Psychoneuroendocrinology (2013) 38, 12—23

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REVIEW

Psychoendocrine and psychoneuroimmunological

mechanisms in the comorbidity of atopic eczema
and attention deficit/hyperactivity disorder
A. Buske-Kirschbaum a,*, J. Schmitt b, F. Plessow a, M. Romanos c,
S. Weidinger d,e, V. Roessner f

a
Department of Biopsychology, Technical University of Dresden, Dresden, Germany
b
Centre for Evidenced-based Healthcare, University Hospital Carl Gustav Carus, Dresden, Dresden, Germany
c
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Würzburg, Würzburg,
Germany
d
Department of Dermatology and Allergy, Technical University of Munich, Munich, Germany
e
Department of Dermatology, University of Kiel, Kiel, Germany
f
Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Dresden, Dresden, Germany

Received 20 June 2012; received in revised form 24 September 2012; accepted 27 September 2012

KEYWORDS
Atopic eczema;
Attention deficit/
hyperactivity disorder;
Inflammatory cytokines;
Prefrontal cortex;
Stress;
Prenatal programming;
Genetics;
Neuroimmunology
Summary Epidemiological data indicate that atopic eczema (AE) in infancy significantly
increases the risk for attention deficit/hyperactivity disorder (ADHD) in later life. The underlying
pathophysiological mechanisms of this comorbidity are unknown. We propose that the release of
inflammatory cytokines caused by the allergic inflammation and/or elevated levels of psycholog-
ical stress as a result of the chronic disease interfere with the maturation of prefrontal cortex
regions and neurotransmitter systems involved ADHD pathology. Alternatively, increased stress
levels in ADHD patients may trigger AE via neuroimmunological mechanisms. In a third model, AE
and ADHD may be viewed as two separate disorders with one or more shared risk factors (e.g.,
genetics, prenatal stress) that increase the susceptibility for both disorders leading to the co-
occurrence of AE and ADHD. Future investigation of these three models may lead to a better
understanding of the mechanisms underlying the observed comorbidity between AE and ADHD and
further, to targeted interdisciplinary primary prevention and treatment strategies.
# 2012 Elsevier Ltd. All rights reserved.

* Corresponding author at: Department of Biopsychology, Technical University Dresden, Zellescher Weg 19, D-01069 Dresden, Germany.
Tel.: +49 351 46339798; fax: +49 351 46337274.
E-mail address: buske@biopsych.tu-dresden.de (A. Buske-Kirschbaum).

0306-4530/$ — see front matter # 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.psyneuen.2012.09.017
Psycho-endocrine-immune mechanisms linking atopic eczema and attention deficit/hyperactivity disorder 13

Contents

1. Atopic eczema: epidemiology, clinical aspects and pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

2. Attention deficit/hyperactivity disorder (ADHD): epidemiology, clinical aspects and pathology . . . . . . . . . . . . 13
3. Comorbidity of AE and ADHD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4. Potential mechanisms of the AE—ADHD relationship . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1. Manifestation and chronification of AE in early childhood — a risk factor for ADHD in later life? . . . . . . . 14
4.1.1. Neuroimmunological pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
4.1.2. Psychological mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.2. The manifestation of ADHD — a triggering factor for the development of AE?. . . . . . . . . . . . . . . . . . . 16
4.3. Comorbidity of AE and ADHD — is a common risk factor ‘‘X’’ the answer? . . . . . . . . . . . . . . . . . . . . . 17
4.3.1. Genetic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.3.2. Prenatal stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
5. Summary and conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19

1. Atopic eczema: epidemiology, clinical
aspects and pathology
Atopic eczema (AE), allergic rhinitis and allergic asthma are
among the most common chronic diseases worldwide and
represent the three major clinical manifestations of atopy.
Currently more than 30% of the population in Western indus-
trialized countries is suffering from at least one atopic dis-
ease and prevalences have been predicted to further
increase in the next decade (Bjorksten et al., 2008; Commi-
tee, 1998; Shamssain, 2007).
AE is the first manifestation of atopy and represents the
most common chronic disorder within the first two years of
life (Illi et al., 2004; Schmitt et al., 2009c; Williams, 2005).
AE is a multifactorial, chronically persistent or chronically
relapsing skin disease characterized by dry skin, intense
pruritus, and inflammatory skin lesions. Although often tri-
vialized, AE constitutes a major public health problem not
only because of its high prevalence rate and substantial
economic costs accrued by health care utilization (Su
et al., 1997; Weinmann et al., 2003), but also because of
its negative impact on the life quality of the affected patients
and their families (Carroll et al., 2005; Lewis-Jones, 2006;
Schmitt et al., 2009a; Wittkowski et al., 2004).
Most recently it could be demonstrated that impairment
of the epidermal skin barrier is a key feature of AE. Null
mutations in the gene that encodes the key epidermal pro-
tein, filaggrin, are the strongest known risk factors to date
(Barker et al., 2007; Baurecht et al., 2007; Palmer et al.,
2006) (see below for more details). Additionally, immunor-
egulatory abnormalities such as hypersecretion of immuno-
globuline-E (IgE), recruitment and activation of eosinophils
and Tcell dysfunction have been found to be key factors in AE
pathology. AE is considered to be biphasic and a switch from a
predominant TH2 immune response in the acute phase
toward a TH1 polarization in the chronic phase is broadly
accepted. The onset of acute AE is strongly associated with
increased production of TH2 cytokines such as IL-4, IL-5, IL-
10, IL-13, IL-17 and IL-31 while consolidation and aggravation
of AE is dominated by a secretion of TH1-derived cytokines,
for example IFN-g, IL-1b, IL-6, IL-8 and TNF-a (Carmi-Levy
et al., 2011; Werfel, 2009). TH2-cytokines are important
stimulators of IgE secretion by B cells and eosinophil recruit-
ment, both known to be strongly involved in the allergic
inflammatory processes of the skin (Del Prete, 1998; Leung
and Bieber, 2003; Novak et al., 2003). TH1 cytokines support
the function of macrophages, NK cells and keratinocytes
(Werfel, 2009). In the majority of AE patients, significant
colonization with Staphylococcus aureus, probably due to a
diminished antibacterial function of the skin is observed. S.
aureus can induce TH2 responses by endotoxins with super-
antigenic properties and thereby act as potent trigger factor
(Roll et al., 2004). Furthermore, a decreased number of
infections during childhood (hygiene hypothesis) and
increased psychosocial stress in everyday life are discussed
to be relevant in AE. Both factors have been found to induce
and consolidate a TH2 immune response and thus, may
trigger AE (Arndt et al., 2008; Flohr, 2003). Taken together,
in AE a genetically inherited defective skin barrier function
and an abnormal predominant TH2 immune response are the
hallmarks of AE pathology. Environmental factors are sugges-
tive to influence the development and course of AE, but their
individual pathological relevance and their interaction with
these hereditary factors are still poorly understood.
2. Attention deficit/hyperactivity disorder
(ADHD): epidemiology, clinical aspects and
pathology
Both main diagnostic schemata for childhood ADHD — the
hyperkinetic disorder in the ICD-10 (WHO, 1996), and the
more broadly conceptualized DSM-IV-TR (APA, 2000), are
defined by the three core symptoms hyperactivity, inatten-
tion and impulsivity that had to be present before school
age. ADHD has been recognized in different cultures and
countries all over the world (Polanczyk et al., 2007). With a
worldwide prevalence of about 5%, the individual regional
prevalence rates range from 2% to over 10% depending on
the diagnostic criteria applied (Polanczyk et al., 2007). In
clinical samples the sex ratio is commonly assumed to be
3—6 boys to 1 girl although epidemiological samples tend
to be more evenly distributed. First symptoms usually
14
appear before 7 years. In up to 75% of affected persons
ADHD symptomatology persists into adulthood (Lara et al.,
2009; Spencer et al., 2007). In children with ADHD comor-
bid psychiatric problems are present in up to 90% of the
patients, e.g. oppositional defiant disorder (ODD; 40%),
conduct disorder (CD; 14%) or anxiety disorders (35%)
(Sprafkin et al., 2007).
Despite considerable research efforts the etiology and
pathophysiology of ADHD still remains unclear. Family,
twin, and adoption studies show a substantial genetic
component with heritability estimates reaching 80% (Elia
and Devoto, 2007). In absence of major gene effects the
etiology is believed to be polygenetic modified by gen-
e  environment interaction. The few risk genes that have
been identified so far indicate alterations in neurotrans-
mission and synaptic plasticity. Meta-analyses point to a
particular role of the candidate genes coding for DRD4,
DRD5, SLC6A3, SNAP-25, HTR1B and NET which are asso-
ciated with neurotransmission and synaptic plasticity in
the dopaminergic, serotonergic and noradrenergic system
(Faraone and Mick, 2010; Gizer et al., 2009). Neurochem-
ical investigations point to a catecholaminergic distur-
bance in ADHD (Roessner and Rothenberger, 2010),
although the mechanisms underlying these metabolic
abnormalities are still unknown (Madras et al., 2005).
Studies of dopamine metabolites in the cerebrospinal fluid
of ADHD patients have been performed, but yielded mixed
results of limited value (Castellanos et al., 1996; Reimherr
et al., 1984; Shaywitz et al., 1977; Shetty and Chase,
1976). Neuroimaging data have identified functional as
well as structural alterations in dopamine-rich regions,
i.e. basal ganglia and prefrontal cortex (PFC) as well as
their associated cortico-striatal circuits (Cherkasova and
Hechtman, 2009). For example, the majority of available
PET studies on dopaminergic neurotransmission in ADHD
patients describe an increase of the dopamine transporter
(DAT) density in these patients (Zimmer, 2009). It is pro-
posed that the elevated D2 receptor levels frequently
observed in ADHD patients are the consequence of a
decrease in extracellular dopamine level, supporting the
dopamine-deficiency hypothesis of ADHD (Montgomery
et al., 2007). Structural imaging studies in ADHD patients
further consistently report reductions of prefrontal volume
as well as cortical thickness in young and adult ADHD
patients (Valera et al., 2007). Moreover, there is evidence
of reduced neuronal activity of the PFC in ADHD patients
(Arnsten, 2009b). The PFC has been implicated in execu-
tive functions including complex cognitive processes such
as initiation and monitoring of action, selective attention
or behavior inhibition (Goto et al., 2010; Miller and Cohen,
2001). Since impairment in several domains of executive
functions such as attention, behavioral inhibition, regula-
tion of motivation an motor control are cardinal features of
ADHD the ‘‘executive function theory’’ of ADHD has been
proposed (Willcutt et al., 2005). To conclude, ADHD is a
complex highly heritable brain disorder. In recent years
genetic and environmental risk factors have been identi-
fied indicating an important role of genes like DRD4 or DAT1
or early exposure to drugs or psychological stress in ADHD.
However, how specific genes interact with adverse envir-
onmental factors and further, relate to various brain
abnormalities observed in ADHD is still unclear.
A. Buske-Kirschbaum et al.
3. Comorbidity of AE and ADHD
Accumulating data indicate a comorbidity of AE and ADHD. A
recently published systematic review summarizing the epi-
demiological evidence of a relationship between AE and
ADHD concluded that AE is independently related to ADHD
(Schmitt et al., 2010). Epidemiological data show that chil-
dren with AE had an approximately 1.5-fold increased risk for
ADHD-symptoms and that the population attributable risk for
ADHD explained by AE is about 10% (Romanos et al., 2010;
Rosner, 2000; Schmitt et al., 2009b). The increasing preva-
lence of AE and ADHD, the enormous costs of both diseases in
terms of human suffering and their economic impacts make it
imperative to elucidate and better understand the under-
lying mechanism of the comorbidity of AE and ADHD.
4. Potential mechanisms of the AE—ADHD
relationship
Despite the compelling evidence of a comorbidity of AE and
ADHD the underlying pathophysiological mechanisms linking
the two disorders are unknown. A better understanding of
these mechanisms, however, is a necessary prerequisite for
targeted and optimized treatment strategies that may have
the potential to prevent and/or decrease the burden of both
conditions. In this paper we discuss three potential, not
mutually exclusive models that may explain the co-existence
of AE and ADHD. It is of importance that all models to
describe a potential causal relationship between AE and
ADHD need to account for the distinct temporal disease
trajectories. While generally AE manifests during the first
two years of life (Wahn and von Mutius, 2001), ADHD is a
clinical diagnosis that can be met with acceptable reliability
not before age 6 (Roessner et al., 2007). But this does not
implicate that ADHD could not be present in much earlier
years and retrospectively various symptoms regularly occur
before age 6. Based on these considerations we propose the
following concepts:
I. the manifestation and chronification of AE in early child-
hood increases the risk for ADHD.
II. the development of ADHD symptoms renders the indi-
vidual more vulnerable to develop AE.
III. AE and ADHD patients share one or several risk factors
that increase the vulnerability for AE and ADHD.
4.1. Manifestation and chronification of AE in
early childhood — a risk factor for ADHD in later
life?
4.1.1. Neuroimmunological pathways
As mentioned before it could be speculated that the manifes-
tation of AE in early life may render the individual more
vulnerable to develop ADHD later in life. The process of allergic
sensitization during the first months of life may be crucial in
this context. Allergic sensitization is associated with increased
activity of TH2 cells and concomitantly, secretion of high
amounts of the anti-inflammatory cytokines IL-4, IL-5, IL-9,
IL-10 and IL-13 (Wahn and von Mutius, 2001). TH2-derived
cytokines play a pivotal role in the chronification of the
Psycho-endocrine-immune mechanisms linking atopic eczema and attention deficit/hyperactivity disorder
inflammatory process orchestrating allergen-specific IgE pro-
duction (IL-4), influx of eosinophils into sites of allergic tissue
inflammation (IL-5) and the recruitment and proliferation of
mast cells and basophils (IL-9) (Leung et al., 2004; Ong and
Leung, 2006). Manifestation and chronification of AE involves
also TH1 and TH17 cells (Durrant and Metzger, 2010). TH17
cells, stimulated by activated eosinophils promote the pro-
duction of pro-inflammatory cytokines such as of IL-1b, IL-6,
IL-8 and TNF-a (Cheung et al., 2008; Di Cesare et al., 2008).
These data clearly suggest that with the onset and chron-
ification of AE, affected children are imposed to significantly
elevated cytokine levels. There is compelling evidence,
however, that inflammatory cytokines can activate neuroim-
mune mechanisms that involve behaviorally and emotionally
relevant brain circuits. In animals it was found that allergen
exposure and/or an allergic reaction results in stimulation of
limbic brain regions as well as avoidance behavior, increased
anxiety or reduced social behavior (Basso et al., 2003; Costa-
Pinto et al., 2005, 2007; Palermo-Neto and Guimaraes, 2000;
Tonelli et al., 2009). In humans, altered neuronal activity of
the anterior cingular cortex (ACC) and the PFC during a
chronic (allergic) episode could be demonstrated using func-
tional magnetic resonance (fMRI), (Rosenkranz et al., 2005;
Verne et al., 2003). The PFC is known to subserve executive
cognitive functions such as planned behavior, decision mak-
ing, motivation and attention (Goto et al., 2010). The ACC is
mainly involved in error detection and conflict monitoring
and plays an important role in the evaluation and adaptation
of behavior (Botvinick, 2007; Mansouri et al., 2009). Struc-
tural and functional alterations in ACC and PFC regions such
as the medial and superior prefrontal and precentral regions
have been linked to various cognitive disturbances, i.e.
deficits in attentional control, decision making, memory
and motor output and are considered key symptoms of ADHD
(Shaw et al., 2006).
The underlying mechanisms of the immuno-neurological
actions during allergic inflammation on ADHD-relevant neu-
ronal networks such as the ACC and the PFC, however, are
still a matter of debate. One potential pathway may be that
cytokines, released by activated TH cells, mast cells and
keratinocytes may access the brain and influence neuronal
activity of these brain areas. Peripheral cytokines may (A)
directly pass the blood brain barrier (BBB) at the circumven-
tricular organs in the brain where the blood brain barrier is
leaky or (B) are transported via cytokine-specific transport
molecules into the brain or (C) induce secretion of central
cytokines by stimulating endothelial cells composing the BBB
or microglial cells (Banks and Erickson, 2010). Alternatively,
peripheral cytokines may indirectly affect CNS structures by
activation of vagal afferent fibers (Raison et al., 2006;
Yarlagadda et al., 2009). Vagal sensory nerves have been
shown to express TNF and IL-1 receptors supporting the role
of the vagus nerve in signaling peripheral immune activation
to the brain (Goehler, 2009; Thayer and Sternberg, 2010).
Vagal afferents provide input via the nucleus solitary tract
(NST) to the paraventricular nucleus (PVN), the central
nucleus of the amygdala, the insula cortex, the ACC and
the PFC (Thayer and Sternberg, 2010). It has been suggested
that the PFC and the ACC are highly sensitive to peripheral
immune changes. Studies using fMRI demonstrated that
increased levels of TNF-a or IL-6 in response to an immuno-
logical challenge were strongly associated with changes of
15
neuronal activity in the ACC and the insula cortex (Eisenber-
ger et al., 2009; O’Connor et al., 2003; Rosenkranz et al.,
2005). Similar results were reported by Capuron et al. (2005)
showing that a 12-week treatment with IFN-a in patients with
chronic hepatitis was accompanied by significant activation
of the ACC. The idea that immune activation is reflected by
altered functioning in specific brain areas such as the PFC or
the ACC is supported by others reporting that changes in
eosinophil, TH cell or NK cell counts were associated with
altered activity of the ACC, the PFC and the orbitofrontal
cortex (OFC) (Ohira et al., 2009; Rosenkranz et al., 2005).
In addition to the direct effects of cytokines on the ACC
and the PFC, cytokines may influence the neuronal activity of
these brain structures indirectly via activation of the
hypothalamus-pituitary-adrenal (HPA) axis. Cytokines such
as IL-1, IL-2, IL-6, IFN-g, IFN-a, TNF-a and IL-10 have been
found to stimulate the HPA axis leading to increased levels of
glucocorticoids (GC) (Hughes et al., 1994; Rivest, 2001;
Stefano et al., 1998). In the PFC and the ACC, a high density
of GC receptors has been shown. High levels of stress-induced
GCs impair cognitive flexibility or working memory both of
which require PFC function (Arnsten, 2009a). While acute
stress has been linked rather to impairment of cognitive
performance, exposure to chronic stress seems to lead to
more extensive alterations including architectural changes
such as dendritic spine loss (Brown et al., 2005; Izquierdo
et al., 2006).
Inflammatory cytokines further lead to altered metabo-
lism of central neurotransmitters such as norepinephrine and
dopamine (Dunn et al., 1999) known to be critically involved
in ADHD pathology. For example, in animal studies adminis-
tration of IL-1, IL-2, IL-6 or IFN-g provoked increased nor-
epinephrine as well as decreased dopamine levels (Anisman
et al., 1996; Zalcman et al., 1994). Comparable changes in
these neurotransmitters have been described in ADHD
patients (Arnsten, 2009b).
In summary, it may be argued that a sustained and exag-
gerated release of (allergic) inflammatory cytokines in AE-
affected children may impact ADHD relevant brain circuits
thereby affecting behavior and motor control, emotional
regulation, or motivational mechanisms. This effect may
be even more profound with a disease onset in early infancy
when the brain is still immature. Due to its sensitivity to
cytokine signals and, on the other hand, its modulating role in
behavioral and cognitive functioning, the HPA axis may be a
target system of immuno-neurological signaling. Exaggerated
cytokine release during sensitization and manifestation of AE
in early life may lead to hyperactivity of the HPA axis with a
downregulation of HPA axis responsiveness during AE chron-
ification. In fact, we and others could show hyperresponsive-
ness of the HPA axis in newborns with atopic disposition (Ball,
2006; Buske-Kirschbaum et al., 2004) while the chronic con-
dition of AE in childhood was linked to hyporesponsiveness of
the system (Buske-Kirschbaum et al., 2003). Thus, malfunc-
tioning of the HPA axis may be a symptom of AE in infancy
which however, may contribute to ADHD development in the
adolescent with a vulnerable (genetic) background. The
latter idea would be supported by recent data showing
significantly decreased HPA axis function in ADHD children
(Chen et al., 2009; Shin and Lee, 2007). Further, a hypor-
esponsive HPA axis has been reported to correspond to
personality characteristics such low sense of control and
16
hostility or disruptive behavior (Oswald et al., 2006; Van
Goozen et al., 2000).
4.1.2. Psychological mechanisms
The misery of living with AE is associated with high levels
of psychological stress (Chamlin, 2006) starting in early
infancy with the onset of the disease. The negative psy-
chosocial effects of childhood AE include an often dysfunc-
tional mother—child relationship characterized by
overprotection, anxiety and less support (Gil et al.,
1987; Pauli-Pott et al., 1999). The torturing pruritus
may cause dysfunctional sleep leading to tiredness, mood
changes and impaired psychosocial and cognitive perfor-
mance in kindergarten or at school (Gruber et al., 2010).
Stigmatization and bullying by peers further leads to feel-
ings of frustration and hopelessness in the AE child and its
family (Magin et al., 2008).
Studies in animals and humans have shown that during
early life the brain is particularly sensitive to stress prob-
ably because of its profound developing changes during this
period. Maternal separation stress in rodents, for example,
increases the density of CRH receptors in various brain
areas such as the PFC, amygdala, hypothalamus, hippo-
campus and cerebellum (Anisman et al., 1998). Elevated
CRH levels have been found to be related to fear behavior
and increased HPA axis (re)activity (Schulkin et al., 1998).
Comparable data have been reported in monkeys showing
that stress in the first months of life such as unpredictable
maternal feeding (Coplan et al., 1996) or spontaneous
adverse behavior by the mother (Sanchez, 2006) increases
central CRH concentrations and induces long-term changes
in HPA axis function. Others noted altered development of
PFC regions such as a reduction of the size of the corpus
callosum (Sanchez et al., 2001). The latter observation
may be of specific interest since brain imaging studies
suggest a smaller than normal size of the corpus callosum
in ADHD (Hynd et al., 1991; Valera et al., 2007). It has been
suggested that the PFC is particularly sensitive to early
childhood stress. For example, after exposure to chronic
stress rat pups showed enduring dendritic retraction in the
PFC and increased anxiety behavior (Pascual and Zamora-
Leon, 2007).
Although the impact of early life stress on brain develop-
ment in humans has been less well studied comparable
effects are likely. It is hypothesized that stress during early
life affects multiple neurotransmitter and neuroendocrine
systems and may imprint ‘‘programs’’ in the developing
human brain altering the set points for the release of neu-
rochemical messengers. This may lead to a long-term altera-
tion of the behavioral and physiological repertoire of the
individual throughout his life leading to an increased vulner-
ability to various (psychiatric) diseases (de Kloet et al.,
2005). For example, foster care and orphanage reared chil-
dren show reduced HPA axis function (Gunnar and Vazquez,
2001) later in life probably due to a downregulation of the
HPA axis at the level of the pituitary in response to a chronic
CRH drive from the hypothalamus (Fries et al., 2005). Com-
parable findings were reported in women suffering from
childhood abuse (Heim et al., 2001). Abnormal HPA axis
function, however, has been documented to be closely linked
to psychiatric disturbances such as depression, schizophrenia
or ADHD (McCrory et al., 2010).
A. Buske-Kirschbaum et al.
In addition, the impact of early life stress on ADHD-
relevant neurotransmitter systems has been found. Mal-
treated girls show evidence of increased catecholamine
synthesis which was positively correlated with the duration
of the maltreatment experience (De Bellis et al., 1994,
1999). Others reported significantly increased dopamine
release in the striatum under stressful conditions in subjects
with low parental bonding during childhood suggesting that
aside severe pediatric trauma (e.g. maltreatment, abuse)
also less adverse experiences such as dysfunctional parent-
ing may impact on neurodevelopment (Pruessner et al.,
2004).
These data support the concept that prolonged expo-
sure to increased early life stress as a result of a chronic
disease condition may be a relevant factor in AE—ADHD
comorbidity. Daily adverse experiences may lead to
increased GC levels in the AE child that may interfere
with the development and maturation of ADHD-
relevant brain structures such as the PFC, the ACC or
the HPA. Structural and functional changes in these brain
regions may result in cognitive impairment and increased
stress vulnerability leading to ADHD- or ADHD-like symp-
tomatology.
4.2. The manifestation of ADHD — a triggering
factor for the development of AE?
There is compelling evidence that the onset and course of
AE is triggered by psychosocial stress (Arndt et al., 2008).
Critical life events such as death of a family member or
family problems have been found to be precipitating fac-
tors of the disease (Picardi and Abeni, 2001). Others could
document that increased levels of everyday stress result in
exacerbation of AE symptomatology (King and Wilson,
1991). The relevance of stress as a triggering factor of
AE is further supported by the effectiveness of psychother-
apeutical interventions such as stress management or
relaxation techniques (Shenefelt, 2003). The mechanisms
of stress-induced exacerbation of AE are still obscure,
however, ‘‘classical’’ psychoneuroimmunological path-
ways, e.g., the regulation of AE-relevant effector cells
by (neuro)endocrine outflow or neural input have been
considered to be good candidates. In fact, we could
demonstrate a significant rise of IgE levels and eosinophil
numbers in AE subjects in response to a laboratory stressor
(Buske-Kirschbaum et al., 2002) while others reported
increased CLA+, IL-5+ and IFN-g+ cells after stress in these
patients (Schmid-Ott et al., 2001). Further, stress has been
found to directly affect skin barrier function by altering
skin barrier homeostasis (Choi et al., 2005). These findings
strongly support that stress can trigger AE and may lead to
an acute manifestation of the disease. It is generally
accepted that ADHD is associated with increased stress
levels due to family-related and peer relationship
problems, impairment of school performance or increased
anti-social and delinquent activity (Danckaerts et al.,
2010). Following this line of reasoning it is tempting to
speculate that elevated stress due ADHD-related
everyday problems may lead to a higher risk of AE
especially in individuals predisposed to atopic disease
(Fig. 1).
Psycho-endocrine-immune mechanisms linking atopic eczema and attention deficit/hyperactivity disorder 17

Figure 1 Potential mechanisms of an AE—ADHD comorbidity (direct effects). AE may trigger ADHD directly via two different
pathways (blue arrows). Increased levels of inflammatory cytokines released during chronic allergic inflammation and/or elevated and
prolonged early life stress due to AE symptomatology impact on neurodevelopment leading to long-lasting changes in ADHD-relevant
brain areas (e.g. prefrontal cortex, basal ganglia, hypothalamus) or ADHD-relevant neurotransmitter systems (e.g. dopaminergic,
catecholaminergic, serotonergic systems). Conversely, ADHD may facilitate the onset and exacerbation of AE (red arrows). ADHD-
related problems cause high levels of psychosocial stress leading to AE-relevant immunological changes via activation of neuroendo-
crine pathways (e.g., HPA axis, sympatho-adrenomedullary system) or via direct nervous inputs. (For interpretation of the references
to color in this figure legend, the reader is referred to the web version of the article.)

4.3. Comorbidity of AE and ADHD — is a common
risk factor ‘‘X’’ the answer?
In the previous chapters we have proposed that AE increases
the risk to develop ADHD and vice versa, that ADHD lead to
increased vulnerability for AE due to (1) exaggerated and
prolonged release of inflammatory mediators and/or (2)
psychological stress resulting from the disease (e.g. AE or
ADHD). Alternatively, it could be speculated that the man-
ifestation of AE does not affect ADHD directly but that both,
AE and ADHD share one or several (yet unknown) factors that
trigger both diseases independently. The most recognized
risk factors described in both diseases are genetic factors as
well as disguided fetal programming by adverse environmen-
tal stimulation in utero.
4.3.1. Genetic factors
AE and ADHD are complex multifactorial traits with a sub-
stantial genetic component (Bieber, 2008; Steinhausen,
2009). However, our understanding of their complex genetic
susceptibility and the environmental factors that precipitate
genetic hereditary risk background into disease manifesta-
tion is still limited. Based on the existing data, in AE and
asthma, locally acting target-organ-specific genes which
affect epithelial barrier function as well as ‘‘atopy’’ and
‘‘inflammation’’ genes which determine immune response
patterns appear to be important (Brown, 2009; Vercelli,
2008). For AE, variants in the FLG gene, which encodes a
key epidermal structural protein, are the strongest known
risk factor (Baurecht et al., 2007; Rodriguez et al., 2009).
Furthermore, several candidate genes with, however, rather
small effects encoding major elements of the immune system
such as innate immune receptors and proteins involved in the
regulation of TH1/TH2 differentiation and effector function
have been reported for various atopic traits (Holloway and
Holgate, 2010). In particular, genetic variants within the TH2-
cytokine locus on chromosome 5q31 such as IL13 polymorph-
isms, and in the gene encoding STAT6, a key regulatory
element of the TH2 immune response, have been consistently
associated with atopy-related traits (Vercelli, 2008; Weidin-
ger et al., 2008). STAT6, however, is highly expressed in the
CNS and is suggested to play a major role in ADHD pathogen-
esis (Yukawa et al., 2005). Future research is necessary to
further elucidate STAT6 gene variants in ADHD patients.
Itch (pruritus) is a key feature of AE. The pathophysiology
of itch is complex and far from being understood (Budden-
kotte and Steinhoff, 2010), but it is tempting to speculate
whether hereditary alterations of central itch-specific neu-
ronal pathways, which overlap with pathways involved in
ADHD, contribute to AE-related pruritus.
ADHD is a complex multifactorial disorder with consistently
high heritability estimates of up to 80% (Freitag et al., 2010;
Romanos et al., 2008). Despite the strong genetic background
both heterogeneity of ADHD and its polygenetic etiology ren-
der the identification of specific genetic variants with impact
on the phenotype somewhat frustrating (Faraone et al., 2008).
A multitude of candidate gene studies mostly focusing on genes
18
involved in the dopaminergic, noradrenergic and serotonergic
neurotransmission systems have been carried out with rather
inconsistent results (Faraone and Mick, 2010). Generally,
meta-analyses have identified some gene polymorphisms exhi-
biting small effects on disease risk such as dopaminergic (DAT,
DRD4, DRD5), serotonergic (HTR1B, 5HTTLPR) as well as other
genes with impact on neurotransmission synaptic plasticity, or
neuronal development (NET, SNAP25, NOS1) (Friedel et al.,
2007; Gizer et al., 2009; Reif et al., 2009). Preliminary obser-
vations from twin studies appear to support the hypothesis of
shared genetic factors influencing the risk for atopic and
behavioral disorders, but more research is needed to clarify
these intriguing observations and to identify potential over-
lapping pathways (Thomsen et al., 2008). Twin studies also
suggest that a substantial proportion of the variance in ADHD
susceptibility can be attributed to environmental (nongenetic)
factors, which might act through interaction with genetic
factors and/or epigenetic dysregulation (Banerjee et al.,
2007). Of note, a number of these environmental factors have
also been implicated in AE such as alcohol and tobacco smoke,
lead exposure during early life as well as prenatal stress
(Linneberg et al., 2006; Pietinalho et al., 2009; Weidinger
et al., 2004).
Since AE and ADHD are strongly determined by genetic
factors, shared genetic risk factors appear plausible. One
limiting factor for a better understanding of genetic
mechanisms which underlie comorbidity is that most genetic
studies to date focus on identifying and characterizing
individual genes that contribute to the susceptibility for a
single disease, and that most of the current genome-wide
association studies are still targeted at independent effects
of single genes. However, the rapid development of high-
throughput experimental tools and novel integrated bioin-
formatics approaches hold the promise of identifying gene
relationships, networks, and gene—gene—environment
interactions on a systems level which may improve our
understanding of complex correlations among disorders such
as AE and ADHD.
4.3.2. Prenatal stress
An adverse prenatal environment can have profound long-
term influences and can alter physiological and behavioral
functions in later life. For example, gestational stress in
animals has been found to be related to neuroendocrine
dysfunctions, i.e. an altered (re)activity of the hypothala-
mus-pituitary-adrenal (HPA) axis (Matthews, 2002), signifi-
cant changes in immunocompetence or changes in brain
architecture in the resultant offspring (Coe et al., 2002;
Huizink et al., 2004; Matthews, 2002). Others reported that
maternal stress results in behavioral differences such as
impaired learning abilities or significant changes in social
behavior (Huizink et al., 2004). Comparable findings were
reported in humans. For example, maternal stress in preg-
nancy is associated with psychopathology later in life includ-
ing symptoms of attention deficits, compulsive behavior and
hyperactivity (Linnet et al., 2003; Schlotz and Phillips,
2009). In a prospective study, Rodriguez and Bohlin (2005)
reported that stress during pregnancy in Scandinavian
women was associated with ADHD symptoms in 7 years old
children especially in boys. Accordingly, data from the Avon
Longitudinal Study of Parents and Children (ALSPAC), a pro-
spective, population-based study show that maternal stress
A. Buske-Kirschbaum et al.
predict hyperactivity and attention deficits in 4-year-old
boys and at a follow-up assessment, in 8-year-old boys and
girls (O’Connor et al., 2002). Recently, a close association
between the severity of ADHD symptoms and the severity of
maternal stress experience during pregnancy was documen-
ted (Grizenko et al., 2008).
It is broadly accepted that the HPA axis is highly susceptible
for prenatal programming. In animals and humans, gestational
stress has been linked to significantly altered HPA axis func-
tions in adolescence and adulthood (Egliston et al., 2007;
Matthews, 2002). The mechanisms involved in transducing
maternal stress to the fetus are little understood. Animal data
suggest that (1) maternal cortisol can pass the placenta and
enter the fetal circulation, (2) maternal cortisol stimulates
placental CRH leading to stimulation of the fetal HPA axis and
(3) maternal stress reduces the uteroplacental blood flow
initiating a fetal stress response with subsequent HPA axis
activation of the unborn (de Weerth and Buitelaar, 2005;
Matthews, 2002). It is assumed that prolonged elevated fetal
glucocorticoid levels lead to abnormalities in the brain devel-
opment including dendritic changes in the PFC (Murmu et al.,
2006) or increased CRH levels in the amygdala, reduction of
hippocampal volume or a downregulation of GC receptors in
the hippocampus finally leading to long-term changes of HPA
axis regulation (Cratty et al., 1995; McEwen, 1991). As men-
tioned before, HPA axis dysfunction is implicated in depres-
sion, anxiety, emotional problems and ADHD. Another long-
term consequence of prenatally induced hyperactivity of the
HPA axis might be deficits in memory and cognition due to
neurotoxic effects on hippocampal cells (McEwen, 1991).
A comparable model exists emphasizing possible effects of
prenatal stress on fetal immune system development which
may lead to an increased risk of AE. In this model hyper-
activity of the fetal HPA axis as a consequence of prolonged or
severe maternal stress (see above) affect the developing
immune system driving it toward an ‘‘atopy-prone’’ immu-
nological profile (von Hertzen, 2002). GCs shift the TH1/TH2
balance toward a TH2 cytokine profile probably by their
suppressive effects on IL-12, the major promoter of the
TH1 response (Calcagni and Elenkov, 2006). Infants are nor-
mally born with a bias toward TH2 responses possibly to avoid
rejection during pregnancy (McGeady, 2004; Wegmann et al.,
1993). One interesting theory holds that a TH2 shift due to
increased levels of fetal cortisol in response to maternal
stress against a background of already heightened TH2-like
activity may potentiate and establish atopy-like immune
responses. Atopic disposition of the infant and/or maternal
allergy during pregnancy may worsen this scenario since
children at risk for atopy show significantly increased pro-
duction of TH2 cytokines when compared to non-atopic
controls (Prescott et al., 1999). It is of note, however, that
this model is highly speculative and needs evaluation by
controlled experimental studies.
The findings support the idea that prenatal stress may be a
relevant factor increasing the risk of AE and ADHD with both
diseases being unrelated (Fig. 2).
5. Summary and conclusions
Accumulating epidemiological data clearly indicate a comor-
bidity of AE and ADHD. This observation is of major relevance
Psycho-endocrine-immune mechanisms linking atopic eczema and attention deficit/hyperactivity disorder 19

Figure 2 Potential mechanisms of an AE—ADHD comorbidity (indirect effects). Environmental or genetic factors may increase the
risk for AE and ADHD leading to AE—ADHD comorbidity with both disorders being not related. For example, fetal programming by
prenatal stress is associated with changes in the developing brain (e.g. decreased neurogenesis in the PFC, decreased serotonergic
function, increased HPA axis activity) that renders the individual vulnerable to develop ADHD. Altered neurochemical functioning such
as increased HPA axis activity leads to an inappropriate control of the developing immune system shifting the immune response toward
a TH2 dominance and thus, an AE-prone immune profile. Similarly, other environmental factors or genetics may contribute to AE—ADHD
comorbidity triggering both disorders via shared pathophysiological mechanisms.

since both, AE and ADHD, are among the most prevalent
chronic conditions in infancy and early adolescence.
In the present paper we have proposed three, not
mutually exclusive models illustrating how AE and ADHD
may become comorbid disorders. We postulate that the
manifestation of chronic allergic inflammation in the AE child
exposes the developing brain to two types of adversities, e.g.
increased levels of inflammatory cytokines and exposure to
increased levels of AE-related, early life stress. Both factors
have been found to interfere with the development of brain
regions (e.g. PFC, ACC, corpus callosum) and neurotransmit-
ter systems (e.g. catecholaminergic and dopaminergic sys-
tem) known to play a crucial role in executive functions
including attention, motivation motor and cognitive control.
Altered maturation of these specific brain circuits or cell
phenotypes may result in persistent neural or neuroendo-
crine changes increasing the risk for ADHD. Another model
was accomplished on the basis of an increasing number of
data showing that the onset of AE may be preceded by
stressful life events or increased levels of everyday stress.
Stress related to ADHD and/or resulting from interpersonal
problems and the family environment may trigger allergic
inflammation via neuroendocrine processes or by direct ner-
vous input. Alternatively, we proposed that multiple factors
that increase the risk for AE as well as for ADHD for example
genetics, fetal programming or other, still unknown factors,
may lead to a co-existence of AE and ADHD with both dis-
orders not being causally related.
It is important to note that although these models are
build on experimental evidence, a significant part of them is
still speculative, awaiting validation by future research.
For example, neuroimaging may be a promising strategy
to further clarify the effect of pro-inflammatory and
anti-inflammatory cytokines on ADHD-relevant brain circuits
and functions. Prospective, longitudinal studies using a life-
style stressor approach and starting in utero may shed more
light on the contribution of stress on the pathology of AE and
ADHD. Recommendations for such future stress and neuroi-
maging studies include the research and focus on sensitive
developmental periods that may mediate the risk for nega-
tive outcomes. In all these studies potential confounding
variables, for example a differential in the levels or types
of AE-relevant allergens in ADHD families or an impact of
medical treatment such as corticosteroids or methylpheni-
date on executive or immune function, respectively, should
be controlled. Integrating informations from multiple levels
of analysis, by studying genetics, neuroimmune, neuroendo-
crine and behavioral processes may help to recognize AE
patients that are at higher risk to develop ADHD in later life
and may lead to effective preventive therapeutic regimens
for AE and ADHD.
Role of the funding source
None.
Conflict of interest
None declared.
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