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ComponentsofbiochemicalstewinWDB:Fungi(moldanditsfragments)Bacteria(anditsfragments)VolatileOrganicCompoundsEndotoxinsActinomycetesSeeAppendix1foradditionaldetails

UnderstandingChronicInflammatoryResponseSyndrome(CIRS)Definition,Diagnosis,andTreatmentByNatashaThomas,M.D.

WhatisCIRS?ADeeperLookatBiotoxinsChronicInflammatoryResponseSyndrome(CIRS),alsoknownasbiotoxinillness,describesagroupofsymptoms,labfindings,andtargetedtestresultsassociatedwithbiotoxinexposure,especiallyingenetically-susceptiblepeople.Mostofwhatweknowaboutbiotoxinillnessistheresultofpractice-basedstudiesdonebyphysicianandresearcher,Dr.RitchieShoemaker.Hisresearchdatesbackto1997.WhenpracticingfamilymedicineintheruralcoastaltownofPocomoke,Maryland,helinkedapreviouslyundefinedillnesstoatoxinproducedbyafish-killingdinoflagellateknownasPfiesteria.Sincethen,Dr.Shoemakerhaslinkedthissamekindofillnesstotoxinsfromwater-damagedbuildings,aswellastoxinsassociatedwithtick-bornmicrobes.Overtime,Dr.ShoemakerdevelopedathoroughdescriptionofthisillnessandcalleditChronicInflammatoryResponseSyndrome(CIRS).Throughhispractice-basedresearch,healsodevelopedmethodstodiagnoseandtreatthisillness,bringingbackhealthtothousandsofpatientsworldwide.ExposuretoBiotoxinsRoutesofexposuremayinclude:

• InhalationinWDB:Occurswhenapatientisexposedtobiotoxinsthroughbreathingwhileinsideawater-damagedbuilding(WDB).WDBcanharboradangerousmixofvariouschemicals,mold,bacteria,andinflammagensthattogethercreatea“biochemicalstew,”whichcausesillness.CIRSisnotcausedbyoneparticularelementofthisbiochemicalstew,butratherthecombinationofthesethingscausing

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multi-systeminflammation.Shoemakerestimatesthat80percentofCIRScasesarecausedbyrepeatedexposuretowater-damagedbuildings.ThesecasesaredesignatedasCIRS-WDB.

• TickorSpiderBite:Patientsmaynotalwaysrealizetheyhavebeenbittenbyatick,thoughtheinfectionstickscarrycanincludeLymedisease(Borreliaburgdorferi)andBabesiosis(Babesiamicroti),amongothers.Thebiteofthereclusespiderspeciesmayalsocausebiotoxinillness.

• Ingestion:Patientswhohaveeatenreeffishcontaminatedwithdinoflagellatealgae(thatproducesCiguateratoxin)maydevelopanillness.ExposuretotheCiguateratoxinoccurswheneatingreeffishthathaveeatensmallerfishthatconsumedthetoxinproducingdinoflagellate.

• DirectContactwithContaminatedWater:PatientsmaybeexposedthroughdirectcontactwithwatercontaminatedbytoxinsinareasoffishkillssuchasPfiesteriaandCyanobacteria,includinginhalationofairborneoraerosolizedtoxinsfromthissource.

Mostbiotoxinshavethestructuralformofionophoreoramphipath.Theseareextremelysmallmoleculescapableofmovingfromcelltocellthroughcellmembraneswithoutbeingcarriedinthebloodstream.Thisabilityofbiotoxinstopassthroughcellmembraneswitheasemeanstheyaredifficultorimpossibletofindinstandardbloodtests.

Howdobiotoxinsgetintothebodyandwhydoesn’ttheimmunesystemtakecareofthem?Asmentioned,biotoxinscanenterthehumanbodythroughinhalation,ingestion,tickorspiderbites,anddirectcontactwithcontaminatedwatersources.Thebiotoxinscancauseacuteillness,butforpeoplewhoaregeneticallysusceptible,theycancauselastingchronicillness.Formanypeople,biotoxinsarerecognizedbytheimmunesystemcorrectly,brokendown,andremovedfromthebody.However,genetically-susceptiblepeoplehaveimmunesystemsthatdonotrecognizethebiotoxinsandfailtoremovethem,leavingthebiotoxinscirculatinginthebodyindefinitely,andcausinginflammationthroughoutthebody.

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DiagnosingCIRSDiagnosingCIRSandbiotoxin-relatedillnesscanbedifficult,ifnotimpossiblewithoutunderstandingbiotoxinsandhowtheycausedamageinthebody.

Figure1.Actionsofbiotoxinsinthebodyofanon-genetically-susceptibleperson

Figure1(above)showsthewaybiotoxinsimpactapersonwhoisnotgeneticallysusceptibletodevelopingbiotoxinillness.Inthissituation,theimmunesystemcorrectlyrecognizesthebiotoxin,leadingtoantibodyproductionandremovalfromthebody.Figure2showsthewaybiotoxinsimpactapersonwhodoeshavegeneticsusceptibility.Theimmunesystemisunabletocorrectlyidentifythebiotoxin,bindit,andremoveit.Thisallowsthebiotoxintorecirculatethroughoutmultiplebodysystemsrepeatedly,causingdamagealongtheway.Inthiscase,thebiotoxincanremaininthebodyindefinitely.

Figure2.Actionsofbiotoxinsinthebodyofagenetically-susceptibleperson

Duetothewaybiotoxinscauseillnessandthewaytheymovethroughoutthebodyanditsvarioussystems,morecommontestingmethodslikebasicbloodtestsarerarelyhelpful.What’smore,themicrobesorirritantsthatreleasedthebiotoxinsintothebodycouldalreadybeeliminatedfromone’ssystem.Thisiswhereevidence-basedmedicineandtestingcomesin.Tolookforbiotoxinsand

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makeadiagnosisincasesofCIRSandbiotoxin-relatedillness,wehavetolookfortheevidenceofthedamagethebiotoxinscauseinvariousbodysystems,particularlytheimmunesystem.

Inmanyothertypesofillness,doctorscantestforthepathogenordisease-causingorganismitself.InsuspectedcasesofCIRS,thebiotoxinstransferfromcelltocellthroughcellmembranessotheyaren’tpresentintheserumoftheblood(that’swhystandardbloodtestsarerarelyhelpfulinthesecases),andmakesfindingthedamagebiotoxinscausethekeytothediagnosis.Thereisacomprehensivesetoftestsweusetofindtheevidenceweneedtodeterminethatbiotoxinsareinvolved.However,firstwemuststartwithacompletemedicalhistoryandphysicalexam.Itisessentialtodocumentallofthesymptomsthepatientisexperiencing,andmedicalhistoryalongwithanyhistoryofknownexposuretocommonsourcesofbiotoxin-producingelements.Aftercollectingallofthisinformation,wemoveontoacomprehensivelistoftests.

SymptomClusterAnalysis:UnderstandingCIRSSymptomsWhileCIRSsymptomsmayappearrandomatfirst,Dr.Shoemaker’sstatisticalanalysisrevealedthatsymptomsdohavecommonalitiesthatallowthemtobebrokeninto13distinctclustersasshownbelow.EachblockbelowinFigure3listsauniqueclusterofsymptoms.

Figure3.The13uniquesymptomclustersusedinsymptomclusteranalysis

DiarrheaAbdominalpain

Numbness

Nu

CongestedsinusesShortnessofbreath

ImpairedmemoryDifficultywithword

finding

Heightenedskinsensitivity

Tingling/Pinsandneedles

DisorientationMetallictasteWateryeyes

WeaknessBodyachesHeadache

SensitivitytolightTroublelearningnewinfo

BlurryvisionNightsweatsMoodswingsIce-pickpain

Redorbloodshoteyes

Deep,persistentfatigue

Troubleconcentrating

DizzinessStaticshocks

ExtremethirstCough

Confusion

JointpainMorningstiffnessMusclecramps

TroubleregulatingbodytemperatureFrequenturination

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NeurotoxinBiotoxinsthatimpactnervesandimpairneurologicfunctionarealsocalledneurotoxins.

PatientsexperiencingCIRSarefrequentlymisdiagnosedwithotherdebilitatingillnesses,oftenleavingapatientsufferingforyears,goingfromdoctortodoctorinsearchofacorrectdiagnosisandtreatment.Commonmisdiagnosesinclude:

• ChronicFatigueSyndrome(CFS)

• Fibromyalgia

• DepressionandAnxiety

• Allergies

• Somatization(ex.Hypochondria)

• AttentionDeficitHyperactivityDisorder(ADD/ADHD)

• IrritableBowelSyndrome(IBS)

• Post-traumaticStressDisorder(PTSD)TestingforCIRS:Visual,Genetic,MRI,andBiomarkerTestingVisualContrastSensitivity(VCS)TestingBiotoxinsandtheinflammatoryresponsetheyproducehavebeenshowntocausenervedysfunction,leadingtoavarietyofneurologicalsymptoms,includingdiminishedVisualContrastSensitivity(abilitytodetectvisualpatterns).AccordingtoDr.Shoemaker’sresearch,thisdecreaseinVCSisduetoareductioninthevelocityofflowofredbloodcellsreachingstructuresintheeyeresponsibleforsendingvisualinformationthroughtheopticnervetothebrain.DuringaVCStest,thepatientisshownaseriesofimagesspecificallycreatedtomeasuretheperson’sabilitytodetectvisualpatterns.Apersonexperiencingabiotoxin-relatedillnesswillperformpoorlyduringthistest.TheVCStestishighlyaccurateandsupportsbiotoxin-relatedillnessdiagnosisin92percentofaffectedpeoplewithonly8percentpresentingasfalsenegative.TheVCStestisperformedattheinitialvisitandisrepeatedateachvisitaftertoassesshowwellthepatientisrespondingtothetreatment.

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AftermakingaclinicaldiagnosisofbiotoxinillnessandperformingVCStesting,wemoveontoasetofspecificlabteststoprovideadditionalinformationthatconfirmsdiagnosisandhelpsgaugetheseverityoftheillness.

GeneticTesting:HumanLeukocyteAntigen(HLA)TestTodetermineifapatientisgeneticallysusceptible,weuseHLADR/DQgenetictesting.TheHumanLeukocyteAntigen(HLA)systemisasetofgenesonchromosome6thatencodeforproteinsonthesurfaceofcellsthatareresponsibleforregulationoftheimmunesysteminhumans.Theseproteinshelpourimmunesystemdistinguishbetweenourowncellsandforeigncells.TheHLAtypeandrelatedimmuneresponseareakeyparttowhetherornotapersongoesontodeveloptheinflammationthatleadstoCIRS.Theimmunesystemiscomprisedoftheinnateimmunesystem(theimmunitywe’rebornwith)andtheadaptiveimmunesystem(immunitywedevelopafterbirth).Theinnateimmunesystemisnon-specificandactsasthefirstlineofdefensebyidentifyingantigens(foreignproteins)tosignaltheadaptiveimmunesystembyreleasinghighlevelsofinflammatorymolecules(suchascytokines),splitproductsofcomplement,andTGFbeta-1.Unlikeantibodies,theinflammatorymoleculesdonothaveaspecifictargetandcannotremovebiotoxins.Theadaptiveimmunesystemprovideslong-termimmunitybycreatingimmunologicalmemoryaftertheinitialexposuretospecificpathogen(suchasabiotoxin).Insusceptiblepeople,theinnateimmunesystem“sees”thebiotoxinsandkeepssignalingtotheadaptiveimmunesystem.However,theadaptiveimmunesystemcannot“see”thebiotoxinsanddoesnotmakeproperantibodiesagainstthem.Thepersistentcarriageofbiotoxinscontinuestotriggertheinnateimmunesystem.Inturn,theoveractiveinnateimmunesystemcreateshighlevelsofinflammationwhichleadstodysregulationofmultiplesystemsinthebodyanddevelopmentofCIRS.Dr.Shoemaker’sreviewofinternationalgeneregistries,matchedbycase-controlledstudies,revealedthat24percentofthepopulationis“moldsusceptible”duetotheirHLAhaplotype,puttingthematriskofdevelopingachronicbiotoxin-relatedillnessfromexposuretowater-damagedbuildings.Dr.Shoemakeralsonotedthat21percentofthepopulationis“Lymesusceptible,”

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CommonTermsandDefinitionsAutoimmunity–Animmuneresponsewherethebodyincorrectlyclassifiesselfcellsasnon-self,causingtheimmunesystemtoattackthebody’sowncellsandtissues.Biomarker–Measurablesubstanceorcharacteristicthatcanshowifvariousprocessesinthebodyarenormalordysfunctional.Cytokines–Cell-signalingmoleculesthathelpdirectimmunesystemcellsandprocesses.MastCellsandBasophils–Typesofimmunesystemcellsthatplayaroleinallergiesandalsoininflammationandautoimmunity.Mitochondria(l)–Astructurewithinacellthatmanagescellmetabolismandproducesenergythecellneedstofunctionproperly.Permeability–Degreetowhichbodytissueslikebloodvesselsandintestinesallowsubstancesororganismstopassthroughthecelljunctionsofthetissueintooroutofthatbodysystem.T-RegulatoryCells–Atypeofimmunecellthathelpscontrolautoimmuneresponseinthebody.

makingthesepatientslesslikelytorespondtoantibioticsforLymediseaseandmorelikelytodevelopchronicillnessinresponsetothebiotoxinspresentaftercontractingLymedisease(“Post-LymeSyndrome”).DependingontheirindividualHLAgenecombinations,apersonmaybesusceptibletooneormorebiotoxin-relatedillness.Forinstance,onepersoncouldbe“moldsusceptible,”whileanotherpersonis“Lymesusceptible,”andanotheris“multi-susceptible.”

BiomarkerTesting:TransformingGrowthFactorbeta-1(TGFbeta-1)TGFbeta-1isamoleculethatplaysanimportantroleincontrollingtheimmunesystembyproducingorsuppressinginflammation.ElevatedlevelsofTGFbeta-1indicatetheoccurrenceofacurrentoveractiveimmuneresponse.Forinstance,peoplewithasthma,multiplesclerosis,andvariousautoimmunediseasesoftenhaveelevatedlevelsofTGFbeta-1.TheseelevatedlevelsofTGFbeta-1damagenormalT-regulatorycellfunctionsthatcontrolorpreventautoimmunity,leavingthepersonatriskforautoimmune-relatedillness.LabValues:TransformingGrowthFactorbeta-1,normalrange<2382pg/ml.BiomarkerTesting:C4aC4aisabiomarkerinvolvedinactivatingaspecificprocessoftheinnateimmunesystemcalledacomplementcascadeandisusefulinevaluatingimmuneresponseinpeoplewithexposuretowater-damagedbuildings(WDB).Byactivatingimmunecellscalledmastcellsandbasophils,increasingsmoothmusclecontraction(smoothmuscleisfoundinbloodvesselsandintestines),increasingvascularpermeability,andcausingmitochondrialdysfunction,elevatedC4alevelscanleadto

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commonCIRSsymptomslikebreathingdifficulty,fatigue,anddysfunctioninthinkingandmemoryprocesses(cognitiveability).Dr.Shoemaker’sresearchshowsthatpatientswithhighC4alevelshavedecreasedbloodflowintothesmallvesselscalledcapillaries,whichimpactsthebraincausingdecreaseinthepatient’scognitiveability.LabValues:C4anormalrangeis0-2830ng/ml.

BiomarkerTesting:MatrixMetallopeptidase9(MMP-9)MatrixMetallopeptidase9(MMP-9)isanenzymeinvolvedinthebreakdownofcellmembranesinthebloodvesselwallswhichallowsinflammatorycompoundstomoveoutofthebloodthroughvesselwallsandintoorgansandtissuessuchasthelung,brain,muscles,joints,andperipheralnerves.InCIRS,cytokinestriggercertaintypesofwhitebloodcellstoreleaseMMP-9intothebloodstream,increasingtheamountofinflammatorycompoundsmovingintotissuesandcausingwidespreadinflammation.BecausecytokineactivityincreasesMMP-9production,MMP-9isanexcellentmarkerof“hidden”cytokineproduction.LabResults:MMP-9normalrangeis85-332ng/ml.

BiomarkerTesting:LeptinLeptinisknownasa“satietyhormone”andismadebyfatcellstohelpregulateenergybalancebyhinderinghunger.Highlevelsofleptinincreasetheamountoffatstoredinthebody,causingweightgain.Inbiotoxin-relatedillness,cytokinesattachtoleptinreceptorsinthehypothalamus,interferingwithleptinsignalingandcreatingleptinresistance.WeightgainduetoleptinresistanceiscommoninCIRSpatients.LabResults:Leptinnormalrange:men0.5-13.8ng/ml;women1.1-27.5ng/ml.

BiomarkerTesting:VascularEndothelialGrowthFactor(VEGF)VascularEndothelialGrowthFactorisasignalproteinproducedbycellsthatstimulatesgrowthofnewbloodvesselsinordertosupplyoxygentothetissueswhenbloodcirculationisinadequate.Inahealthybody,decreasedbloodflowincapillariesandresultinglowoxygensupplywilltriggerthereleaseofHypoxia-InducibleFactor(HIF).HIFstimulatestheproductionofVEGFanderythropoietin(EPO).VEGFincreasesbloodflowbycreatingnewbloodvessels,whileEPOincreasesproductionofredbloodcells;bothhelptoincreaseoxygensupplytothecells.InCIRS,VEGFissuppressedduetohighcytokinelevelswhichcausespooroxygensupplytothetissues,resultinginmusclecrampingandpost-

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CeliacDiseaseCeliacdiseaseisanautoimmuneillnessinwhichthebodylaunchesanimmuneattackinthesmallintestineandotherareasofthebodywhenglutenisingested,damagingthebody’sabilitytoabsorbnutrientsfromfoodandcontributingtooverallinflammationinthebody.

exertionalfatigue(aperiodofextremeexhaustionafterexerciseorstrenuousphysicalactivity).LabResults:VEGFnormalrangeis31-86pg/ml.

BiomarkerTesting:Anti-GliadinAntibody(AGA)

Anti-GliadinAntibodies(AGA)areproducedinresponsetogliadinfoundingluten.Glutenisaproteinfoundincertaingrainslikewheat,barley,andrye.AGAisoneoftheantibodiesthatcontributetoceliacdisease.Glutenismadeupofapproximately45percentgliadinand55percentglutenins.Thebodybreaksdowngliadinintochainsofaminoacidscalledpeptides.Inordertousethesepeptides,ourintestinalcells,tightlysealedlikeaninterlockinggateway,havetopullaparttoformopeningstoletthepeptidegothrough.Forhealthypeople,thesegatewayopeningscloseimmediatelyafterallowingthepeptidesthrough.IncertainCIRSpatientsandpatientswithceliacdisease,thegliadinpeptidescauseaninflammatoryandimmunereactionthatpreventstheopeningsbetweentheintestinalcellsfromclosingproperly.Inthiscase,strictlyfollowingagluten-freedietiscrucial.LabResults:AGAnormalrangeis0-19units.BiomarkerTesting:MelanocyteStimulatingHormone(MSH)MSHisahormonemadeinthepituitaryglandthatplaysacrucialroleinregulatingmanyotherhormones,inflammationresponses,anddefensesagainstforeignmicrobes.LeptininfluencesMSHproduction,however,duringaninflammatoryresponsewhereexcesscytokinesinterferewithleptinreceptors,MSHlevelsdrop.DeficiencyofMSHisverycommoninpatientswithCIRSandoftendoesnotreturntonormallevelsdespitetreatment.LowMSHincreasessusceptibilitytomoldillness,chronicfatigue,chronicpain(fromdecreasedendorphinproduction),insomnia(fromdecreasedmelatoninproduction),sexualdysfunction,andotherhormonalabnormalities.Inhealthypeople,ariseinleptinlevelswouldtriggerthebraintocreatemoreMSH.Inapatientwithbiotoxin-relatedillness,thisprocessfailswhenariseinleptinlevelsdoesn’tresultinthecreationofmoreMSHduetocytokineinterferencewithleptinreceptors.When

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MSHlevelsdon’trise,thebodyproducesmoreleptin,leadingtoleptinresistanceandcausingweightgainandproteinwasting.Inaddition,MSHplaysakeyroleinclosingtheintestinalgatewayopeningscreatedintheprocessingofgliadinpeptidesdiscussedintheprevioussectionandpreventinginflammation.LowMSHlevelsallowinflammationtoriseoutofcontrolandcausethoseintestinalgatewaystoremainopen,leadingtoaconditioncommonlyknownasleakygut(gutpermeability).Additionally,80percentofpatientswithlowMSHhaveMARCoNS(MultipleAntibioticResistantCoagulaseNegativeStaph).MARCoNSisdetectedthroughanAPI-Staphcultureofnasalbacteria.MARCoNSsecretetoxinsthatdecreaseMSH,makingitcriticaltotreatMARCoNStobringMSHlevelsbacktonormal.LabResults:MSHnormalrangeis35-81pg/ml.

BiomarkerTesting:Anti-DiureticHormone(ADH)andOsmolalityAnti-DiureticHormone(ADH),alsoknownasvasopressin,isahormonemadeinthehypothalamusthatcontrolsthebody’sabilitytoholdontofreewater.Osmolalityistheconcentrationofallchemicalparticles(suchassodium,potassium,andcalcium)thatareinthefluidpartofblood(serum).InBiotoxinillnesspatients,alackofregulationofsaltandwaterbalanceisapparentwhenADHislow(ortoohigh)butosmolalityisrelativelyhigh(ortoolow).Affectedpatientswillexperiencefrequenturination,dehydration,excessivethirst,anddehydration-relatedmigraineheadaches.Asthesodium(salt)levelinthebloodrisesbecauseofalackoffreewater,thepatient’ssweatwillalsocontainmoresalt.Theelectricalpropertiesoftheincreasedsaltcreateabattery-likeeffectthatincreasesstaticelectricalshocks.LabResults:ForADHnormalrangeis1.0-13.3pg/ml;ForOsmolalitynormalrangeis278-305mOsm/kg.

BiomarkerTesting:AdrenocorticotropicHormone(ACTH)andCortisolAdrenocorticotropicHormone(ACTH)isaveryimportantregulatoryhormonereleasedbythepituitaryglandtosignaltheadrenalglandstoproducecortisol.Cortisolisasteroidhormoneproducedbyadrenalglandsandisinvolvedinseveralprocessesinthebody,includingcreationofnewglucose(bloodsugar),regulatingglycogenstorageintheliver,immuneregulation,andthephysicalresponsetostresscommonlyknownas“fightorflight.”Normally,cortisolisreleasedinaregularpattern–levelsriseintheearlymorning(peakingaround8

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am)anddropintheevening.Chronicstresscausedbyinflammationorprolongedillnesscausescortisolproductiontobecomeirregularanddisruptsthebody’sabilitytodealwithnormaldailystressorssuchassleepdisturbance,bloodsugarimbalances,oremotionalstress.Usually,whencortisollevelsriseordrop,asignalissenttothehypothalamusandthentothepituitaryglandtoadjusttheproductionofACTH.InCIRSpatients,thisfeedbackmechanismisdisruptedduetohormonedysregulation,resultinginsymptomssuchasdaytimefatigue,nighttimeinsomnia,dizziness,andlowbloodsugar.LabResults:ForACTHnormalrangeis8-37pg/ml;forCortisolnormalrangesare-a.m.4.3-22.4andp.m.3.1-16.7ncg/dl.

BiomarkerTesting:PlasminogenActivatorInhibitor-1(PAI-1),Anti-cardiolipinAntibodies(ACA),andVonWillebrandFactorPlasminogenActivatorInhibitor-1(PAI-1),Anti-cardiolipinAntibodies(ACA),andVonWillebrandFactorarebiomarkersforabnormalbleedingconditions.Allthreeofthesebiomarkersplayaroleinbloodclotting.InflammatoryconditionssuchasCIRScancauseelevatedPAI-1,whichcanincreasetheformationofbloodclotsaswellasfibrosis(abnormalformationofconnectivetissue).ACAareantibodiesthattargetourowntissuesbyinterferingwiththephospholipidproteinsincellmembranes.ACAareelevatedinconnectivetissuedisorderssuchassclerodermaandlupus,andareassociatedwithfirsttrimestermiscarriages.Together,thecombinationofPAI-1andACAstronglyincreasestheriskofstroke,heartattack,anddeepveinthrombosis(DVT).CIRSpatientscanalsodevelopatypeofacquiredVonWillebrandSyndrome,whichpreventsbloodfromclottingproperly,leadingtosymptomsoffrequentorheavynosebleedsandheavyperiodsinwomen.

BiomarkerTesting:VasoactiveIntestinalPeptide(VIP)VasoactiveIntestinalPeptide(VIP)isaveryimportantneuropeptideproducedinmanyplacesinthebodyincludingthegut,pancreas,andthehypothalamusinthebrain.LikeMSH,VIPhelpsregulateinflammationthroughoutthebody.VIPalsohelpsregulatebloodflowandexerciseresponseofthepulmonaryartery(thearterythatmovesbloodfromthehearttothelungstopickupoxygen).InpatientswithlowVIPlevels,pressureinthepulmonaryarterybuildsduringexercisecausingshortnessofbreathanddifficultywithexercise.VIPreplacement

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istheimportantlaststepofDr.Shoemaker’sprotocol,restoringhealthforchronicallyillpatients.LabResults:VIPnormalrangeis23-63pg/ml.

MRITestingwithNeuroQuant®AnalysisAnewertoolinthediagnostictoolboxisanFDA-clearedsoftwareprogramcalledNeuroQuantthatanalyzesstandardMRIbrainscansforstructuraldamageandshrinkingofbrainvolume(atrophy).Thesoftwareusesinformationgatheredfromthousandsofbrainscanstofindtheseareasofdamagewithgreateraccuracythanwhatisoftenpossibletofindwithanalysisdonebyaradiologist.Damagetospecificstructuresinthebraincanbelinkedtospecificbiotoxins.Forexample,biotoxinsfrommoldhavebeenfoundtoimpactdifferentstructuresinthebrainthanbiotoxinsfromLymedisease.NeuroQuantisapromisingnewavenueinthediagnosisofbiotoxin-relatedillnesses.

TheShoemakerProtocol:TreatmentforBiotoxinIllness

Step1:RemovalfromExposureThefirstandmostimportantstepisforthepatienttoberemovedfromthesourceofexposure!Theotherstepsintheprotocolwillnotbeeffectiveifthepatientisexperiencingrepeatedexposure.Water-damagedbuildingsandthebiochemicalstewfoundinsidearethemostcommonsourceofexposureforCIRSpatients.(Foradditionalinformationonthebiochemicalstewfoundinwater-damagedbuildings,seeAppendix1).

NIOSH(NationalInstituteforOccupationalSafetyandHealth)estimatesthatupto50percentofallAmericanbuildingshavewaterdamage.Sourcesofwaterdamagecancomefromslowleakingpipes,poorfittingdrains,poorlyventilatedcrawlspaces,waterintrusioninthebasementandroofleaks,tonamejustafew.

Todeterminewhetheryourhomeorworkplacehasbeenwaterdamaged,testingbyanaccreditedlablikeMycometricsisrequired.MycometricsusesMSQPCR(Mold-SpecificQuantitativePolymeraseChainReaction)analysis,alsoknownasEnvironmentalRelativeMoldinessIndex(ERMI)oritsderivativeHERTSMI-2(HealthEffectsRosterofTypeSpecific[Formers]ofMycotoxinsand

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Inflammagens,secondversion).ERMItestsformorethanthirtytypesofmoldwhileHERTSMI-2testsforthefivetypesofmoldmostcommonlyinvolvedinCIRS.

IfERMIorHERTSMI-2testsindicatewaterdamagehasoccurred,anindoorairqualityspecialist(IAQ)shouldbeconsultedinordertodiagnosethecauseofwaterdamageandhelpensureproperremediation.

Step2:RemovalofBiotoxinsCSM(cholestyramine)isanon-absorbablepolymerresinthathasbeenFDA-approvedforuseinloweringcholesterol.Duetoitschemicalstructure,CSMhasanetpositiveelectricalchargethatattractsandbindsnegativelychargedbiotoxins.

InCIRSpatients,whentheliversecretesbileduringdigestion,thebilecontainssomeofthebiotoxins.BeforestartingCSM,thebiotoxinsinthebilearereabsorbedintheintestineandcycledbacktotheliverduringthenormalbilecirculationprocess.OncethepatienthasstartedtakingCSM,itbindsthebiotoxinsasdescribedaboveandthencarriesthemoutthroughthestool,stoppingthemfrombeingreabsorbedandcycledbacktotheliver.Overtime,CSMremovesmoreandmorebiotoxinsfromthebody.CSMmustbetakenonanemptystomachorbetweenmeals.ThetypicaldoseofCSMis4mgfourtimesdaily.CSMcancauseconstipation,bloating,acidreflux,andheartburn.Supplementationwithmagnesiumcanhelpeasethesymptomsofconstipation.

InpatientswhoareunabletotolerateCSMduetoitsgastrointestinalsideeffects,Welcholmightbeused.LikeCSM,Welcholisabileacidbindingresin,butithasfewersideeffects.WelcholislesseffectivethanCSMbecauseitonlyhas25%ofthebindingsitesfoundinCSM.Hence,itwilltakelongertonormalizelabvaluesandsymptomswhentreatingwithWelcholcomparedtoCSM.

Inhisresearch,Dr.Shoemakertriedotherbindingagentssuchascholestipol,charcoal,claysuchasbentonite,chitosan,andpectin.Unfortunately,hehasnotseenthesamechangeinlabvaluesusingthesebinders.

TreatmentwithCSMorWelcholmustbecontinuedforaminimumof30daysanduntilthepatient’sVCSscorehasnormalized.

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MARCoNSandYourDogInDr.Shoemaker’sresearch,hediscoveredthatdogscanalsobecarriersofMARCoNS.Cats,however,arenotMARCoNScarriersandareunaffectedbyit.

Step3:TreatMARCoNSAfterthefirstmonthoftreatmentwithCSM,patientswhosenasalculturetestedpositiveforMARCoNS(MultipleAntibioticResistantCoagulaseNegativeStaph)needtobetreateduntilcolonizationisgone.MARCoNSsecretetoxinsthatlowerMSH(MelanocyteStimulatingHormone),producesubstancesthatdestroyredbloodcells(hemolysins),andraisecytokinelevels.AnasalspraycalledBEG(Bactroban/EDTA/Gentamicin)isusedtodestroyMARCoNS.BactrobanandGentamicinworktogetheragainsttheMARCoNSwhileEDTAdissolvestheprotectivebiofilmthatthebacteriaproduces.Biofilmisaslime-likesubstancecreatedbybacteriatohelpthemattachtoasurface,sticktoeachothertoformcolonies,andtoprotectthemselvesfromimmuneattackorantibiotics.ThebiofilmcreatedbytheMARCoNSbacteriaispartofwhatcreatesitsantibioticresistance.WhenfirstbeginningtreatmentforMARCoNS,somepatientsmayfeeltheirsymptomsgetworseinthebeginning.Thereasonisbecauseasthebiofilmisbrokendown,theencasedbacteriaisexposedalongwithitstoxins,resultinginatemporaryincreaseintoxinlevels.

MARCoNStreatmentcontinuesfor30days,followedbyanewnasalculturetesttomakesuretheMARCoNScolonizationisgone.IfthecultureisstillpositiveforMARCoNSafterthefirst30daysoftreatment,othersourcesmustbeinvestigated.AfewsourcesofcontinuedMARCoNSexposureincludethefamilydog,infectedrootcanalteeth,oradeep-seatedjawbonecavitation(weakenedareaofthejawbonethatharborsbacteria,eventuallykillingthebonetissueandleavingenclosedspacesofdecomposingboneandteemingwithbacteria).Abiologicaldentistwilloftenneedtobeconsultedregardinganysuspectedinfectionsinrootcanalteethorpotentialcavitations.

Step4:CorrectionofAnti-GliadinAntibodiesInpatientswithbiotoxinillnesswhohavelowMSH,thereisanincreasedriskofinflammationandautoimmunedisease.IfthosepatientsalsohavehighlevelsofAnti-GliadinAntibodies,theyneedtoremainonagluten-freedietforatleastthreemonths,potentiallylonger.Thesepatientsshouldalsobeevaluatedforceliacdisease.

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Step5:CorrectionofAndrogensPatientswithbiotoxinillnessoftendevelopanimbalanceoftheirandrogen-basedhormones,suchasdehydroepiandrosterone(DHEA)andtestosterone.Currentresearchsuggeststhisimbalancecouldbecausedbyanincreaseinanenzymecalledaromatase,whichchangestestosteronetoestradiol(aformofestrogen).RecommendedtreatmentwouldbesupplementationwithhighqualityDHEAorhumanchorionicgonadotrophin(HCG).VasoactiveIntestinalPeptide(VIP)treatmentcouldbeconsideredatthissteptostabilizethearomataseenzyme.

Step6:CorrectionofADH/OsmolalityDysregulationDesmopressin(DDAVP)isasyntheticformofADH(Anti-diureticHormone)thathelpscorrectwaterlossanddehydrationforpatientswithbiotoxinillness.DDAVPisavailableasanasalsprayortabletmedication.Bloodserumosmolality(concentrationofchemicalsinbloodserumorplasma)andbloodsodiumlevelsneedtobemonitoredwithextremecautionwhileonthismedication.Step7:CorrectMMPandVEGFThetreatmenttocorrectMMPandVEGFdependsonthepatient’sleptinlevel.Ifthepatient’sleptinlevelislessthan7,supplementingwithhighdoseOmega-3fattyacids(2.4gmEPAand1.8gmofDHA)workstocorrecttheimbalance.Ifthepatient’sleptinlevelishigherthan7,thepatientmaybeprescribedActos(45mgoncedaily)for30days.Actosmaycauselowbloodsugarandalsohasablackboxwarningofincreasedriskofbladdercancerwithlong-termuse.

Patientsmuststrictlyfollowalowamylosedietduringthisstepoftheprotocol.Amyloseisatypeofstarchmadeoflongchainsofglucose(sugar).Thedietcallsforavoidingmanystarchesandformsofsimplesugars.SeeAppendix2foralistoffoodstoeliminatewhileonalowamylosediet.

Step8:CorrectC3aForpatientswithhighC3alevels,theimmunesystemisbeingtriggeredbycellmembranesinthepresenceofmicrobesthatcauseLymedisease.TheprimaryLymeinfectionneedstobetreatedwithantibioticsasappropriatebeforemovingtothenextstepintheprotocol.Thepatientwillalsobeprescribedahighdosecholesterolmedication(oftenZocor80mg)alongwithaCoQ10supplement.

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Step9:CorrectC4aC4aisbiomarkerthatshowshowseverethepatient’scaseofCIRSis.Treatmentwitherythropoietin(Procrit)reducesC4a.Procrithasablackboxwarningduetoincreasedriskofbloodclots.ThedecisionwhetherornottouseProcritisbasedonindividualpatientassessmentandrequiresclosemonitoring,extremecaution,andthepatient’sinformedconsent.IfProcritcannotbeused,thenVIPshouldbeconsidered.

Step10:CorrectTGFbeta-1Cozaar(Losartan)canbeusedtolowerTGF-beta-1anddecreasetheriskofautoimmuneresponseandillness.PatientswithlowbloodpressurewhocannottakeCozaarshouldbeconsideredforVIPtreatmentatthisstepinstead.

Step11:VasoactiveIntestinalPeptide(VIP)Vasoactiveintestinalpeptide(VIP)isa28aminoacidregulatoryneuropeptidewithmanybeneficialphysiologicaleffects.Inhisresearch,Dr.ShoemakernotedlowlevelsofVIPin98percentofthepatientswithbiotoxinillness.Incontrast,only10percentofcontrolpatientshadlowVIPlevels.

VIPrestoresregulationoftheinflammatoryprocessesthathavegoneawryinbiotoxinillness.Italsonormalizesgenomics,downregulatesaromatase(enzymethatconvertstestosteronetoestrogen),lessenschemicalsensitivities,releasesendorphins,andreducesthe“sicker-quicker”phenomenon.The“sicker-quicker”phenomenonoccursinsomepatientsfollowingre-exposuretowater-damagedbuildings.VIPisthoughttobeinvolvedindownregulatingC4aproduction,whichmaybethekeytoreducingthe“sicker-quicker”phenomenon.

VIPtreatmentistheverylaststepintheShoemakerprotocol.Bythistime,mostpatientsalreadyfeelmuchbetterbutsomewillrequirethislaststepintheprotocol.BeforestartingVIPtreatment,allofthepriorstepsoftheprotocolmusthavebeencompletedsuccessfully.Also,itiscriticaltomakesuretheVCStestisnormal,MARCoNScultureisnegative,andinthecaseofwater-damagedbuildings,thatthesourceofexposurehasbeensuccessfullyremediated(ERMIresultislessthan2orHERTSMI-2resultislessthan10).IfallthestepsoftheprotocolarenotcompletedandifthereisongoingexposuretoWDB,theVIPtreatmentwillnotwork.

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Ifalloftheaboveconditionsaremet,VIPtreatmentcanbegin.VIPadministrationshouldbefollowedbytheprescribingdoctor.FirstdoseofVIPshouldbeadministeredinthedoctor’soffice.Thispartoftheprotocolincludesmeasuringlabs(lipase,TGFBeta1,C4a)rightbeforeVIPadministrationand15minutesafter.Labsshouldberepeatedin30days.IfthereisanelevationintheinflammatorymarkersafterVIPadministration,thisindicatesthereisanongoingexposuretobiotoxins.Iflipaseincreasesorthepatientdevelopsabdominalpain,VIPtreatmentshouldbestopped.

Dr.ShoemakerandtheShoemakerProtocolDr.RitchieShoemakerisapioneerintheresearchanddiscoveryofbiotoxinillness(ChronicInflammatoryResponseSyndrome)andtheimpactsofexposuretowater-damagedbuildings.

Inthetimesincehisfirstbreakthroughintheareaoftoxin-relatedillnessesin1997,hehascontinuedtoresearch,study,test,anddeveloptreatmentoptionsforpatientscommonlymisdiagnosedwithalonglistofillnessesandhelpthemrecover.Hehaspublishedeightbooks,produceddozensofmedicalpapersincollaborationwithotherresearchersfromallovertheworld,emphasizedtheconceptofevidence-basedmedicine,andthroughthatevidencecreatedauniquetreatmentprotocolthathashelpedcountlesspatientsrecovertheirhealth.

Despitebeingtechnicallyretired,Dr.Shoemakercontinuestoresearchtheconnectionbetweenbiotoxinsandgenetics,aswellasdiagnosticandtreatmentoptionsforbiotoxin-relatedillnesses.Currently,Dr.ShoemakerisusingPAXgenetestingtoresearchtheroleofgenomicsfordiagnosisandtreatmentofbiotoxinillness.HeisalsocontinuinghisresearchwithNeuroQuantanalysisofMRIbrainscansasadiagnostictoolforidentifyingspecificbiotoxinsandtheirimpactsonthebrain.Hispersistenceanddedicationinraisingawarenessofbiotoxin-relatedillnessesalongwiththeirsourcesandtreatmentshasbenefitedthelivesofcountlesspatientsacrosstheglobeandwillundoubtedlychangethecourseofmedicineinthefuture.

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APPENDISES

APPENDIX1

BiochemicalStewThecomponentsofthe“biochemicalstew”foundinwater-damagedbuildingscanbeacomplexmixtureofavarietyofthefollowing:Fungi-related Mold,Conidia,HyphalFragments,SpirocyclicDrimanes,Mannans,

Aspergilluspenicilloides,Aspergillusversicolor,Wallemiasebi,Stachybotryschartarum,Chaetomiumglobosum

Bacteria-related Gram-negativebacteria,Gram-positivebacteria,Actinomycetes,Mycobacteria,Mycoplasma,Actinobacteria,Chlamydia,Nocardia,Hemolysins

Inflammagens Bioaerosols(organicdust),BetaGlucans,InorganicXenobiotics,Siderophores

VOCs MicrobialVolatileOrganicCompounds,ChemicalVolatileOrganicCompounds,BuildingMaterialVolatileOrganicCompounds

Particulates CoarseParticulates,FineParticulates,UltrafineParticulates,Nano-sizedParticulates

Other CellFragments,CellWallComponents,Endotoxins,Proteinases,Chitinases,Inflammagens,Lipopolysaccharides

APPENDIX2

Dr.Shoemaker’sNo-AmyloseDietThelistoffoodsbelowshouldbecompletelyeliminatedwhilethepatientisonDr.Shoemaker’sNo-AmyloseDietduringStep7oftheShoemakerProtocol.FoodstoEliminate:

! Bananas

! Grains:Wheat,Rice,Rye,Oat,Barley,andMillet

! HiddenSugars:Glucose,Dextrose,Sucrose,Maltodextrin,Sugar,CornSyrup,HighFructoseCornSyrup

! AllFoodsGrownUnderground:Beet,Carrot,Parsnip,Radish,Potato,SweetPotato,Yam,Peanuts(Exception:GarlicandOnionsareallowed.)

! ProcessedFoods:FastFood,SoftDrinks,CommercialFruitJuic

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RESOURCES

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2. BerryY.APhysician’sGuidetoUnderstandingandTreatingBiotoxinIllness:BasedontheworkofRitchieShoemaker,M.D.Presentation:April3,2014.

3. ClaytonEW,AlegriaM,BatemanL,ChuL,CleelandCS,DiamondB,GaniatsT,KellerB,KlimasN,LernerAM,MulrowC,NatelsonB,RoweP,ShalanskiM.BeyondMyalgicEncephalomyelitis/ChronicFatigueSyndrome:RedefininganIllness:ReportGuideforClinicians.InstituteofMedicine.2015.

4. GreenblattJM,BroganK.IntegrativeTherapiesforDepression:RedefiningModelsforAssessment,Treatment,andPrevention.CRCPress:BocaRatonFL,2016.

5. KanePC,FosterJS,KaneE.TheDetoxxBook:DetoxificationofBiotoxinsinNeurotoxicSyndromes–Physician’sGuide.BodyBio:MillvilleNJ,2009.

6. McMahonSW,ShoemakerRC,RyanJC.ReductioninForebrainParenchymalandCorticalGreyMatterSwellingacrossTreatmentGroupsinPatientswithInflammatoryIllnessAcquiredFollowingExposuretoWater-DamagedBuildings.JournalofNeuroscienceandClinicalResearch.2016;1:1.

7. ShoemakerRC.DesperationMedicine.GatewayPress:BaltimoreMD,2001.

8. ShoemakerRC,SchallerJ,SchmidtP.MoldWarriors:FightingAmerica’sHiddenHealthThreat.GatewayPress:BaltimoreMD,2005.

9. ShoemakerRC,HudnellHK,HouseDE,vanKampenA,PakesGE.AtovaquonePlusCholestyramineinPatientsCoinfectedwithBabesiamicrotiandBorreliaburgdorferiRefractorytoOtherTreatment.AdvancesinTherapy.Jan/Feb2006;23:1.

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10. ShoemakerRC.SurvivingMold:LifeintheEraofDangerousBuildings.OtterBayBooks:BaltimoreMD,2010.

11. ShoemakerRC,MarkL,McMahonS,ThrasherJ,GrimesC.Researchcommitteereportondiagnosisandtreatmentofchronicinflammatoryresponsesyndromecausedbyexposuretotheinteriorenvironmentofwater-damagedbuildings.PolicyholdersofAmerica.2010July27:1-161.

12. ShoemakerRC,HouseD,RyanJC.Structuralbrainabnormalitiesinpatientswithinflammatoryillnessacquiredfollowingexposuretowater-damagedbuildings:avolumetricMRIstudyusingNeuroQuant®.NeurotoxicologyandTeratology.2014Sep-Oct;45:18-26.