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Internal Medicine Review Inflammation Induced Chronic Fatiguing Illnesses October 2017
Copyright 2017 Internal Medicine Review. All Rights Reserved. Vol. 3, Issue 11
1
Inflammation Induced Chronic Fatiguing Illnesses: A steady march towards
understanding mechanisms and identifying new biomarkers and therapies.
Ritchie C. Shoe maker1,4*, Andrew Heyman2, Annalaura Mancia3 and James C Ryan4
Authors details:
1Center for Research on
Biotoxin-Associated Illnesses,
Pocomoke, MD, USA
2 Integrative Medicine, George
Washington University,
Washington DC, USA
3Department of Life Science
and Biotechnology, University
of Ferrara, Ferrara, Italy
4ProgeneDX, LLC, Deerfield
Beach, FL USA
*Corresponding author:
Ritchie C. Shoe maker1,4*
Email:
ritchieshoemaker@msn.com
Abstract
Illnesses characterized by chronic fatigue are often
defined by symptoms and not by objective biomarkers that
support both diagnosis and treatment. Without readily
obtained biomarkers, clinical management can be
compromised by lack of certainty. This uncertainty creates a
wide spectrum of possible therapies that in many cases is
reduced to trial and error medicine, resulting in patient
frustration and resource exhaustion, with little improvement
in health status. Modern medicine must leverage modern
science to bring common research tools into the clinic for
patient diagnostics. Using biomarkers previously confirmed
as useful in diagnosis and treatment of chronic inflammatory
response syndrome (CIRS), including transcriptomics, the
authors present evidence of benefit in assessment of a
“symptoms-only illness.” These immune biomarkers, such as
transforming growth factor beta (TGFb), vasoactive intestinal
peptide (VIP), melanocyte stimulating hormone (MSH), split
products of complement activation, and many others
discussed here, are now available for use as clinical
diagnostics, but rarely ordered in cases of chronic illness. In
cases of cognitive decline, new technology for brain MRI
analysis, NeuroQuant, can pick up small changes in brain
structures that are frequently missed by radiologists, but
consistently shown in CIRS. By focusing on persistent
symptoms seen in antibiotic-treated Lyme disease (Post-Lyme
Syndrome, PLS), CIRS-biomarkers have utility to define both
an initial infectious process and a subsequent inflammatory
illness. Genomic testing can determine predisposition to
chronic stages of Lyme after acute illness and use of Next
Generation Sequencing now brings transcriptomics to the
Lyme community, to assess remaining abnormalities at any
given treatment stage of PLS. Application of these new,
objective testing offerings will reveal the molecular
pathophysiology of illness, avoiding over-reliance on
symptoms and antibody testing alone. This will help providers
direct highly targeted therapies on an individual basis, in this
era of personalized medicine.
Key words: CIRS, inflammation, Lyme disease, fatigue,
transcriptomics, biomarkers
Internal Medicine Review Inflammation Induced Chronic Fatiguing Illnesses October 2017
Copyright 2017 Internal Medicine Review. All Rights Reserved. Vol. 3, Issue 11
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Section 1
Background:
Fatigue is a normal part of life, but it
can also be a symptom of disease, including
serious illnesses. It is a common complaint
in primary care, exceeded only by
complaints of cough. Five to seven per cent
of patients seeking primary care have a
primary complaint of fatigue, with this
proportion being remarkably consistent
across Western countries (1, 2).
General practitioners perform
investigations in only half of patients (1, 3,
4) complaining of fatigue, and few of these
tests yield abnormal results. Even so, the
high incidence of the fatigue complaints
means that laboratory tests for fatigue
account for almost 5% of the total number of
laboratory tests ordered by general
practitioners (1, 3, 4).
A diagnosis is made in less than half
of patients with fatigue; furthermore, many
of the diagnoses are descriptive, such as
stress, or are one of the many synonyms for
fatigue itself. Patients understand that an
underlying identifiable disease may not be
present, though patients’ and doctors’ be liefs
are sometimes mismatched, with a higher
proportion of doctors than patients
considering the particular problem to be
psychological (4).
Section 2
The Evaluation of Fatigue: Challenges of
Differential Diagnosis
The differential diagnosis of
persistent fatigue encompasses all medical
disciplines. For example, anemia,
hypothyroid ism, Addison’s disease, chronic
liver disease, neuromuscular diseases, sleep
disorders, and depression can all present as
idiopathic fatigue (5). Thus, Fukuda et al.
(6) called for a consensus on a clinical
definition of persistent fatigue, as well as
inclusive and exclusive criteria for
diagnosis.
Exclusion criteria for persistent
fatigue illness includes:
Untreated hypothyroidism
Respiratory/food allergies
Sleep apnea
Narcolepsy
Drug abuse
Adverse effects of
medications
Severe obesity
Previously diagnosed medical condi-
tions with uncertain resolutions (such as
Hepatitis B or C). Fatigue illness, or persis-
tent fatigue, is associated with a
multisystem, multi-symptom illness, demon-
strating a correlation with various infectious
diseases, immune disturbances, hypo-
thalamic-pituitary axis (HPA) or autonomic
dysfunction, and psychiatric disorders. It is
prevalent in 0.2% to 1% of the population
worldwide, occurring in women 3-7 times
more than in men, rarely diagnosed in
children less than 10 years of age, and
amongst all races and socioeconomic strata
(7, 8). It is characterized as debilitating
fatigue with impaired concentration, short-
term memory and sleep, as well as
widespread musculoskeletal pain (9, 10).
Persistent fatigue lacks clearly
defined etiological mechanisms, mainly
because of the dualistic model of medical
illness, which assumes the mind and body
are separate entities (5); however, it
typically develops acutely following the
onset of a respiratory or gastrointestinal
infection (8). The prevailing etiologic
hypothesis regards the disorder as a
multifactorial condition, whereby genetic
and environmental factors, including
infections, interrelate to impede the ability
to control and manage chronic stress, pain,
and fatigue (7).
Internal Medicine Review Inflammation Induced Chronic Fatiguing Illnesses October 2017
Copyright 2017 Internal Medicine Review. All Rights Reserved. Vol. 3, Issue 11
3
Other pathogenic mechanisms have
been implicated. For example, a number of
viruses including enteroviruses, particularly
Coxsackie B., herpes virus infections,
influenza, retroviruses, Epstein-Barr virus
(EBV), and human T-cell lymphotropic
virus-2 (5, 7, 8). Other infections include
chronic Lyme disease, as well as other
pathogens such as Brucella abortus,
Campylobacter jejuni, Mycoplasma
pneumoniae, and Toxoplasma gondii (5).
Figure 1 Evaluation and Classification of Unexplained Chronic Fatigue (Fukuda et al., 1994)
Internal Medicine Review Inflammation Induced Chronic Fatiguing Illnesses October 2017
Copyright 2017 Internal Medicine Review. All Rights Reserved. Vol. 3, Issue 11
4
Jones & Jenson (8) note the
similarities between persistent fatigue
symptoms and those experienced by patients
suffering from autoimmune disease and
other inflammatory disorders, underscoring
a potential primary mechanism within the
immune system for the pathogenesis of
chronic fatigue. Further, they report on
additional immunologic alterations
including hypo- and hyper-
gammaglobulinemia, immunoglobulin
subclass deficiencies; together with
dysfunctions of both NK cells and
monocytes. Other biological bases of illness
hypotheses include energy metabolism
alterations related to exercise and post-
exertion malaise, stress, sleep responses and
lack of regulation in HPA axis.
Section 3
Fatigue: From Symptoms to Biomarkers
After completing a medical history
and performing a careful physical exam,
physicians quickly look to see what could
cause the fatigue by searching for diagnostic
biomarkers, often found in standard blood
tests as well as an EKG or chest x-ray, for
example.
Increasingly, we are finding these
standard diagnostic tests are normal in ever-
enlarging groups of patients with chronic
fatiguing illnesses. Adding to the medical
problem is the concern that if “all tests are
normal, ” is there really an illness after all?
This current paradigm leaves attending
physicians to show what a patient has in part
by showing what he or she has; and does not
have. Far too often, as the march of
scientific advance has shown, “all tests
normal, ” simply means, “all the tests that we
knew about were normal.” There are 20,000
protein coding genes and another 30,000
non-protein coding genes that underlie our
physiology. Now that we know so much
more about regulation of differential gene
expression (transcriptomics) than even two
years ago, the support for claims that “all
tests are normal” disappears.
We often learn more about fatigue by
looking at concomitant symptoms and
conditions of the fatigued patient. Fatigue
from a malignancy may have different
associated features from those seen in
fibromyalgia or Chronic Fatigue
Syndrome/Myalgic Encephalitis (CFS/ME)
(9, 10), but fatigue alone does not define any
of these illnesses. Cancer might be shown to
be present by biopsy, but what biomarkers
do we see that define CFS/ME objectively?
There are none.
Here is the problem: symptoms-
based diagnoses lack (i) specificity in
differential diagnosis and (ii) definition of
relevant pathophysiology. With no
physiologic mechanisms available to
measure responses to treatment, attempts to
correct illness more likely than not (a) lead
to anecdotal improvement in symptoms, if
any; (b) provide no mechanism that supports
early detection, effective intervention and
prevention; (c) demonstrate no mechanisms
to identify what therapeutic targets have
been reached; (d) inform us what
abnormalities remain uncorrected.
Fatigue has features that help us
stratify illnesses diagnosed by symptoms in
the absence of biomarkers. Loss of
restorative, restful sleep is a dominant
feature of inflammatory illnesses, which can
also disrupt normal circadian rhythms
affecting sleep, especially with the reduction
from normal levels of regulatory neuro-
peptides (see MSH and VIP sections).
Fatigue that is worsened after trying to do
more than normal, when “normal” days are
dominated by lifestyle-altering fatigue, has
been given several jargon names. “Post-
exertional malaise,” or “delayed recovery
from normal activity,” and “push-crash,”
come to mind. This symptom usually
implies defective production of energy
Internal Medicine Review Inflammation Induced Chronic Fatiguing Illnesses October 2017
Copyright 2017 Internal Medicine Review. All Rights Reserved. Vol. 3, Issue 11
5
molecules (ATP) from mitochondrial break
down of glucose. As we have recently
learned (see transcriptomics, below), the
mitochondrial problem can possibly be due
to decreased capillary blood delivery of
oxygen, or abnormal control of
mitochondrial genes encoded in our nuclear
DNA as shown by RNA Seq. Others feel
that metabolic abnormalities in mitochon-
drial function are key (11).
Of note, Ryan (12) has shown that
transcriptomics can also show marked
abnormalities in ribosomal gene expression
using RNA Seq, as a separate but dominant
feature of chronic fatiguing illnesses. This
exciting, but previously unreported finding,
casts a new bright light on chronic fatigue.
Capillary hypoperfusion, abnormal-
ities in activity of nuclear encoded
mitochondrial genes or ribosomal gene
abnormalities are readily used as
biomarkers. Having these validated
biomarkers creates the potential for
enhanced precision in subsequent patient
evaluations. For example, if one is looking
for possible mitochondrial dysfunction,
knowing that there are abnormalities in
nuclear encoded mitochondrial genes
provides the capability to stratify new
conditions by the pre-existing gene
abnormalities.
Section 4
A New Model of Inflammation: CIRS
When fatigue is associated with a
multisystem, multi-symptom illness, the
differential diagnosis narrows, with
inflammatory illnesses leading the way.
Among the possible diagnoses often given
weight are Lyme disease and a chronic
inflammatory response due to exposure to
environmental sources of biotoxins.
Chronic Inflammatory Response
Syndrome (CIRS) is an acute and chronic,
systemic inflammatory response syndrome,
most frequently acquired following exposure
to the interior environment of a water-
damaged building with resident toxigenic
organisms, including, but not limited to
fungi, bacteria, actinomycetes and
mycobacteria, as well as inflammagens such
as endotoxins, beta glucans, hemolysins,
proteinases, mannans and possibly
spirocyclic drimanes; as well as volatile
organic compounds (VOCs) (13). Other
sources of CIRS could be consumption of
reef fish containing neurotoxins produced by
marine algae (14) or exposure to
cyanobacteria in fresh water ponds lagoons
and lakes (15).
We note the absence of confirmed
biomarkers for other symptom-only
syndromes: Post Traumatic Stress Disorder
(PTSD), fibromyalgia, CFS/ME, depression
and autism spectrum disorder, for example.
What biomarkers create therapeutic targets
for new interventions? Many proteomic tests
have been used for more than 20 years
without confirmation of benefit as
biomarkers.
Section 5
The New World of Objective Biomarkers
Measuring levels of selected proteins
is critical to understanding physiology, and
is typical for most medical exams and
essential for diagnosis and monitoring CIRS.
However, it becomes difficult to measure
multiple proteins simultaneously, limiting
deployment of proteomic markers in a
clinical setting. We now are expanding upon
use of proteomics to include new biomarkers
found through CIRS research on gene
expression. Symptom-only diagnoses are
being investigated for unique abnormalities
in differential gene activation. We can no
longer say all tests are normal. Even better
than just aiding diagnosis, transcriptomics
can identify targets of interventions, which
in turn have brought new therapies to
publication (12).
Internal Medicine Review Inflammation Induced Chronic Fatiguing Illnesses October 2017
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Additionally, with abnormalities in
executive cognitive functions found in over
90% of CIRS illnesses (Table 1), what
biomarker documents these abnormalities
and confirms an organic cause for cognitive
deficits?
Table 1 Symptoms in various CIRS conditions
Symptoms
Controls
Cyano
WDB-1
WDB-2
WDB-3
PEAS
Ciguatera
Lyme
N=
239
10
156
288
21
42
100
352
Fatigue
6
100
89
83
100
70
91
94
Weak
<5
80
75
70
84
-
83
89
Ache
8
90
77
68
95
43
77
81
Cramp
<5
80
66
56
63
14
68
77
Unusual Pains
<5
50
62
51
42
-
82
86
Ice Pick Pain
<5
40
49
41
-
-
45
82
Headache
9
90
78
66
84
73
78
88
Light Sensitivity
<5
90
71
66
89
68
67
85
Red Eyes
<5
50
52
48
63
68
48
61
Blurred Vision
<5
40
61
56
63
-
53
66
Tearing
<5
30
41
48
63
-
28
55
SOB
11
60
78
63
74
57
63
77
Cough
7
50
72
53
53
43
62
71
Sinus Congestion
8
60
79
65
74
41
70
68
Abdominal Pain
<5
60
61
39
37
41
79
42
Diarrhea
<5
50
48
39
21
57
72
51
Joint Pain
11
70
75
53
84
-
62
88
Morning Stiffness
6
70
72
44
-
-
59
80
Memory Impairment
<5
80
83
66
68
84
81
80
Difficulty Concentrating
<5
70
81
62
53
35
83
82
Confusion
<5
40
75
57
26
24
66
72
Decreased Word Finding
<5
80
81
66
11
-
80
84
Decreased Assimilation
<5
80
72
65
37
-
78
88
Disorientation
<5
30
51
40
11
-
28
33
Mood Swings
<5
20
69
65
-
-
42
65
Appetite Swings
<5
50
58
58
-
-
61
77
Sweats (Night)
<5
50
61
54
-
-
42
68
Difficulty Reg. Body
Temp
<5
50
63
60
-
-
67
72
Excessive Thirst
<5
60
69
54
-
-
59
71
Increased Urinary
Frequency
<5
60
66
58
-
-
66
75
Increased Static Shocks
<5
40
41
44
-
-
38
32
Numbness
<5
40
48
44
37
-
74
66
Tingling
<5
40
61
51
47
-
78
71
Vertigo
<5
40
39
48
42
16
29
37
Metallic Taste
<5
40
45
36
47
-
46
38
Internal Medicine Review Inflammation Induced Chronic Fatiguing Illnesses October 2017
Copyright 2017 Internal Medicine Review. All Rights Reserved. Vol. 3, Issue 11
7
While still in its infancy, use of
volumetric central nervous system software
programs (16, 17) shows remarkable detail
of the brain structures that led to the ability
to detect and treat atrophy of multiple grey
matter nuclei (18). Said another way, if short
term memory is deteriorating or if
individuals can’t remember what they just
read or where they left their car, objective
abnormalities in brain volumes can be
demonstrated to define an underlying illness.
These findings have effectively ended the
idea that “it is all in your head.” The illness
can now be detected with brain testing.
As we will present, sources of CIRS
are diverse and are readily identified by
examination of exposures, symptom clusters
and abnormalities in innate immune
responses. Now that sophisticated testing
modalities, such as innate immune
proteomics; NeuroQuant (FDA-cleared
since 2006); and transcriptomics, which
accurately demonstrates the enormous
complexity of differential gene activation;
are available, we can reliably leave behind
diagnosis by symptom recording alone.
For example, use of transcriptomics
can reliably demonstrate presence of gene
expression patterns in patients that match
those known to occur following
deoxynivalenol (DON) exposure in cell
culture and animal models. If a patient is
sickened by exposure to a water-damaged
building (WDB), we want to show actual
abnormal gene activation referenced by
published pathways involving trichothe-
cenes, especially by MAP kinases (19), and
not simply show possible exposure by
finding those mycotoxins in body fluids. We
know for example, that ingestion of a wide
variety of foods will cause urinary excretion
of mycotoxins, with such findings found
universally and not just in a few sickened
patients (20), and thus cannot be equated
with causation of illness (13). The converse
also applies, trichothecene exposure is not
likely to be extant in the absence of up-
regulation of MAP kinases. As with all
biomarkers, reliance on published, solidly
peer-reviewed literature must form the basis
for validation.
Without use of biomarkers, the
possibility of mis-diagnosis in symptom-
only illness is quite large; frequency of mis-
diagnosis of sub-divisions of the same
illness can become overwhelming. For
CIRS-WDB, we already have a case
definition that demands use of published,
objective biomarkers and effective therapies:
2008 US Government Accountability
Office case definition:
(1) Potential for exposure
(2) Symptoms similar to those seen in
published literature
(3) Labs similar to those seen in
published literature
(4) Response to therapy
Contrast CIRS-WDB to symptoms-only
diagnoses. CIRS-WDB has an extensive
peer-reviewed literature on symptoms,
ancillary testing, proteomics, CNS
volumetric studies, transcriptomics and the
above clinical case definition published by a
Federal agency. Moreover, CIRS has
survived multiple legal challenges to
admissibility in state and Federal courts.
CIRS diagnostic and treatment protocols are
peer-reviewed and published, with treatment
effectively correcting proteomics (21),
genomics (12, 22) and grey matter nuclear
atrophy (18). Understanding that there are
no studies showing dramatic or effective
treatment of symptom-only diagnosed
illness, like fibromyalgia, Post Traumatic
Stress Disorder, (PTSD) or CFS/ME, and
that CIRS is readily shown to have effective
treatment protocols, we can ask if there are
similarities. Take look at the symptom
rosters of known CIRS illnesses (Table 1).
Now look at symptom rosters for CFS/ME
and fibromyalgia (Table 2).
Internal Medicine Review Inflammation Induced Chronic Fatiguing Illnesses October 2017
Copyright 2017 Internal Medicine Review. All Rights Reserved. Vol. 3, Issue 11
8
Table 2. Symptoms of CFS and ME (10)
Symptom
Fukuda CFS
ME
Persistent chronic fatigue
Yes
Yes
Six or more months
Yes
Yes
Post-exertional neuro-immune exhaustion
No
Yes
Cognitive
Yes
Yes
Sore throat
Yes
Yes
Lymph nodes
Yes
Yes
Muscle pain
Yes
Yes
Multi-joint pain
Yes
Yes
Abdominal pain
No
Yes
Headaches
Yes
Yes
Unfreshing sleep
Yes
Yes
Post exertion malaise
Yes
Yes
Chemical sensitivity
No
Yes
Orthostatic intolerance
No
Yes
Air hunger
No
Yes
Impaired thermal regulation
No
Yes
Let’s now ask if exposure to the
interior environment of WDB occurs in
fibromyalgia patients or CFS/ME patients.
According to the National Institute for
Occupational Safety and Health (NIOSH)
(23), such exposure happens in about 50%
of US buildings. Does fibromyalgia or
CFS/ME or PTSD protect patients from
adverse environmental exposures or
personal lifestyle effects? No. What
biomarkers for a fibromyalgia patient newly
found to have CIRS separates him/her from
a classic CIRS-WDB patient?
If a CFS/ME patient is exposed to a
WDB, and his illness is made worse, do we
still call the illness CFS/ME? Even though
the recommended CIRS labs are covered by
all major insurance carriers, they are rarely
requested in CFS/ME or fibromyalgia cases
in primary care practices (unpublished; data
from practices of Drs. Shoemaker and
Heyman). When a CFS/ME patient finds a
provider who performs a CIRS battery of
labs, with confirmation of CIRS, there is no
objective baseline for the original diagnosis:
there no longer is any way to determine if
the original illness was in fact CIRS and not
CFS/ME or fibromyalgia.
Laboratory studies are the required
foundation for CIRS. These labs reflect the
physiology of the illness. Here, however, is
an important point: They are rarely specific
for any one source or precipitating cause of
CIRS – it can certainly be from a WDB, but
also Lyme disease, ciguatera, Pfiesteria,
VOCs and others. Therefore, it is important
for the clinician to identify the cause of
CIRS, as well as confirming the diagnosis of
CIRS itself.
Controlling for known variables-1
We know there are risk factors for
CIRS beyond simple exposure. First, we
can demonstrate individual susceptibility, a
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9
concept based on the epidemiologic
construct of relative risk (RR). If the
incidence of an abnormality in the case
population is twice the incidence in the
control population, there is increased
relative risk and individual susceptibility is
postulated, even when we don’t necessarily
know the precise cause of the increased
relative risk.
One of the first questions in the early
days of clinical management of biotoxin
illnesses was, “What was going on such that
three out of ten people got sick swimming in
an area of the Pocomoke River (Maryland)
where fish-killing dinoflagellates were
found in 1997 (24, 25)?” Was the
confounder race, gender, age; use of alcohol,
cigarettes, or other medications? Duration of
exposure? Route of exposure? Underlying
illness?” No, to all these reasonable ideas.
The answer simply was immune response
genes stratified by HLA DR.
Section 6
HLA DR by PCR: genetic susceptibility in
CIRS Found on chromosome 6 in the
Human Leukocyte Antigen complex, HLA
DR has been widely used for years in tissue-
typing patients in preparation for organ
transplants but it also underlies the
mechanism by which antigen presenting
cells identify antige ns as “foreign.” When
foreign antigens are presented to
lymphocytes by HLA DR, the complex
process that leads to antibody production
begins. If the antigen presentation process is
defective (26), as we see in PLS, there will
be no production of protective antibodies.
Without antibody production, there is
nothing to stop the ever-expanding
inflammatory cascades responding to the
ongoing carriage of antigen. The normally
protective innate immune response becomes
destructive, as described in a classic short
essay by Lewis Thomas in 1972, “the host
becomes the disease.” (27 )
This permissive of HLA DR
becomes vitally important when a physician
is searching to make a diagnosis by
demonstrating presence of an antibody. If
defective antigen presentation is present, as
may be the case in acute Lyme disease,
laboratory confirmation of presence of an
antibody is problematic.
For 95% of patients with known
CIRS-WDB, increased relative risk (> 1.9)
for acquisition of illness is associated with
just 6 of 54 major HLA haplotypes
(unpublished practice data). These 6
haplotypes are found in roughly 24% of the
population at large (28). Similarly, only four
HLA haplotypes are associated with roughly
95% of patients with chronic symptoms
following antibiotic treatment for Lyme
disease, or Post Lyme Syndrome (PLS).
These four haplotypes were found in 22% of
all our patients initially infected by Lyme.
HLA DR haplotypes consist of HLA
alleles that will be passed on to offspring.
Use of HLA typing becomes important for
epidemiologic risk assessment but it also is
important in considering who else in a
family might be predisposed to heightened
inflammatory responses following exposure
to biotoxins and inflammagens.
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10
CIRS HLA Sequences
Table 3. HLA DR haplotypes associated with elevated relative risk for the CIRS categories
shown
DRB1
DQ
DRB3
DRB4
DRB5
Multisusceptible
4
3
53
11/12
3
52B
14
5
52B
Mold
7
2/3
53
13
6
52A, B, C
17
2
52A
*18
4
52A
Borrelia, post Lyme
Syndrome
15
6
51
16
5
51
Dinoflagellates
4
7/8
53
Multi Antibiotic
Resistant Staph
epidermidis
(MARCoNS)
11
7
52B
Low MSH
1
5
No recognized
significance
8
3,4,6
Low-risk Mold
7
9
53
12
7
52B
9
3/9
53
Controlling for known variables-2
The next concept involves hormonal
abnormalities that affect metabolic changes.
Our focus is not on insulin, thyroxine or
cortisol, but instead we look at regulatory
neuropeptide hormones, especially
vasoactive intestinal polypeptide (VIP) and
alpha melanocyte stimulating hormone
(MSH). Direct measurement of VIP is
possible but is misleading, as the crucial
problem with VIP physiology is variable
production of one of its two receptors (29).
MSH testing is readily available in
commercial labs, but replacement therapy is
not available for use in humans. VIP is
available as a therapeutic agent; exogenous
administration has shown great benefit in
CIRS patients and in those with grey matter
nuclear atrophy.
Regulatory neuropeptide hormones
affect (i) hypothalamic hormone function;
(ii) pituitary hormone production; (iii)
peripheral hormone regulation by pituitary
hormones; (iv) immune cell and innate
immune functions; (v) cytokine physiology,
(vi) limbic system activity; (vii) genomic
activity; (viii) pulmonary artery pressure;
among other functions (21).
Section 7
MSH MSH deficiency is important in
CIRS. MSH is made in the hypothalamus
and to a lesser extent in part of the pituitary.
It is a regulatory neuropeptide. What this
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means is that it is a protein that regulates
inflammation and immunity; regulates other
hormone functions, especially pituitary
hormones and peripheral hormones; it has
important regulatory features in the limbic
system, circadian rhythms, pain perception
and weight. MSH “patrols” the periphery of
the skin, respiratory system, gastrointestinal
tract and blood. In the gut, MSH is invested
in just about every cell, including tight
junctions between them. Deficiency of MSH
will result in what others call leaky gut.
MSH deficiency was one of the first
elements found while looking for features
important in the pathophysiology of CIRS
(29). The role of MSH in prevention of
hormonal abnormalities is best seen in low
MSH cases. Here we find lack of normal
regulation in adrenocorticotropin hormone
(ACTH) and cortisol in approximately 67%
of patients. We find lack of regulation of
antidiuretic hormone (ADH) and osmolality
in 80% of patients. Androgen abnormalities,
particularly including upregulation of
aromatase, are found in 50% of CIRS cases.
Understanding the impact of hormone
dysregulation requires looking at feedback
loops involving central and peripheral
hormones.
Another correlation of MSH
deficiency in CIRS is the presence of
biofilm-forming, multiply resistant
coagulase negative staphylococci in deep
aerobic nasopharyngeal cultures, essentially
found exclusively in those with low MSH.
Controlling for known variables-3
Innate immune inflammatory
elements in CIRS act in an ever-expanding
web of receptor-based responses. Th-1, Th-
2 and Th-17 responses; together with
coagulation and complement activation; all
participate in amplified inflammatory
responses to persistence of carriage of
antigens.
Section 8
MMP9, C4a, TGF beta-1
We use three separate labs in our
approach to detection of innate immune
inflammation. Remember that CIRS has its
basis in systemic inflammatory response
syndromes. In SIRS, acute patients will have
activation of pro- and anti-inflammatory
cytokines, Th-17 immunity, complement,
clotting abnormalities and more. All of these
entities are important in CIRS.
We use matrix metalloproteinase-9
(MMP-9), transforming growth factor beta
(TGF beta-1) and split product of
complement 4 (C4a) as the main diagnostic
and prognostic variables to assess for
inflammation seen in CIRS. The
complement system can be activated to the
point that some people with elevated C4a
are suffering from auto-activation of
MASP2, the enzyme that cleaves C4a (30).
Remo val from exposure doesn’t stop
production of C4a. This so called “sicker,
quicker” process is recognizable with
persistent elevation and “elevated e levation”
of C4a.
Delivery of oxygen in capillary beds
is reduced in CIRS. This reduced delivery
sets off alarm signals through the activity of
a nuclear transcription factor, hypoxia
inducible factor (HIF). Low oxygen in tissue
means HIF will be turned on. HIF being
turned on means vascular endothelial growth
factor (VEGF) will be released. VEGF is
intimately linked to TGF beta-1, which in
turn is linked to countless genomic pathways
leading to fibrosis, differential gene
activation, the “leakiness” of blood brain
barrier and a host of effects on beneficial T-
regulatory cells.
The schematic entitled “The
Biotoxin Pathway” (Figure 2) released in
2011, illustrates how many of these general
principles are tied together. Our next release
will include differential gene activation.
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Controlling for known variables-4
Immunomodulatory responses can be
affected by microbes resident in areas of the
body distant from blood. It seems hard to
imagine just what is going on in the gut, but
given the onslaught of discussion on the
intestinal microbiota and its effect on
immune reactivity and brain activity, we can
expect to know more soon.
Section 9
MARCoNS
No discussion of biomarkers in MSH
deficient patients can possibly be complete
without emphasizing the importance of
multiply antibiotic resistant coagulase
negative staphylococci (MARCoNS).
Following the initial recognition of the
importance of MARCoNS in chronic fatigue
and chronic pain (31) published by the
group at Newcastle University (Australia)
led by Henry Butt and Tim Roberts, special
cultures that permitted these slow growing
commensals to be identified (API-STAPH)
became available to primary care providers
in the US. Not only has subsequent research
confirmed the Newcastle observations but
we now think that extracellular compounds
made by previously “b enign” organisms are
driving gene responses. Moreover,
preliminary mass spectrometry data suggests
that biofilm-forming MARCoNS make a
polycyclic ether compound similar to
palytoxin, a dinoflagellate toxin (data not
published).
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One point must be made: without
eradication of MARCoNS, there will be no
clinical improvement. For those who
consider worsening of clinical status with
use of antibiotics as suggestive of an occult
infection, often reported by some as
indicative of Lyme, do not forget that
antibiotic treatment of MARCoNS also
causes a similar syndrome. If no culture is
done, an unsupported diagnosis might be
made.
Controlling for known variables-5
Pertinent Negatives
As part of evaluation of objective
parameters to define CIRS, we also look for
objective parameters that are not abnormal.
These would include commonly used tests
as a CBC, CMP, immunoglobulins, thyroid
studies, antinuclear antibodies (ANA) and
many more. The differential diagnosis is
activated by showing what is present in
CIRS and what is not present in CIRS.
Interestingly, a commonly used test of
inflammation, the sedimentation rate, is
invariably normal in CIRS. C-reactive
protein, an acute phase reactant that
activates interleukin-6 (IL-6), also is usually
normal in CIRS.
Section 10
VCS Visual contrast sensitivity (VCS)
testing has been used clinically for years and
remains the most accurate test for functional
vision (25). Contrast is one of the seven
main functions of the optic nerve that
provides the neurologic basis of vision.
When we test for contrast, we control for
other elements of vision such as near vision,
far vision, static, motion, peripheral vision
and night vision; we are looking only at
contrast. Contrast is the ability to see an
edge. What this means is that if I look at a
door frame and I see a white background
and a black door frame, I can identify what
is background and what is frame very easily.
Contrast sensitivity looks at the graded
change of contrast at different light
frequency (cycles per degree of visual arc)
that we use to make a grid of five separate
frequencies. This grid begins at 1.5 cycles
per degree of visual arc extending in discrete
intervals (3, 6, 12, 18) up to 18 cycles per
degree of visual arc. Remember visual
acuity is tested at 24 cycles per degree of
visual arc.
Dr. Ken Hudnell, neurotoxicologist
for the US EPA in Research Triangle Park,
NC, was the first to use VCS testing in
biotoxin illnesses. His landmark work in
1997 (32) paved the way for others to
follow. Our group was able to reproduce the
observations of Dr. Hudnell of visual
contrast being abnormal in that same fish
killing dinoflagellate (Pfiesteria) illness, but
treatment beginning with cholestyramine,
the first step of what is now a 12-step
protocol, reversed the visual contrast
abnormalities. With re-exposure, however,
visual contrast deficits reappeared, identical
to the initial deficits, usually within 36
hours.
Section 11
Cluster analysis
When we use persistent health
symptoms as a group of 37, recorded by a
trained health care provider in a medical
history (never use patient-completed
checklists), we can collate individual
symptoms into groups, called clusters.
Statistically, these clusters of symptoms, 13
in number, comprising 35 symptoms, yield a
diagnostic capability to separate out CIRS
from essentially all others syndromes and
diseases. If a patient is confirmed to have 8
or more clusters of symptoms, the likelihood
of presence of CIRS exceeds 95%.
When combined with VCS deficits,
symptom clusters can yield an accuracy in
diagnosis of 98.5% (that means the sum of
false positives and false negatives is less
than 2%).
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Cluster Analysis of Symptoms
Individual categories:
1. Fatigue
2. Weakness, assimilation, aching,
headache, light sensitivity
3. Memory, word finding
4. Concentration
5. Joint, AM stiffness, cramps
6. Unusual skin sensations, tingling
7. Shortness of breath, sinus congestion
8. Cough, thirst, confusion
9. Appetite swings, body temperature
regulation, urinary frequency
10. Red eyes, blurred vision, sweats,
mood swings, icepick pains
11. Abdominal pain, diarrhea, numbness
12. Tearing, disorientation, metallic taste
13. Static shocks, vertigo
A positive cluster analysis for biotoxin
illness is presence of 8 or more of 13
clusters.
Note: symptoms of unusual pain and tremors
did not sort into individual categories
Even though the combination of
symptom clusters with VCS is accurate for
diagnosis, we use laboratory studies as an
additional layer of assessment for diagnostic
certainty and to provide a method for
following the effects of treatment on clinical
status. These tests of immune function help
us hone in on (i) where the inflammation of
the illness is active; (ii) what inflammation
is doing; and (iii) how inflammation is
doing. We use labs to follow patients,
monitor their progress, document
achievement of endpoints and to document
relapse.
If we had the ability to use a few
proteomic tests to tell us all we need to
know about treatment, we wouldn’t need
transcriptomics. Since transcriptomics tells
us so much more than proteomics, we
employ both approaches to identify complex
clinical syndromes.
Section 12
Transcriptomics
The most sophisticated genomic
testing available today is transcriptomics.
We look at differential gene activation using
a Next Generation DNA Sequencer. The
Human Genome Project, completed in the
early 2000’s at the cost of billions of dollars,
identified thousands of genes that code for
proteins. What we saw then was the total
genome structure, including duplicate copies
called copy number variation (CNVs). Later,
we learned that everyone had slight
variations in their genes, called single
nucleotide polymorphisms or SNPs. Many
of these SNPs are now known to be
important markers of disease because they
can indicate a change in protein function or
activity. However, these SNPs are fixed and
do not change throughout your life. The
most impactful modulator of cellular activity
is likely differential gene expression, since
the amount of the gene expressed is
ultimately in control of protein levels and
cellular output. Based on current conditions,
the genome will output a certain
combination of genes, but when the
conditions change, the gene output will
change to best adapt to the new conditions
or demands. This is generally what
determines one’s day to day, or even
morning to night physiology.
What neither the first sequencing of
the human genome, nor the later
identification of various SNPs, could
identify is this dynamic yet critical
differential gene activity.
Remarkably, environmental stimuli,
and there are many, can cause gene
activation in minutes, if not faster. Such
rapid changes in gene activity provide
incredibly precise adaptations of the host to
a rapidly changing environment. If the host
is a one-celled creature, like bacteria or a
fungus, it might be easier to conceive of the
survival benefits that accrue from rapid
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15
responses to moisture, foodstuffs and
chemical signals. Yet the same concepts
apply to “higher,” more complicated life-
forms, like humans, as well.
We now know that the static genome
is actively manipulated, constantly
increasing production of some gene
transcripts and decreasing others in response
to its environment. Regulation is complex:
nuclear transcription factors and newly
discovered long non-coding RNAs, together
with microRNAs and circular RNAs, as well
as methylation and acetylation (don’t forget
demethylation and deacetylation!) can shut
off and turn on gene expression. If this
sounds complicated, it is. Research into the
interacting complexities of so many layers
of regulation has progressed beyond its
infancy, but new discoveries are published
every month.
We are at the beginning of a new era
in science where we can use genomics,
transcriptomics for those that are sticklers
for words, to our advantage in that we could
find a distinct fingerprint for CIRS from
water-damaged buildings, from ciguatera
and from PLS. The application of genomics
to human illness is just in its infancy but it
has catapulted us into the age of
personalized medicine.
We will return to a discussion of
transcriptomics as an important biomarker
for diagnosis and treatment of Lyme disease
below.
Section 13
Pulmonary artery pressure
Additional objective indicators of
physiologic complications due to an
inflammatory response syndrome are
obtained through echocardiography.
“Echos” are usually done resting, most often
performed to assess function of the left
ventricle as well as to assess the pumping
function of the heart. Each echo will assess
function of multiple cardiac structures; we
are interested in the velocity of the tricuspid
regurgitant flow, also called the tricuspid jet.
Blood can go backwards from the right
ventricle to the right atrium passing “the
wrong way” across the tricuspid valve. The
rate of backwards flow is measured in
meters/second. The velocity is recorded
accurately by the machine on at least four
separate views during a routine
echocardiogram. Curiously, cardiac
sonographers are trained to label the
tricuspid jet qualitatively as either absent,
trace, mild or moderate. This is an
unfortunate problem in that the CIRS health
provider needs to know whether or not there
is elevated pulmonary artery pressure, a
result that must be calculated. Since the echo
machine generates numbers for each of the
four ways the jet is measured, an average
can be generated.
We use the tricuspid jet velocity to
calculate the pulmonary artery pressure
indirectly. We square the tricuspid jet
number and then multiply that number by 4.
To that product, we add the right atrial
pressure (usually between 5 and 10 mm) to
give us a calculated pulmonary artery
pressure. Any resting pulmonary artery
pressure (PASP) greater or equal to 30mm
of Hg is consistent with pulmonary
hypertension. Any tricuspid jet greater than
2.5 meters per second will arouse concern
about pulmonary artery systolic pressure in
people with CIRS.
For individuals with normal
pulmonary artery pressure at baseline or
patients with health symptoms such as
unexplained cough, shortness of breath or
chest pain, it can be useful to perform stress
echocardiography. In this modification of
the basic echo technique, an individual has
two sonograms done. The first is at baseline,
as discussed. The second is done after
maximal exercise, requiring a target heart
rate of 90% of predicted.
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Stress testing is most often
performed to look for problems with
performance of the left ventricle. Exercise
stress testing is a fundamental diagnostic aid
that can help identify the presence of
coronary artery disease. In our example, we
are not looking for left ventricular problems;
we want to know the pulmonary artery
pressure change with exercise. Any rise in
PASP pressure over 8 mm of Hg is
abnormal.
The mechanics of performing a
stress echo can become problematic. Here is
someone, following possibly 11 minutes of
maximal exercise, for example, exhausted,
breathing heavily and leaning forward after
the stress portion of this stress echo. Now
the echo sonographer will insist that within
30 seconds the patient lie down. The out of
breath patient lies down on the exam table
for a repeat measurement of tricuspid jet.
As you might imagine, most
sonographers are not asked to interrogate the
tricuspid valve after exercise. It helps to talk
to your cardiopulmonary staff to make sure
they know exactly where they are going to
place their transducer before the exercise
begins.
We use pulmonary artery pressure as
an inclusion criterion for use of vasoactive
intestinal polypeptide (VIP) as treatment. If
PA pressure rises more than 8 mm, the
indication for use of VIP becomes stronger.
Section 14
VO2 max and anaerobic threshold
Another important cardiovascular
diagnostic test is a cardiopulmonary exercise
test (CPET). While the name of this test
sounds like a stress echo, it is different. This
test measures oxygen use and carbon
dioxide production in performance of
exercise, usually on a bicycle. The test is
somewhat cumbersome in that a patient is
strapped to EKG monitors and is peddling
maximally on a bike all the while breathing
with hoses, tubes and a mask used to record
oxygen consumption.
In our earlier discussion of CFS/ME,
we discussed the absence of a biomarker for
CFS/ME. In 2015, the Institute of Medicine
(IOM) emphasized the importance of
cardiopulmonary exercise testing (CPET) in
their redefinition of chronic fatigue
syndrome as Systemic Exercise Intolerance
Disorder (SEID) (9). This effort fell short,
however, of making CPET a biomarker
necessary to diagnose SEID. The IOM
simply returned to an updated, but still
inadequate, non-specific symptom-only
definition, one that essentially applies to
100% of all CIRS cases.
Much is known about the importance
of VO2 max (milliliters of oxygen
consumed per kilogram per minute) as this
is an important mechanism used to classify
possible disability. We know that there is a
difference between VO2 max of women and
men. We also know that age has a role in
normal ranges for VO2 max. Based on our
practice data (unpublished), it is not unusual
in the face of chronic fatiguing illness for a
50-year-old woman to have a VO2 max of
approximately 20 ml per kilogram per
minute (with slightly higher values for men)
raising the diagnosis of chronic fatiguing
illness.
The tables for Cardiovascular Fitness
Classification are published in the AMA
Guides to Evaluation Disability and
Impairment; Social Security uses VO2 max
as one of the key elements in assessing
disability.
Functionally, even more important
than VO2 max is a delineation of anaerobic
threshold (AT). This is the maximum level
of activity achieved through available
oxygen (aerobic metabolism). Mitochondria,
the energy powerhouses of the cell, need
oxygen to break down fragments of glucose,
releasing water, carbon dioxide and energy
(ATP). For those with low AT, even
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walking slowly up a flight of stairs results in
reduced oxygen delivery, in turn diminis-
hing aerobic energy production. When AT is
exceeded, as in the stairs example, oxygen is
not available as needed for mitochondria to
produce the full complement of 38 ATP
from a single molecule of glucose. Without
oxygen to supply the electron transport
chain, a single glucose molecule will now
just provide two molecules of ATP, or a 5%
efficiency in the face of oxygen depletion. In
turn, as glucose and glycogen stores are
quickly exhausted, the energy depleted cell
looks for additional sources of fuel. In the
face of low MSH, leptin resistance is often
present, preventing normal use (through
direct beta oxidation) of fatty acids for fuel
(the “second wind” most runners have
experienced). In “desperation,” lean body
mass, our protein reserves, are broken down
into amino acids, with direct conversion of
amino acids (especially alanine and
glutamine) to glucose. The demand for ATP
may create protein wasting syndromes that
conserve fat reserves (the more detailed
physiology can get complicated).
If AT is depressed, even trying to do
a few things extra when a patient has a day
with a bit more energy than most, results in
glycogen depletion. Don’t forget, glycogen
replenishment is a slow process: patients
will feel exhausted until their “batteries are
recharged.” Terms for this commonly
observed phenomenon include “push/crash;”
“delayed recovery from normal activity;”
and “post-exertional malaise.” Simply
stated: the patient did too much.”
But contrary to the IOM opinion,
low AT is not uncommon, not just SEID. In
CIRS, the oxygen delivery problem is
complicated by lack of normal blood flow
into capillary beds, not to mention nuclear
encoded mitochondrial gene problems. Still,
capillary hypoperfusion is the mechanism
that underlies deficits in VCS which is a
hallmark of CIRS.
Section 15
von Willebrand’s factors
Additional problems in CIRS
paradoxically include both excessive
clotting and bleeding. Just like in sepsis,
where multiple inflammatory mediators are
activated including complement, Th1, Th2
and Th17, coagulation defects also appear.
So too for CIRS: two thirds of CIRS patients
will have abnormalities in a comprehensive
von Willebrand’s profile (data not
published).
In CIRS, shortness of breath will be
reported by over 80% of patients. Asthma
might be involved, but restrictive lung
disease, interstitial lung disease and
pulmonary emboli are all primary features of
the differential diagnosis. Similarly, when
exposure to a building results in unexplained
nosebleeds and hemoptysis, immediately
think o f acquired vo n Willebrand’s disease
(AvWD), an easily treated condition using a
medication (DDAVP) that costs about a
nickel. If the differential diagnosis didn’t
include AvWD, uncontrolled hemorrhage
might follow.
Conversely, elevated levels of vWF
raise the risk of intravascular clotting, with
deep vein thrombosis and pulmonary emboli
possible. Whenever, for example, a patient
suffers clotting around an intravenous
catheter (especially PICC lines), make sure
that elevated vWF factors are not the
underlying problem.
Section 16
NeuroQuant
For most medical practices,
NeuroQuant (NQ) might appear to be just be
a spin-off of MRI of the brain, but for CIRS
providers, NQ has made (i) identification
and (ii) separation of CIRS-WDB, CIRS-
PLS, traumatic brain injury, PTSD,
ciguatera and multi-nuclear atrophy
straightforward. When added to an MRI of
the brain, NQ is found to be an illness-
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specific indicator. Use of sequential NQ
testing has shown there is much more
plasticity of an injured brain to heal than
once thought (18). With low cost, rapid
turnaround times and no need for contrast
dyes, NQ adds powerful weight to
assessment of cognitive dysfunction,
including evaluation of possible risk for
development of dementia.
As all research efforts to date in the
CIRS movement, data driven studies
involving institutional review board
approval (IRB), good statistics and good
science have carried the day. We can look at
a General Morphometry Report (GMR)
produced by NQ, rapidly identify
microscopic interstitial edema, atrophy and
patterns of brain injury accurately. Much of
the unsupported ideas about PTSD being
purely a psychiatric condition will need to
be re-evaluated now that we have
indications of a unique volumetric measure
that correlates with symptoms. Now that we
can use NQ to identify and correct grey
matter nuclear atrophy, we hope a new era
will arrive in the field of treatment of
neurodegenerative illnesses.
Section 17
Summary of biomarkers in CIRS
As opposed to chronic fatiguing
illnesses that have no biomarkers, CIRS has
(i) exposures; (ii) cluster analysis of
symptoms; (iii) differential diagnosis; (iv)
VCS testing; (v) proteomics; (vi) genomics;
(vii) pulmonary hypertension; (viii) low
VO2 max; (ix) depressed AT; and (x)
specific objective findings showing specific
brain injury.
Now that we know of the remarkable
abnormalities of (xi) ribosomal and (xii)
nuclear encoded mitochondrial gene
expression, we have access to sophisticated
markers that are abnormal at baseline, with
therapy bringing interval improvement. Two
tubes of blood and a few weeks will bring
the remarkable research discoveries to direct
patient care.
We no longer need to guess about
executive cognitive dysfunction: we follow
NQ sequentially with treatment. The
diagnosis is no longer complicated or drawn
out: just take the history and do the testing.
Now that we can combine
transcriptomics with proteomics, precision
in diagnosis and treatment has never been
higher. Biomarkers lead the way to defined
and published treatment protocols. If one
wanted to decide to look for the evidence
showing CIRS is present in a fatigued
patient, no longer would speculation and
clinical opinion be the gold standard for
diagnosis and treatment. The era of
symptom-only diagnoses applied to that
patient would become past history.
Section 18
Applying the CIRS Model to Lyme
disease
Few illnesses in American medicine
over the last 30 years have created such
bickering (and worse) among health
professionals and patients alike as Lyme
disease. Where else do we see patient
advocates intensely hurling insults at
physicians who say treatment of Lyme is
easy? Or those same docs viciously
attacking the “Lyme literate” docs who say
the infection is difficult to clear and is often
confounded by coinfections. Both sides of
the Lyme issue will seemingly be quick to
argue about any aspect of this increasingly
common vector-associated illness. From the
time needed to transmit a Borrelia spirochete
from tick salivary glands to treatment of
grey matter nuclear atrophy seen on
NeuroQuant, there is just too little
agreement.
In years gone by (Lyme was first
named in 1975), no one argued that about
20% of patients confirmed to have Lyme
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would go on to develop a symptoms-only
illness called Post Lyme Syndrome (PLS).
Those who advocated use of short courses of
antibiotics as the only needed treatment
started defining the PLS as myofascial pain
and fibrositis. Mainstream medicine did not
really accept these terms. By 1990, how-
ever, the American College of Rheumato-
logy codified (33) a new entity that provided
a ready explanation for PLS: fibromyalgia.
With major manufacturers of a non-curative
prescription medication making billions of
dollars (Lyrica generated sales of $5.1
billion in sales in 2016 alone) on treatment
of fibromyalgia, now a diagnosis accepted
by insurers for reimbursement, fibromyalgia
fit nicely into modern American medical
practice. Patients suffering from a vague
diagnosis that lacked any objective
biomarkers learned that they had to live with
chronic pain, pay their therapists and try to
find some quality of life. And fibromyalgia
wasn’t just from Lyme. Auto accidents,
especially whiplash, created a new breed of
personal injury attorneys, collecting dama-
ges for the feared illness, initiated and
caused by the 40-mile per hour rear end
collision. Unfortunately, physical abuse too
could result in classic fibromyalgia.
The symptoms seen in fibro are
familiar to all CIRS practitioners: pain,
fatigue, mood swings, weight problems,
sleep disturbance and even respiratory
illness. These symptoms are consistent with
what is recorded in cases of MSH deficiency
(Table 1).
The problem with PLS (and fibro
too) remains absence of reliable biomarkers.
In CIRS-WDB, those objective parameters
can be sorted by stage of treatment (before,
after, with relapse, with re-treatment and off
meds; all compared to controls (Table 3).
Table 3. CIRS biomarker test values for normal controls, untreated, treated and
relapsed patients. Other column includes chronic ciguatera and cyanobacteria patients. All
data from private practice of RS
Control
Untreated
Treated
Relapse
Other/treate
d
N=
13
101
58
64
11
C4a
3886
6449
4710
8688
5846
MMP-9
327
279
270
339
329
VEGF
60
73
46
59
52
vWF
0.18
0.45
0.16
0.45
0.43
TGF
3621
8149
5369
7268
7452
CD4+CD25
4.66
2.99
4.06
3.05
3.86
CD4+CD25++CD127
4.25
2.68
3.72
2.84
3.33
In Table 4, the data show what
happens when a proven Lyme patient with
symptoms refractory to antibiotics is seen
and treated by a CIRS doc. The persistent
innate immune activation created by the
known infectious disease is not successfully
treated by antibiotics. CIRS treatments work
just as well in CIRS-PLS as they do in
CIRS-WDB. With both sides of the Lyme
argument, (“Antibiotics forever versus
antibiotics for never”) not even willing to
talk to each other civilly, we submit that the
time has arrived to change the argument.
What remains remarkable is the
paucity of published papers on Lyme and
what lab abnormalities and symptom
complexes are associated with (i) acute
Lyme before antibiotics; (ii) Lyme after
antibiotics; and (iii) persistently
symptomatic Lyme.
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Table 4. CIRS biomarker test values for different stages of Lyme disease. All data from
private practice of RS.
Control
Base
Post Abx
Post CIRS
N=
13
34
29
31
TGFB
3621
6782
8967
4890
C4a
3886
8149
6710
4120
C3a
1124
1284
384
410
i-Treg
4.66
2.94
3.02
4.16
t-Treg
4.25
2.44
2.98
3.86
Even though we don’t have any large
cohorts reported from the antibiotic arm of
Lyme stratified by lab test results, we have
even fewer clinical trials from the
“antibiotics for never” group. Not
surprisingly, MMP9 is listed by PubMed
(accessed 5/10/2017) in three Lyme papers;
TGF beta-1 in another 3; MSH none;
NeuroQuant none.
Compare what we know about
diagnosis, treatment and re-exposure in
CIRS-WDB (Table 3) to sequential steps of
intervention in Lyme (Table 4). Despite the
thousands of Lyme papers available on
PubMed (and many more not indexed on
PubMed), what accounts for such an
unexpected absence of delineation of the
effects of treatment on inflammatory
markers in Lyme patients? We see
individual studies in animals; we see
selected cases presenting before treatment,
with the study authors discussing a new
finding, call it “XYZ,” but rarely do we see
the results of treatment upon that finding.
There is little clinical data in the Lyme
literature that shows the benefit of any
treatment using objective parameters.
Without objective before and after clinical
findings in Post Treatment Lyme, there is
little the careful physician can rely on to
show benefit (or not) of antibiotic therapy.
Changes in patient-reported symptoms
aren’t b iomarkers.
Symptom-only based studies touting
benefit, or paradoxically no benefit, of long
term antibiotic therapy are not persuasive.
Similarly, long term antibiotic use has its
own troubling side effects, especially with
antibiotic resistance and horizontal gene
transfer taken into account.
How does a careful patient know
what to do about an illness that might be
Lyme? Do a test! We want a blood test or
some other indicator that will be positive
when Borrelia is living inside the human
host that would then turn negative when the
organism is gone. Labs have looked for such
a marker for 40 years without satisfactory
findings. Show us the physiology.
Further, is there an inflammatory
marker that rises with exposure to Borrelia,
creates genomic activation that in turn
sickens the patient with illness persisting
beyond death of the bacteria? Clearly, that is
the case as noted in Table 4 above. If an
inflammatory marker appears and is not
responsive to antibiotics, as Table 4 also
shows, what basis does the careful patient
have to say treat with more antibiotics? If
we had a biomarker that would help us
decide what to do, that would be ideal. As
we sit here now that biomarker has not been
identified in published research.
A word on Lyme testing is in order.
Currently, the only tests licensed by the US
FDA and Health Canada Medical Devices
Branch are two serologic assays: the two-
tiered ELISA; and IgM and IgG Western
blot. Other tests, like PCR, seemingly
useful, still aren’t licensed (an excellent
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21
review and meta-analysis is found in (34). A
large number of assays, mostly from CLIA-
approved labs, are available commercially
(see Tables and figures in (34). Do any of
these tests show a biomarker that changes
with inflammatory responses? No.
Do any of the serologic tests
available make much difference in treatment
of putative Lyme patients either by (i)
reducing incidence of symptomatic Lyme or
(ii) reducing costs of diagnosis? The
answers are the same but might be
considered surprising. No (35). In Europe,
attempts to use the two-tiered system
employed by Canada and the US did not fare
well. Specificity was 95% but sensitivity
was variable and was too low for reliability
(36). In the US, the 2-tiered sero-diagnostic
testing algorithm that employs ELISA,
followed by Western blot testing, performs
well in later stage Lyme, but not for early
erythema migrans patients [EM (+)]. This
approach has been employed for over 10
years, despite missing 33% of convalescent
cases. Newer improvements in modification
of the two-tiered testing system (37) show
promise but will still fail to show (i)
presence or absence of living Lyme
organisms and won’t show (ii) inflammatory
responses.
The poor performance of all
commercially available Lyme tests was
shown recently (38). Sensitivities ranged
from 30.6% to 86.2%. These authors suggest
that negative lab tests do not rule out Lyme
but are unable to show what rules IN Lyme.
Section 19
Search for biomarkers for Borrelia in
Lyme that will also show CIRS
Reliable testing to show living
spirochetes in symptomatic Lyme patients
has been sought for nearly 40 years. Aside
from culture, countless labs have been
offered, but to date, each has not been
substantiated over time. Antibody testing in
long-term illness is limited by the absence of
ability to tell a physician (i) when the
exposure occurred; (ii) whether an illness
occurred; (iii) whether the illness is still
present; (iv) whether there were multiple
exposures; (v) whether there have been
multiple illnesses; or (vi) if the present
illness is progressive.
Symptoms are not suitable for use as
biomarkers; they are non-specific and
reporting can be subject to multiple possible
biases. We already know that symptoms of
chronic fatiguing illnesses are essentially
uniform across multiple diseases (Table 1).
Symptoms of CIRS are also essentially the
same as pre-treatment Lyme. Post-Lyme
Syndrome, a diagnosis assigned to Lyme
patients still sick despite reasonable use of
antibiotics, is not associated with defining
symptoms.
Finally, a newly codified case
definition of Chronic Lyme Disease has
appeared in peer-reviewed literature (39).
Once again, we are not given any single
method to show reliably that living Lyme
organisms are responsible for symptoms.
Instead, we are given directions to use
clinical judgment as we use symptoms,
maybe with culture, molecular testing (not
specified) or “some other technology that
directly identifies presence” of Borrelia.
What technology directly identifies
presence of Borrelia? We need a
biomarker!
Use of transcriptomics brings reason
for optimism for a test that shows both
active infection and provides a mechanism
for monitoring progress of therapy. The
answer lies in differential gene activation
associated with infection; monitoring
therapy in a patient is accomplished by
sequential studies over time to show
correction of differential gene activation.
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22
The target is to restore gene activity back to
normal control levels.
Bouquet is the lead author of the first
“sizable” study on acute Lyme patients,
defined by tick bite with (+) EM rashes,
published in 2016 (40). This small
case/control study (29 patients and 13
controls) measured transcriptomics at (i)
initial date seen; (ii) after three weeks of
antibiotics; and (iii) after six months. 15
patients were “fully recovered” from
infection (by symptoms) by 6 months, with
13 still symptomatic. This study does not
support the idea that three weeks of
antibiotics alone will ensure a successful
therapy. What we need is the biomarker that
transcriptomics could provide to show
resolution of inflammatory contribution to
illness.
Marked differences in gene
activation/suppression in cases/controls was
noted in 1,235 genes at baseline, with 1,060
genes still showing differences after three
weeks of antibiotics. At 6 months follow-up,
636 genes were still abnormal compared to
controls, but surprisingly, there were no
differences in abnormal gene activation at
six months between “fully recovered” versus
patients with ongoing symptoms. This
finding returns us to the question of (i)
whether symptoms remain a better clinical
indicator of health compared to objective
biomarkers; (ii) and of possible greater
importance, what is the source of persistent
gene activation left uncorrected by
antibiotics alone? Without use of CIRS
biomarkers, we are left to perform another
study to identify the reason for the persistent
transcriptomic abnormalities.
Almost lost in the discussion in
Bouquet’s paper is downregulation of
eukaryotic initiation factor 2 (eIF2)
signaling at each of the three-time points.
eIF2 modulates ribosome-transfer RNA
binding, or the initiation of translation, this
first step in production of protein from
messenger RNA. We have also seen
downregulation of ribosomal genes in
patients with nasal colonization of biofilm-
forming multiply antibiotic resistant
coagulase negative staphylococci; eIF2
downregulation is not a finding specific for
Lyme patients. Ryan, et al (12) showed a
decrease in ribosomal gene activity after the
final step in a CIRS treatment protocol with
use of exogenous vasoactive intestinal
polypeptide (VIP). We feel the sequential
tracking of ribosomal gene activity
throughout illness and treatment can be
highly indicative of health status.
Bouquet also notes overlap of gene
pathways in Lyme with lupus, rheumatoid
arthritis and Chronic Fatigue Syndrome. No
attempt was apparently made to compare
genomics of Lyme to ciguatera genomics
(22). In addition, pathway data will be
strengthened by recording in larger sample
sizes, owing to multiple test corrections
needed when analyzing tens of thousands of
genes simultaneously.
With 20,000 protein-coding genes
and even more non-coding regulatory genes,
each having the potential for significant
roles in Lyme versus other inflammatory
illnesses, enhanced data mining from white
blood cell gene expression may hold
promise for greater benefit in our search for
a reliable dual functioning Lyme biomarker.
Bouquet noted a group of eight genes
found upregulated in acute Lyme compared
to controls, most were pro-inflammatory
cytokines: interferon gamma (IFNG),
interleukin-1 beta (IL-1B), tumor necrosis
factor alpha (TNF), interleukin-6 (IL-6),
transforming growth factor beta (TGF beta-
1); anti-inflammatory cytokine interleukin-4
(IL-4), colony stimulating factor 2 (CSF2)
and cell surface marker CD40L (a
costimulatory protein found on antigen
presenting cells).
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23
Figure 3
Figure 4
Figures 3 and 4. Selected genes that have been repor ted to be up regulated in Lyme disease at acute exposure
(Figure 1) and after a 3-week course of antibiotics (Figure 2). Four patients are represented at different times
post exposure: A - 53yo F at acute exposure, B - 48yo F at 10 years post diagnosis, C - 20yo M at 6 months
post diagnosis, D - 38yo M at 1 year post diagnosis. Patient gene expression is shown with red indicating
elevated and blue indicating depressed gene expression relative to a control database with greater intensity of
color indicating greater differential expression. Gray indicates expression levels below limit of sensitivity.
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24
Bouquet also reported genes up-
regulated in Lyme patients after antibiotics
include toll like adapter molecule 1
(TICAM1), nuclear factor kappa-B (NF-kB),
tumor necrosis factor super-family 11
(TNFSF11), triggering receptor expressed
on myeloid cells 1 (TREM-1) and
transcription factor RELA proto-oncogene,
NF-KB subunit (RELA), as well as IL1B,
TNF, IFGN, CSF2 and CD40L.
When used as biomarkers for acute
Lyme and Lyme after antibiotics,
respectively, as shown in Figures 3 and 4,
the markers correctly identify one patient
with acute Lyme (patient A) but would not
support the diagnosis of acute Lyme made in
three other (patients B, C, D) cases
diagnosed previously with Lyme. Patients B
and C were diagnosed clinically without
biomarkers of ECM, positive ELISA or tick
bite followed by flu-like illness, with
duration of illness being 120 months and 6
months respectively. Patient D also did not
have a consistent presentation of acute Lyme
with a tick bite, followed by flu-like illness
and physician-witnessed ECM rash. The
question remains as to how long a patient
should be treated with protocols for acute
Lyme after that diagnosis is no longer
supported by recognized transcriptomic
biomarkers. Each of the three not confirmed
to have acute Lyme by transcriptomics, but
still receiving antibiotics, were subsequently
shown to have CIRS-WDB with multiple
confirming biomarkers and excellent
recoveries obtained using CIRS treatment
protocols (21). Each of these three patients
had NeuroQuant consistent with CIRS-
WDB but not with CIRS-PLS.
Bouquet does not report any
microRNA data. Based on preliminary data
from our group we feel that microRNA may
yield important clues to the pathophysiology
of acute Lyme, an illness that is possibly
defined better by transcriptomics than by
antibody formation. Moreover, identification
of microRNA abnormalities poses an
intriguing opportunity for transcriptomically
active interventions shown to be beneficial
in CIRS-WDB.
We are now poised to apply the work
of Bouquet to our own group of EM (+)
patients. We will look at messenger
(mRNA) and microRNA at baseline
diagnosis; after antibiotics; after use of our
patent pending CIRS treatment protocols
(Patent 131/961642)); and after 6 months of
no Rx. Perhaps CIRS treatment can
normalize the genes that Bouquet found to
remain abnormal despite antibiotics and
passage of time. By looking at microRNA at
each stage of the Lyme illness, we hope to
define mechanisms of regulation of DNA
expression possibly gone awry in PLS.
Given that Lyme is a high-profile
illness, as manifested by inter-physician
group arguments and public awareness, the
role of Next Generation Sequencing (NGS)
has societal merit, but the role of NGS is no
less important for other chronic fatiguing
illnesses. Fibromyalgia and CFS/ME
demand reliable diagnostic measures that
will also serve as indicators for evaluation of
treatment.
We consider treatment successful
when (i) symptoms of treated cases equal
controls; (ii) VCS of treated cases equals
controls; (iii) proteomics of treated cases
equals controls; (iv) MARCoNS assays of
treated cases are no different from controls;
and (v) transcriptomics of treated cases
equal controls.
As a further word on the concept of
“high profile,” CIRS-WDB affects far more
people than Lyme in the US; causes far
greater financial burden than Lyme in the
US and results in far more litigation than
Lyme in the US. The basic need of access to
a safe school, a safe work place and a safe
residence is not questioned. CIRS-WDB
already has multiple biomarkers that
demonstrate presence of illness and
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25
progression of treatments. Let the use of
objective biomarkers, as in CIRS-WDB,
become a similar goal for Lyme, CFS/ME
and fibromyalgia.
Section 20
CIRS Treatment Protocol
Treatment for CIRS is a lengthy
process designed to (i) first remove the
patient from the exposure(s); (ii) modulate
both stress responses and inflammatory
responses; (iii) decrease the inflammatory
burden and allostatic load; (iv) repair
damage to organs systems.
Allostatic load is defined by
McEwen (41) as “wear and tear” or overload
in response to being in a chronic state of
allostasis (change). Sleep deprivation,
maladaptation, poor nutrition, and exercise
habits contribute to this weathering effect.
Initial increase in stress and change is good
for the body and the brain, but chronic
stimulation and increased allostatic load can
be detrimental. Patients with CIRS have an
increased allostatic load due to the
chronicity of the inflammatory response and
consequent metabolic derangements.
Reduction of internal metabolic resources
leads to loss of physiologic and psychologic
resiliency as a result, and creates
vulnerability for more permanent injury to
the brain, organ and microvascular systems.
An 11-step treatment protocol for
CIRS has been developed over the last two
decades. Proper diagnosis relies on a
combination of detailed history, physical
examination and diagnostic data highlighted
throughout. Evaluation needs to include
determining the potential biotoxin exposure,
length of exposure / re-exposure and co-
morbid conditions.
The treatment process is staged and
progressive. Detailed patient education and
encouragement are paramount. CIRS is a
complex immunological disorder resulting
from uncontrolled inflammation involving
primarily the innate immune system. Some
patients move quickly through the protocol
while others do not. Some individuals can
“get stuck” in one treatment step or often
even “backslide” into an alre ady completed
step. Treatment is highly individualized
depending on exposure and concurrent
disease states but in each patient the basic
format of the protocol is invariant.
Therefore, the CIRS treatment protocol will
take time and requires a significant amount
of patient education and support.
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26
Section 21
Conclusion
CIRS is a neuroregulatory-
inflammatory disease process found in
genetically susceptible patients, initiated by
exposure to a biotoxin(s). The chronic
inflammation that ensues leads to a multi-
symptom, multisystem condition that
presents as a fatiguing illness. CIRS is
commonly found in the general population.
While often not well recognized in the
general medical community, the recognition
of the CIRS patient has implications for
reducing health care costs and solving a
debilitating disease complex for which there
is now evidence-based diagnostic and
treatment criteria.
Future research should focus on
refining the treatment protocol, determining
the role of transcriptomics in chronic
inflammatory processes and exploring the
relationship and overlap between CIRS and
other common conditions such as
cardiovascular disease, diabetes and obesity,
chronic pain syndromes, concussion and
brain injury, and neurodegenerative
disorders.
Section 22
Summary:
Taken together, for all diagnoses
made by symptoms only, there is a need for
biomarkers of pathology that aid in
diagnosis and lead to interventions that yield
effective therapeutics. Each step of CIRS
treatment is based on published, peer
reviewed literature originally produced from
the CIRS-WDB community. The
concordance of proteomic features of these
illnesses of diverse origin is not surprising in
that the innate immune responses are
limited. The diversity of protein/gene
functions are served by different
combinations of gene activation/suppression
that eventually yield a final common
proteomic pathway. Although the Bouquet
work on Lyme transcriptomics has made the
first mark, as of yet, no one has presented
adequate data to bring a transcriptomic case
definition to any phase of Lyme.
Understanding that there is still a substantial
need for broad-based studies using NGS and
newer concepts, including all biomarkers for
CIRS, as we take the next step beyond
antibodies, we can begin to bear down on
the inflammatory illness called Lyme
disease.
Acknowledgement We wish to
acknowledge support from a clinical
research grant from Standard Process, Inc,
Palmyra, Wisconsin.
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27
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