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Medical Hypotheses xxx (2012) xxx–xxx
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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy
Latent viral immune inflammatory response model for chronic
multisymptom illness q
CDR Sean R. Maloney a,b, Susan Jensen b, Virginia Gil-Rivas c, Paula Goolkasian c,⇑
a
Deployment Processing Command-EAST, PCS Box 20086, Building 309, Camp Lejeune, NC 28542, United States
W.G. (Bill) Hefner VA Medical Center, 1601 Brenner Avenue, Salisbury, NC 28144, United States
c
University of North Carolina, Charlotte 9201, University City Blvd., Charlotte, NC 28223, United States
b
a r t i c l e
i n f o
Article history:
Received 8 March 2012
Accepted 17 November 2012
Available online xxxx
a b s t r a c t
A latent viral immune inflammatory response (LVIIR) model is presented which integrates factors that
contribute to chronic multisymptom illness (CMI) in both the veteran and civilian populations. The LVIIR
model for CMI results from an integration of clinical experience with a review of the literature in four
distinct areas: (1) studies of idiopathic multisymptom illness in the veteran population including two
decades of research on Gulf War I veterans with CMI, (2) new evidence supporting the existence of
chronic inflammatory responses to latent viral antigens and the effect these responses may have on
the nervous system, (3) recent discoveries concerning the role of vitamin D in maintaining normal innate
and adaptive immunity including suppression of latent viruses and regulation of the immune inflammatory response, and (4) the detrimental effects of extreme chronic repetitive stress (ECRS) on the immune
and nervous systems.
The LVIIR model describes the pathophysiology of a pathway to CMI and presents a new direction for
the clinical assessment of CMI that includes the use of neurological signs from a physical exam, objective
laboratory data, and a new proposed latent viral antigen–antibody imaging technique for the peripheral
and central nervous system. The LVIIR model predicts that CMI can be treated by a focus on reversal of
immune system impairment, suppression of latent viruses and their antigens, and healing of nervous system tissue damaged by chronic inflammation associated with latent viral antigens and by ECRS.
In addition, the LVIIR model suggests that maintaining optimal serum 25 OH vitamin D levels will maximize immune system suppression of latent viruses and their antigens and will minimize immune system
inflammation. This model also emphasizes the importance of decreasing ECRS to improve immune system function and to minimize nervous system injury from excess serum glucocorticoid levels. The proposed model supports growing evidence that increasing omega 3 essential fatty acid levels in nervous
system tissues may decrease inflammation in the nervous system and improve neural plasticity and
recovery from neuronal injury.
! 2012 Elsevier Ltd. All rights reserved.
Introduction
The latent viral immune inflammatory response (LVIIR) model
describes a pathway to chronic multisymptom illness in both military and civilian populations and may stimulate new methods for
the clinical evaluation and treatment of individuals with these conditions. The term ‘‘chronic multisymptom illness’’ (CMI) was first
developed by the US Center for Disease Control and Prevention in
q
Parts of this manuscript were presented at the Navy Operational Medicine
Readiness Conference, Camp Lejeune, NC, 12–13 June 2010 and at the Virginia
Association of Nurse Anesthetists Annual Meeting, Virginia Beach! VA, 25 September 2011.
⇑ Corresponding author. Address: Department of Psychology, UNC Charlotte,
9201 University City Blvd., Charlotte, NC 28223, United States.
E-mail address: [email protected] (P. Goolkasian).
1994 to define an idiopathic symptom complex that was based
on a factor analysis of symptoms frequently reported by veterans
returning from the first Gulf War [1,2]. CMI’s were defined by the
presence for at least 6 months of one or more symptoms from
two symptom clusters: (a) general fatigue, mood, and cognitive
disorders, and (b) musculoskeletal pain.
The LVIIR model is also used to explain an expanded list of signs
and symptoms of idiopathic illnesses affecting veteran and civilian
populations. Examples of other idiopathic illnesses might include
mental health disorders such as post-traumatic stress disorder
(PTSD), anxiety, and depression associated with physical symptoms and idiopathic physical conditions including pain syndromes,
rashes, headaches, irritable bowel syndrome, sleep disorders, and
cardiac arrhythmias. The LVIIR model suggests that, when CMI extends from affecting the nervous system to other organ systems or
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http://dx.doi.org/10.1016/j.mehy.2012.11.024
Please cite this article in press as: Maloney CSR et al. Latent viral immune inflammatory response model for chronic multisymptom illness. Med Hypotheses (2012), http://dx.doi.org/10.1016/j.mehy.2012.11.024
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CDR Sean R. Maloney et al. / Medical Hypotheses xxx (2012) xxx–xxx
tissues of the body, it may become an idiopathic multisystem illness. This paper proposes that a CMI may be influenced by the
interaction of several simultaneous factors such as; non viral antigenic stimulation of the immune system, neural toxins, medications that suppress the immune system, CNS post concussive
changes, nutritional deficiencies, and pre-morbid mental health
conditions.
The latent viral immune inflammatory response (LVIIR) model
was developed as the result of combining clinical experience with
a review of the literature in four distinct areas. (1) A brief review of
idiopathic multisymptom illness in the veteran population since
the US Civil War including two recent decades of research on veterans involved in conflicts in Western Asia including Kuwait, Iraq
and Afghanistan. (2) New evidence supporting chronic inflammatory responses in the nervous system to latent viral antigens
including those of the herpetic family of viruses and the effect that
these responses may have on the nervous system. (3) Recent discoveries concerning the role of vitamin D in maintaining normal
innate immunity, normal adaptive immunity, and the suppression
of latent viruses. (4) The detrimental effects of extreme chronic
repetitive stress (ECRS) on the immune system and the nervous
system. In addition, the LVIIR model’s explanation of CMI is based
on the extensive clinical experience of the first two authors in
treating service members deploying to and returning from the
war zones in Afghanistan and Iraq, in veterans at a Department
of Veterans Affairs, VA Medical Center, and in civilian populations
including children.
CMI & other idiopathic multisystem illnesses
Idiopathic and disabling war related illnesses with similar
symptoms and signs have been documented since the US Civil
War [3]. They are often described as clinical syndromes for which
the underlying causes of the signs and symptoms are not well
understood. There are multiple factors associated with CMI and
other idiopathic war related illnesses including ECRS, trauma,
and some factors unique to specific conflicts [4]. Examples of unique factors might include infection and malnutrition during the
US Civil War, exposure to chlorine and mustard gases during World
War I, malnutrition and exposure to harsh weather during World
War II and the Korean War, exposure to ‘‘agent orange’’ during
the Vietnam War, and exposure to concussions from improvised
explosive devices, numerous potential toxins, vaccines, and medications during recent wars in Kuwait, Iraq and Afghanistan.
Even with variations in experiences and exposures during different conflicts, chronically disabled veterans have presented with
CMI and other idiopathic multisystem illnesses that have similar
but perplexing characteristics. Symptoms are present in these illnesses that do not have an apparent medical explanation and laboratory tests, which measure severity and identify the causes of
CMI and other multisystem idiopathic illnesses are notably absent.
At times, there is progressive disability and, occasionally, signs and
symptoms resolve spontaneously. Idiopathic syndromes have been
identified in varied locations in the world at different times for at
least the past one and one-half centuries. Most of the veterans afflicted with CMI or other idiopathic war related illnesses (i.e.,
chronic pain syndromes) have sustained some known form of ECRS
from exposure to traumatic and stressful experiences. CMI and
other idiopathic multisystem illnesses, however, have also appeared in non-deployed service members and in civilian populations [1–6].
The LVIIR model presents one plausible pathway to idiopathic
multisymptom illnesses or clinical syndromes that have occurred
in different locations and following different conflicts for the past
one and one-half centuries. The LVIIR model may also prove to be
consistent with many recent epidemiological, neuropsychological
(including PTSD [7]), toxicological, and immunological studies of
idiopathic war related illnesses [6–9].
Role of latent herpetic viruses in the nervous system
Latent herpetic viruses have been infecting people for thousands of years [10]. The inflammatory nature of latent herpes zoster and herpes simplex I & II viruses in tissues of the nervous
system and in other tissues of the body has been well documented
[11–15]. The LVIIR model proposes that inflammation caused by
the interaction of the immune system and latent herpetic viral
antigens may be associated with hyper-excitability of sensory ganglia (i.e., herpes zoster neuritis) and of other neurons of the nervous system (i.e., herpes simplex I vestibular neuronitis, etc.)
with or without clinically significant replication of either entire latent viruses or their DNA/RNA and with or without recurrent latent
viral infection or nerve cell death. Latent herpetic viruses (and possibly latent viral antigens alone) have the ability to travel between
sensory ganglia and innervated tissues of the body [16] and may
also migrate from neurons of peripheral sensory ganglia to other
neurons of the central nervous system.
This hypothesis that latent viral antigens may be present and
trigger an immune inflammatory response is supported by a recent
study involving varicella zoster virus, glycoprotein E-Specific, CD4+
T cells. Circulating gE-specific CD4+ T cells were detected at a relatively high frequency in healthy donors with normal immune systems. This finding would be compatible with frequent exposure to
replicative cycle antigens in these healthy donors [17]. Varicella
zoster virus (VZV) specific T cell responses may be vital in the prevention of latent viral reactivation.
In a mouse model, cytotoxic (killer) Cd8 T cells have been
shown to block HSV I reactivation from latency in sensory neurons
(trigeminal ganglia). HSV I infected trigeminal ganglia cells, infiltrated with Cd8+ T cells, were able to produce HSV I immediate
and early proteins, but did not produce HSV I late proteins or infectious virions. Cd8+ T cells prevented reactivation of HSV I without
destroying the infected neurons [18].
Elevated IgG levels to cytomegalovirus have also been implicated in rapid cognitive decline in older individuals (age 60–100)
over a 4 year period [19]. Persistent latent viral DNA/RNA, in the
presence or absence of infectious virus replication, can result in
the loss of normal cell homeostasis and in an inflammatory response associated with antigenic viral proteins. The antigenic
inflammatory response could result in demyelination or oligodendroglia cell death [20].
Considerable time may be required to reverse synaptic or possibly neural network long-term potentiation and depression changes
even after the latent viral immune inflammatory response has resolved. Reversal of changes may also be incomplete in severe cases
of a latent viral immune inflammatory response due to irreversible
neuronal changes, injury, or even cell death. The role of inflammatory responses in pain was also highlighted in a a recent review
[21] of sensory neuron function. Specifically, the researchers concluded that ‘‘recent evidence suggests that up regulated expression
of inflammatory cytokines in association with tissue damage or
infection triggers the observed hyper-excitability of pain sensory
nerves’’. Furthermore, chemokine and chemokine receptor expression in sensory ganglia may contribute significantly to virusassociated neuropathic pain syndromes [21]. Application of
prolonged or intense noxious stimulation to sensory ganglia is
thought to rearrange synaptic strength as in long term potentiation
[22]. Chronic pain associated with hyperalgesia to pin prick and/or
allodynia to touch may be a result of or related to detrimental synaptic plasticity at the sensory, spinal cord, or higher level. Chronic
excessive indirect (through the cortex) somatosensory or autonomic afferent nerve input to the limbic system may result in
Please cite this article in press as: Maloney CSR et al. Latent viral immune inflammatory response model for chronic multisymptom illness. Med Hypotheses (2012), http://dx.doi.org/10.1016/j.mehy.2012.11.024
CDR Sean R. Maloney et al. / Medical Hypotheses xxx (2012) xxx–xxx
detrimental long term potentiation or long term depression of synapses especially in the hypothalamus, hippocampus, and amygdala. The resulting detrimental neural plasticity changes in the
CNS may play a significant role in symptoms (i.e., pain, fatigue, increased startle reflex, sleep problems, rage, PTSD, anxiety, depression, decreased concentration, and decreased short term memory)
experienced by veterans with CMI’s or other idiopathic war multisystem illnesses [23–26].
Further support for a latent viral immune inflammatory response model for CMI comes from our recent retrospective study
conducted at a veteran’s hospital [27]. The study reviewed the successful use of long term (6 to 18+ months) antiviral therapy (acyclovir and valacyclovir) in the treatment of US veterans with
chronic, often disabling, pain syndromes attributed to atypical herpetic viral reactivation. These pain syndromes were associated
with the presence of hyperalgesia to pinprick, subtle or atypical
rashes, pain, and burning or itching sensation. The veterans had
elevated/positive antibody titers to at-least one herpetic virus
including varicella zoster and herpes simplex I & II. One or more
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of these latent viruses were suspected of causing the veteran’s pain
syndromes. Reported improvement in signs and symptoms ranged
from 78% to 97% with moderate dose, long term, antiviral therapy
(6–18 months)[27].
In another study [28], twelve patients with central nervous system dysfunction including long-standing fatigue were treated with
Valganciclovir for 6 months. The patients had symptoms for
1–8 years and had high IgG antibody titers to Human Herpes-6
virus and Epstein Barr Virus. Nine of the 12 patients experienced
near resolution of their symptoms and were able to return to fulltime work or normal activity levels. IgG antibody titers, in those
patients who responded, dropped significantly with treatment.
Also, a case study [29] of three children/adolescents with disabling chronic pain syndromes (greater than 1 year duration) reported such significant improvement in symptoms when treated
with long term antiviral therapy (acyclovir or valacyclovir) that
they were able to return to school. All three children had elevated
IgG antibody titers to varicella zoster and one had elevated IgG
antibody titers to HSV I. Two had chronic prominent but atypical
Fig. 1. Low vitamin D3 and vitamin 25(OH)D3 stores and immune system function.
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rashes which resolved with long-term (greater than 6 months)
antiviral therapy. Elevated IgG antibody titers to varicella zoster
and herpes simplex I dropped in two individuals for which follow
up antibody titers were available. When antiviral medication was
stopped, one child experienced acute flare-ups of pain and
disability.
When taken together the three studies re-enforce the concept
that IgG antibodies to latent viruses can go up without overt signs
of acute viral infection and later go down with treatment and/or
resolution of symptoms. These studies suggest that some CMI
and other chronic idiopathic multisymptom illnesses may have a
viral component.
Vitamin D and immune system function
The immune system’s response to latent viruses and their viral
antigens may be adversely affected by vitamin D insufficiency and
deficiency. Fig. 1 provides a detailed exploration of the different
forms of vitamin D in the serum and other tissues of the body in
order to explain the relationship between the immune system
and vitamin D. Vitamin D3, cholecalciferol, is formed in the basal
layer of the skin under the influence of ultra violet B sunlight. Cholecalciferol is stored in adipose tissue of the body. Vitamin D3 and
its metabolites are also present in the blood serum and are attached to vitamin D binding protein (DPB). As vitamin D3 passes
through the liver, it is converted to 25 OH D3 and stored in the
liver.
Vitamin D3 is poorly soluble in an aqueous environment and
highly soluble in a lipid environment. When vitamin D3 in the diet
and production of vitamin D3 from skin exposure to ultra violet B
sunlight are low, body fat may sequester vitamin D3 from the serum due to vitamin D3’s high lipid solubility. Thus a higher percent
body fat may contribute to lower serum vitamin D3 levels when intake and production of vitamin D3 are low. Vitamin D3 is transported in vascular and interstitial tissues attached to vitamin D
binding protein (DBP) [30]. Plasma concentration of DBP is approximately 20 times greater than the total concentration of vitamin D3
and its metabolites.
Low serum 25 OH vitamin D3 levels can lead to secondary
hyperparathyroidism [31]. Parathyroid hormone is known to stimulate the kidney’s conversion of serum 25 OH vitamin D3 to serum
1,25(OH)2 vitamin D3, the active form of vitamin D3 [31]. This may
explain why serum 1,25(OH)2 vitamin D3 levels can be variable
(including paradoxically normal to elevated) in patients with
chronic vitamin D deficiency and are an unreliable measure of vitamin D status.
The presence of 1 alpha hydroxylase in many vitamin D
target cells of the body (in addition to proximal renal tubular
cells) is consistent with autocrine, intracrine, and paracrine functions for 1,25(OH)2D3 in the regulation of cell proliferation and
differentiation. Both vitamin D activating (25-hydroxylase and 1
alpha-hydroxylase) enzymes and vitamin D metabolizing (24hydroxylase) enzyme are present in some cells of the immune
system including macrophages and mature dendritic cells. Strict
regulation of these enzymes within immune system cells is consistent with an autocrine and paracrine role of vitamin D3 in the
immune system [32].
Macrophages and mature dendritic cells of the innate immune
system are able to process antigens and then are able to activate
and stimulate resting B lymphocytes and T lymphocytes by presenting processed antigens to them [33]. When B and T lymphocytes are activated by these cells and proliferate, both B and T
lymphocytes express a 1,25(OH)2D3 vitamin D receptor (VDR).
When extracellular 25(OH)D3 levels are normal, macrophages
and mature dendritic cells are able to convert adequate
25(OH)D3 to 1,25(OH)2D3 (active vitamin D3) within their cells.
After exportation of the newly processed 1,25(OH)2D3 out of these
cells, the increased extracellular 1,25(OH)D3 levels provide negative feedback to activated B and T lymphocytes to limit the proliferation of B lymphocytes, IgG, T lymphocytes and associated
inflammatory cytokines of the adaptive immune system [33]. The
production of active vitamin D, 1,25(OH)2D3, at the site of inflammation permits higher concentrations of active vitamin D than
might be achieved through normal diffusion from the serum. This
partial uncoupling of interstitial serum 1,25(OH)2D3 from serum
1,25(OH)2D3 may explain why serum 25(OH)D3 (rather than serum
1,25(OH)2D3) may be the controlling factor for limiting inflammation due to negative feedback by extracellular paracrine
1,25(OH)2D3.
When normal serum and interstitial 25 OH vitamin D3 levels are
present, antigenic stimulation of the macrophage/monocyte tolllike receptor 2/1 (TLR2/1) up-regulates these cell’s expression of
vitamin D receptor (VDR) and 25 OH vitamin D-1a-hydroxylase
(1-OHase). Intracellular 25 OH vitamin D3 1a-hydroxylase converts
intracellular 25 OH D3 to 1,25(OH)2 D3 which then stimulates the
intracellular production of a cathelicidin in monocytes/macrophages. Human cathelicidin is a peptide that induces the destruction of infectious agents and improves innate immunity [34,35].
Cathelicidin has been shown to have direct antiviral activity
against adenovirus and herpes simplex virus in vitro [36].
When serum, interstitial, and monocyte/macrophage intracellular 25 OH vitamin D3 levels are lower (vitamin D insufficiency/deficiency states), the intracellular production of cathelicidin is
decreased and the effectiveness of monocyte/macrophage suppression of infectious agents is compromised. Impaired monocyte/macrophage function combined with an increased but ineffectual,
antigen stimulated, B lymphocyte and T lymphocyte response
may result in impaired suppression of latent viral antigens/viruses
and an increased and chronic latent viral immune inflammatory
response.
Dendritic cells of the innate immune system are important for
immune system surveillance and dendritic cells also have a vitamin D (VDR) receptor [37]. Cell culture experiments support the
hypothesis that vitamin D has significant anti-viral effects especially against enveloped (including herpetic) viruses [38]. Low vitamin D status and the presence of Epstein Barr virus appear to have
a detrimental synergistic effect on the immune system facilitating
the activation of auto-reactive T cells and increasing the inflammatory reaction to Epstein Barr virus [39].
In August of 2008, an article [40] reviewed a growing body of
literature describing the low vitamin D3 stores in patients with
chronic pain and the need for vitamin D3 supplementation in these
patients. A retrospective study [41] of veteran’s charts at the Salisbury, NC. VA Medical Center examined the rate of vitamin D insufficiency and deficiency in a sample of 400 veterans, including those
who had chronic disabling pain syndromes. A majority (70.5%) had
serum 25 OH vitamin D3 levels below Lab Corp of America’s lower
limits of normal (<32 ng/ml), and 34% were vitamin D deficient
(<20 ng/ml). Within the African American subset of veterans in this
study, 93% were below the lower limits of normal and 68% were
vitamin D deficient. The increased pigmentation in the skin of African Americans may have resulted in greater blocking of ultra violet
B sunlight and reduced production of vitamin D3. In this study, veterans with low serum vitamin D levels were almost twice as likely
to develop a chronic pain syndrome compared to veterans with
normal vitamin D levels.
A second large study of veterans in six Dept. of Veterans Affairs,
medical centers in the Southeastern United States demonstrated
wide spread vitamin D deficiency that resulted in high medical
costs [42]. This study also reported an especially high risk of vitamin D deficiency in African American veterans. Both studies
[41,42] are consistent in reporting high rates of low serum 25 OH
Please cite this article in press as: Maloney CSR et al. Latent viral immune inflammatory response model for chronic multisymptom illness. Med Hypotheses (2012), http://dx.doi.org/10.1016/j.mehy.2012.11.024
CDR Sean R. Maloney et al. / Medical Hypotheses xxx (2012) xxx–xxx
vitamin D3 levels in the veteran population, thus, chronically low
vitamin D levels may be one factor that could contribute to impairment of the immune system and to the development of a latent viral immune inflammatory response.
Stress, immune system function, and PTSD
The effect of severe acute and ECRS on vitamin D metabolism,
consumption and storage is not known. Severe acute stress and
ECRS with increased glucocorticoid production, however, may impair vitamin D metabolism as has been demonstrated with the use
of exogenous corticosteroids including prednisone [43]. ECRS may
have particular relevance in the case of idiopathic CMI’s and other
idiopathic multisystem illnesses due to its independent negative
effects on immune system functioning and on the central nervous
system [44,45].
Overtime, ECRS is known to cause hyperplasia of the adrenal
gland, increased glucocorticoid secretion, and atrophy of the thymus gland, which is one source of T lymphocytes [44]. Fig. 2 demonstrates how ECRS may relate to immune system function.
Sympathetic fibers of the autonomic nervous system innervate
bone marrow, thymus, spleen, and lymph nodes. All lymphocytes
have adrenergic receptors. Stimulation of the hypothalamic–pituitary–adrenal axis or of the sympathetic–adrenal–medullary axis by
ECRS results in the secretion of adrenal hormones including epinephrine, norepinephrine, and cortisol [46,47]. Exposure to ECRS,
in contrast to acute stress, has been shown to have negative effects
on almost all functional measures of the innate and adaptive immune systems [46]. Impairment of the cellular immune response
has been shown to often result in higher antibody levels against latent viruses [46–48].
Delayed-type hypersensitivity reactions have been examined in
human participants to evaluate cellular immunity. T lymphocytes
5
recognize an antigen introduced into the skin, then proliferate, secrete cytokines, and start an acute cellular immune system inflammatory reaction to clear the antigen from the skin. Chronic stress
has been shown to impair or decrease delayed-type hypersensitivity reactions [49].
It is difficult to directly explain PTSD with its behavioral and
psychological manifestations by employing a LVIIR model based
on physical signs, laboratory tests, and proposed imaging techniques. However, physical factors, which appear to increase the
risk of PTSD may be consistent with the multi-factor LVIIR model.
Factors from epidemiological studies [7] that appear to increase
the risk of PTSD in veterans and others include: sex (female), age
(younger age greater than older age), race and ethnicity (African
American and Hispanic individuals).
Specifically, in states of insufficient vitamin D production or
intake, a higher percent body fat in females may lead to a greater amount of vitamin D dissolved in lipid tissue thus lowering
serum and interstitial 25(OH)D3 concentrations available for immune system function and regulation. African American and Hispanic individuals often have greater protection from ultra violate
B sunlight due to increased pigmentation in the skin. As a result
of this natural sun block, they produce vitamin D slowly and
generally have low serum vitamin D levels when overall sun
exposure to skin is inadequate for sufficient vitamin D production. Finally, there may be two or more possible explanations
for the higher risk of PTSD in younger verses older individuals,
which are consistent with the LVIIR model. One possible explanation is that there is greater capacity for neural plasticity in
the brains of younger individuals making them more susceptible
to detrimental synaptic long-term potentiation or depression effects of ECRS or a LVIIR. A second possible explanation is that
younger individuals may experience greater glucocorticoid production detrimental to the central nervous and immune system
function as part of a response to ECRS or to stress associated
with a LVIIR.
The LVIIR model
The proposed LVIIR model hypothesizes that latent viral antigens may trigger a latent viral immune inflammatory response in
the setting of an impaired immune system often associated with
low vitamin D stores and psychological/physical stressors. This
new model is presented in Fig. 3 and is described by the following
statements.
(a) A host cell containing latent viral DNA/RNA is able to produce antigen glycoproteins and other antigen molecules
with or without clinically significant RNA/DNA or complete
virus replication [18].
(b) A LVIIR can be triggered by latent viral antigens and an
impaired immune system. Two significant factors that may
adversely affect immune system function include: vitamin
D insufficiency or deficiency and extreme chronic repetitive
stress.
(c) Extreme chronic repetitive stress can overstimulate the
hypothalamic–pituitary–adrenal (HPA) axis [44,50,51]
resulting in atrophy of the thymus gland and reduction in
the production and population of T lymphocytes [44].
(d) A LVIIR may include increased production of B lymphocyte
IgG immunoglobulin and other immune system inflammatory molecules (i.e., certain cytokines) with or without significant latent viral replication, and with or without
clinically significant total white blood cell count elevation
or other clinical signs of infection.
Fig. 2. Extreme chronic repetitive stress (ECRS) and immune system function.
Please cite this article in press as: Maloney CSR et al. Latent viral immune inflammatory response model for chronic multisymptom illness. Med Hypotheses (2012), http://dx.doi.org/10.1016/j.mehy.2012.11.024
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Fig. 3. Latent viral immune inflammatory response (LVIIR) model.
(e) A LVIIR can be amplified by or made worse by a second
inflammatory antigen, allergen, or other inflammatory
chemical [52].
(f) Latent viral antigens and their accompanying inflammatory
response are proposed to spread in many ways to tissues
of the body including: from the host cell to nearby cells,
through the blood circulation, and through axonal transport
from the peripheral nervous system to the CNS and from the
peripheral nervous system to other tissues of the body
innervated by these latent viral host cells [16].
(g) The antigens of any latent or combination of latent viruses at
the same time can stimulate a LVIIR. Due to the prevalence
of latent herpetic viruses in the human population and particularly in the nervous system, herpetic viruses are proposed to be the most common viruses (but not necessarily
the only latent viruses [52] capable of causing a LVIIR.
(h) The tissue locations of latent viral antigens causing the
inflammatory response determine the initial clinical symptoms and signs.
Varicella zoster and herpes simplex I & II are scattered in latent
form in nervous system tissue. The scattered nature of these herpetic latent viruses in the nervous system may explain the variations in symptoms and signs experienced by individuals with
CMI. These herpetic latent viruses also provide a ready source of
antigens in the setting of immune system impairment. Likewise,
latent Epstein Barr virus contained in B Lymphocytes [16] may
spread viral antigen and an immune system mediated inflammatory response to the central nervous tissue and other tissues of
the body.
CMI and other idiopathic multisystem illnesses are progressive
and disabling. Extreme chronic repetitive stress and vitamin D
insufficiency/deficiency are proposed to be two common predisposing and perpetuating factors for a CMI or other idiopathic multisystem illness due to a LVIIR. They may not, however, be the only
predisposing factors for impaired immune system function and the
development of these conditions in otherwise healthy individuals.
Severe chronic pain associated with a LVIIR herpetic sensory
neuritis/ganglionitis may produce a secondary, ongoing, source of
ECRS resulting in chronic stimulation of the hypothalamic–pituitary–adrenal axis and increased glucocorticoid production. Chronic
increased production of glucocorticoids may have adverse effects
on limbic system function (particularly the amygdala, and hippocampus) and the frontal lobe of the brain independent of any direct
LVIIR effect [45].
The presence of hyper-excitability of nerve cells due to a LVIIR
as well as neuroplasticity changes in the nervous system due to
long-term synaptic potentiation and depression could physiologically explain exaggerated responses to painful or other stimuli in
nervous system cells. Hyper-excitability in sensory nerves or the
spread of an antigen driven immune inflammatory response to
nearby motor nerves could explain exaggerated peripheral motor
responses or other exaggerated nervous system efferent responses
in the parasympathetic and sympathetic autonomic nervous system. A very severe immune inflammatory response could result
in nervous system tissue injury and cell death.
Clinical assessment
Objective methods for the clinical assessment of idiopathic
CMI’s and other idiopathic multisystem illnesses are important.
To determine a diagnosis of LVIIR, it may be helpful during the
initial medical history and physical exam to record symptoms
and to test for signs of possible neuronal hyper excitability due
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CDR Sean R. Maloney et al. / Medical Hypotheses xxx (2012) xxx–xxx
to inflammation in the peripheral nervous system (including cranial, spinal, and peripheral nerves). Examples of pertinent symptoms and signs in sensory nerves include: neuropathic pain,
itching and burning sensations associated with hyperalgesia to
pin prick and allodynia to touch in the skin. Examples in a cranial
nerve might include ringing in the ears and episodes of dizziness
associated with decreased balance on heel to toe walking with
the eyes closed in the absence of peripheral neuropathy and cerebellar dysfunction; and examples involving the autonomic nervous
system might include increased or decreased peristalsis of the bowel (diarrhea or constipation associated with irritable bowel syndrome), exaggerated hyperhidrosis (sweating) in the palms and
soles, and tachycardia or bradycardia of the heart with exaggerated
sympathetic or parasympathetic stimulation. The presence of
physical symptoms and signs consistent with neuronal inflammation and secondary hyper excitability in scattered parts of the nervous system provides one possible physiological explanation for
CMI and other idiopathic stress related multisystem illnesses based
on the LVIIR model.
When possible, symptom improvement should be assessed
objectively and if monitored, patients can easily recognize resolution of chronic tinnitus and improvement in fatigue level, endurance. Similarly, improvement in psychological and cognitive
issues such as irritability, anxiety, PTSD symptoms, decreased concentration, and decreased short term memory are often noted by
spouses and other family members first and can be measured
through psychological and cognitive testing. Chronic pain symptoms are often the last to resolve and are the most difficult to
quantify. Pointing out resolution of easily monitored signs often
encourages compliance with treatment regimens that must continue for 6–18 months for significant improvement and to up to
36 months to reach maximum medical benefit.
The LVIIR model and some previous research findings
[28–29,46–48] predict that monitoring fluctuations in specific latent viral IgG antibody concentrations in the blood serum may help
to identify the primary latent virus(s) stimulating the immune
inflammatory response and may be useful in monitoring responses
to specific treatments. Monitoring of other non-specific proinflammatory cytokine molecules (especially IL-1, IL-6, and
TNFalpha [46] participating in an immune inflammatory response)
before, during, and after treatment may also help in identifying
the presence and severity of a LVIIR and in documenting successful
treatment of this response [53].
Monitoring specific viral antigen or antigen–antibody complex
levels in the blood serum (if present) or in immune system cells
may also provide a way to identify and quantify the latent viruses
that are contributing to an inflammatory response. It may also provide specific information concerning the effectiveness of the immune system in suppressing a latent virus and its antigens, and
the effectiveness of a specific treatment. Exposing blood serum,
blood cells, or other tissue samples to specific viral antibodies
tagged with a fluorescent dye [54] or with a radionuclide may permit the identification and quantification of specific latent viral
antigens present in the blood serum, blood cells or other tissue
samples.
Although imaging techniques for the diagnosis of LVIIR is
unavailable, the potential to develop such a technique already exists. To verify the presence and location of a LVIIR, an imaging test
that connects a specific viral antigen to a latent viral immune
inflammatory response in a specific location of the nervous system
(or other tissue in the body) is needed. Engineered antibody type
molecules, including bivalent antibody fragments tagged with
radioactive nuclides, have been used previously to locate antigens
on tumor cells [55].
Radionuclide tagged, specific latent viral antibody type, molecules could be engineered that would migrate to target nervous
7
system or other body tissues/cells which are experiencing a LVIIR.
Once there, the molecules with antibody characteristics (but of
smaller size that typical IgG antibodies) could bind to specific latent viral antigens, which are triggering the immune inflammatory
response. Increased concentrations of the radionuclide tagged antibody-antigen complexes in affected tissues could be imaged [55].
The identified structures/locations from viral antigen–antibody
complex imaging must correlate with the patient’s signs and
symptoms. The technique must also verify that the inflammatory
process has resolved when the patient’s signs and symptoms resolve and the patient recovers.
In recent years, functional imaging techniques including positron emission tomography and functional MRI have enabled
researchers to explore brain neuroplasticity and to examine
remodeling of neural systems and their components changed by
disease or injury. Functional neuroimaging may also complement
behavioral assessments by allowing the observations of neural networks controlling perceptions, cognition, and short-term memory
[56,57]. Correlation of the locations of viral antigen–antibody
inflammatory responses in the nervous system (through radionuclide imaging) with functional MRI or other new imaging techniques of the central nervous system may help to explain many
of the behavioral changes seen in CMI and other idiopathic multisystem illnesses and may assist in monitoring central nervous system recovery from these disorders.
The LVIIR model suggests that resolution of these illnesses can
be objectively monitored by the gradual decrease in the following:
clinical symptoms and signs of these illnesses, participating latent
viral antigen production, latent virus antibody–antigen complexes
in affected tissues, latent viral IgG antibody titers in the serum that
are specific to any participating latent viruses, and the quantity of
immune system molecules including cytokines participating in the
inflammatory response.
Predictions from the LVIIR model
Based on the LVIIR model, treatment of CMI and other idiopathic multisystem illnesses requires reversing the latent viral immune inflammatory response. This might be accomplished by
restoring the innate and adaptive immune systems’ ability to suppress latent viruses and their antigens and by eliminating detrimental immune system hyperactivity, if present. Achieving these
two goals will require the early recognition and reduction of treatable predisposing or perpetuating factors for immune system
impairment. Possible treatable predisposing or perpetuating factors for a LVIIR include vitamin D insufficiency/deficiency, chronic
extreme repetitive stress, and other nutritional factors, medications, infections, toxins, or diseases that might adversely affect
the immune system.
The LVIIR model predicts that maintaining optimal serum
25(OH)D3 levels for immune system health may be one of the most
important methods to treat and prevent a CMI and other idiopathic
multisystem illnesses. Treatment of chronic low vitamin D states
can be challenging especially in individuals with a high percent
body fat or poor vitamin D absorption. Treatment can also be challenging in individuals without adequate sun exposure and in those
individuals who are intolerant to ultra violet B sunlight.
The body’s production of vitamin D3 varies during the year
based on sun exposure. Factors influencing exposure include distance of the sun from the earth and duration of daylight (time of
year), atmospheric conditions (cloud cover, pollution in the air,
etc.), percentage of skin exposed, duration of sun exposure, and
use of sun blocking agents. Dietary intake of vitamin D fortified
foods and vitamin D supplements can also affect serum
25(OH)D3 levels.
Please cite this article in press as: Maloney CSR et al. Latent viral immune inflammatory response model for chronic multisymptom illness. Med Hypotheses (2012), http://dx.doi.org/10.1016/j.mehy.2012.11.024
8
CDR Sean R. Maloney et al. / Medical Hypotheses xxx (2012) xxx–xxx
Serum concentration levels of 25(OH)D3 are quite small and are
commonly measured in the United States in nanograms (10!9 g)
per ml. In our clinical experience [41] stopping over the counter
vitamin D, multi-vitamin, and fish oil supplements, and avoiding
increased sun exposure (sun bathing) for 2–3 days before testing
for serum 25(OH)D3 levels produces consistent levels that represent body stores of vitamin D. Avoiding vitamin fortified foods
for 12–24 h before the blood test is also helpful. The threshold
and optimal levels of serum 25(OH)D3 levels for immune system
health is not known and will have to be determined by further
studies. In our clinical experience, CMI’s and other idiopathic multisystem illnesses do not improve significantly or resolve in
affected individuals until serum 25(OH)D3 levels are maintained
at threshold level of approximately 50–60 ng/ml for at least
6–18 months. Effectiveness of and compliance with a treatment
regimen (combination of increased sun exposure, when possible,
and vitamin D supplementation) to raise serum 25(OH)D3 levels
can only be determined by monitoring serum 25(OH)D3 levels.
Long term oral vitamin D supplementation in most CMI patients
with normal bowel absorption and body weight can be limited to
3000–4000 IU per day of D3, cholecalciferol, to avoid vitamin D
toxicity [58]. The LVIIR model also suggests that treatment with
oral 25(OH)D3 or a combination of D3 and 25(OH)D3 may be more
effective than treatment with vitamin D3 alone in quickly improving innate and adaptive immune system function including the
suppression of latent viruses and the reduction of immune system
inflammation without causing hypercalcemia. The use of oral
25(OH)D3 would bypass factors which might interfere with the
conversion of D3 to 25(OH)D3 by the liver.
Treatment of the psychological manifestations of CMI’s and
other idiopathic multisystem illnesses (anxiety, depression, PTSD,
sleep disturbances, decreased short term memory and decreased
concentration, etc.) with medical and psychological treatments is
also very important. According to the LVIIR model, the path to
recovery from a well established CMI or other chronic idiopathic
multisystem illness takes a considerable amount of time (6–
18 months for significant improvement and up to 36 months to
reach maximum medical improvement). The body must recover
optimal immune system function, suppress latent viruses and clear
their antigens from tissues of the body including the nervous system, and finally undo any detrimental neural plasticity changes
including synaptic long-term potentiation and depression.
Omega 3 fatty acids have been proposed as a safe anti-inflammatory treatment of neuropathic pain [59], to improve psychiatric
health, and to increase resilience of the brain including modulation
of the inflammatory cascade following traumatic brain injury [60–
62]. Based on some pilot data from the first two authors, the
threshold for successful treatment of nervous or other tissue
inflammation in veterans and active duty personnel with idiopathic CMI’s or other idiopathic multisystem illnesses is 1800 mg
of omega 3 essential fatty acid per day in 2–3 divided doses with
food.
Medications that interfere with vitamin D metabolism [43]
(corticosteroids and prednisone) and neuroleptic medications,
which have been shown to increase hepatic metabolism of vitamin
D [63] (including phenytoin and phenobarbitol), should be used
sparingly and avoided if possible. There may be other medications
such as newer neuroleptic medications that also interfere with
vitamin D metabolism.
The use of antiviral medication may be helpful when the latent
viruses causing a latent viral immune inflammatory response
(LVIIR) can be identified [27–29]. Based on pilot data in adolescents
and adult veterans with normal kidney function, the threshold
doses for successful treatment of CMI or other idiopathic multisystem illnesses associated with herpes zoster and simplex 1 & II was
approximately 400 mg PO 5 times a day for acyclovir and approx-
imately 1500 mg per day in divided doses for valacyclovir. Treatment lasted 6–18 months or longer, and antiviral treatment was
used prior to the realization of chronic low vitamin D stores in
these patient populations.
In spite of generally good responses to antiviral therapy, relapses in the symptoms of CMI and other idiopathic multisystem
illnesses were not uncommon when antiviral therapy was stopped
[27,29]. Nine years after initial evaluation, the pediatric case with
relapsing symptoms (when antiviral therapy was discontinued)
was diagnosed with chronic vitamin D deficiency with a serum
25 OH vitamin D3 level of 12.9 ng/ml (normal range 32–100 ng/
ml – Lab. Corp. of America, 2008). The relapses of symptoms that
occurred in this pediatric case and in many of our veterans may
have resulted from a continued immune system impairment from
low vitamin D stores. Other limitations of antiviral treatment included GI side effect of nausea with acyclovir treatment and difficulty with compliance to multiple dosing when taking long-term
acyclovir (400 mg PO 5 times per day).
Summary and conclusions
A LVIIR model is proposed explain multi-factor CMI’s, other idiopathic multisystem illnesses, and some associated mental health
disorders. War environments expose soldiers and often civilians to
adverse weather, toxic substances, insects, infectious diseases, extreme chronic repetitive stresses, and injury. The use of uniforms
that cover the body from head to toe, have been a main method
of protection for soldiers from adverse environmental exposures
throughout the last two centuries. During the current conflicts in
Iraq and Afghanistan, protective clothing, frequent or prolonged
deployments, working long hours in doors or in vehicles, and night
operations keep the skin out of contact with ultra violate B light.
The avoidance of sun exposure to skin in the civilian population
has also become prevalent in recent years. The lack of sun exposure
poses a significant risk for vitamin D depletion and immune system
dysfunction in both the civilian and military populations.
Those exposed to war frequently experience severe anxiety over
possible injury. They may also experience ECRS associated with actual injury or illness, the witnessing of severe violence and injury,
and isolation from family. ECRS associated with war environments
and particularly with combat exposure can lead to over stimulation of the hypothalamic–pituitary–adrenal axis [44,50,51] and to
impairment of the immune system and the CNS. Central nervous
system impairment, associated with ECRS and a LVIIR, may mimic
or confound symptoms of a post concussive syndrome or mild
traumatic brain injury. The natural course of a concussion or mild
brain injury is improvement over a relatively short period of time.
The natural course over time of a CMI or other idiopathic multisystem illnesses is often no improvement or worsening until major
perpetuating factors of immune system dysfunction are resolved
and detrimental neuroplasticity changes in the nervous system
are reversed. Finally, a latent viral immune inflammatory response
may be compounded by other factors particular to specific
conflicts.
The proposed LVIIR model will require verification through
further testing and evaluation. New diagnostic studies based on
antibody–antigen complex laboratory testing and imaging technologies will have to be developed and tested. The optimal serum 25
OH vitamin D3 level for immune system health will have to be
determined and the optimal treatments for LVIIRs will have to be
verified.
The most immediate and perhaps most important change to our
evaluation and treatment of veterans and other civilians with, disabling, chronic multi-symptom illness and other idiopathic multisystem illnesses may be the testing for and treatment of low
Please cite this article in press as: Maloney CSR et al. Latent viral immune inflammatory response model for chronic multisymptom illness. Med Hypotheses (2012), http://dx.doi.org/10.1016/j.mehy.2012.11.024
CDR Sean R. Maloney et al. / Medical Hypotheses xxx (2012) xxx–xxx
vitamin D states, treatment of nervous system inflammation if
present, and the elimination of ECRS in order to restore normal immune system function and to minimize any ongoing damage to the
nervous system from a LVIIR.
Conflict of interest
None of the authors or co-authors have any financial or personal
relationships that could inappropriately influence their work.
[18]
[19]
[20]
[21]
[22]
Acknowledgments
This article is based in part upon work supported by the Office
of Research and Development of Veterans Affairs, W.G. (Bill) Hefner VA Medical Center, Salisbury, NC. This article has been
screened by the Research Committee and edited by the Public Affairs Office (Ms. Carolyn Waters) at the W.G. (Bill) Hefner VA Medical Center, Salisbury, NC. Sean Maloney M.D. is currently on
military leave in the US Navy and Susan Jensen M.D. has recently
retired from the W.G. (Bill) Hefner VA Medical Center, Salisbury,
NC. The ideas expressed in this paper are the sole responsibility
of the authors and do not represent those of Veterans Affairs or
the US Navy.
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