sick building syndrome is a distinct clinical entity: we...
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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 Double blinded, placebo controlled
trialstrials 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 Documentation of acquisition of
illnessillness 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, Shortness of breath,
sinussinus 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
1.240Pediatric controls
12.2112Pediatric cases
19.8288Cases2.7239Controls
AverageSymptomsN=
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
16.1 62.3 97.780.923.9156Previous
cases
15.733.563.5100.260.8 65Pediatric
cases
18.3 56.589.677.437.1288Cases
27.068.5136.8124.377.5239Controls
EDCBAN=
HLA Disequilibrium, HLA Disequilibrium, Relative Risk > 2.0Relative Risk > 2.0
CHILDADULT
---19 OTHER LINKAGES
110260457N=
-2.6-17-2-52A
-2.1-13-6-52ABC
2.6--12-3-52B
5.32.9-11-3-52B
2.12.3-7-2/3-53
4.43.6-4-3-53
CasesControl
HLA-DR
RESULTS: Parameters of RESULTS: Parameters of Diagnostic Significance: Diagnostic Significance:
p<0.001p<0.001
well illwellill
NDND6%44%ACTH/cortisold
ys
NDND3%80%MARCoNS +
NDND14%65%ADH/osmo dys
017015VEGF % >200
027038VEGF % < 31
187419225506MMP9, mean
45.69.423.215.3MSH, mean
ChildAdult
well illwellill
NDND325Erythropoietin % <
7.3
NDND39Erythropoietin % >
27.7
NDND14398Interferon alpha
0.54.30.85.9IL-1B
0.38.60.510.2IL-10
55342396317287C4a
102757285> 1100C3a
ChildAdult
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
5040
30
2010
0
ACLAAGA
MBP
IgA IgG IgM IgA IgG
Pediatric AutoantibodiesPediatric Autoantibodies
AGAACLA
58% 12%16% 12% 6%CasesN=50
3%3% 3% 0 0ControlsN=40
IgGIgAIgMIgGIgA
Mold toxin illness isn’t allergy Mold toxin illness isn’t allergy
Mean IgE, by illness, all patients Mean IgE, by illness, all patients
43238
Nasal steroid + 1 other med, > 6
months/year
Nasal allergy
56745
Inhaled steroids + 1 other med, > 6
months/year
Asthma cases
31367Confirmed caseMold cases
24234No illnessControls
IgECases N=
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 Significant objective differences exist between cases and controlscases and controls
Findings support inflammatory cascades initiated Findings support inflammatory cascades initiated by toxin exposure in genetically susceptible by toxin exposure in genetically susceptible patientspatients
Abnormalities in innate immune responses point Abnormalities in innate immune responses point the way to additional interventionsthe way to additional interventions
Use of a predictive model could make diagnosis Use of a predictive model could make diagnosis easiereasier