline study. these were distributed fairlyevenly across the clinics. the mean patient age was 48.2years and the mean duration of illness was 14.3 years. most patients were female andthe vast majority were white. the mean bmi was 26.6. more than three-fourths of thepatients had a college education
and nearly all were insured. while about three-fourths wereunemployed only 14 percent were receiving unemployment benefits. there were statisticaldifferences in the demographics between all the clinics in thesemeasures except the proportion not working. the patients in thesespecialty clinics may not be representative of cfs patientsin other healthcare settings as they were all highly educated
and with sufficientsocioeconomic support to be able to navigate their way tothese specialized centers. most patients had beenseen and evaluated by more than one physician priorto coming to their clinic. we found significantheterogeneity in the patients overall butthere were very few differences between clinics inthese average measures. this is illustrated here forfunctional status as measured by the eight subscales of thewell validated instrument sf 36.
the box plot shows thefull range of values. the top and bottom of the boxis the 75th and 25th percentile. the bar in the middleis the median and the small diamondis the mean. while you can see there issignificant heterogeneity in these measures overall, there is no significantdifference between the clinics. in this scale higher scoresindicate better functioning. if we compare these values
to healthy controls thered bars indicate the mean of the 213 healthycontrols we enrolled and these values comparewell with other studies. the important feature to note is that the patients showsignificant functional impairment, particularlyfor vitality and physical functioning, butthere is relative preservation of mental healthand role emotional. the data in our study confirmsthe seriousness of this illness
and the extent ofimpairment experienced by patients with cfs. we are continuing this study tocollect longitudinal measures of illness characteristics andto enroll groups of patients that have been understudied,specifically pediatrics, severely ill or homeboundpatients and patients within two years ofonset of the illness. we are also enrollinghealthy controls and ill comparison groups whomay present similarly to cfs.
in addition, we arecollecting blood and saliva on those enrolled so that theycan be tested for bio markers that have shown promisein smaller studies. results from this study willhelp to find patient subgroups that reflect different causes or that could suggesttargeted therapies. finally, the data clearlyshow that the patients in these specialtyclinics are highly educated with significant financial andsocial support that enable them
to reach these expertphysicians. again, this emphasizes the needfor dissemination of knowledge about cfs to the broadermedical community. it is clear thatdespite decades of work, cfs remains a challengefor clinicians. patients have difficultyfinding compassionate and appropriate care. physicians and other healthcareworkers need evidence-based information about cfs.
cdc has responded to thisneed by developing a series of continuing medicaleducation courses. in 2012 and 2013 wepartnered with medscape to present two round tablediscussions that were targeted to primary care physicians. these reached more than22,000 physicians and more than 6,000 continuing medicaleducation credits were issued. currently cdc has two freeonline courses available on the cfs website.
these are accreditedfor physicians, nurses and otherhealthcare professionals. however, cfs is rarelycovered in medical schools and this leaves avacuum of knowledge so we've begun the process of developing standardizedpatient videos accompanied by educational curriculumfor the med ed portal. this is a free online serviceprovided by the association of american medical colleges.
the materials are peer reviewed and once approvedare made available to medical schoolfaculty free of charge. finally, cdc is continuingcommunication with the general publicand advocacy community. an important part of thishas been the introduction of patient-centered outreach and communicationcalls, pcoca calls. these are one-hourteleconferences
that are available toll freein the u.s. they began in 2012 and are generallyheld twice a year. the format is that cdcuses the first ten minutes to give an update on currentactivities of the cfs program and then an outsideexpert or group of experts presentsinformation on a topic of interest to the community. these talks generally last 35to 40 minutes and are followed by answers to questionssubmitted to the pcoca email.
topics have included identifyingpatients for clinical studies, exercise, infectionand immunity in cfs, cfs and cognitive function,sleep research and cfs, stanford's research program, and self-managementstrategies in cfs. we are grateful to all theexperts who graciously gave of their time toshare their insights with the patientsand their families. most recently we'vebegun a new initiative
to include broadstakeholder collaboration into developing educationalmaterials, including the viewpointsof patients, medical professionalorganizations, medical educationalorganizations, expert clinicians and government agencieswill help assure the quality and usefulness of these products and help facilitatebroader dissemination in the medical communityat large.
our first focus willbe modification of the cdc cfs web page toincorporate recommendations of the institute of medicine. i'd now like to turn thepodium over to dr. komaroff who will talk to usabout those initiatives. [ applause ] dr. unger and thanks to the cdc for organizing thissession today. i was asked to speak about threerecent authoritative reports
that -- in which experts, manyof them from outside the field of chronic fatigue syndrome, evaluated the evidencethat's been published. the three authoritative reports,the first is from the institute of medicine of the nationalacademies of science, which issued a 300 page report in which the panelreviewed the literature of nearly 9,000 publishedarticles, and concluded that me/cfs, which isthe name that i will use,
is a biologically-basedillness as dr. jaffe said, and proposed a newcase definition as well as a new name. the second report was fromthe nih, which held a pathways to prevention conference with a follow-up reportdrawing similar conclusions about the biology of me/cfs. and then finally the federalagency for healthcare research and quality commissioned anindependent review that focused
on diagnosis and treatment. the institute of medicine reportfirst addressed the question of the scope and theseriousness of me/cfs, drawing heavily i might sayon published studies from cdc. consistent with dr. unger'ssummary, the institute concluded that between 800,000 and2.5 million americans have the illness. the institute also agreedwith dr. unger's summary that the costs of the illnessto society were substantial,
as much as $51 billion annually. based on their review, theinstitute panel concluded that, "me/cfs is a seriouschronic systemic disease that often can profoundlyaffect the lives of patients," and that me/cfs is not, asmany clinicians believe, a psychological disorder. then the institute of medicinepanel turned to an important and obvious question, onethat probably has been asked by every clinician andinvestigator involved
with me/cfs, which is: given that me/cfs isdefined exclusively by subjective symptoms, symptoms that any human beingcan say they have, are there any confirmatoryunderlying objective biological abnormalities in these patientscompared to healthy subjects and compared to patients withother fatiguing illnesses? and that includes comparison with the biologicalabnormalities reported
in some psychiatric illnesses. the institute of medicinefound considerable evidence of underlying neurologicalabnormalities as reflected by many differentdiagnostic technologies. those singled outfor special mention by the panel included slowedinformation processing, problems with white matterintegrity, neuroinflammation, impairment of working memory, hypothalamic pituitaryaxis abnormalities,
and autonomic abnormalities. the nih report wasin general agreement with the instituteon this issue. the institute ofmedicine also concluded that there were considerableimmunologic abnormalities in patients with me/cfs. they highlighted two as beingparticularly well substantiated: impaired natural killer cellfunction that correlated with illness severity, andincreased cytokine levels
in blood suggesting a stateof chronic immune activation. as was stated by dr. lappand dr. unger, the institute of medicine noted thatmany but not all patients with me/cfs report that theirillness began following an acute infectious-like illnesscharacterized by fever, myalgias, respiratory,gi, neurologic symptoms, along with severe fatigue, an illness from which thepatients say they feel they have never recovered.
indeed the medical literatureincludes many reports of post-infectiousfatigue syndromes linked to well-documentedacute infections. for this reason many havewondered if at least some cases of cfs may be initiated oreven perpetuated by infection. the institute panelconcluded that there is, " sufficient evidence suggestingthat me/cfs follows infection with epstein-barr virus and possibly otherspecific infections--
viral, bacterial andpossibly protozoal." nih report concurred in this andcalled specifically for research on the possible role ofherpes viruses in me/cfs. there have been severalcase definitions proposed for this illness. perhaps the most widely used isthe case definition developed under the leadership ofcdc and published in 1994. the institute of medicine panelproposed a new case definition that it hoped would besimpler and shorter,
easier to apply consistentlyacross patients, likely to result infewer false negative and false positiveclassifications and likely to be a better predictorboth of response to therapy as well as prognosis. the key elements of theproposed new case definition by the institute are firstpost-exertional malaise defined as a prolonged worsening ofa patient's baseline symptoms after physical or cognitive
or orthostatic challenge,exertion or stress. the second component,unrefreshing sleep, that is defined asregularly, like every morning, feeling unrefreshedafter sleeping many hours and apparently sleeping soundly. third, cognitive impairmentsof a wide variety of types that are made worse by exertion,effort, stress or time pressure. and then finally,orthostatic intolerance, symptoms that worsenupon assuming
and maintaining an erectposture and that are improved, if not completelyeliminated, by lying back down or elevating the feet. the complete language of the proposed case definitionis shown in this slide. i'm not going to read it allin the interests of time. you can go through it. it's shorter thanprior case definitions, it's less complicatedin some respects,
but it's still not simple. but at the moment i think itmay be about the best we can do. the new case definition,like most that preceded it, does not includelaboratory studies. me/cfs remains a multi-systemdisease for which we do not yet have a singlediagnostic biomarker. indeed, until there is a goldstandard pathological finding for the illness, i don'tthink it will be possible to test the accuracyof any case definition,
not the false negative orthe false positive rate, because there willbe no gold standard against which to test it. it will, however, be possibleto compare the performance of different alternative casedefinitions against each other in large numbers of patients,and that already is under way. and as pointed out by theagency for healthcare research and quality, a newcase definition like this one does need to betested empirically to verify
that it is superiorto its predecessors. the name chronic fatiguesyndrome was first coined in 1988 by a groupconvened by cdc. as a member of thatgroup, i would note that we were all focused reallyon developing a case definition. no one really thoughtabout the name. and when someone proposed thename chronic fatigue syndrome, sort of people said, why not? that was a big mistake.
many of the patientsand clinicians believe that that name, chronicfatigue syndrome, trivializes and stigmatizes thisoften devastating illness, and i certainly agree. many different nameshave been proposed, as dr. lapp summarized. the new name proposed bythe institute of medicine, systemic exertional intolerancedisease, has some merits. it focuses on a corecomponent of the illness,
but i think it's too early to determine whetherthis new name is going to be widely adopted by both theclinician and patient community. in summary, the instituteof medicine and the nih reportsconclude that patients with me/cfs have anunderlying objective biological abnormalities, that theirsymptoms are not imaginary. however, none of these biologicabnormalities is so sensitive and specific that it constitutesa biomarker, a diagnostic test.
me/cfs is an importantdisease causing great suffering to many individuals and theirfamilies and billions of dollars in lost productivity to society. finally, more researchis urgently needed and indeed the nih along with cdc has recentlyannounced its intention to expand its focus onthis illness, particularly in its intramural program asdescribed next by dr. avi nath. thank you very much forinviting me to speak
at the cdc grand roundsand it's a pleasure to talk about our planned study at thenational institutes of health. so, as some of you knowthe national institutes of health has had along standing interest in chronic fatigue syndrome. in december of 2014 nihsponsored a pathways to prevention workshop toadvance research on me/cfs. in september 2015 dr. franciscollins, who is the director of nih, tasked theintramural program
to develop a research protocol to study the illnessusing the unique resources that are available atthe intramural program. the relationship of infectionsto the onset of me/cfs and the large body ofliterature identifying a variety of interesting but inconsistentimmune abnormalities in these patientsprovide a rationale for further studiesof immune regulation. for example, twostudies from a group
in norway showed delayedclinical improvement in patients followingtreatment with rituximab, which is a monoclonal antibodythat depletes these cells, however, these studieswere small and the immune profiles werenot measured in these patients. so as we've heard, patients with me/chronic fatigue syndromecan be associated with a variety of precipitating factors. our studies will be focused ona defined subset of patients
who have a viral illnessat onset of their illness and these patients are likely to have quite similarimmune profiles. our hypothesis is that post-infectious me/cfs istriggered by a viral illness that results in immunemediated brain dysfunction, and to address this we haveproposed a three-phase study. the first phase is across-sectional study which will define the phenotype
and the pathophysiologyof the disease. phase two will validatethe biomarkers in a longitudinal study, and phase three will be anearly phase intervention trial to target the biomarkersidentified in phase two. so for the purpose of this talki'm going to focus on phase one, and the first aimof this study is to define the clinical phenotypeand using in-depth assessments of all domains of theillness as listed here.
aim two of the study is todefine the physiological basis of fatigue using functionalmri scan of the brain to define the braincircuits that are involved, do detailed metabolic studiesin a metabolic chamber, and do transcranialmagnetic stimulation as well as very detailedautonomic testing. each of these testswill be performed before and after exercise. the third aim of the study is
to conduct a detailedimmunological study in blood as well as cerebrospinalfluid including a screen for autoantibodiesto neural antigens. we will also fully explorethe gut and oral microbiome and apply proteomics andmetabolomics approaches to the cerebrospinal fluid. the fourth aim of the studywill utilize a variety of novel approaches toexplore whether cells or serum from patients can be used toexperimentally reproduce some
of the features of the illness. we will determine if there is aninherent metabolic abnormality in neurons derived fromstem cells and cultures from these patients,and if exposure of spinal fluid will inducethe functional abnormalities in these cells. we will also generatehumanized mice using blood cells from patients and determine if the clinical phenotype canbe reproduced in these animals.
if these experimentalsystems are able to reproduce the clinical orbiologic abnormalities seen in these patients, it would bea major step towards identifying the cause and thepathophysiology of the illness, and for developing a variety of treatment approachesto these patients. so for the purpose ofour phase one study, we plan to recruitpatients primarily from well-characterized cohorts,
particularly the cdc's mcamstudy described earlier by dr. unger. selection criteria will includedocumentation of the acute onset and duration of fatiguingillness for more than six months but less than five years. all patients will havepost exertional malaise and full criteria of the1994 research case definition and the canadian consensuscriteria as mentioned earlier. the study population willinclude 40 post infectious
me/cfs patients, 20healthy controls, 20 post lyme diseasepatients who are asymptomatic, that means they do not havefatigue, and 20 patients with functional movementdisorders. these studies are still beingrefined and rely on the talent and expertise of a large numberof investigators listed here. i would like to particularlythank dr. brian walitt who is the lead clinicalinvestigators of this study at nih and drs.
unger and lipkin as membersof the executive committee for their valuable advice. the intramural programat nih is looking forward to the new insightsthat will come from the concertedresearch into this illness. we expect that synergybetween the cdc's work, nih, intramural studies and researchers worldwidewill allow therapies to be identified.
we do have time forsome questions. i would ask everybody tokeep their questions brief so that we have time forour experts to answer them. and first susan,do you have some? a question from ouronline audience. why isn't the cdc/nih as awhole bringing pressure to bear on researchers andeducating treating physicians to use far more extensive anddetailed survey instruments and be far more precisein their description
of the symptom presentationand pathogenesis. okay. i think that we arepublicizing the importance of using instruments to precisely characterizethe illness and we are in the process of publishingthe baseline results of the mcam study whichwill absolutely specify the instruments that we are using and how they can helpin other studies. and i believe we've been workingwith nih and we are going
to be sharing a lot of the sameinstruments and approaches. i agree. so we aredelighted to be able to share whatever informationwe have and to work very closely with the cdc as dr.unger mentioned to achieve those goals. there are two microphoneson either side. if you do have a question youneed to use the microphone because this is being recorded. susan. another ofour viewers would
like to know all the specificsteps that are being taken to educate medical students in medical schools usingthe latest information from the 2015 instituteof medicine me/cfs report. okay. well, we are -- we havejust started our medical student curriculum, as i mentioned,through the med ed portal. this incorporates -- so westarted it before the 2015, but the educationalcurriculum that goes along with it gives the referencesfor the iom -- the iom report.
in addition, we have ourcollaborative process ongoing -- or it's just being startedwhere we are trying to work with medical educatorsto find out what kind of materials they wantand can easily incorporate into their classes. the advantage of the med-edportal is that it is online and it is free for faculty and actually medical studentsactually can have access to it independentlyas well so we think
that will be a useful start. the collaborative work group iswhat we hope will also be giving us advice as to whatwould be most helpful. yes. dr. nath, could i ask youto be a little more detailed about the patient advisorycommittee, how you intend to incorporate patientinput into the nih study, and could i also ask -- i don'tknow if you have the answer to this about external fundingfrom nih to other researchers on the outside, possibly throughrfa's that might be developed.
excellent questions,i'm delighted to try to address both of them. so firstly i think input from the patients is absolutelycritical for any disease that you want to study. they are the ones who reallyexperience the symptoms and live it -- livewith it from day to day. so as physicianswhatever input we can get from patients is very importantto whatever mechanism it is.
any physician will tell youthat you learn a lot more from talking to patients thanyou do from reading any kind of textbook, journal orwhatever medical literature that is available. so careful listening toparents is absolutely critical. so with that in mind, you know, i grew up in the early aidsepidemic and i saw interactive with act up and other patientforums whereby they had a great impact on the way diseasewas handled, treated
and moved the federal governmentto make changes at every level. and so we understandthe importance of it and there are effortsunder way to put that advisory group together. so, you know, people who aresenior to myself want to look at it from all perspectivesand put together a proper group that will address both theintramural and extramural teams. so i think thoseefforts are under way and we are lookingforward to that input.
with regards to external fundingthat's, again, beyond my area of authority and so i knowthere is a lot of interest in being able tomake that happen, a lot of advocacy groups haveapproached nih with that effort. i think the heart isin the right place and all those thingswill be done. i think it's probablyjust a matter of time before you willsee all these things happen but there is no lack ofinterest in making that --
achieving those goals. thanks. steve monroe,associate director for lab science and safety. i have a question for dr. nath. given the consensus on therole of immune disregulation and the symptoms of the disease,can you elaborate a little bit on the kinds of functionalimmune assays that you are projecting todo with the upcoming study. i've put together a panel
of really outstandingimmunologists to guide me. although i do considermyself a neuroimmunologist, there are people -- everyimmunologist is not the same. people who specialize in tcells and p cells and nk cells and so on and so forth. so what i did was icalled upon dr. neal young who is an expert immunologistat nih and ronald germain who is a nationalacademy science member. so we sat and discussedvarious kinds of things.
i think what we're going to dois we're going to collect a lot of lymphocytes bothfrom blood and from csf. initially, we willbe storing them and what we will be doing islooking at cell-free fluid in the csf and the serumfor not just a small number of cytokines, actually1500 lysates, analytes, ok. but we want to be very,very comprehensive. and i have developed aproteomics assay in my own lab that will look at aboutat least 2500 proteins.
so when we look at thatcomposite i think it will be very clear to us what celltypes may be dysfunctional in these patients and how wecan subgroup those individuals and that will then allow usto go back and now say ok, well this looks like an nk cellfunction, let's look at it, or this looks likea b cell function. because there arejust numerable amounts and just very time-consumingtedious assays for each cell type thatyou could potentially do,
or interactions betweencell types. instead of doingthat at the get go, and everything youcan possibly think, i think that's a good screeningtool and then we can focus on the real aspects that wethink are really dysfunctional. do you think primary careproviders can offer appropriate services to chronic fatiguepatients or would it be better for them to referto specialists? well, i would -- i guessdr. lapp and i can both --
yes, i think primary careproviders can provide adequate services, particularly ifthey have people in id, neurology backups whensomething doesn't add up. but primary care providersneed to be better educated than most are currently. i would agree with that andas a primary provider myself, and former family physicianand internist and pediatrician, we are at the forefront. the family physicians, thefamily doctors are the ones
who really see the majority of these cases first,not the specialists. so as tony has pointedout it's very important for these providers tobe educated and know how to recognize the patientswhen they walk in the door. i should point out we found fromprevious studies done by the cdc that not only theprimary providers but also the mid-levelproviders are doing a lot of the diagnosing and initialtreatment of patients, too.
so i think it's veryimportant to address that group of individuals. while i have the microphonei would like to say that since the iom reportcame out and the p2p report that we've seen a great deal ofmovement from the government. the patients alwayswant to hear that, that there is somethingbeing done. from my perspective working with this wonderful group i'veseen a lot of movement on behalf
of the cdc and thenational institute of health and even some positivestatements from dr. franciscollins who seems to be supporting amovement for more research into chronic fatigue syndrome. i hope that's goodnews to the patients. it is good news. i'm brenda robertson and i'ma nurse at emory and grady, my background is communityhealth and divinity,
and i want to know if there'sanyone at the cdc or nih or beyond looking at researchand environmental triggers such as the chemicalloads that have been added to the food industry since the'70s and '80s like phosphates, fructose and citric acid, andi wondered if anyone's looking at that as serious triggers because this is awidespread illness. we don't have a specificfocus on that. we are aware that thereare environmental triggers
in some patients, but it issomething that we have in mind but we don't have an activeprogram in that right now. at the intramural program wereally don't have that kind of expertise, our focus willreally be on immune dysfunction, but the samples willcertainly be stored. i think once the extramuralcommunity gets involved that have expertise in thoseareas we would be delighted to work with them and providethem whatever resources we have in samples, patient samples.
i'd like to ask fora hand for our panel of speakers one more time. and please join us next monthfor public health grand rounds.
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