Sick Building Syndrome Sick Building Syndrome is a distinct clinical is a distinct clinical entity: we have the entity: we have the

proofproofSenate Health, Education, Labor and Pension Senate Health, Education, Labor and Pension

CommitteeCommittee1/12/061/12/06

Ritchie C. Shoemaker MDRitchie C. Shoemaker MDCenter for Research on Biotoxin Associated IllnessesCenter for Research on Biotoxin Associated Illnesses

Pocomoke, MdPocomoke, Md

Proof of CausationProof of Causation

Koch’s PostulatesKoch’s Postulates Repetitive exposure trialsRepetitive exposure trials Double blinded, placebo controlled trialsDouble blinded, placebo controlled trials Prospective hyperacute acquisition Prospective hyperacute acquisition

studiesstudies Reproducibility at multiple sitesReproducibility at multiple sites Peer-reviewed publicationsPeer-reviewed publications EVIDENCE-BASED MEDICINE!EVIDENCE-BASED MEDICINE!

Treatment leads to Treatment leads to definitiondefinition

Prior studies showed there were Prior studies showed there were health problems in patients exposed health problems in patients exposed to water-damaged buildings hosting to water-damaged buildings hosting toxigenic organisms, including fungitoxigenic organisms, including fungi

Effective therapy, beginning with Effective therapy, beginning with cholestyramine, gives us the ability cholestyramine, gives us the ability to correct and then study the diseaseto correct and then study the disease

Multiple sequential stepsMultiple sequential steps

Application of causationApplication of causation

Case definitionCase definition Individual casesIndividual cases ScreeningScreening Documentation of acquisition of illnessDocumentation of acquisition of illness Risk managementRisk management

– High risk occupationsHigh risk occupations– New hires in water-damaged buildingsNew hires in water-damaged buildings– Verify effective remediation occurredVerify effective remediation occurred

Case definition-1Case definition-1

103 patients /43 buildings (Brescia, Italy)103 patients /43 buildings (Brescia, Italy) 156 patients /150 buildings (Saratoga, NY)156 patients /150 buildings (Saratoga, NY) 21 patients/ 5 buildings (NT and T)21 patients/ 5 buildings (NT and T) 288 patients /125 buildings (ASTMH)288 patients /125 buildings (ASTMH) 26 patients/5 buildings (DB-PC trial)26 patients/5 buildings (DB-PC trial) 20 patients in hyperacute model (ASM 20 patients in hyperacute model (ASM

biodefense conference)biodefense conference) 40 patients, eight year follow-up40 patients, eight year follow-up 152 patients, age under 19152 patients, age under 19

Case definition-2Case definition-2

FIRST TIERFIRST TIER

Potential for exposurePotential for exposure Multisystem, multisymptom illnessMultisystem, multisymptom illness Absence of confoundersAbsence of confounders Differential diagnosisDifferential diagnosis

Case definition-3Case definition-3

SECOND TIERSECOND TIER

Genetic susceptibility; HLA DR by PCRGenetic susceptibility; HLA DR by PCR Hypothalamic impairment; low MSHHypothalamic impairment; low MSH Neurotoxic illness; VCS deficitNeurotoxic illness; VCS deficit Cytokine activation; MMP9 elevationCytokine activation; MMP9 elevation Pituitary involvementPituitary involvement

– ACTH/cortisolACTH/cortisol– ADH/osmolalityADH/osmolality

Why use such unusual Why use such unusual tests?tests?

Biologically produced neurotoxins activate Biologically produced neurotoxins activate innateinnate immune responses NOT immune responses NOT acquiredacquired immune responsesimmune responses

Illness is hidden by looking only at Illness is hidden by looking only at “standard lab tests”“standard lab tests”

Illness is obvious to anyone when looking Illness is obvious to anyone when looking at what is wrongat what is wrong

Tests might look unusual, but are readily Tests might look unusual, but are readily available to any physician; insurance available to any physician; insurance approved, Medicare approvedapproved, Medicare approved

Is mold illness rare?Is mold illness rare?

NO!NO!

We see 10 new patients a weekWe see 10 new patients a week Total in treatment data base exceeds Total in treatment data base exceeds

29002900 mold illness patients mold illness patients Total biotoxin illness patients Total biotoxin illness patients

exceeds exceeds 50005000 We have data on over We have data on over 40004000 controls controls

Fat Cell

Surface (“Toll”)

receptor

Biotoxin(HLA susceptible)

Increased Cytokines

Increased Leptin

Leptin receptor

Nerve cell

Body acquires

biotoxins or

toxin-producing

organisms from

food, water, air,

or insect bites

CapillariesIn genetically susceptible people, biotoxin binds to fat-cell receptors,

causing continuing, unregulated production of cytokines.

Removal from the body

Biotoxins have direct effects, including impairment of nerve cell function. One result is poor performance on contrast sensitivity test.

Excessive cytokine levels can damage leptin receptors in the hypothalamus.

High cytokine levels in the capillaries attract white blood cells, leading to restricted blood flow, and lower oxygen levels. Reduced VEGF leads to fatigue, muscle cramps, and shortness of breath (may be over-ridden by replacement with erythropoietin).

In most people, biotoxins are either removed from the blood by the liver or attacked by the immune system, broken down, and excreted harmlessly. In people who don’t have the right immune-system genes, however, biotoxins can remain in the body indefinitely.

Damaged leptin receptors lead to reduced production by the hypothalamus of MSH, a hormone with many functions.

Reduced ADH

Cytokine-related symptoms

High levels of cytokines produce flu-like symptoms: Headaches, muscle aches, fatigue, unstable temperature, difficulty concentrating.High levels of cytokines also result in increased levels of several other immune-response related substances, including TNF, MMP-9, IL-1B, and PAI-1. MMP-9 delivers inflammatory elements from blood to brain, nerve, muscle, lungs, and joints. It combines with PAI-1 in increasing clot formation and arterial blockage.

Fat cells then produce more leptin, leading to obesity (which doesn’t respond to exercise and diet).

Biotoxin

(HLA susceptible)

Biotoxin

(not HLA

susceptible)

Immune system symptoms

Patients with certain HLA genotypes (immunity-related genes) may develop inappropriate immunity. Most common are antibodies to:-- Myelin basic protein (often from fungal biotoxins; affects nervous-system functions)-- Gliadin (affects digestion)-- Cardiolipins (affects blood clotting)The “complement” alternative immune pathway may be triggered (detectable as an increase in levels of the proteins C3a C4a).

Reduced sex hormones

Reduced MSH can cause the pituitary to produce lower levels of anti-diuretic hormone (ADH), leading to thirst, frequent urination, and susceptibility to shocks from static electricity.

Reduced MSH can cause the pituitary to lower its production of sex hormones.

Changes in cortisol and ACTH levels

The pituitary may produce elevated levels of cortisol and ACTH in early stages of illness, then drop to excessively low levels later. (Patients should avoid steroids such as prednisone, which can lower levels of ACTH.)

Resistant Staph bacteria

Colonies of Staph bacteria with resistance to multiple antibiotics may develop in mucous membranes. The bacteria produce substances that aggravate both the high cytokine levels and low MSH levels.

Gastrointestinal problems

Lack of MSH can cause malabsorption in the gut, resulting in diarrhea. This is sometimes called “leaky gut” and resembles (but is not) celiac disease. Patients must avoid gluten, whey, and amylose.

Prolonged illness

White blood cells lose regulation of cytokine response, so that recovery from other illnesses, including infectious diseases, may be slowed.

Sleepdisturbance

Production of melatonin is reduced, leading to light, non-restorative sleep.

Chronic pain

Endorphin production is suppressed. This can lead to chronic, sometimes unusual, pain.

Rev. 10, 12-12-05

Stage 1: Biotoxin effects

Stage 2: Cytokine effects

Stage 3: Reduced VEGF

Stage 4: Immune effects

Stage 5: Low MSH

Stage 6: Resistant Staph bacteria

Stage 7: Pituitary hormone effects

© G. Alexander 2004

The Biotoxin Pathway

Reduced MSH

Increased Cytokines

VIP AVP

Hypothalamus

Sx CLUSTER ANALYSISSx CLUSTER ANALYSIS FatigueFatigue Weak, assimilation, Weak, assimilation,

aching, headache, light aching, headache, light sensitivitysensitivity

Memory, wordsMemory, words ConcentrationConcentration Joint, AM stiff, crampsJoint, AM stiff, cramps Unusual skin sensations, Unusual skin sensations,

tinglingtingling Shortness of breath, sinusShortness of breath, sinus Cough, thirst, confusionCough, thirst, confusion

Appetite, body Appetite, body temperature regulation, temperature regulation, urinary freq.urinary freq.

Red tearing eyes, Red tearing eyes, blurred vision, sweats, blurred vision, sweats, mood, ice-pick painsmood, ice-pick pains

Abdominal pain, Abdominal pain, diarrhea, numbnessdiarrhea, numbness

Tearing, disorientation, Tearing, disorientation, metallic taste metallic taste

Static shocks, vertigoStatic shocks, vertigo

Total SymptomsTotal Symptoms

   N=N=AverageAverage

SymptomsSymptoms

ControlsControls 239239 2.72.7

CasesCases 288288 19.819.8

Pediatric Pediatric controlscontrols 4040 1.21.2

Pediatric casesPediatric cases 112112 12.212.2

Testing from Neurotoxicology Testing from Neurotoxicology

Visual Contrast Sensitivity (VCS)Visual Contrast Sensitivity (VCS)– used over 40 years by DOD (Air Force) used over 40 years by DOD (Air Force)

and in studies of non-biological toxicantsand in studies of non-biological toxicants

– Reproducible, reliable, portable, non-Reproducible, reliable, portable, non-invasive, cheap! invasive, cheap!

– Just about the best marker beyond 4 Just about the best marker beyond 4 days of biotoxin-associated/cytokine days of biotoxin-associated/cytokine illnessillness

Visual Contrast SensitivityVisual Contrast Sensitivity

Non-invasive measure of contrastNon-invasive measure of contrast

Neurologic function of optic nerveNeurologic function of optic nerve

Eliminates near, far, color, static, motion, Eliminates near, far, color, static, motion, peripheral visionperipheral vision

Visual acuity better than 20/50Visual acuity better than 20/50

Controlled light > 70 foot lambertsControlled light > 70 foot lamberts

Used in prior studies for Used in prior studies for screening/monitoringscreening/monitoring

VCS

Acuity

Measuring Visual-Pattern Detection Function:Visual Contrast Sensitivity

Hig

h to

Low

Con

tras

t

Low to High Spatial Frequency (Cycles per Degree of Visual Arc)

VCS resultsVCS results

   N=N= AA BB CC DD EE

ControlsControls 239239 77.577.5 124.3124.3 136.8136.8 68.568.5 27.027.0

CasesCases 288288 37.137.1 77.477.4 89.689.6 56.556.5 18.3 18.3 

Pediatric Pediatric casescases   6565 60.860.8 100.2100.2 63.563.5 33.533.5 15.715.7

Previous Previous casescases 156156 23.923.9 80.980.9   97.797.7   62.362.3   16.116.1

HLA Disequilibrium, HLA Disequilibrium, Relative Risk > 2.0Relative Risk > 2.0

HLA-DRHLA-DR

ControlControl CasesCases

ADULTADULT CHILDCHILD

4-3-534-3-53 -- 3.63.6 4.44.4

7-2/3-537-2/3-53 -- 2.32.3 2.12.1

11-3-52B11-3-52B -- 2.92.9 5.35.3

12-3-52B12-3-52B -- -- 2.62.6

13-6-52ABC13-6-52ABC -- 2.12.1 --

17-2-52A17-2-52A -- 2.62.6 --

19 OTHER 19 OTHER LINKAGESLINKAGES -- -- --

N=N= 457457 260260 110110

RESULTS: Parameters of RESULTS: Parameters of Diagnostic Significance: Diagnostic Significance:

p<0.001p<0.001

  

AdultAdult ChildChild

illill wellwell illill well well

MSH, meanMSH, mean 15.315.3 23.223.2 9.49.4 45.645.6

MMP9, meanMMP9, mean 506506 225225 419419 187187

VEGF % < 31VEGF % < 31 3838 00 2727 00

VEGF % >200VEGF % >200 1515 00 1717 00

ADH/osmo dysADH/osmo dys 65%65% 14%14% NDND NDND

ACTH/ACTH/cortisoldyscortisoldys 44%44% 6%6% NDND NDND

MARCoNS +MARCoNS + 80%80% 3%3% NDND NDND

  

AdultAdult ChildChild

illill wellwell illill well well

C3aC3a > 1100> 1100 285285 757757 102102

C4aC4a 72877287 631631 42394239 553553

IL-10IL-10 10.210.2 0.50.5 8.68.6 0.30.3

IL-1BIL-1B 5.95.9 0.80.8 4.34.3 0.50.5

Interferon alphaInterferon alpha 398398 1414 NDND NDND

Erythropoietin % < Erythropoietin % < 7.3 7.3 2525 33 NDND NDND

Erythropoietin % > Erythropoietin % > 27.727.7 99 33 NDND NDND

RESULTS: Parameters of RESULTS: Parameters of Diagnostic Significance: Diagnostic Significance:

p<0.001p<0.001

Cases by WingspanCases by Wingspan

CASES WS>HT CASES, n=120 (63%)

CONTROLS WS>HT, n=19 (19%)

CASES WS<HT, n=72

CONTROLS WS<HT, N=81

50

40

30

20

100

ACLAAGA

MBP

IgA IgG IgM IgA IgG

Pediatric AutoantibodiesPediatric Autoantibodies

  

ACLAACLA AGAAGA

IgAIgA IgGIgG IgMIgM IgAIgA IgGIgG

ControlsControlsN=40N=40   00   00   3%3% 3% 3%    3%3%

CasesCasesN=50N=50   6%6% 12% 12%  16% 16%    12%12% 58% 58% 

Mold toxin illness isn’t allergy Mold toxin illness isn’t allergy

Mean IgE, by illness, all patients Mean IgE, by illness, all patients

   Cases N=Cases N= IgEIgE

ControlsControls No illnessNo illness 234234 2424

Mold casesMold cases Confirmed caseConfirmed case 367367 3131

Asthma Asthma casescases

Inhaled steroids + 1 Inhaled steroids + 1 other med, > 6 other med, > 6

months/yearmonths/year 4545 567567

Nasal Nasal allergyallergy

Nasal steroid + 1 Nasal steroid + 1 other med, > 6 other med, > 6

months/yearmonths/year 3838 432432

CONCLUSIONSCONCLUSIONS Mold illness is a distinctive, readily recognizable Mold illness is a distinctive, readily recognizable

clinical entity in adults and childrenclinical entity in adults and children

Significant objective differences exist between cases Significant objective differences exist between cases and controlsand controls

Findings support inflammatory cascades initiated by Findings support inflammatory cascades initiated by toxin exposure in genetically susceptible patientstoxin exposure in genetically susceptible patients

Abnormalities in innate immune responses point the Abnormalities in innate immune responses point the way to additional interventionsway to additional interventions

Use of a predictive model could make diagnosis Use of a predictive model could make diagnosis easiereasier