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From the Townsend Letter
November 2016

Potential Proof of Chemical Sensitivities
by Laurie Dennison Busby, B.Ed.
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Patients with multiple chemical sensitivities (MCS) may present with airway symptoms, especially upper airway nasal symptoms; sometimes cutaneous symptoms; and/or adverse drug reactions (ADR).1-3  Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are frequent comorbidities, and patients with CFS have a,"high prevalence" of idiopathic nonallergic rhinopathy.4,5

I deveoped CFS-MCS after a series of insults to my health within a year's time; the last one was a pesticide exposure immediately followed by a virus that lasted months.  I was left with headaches, upper airway reactions, crimson crescents on my pharyngeal pillars, swollen lymph nodes in my neck, and ADR among other symptoms.

If I tried to go into a clothing store, in addition to upper airway symptoms,  I would get a headache in the back of my head and the swollen lymph nodes in my neck and joints in my hands would hurt.  It appeared my immune system, which had geared up to fight the virus, was now fighting everything (and might partially account for the latter two symptoms).

At the two year mark, during a partial thyroidectomy due to a tumor, at my urging and because during the surgery the lymph nodes looked "so deteriorated," the surgeon took a lymph node too.  It came back reactive hyperplasia. (I was also developing Hashimoto's thyroiditis.)

I now know I carry HLA-DR4, one of the immune system genes associated with risk of developing hypersensitivity conditions, respiratory sensitivities and chronic urticaria.6,7

I also believe I probably have lower levels or activity of some xenobiotic metabolizing enzymes.  This may be due to a genetic predisposition (my mom's side of the family require lower doses of a medicine and are prone to ADR) and/or subtle damage done to the liver during the infection.

When I started searching for answers, I found there is some "potential proof" out there of the existence of and possible mechanisms behind chemical sensitivities.  So while some doctors and researchers continue to debate the validity of this illness, this is what others have already found:

Airborne chemicals or irritants, even in natural fragrances, encountered in everyday life have been reported as triggers of symptoms in asthma, pregnancy, migraines, and seizures, and an increased sense of smell has been reported by patients during pregnancy and some infections.8-12  The descriptions, in those other conditions, sound similar to MCS:

"Odorants … especially perfume, may trigger migraine attacks after a few minutes of exposure.10  Other triggers included paints, cleaning products, beauty products, cooking smells, and foul odors in migraine and cigarette smoke, spices, and coffee in pregnancy.9,10

While there are multiple ways the brain may have become effected, some infectious agents have been found to make their way to the areas of the brain that may be associated with some of the symptoms in MCS.

In CFS, Epstein-Barr virus (EBV) and human herpes virus 6 (HHV-6) are often cited as confections, with increased HHV-6 antibody titers in 47% of patients in one CFS cohort.13,14 

In autopsies of people without signs of systemic infection,"…  the frequency of HHV-6 DNA in the olfactory bulb/ tract region was among the highest in the brain regions examined."15

"Viruses injected into the nasal cavity have been found to enter olfactory neurons, replicate, travel into the olfactory bulb and then into the central nervous system (CNS)," due to,"the close proximity and the synaptic connections between the nasal cavity and the CNS."16

In mice, following intranasal inoculation with herpes simplex virus (HSV)  strains, these viruses, " … were found to infect chemosensory neurons in the vomeronasal organ (the pheromone detector)."17  HSV-1 then transmitted to the accessory olfactory bulb, amygdala, and olfactory and trigeminal systems. "HSV-2 strain 186 predominantly attacked the brainstem including the trigeminal system… . "17

When, " … mice were inoculated with HSV-1 by the corneal route … HSV-1 latency was detected predominantly in the trigeminal ganglia, brainstem, olfactory bulbs, and temporal cortex.  Latent HSV-1 infection was associated with chronic inflammation… "18

Sensory neurons, "… situated in the trigeminal ganglion, densely innervate the nasal mucosa at their peripheral endings and terminate centrally in the trigeminal nucleus of the brain stem.  Electrical and chemical activation of nasal trigeminal neurones has been shown to cause brain stem c-FOS production … "19

This trigeminal pathway may, in part, help explain my headaches.

"The nasal mucosa is one of the anatomical region which have the highest density of sensory innervation."20

In some instances, an initial environmental exposure (infectious or chemical) may have triggered epithelial damage and in response, increased sensory neuron neurogenesis as a repair mechanism, "Olfactory neurogenesis … is stimulated by epithelial damage… . olfactory sensory neurons arise after biochemical or mechanical stress of rat and mouse olfactory epithelial cell cultures… . stress disrupts cell surface contacts to induce the immediate neuronal precursors to undergo final differentiation into olfactory sensory neurons. This may be a mechanism for enhanced neurogenesis after epithelial damage."21

In MCS and MCS-related disorders, there was nasal nerve fiber proliferation, "Preliminary data indicate the nasal pathology of these disorders is characterized by defects in tight junctions between cells, desquamation of the respiratory epithelium, glandular hyperplasia, lymphocytic infiltrates, and peripheral nerve fiber proliferation."1

In MCS, the increased density of nerves in the nose, along with their possible projections throughout the trigeminal pathway, may help explain anecdotal reports by patients with MCS that their fragrance-induced respiratory symptoms are a little less severe if they temporarily breath through their mouths rather than their nose (for example, during an elevator ride with someone wearing perfume).1 

In response to an odor provocation challenge test, a person with suspected odor-induced dysphonic symptoms, " … responded differently to the odors when presented nasally verses orally.  Oral breathing showed less severe and less frequent laryngeal hypersensitivity reactions."22

In healthy volunteers, "… . nasal challenge with bradykinin (BK) causes a sensation of sore throat which is just as intense as that caused by oropharyngeal challenge and with the sensation of sore throat persisting for a longer period on nasal challenge when compared with oropharyngeal challenge."23 

In chronic rhinosinusitis, MCS, CFS, and infection, BK, nerve growth factor (NGF), and/or substance P (SP) may be increased.13,24-28

In chronic rhinosinusitis, "The concentration of sensory neuropeptides is increased in the nasal mucosa …  In contrast, the activity of the enzymes involved in the degradation of these sensory neuropeptides is markedly reduced."24  The decease in dipeptidylpeptidase IV (DPPIV) activity has, "…been shown to contribute to the severity of chronic inflammatory rhinitis."25

In one CFS cohort, some patients may have increased BK due to decreased C1 inhibitor.13  In one MCS cohort, after provocation, NGF was increased in nasal lavage.26  In another MCS cohort, "Plasma levels of substance P, vasoactive intestinal peptide and nerve growth factor … were elevated … "27  "Exposure to volatile organic compounds (VOCs) increased plasma levels of all parameters," and "enhanced skin wheel responses induced by histamine…"27  "These results indicate that exposure to VOC may enhance neurogenic inflammation with concomitant enhancement of histamine-induced responses."27  Exposure to VOCs did not have these effects in normal subjects.27

In addition to the ability of VOCs to trigger an increase in NGF and SP in MCS, viral infections may decrease neutral endopeptidase, and other enzymes needed to degrade BK and/or SP, by 40%.28

In turn, BK and NGF may increase neuronal excitation and sensitivity.  NGF can, " … augment neuronal sensitivity (sensitization) to noxious stimuli."29  One way BK and/or NGF can excite or sensitize sensory nerves is by activating transient receptor potential A1 and V1 (TRPA1 and TRPV1), known as the irritant receptor and capsaicin receptor respectively.30,31

When compared to asthmatics, patients with MCS and asthma-like symptoms were found to be more sensitive to inhaled capsaicin, a TRPV1 agonist.32  Lidocaine, which effects sensory nerves, reduced the symptoms indicating the mechanisms behind chemical sensitivity,"may originate in the sensory nervous system."32

In an animal model, after nasal stimulation with capsaicin (" … to identify neurons involved in processing of nociceptive nasal stimuli,  … "), "Mean number of FOS(c-fos) positive neurons per section (in brainstem) was significantly higher in capsaicin group… "33

TRPA1 and TRPV1 are expressed on trigeminal nerves.34  TRPA1, "… is expressed in sensory nerves and mediates cold, mechanical, and chemical nociception," and is also activated by, "… pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil   …"31,35  Tear gas also activates TRPA1, and its resulting irritation may be due to activation of TRPA1.36

TRPV1 has been found to be increased in the nose in idiopathic rhinitis and on the scalp in migraine.37,38  Polymorphisms for TRPA1 have been found in asthmatic children, and possibly TRPV1 in migraineurs.39,40

Conversely, reactions were attenuated 75-100% in animals missing TRPV1 and/or TRPA1.41  "Null mutants of the capsaicin receptor TRPV1 and of the chemoreceptor TRPA1, as well as double knockout mice, were used as tissue donors… TRPV1 mice showed 75% reduced desflurane (irritating volatile anesthetic) responses, and TRPA1 and double-null mutants showed no response at all."41

TRPV1 antagonists were able to attenuate c-fos in the trigeminal brainstem in animal models of migraine, "Inflammatory up-regulation of c-fos in the trigeminal brainstem complex was dose-dependently and significantly reduced by both TRPV1 antagonists."42

An ongoing viral infection or another ongoing environmental exposure could activate TRPA1 and TRPV1, "… infection causes upregulation of TRP channels … "43 "Early upregulation of TRPA1 and TRPV1 expression occurred 2-4 h post infection.  This was independent of replicating virus as virus-induced soluble factors alone were sufficient to increase channel expression 50-fold and 15-fold, respectively."43

Increased BK, NGF, and/or SP, along with increased TRPA1 and/or TRPV1 activation, may partially explain why some people react to lower levels of airborne chemicals or irritants.  In addition to the increase in NGF and SP at baseline and further increased after VOC exposure in MCS and the possible increase in BK In CFS, TRPV1 was increased in patients with CFS after exercise.44

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