10/23/2019 - Proof of causation
Throughout medical history new medical ideas are rarely greeted with open arms and joy. The usual approach and indeed, the scientific approach are to look at new ideas with skepticism and as an unproven hypothesis. The timeline between introduction of a new idea to assimilation into the standard of care is measured in years not in months.
The concept of a chronic inflammatory response syndrome (CIRS) has been discussed as a novel idea beginning in 1998 under the name as a chronic neurotoxin-mediated illness. CIRS itself is codified in 2010. There is robust CIRS literature with over 500 physicians nation-wide and a smaller number worldwide using principles that are peer-reviewed and published. Looking at water damaged buildings as a source, over 30 different kinds of elements have been associated following exposure with an acquisition of inflammatory responses. These inflammatory responses are innate, not acquired. This is not allergy.
CIRS is readily identifiable. There is a case definition for CIRS. There are multiple published case/control studies; two placebo-controlled, double blinded clinical trials; and papers ranging from study of injury to brain (using NeuroQuant) to transcriptomics looking at the hallmark that is molecular hypometabolism. Proteomics have been well described as well.
Beginning in 2001, some of the early concepts of exposure to water-damaged buildings hurting people were tested in American courts. The challenge was to show causation. Causation is not shown just by association of an abnormality found in a case but not in control, but case/control studies are useful in supporting prospective exposure trials that will determine risk and causation.
Beginning in 2003, a prospective trial protocol, called sequential activation of innate immune elements (SAIIE) began to win court cases. Simply stated, the protocol would show the possibility of someone who met a case definition for a water-damaged building patient to go through the published, peer-reviewed clinical trial, comparing the labs that were drawn before treatment at baseline to after treatment (AC1). We expect to see reduction of abnormalities in proteomics. There will be a genetic basis (HLA) showing relative risk that does not change; it is the proteomics and hormone abnormalities that show the defining markers for this illness.
The prospective trial begins after the blood is drawn for AC1. Patients at that time have already proven their home, for example, is safe as judged by microbiologic testing. There will no evidence of amplified growth of particular fungi, actinomycetes and gram-negative rods releasing endotoxins in that environment, compared to one in which the building is considered to be possibly causing the illness. AC1, say done on a Friday, is followed by three days of time away from a potentially affected building, off all meds, with blood done now three days later on Monday (HOC or home off cholestyramine). This step of the trial lets us access what exposures to the ubiquitous fungi of the world actually are doing. If there is no evidence of water-damage and no evidence of biologic amplification, HOC values have been shown to remain unchanged and will equal AC1 values. After blood is drawn for HOC on Monday morning, patients will
then enter the affected building, either a school or workplace in this example for an average day of exposure. This exposure begins BOC1.
The same blood tests as in AC1 and HOC will be drawn the following day, Tuesday, completing BOC1, building off cholestyramine Day 1, as that will tell us what inflammatory events took place during the first day of exposure. Following the blood draw on Tuesday, testing the same labs, then BOC2, is begun. This will tell us what happened on Day 2 of exposure. BOC2 blood work is drawn on Wednesday with re-exposure for BOC3 occurring on Wednesday afternoon. On Thursday morning, the last blood is drawn for BOC3 and the trial has ended.
If the patients become ill during the three days of exposure but not ill with the three days out of exposure, we can predict that there will be hard objective data showing abnormalities consistent with published data. Even better, there will be no confounding exposures!
What we look at on Day 1 is a rise of C4a and TGF beta-1. These are rapidly changing elements of complement and then Th-17 analogs. We also will see a fall in factor VIII of von Willebrand’s profile with a recovery by Day 3 of the trial. For von Willebrand’s profile we will see a continued fall of von Willebrand’s antigen and ristocetin associated cofactor by Day 3. Bleeding (nose or lung) often occurs here.
On Day 2 we will see a rise of leptin in that it marks the effect of cytokine binding to the leptin receptor in the hypothalamus. With cytokine elevation impacting on the leptin receptor, leptin levels will rise on Day 2 and not on Day 1.
On Day 3, we look at the complex effect of cytokines on endothelial cells causing the initiation of gene activation for MMP-14 with subsequent cleavage to make MMP-9. MMP-9 becomes a measurement of cytokine activation.
We also look at VEGF as levels will rise rapidly on Day 1. This rise of VEGF will subsequently trigger a feedback loop involving TGF beta-1 to suppress VEGF such that we will see a fall of VEGF by the end of Day 3.
In a published rubric of scoring we look at symptom reproducibility within three days and lab reproducibility of baseline in three days. If we find partial changes, that will get partial credit.
The difference between cases and controls is extraordinary. There are very few “close calls.” Should we have prospective reacquisition trials showing the elements of risk, we have completed the due diligence in proving causation. One may choose to argue about C4a and TGF beta-1. With that in mind, there is ample peer-reviewed, published literature looking at these important parameters as markers for injury.
Suffice to say, SAIIE is complex but the basic concept is simple. We should be able to show the same abnormalities in BOC that we found in baseline consistent with sequential gene activation