Atopic Dermatitis

Thomas Bieber, M.D., Ph.D.

N Engl J Med 2008; 358:1483-1494April3, 2013DOI: 10.1056/NEJMra074081
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Atopic dermatitis, or eczema, is a common skin disease that is often associated with other atopic
disorders, such as allergic rhinitis and asthma.1 The clinical manifestations of atopic dermatitis

(Figure 1Figure 1
Clinical, Histologic, and Immunohistochemical Aspects of
Atopic Dermatitis.) vary with age; three stages can often be identified. In infancy, the first
eczematous lesions usually emerge on the cheeks and the scalp. Scratching, which frequently
starts a few weeks later, causes crusted erosions. During childhood, lesions involve flexures, the
nape, and the dorsal aspects of the limbs. In adolescence and adulthood, lichenified plaques affect
the flexures, head, and neck. In each stage, itching that continues throughout the day and worsens
at night causes sleep loss and substantially impairs the patient's quality of life.
The hallmarks of atopic dermatitis are a chronic, relapsing form of skin inflammation, a
disturbance of epidermal-barrier function that culminates in dry skin, and IgE-mediated
sensitization to food and environmental allergens.2 The histologic features of acute eczematous
patches and plaques are epidermal intercellular edema (spongiosis) and a prominent perivascular
infiltrate of lymphocytes, monocyte macrophages, dendritic cells, and a few eosinophils in the
dermis. In subacute and chronic lichenified and excoriated plaques, the epidermis is thickened
and its upper layer is hypertrophied.
Two hypotheses concerning the mechanism of atopic dermatitis have been proposed. One holds
that the primary defect resides in an immunologic disturbance that causes IgE-mediated
sensitization, with epithelial-barrier dysfunction regarded as a consequence of the local
inflammation. The other proposes that an intrinsic defect in the epithelial cells leads to the barrier
dysfunction; the immunologic aspects are considered to be an epiphenomenon.
In this review, I arrange the disparate pieces of the puzzle into a coherent picture, question
prevailing hypotheses, and integrate the results of recent research in a way that has implications
for the clinical management of atopic dermatitis.

Epidemiology of Atopic Dermatitis

The prevalence of atopic dermatitis has doubled or tripled in industrialized countries during the
past three decades; 15 to 30% of children and 2 to 10% of adults are affected.3 This disorder is

often the prelude to an atopic diathesis that includes asthma and other allergic diseases. Atopic
dermatitis frequently starts in early infancy (so-called early-onset atopic dermatitis). A total of
45% of all cases of atopic dermatitis begin within the first 6 months of life, 60% begin during the
first year, and 85% begin before 5 years of age. More than 50% of children who are affected in
the first 2 years of life do not have any sign of IgE sensitization, but they become sensitized
during the course of atopic dermatitis.4 Up to 70% of these children have a spontaneous
remission before adolescence. The disease can also start in adults (so-called late-onset atopic
dermatitis), and in a substantial number of these patients there is no sign of IgE-mediated
sensitization.5 The lower prevalence of atopic dermatitis in rural as compared with urban areas
suggests a link to the hygiene hypothesis, which postulates that the absence of early childhood
exposure to infectious agents increases susceptibility to allergic diseases.6 This concept has
recently been questioned with regard to atopic dermatitis, however.3,7

Genetics of Atopic Dermatitis

The concordance rate for atopic dermatitis is higher among monozygotic twins (77%) than
among dizygotic twins (15%).8 Allergic asthma or allergic rhinitis in a parent appears to be a
minor factor in the development of atopic dermatitis in the offspring, suggesting atopic
dermatitisspecific genes.9
Genomewide scans10 have highlighted several possible atopic dermatitisrelated loci on
chromosomes 3q21,11 1q21, 16q, 17q25, 20p,12 and 3p26.13 The region of highest linkage was
identified on chromosome 1q21, which harbors a family of epithelium-related genes called the
epidermal differentiation complex.14 Most of the genetic regions associated with atopic
dermatitis correspond to loci associated with psoriasis, although these two diseases are rarely
linked. Also, the genomic associations revealed by these scans do not overlap with allelic variants
that are frequent in allergic asthma15; this finding is consistent with epidemiologic data.3,4,16
Several candidate genes have been identified in atopic dermatitis,9,17 notably on chromosome
5q31-33. All of them encode cytokines involved in the regulation of IgE synthesis: interleukin-4,
interleukin-5, interleukin-12, interleukin-13, and granulocytemacrophage colony-stimulating
factor (GM-CSF). These and other cytokines are produced by two main types of T lymphocytes.
Type 2 helper T cells (Th2) produce interleukin-4 as well as interleukin-5 and interleukin-13, two
cytokines that up-regulate the production of IgE. Type 1 helper T cells (Th1) produce mainly
interleukin-12 and interferon-, which suppresses production of IgE and stimulates production of

IgG antibodies (Figure 2AFigure 2

The Th1Th2 Paradigm and Its Role in
Allergy and the Skin as the Site of Initiation for Sensitization.). Mutations that affect the function
of the promoter region of the lymphocyte-attracting chemokine RANTES (regulated on
activation, normal T-cell expressed and secreted) (17q11) and gain-of-function polymorphisms in
the subunit of the interleukin-4 receptor (16q12) have been identified in patients with atopic
dermatitis. Polymorphisms of the gene encoding the cytokine interleukin-18,18 which contributes
to the shift of Th1 and Th2 cross-regulation toward Th1-mediated responses (so-called Th1
polarization), or polymorphisms of the genes encoding receptors of the innate immune

system19,20 may contribute to the imbalance between Th1 and Th2 immune responses in atopic
dermatitis. In persons with atopic dermatitis, a genetically determined dominance of Th2
cytokines affects the maturation of B cells and a genomic rearrangement in these cells that favors
isotype class switching from IgM to IgE.
Since dry and scaly skin is a symptom of both atopic dermatitis and ichthyosis vulgaris, the most
common autosomal dominant disorder of keratinization, both diseases might overlap genetically.
After the filaggrin gene (FLG) on chromosome 1q21.3, which encodes a key protein in epidermal
differentiation, was identified as the gene involved in ichthyosis vulgaris,21 several loss-offunction mutations of the gene were identified in European patients with atopic dermatitis,22-25
and other, distinctive FLG mutations in Japanese patients have been reported.25,26 Mutations of
FLG occur mainly in early-onset atopic dermatitis and indicate a propensity toward asthma.
There is, however, no association between mutant FLG and allergic airway diseases without
atopic dermatitis. Since FLG mutations are identified in only 30% of European patients with
atopic dermatitis, genetic variants of other epidermal structures, such as the stratum corneum
tryptic enzyme or a new epidermal collagen, may be important.27,28
Atopic dermatitis is a complex genetic disease that arises from genegene and geneenvironment
interactions. The disease emerges in the context of two major groups of genes: genes encoding
epidermal or other epithelial structural proteins, and genes encoding major elements of the
immune system.

Barrier Function of the Skin

Physical Barrier
An intact epidermal compartment is a prerequisite for the skin to function as a physical and
chemical barrier. The barrier itself is the stratum corneum, the brick and mortarlike structure of
the upper epidermal layer.29 An alteration of the barrier that causes increased transepidermal
water loss is a hallmark of atopic dermatitis. Intercellular lipids of the epidermal horny layers are
provided by lamellar bodies, which are produced by exocytosis from upper keratinocytes.
Changes in skin ceramides that are secondary to variations in the pH of the stratum corneum can
disturb maturation of lamellar bodies and impair the barrier. 30 Alterations in the expression of
enzymes involved in the subtle balance of epidermal adhesion structures are also likely to
contribute to the breakdown of the epidermal barrier in patients with atopic dermatitis.27,31
Whether these epidermal alterations are primary or are secondary to the underlying inflammation
remained unclear until immunohistochemical32 and genetic studies highlighted the importance of
FLG mutations in atopic dermatitis. FLG contributes to the keratin cytoskeleton by acting as the
template for the assembly of the cornified envelope; moreover, breakdown products of FLG
contribute to the water-binding capacity of the stratum corneum.33 Genetic variants of FLG in
atopic dermatitis that lack the capacity to be proteolytically cleaved have been identified,22 but
other genetically determined alterations of the epidermis (e.g., changes in the cornified envelope
proteins involucrin and loricrin) or lipid composition are also likely to contribute to barrier
dysfunction.14 Underlying inflammation can alter the expression of genes such as FLG that are
involved in epidermal-barrier function,34 allowing increased transepidermal penetration of
environmental allergens35,36 and, in collaboration with pruritus, fostering inflammation and
sensitization.36,37

The Innate Immune System

Epithelial cells at the interface between the skin and the environment are the first line of defense
of the innate immune system.38 They are equipped with a variety of sensing structures, which
include the toll-like receptors (TLRs),39 C-type lectins, nucleotide-binding oligomerization
domainlike receptors, and peptidoglycan-recognition proteins.40 At least 10 different TLRs
have been described in humans; they bind to bacterial, fungal (both cell walls), or viral structures
(DNA or RNA with so-called cytosine phosphate guanidine [CpG] motifs), and to other microbial
structures termed the pathogen-associated molecular patterns. TLR-mediated activation of
epithelial cells induces the production of defensins and cathelicidins families of antimicrobial
peptides.38
The skin produces the cathelicidin LL-37; the human -defensins HBD-1, HBD-2, and HBD-3;
and dermcidin. The inflammatory micromilieu initiated by interleukin-4, interleukin-13, and
interleukin-10 down-regulates these antimicrobial peptides in the skin of patients with atopic
dermatitis.40-43 For these reasons, it is difficult to manage microbial infections of the skin in
patients with atopic dermatitis. Lesional and normal-looking skin is extensively colonized by
bacteria such as Staphylococcus aureus or fungi such as malassezia. Patients with atopic
dermatitis are predisposed to eczema herpeticum and eczema vaccinatum because of a reduced
production of cathelicidin, which has potent antiviral activity.44,45

Immunopathologic Mechanisms of Atopic Dermatitis

Initial Mechanisms of Skin Inflammation
Early-onset atopic dermatitis usually emerges in the absence of detectable IgE-mediated allergic
sensitization,4 and in some children mostly girls such sensitization never occurs.5 The
initial mechanisms that induce skin inflammation in patients with atopic dermatitis are unknown.
They could entail neuropeptide-induced, irritation-induced, or pruritus-induced scratching, which
releases proinflammatory cytokines from keratinocytes, or they could be T-cellmediated but
IgE-independent reactions to allergens present in the disturbed epidermal barrier or in food (socalled food-sensitive atopic dermatitis). Allergen-specific IgE is not a prerequisite, however,
because the atopy patch test can show that aeroallergens applied under occluded skin induce a
positive reaction in the absence of allergen-specific IgE.46,47

The Initiation Site of Sensitization

In patients with early-onset atopic dermatitis, IgE-mediated sensitization often occurs several
weeks or months after the lesions appear,4 suggesting that the skin is the site of the sensitization.
In animal models, repeated epidermal challenge with ovalbumin induces ovalbumin-specific IgE,
respiratory allergy, and eczematous lesions at the application site.48 A similar process is likely in
humans (Figure 2B).
Epidermal-barrier dysfunction is a prerequisite for the penetration of high-molecular-weight
allergens in pollens, house-dust-mite products, microbes, and food. Molecules in pollens and
some food allergens drive dendritic cells to enhance Th2 polarization.49,50 There are numerous
T cells in skin (106 memory T cells per square centimeter of body-surface area), nearly twice the

number in the circulation.51,52 Moreover, keratinocytes in atopic skin produce high levels of the
interleukin-7like thymic stromal lymphopoietin that signals dendritic cells to drive Th2
polarization.53 By inducing the production of large amounts of cytokines such as GM-CSF or
chemokines, widespread skin inflammation can affect adaptive immunity,54 alter the phenotype
of circulating monocytes,55-57 and increase the production of prostaglandin E2 58 in atopic
dermatitis. All these factors provide signals required for strong skin-driven Th2 polarization, and
for this reason, the skin acts as the point of entry for atopic sensitization and may even deliver
signals required for allergenic sensitization in the lung or the gut. The development of
sensitization and atopic dermatitis in a bone marrow recipient after engraftment of hematopoietic
stem cells from an atopic donor59 provides support for the role of the hematopoietic system as a
factor in addition to the genetically determined epidermal-barrier dysfunction in atopic
dermatitis.
Antigen-specific IgE is the major recognition structure for allergens on mast cells and basophils.
It may also be instrumental for the induction of allergen-specific tolerance or in antiinflammatory
mechanisms,60 but whether such events underlie spontaneous remissions of atopic dermatitis
remains to be explored.

Dendritic Cells
Epidermal dendritic cells in atopic dermatitis bear IgE61 and express its high-affinity receptor
(FcRI).62-64 In skin lesions, dendritic cells of the plasmacytoid lineage,65 which have potent
antiviral activity by virtue of interferon- production, are almost absent.66 In contrast, two
populations of myeloid dendritic cells are present: Langerhans' cells and inflammatory dendritic
epidermal cells.67 In atopic dermatitis, but not in other conditions, there is a high-density display
of FcRI by both types of cells. Langerhans' cells occur in normal skin, but inflammatory
dendritic epidermal cells appear only in inflamed skin. They take up and present allergens to Th1
and Th2 cells, and possibly also to regulatory T cells.60 On ligation of FcRI by IgE, Langerhans'
cells produce interleukin-16, which recruits CD4+ T cells to the skin.68 Apart from interleukin16, Langerhans' cells produce only a limited range of chemokines and almost no proinflammatory
cytokines.69 On allergen capture, Langerhans' cells contribute to Th2 polarization by an
unknown mechanism, and inflammatory dendritic epidermal cells lead to Th1 polarization by
producing interleukin-12 and interleukin-18 and releasing proinflammatory cytokines. In the
atopy patch test, high numbers of inflammatory dendritic epidermal cells invade the epidermis 72
hours after allergen challenge, and they and Langerhans' cells up-regulate their display of
FcRI.70

A Biphasic T-CellMediated Disease

Allergen-specific CD4+ and CD8+ T cells can be isolated from the skin lesions of patients with
atopic dermatitis. Inflammation in atopic dermatitis is biphasic: an initial Th2 phase precedes a
chronic phase in which Th0 cells (cells that share some activities of both Th1 and Th2 cells) and

Th1 cells are predominant (Figure 3Figure 3

Acute and Chronic Phases of IgE
and T-CellMediated Atopic Dermatitis.).71 The Th2 cytokines interleukin-4, interleukin-5, and

interleukin-13 predominate in the acute phase of the lesions, and in chronic lesions there is an
increase of interferon-, interleukin-12, interleukin-5, and GM-CSF72; these changes are
characteristic of Th1 and Th0 predominance. Th0 cells can differentiate into either Th1 or Th2
cells, depending on the predominant cytokine milieu. The increased expression of interferon-
messenger RNA by Th1 cells follows a peak of interleukin-12 expression, which coincides with
the appearance of inflammatory dendritic epidermal cells in the skin. Normal-looking skin in
patients with atopic dermatitis harbors a mild infiltrate, strongly suggesting the presence of
residual inflammation between flares.73
Recruitment of T cells into the skin is orchestrated by a complex network of mediators that
contribute to chronic inflammation. Homeostatic and inflammatory chemokines produced by skin
cells are involved in this process.74,75 Inflammatory cells and keratinocytes in the skin lesions
express high levels of chemoattractants,76-78 and the keratinocyte-derived thymic stromal
lymphopoietin induces dendritic cells to produce the Th2-cellattracting thymus and activationregulated chemokine, TARC/CCL17. In this way, they may amplify and sustain the allergic
response and the generation of interferon-producing cytotoxic T cells,79 as suggested by in
vitro studies. Interferon- produced by Th1 cells has been implicated in the apoptosis of
keratinocytes induced by the cell-death receptor Fas.80
The role of regulatory T cells in atopic dermatitis81 has also been examined. High levels of
expression of the alpha chain of the interleukin-2 receptor (CD25) and the transcription factor
FOXP3 are characteristic of these cells. There is an increased pool of circulating regulatory T
cells in atopic dermatitis,82 but the skin lesions are devoid of functional regulatory T cells.83 The
complexity of the regulatory T-cell compartment is not yet fully understood, and the role of
regulatory T cells in the regulation of chronic inflammatory skin disease is elusive.

Staphylococcus aureus
Suppression of the innate immune system of the skin by the inflammatory micromilieu of atopic
dermatitis explains the colonization of the skin by S. aureus in more than 90% of patients with
atopic dermatitis. 83 This feature contributes to allergic sensitization and inflammation (Figure

4Figure 4
Multiple Pathways of Staphylococcus aureusDriven Sensitization
and Inflammation.). Scratching increases the binding of S. aureus to the skin, and the increased
amount of S. aureusderived ceramidase can aggravate the defect in the skin barrier. S. aureus
enterotoxins84 increase the inflammation in atopic dermatitis and provoke the generation of
enterotoxin-specific IgE, which correlates with the severity of the disease. 85 These enterotoxins
interact directly with class II molecules of the major histocompatibility complex and the beta
chain of the T-cell receptor to induce an antigen-independent proliferation of T cells. They also
up-regulate the expression of the skin-homing receptor cutaneous lymphocyte-associated antigen
on T cells and the production of keratinocyte-derived chemokines that recruit T cells. By
inducing the competing -isoform of the glucocorticoid receptor in mononuclear cells,
enterotoxins contribute to the emergence of a resistance to local corticosteroid treatment. S.
aureus enterotoxins also induce the expression of the glucocorticoid-induced protein ligand
related to the tumor necrosis factor receptor on antigen-presenting cells, resulting in an inhibition

of the suppressive activity of regulatory T cells.86

Mechanism of Pruritus
The most important symptom in atopic dermatitis is persistent pruritus, which impairs the
patient's quality of life. The lack of effect of antihistamines argues against a role of histamine in
causing atopic dermatitisrelated pruritus.87 Neuropeptides, proteases, kinins, and cytokines
induce itching. Interleukin-31 is a cytokine produced by T cells that increases the survival of
hematopoietic cells and stimulates the production of inflammatory cytokines by epithelial cells. It
is strongly pruritogenic, and both interleukin-31 and its receptor are overexpressed in lesional
skin.88-90 Moreover, interleukin-31 is up-regulated by exposure to staphylococcal exotoxins in
vitro. These findings implicate interleukin-31 as a major factor in the genesis of pruritus in atopic
dermatitis.

Autoimmunity in Atopic Dermatitis

In addition to IgE antibodies against food and aeroallergens, serum specimens from patients with
severe atopic dermatitis contain IgE antibodies against proteins from keratinocytes and
endothelial cells such as manganese superoxide dismutase and calcium-binding proteins.91,92
The serum levels of these IgE autoantibodies correlate with disease severity. Scratching probably
releases intracellular proteins from keratinocytes. These proteins could be molecular mimics of
microbial structures and thus could induce IgE autoantibodies.93 About 25% of adults with
atopic dermatitis have IgE antibodies against self-proteins.94 In these patients, early-onset atopic
dermatitis, intense pruritus, recurrent bacterial skin infections, and high serum IgE levels are
hallmarks of the disease. Furthermore, IgE antibodies against self-proteins can be detected in
patients with atopic dermatitis as early as 1 year of age.94 Some autoallergens in skin are also
strong inducers of Th1 responses.92 IgE antibodies in atopic dermatitis can be induced by
environmental allergens, but IgE antibodies against autoantigens in the skin can perpetuate the
allergic inflammation. Thus, atopic dermatitis seems to stand at the frontier between allergy and
autoimmunity.

A Unifying Hypothesis
One classification distinguishes an IgE-associated form of atopic dermatitis (i.e., true atopic
dermatitis, formerly called extrinsic atopic dermatitis) from a nonIgE-associated form
(nonatopic dermatitis, formerly called intrinsic atopic dermatitis).95 This division implies that
nonatopic dermatitis and atopic dermatitis are two different diseases. However, since dry skin is
an important sign of both conditions, and the absence of IgE-mediated sensitization may be only
a transient factor, there is a need to reconcile these divergent hypotheses. A new picture emerges
from recent findings, in which the natural history of atopic dermatitis has three phases (Figure

5Figure 5
GeneGene and GeneEnvironment Interactions in the Natural
History of Atopic Dermatitis.). The initial phase is the nonatopic form of dermatitis in early
infancy, when sensitization has not yet occurred. Next, in 60 to 80% of patients, genetic factors
influence the induction of IgE-mediated sensitization to food, environmental allergens, or both

this is the transition to true atopic dermatitis. Third, scratching damages skin cells, which release
autoantigens that induce IgE autoantibodies in a substantial proportion of patients with atopic
dermatitis.

Clinical Implications
Since the barrier dysfunction of the skin and chronic inflammation are characteristic of atopic
dermatitis, long-term clinical management should emphasize prevention, intensified and
individually adapted skin care, reduction of bacterial colonization by means of local application
of lotions containing antiseptics such as triclosan and chlorhexidine, and most important
the control of inflammation by the regular use of topical corticosteroids or topical calcineurin
inhibitors. In children, before and after the diagnosis of IgE-mediated sensitization, measures that
prevent exposure to allergens should be beneficial. The current therapy of atopic dermatitis is
reactive treating the flares but management should include early and proactive intervention
with effective and continuous control of the skin inflammation and S. aureus colonization. This
strategy has proved to be effective in reducing the number of flares.96 When applied early in
infancy, it could potentially help to reduce later sensitization to environmental antigens and
autoallergens.

Conclusions
Recent insights into the genetic and immunologic mechanisms that drive cutaneous inflammation
in atopic dermatitis have led to a better understanding of the natural history of this disease and
have highlighted the critical role of the epidermal-barrier function and the immune system. Both
contribute to IgE-mediated sensitization and should be considered as major targets for therapy.
New developments aimed specifically at the molecular defects in the stratum corneum could
provide a customized way to improve the barrier function. Early and proactive management
could improve the outcome and quality of life for patients with atopic dermatitis.
Supported by grants from the German Research Council and the Atopic Dermatitis and Vaccinia
Immunization Network of the National Institute of Allergy and Infectious Diseases.
Dr. Bieber reports receiving consulting fees from Novartis. No other potential conflict of interest
relevant to this article was reported.
I thank Drs. W. Burgdorf, M. Noethen, and H. Williams for their review of an earlier version of
the manuscript and helpful discussion, and I thank all colleagues, fellows, and students who have
studied the genetics and inflammatory mechanisms of atopic dermatitis with me.

Source Information
From the Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
Address reprint requests to Dr. Bieber at the Department of Dermatology and Allergy, University
Medical Center, Sigmund-Freud-Str. 25, 53105 Bonn, Germany, or at thomas.bieber@ukb.unibonn.de.

Mutual Antagonism of T Cells Causing Psoriasis

and Atopic Eczema
Stefanie Eyerich, Ph.D., Anna T. Onken, M.D., Stephan Weidinger, M.D., Andre Franke, M.D.,
Francesca Nasorri, Ph.D., Davide Pennino, Martine Grosber, M.D., Florian Pfab, M.D., Carsten B.
Schmidt-Weber, Ph.D., Martin Mempel, M.D., Ruediger Hein, M.D., Johannes Ring, M.D., Ph.D.,
Andrea Cavani, M.D., Ph.D., and Kilian Eyerich, M.D., Ph.D.
N Engl J Med 2011; 365:231-238July 21, 2011DOI: 10.1056/NEJMoa1104200
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Citing Articles (27)
Letters
Abstract
The simultaneous occurrence of psoriasis driven by type 1 helper T (Th1) cells and type 17 helper
T (Th17) cells and atopic eczema dominated by type 2 helper T (Th2) cells is rare. Here, we
describe three patients with co-occurring psoriasis and atopic eczema with an antagonistic course
and distinct T-cell infiltrates in lesions from psoriasis and those from atopic eczema. Sensitized
patients with psoriasis had a reaction to epicutaneous allergen challenge, with clinically and
histologically verified eczema lesions containing a large number of allergen-reactive T cells.
These findings support a causative role for T cells triggered by specific antigens in both psoriasis
and atopic eczema. (Supported by the German Research Foundation and others.)
Psoriasis and atopic eczema are prevalent, influence health-related quality of life, are associated with
concomitant illness, and pose an economic burden. Whether these diseases are epithelial or
immunologic disorders is debated. Both involve complex interactions of hereditary factors and
environmental influences. Besides altering the skin barrier, these conditions lead to a systemic T-cell
driven immune response with primary involvement of not only the skin but also other sites such as
joints (in psoriatic arthritis) or airways (in asthma and rhinitis). Whereas atopic eczema arises from a
systemic Th2-celldominated immune shift characterized by frequent elevations of total and allergenspecific IgE levels,1 psoriasis is caused by an immune response driven by Th1 cells, which secrete high
levels of interferon-, and by Th17 cells, which secrete high levels of interleukin-17A, interleukin-17F,
and interleukin-22.2 In view of their opposing immune mechanisms, one would expect these diseases
to be mutually exclusive. Indeed, cases of concomitant psoriasis and atopic eczema are rare.3

Methods
We evaluated three patients with concomitant psoriasis and atopic eczema and an additional five
patients with psoriasis and allergic contact dermatitis to nickel. Diagnoses were made on the basis of
clinical presentation, personal history, laboratory findings, and the results of epicutaneous patch testing.
In addition, genomic DNA was extracted from leukocyte specimens obtained from the patients and
tested for HLA-Cw6 alleles as well as the four most common filaggrin polymorphisms (R501X,

2282del4, R2447X, and S3247X), as described previously.4,5 The clinical presentation of the patients
was evaluated by means of the psoriasis area-and-severity index (PASI) and the Scoring Atopic
Dermatitis (SCORAD) index. (For details of these grading schemes, see the Supplementary Appendix,
available with the full text of this article at NEJM.org.) An epicutaneous challenge to nickel and atopy
patch testing of Dermatophagoides pteronyssinus were performed according to standardized
protocols.6,7 The study was approved by the local ethics committee, and all patients provided written
informed consent.
From each patient, punch-biopsy specimens were obtained simultaneously from eczema and psoriasis
lesions while the involved areas were under local anesthesia. Biopsy specimens were immediately
divided into two parts. One part was fixed in paraformaldehyde for histologic analysis; from the other
part, T-cell lines were isolated and further investigated in vitro, as described previously.8 The cytokine
profile of T-cell lines was determined after stimulation with phorbol myristate acetateionomycin for 6
hours in the presence of brefeldin A, and intracellular cytokine accumulation was measured by means
of three-color flow cytometry, as described previously.9,10 In addition, T-cell lines were stimulated
with anti-CD3 and anti-CD28 antibody for 72 hours, and secretion of interferon-, interleukin-4,
interleukin-17, and interleukin-22 levels was quantified by means of commercially available enzymelinked immunosorbent assay (ELISA) kits (R&D Systems).
T-cell specificity was investigated in coculture systems of 105 T cells with 3104 autologous
monocytes and 5 g of natural D. pteronyssinus per milliliter (in Patients 1, 2, and 3) or 20 g of nickel
sulfate per milliliter (in Patients 4 through 8), as described previously.8 Two methods were used: the
carboxyfluorescein succinimidyl ester diacetate (CFSE-DA) assay and the thymidine-incorporation
method. In the former, T cells were marked with 0.5 M of the fluorescent dye CFSE-DA and
subsequently cocultured as described above. (CFSE-DA stains cells and is divided between them after
cell division; a decline in CFSE-DA expression reflects T-cell proliferation.) After 5 days, T cells were
also stained with CD69 (a marker of activated T cells), and fluorescence intensity was measured by
flow cytometry. In the latter method, T cells were cocultured for 72 hours as described above. Cell-free
supernatant was obtained for quantification of cytokine secretion by means of ELISA, and
subsequently 10 g per milliliter of 3H-thymidine was added to the coculture for an additional 12
hours. Thymidine incorporation was measured by means of a beta-counting device, as described
previously.8 Results are expressed as the proliferation index (i.e., the counts per minute for stimulated
T cells divided by the counts per minute for the negative controls).

Results
Characteristics of the three patients with concomitant psoriasis and atopic eczema are shown in Table

1Table 1
Characteristics of the Three Patients with Atopic Eczema and Psoriasis and
Five Additional Patients with Psoriasis and Allergic Contact Dermatitis (from Nickel). and Figure

1Figure 1
Patients with Concomitant Psoriasis and Atopic Eczema (AE).. Although
the clinical courses of psoriasis and atopic eczema rarely overlapped, indicating independent regulation
of the two immune phenotypes, all three patients had periods with active lesions of both diseases.

During such periods, skin-biopsy specimens were obtained from psoriasis lesions and atopic eczema
lesions at the same time. Histologic analysis of the specimens showed typical features of each disease,
such as acanthosis, elongated rete ridges, and neutrophilic microabscesses in psoriasis lesions and
spongiosis as well as a mixed infiltrate of T cells, eosinophils, and granulocytes in atopic eczema
lesions (Figure 1A).
Parallel occurrence of antagonistic inflammatory skin reactions may require distinct antigen triggers. In
all our patients, the T cells derived from psoriasis lesions and those derived from atopic eczema lesions
differed in their cytokine profile. Psoriasis lesions contained a large number of Th1 and Th17 cells,
whereas atopic eczema lesions have higher amounts of Th2 and Th22 cells (Figure 1A and Figure

2AFigure 2
Antigen-Specific Eczematous Reactions on Epicutaneous Challenge in
Patients with Psoriasis and Allergic Sensitization.).11,12 Accordingly, secretion of the Th1 and Th17
cytokines interferon- and interleukin-17 was greater in psoriasis-derived T-cell lines, whereas T cells
from atopic eczema lesions secreted greater amounts of interleukin-4 in vitro. Interleukin-22 is
produced by both Th17 and Th22 cells and was released in similar amounts in the psoriasis lesions and
atopic eczema lesions (Figure 1D and Figure 2C).
Psoriasis lesions regularly develop after mechanical trauma or skin irritation (Koebner's
phenomenon).13 To evaluate whether nonspecific responses such as Koebner's phenomenon or antigenspecific T-cell responses predominate, we performed a challenge with the major house-dust mite
allergen, D. pteronyssinus (atopy patch test). Clinical and histologic signs of eczema developed in
Patients 1 and 2. Eczema-invading T cells were mostly Th2 cells,7,14 a large number of which reacted
to D. pteronyssinus allergen challenge in vitro after antigen presentation by autologous monocytes
(Figure 2A, 2D, and 2E).
To determine whether psoriasis and eczema are caused by opposing T-cell subsets or antigen-specific T
cells, we expanded testing to include eczema-inducing agents that typically elicit a Th1- and Th17-cell
immune response, such as nickel. On epicutaneous challenge with the hapten nickel, five additional
patients with psoriasis and a known sensitization to nickel (allergic contact dermatitis) (Table 1) had an
eczema reaction (Figure 2B). Histologic analysis of biopsy specimens from fresh psoriasis lesions and
from patch testinduced eczema, obtained at the same time, confirmed the clinical diagnosis. Whereas
the cellular infiltrate in atopic eczema lesions was dominated by Th2 cells, the infiltrate in allergic
contact dermatitis lesions, like the infiltrate in psoriasis lesions, was dominated by Th1 and Th17 cells
(Figure 2C). This finding may explain why psoriasis in combination with allergic contact dermatitis is
much more common than psoriasis in combination with atopic eczema. A large percentage of T cells
derived from allergic contact dermatitis lesions reacted to nickel in vitro, whereas few T cells were
reactive to nickel in psoriasis lesions (Figure 2D and 2E).
Besides the differences in their cellular infiltrates, atopic eczema lesions and psoriasis lesions could
also be distinguished according to skin colonization with microorganisms and filaggrin expression.
Namely, all atopic eczema lesions, but not psoriasis lesions, were colonized with Staphylococcus
aureus, as determined by smear-test culture. Furthermore, filaggrin expression, measured
immunohistochemically, was higher in psoriasis lesions than in atopic eczema lesions (Figure 1A).

Discussion
Our findings suggest that an intrinsic epithelial abnormality is not the basis of the pathogenesis of

psoriasis or atopic eczema. Rather, specific T cells migrate into the skin in response to distinct antigen
triggers and determine the outcome of an inflammatory skin disease that is, atopic eczema or
psoriasis. Thus, antigens differ in the skin reactions they elicit. The specific antigen exposures that lead
to psoriasis are undefined.
Besides indicating antigen dependence, our findings shed light on how the local cytokine
microenvironment directs cutaneous immunity. The fact that atopic eczema lesions, but not psoriasis
plaques, were colonized with S. aureus confirms that Th17 and Th1 cells induce an innate immune
response in the skin that is partially antagonized by Th2 cells.8,15 Furthermore, the lower filaggrin
expression in atopic eczema lesions is consistent with the finding that Th2 cytokines inhibit expression
of the filaggrin gene in vitro.16
Formerly, topical glucocorticoids and systemic immunosuppressive drugs were the only therapies for
both psoriasis and atopic eczema. An understanding of the molecular basis of both diseases has led to
the development of more targeted biologic therapies. The diversity of psoriasis and atopic eczema is
reflected by the responses to these targeted biologic agents.
For psoriasis, molecules inhibiting the pro-inflammatory molecule tumor necrosis factor (TNF-) are
highly effective. In our study, while Patient 1 was receiving TNF- antibodies (infliximab, which was
discontinued after two injections because of a severe adverse event [temperature up to 39C, arthritis
symptoms, weakness, and vomiting] and adalimumab), his psoriasis lesions cleared, but his atopic
eczema lesions at other sites were exacerbated (Figure 1A, clinical course). Thus, blocking a Th1mediated and Th17-mediated immune disease with a specifically targeted agent may result in a flare of
Th2-mediated disease.
Another promising therapy for psoriasis is the Th2 cytokine interleukin-4,17 which counteracts the
effects of interferon- and interleukin-17 on keratinocytes.8,15 However, since Th2 cytokines are
overproduced by the cellular infiltrate of atopic eczema lesions, interleukin-4 would not be expected to
ameliorate skin symptoms of atopic eczema. In fact, biologic drugs specifically inhibiting one T-cell
subset appear to be ineffective for the treatment of co-occurring psoriasis and atopic eczema. Instead,
our patients benefited from less specific therapy, aimed at general T-cell suppression: in Patient 1,
psoriasis and atopic eczema lesions cleared after receipt of the antiinterleukin-12 p40-subunit
antibody ustekinumab, which targets Th1 and Th17 cells (Figure 1A). Ustekinumab is effective in
treating psoriasis,18 whereas evidence-based data regarding its effect on atopic eczema are lacking.
However, since there are reports that Th1 and Th17 respond to microbial antigens (e.g., the S. aureus
infecting our patients with atopic eczema) and to self-antigens released after cell damage, during the
chronic phase of atopic eczema,1,8 ustekinumab could partially improve atopic eczema lesions.
Cyclosporine suppresses all T-cell subpopulations through calcineurin inhibition and was a highly
effective treatment for both psoriasis and atopic eczema lesions in Patient 2 (Figure 1B, clinical
course).
In summary, we describe the rare simultaneous occurrence of two supposedly antagonistic diseases,
psoriasis and atopic eczema. Within the same patients, distinct T-cell subpopulations were found to
infiltrate the same organ: predominantly Th1 and Th17 cells in psoriasis and Th2 cells in atopic
eczema. On epicutaneous challenge with eczema-inducing antigens, patients with psoriasis and
sensitization against these antigens do not react with an unspecific triggering of psoriasis plaques
(Koebner's phenomenon), but typical eczematous lesions containing antigen-reactive T cells do
develop. Our observations suggest that distinct, antigen-specific T-cell subsets determine the
pathogenesis of psoriasis and atopic eczema.
Supported by grants from Deutsche Forschungsgemeinschaft (EY97/1-2 and WE2678/4-1),
Kommission Klinische Forschung of the Klinikum Rechts der Isar Munich,

Hochschulwissenschaftsprogramm of the Technische Universitt Munich, Bayerische

Forschungsstiftung, the National Genome Research Network (01GS0809 and 01GS0818), and the
Christine Khne Center of Allergy Research and Education.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. S. Eyerich and Onken contributed equally to this article.
We thank Juliette Kranz for technical assistance.

Source Information
From the Center of Allergy and Environment (ZAUM), Technische Universitt and Helmholtz Center
Munich (S.E., D.P., C.B.S.-W.), and the Department of Dermatology and Allergy, Technische
Universitt Munich (A.T.O., M.G., F.P., R.H., J.R., K.E.) both in Munich; the Department of
Dermatology, Allergology, and Venerology (S.W.) and the Institute of Clinical Molecular Biology
(A.F.), University Hospital SchleswigHolstein, Campus Kiel, Kiel; and the Department of
Dermatology, Venereology, and Allergology, University Medicine Gttingen, Gttingen (M.M.) all
in Germany; and the Laboratory of Experimental Immunology, Istituto Dermopatico dell'Immacolata,
Rome (F.N., A.C.).
Address reprint requests to Dr. Kilian Eyerich at the Department of Dermatology and Allergy,
Technische Universitt Munich, Biedersteiner Strae 29, 80802 Munich, Germany, or at
kilian.eyerich@lrz.tum.de.

SRN Allergy
Volume 2014 (2014), Article ID 354250, 7 pages
http://dx.doi.org/10.1155/2014/354250

Review Article
Atopic Dermatitis: Natural History, Diagnosis, and Treatment
Simon Francis Thomsen

Department of Dermatology, Bispebjerg Hospital, Bispebjerg Bakke 23, 2400 Copenhagen NV,
Denmark

Received 24 February 2014; Accepted 18 March 2014; Published 2 April 2014

Academic Editors: C. Pereira and Z. Zhu

Copyright 2014 Simon Francis Thomsen. This is an open access article distributed under the
Creative Commons Attribution License, which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Abstract

Atopic dermatitis is an inflammatory skin disease with early onset and with a lifetime prevalence
of approximately 20%. The aetiology of atopic dermatitis is unknown, but the recent discovery of
filaggrin mutations holds promise that the progression of atopic dermatitis to asthma in later
childhood may be halted. Atopic dermatitis is not always easily manageable and every physician
should be familiar with the fundamental aspects of treatment. This paper gives an overview of the
natural history, clinical features, and treatment of atopic dermatitis.
1. Definition

Atopic dermatitis is a common, chronic, relapsing, inflammatory skin disease that primarily
affects young children. Atopy is defined as an inherited tendency to produce immunoglobulin E
(IgE) antibodies in response to minute amounts of common environmental proteins such as
pollen, house dust mites, and food allergens. Dermatitis derives from the Greek derma, which
means skin, and itis, which means inflammation. Dermatitis and eczema are often used
synonymously, although the term eczema is sometimes reserved for the acute manifestation of the
disease (from Greek, ekzema, to boil over); here, no distinction is made. Over the years, many
other names have been proposed for the disease, for instance, prurigo Besnier (Besniers itch),
named after the French dermatologist Ernest Besnier (18311909). Allergic sensitization and
elevated immunoglobulin E (IgE) are present in only about half of all patients with the disease,
and therefore atopic dermatitis is not a definitive term.
2. Epidemiology

Atopic dermatitis affects about one-fifth of all individuals during their lifetime, but the
prevalence of the disease varies greatly throughout the world [1]. In several so-called
industrialised countries, the prevalence increased substantially between 1950 and 2000 so much
that many refer to as the allergic epidemic. However, current indications point to eczema
symptoms having levelled off or even having decreased in some countries with a formerly very
high prevalence, such as the United Kingdom and New Zealand. This indicates that the allergic
disease epidemic is not increasing continually worldwide. Nevertheless, atopic dermatitis remains
a serious health concern, and in many countries, particularly in the developing world, the disease
is still very much on the rise.

2.1. Natural History

Around 50% of all those with atopic dermatitis develop symptoms within their first year of life,
and probably as many as 95% experience an onset below five years of age [2]. Around 75% with
childhood onset of the disease have a spontaneous remission before adolescence, whereas the
remaining 25% continue to have eczema into adulthood or experience a relapse of symptoms
after some symptom-free years. Many with adult-onset atopic dermatitis or atopic dermatitis
relapsing in adulthood develop hand eczema as the main manifestation. In some patients, this
constitutes a serious concern as it may affect their choice of career or employment and in some
cases it may even lead to an early exit from the labour market.

Around 5075% of all children with early-onset atopic dermatitis are sensitized to one or more
allergens, such as food allergens, house dust mites, or pets, whereas those with late-onset atopic
dermatitis are less often sensitized [3]. However, intake of foods or exposure to airborne allergens

is rarely the cause of exacerbations in atopic dermatitis; many patients with the disease are
sensitized to foods without this playing a role in eczema activity. Atopic dermatitis, particularly
severe disease, in a child heralds other atopic diseases. A child with moderate to severe atopic
dermatitis may have as much as 50% risk of developing asthma and 75% risk of developing hay
fever [4].
2.2. Risk Factors

The risk of developing atopic dermatitis is much higher in those whose family members are
affected. For example, the concordance rate of atopic dermatitis in monozygotic twins is around
75%, meaning that the risk of the disease in the twin sibling is 75% if the cotwin is affected [5].
In contrast, the risk in dizygotic twins is only 30%. This shows that genetic factors play a role in
the susceptibility to atopic dermatitis. However, as there is not complete concordance between
monozygotic twins, who share all their genes, environmental and developmental factors must
play a role too. As such, atopic dermatitis is a complex genetic disease arising from several genegene and gene-environment interactions.
2.2.1. Genetics

Many genes have been associated with atopic dermatitis, particularly genes encoding epidermal
structural proteins and genes encoding key elements of the immune system. A recent and
interesting genetic discovery is the documented strong association between atopic dermatitis and
mutations in the filaggrin gene, positioned on chromosome 1 [6]. The filaggrin gene is the
strongest known genetic risk factor for atopic dermatitis. Around 10% of people from western
populations carry mutations in the filaggrin gene, whereas around 50% of all patients with atopic
dermatitis carry such mutations. Filaggrin gene mutations give rise to functional impairments in
the filaggrin protein and thereby disrupt the skin barrier. The clinical expression of such
impairments is dry skin with fissures and a higher risk of eczema. Not all patients with atopic
dermatitis have these mutations and other genetic variants have also been incriminated [7]. It is
the combined action of all these genetic variants along with environmental and developmental
risk factors that cause atopic dermatitis.
2.2.2. Environment

Although many different environmental risk factors have been considered potentially causative
for atopic dermatitis, only a few are consistently accepted. For example, there is substantial
evidence that our western lifestyle leads to some of the reported increase in eczema occurrence
over the past years although this has not pointed to specific environmental risk factors or has
translated directly into functional preventive measures [8]. Many advocate the hygiene
hypothesis when explaining the rapid increase in eczema prevalence [9]. This hypothesis states
that the decrease in early childhood exposure to prototypical infections, such as hepatitis A and
tuberculosis, has increased susceptibility to atopic diseases [10]. The hypothesis is supported by

the observations that the youngest among siblings has the lowest risk of atopic dermatitis and that
children who grow up in a traditional farming environment where they are exposed to a variety of
microflora, for instance, from unpasteurized cows milk, livestock, and livestock quarters, are
protected to some extent against developing the disease and against allergic diseases in general
[11]. In contrast, disease development is probably positively correlated with duration of
breastfeeding [12], whereas several studies have linked a high social position of the parents to an
increased risk of atopic dermatitis in the child [13]. Although such observations are not easy to
interpret, they may also lend support to the hygiene hypothesis or at least to the generally
accepted theory that eczema occurs in genetically susceptible individuals who are exposed to a
certain disadvantageous environment.
3. Pathophysiology

Two main hypotheses have been proposed to explain the inflammatory lesions in atopic
dermatitis. The first hypothesis concerns an imbalance of the adaptive immune system; the
second hypothesis concerns a defective skin barrier. Although these two hypotheses are not
thought to be mutually exclusive, they may complement each other.
3.1. Immunological Hypothesis

The theory of immunological imbalance argues that atopic dermatitis results from an imbalance
of T cells, particularly T helper cell types 1, 2, 17, and 22 and also regulatory T cells [14]. In the
allergic (atopic dermatitis) stateparticularly in acute eczemathe Th2 differentiation of naive
CD4+ T cells predominates. This causes an increased production of interleukins, primarily IL-4,
IL-5, and IL-13, which then leads to an increased level of IgE, and the Th1 differentiation is
correspondingly inhibited.
3.2. The Skin Barrier Hypothesis

The theory of skin barrier defects is more recent and has its origin in the observation that
individuals with mutations in the filaggrin gene are at increased risk of developing atopic
dermatitis [6]. The filaggrin gene encodes structural proteins in the stratum corneum and stratum
granulosum that help bind the keratinocytes together. This maintains the intact skin barrier and
the hydrated stratum corneum. With gene defects, less filaggrin is produced, leading to skin
barrier dysfunction and transepidermal water loss, which causes eczema. There is evidence to
suggest that the impaired skin barrier, which results in dry skin, leads to increased penetration of
allergens into the skin, resulting in allergic sensitization, asthma, and hay fever [15]. Preventing
dry skin and active eczema early in life via application of emollients may constitute a target of
primary prevention of progression of eczema into allergic airways disease.
4. Histopathology

A skin biopsy taken from a site with acute atopic eczema is characterised by intercellular oedema,
perivascular infiltrates primarily of lymphocytes, and retention of the nuclei of the keratinocytes
as they ascend into the stratum corneumso-called parakeratosis. Chronic eczema is dominated
by a thickened stratum corneum, so-called hyperkeratosis, a thickened stratum spinosum
(acanthosis), but sparse lymphocytic infiltrates.
5. Diagnosis and Clinical Presentation

The appearance of the individual skin lesion in atopic dermatitis does not differ from other
eczemas such as contact eczema. In its acute form, eczema is characterised by a lively red
infiltrate with oedema, vesicles, oozing, and crusting; lichenification, excoriations, papules, and
nodules dominate the subacute and chronic form. Accordingly, the diagnostic approach builds
upon other characteristics such as the distribution of the eczema as well as associated features of
the patient. The typical patient with atopic dermatitis is a person with:an early onset of itchy
eczema localised at typical sites such as the flexures of the elbows and knees in an atopic patient
or in a person with a familial predisposition to atopic disease.

The most widely used diagnostic criteria for atopic dermatitis were developed by Hanifin and
Rajka in 1980 and were later revised by the American Academy of Dermatology (Table 1) [16].
tab1
Table 1: Diagnostic criteria for atopic dermatitis.

This set of criteria is primarily useful in clinical practice; another set of diagnostic questions
widely used in epidemiological research was developed by the UK Working Party in 1994 (Table
2) [17].
tab2
Table 2: Therapeutic approaches to atopic dermatitis.

The severity of eczema can be graded according to several scoring systems such as SCORAD
[18] and EASI [19].
5.1. Typical Manifestations

Although this description fits many with the disease, the clinical presentation of atopic dermatitis
is often more elaborate with a large variation in the morphology and distribution of the eczema
combined with various other features. However, many patients with atopic dermatitis have a
general tendency to present with dry skin (xerosis) due to the low water content and an excessive
water loss through the epidermis. The skin is pale because of increased tension in the dermal
capillaries and the ability to sweat is reduced. There is an increased cholinergic response to
scratch, so-called white dermographism or skin-writing, resulting in hives at the affected site. The
palms of the hands and feet may show hyperlinearity, and the individuals hair is dry and fragile.
Often, there is a double skinfold underneath the inferior eyelid (Dennie-Morgan fold) that
becomes exaggerated in times of increased disease activity. The eye surroundings may be
darkened due to postinflammatory hyperpigmentation.

Atopic dermatitis can be grouped into three clinical stages, although these may be difficult to
reproduce in the individual patient [2].
5.1.1. Atopic Dermatitis of Infancy

Infants experience eczema that is often localised to the face, scalp, and extensor aspects of the
arms and legs, but it can also be widespread. The lesions are characterised by erythema, papules,
vesicles, excoriations, oozing, and formation of crusts.
5.1.2. Atopic Dermatitis of Childhood

In toddlers and older children, the eczema lesions tend to shift location so that they are often
confined to the flexures of the elbows and knees as well as the wrists and ankles, although it can
occur at any site. In general, the eczema becomes drier and lichenified with excoriations, papules,
and nodules.
5.1.3. Atopic Dermatitis of Adolescence and Adulthood

In adult patients, the lesions frequently localise to the face and neck, head-and-neck dermatitis,
and a considerable portion of patients, around 30%, develop atopic hand eczema, which may
interfere with workplace activities.
5.2. Special Manifestations

Some patients may present with several other common, benign skin conditions, for example,
pityriasis alba, which is a condition characterised by dry, pale patches on the face and upper arms,

and keratosis pilaris, which manifests as small, rough keratotic papules particularly on the upper
arms and thighs. Atopic winter feetdermatitis plantaris siccaa condition usually seen in
school-aged children is characterised by symmetric eczema on the weight bearing areas of the
soles of the feet. Earlobe eczema, eczema of the nipple, and eczema around the margins of the
mouth (cheilitis) can be particularly troublesome and often involve infection with staphylococci.
Keratoconus and cataracts sometimes complicate atopic dermatitis.
5.3. Aggravating Factors

In many patients, atopic dermatitis takes a chronic, relapsing course when it is not possible to
predict periods of activity or pinpoint aggravating factors. However, several exposures are well
known for aggravating eczema and should be avoided. A large number of patients are sensitive to
woollen clothing, which aggravates itching and discomfort. Hot water may also exacerbate
itching, and long baths should be avoided. Several infections, notably staphylococci, are frequent
causes of exacerbations as various foods are, particularly in cases where a patient is sensitized to
the food. Food avoidance should be advocated only if a patient has documented allergy to a
suspected food and not on the basis of asymptomatic sensitization alone. Another phenomenon
that can lead to the eczema worsening is contact urticaria, which is a reaction following skin
exposure to a food, for example, citrus fruits or tomatoes. The skin around the mouth is often the
site of such a reaction. Lastly, many patients report that stressful living aggravates their eczema.
5.4. Differential Diagnoses

Several diseases present with a skin rash that resembles atopic dermatitis. However, careful
evaluation of the morphology and localization of the rash combined with information about the
individual patient usually leads to a diagnosis. Diseases that sometimes resemble atopic
dermatitis are scabies, seborrheic dermatitis, and contact dermatitis.
5.5. Complications

Several microorganisms, such as bacteria, viruses, and fungi, can complicate the eczema (causing
superinfections). The skin of the patient with atopic dermatitis is often colonised with
Staphylococcus aureus, particularly when the eczema is not well controlled. The mere presence
of such bacteria does not require antibiotic treatment. However, if staphylococci become
invasive, oozing crusted lesionsimpetigocan be the result, which indicates the need for
topical or, preferably, oral antibiotics [20]. Some advocate skin washing with antiseptic remedies,
such as chlorhexidine, as this lowers the number of bacteria on the skin; however, chlorhexidine
can lead to secondary sensitization. Due to deficiencies in the production of antimicrobial
peptides in the skin, patients with atopic dermatitis also have a greater risk of several viral
infections, for example, molluscum contagiosum, caused by a pox virus, which gives small,
umbilicated, dome-shaped, pearly coloured papules. Another typical superinfection of the skin in
atopic dermatitis patients is herpes virus. If such a herpes infection spreads, it can cause eczema

herpeticum, which is a widespread vesicular eruption, typically localised to the face, scalp, and
upper chest. Eczema herpeticum requires systemic antiviral treatment.
6. Treatment

Atopic dermatitis is not curable, and many patients will experience a chronic course of the
disease. Accordingly, the treatment of atopic dermatitis aims to [21](1)minimise the number of
exacerbations of the disease, so-called flares,(2)reduce the duration and degree of the flare, if
flare occurs.

The first aim relates primarily to prevention; the second aim relates to treatment. Prevention is
best attained by trying to reduce the dryness of the skin, primarily via daily use of skin
moisturising creams or emollients along with avoidance of specific and unspecific irritants such
as allergens and noncotton clothing. When dryness is reduced, the desire to scratch will lessen
and the risk of skin infection will decrease. Avoiding long, hot baths further prevents skin
dryness, but when a bath is taken, an emollient should be applied directly after it to secure a
moist epidermis and augment the skin barrier function. Reducing the flare is warranted when
actual eczema occurs or when mild intermittent eczema worsens. Management of an eczema
exacerbation requires medical treatment often in the form of corticosteroid creams. In addition to
topical treatment, severe acute or chronic eczema often requires systemic immunosuppressant
drugs or phototherapy (ultraviolet, UV light).
6.1. Emollients: Maintaining an Intact Skin Barrier

The use of emollients in the management of atopic dermatitis is pivotal. They should be applied
several times a day, and a systematic use has been shown to reduce the need for corticosteroid
creams [22, 23]. The main reason for intensive use of an emollient is its ability to increase the
hydration of the epidermis, mainly by reducing the evaporation, as it acts as an occlusive layer on
the top of the skin. As such, emollients have no direct effect on the course of the eczema.
However, the appearance of the skin is enhanced and itching is reduced. Other moisturizers have
more complex modes of action as they act by restoring the structural (lipid) components of the
outer skin layers, thereby reducing cracks and fissures. Others act by attracting water molecules
from the air in order to moisturize the skin. The choice of emollient depends on the individual
patient. It is generally recommended that a thick (with a high fat content) cream or ointment is
used for the driest skin, whereas creams and lotions with a higher water content are used only for
very mild eczema. Such creams must be applied several times a day because of their rapid
absorption into the skin. It is important to recommend an emollient without perfume or other
potential allergens as they may provoke secondary allergic sensitization. Those with chronic, dry
eczema benefit from tar preparations in the form of creams and occlusive bandages.
6.2. Topical Corticosteroids

Topical corticosteroids are the mainstay of the treatment for moderate to severe atopic dermatitis,
both in children and adults. Corticosteroids are hierarchically grouped into different classes based
on their vasoconstrictory abilities. For ease, four classes are considered: mild, moderate, strong,
and very strong preparations (Table 3).
tab3
Table 3: Topical corticosteroids.
6.2.1. How Should Corticosteroids Be Applied?

Most patients benefit from treatment with mild to moderate corticosteroid preparations, whereas
only a small subsetthose with severe diseaseneeds potent preparations; very strong
preparations are rarely needed. Mild and moderate corticosteroid creams are reserved for
children, while adults can be treated with stronger preparations. Mild and moderate
corticosteroids should be used chiefly for treating eczema on body sites where the skin is thin,
notably in the face, axillae, groins, and anogenital area, whereas strong corticosteroids should be
used for treating eczema on the rest of the body. Unlike medications used for treating asthma and
allergic rhinitis, creams for atopic dermatitis are not prepared with a fixed amount of drug release
per round of usage. Instead, the rule of the fingertip unit (FTU) must be applied. A fingertip
unit is the amount of cream or ointment squeezed from a standard tube along an adults fingertip
a fingertip is from the very end of the finger to the distal crease in the finger. One FTU is
sufficient to treat an area of skin twice the size of the flat of an adult hand with the fingers
together (Table 4).
tab4
Table 4: Fingertip unit.

As one FTU equals roughly 0.5g cream, the amount needed to adequately treat an entire adult
body surface once is 20g, whereas a 1-2-year-old child, for instance, requires about 7g.
6.2.2. Proactive and Reactive Treatment

Corticosteroid creams are used both for treating acute flares of atopic dermatitis and for
maintenance therapy; that is, prevention of disease relapses when the acute flare is under control.
For treating acute flares, one daily application is recommended of the cream with the lowest
potency deemed sufficient to clear the eczema within 1-2 weeks [24]. When the eczema flare is
well controlled, that is, when the rash is quiescent and particularly when the itch has subsided
substantially, use of the corticosteroid cream should be tapered off to two to three weekly

applications for an additional 1-2 weeks. Another tapering approach is to use a lower potency
cream daily for 1-2 weeks. However, patients may find this approach slightly more difficult to
manage. In theory, treatment could be discontinued at the end of the tapering period if the flare is
sufficiently under control, but in many patients the eczema relapses, and an additional round of
treatment is required. If this is the case, it is preferable to continue the maintenance treatment,
applying the corticosteroid cream two to three times weekly on those sitesfor instance, the
elbow creaseslikely to become active again if treatment is discontinued. This strategy is called
the proactive treatment strategy, as compared with the reactive strategy, which recommends
intermittent use of the corticosteroid preparation according to the activity of the eczema. The
proactive treatment strategy is being increasingly advocated because the overall quantity of
corticosteroid cream used is smaller than that used with the reactive treatment strategy;
additionally, the risk of an exacerbation of the eczema is smaller when using the proactive
treatment strategy.
6.2.3. Side Effects

Patients and physicians alike fear the cutaneous and systemic side effects from using topical
corticosteroids. However, although topical corticosteroids can cause thinning of the skin,
teleangiectasies, and stretch marks, when used properly, the risk of side effects is very small. It is
essential that physicians try to reassure parents of atopic children and the patients themselves and
explain that this fear of side effects should not inhibit the use of corticosteroids since insufficient
use can cause worsening of the eczema. Including the patient (and the parents) in the treatment
plan is paramount. Rather than dictating what is best for the child, physicians should discuss the
parents concerns in order to avoid disrupting the physician-patient-parent relationship, which
would ultimately lead to complications for the child.
6.3. Calcineurin Inhibitors

Pimecrolimus cream and tacrolimus ointmentalso termed topical calcineurin inhibitorsare

newer formulations used both for the treatment of acute flares and for maintenance therapy of
atopic dermatitis [25]. Pimecrolimus has the potency of a mild corticosteroid cream, whereas
tacrolimus corresponds to a moderate to strong topical corticosteroid. The side effects of
corticosteroids, such as thinning of the skin, are not seen with topical calcineurin inhibitors, and
this allows daily treatment for longer periods. Topical calcineurin inhibitors can also be used in
the proactive treatment strategy.
6.4. Phototherapy

Widespread eczema benefits from treatment with UV light. Narrowband UVB light is particularly
suitable for treating adults with recalcitrant eczema. Broadband UVA light and a combination of
UVA light and the photosensitizing drug psoralene can also be used to treat severe recalcitrant
eczema. Difficult-to-treat atopic dermatitis often clears with 1-2 months phototherapy three to

five times a week, preferably combined with topical corticosteroids. Nevertheless, as

phototherapy causes premature aging of the skin and increases the risk of skin cancer in the long
run, it should be prescribed with caution.
6.5. Systemic Immunosuppressant Treatments

Short-term tapered treatment with oral corticosteroids is recommended for acute flares of severe,
widespread atopic dermatitis, preferably in combination with topical corticosteroids. As
Staphylococcus infections often trigger such flares, oral antibiotics should be prescribed
simultaneously. Due to the risk of side effects, continuing treatment with oral corticosteroids is
not recommended. Instead, tapering should be done while introducing a second
immunosuppressant drug, for example, azathioprine, methotrexate, or cyclosporine A, for very
severe, chronic, relapsing atopic dermatitis [26]. Such treatment should be administered from
specialised clinics or, preferably, from hospital dermatology departments.
6.6. Other Medications

Specific immunotherapy in patients with atopic dermatitis mainly has an effect on upper airway
symptoms if the patient has concomitant allergic rhinitis, whereas the effect on the activity of the
eczema is negligible.

Oral antihistamines are recommended for itching but have no effect on the activity of the eczema.
Nonsedating antihistamines should be used, but when night-time itching interferes with sleep,
sedating antihistamines are recommended.
Conflict of Interests

The author declares that there is no conflict of interests regarding the publication of this paper.
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Ann Dermatol. Aug 2013; 25(3): 292297.

Published online Aug 13, 2013. doi: 10.5021/ad.2013.25.3.292
PMCID: PMC3756192

Improvement of Atopic Dermatitis Severity after

Reducing Indoor Air Pollutants
Hye One Kim, Jin Hye Kim, Soo Ick Cho, Bo Young Chung, In Su Ahn, Cheol Heon Lee, and Chun
Wook Park
Department of Dermatology, Kangnam Sacred Heart Hospital, College of Medicine, Hallym
University, Seoul, Korea.
Corresponding author.
Corresponding author: Chun Wook Park, Department of Dermatology, Hallym University Kangnam
Sacred Heart Hospital, 1 Singil-ro, Yeongdeungpo-gu, Seoul 150-950, Korea. Tel: 82-2-829-5221, Fax:
82-2-832-3237, Email: moc.narap@pamred
Author information Article notes Copyright and License information
Received December 27, 2011; Revised June 1, 2012; Accepted June 10, 2012.
Copyright 2013 The Korean Dermatological Association and The Korean Society for Investigative
Dermatology
This is an Open Access article distributed under the terms of the Creative Commons Attribution NonCommercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly
cited.
This article has been cited by other articles in PMC.
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Abstract
Background
Recent epidemiologic studies have shown that environmental contaminants such as air pollution and
tobacco smoke play an important role in the pathophysiology of atopic dermatitis (AD).

Objective
The aim of this study was to evaluate the relationship between the severity of AD and indoor air
pollution.

Methods
The study population consisted of 425 children from 9 kindergartens, Korea. The authors surveyed the
prevalence of AD and evaluated disease severity by the eczema area and severity index (EASI) score
and investigator's global assessment (IGA). After measuring indoor air pollution, a program to improve
indoor air quality was conducted in 9 kindergartens. Seven months later, the prevalence and disease
severity were evaluated.

Results
The initial prevalence of AD was 8% and the mean EASI score was 2.37. The levels of particulate
material 10 (PM10) and carbon dioxide (CO2) were higher in some kindergartens compared to the
normal values. Subsequent to the completion of the indoor air quality improvement program, the mean
PM10 level was significantly decreased from 182.7 to 73.4 g/m3. After the completion of the program,
the prevalence of AD and the mean EASI were decreased, and the changes were both statistically
significant. The mean number of hospital visits decreased from 1.3 per month during the first survey to
0.7 per month during the second survey, which was statistically significant.

Conclusion
Indoor air pollution could be related to AD. The reduction of PM10 through improving indoor air
quality should be considered in kindergartens and schools in order to prevent and relieve AD in
children.
Keywords: Atopic dermatitis, Improvement, Indoor air pollutants, Severity
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INTRODUCTION
Atopic dermatitis (AD) is a chronic, itching and eczematous skin disease, which particularly affects
subjects in early or late childhood. The prevalence of AD has been reported to be between 5% and 10%
in the general population, and it has been increasing continuously worldwide in the recent decades1.
This increase suggests that the pathogenesis of AD may be attributed to both genetic predisposition and
environmental factors. There is much disagreement between the results of several epidemiological
surveys, which studied the relationships between AD and environmental factors. Some studies
portrayed that more industrialization and urbanization augments the prevalence of AD, whereas others
presented no such relationship2-5.
There have been several epidemiological studies on the relationship between AD and air pollution.
However, there is little clinical evidence in the literature. A few studies reported the relationship
between AD and the environment. Wen et al.6 showed that fungus on walls, house renovation and
house painting are significantly associated with AD. Arnedo-Pena et al.7 reported that the annual
average concentration of carbon monoxide (CO) is also associated with the prevalence of AD.
This study is designed to evaluate the effect of indoor air quality on the severity of AD. We surveyed
the prevalence and severity of AD in 9 kindergartens in Guro-gu, Seoul in collaboration with the Gurogu public health center. After improving the indoor air quality through frequent cleaning and
vacuuming, we evaluated the changes in clinical signs and symptoms among children with AD.
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MATERIALS AND METHODS

Subjects
Of the 301 kindergartens in Guro-gu, Seoul, 9 were randomly selected for on-site surveys, which
included physical examinations by a dermatologist. A total of 425 children (males, 210; females, 215)

aged from 1 to 5 years were enrolled in the study. AD patients were diagnosed by a single
dermatologist during the study. Exclusion criteria included any skin disorders other than AD in the area
to be treated as well as children with any other systemic diseases. We received voluntary informed
consent form the patients' parents.

Methods
1) Program for improving indoor air quality
Indoor air quality measurements included indoor temperature, humidity, particulate materials (PM10),
CO, carbon dioxide (CO2) and formaldehyde (HCHO) in accordance with the official test standard of
indoor air quality (Notification no. 2008-73 of the Ministry of Environment), gauged by a simplified
measuring instrument (Model: LD-3B; Sibata Scientific Technology Ltd., Tokyo, Japan). Each
kindergarten conducted general cleaning every week during the first survey and changed the frequency
of general cleaning to every 2 or 3 days during the second survey. To improve indoor air quality,
several daily practices were instituted: (1) elimination of fine dust, cobweb and mold spores on the
walls, ceilings, bookshelves, floors and bedding; (2) steam sterilization of chairs, desks and other
furniture in the hall and the gymnasium; and (3) removal of floating matters and mites in the bedding
by steam cleaning.
2) Evaluation of atopic dermatitis
AD was diagnosed based on the Korean diagnostic guideline for AD8 and the patients were evaluated
by a single dermatologist during the study. The objective skin manifestations of AD patients were
checked for the point prevalence at the time of examination. The extent of skin lesions was estimated
based on the Nine's rule and the severity of AD was evaluated by the eczema area and severity index
(EASI) score and investigator's global assessment (IGA) measurement (a static 6-point measure of
disease severity based on an overall assessment of skin lesions: 0=clear, no inflammatory signs of AD;
1=almost clear, just perceptible erythema and just perceptible population/infiltration; 2=mild disease,
mild erythema and population/infiltration; 3=moderate disease, moderate erythema and moderate
population/infiltration; 4=severe disease, severe erythema and severe population/infiltration; and
5=very severe disease, severe erythema and severe population/infiltration with oozing/crusting)9. Their
parents were asked on the phone as to whether they regarded their children as AD patients or not. The
evaluation and improvement of indoor air quality in kindergartens were attempted in collaboration with
the Guro-gu public health center.
The first survey was conducted in order to collect data on the prevalence, severity and hospital visits of
AD among children in kindergartens of Guro-gu, Seoul, between March and April of 2009. The second
survey was conducted between November and December of 2009 in order to assess changes after the
completion of the program for improving indoor air quality. The mean number of hospital visits per
month in AD patients was calculated for each survey.

Statistical analysis
The paired t test was applied in order to compare the EASI score, decrease in the number of hospital
visits and PM10/CO2 level between the first and second surveys. A p-value of <0.05 was considered as
being statistically significant.
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RESULTS
Program for improving indoor air quality
Table 1 presents the baseline value of indoor air quality. The baseline value of PM10 is usually under
150 g/m3, particularly under 100 g/m3 in medical institutes and child, elderly and postpartum care
centers; hence, the authors considered that an optimal value of PM10 in kindergartens should be under
100 g/m3.
Table 1
Baseline values of indoor air in nine kindergartens
Table 2 conveys the changes in PM10 and CO2 levels during the first and second surveys. CO and
HCHO were not detected in any kindergarten. In the first survey, all of the 9 kindergartens showed a
higher PM10 level than the baseline value, and 3 kindergartens showed a higher CO2 level than the
baseline value. In the second survey after the program, the PM10 level dropped under the baseline value
in 7 of the 9 kindergartens. Three kindergartens still showed a higher CO2 level. Five kindergartens
satisfied the environmental standards for both PM10 and CO2 levels. The mean PM10 level decreased
from 182.723.68 to 73.422.05 g/m3 with statistical significance, while the mean CO2 level did not
change significantly (from 934384.4 to 1,040540.4 ppm). The detection sites included 2 classrooms,
4 study rooms and 3 corridors. All sites showed improvement in the PM10 level after the program; yet,
in 3 study rooms, the CO2 level increased.
Table 2
Measurement results of indoor air in nine kindergartens

Prevalence of AD
During the first survey, 123 children (28.9%, 63 boys and 60 girls) were reported as AD patients by
their parents via telephone interviews. However, 34 (8%, 20 boys and 14 girls) of the 425 children were
diagnosed with AD by medical examination. The parents of 8 children (23.5%; 5 boys and 3 girls) of
the 34 AD patients reported that their children had no AD. The prevalence of AD in each kindergarten
varied from 3% to 15% (Table 3); however, there were no statistically significant differences between
the 9 kindergartens (p>0.05). However, between the first and second surveys, 15 children moved to
other kindergartens or dropped out before the second survey, leaving the study with 410 children.
During the second survey, 3 children were newly diagnosed with AD, and 6 of 34 AD patients in the
first survey moved to other kindergartens; thus, 31 (7.6%, 19 boys and 12 girls) of the total 410
children were classified as having AD.
Table 3
Prevalence of atopic dermatitis in 9 kindergartens during first survey
The mean EASI score decreased from 2.371.08 in the first survey to 1.191.25 in the second survey
(Fig. 1), and the difference was statistically significant (p<0.05).
Fig. 1

The comparison of atopic dermatitis improvement and the EASI score between the first and second
surveys at 9 different kindergartens (A to I). The mean EASI score decreased from 2.37 in the first
survey to 1.19 in the second survey (p<0.05). All ...
The IGA score showed much improvement after the completion of the program. The IGA scores in the
first survey were as follows: IGA 1 (almost clear) in 20 children, IGA 2 (mild) in 8 children and IGA 3
(moderate) in 6 children. In the second survey, the score was changed as follows: IGA 0 (clear) in 9
children, IGA 1 (almost clear) in 15 children, IGA 2 (mild) in 5 children and IGA 3 (moderate) in 2
children (Fig. 2).
Fig. 2
Atopic dermatitis patients were evaluated and grouped according to the IGA score as follows: 20
patients in IGA 1 (almost clear), 8 patients in IGA 2 (mild) and 6 patients in IGA 3 (moderate). After
performance of the program, 9 patients were in IGA 0 ...
The mean extent of the skin lesion decreased from 7.06% in the first survey to 4.22% in the second
survey with statistical significance (p<0.05) (Fig. 3).
Fig. 3
The mean extent of the skin lesion decreased from 7.06% in the first survey to 4.22% in the second
survey (p<0.05).
The mean number of hospital visits of 15 AD patients decreased from 1.3 per month in the first survey
to 0.7 per month in the second survey, and the difference was statistically significant (p<0.05). During
this period, none of the patients required additional hospital visits.
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DISCUSSION
The prevalence of allergic diseases including AD, asthma and allergic rhinitis has increased, keeping
pace with industrial development due to multifactorial causes. Environmental pollution has been
considered as an exacerbating factor of AD; however, only a few studies have supported this
assumption.
Interior decoration materials and building materials used in Western-style buildings for durability and
insulation are known to cause indoor air pollution. As most buildings in Korea are Western-style, the
detection of these materials is essential. In Korea, the indices for indoor air pollution include CO, CO2,
HCHO, nitrogen dioxide, ozone, fine dust (PM10), volatile organic compounds, radon, asbestos and
total bioaerosol10. In this study, CO, CO2, HCHO and PM10 were analyzed to assess indoor air quality
in 9 kindergartens. Although CO and HCHO were within the normal range in all kindergartens, the
CO2 level was higher than the normal value in 3 kindergartens, and the PM10 level was higher in 8
kindergartens. After the completion of the program for improving air quality, the PM10 level
dramatically decreased and the PM10 level above the baseline value was detected only in 2
kindergartens. However, the CO2 level demonstrated variable changes.
There have been only a few studies on the relationship between AD and indoor air pollution, although
many studies on the relationship between asthma and indoor air pollution have been found in the
literature. Moon et al.11 have demonstrated that the aldehyde level is not significantly different
between houses of AD patients and control subjects. Hagerhed-Engman et al.12 have indicated that

there is a close relationship between indoor molds and AD. However, their result is questionable
because the magnitude of molds was assessed using subjective odor, not an objective method. In our
study, the EASI score decreased from 2.37 to 1.19 and the IGA score was improved, suggesting that
indoor air quality improvement relieved symptoms of AD. After the completion of the program for
improving indoor air quality, the frequency of hospital visits was the same as before in 10 of the 34 AD
patients and lower than before in 15 AD patients. Nine AD patients did not take any medical services
before and after the program. The mean number of hospital visits decreased from 1.3 to 0.7 per month
in 15 AD patients with statistical significance. The mean value of EASI scores was low, which did not
suggest an improvement of AD. The decrease of hospital visits could reflect the improvement of AD
better rather than the EASI score.
PM means a mixture of solid particles and liquid droplets suspended in air. The definition of PM10 is
fine dust less than 10 m in diameter, which is not filtered by oral and nasal mucous membranes and
infiltrates deeply into the respiratory organs. PM10 hinders lung function by sticking to the bronchus
and pulmonary alveoli13. PM10 includes harmful materials, such as sulphate, nitrate, acid and all sorts
of heavy metal. It shows a very slow sedimentation rate; thus, it stays for a relatively long time in the
air. Numerous studies on the toxic properties of PM in the human body have been carried out in the air
pollution field14. Some previous studies have shown that PM in air pollution influences the
aggravation of asthma attacks and chronic respiratory diseases15,16. It has been reported that PM
increases tumor necrosis factor- and interleulin (IL)-1 in pulmonary alveoli mRNA of IL-1, IL-1,
IL-8 and granulocyte macrophage colony stimulating factor17,18. Increased amounts of
proinflammatory cytokines contribute to the deterioration of chronic respiratory diseases as well as
several skin diseases such as AD.
Due to the fact that fine dust between 10 to 30m carries dust mites19, it can exacerbate the symptoms
of AD. It has been documented that a high prevalence of AD is related to the environment with
abundant fine dust20,21. In our study, symptoms of AD were improved by reducing the amount of
PM10.
CO2 is a colorless and odorless gas. It is harmless in low density. High-density CO2 in limited
restricted indoor space indicates insufficient ventilation due to congested indoor harmful substances,
namely, of the decreasing air quality. It is used as a representative index of indoor air quality22.
Modern-style, highly sealed buildings without supplementary equipment for ventilation cannot provide
fresh air; hence, the environmental quality of such living spaces is low, especially in long-term
dwellings. CO2 concentrations between 1,000 to 2,000 ppm can cause headache, hypertension,
vomiting and fatigue in healthy adults and more severe symptoms in the elderly people and children. In
our study, the indoor CO2 level was higher than the baseline value. Subsequent to the completion of the
program for improving air quality, the results varied from kindergarten to kindergarten. This may be
due to different detection sites, such as classrooms, corridors and study rooms. Most study rooms
indicated a higher CO2 concentration than the baseline value due to a relatively large number of
students in narrow space. Further, the program contents did not include ventilation by opening the
windows and entrance doors in order to decrease the CO2 concentration. The program for improving
indoor air quality were conducted in 3 different methods; (1) removal of fine dust, spider web and mold
spores in the wall and ceiling; (2) sterilization of desks, chairs and other teaching materials through
steam heating after the removal of dust; and (3) reduction of fine dust, molds and dust mites through
elimination of dust mites and floating matter as well as by steam cleaning the bedding. The program
was designed to decrease amounts of fine dust and CO2. After conducting the program, the PM10 level

decreased in all 9 kindergartens, while the CO2 level showed variable results. This result may be
attributed to different detection time, for example, school hours or between-classesbreaks, or before or
after ventilation.
The prevalence of AD in 9 kindergartens located in Guro-gu, Seoul was 8%. The mean EASI score was
2.37 and the mean body surface area was 7.06%. After the completion of the program, the prevalence
dropped to 7.6%, the mean EASI score decreased to 1.19, and the mean body surface area decreased to
4.22%. The IGA score also improved. The mean number of hospital visits also decreased from 1.3 to
0.7 per month in 15 patients. In conclusion, the results of this study suggest that the program for
improving indoor air quality could improve the clinical symptoms and signs of AD as well as decrease
the PM10 level. Further studies on the relationship between AD and PM10 level are needed in order to
confirm our results.
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ACKNOWLEDGMENT
This research was supported by the Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 20110013003 and No. 2011-0004436) and by a grant from Amore Pacific Co. Ltd, 2011.
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Air Quality and Climate, 7th International Conference; 1996 Jul 21-26; Nagoya, Japan. 1996.

Abstract
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
ACKNOWLEDGMENT
References

Articles from Annals of Dermatology are provided here courtesy of Korean Dermatological
Association and Korean Society for Investigative Dermatology

Epidemiology:
January 2011 - Volume 22 - Issue 1 - p S222
doi: 10.1097/01.ede.0000392368.39860.df
Abstracts: ISEE 22nd Annual Conference, Seoul, Korea, 28 August-1 September 2010: Air Pollution Exposure Characterization and Health Effects

Correlation Between Environmental Factors and Atopic

Dermatitis
Hyun Lee, Jung1,2; Joo Bae, Mun2; Il Lee, Sang1,2; Mo Ahn, Kang1,2; Kwan
Cheong, Hae3; Boong Kim, Kyo4; Woon Lee, Sang2; Min Suh, Jung1; Hye
Kim, Eun3; Sin Lee, Kwang2

Free Access

Article Outline

Author Information
1Department

of Pediatrics, Samsung Medical Center, Seoul, Republic of Korea; 2Environmental

Research Center, Samsung Medical Center, Seoul, Republic of Korea; 3Department of Social and
Preventive Medicine, Sungkyunkwan University School of Medicine, Suwon, Republic of Korea; and
4Research Institute of Public Health and Environment, Seoul, Republic of Korea.
Abstracts published in Epidemiology have been reviewed by the societies at whose meetings the
abstracts have been accepted for presentation. These abstracts have not undergone review by the
Editorial Board of Epidemiology.
PP-31-011
Back to Top | Article Outline
Background/Aims:

It is well documented that the environmental factors, such as air pollutions, volatile organic compounds
(VOCs), and suspended bacteria and molds, are important for the development of atopic disease and for
triggering atopic symptoms. But there are not enough universal results, which verify the relations. The

low allergen room is aimed to minimize the environmental factors that could aggravate the atopic
dermatitis. It is designed to remove inhalant allergens, dust, and micro-organisms, which could cause
allergic symptoms, and minimize exposure to indoor air pollutants such as VOCs and formaldehyde.
The purpose of this study was to verify if improvement in indoor environment can relieve the clinical
manifestations of atopic dermatitis and to find the relationship between indoor environment and
severity of atopic dermatitis.
Back to Top | Article Outline
Methods:

A total of 35 children (mean age, 24.3 months) with severe atopic dermatitis (Severity Scoring of
Atopic Dermatitis [SCORAD] > 15) and 21 children from a day-care center without atopic dermatitis
(mean age, 37.4 months) were recruited. Patients with severe atopic dermatitis were admitted in the low
allergen room for 34 days (mean, 3.32 days) to see whether clinical symptoms were improved by
temporary changing the patient's residential environment while maintaining the regular medical
treatment. Severity was assessed using the SCORAD. We compared residential environment in their
homes with environment of the low allergen room by measuring indoor air pollutants. Dust,
formaldehyde, VOCs (benzene, toluene, ethyl-benzene, xylene, and styrene), carbon monoxide, carbon
dioxide, nitrogen dioxide, ozone, suspended fungi, and bacteria were analyzed.
Back to Top | Article Outline
Results:

SCORAD score was reduced from 44.3 10.9 to 33.2 8.5 by hospitalization in low allergen room.
Wilcoxon Signed-Rank test showed significant improvements of symptom scores in patients with
atopic dermatitis (P < 0.001) and suspended fungi (P = 0.010) was significantly high in residential
environment compared to the low allergen room.
Back to Top | Article Outline
Conclusion:

The change in residential environment is likely to improve clinical symptoms of atopic dermatitis. It is
presumed that particulate matter, formaldehyde, suspended bacteria, and suspended fungi could
aggravate atopic dermatitis, but it is too early to conclude that particulate matter, formaldehyde,
suspended bacteria, and suspended fungi act as aggravating factors in atopic dermatitis. Further studies
are needed for clarifying the relationship between indoor environment and the severity of atopic
dermatitis.
2011 Lippincott Williams & Wilkins, Inc.
Clin Exp Immunol. Apr 2010; 160(1): 19.
doi: 10.1111/j.1365-2249.2010.04139.x
PMCID: PMC2841828

The hygiene hypothesis for autoimmune and

allergic diseases: an update
H Okada, C Kuhn, H Feillet, and J-F Bach
INSERM U1013, Necker-Enfants Malades Hospital, Paris, France
J.-F. Bach, INSERM U1013, Hpital Necker-Enfants Malades, 161 rue de Svres 75015 Paris, France.
E-mail: rf.secneics-eimedaca@hcab.siocnarf-naej
Author information Article notes Copyright and License information
Accepted January 21, 2010.
Copyright Journal Compilation 2010 British Society for Immunology
This article has been cited by other articles in PMC.
Go to:

Abstract
According to the hygiene hypothesis, the decreasing incidence of infections in western countries and
more recently in developing countries is at the origin of the increasing incidence of both autoimmune
and allergic diseases. The hygiene hypothesis is based upon epidemiological data, particularly
migration studies, showing that subjects migrating from a low-incidence to a high-incidence country
acquire the immune disorders with a high incidence at the first generation. However, these data and
others showing a correlation between high disease incidence and high socio-economic level do not
prove a causal link between infections and immune disorders. Proof of principle of the hygiene
hypothesis is brought by animal models and to a lesser degree by intervention trials in humans.
Underlying mechanisms are multiple and complex. They include decreased consumption of
homeostatic factors and immunoregulation, involving various regulatory T cell subsets and Toll-like
receptor stimulation. These mechanisms could originate, to some extent, from changes in microbiota
caused by changes in lifestyle, particularly in inflammatory bowel diseases. Taken together, these data
open new therapeutic perspectives in the prevention of autoimmune and allergic diseases.
Keywords: allergy, autoimmunity, regulatory T cells
Go to:

Introduction
Changes of lifestyle in industrialized countries have led to a decrease of the infectious burden and are
associated with the rise of allergic and autoimmune diseases, according to the hygiene hypothesis.
The hypothesis was first proposed by Strachan, who observed an inverse correlation between hay fever
and the number of older siblings when following more than 17 000 British children born in 1958 [1].
The original contribution of our group to the field was to propose for the first time that it was possible
to extend the hypothesis from the field of allergy, where it was formulated, to that of autoimmune
diseases such as type 1 diabetes (T1D) or multiple sclerosis (MS) [2]. The leading idea is that some
infectious agents notably those that co-evolved with us are able to protect against a large spectrum
of immune-related disorders. This review summarizes in a critical fashion recent epidemiological and
immunological data as well as clinical studies that corroborate the hygiene hypothesis.
The strongest evidence for a causal relationship between the decline of infections and the increase in
immunological disorders originates from animal models and a number of promising clinical studies,
suggesting the beneficial effect of infectious agents or their composites on immunological diseases.

In this review, we shall attempt to evaluate the arguments in favour of the hygiene hypothesis with
particular interest on the underlying mechanisms.
Go to:

Evolving epidemiology of allergic and autoimmune diseases

The rising incidence of atopic and autoimmune diseases
In 1998, about one in five children in industrialized countries suffered from allergic diseases such as
asthma, allergic rhinitis or atopic dermatitis [3]. This proportion has tended to increase over the last 10
years, asthma becoming an epidemic phenomenon [4]. The increasing prevalence of asthma is
important in developed countries (more than 15% in United Kingdom, New Zealand and Australia) but
also in developing countries, as illustrated by a prevalence greater than 10% in Peru, Costa Rica and
Brazil. In Africa, South Africa is the country with the highest incidence of asthma (8%) [5].
Unfortunately, data from most other African countries are unavailable [6]. The prevalence of atopic
dermatitis has doubled or tripled in industrialized countries during the past three decades, affecting 15
30% of children and 210% of adults [7]. In parallel, there is also an increase in the prevalence of
autoimmune diseases such as T1D, which now occurs earlier in life than in the past, becoming a serious
public health problem in some European countries, especially Finland, where an increasing number of
cases in children of 04 years of age has been reported [8]. The incidence of inflammatory bowel
diseases (IBD), such as Crohn's disease or ulcerative colitis [2] and primary biliary cirrhosis [9] is also
rising. Part of the increased incidence of these diseases may be attributed to better diagnosis or
improved access to medical facilities in economically developed countries. However, this cannot
explain the marked increase in immunological disorder prevalence that has occurred over such a short
period of time in those countries, particularly for diseases which can be diagnosed easily, such as T1D
or MS [1012].

The decreasing incidence of infectious diseases

Public health measures were taken after the industrial revolution by western countries to limit the
spread of infections. These measures comprised decontamination of the water supply, pasteurization
and sterilization of milk and other food products, respect of the cold chain procedure, vaccination
against common childhood infections and the wide use of antibiotics. The decline is particularly clear
for hepatitis A (HAV), childhood diarrhoea and perhaps even more spectacular for parasitic diseases
such as filariasis, onchocercosis, schistosomiasis or other soil-transmitted helminthiasis [13]. In
countries where good health standards do not exist, people are chronically infected by those various
pathogens. In those countries, the prevalence of allergic diseases remains low. Interestingly, several
countries that have eradicated those common infections see the emergence of allergic and autoimmune
diseases.

Uneven distribution
The geographical distribution of allergic and autoimmune diseases is a mirror image of the
geographical distribution of various infectious diseases, including HAV, gastrointestinal infections and
parasitic infections. There is an overall NorthSouth gradient for immune disorders in North America
[14], Europe [2] and also in China [15] with intriguing exceptions such as asthma in South America or
T1D and MS in Sardinia. There is also a WestEast gradient in Europe: the incidence of T1D in
Bulgaria or Romania is lower compared to western Europe, but is increasing fast [16]. This gradient

cannot be fully explained by genetic differences. Indeed, the incidence of diabetes is sixfold higher in
Finland compared to the adjacent Karelian republic of Russia, although the genetic background is the
same [17].
Additionally, migration studies have shown that offspring of immigrants coming from a country with a
low incidence acquire the same incidence as the host country, as rapidly as the first generation for T1D
[18] and MS [19,20]. This is well illustrated by the increasing frequency of diabetes in families of
immigrants from Pakistan to the United Kingdom [21] or the increasing risk of MS in Asian
immigrants moving to the United States [22]. The prevalence of systemic lupus erythematosus (SLE) is
also much higher in African Americans compared to West Africans [23].
These data do not exclude the importance of genetic factors for those immunological disorders, as
assessed by the high concordance of asthma, T1D or IBD in monozygotic twins: for example, the
concordance rate for atopic dermatitis among monozygotic twins is high (77%) compared to dizygotic
twins (15%) [7]. The difference in some genetic factors according to ethnicity [human leucocyte
antigen (HLA) gene difference between Caucasian and Asian, for example] is well documented, but
probably plays a minor role in geographical distribution in view of migrant data.

Search for risk factors at the origin of the increase of immunological disorders
Several factors, such as socio-economic indices, may explain the difference in the prevalence of
immunological disorders according to time and geographical distribution. In fact, there is a positive
correlation between gross national product and incidence of asthma, T1D and MS in Europe [2]. This is
true at the country level, but also at that of smaller regions, such as Northern Ireland, where the low
incidence of T1D is correlated with low average socio-economic level, as evaluated by conventional
indices [24]. Similar results have been obtained in the province of Manitoba in Canada for Crohn's
disease [25]. This correlation has even been demonstrated at the individual level for atopic dermatitis,
as family income is correlated directly with the incidence of the disease [26]. However, this does not
pinpoint which factor within the socio-economic indices is directly responsible for the immunological
disorder. Several epidemiological studies have indicated a positive correlation between sanitary
conditions and T1D [24] or MS [27], suggesting a possible role of infections. Other factors are often
incriminated, such as air pollution for asthma [28], but their role has not been demonstrated
convincingly. For example, it has been shown that in East Germany before the fall of the Berlin Wall,
where the air pollution was greater, the incidence of asthma was lower than in West Germany [29].
Vitamin D production is linked to sun exposure, and has been shown recently to have
immunomodulatory effects [30]. However, this does not explain the WestEast gradient of T1D in
Europe, or the huge difference between Finland and its neighbouring Karelian region, where people
have the same sun exposure level [31].

Epidemiological data indicating a direct link between the decreasing level of

infectious burden and the rising incidence of immunological disorders
Several epidemiological studies have investigated the protective effect of infectious agents in allergic
and autoimmune diseases. The presence of one or more older siblings protects against development of
hay fever and asthma [1], of MS [32] and also of T1D [33], as does attendance at day care during the
first 6 months of life in the case of atopic dermatitis and asthma [34].
Interestingly, exposure to farming and cowsheds early in life prevents atopic diseases, especially if the
mother is exposed during pregnancy [35,36]. It has also been shown that prolonged exposure to high
levels of endotoxin during the first year of life protects from asthma and atopy [37]. However, these

data have been contradicted by other studies showing an increased prevalence of asthma correlated
with higher levels of endotoxins in urban housing [38,39]. The level of endotoxins is higher in farms as
compared to cities, and subjects are in contact with a greater variety of microbial compounds in farms,
which could explain this discrepancy.
Do helminth parasites protect against atopy? Epidemiological data of cross-sectional studies revealed
that Schistosoma infections have a strong protective effect against atopy, as reviewed recently [40].
Hookworms such as Necator americanus also seem to protect from asthma. In contrast, Ascaris
lumbricoides and Trichuris trichiura have no significant effect on disease. Parasitic infections have
been almost eradicated in European countries since the Second World War, concomitant with the
increase of atopy and allergy. This trend can explain part of the epidemiological difference between
Europe and Africa, but cannot explain readily the intra-European NorthSouth gradient.
Go to:

Proof of principle of the causal relationship between decline of

infectious diseases and increase of immunological disorders
We have seen that there is a strong correlation between changes in lifestyle and modifications of the
incidence of allergic or autoimmune diseases, but this does not prove a causal relationship between
these two observations. This is a crucial question, as many factors unrelated to infections are a
consequence of lifestyle, such as food habits, quality of medical care or dinner time gradient from
North to South Europe. The answer to this question comes from animal models of autoimmune and
allergic diseases and, to a lesser degree, from clinical intervention studies.

Animal models
The incidence of spontaneous T1D is directly correlated with the sanitary conditions of the animal
facilities, for both the non-obese diabetic (NOD) mouse [2] and the bio-breeding diabetes-prone (BBDP) rat [41]: the lower the infectious burden, the higher the disease incidence. Diabetes has a very low
incidence and may even be absent in NOD mice bred in conventional facilities, whereas the incidence
is close to 100% in female mice bred in specific pathogen-free (SPF) conditions. Conversely, infection
of NOD mice with a wide variety of bacteria, virus and parasites protects completely (clean NOD
mice) from diabetes [2]. Similarly, mycobacteria (e.g. complete Freund's adjuvant) prevent induction of
experimental autoimmune encephalomyelitis [42] and ovalbumin-induced allergic asthma [43]. Data
obtained in our laboratory show that living pathogens are not required, as bacterial extracts are
sufficient to afford protection [44].

Increased atopy after anti-parasitic treatments

It has been shown that helminth eradication increases atopic skin sensitization in Venezuela [45], in
Gabon [46] and in Vietnam [40]. However, in a small study of 89 Venezuelan adults and children with
asthma there was a clinical improvement, and specific immunoglobulin E (IgE) levels decreased after
anti-helminthic treatment [47], while a similar deworming treatment showed no effect in Ecuador [48].
It is difficult to explain these contradictory data, which may relate to the complexity of asthma
pathophysiology. In the same vein, one might also mention the increased atopy observed after
vaccination with Streptococcus pneumoniae in South Africa [49].

Prevention of allergic and autoimmune diseases by infections

In a prospective study in Argentina, 12 patients with MS with high peripheral blood eosinophilia were
followed. These patients presented parasitic infections and showed a lower number of MS
exacerbations, increased interleukin (IL)-10 and transforming growth factor (TGF)- secretion by
peripheral blood mononuclear cells (PBMC) [50].
Similarly, deliberate administration of ova from the swine-derived parasite Trichuris suis, every 3
weeks for 6 months to 29 patients with active Crohn's disease, improved symptoms in 21 of 29 patients
(72%) with no adverse events [51]. T. suis ova were also given to patients with active ulcerative colitis,
with significant improvement (43% improvement versus 17% for placebo) [52].
Another helminth, Necator americanus, has also been used in Crohn's disease, patients being
inoculated subcutaneously with infective larvae. There was a slight improvement of symptoms, but the
disease reactivated when immunosuppressive drugs were reduced [53].

Probiotics
Probiotics are non-pathogenic microorganisms that are assumed to exert a positive influence on host
health and physiology [54]. Encouraging results were first shown in a double-blind randomized
placebo-controlled trial in Finland, where Lactobacillus GG taken daily by expectant mothers for 24
weeks before delivery and postnatally for 6 months could decrease significantly the incidence of atopic
dermatitis [55]. Perinatal protection lasted up to 7 years [56]. Another trial showed improvement of
atopic dermatitis using other strains of probiotics [57]. However, a German group using the same
protocol did not find any protective effect after 2 years [58]. Additionally, a recent study of 445
pregnant women in Finland who were treated with the same protocol as the initial Finnish study, but
with freeze-dried Lactobacillus GG, failed to show any significant effect on eczema, allergic rhinitis or
asthma 5 years after treatment. The only difference observed was a decreased IgE-associated allergic
disease in caesarean-delivered children [59].
In T1D, only experimental data are available. The protective effect of a probiotic [60] and a bacterial
extract [44] was reported on the onset of diabetes in NOD mice. A pilot study in humans, the PRODIA
study (probiotics for the prevention of beta cell autoimmunity in children at genetic risk of type 1
diabetes), was begun in 2003 in Finland in children carrying genes associated with disease
predisposition [61].
The case of probiotics in IBD is more complex because of the possible local anti-inflammatory effect,
which could explain the relief of symptoms without changes in disease progression, as implicated in the
hygiene hypothesis. Following a number of uncontrolled studies in a small cohort of 14 paediatric
patients with newly diagnosed ulcerative colitis, probiotic treatment induced a significant rate of
remission compared to the control group (93% versus 36%) and a lower relapse rate [62].
In brief, there are data suggesting that probiotics may have a favourable role in immune disorders, but
the case is far from proven and requires further investigation. Additionally, although side effects are
very low they might not be non-existent, as shown in a set of patients with acute pancreatitis [63].
Thus, probiotics should not be considered as totally harmless, particularly in the immunodeficient host,
and more safety studies are needed. As mentioned by Sharp et al., probiotics may have unpredictable
behaviour like all microorganisms, such as unanticipated gene expression in non-native host
environment, or acquired mutations occurring spontaneously via bacterial DNA-transfer mechanisms.

Is there a role for microbiota changes in the hygiene hypothesis?

The human gut is the natural niche for more than 1014 bacteria of more than 1000 different species
[64]. Immediately after birth, the human gut is colonized with different strains of bacteria. This
commensal microbiota is important in shaping the immune system, for other basic physiological
functions [65] as well as for the integrity of the intestinal barrier [66]. Interestingly, the intestinal flora
was different in a small group of allergic Estonian and Swedish children compared to the control group,
with a higher count of aerobic bacteria such as coliforms and Staphylocccus aureus and a decreased
proportion of Lactobacilli, or anaerobes such as Bifidobacterium or Bacteroides[67,68]. However, this
difference was not seen in a larger birth cohort study comparing three European baby populations [69].
Additionally, this study showed a slower acquisition of typical faecal bacteria such as Escherichia coli,
especially in children delivered by caesarian section or children without siblings. It should be noted that
all these studies were based on the analysis of culturable bacteria, and only atopic dermatitis and skin
prick test were evaluated.
In autoimmune diseases the microbiota also seems to modulate the immune response. In NOD mice
deficient for the myeloid differentiation primary response gene 88 (MyD88) signalling molecule it has
been shown that microbiota protect mice from diabetes via a MyD88-independent pathway [70]. Using
the metagenomic approach, it has been demonstrated that the biodiversity of the faecal microbiota of
patients with Crohn's disease is diminished, especially for the Firmicutes phylum [71,72].
Faecalibacterium prautsnitzii is one of the Firmicutes that was particularly depleted, and it has been
shown that this deficient commensal bacterium could improve IBD in a murine model of the disease
[73]. This protective effect was also obtained with the supernatant of F. prautsnitzii culture,
demonstrating the importance of one of the secreted molecules for its anti-inflammatory effect. Another
bacterium, Bacteroides fragilis, has also been shown to protect animals from experimental colitis, and
this protective effect was linked to a single microbial molecule, polysaccharide A [74]. As mentioned
above, with regard to IBD these data must be interpreted with caution before extrapolating to other
autoimmune disorders where the disease site is extra-intestinal. First, the respective anti-inflammatory
and immunomodulatory effects of protective bacteria remain to be determined. Secondly, this
protective effect should be discussed in the context of disease-promoting bacteria such as Helicobacter
hepaticus.
In brief, there is an increasing amount of data showing that microbiota changes could contribute to the
modulation of immune disorders but evidence is still slim, except in IBD. It is to be hoped that studies
which provide a fair description of the molecular changes following intestinal infections will help in
analysing the question further. The recent report by Fumagalli et al. is a good illustration of this new
approach [75].
Go to:

Mechanisms of the hygiene hypothesis

When considering the multitude of infectious agents that can induce protection from various
immunological disorders, it is not surprising that more than one single mechanism has been found.

T helper type 1 (Th1)Th2 deviation

Th1Th2 deviation was the first major candidate mechanism for explaining the protective influence of
infectious agents from immunological disorders. Th1 T cells produce inflammatory cytokines such as
IL-2, interferon (IFN)- and tumour necrosis factor (TNF)- that are operational in cell-mediated

immunity (including autoimmune diabetes). In contrast, Th2 T cells that produce IL-4, IL-5, IL-6 and
IL-13 contribute to IgE production and allergic responses. Given the reciprocal down-regulation of Th1
and Th2 cells, some authors suggested initially that in developed countries the lack of microbial burden
in early childhood, which normally favours a strong Th1-biased immunity, redirects the immune
response towards a Th2 phenotype and therefore predisposes the host to allergic disorders. The problem
with such an explanation is that autoimmune diseases, which in most cases are Th1 cell-mediated, are
protected by infections leading to a Th1 response and that atopy may be protected, as seen above, by
parasites which induce a Th2 response. These observations fit with the concept of a common
mechanism underlying infection-mediated protection against allergy and autoimmunity. Several
hypotheses may explain these common mechanisms.

Antigenic competition /homeostasis

It has been known for several decades that two immune responses elicited by distinct antigens
occurring simultaneously tend to inhibit each other. Numerous mechanisms were evoked to explain
antigenic competition that might be pertinent to the hygiene hypothesis. The development of strong
immune responses against antigens from infectious agents could inhibit responses to weak antigens
such as autoantigens and allergens. Among the mechanisms that explain antigenic competition,
attention has been drawn recently to lymphocyte competition for cytokines, recognition for major
histocompatibility complex (MHC)/self-peptide complexes and growth factors necessary to the
differentiation and proliferation of B and T cells during immune responses within the frame of
lymphocyte homeostasis. Similarly to red blood cell mass, which is restored to normal levels after a
haemorrhage with the help of erythropoietin, CD4 and CD8 T lymphocytes are restored to normal
levels after a lymphopenia. Homeostatic factors that play an equivalent role to that of erythropoietin
have not been elucidated completely; however, cytokines such as IL-2, IL-7, and IL-15 are known to
play a crucial role. Regulatory T cells that we discuss below may also be implicated in the mechanism
of antigenic competition.

Immunoregulation
Another mechanism involves regulatory T cells which can suppress immune responses distinct from
reponses against the antigen in question, here antigens expressed by infectious agents (a phenomenon
called bystander suppression). The problem is complicated by the multiplicity of regulatory
lymphocytes involving diverse cytokines that mediate their differentiation or their regulatory effects.
The role of CD4+CD25+forkhead box P3 (FoxP3+) T cells has been suggested by transfer experiments
performed in a murine parasite model [76]. The role of such cells is also suggested by the observation
that CD28/ NOD mice devoid of CD4+CD25+ FoxP3+ regulatory T cells (Tregs) lose their sensitivity
to the protective effect of bacterial extract (our unpublished data). It has also been reported that in cord
blood from newborns of mothers exposed to farming, CD25+FoxP3 cells were up-regulated [77]. This
observation should be interpreted with caution because of the uncertain specificity of these markers in
man.
Other data suggest a role for IL-10-producing B cells [78], natural killer (NK) T cells [79] and more
generally cytokines such as IL-10 [80] and TGF-[81] whatever the cell type producing these
cytokines. More work is needed in experimental models to delineate further the involvement of
regulatory mechanisms in the protective effects of the various infections relevant to the hygiene
hypothesis. It might emerge that different mechanisms are operational according to the protective
infection.

Non-antigenic ligands
All the mechanisms mentioned previously are based on the notion that the hygiene effect is due to the
decrease of immunological responses elicited against infectious agents. A number of experiments
indicate that infectious agents can promote protection from allergic diseases through mechanisms
independent of their constitutive antigens, leading to stimulation of non-antigen specific receptors. This
concept is well illustrated by the example of Toll-like receptors (TLRs). Knowing the capacity of TLRs
to stimulate cytokine production and immune responses, it might be predicted that TLR stimulation by
infectious ligands should trigger or exacerbate allergic and autoimmune responses. This has indeed
been demonstrated in some experimental models [82,83].
Surprisingly, and paradoxically, it has also been observed that TLR stimulation could prevent the onset
of spontaneous autoimmune diseases such as T1D in NOD mice, an observation made for TLR-2, -3,
-4, -7 and -9 [84] (and our unpublished data). In this model, treatment with TLR agonists before disease
onset prevents disease progression completely. The mechanisms underlying such protections are still ill
defined, but could involve production of immunoregulatory cytokines and the induction of regulatory T
cells or NK T cells. Similar data have been observed in an ovalbumin-induced model of asthma [85].
Concerning HAV, it was shown initially that atopic diseases were less common in subjects that have
been exposed to the virus [86]. It was difficult to say whether this association was due to a direct
protective effect of HAV infection or explained only by the fact that HAV exposure is a matter of poor
hygiene. Data obtained by Umetsu et al. have shown that HAV could influence T cells directly, notably
Th2 cells that express the HAV receptor [87], a finding corroborated by the observation that atopy
prevalence is associated with HAV receptor gene polymorphisms in anti-HAV antibody-positive
subjects. In fact, recent data indicate that the HAV receptor, the TIM-1 protein (T cell, immunoglobulin
domain and mucin domain), could play an important role in the severity of HAV and its putative effect
on atopic diseases.

Geneenvironment interactions
An interesting approach to identify mechanisms underlying allergic and autoimmune diseases consists
in searching for associations between these diseases and polymorphisms of various genes, notably
those coding for molecules involved in immune responses. It is interesting to note that such an
association has been found for genes implicated in the control of infection. Among them,
polymorphism in genes of the innate immune response such as CD14, TLR2, TLR4, TLR6 or TLR10,
and intracellular receptors such as NOD1 and NOD 2 [also known as caspase-recruitment domain
(CARD)4 and CARD15, respectively], appears to be important [88,89]. Mouse studies have shown that
these geneenvironment interactions explain a proportion of the phenotypic variance. One of those
genes is CD14, which is important in lipopolysaccharide (LPS)/TLR-4 signalling. Many association
studies have highlighted the role of the CD14159CT polymorphism and allergic inflammation [90].
Go to:

Therapeutic strategies
The notions presented above open new, interesting, therapeutic perspectives for the prevention of
allergic and autoimmune diseases. Of course, contaminating children or adults at high risk of
developing these diseases by infectious agents cannot be envisioned, at a time when medical progress
has allowed the reduction of major infectious diseases. It should be mentioned, however, that even if
we do not believe that this is not the best strategy for the future, some groups have used living parasites
such as T. suis in the prevention of IBD, as mentioned above, or living Lactobacilli in the prevention of

atopic dermatitis. These approaches present the obvious limitation of insufficient standardization, and
hazards linked to unpredictable disease course in subjects presenting an unknown immunodeficiency
by contamination with xenogeneic virus in the case of swine-derived parasites.
Conversely, the use of bacterial extracts, already shown to be efficacious in a number of experimental
models and in the clinic, such as OM-85 in T1D, should be envisioned seriously [44]. These extracts,
which represent the mixture of a wide spectrum of chemically ill-defined components, are also
submitted to the criticism of poor standardization. On the other hand, they are a better representation of
the various components of bacteria known for their protective effects. The same comments apply to
parasitic extracts, shown to be effective in T1D [91]. In the long-term future, one would like to use
chemically defined components of protective infectious agents, such as TLR agonists, polysaccharide A
or the active substance secreted by F. prautsnitzii. In any event, the use of bacterial extracts or
chemically defined products will be confronted with the double problem of the timing of administration
(sufficiently early in the natural history of the disease), and of safety. Indeed, any side effects are
unacceptable in young subjects who are apparently healthy and whose risk of developing the disease in
question is not demonstrated absolutely.
Go to:

Disclosure
None of the authors has conflicts of interest to declare, or any relevant financial interest, in any
company or institution that might benefit from this publication.
Go to:

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Abstract
Introduction
Evolving epidemiology of allergic and autoimmune diseases
Proof of principle of the causal relationship between decline of infectious diseases and increase

of immunological disorders
Mechanisms of the hygiene hypothesis
Therapeutic strategies
Disclosure
References

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for
Immunology
Return to Article
The British Journal of Dermatology

Atopic Dermatitis and the 'Hygiene Hypothesis':

Too Clean to be True?
C. Flohr, D. Pascoe, H.C. Williams
Disclosures
The British Journal of Dermatology. 2005;152(2):206-216.

Comment

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Background: The so-called 'hygiene hypothesis' postulates an inverse relationship between atopic
dermatitis (AD) and an environment that leads to increased pathogen exposure.
Objectives: We sought to systematically identify, summarize and critically appraise: (i) the
epidemiological evidence to suggest that environmental exposures that lead to an increase in microbial
burden reduce the risk of AD; (ii) whether any specific infections have been shown to reduce AD risk;
(iii) whether there is a link between immunizations, use of antibiotics and AD risk; and (iv) to comment
on the new therapeutic approaches in AD that have evolved out of the 'hygiene hypothesis'.
Methods: We searched Medline from 1966 until August 2004 to identify relevant studies for inclusion.
Differences in study design and populations did not allow formal meta-analysis. Studies were therefore
described qualitatively.
Results: We identified 64 studies that were relevant to our review, 27 (42%) of which were of
prospective design. There was prospective evidence to support an inverse relationship between AD and
endotoxins, early day care and animal exposure. Two well-designed cohort studies have found a
positive association between infections in early life and AD, and measles vaccination and AD.
Antibiotic use was consistently associated with an increase in AD risk even into the antenatal period,
although a few studies did not reach conventional statistical significance. A few small randomized
controlled trials have suggested that probiotics can reduce AD severity and that probiotics may also be
able to prevent AD to some degree.
Conclusions: Although population-based studies have suggested a consistent inverse relationship
between AD and increasing family size, this does not seem to be explained by a straightforward
increased exposure to a single environmental pathogen. The effect seen with early day care, endotoxin
and animal exposure may be due to a nonpathogenic microbial stimulus of a chronic or recurrent
nature. This would also explain the risk increase associated with antibiotic use. Caution should prevail
in the prescribing of antibiotics early in life, especially in children with a family history of AD. Larger
well-designed pragmatic trials on probiotics and the prevention and treatment of AD are now needed to
inform whether such interventions should be used in routine clinical practice.
The past three decades have witnessed a marked rise in the prevalence of atopic dermatitis (AD) in
some countries.[1] Although family history has been demonstrated to play an important role in AD
susceptibility, genetics alone cannot explain the increase in AD prevalence.[2,3] Current
epidemiological research has therefore focused on identifying possible environmental factors that are
associated with increased AD risk. AD is more common in urban than in rural communities.[4,5] In
addition, migrant studies have demonstrated that immigrants take on the risk of the community to
which they move, with AD being more prevalent in western industrialized countries than in developing
nations.[6,7] The risk of developing AD is also higher in children growing up in smaller families and
families of higher socioeconomic status.[8-10] All this strongly suggests an environmental aetiology
linked with a 'western lifestyle'. In response to an increasing recognition of the role of the environment
in allergic disease, the so-called 'hygiene hypothesis' was formulated in the late 1980s based on the
observation that AD and other allergic diseases were noted to be less common in children growing up
with larger numbers of older siblings.[11]
At the time, it was speculated that this might be because of a higher exposure to certain viral and
bacterial pathogens. This theory has stimulated a large body of epidemiological and immunological
research. Some have suggested that allergic disease occurs when the developing immune system is
deprived of the obligatory stimulation through certain microbial antigens.[12] Immunologically, there
is evidence to suggest that this is partly due to an imbalance between type 1 and type 2 T helper (Th)
cells. However, the immunological processes ultimately leading to allergic disease are more complex
than this. The current hypothesis is that so-called regulatory T cells play a crucial role in the switch
between atopic and nonatopic phenotypes, possibly induced through nonpathogenic microbial

stimulation of dendritic cells at the level of the gastrointestinal mucosa or other lymphoid tissues (Fig.
1).[13-15]

(Enlarge Image)
The postulated link between allergic disease and the gutmicroflora. Chronic stimulation of gutassociated lymphoid tissuethrough normal gut flora and other non pathogenic microbialantigens might
ensure the development of a T-helper 1- regulatoryT cell-dominated cytokine milieu and therefore
prevent clinicalexpression of allergic disease. Regulatory T cells may have a role in this through the
production of anti-inflammatory cytokines such asinterleukin (IL)-10 and transforming growth factor
(TGF)-b. DC,Dendritic cell; TH, T helper cell; rTc, regulatory T cell. Source:C.Flohr.
Most of the research on allergic diseases and the 'hygiene hypothesis' has focused on asthma to date.
Much less is known about the links between AD, infections and endotoxin exposure.[16,17] It is
possible that the epidemiology of AD may be quite different from that of asthma.[18] To our
knowledge, this is the first systematic review of the epidemiological literature focusing exclusively on
AD and the 'hygiene
We conducted a systematic review of the epidemiological literature through searches of Medline from
1966 until August 2004 to address the following four questions: (i) Is there any evidence that the risk of
AD is related to environmental exposures that alter microbial burden? (ii) Which specific infections
have been associated with a reduced AD risk? (iii) Is there a link between immunizations, use of
antibiotics and AD risk? (iv) What are the new therapeutic approaches in AD that have evolved out of
the 'hygiene hypothesis'?
Search terms included the Cochrane Skin Group search strategy for AD,[19] combined with the
following Medline search terms: hygiene hypothesis, hygiene, day care, siblings, birth order, animals,
agriculture, farming, antibacterial agents, hepatitis A, hepatitis B, Helicobacter pylori , measles,
rubella, chickenpox, herpes simplex, tuberculosis, tuberculin response, vaccination, immunization,
Mycobacterium bovis , endotoxin, probiotics, intestinal microflora, Lactobacillus, Mycobacterium
vaccae, endoparasites, helminthiasis, helminths, Necator americanus, Trichuris, Ascaris lumbricoides ,
schistosomiasis, Enterobius . The online search was supplemented by an extensive hand search of the
literature through references identified from retrieved articles and by contact with various experts in the
field. We identified a total of 1178 papers, of which 64 studies were directly related to the topic of this
review. Only studies which specifically measured AD as an outcome were included. No other exclusion
criteria were used. Meta-analysis was not considered appropriate due to heterogeneity in study design,
types of participants and diagnostic criteria. Instead, we analysed studies qualitatively and present
individual study data in table form. Odds ratios (ORs) and 95% confidence intervals (CIs) as a measure
of the association between exposure and AD were calculated where these were not given in the original
publication.
Basic Hygiene day care attendance, anthroposophic lifestyle, living on a farm and pets have all been
examined as potential risk factors for allergic disease, including AD, as they at least theoretically
increase exposure to microbes (see Table 1 for a summary of the study results).
Basic Hygiene. Only one large birth cohort study, the Avon Longitudinal Study of Parents and
Children, has so far addressed the question of whether cleanliness in terms of general hygiene, such as
frequency of washing, is associated with an increase in AD risk. Children were seen at 6 and 3042
months of age, and a moderate increase in AD risk was found with higher levels of personal hygiene,

measured as an empirical hygiene score from 1 to 14 (baseline adjusted OR 104, 95% CI 101-107;
Table 2 ).[20]
Day Care. Two birth cohort studies, one from the U.S.A. and one from Denmark, have detected an
inverse relationship between day care attendance and AD. In the U.S. study, children who had attended
day care during the first year of life were at a 70% lower risk of AD at 6 years of age than those who
did not attend day care (adjusted OR 030, 95% CI 010-080; Table 2 ).[21] Risk reduction associated
with day care attendance at 6 months and AD before age 18 months was more moderate but still
significant in the larger Danish cohort (adjusted incidence rate ratio 082-95% CI 070-096).[22]
Whereas the U.S. study was entirely questionnaire based and therefore more vulnerable to recall bias, a
subgroup of participants in the Danish cohort underwent physical examination by a dermatologist to
validate questionnaire findings.
Anthroposophic Lifestyle. Current AD has been shown to be more than 70% less common among 513-year-old children growing up in anthroposophic communities in comparison with schoolchildren
from a nonanthroposophic background in a Swedish casecontrol study (OR 028, 95% CI 013-061;
Table 2 ).[23] [The anthroposophic movement ('anthroposophy': Greek for 'wisdom of man') was
founded by Rudolf Steiner in the early twentieth century. Anthroposophical philosophy has been
applied to many domains of life since then, including agriculture and medicine.] Results for AD were,
however, only presented in univariate analysis, and the real association is therefore most likely to be
weaker when potential confounders are taken into account. It is possible that part of the reduction in
AD risk seen in this study is due to the restricted prescribing of antibiotics and vaccinations by
anthroposophic doctors, potentially resulting in a higher exposure to microbes. In addition, dietary
factors may play an important role in AD risk reduction. Anthroposophic families frequently consume
fermented vegetables rich in Lactobacillus, and dietary supplementation with Lactobacillus GG has
previously been shown to change the gut microflora and to reduce AD risk.[24,25]
Farm Environment. As yet another extension of the 'hygiene hypothesis', it has been postulated that
children growing up on farms are at a reduced risk of developing allergic disease, possibly due to
consumption of unpasteurized farm milk rich in lactobacilli and frequent contact with farm animals.
However, studies from Austria,[26] Germany,[27] Switzerland,[28] Finland[29] and Denmark[21]
found no statistically significant association between living on a farm and AD. Only one very large
historical cohort study among Swedish conscripts found a small reduction in physician-diagnosed AD
associated with living on a farm in the subcohort born after 1971 (adjusted rate ratio 093, 95% CI
089-098; Table 2 ).[30]
Animals. Whereas three cross-sectional studies from Sweden[31,32] and Ethiopia[33] found no
statistically significant association between exposure to domestic animals and AD risk at age 7-11
years, four cohort studies from Norway,[34] Germany,[35] the U.S.A.[36] and Denmark[22] have
indicated that an early life exposure to a pet, especially a dog, in the house can protect against AD at
least until 4 years of age, with ORs ranging from 040 to 087 ( Table 2 ). In the U.S. birth cohort, this
effect was also significantly associated with a reduction in specific IgE to environmental allergens and
increased interleukin (IL)-10 levels.
Endotoxins. Endotoxins, a group of lipopolysaccharides found on the cell surface of Gram-negative
bacteria, have been postulated as an explanation of why pets and a farm environment may be protective
against allergic disease, not least because endotoxins are known to be inducers of IL-10 and interferon.[37,38] Two birth cohort studies (one from Germany and one from the U.S.A.) have so far
exclusively studied endotoxin exposure and AD risk. Both showed an inverse relationship between
endotoxin and AD at high levels of exposure at 1 year of age (adjusted OR 050, 95% CI 028-088 and
adjusted OR 076, 95% CI 061-096, respectively).[39,40] In the German cohort, the protective effect
seen at age 1 year had disappeared by age 2 years ( Table 2 ).[41]

More direct evidence for and against the 'hygiene hypothesis' in AD comes from studies that have
examined the relationship between specific infections and AD (see Table 1 for a summary of the study
results).
A large British historical cohort study, using a general practitioner research database, examined the
effect of prenatal infections on AD. This study found a significant, albeit small increase in AD risk
associated with two or more antenatal infections (adjusted hazard ratio 116, 95% CI 107-126; Table 3
).[42]
More work has been done on common viral and bacterial childhood infections, such as chickenpox,
mumps, whooping cough, measles, diarrhoeal disease and pneumonia. All nine studies have indicated a
positive association between past childhood infections and AD, although results in some studies did not
reach conventional statistical significance. Two carefully conducted recent birth cohort studies from the
U.K.[43] and Denmark[22] confirmed the findings from cross-sectional work,[44-50] indicating an
30% higher risk of developing AD in those who had been frequently exposed to infections. However,
analysis of individual infections yielded ORs close to 1, with a nonsignificant trend towards an increase
in risk. It may therefore not be a specific pathogen but pathogenic microbial burden per se that has an
impact on AD development. There was also a significant sibling effect where examined, in that higher
numbers of older siblings reduced AD risk, and this effect remained after adjustment for infections,
suggesting that the sibling effect was early and independent of infections ( Table 3 ).[22,42]
Although extremely common across the world, hepatitis, herpes simplex virus and H. pylori infection
have received little attention from the allergy community. A large cross-sectional questionnaire survey
among first-year university students in Spain and Germany found no association with AD.[51]
However, a recent cross-sectional questionnaire study among adults who were participating in a U.K.
community-based H. pylori eradication trial indicated a 30% reduction in AD risk among infected
participants (adjusted OR 070, 95% CI 054-091). In the latter study, AD diagnosis was made purely
on the basis of whether participants were using topical corticosteroids or not ( Table 3 ).[52]
Chronic gut worm infections are strong inducers of a Th2-dominated host cytokine profile. Total serum
IgE levels in the host are often high, similar to AD and other allergic disease. One would therefore
expect a synergistic effect of parasite infection on allergic disease.[17] However, cross-sectional studies
indicate that certain endoparasites, such as hookworm, Ascaris lumbricoides and Schistosoma
haematobium can be protective against asthma and atopy.[53] In this context, AD has received little
attention. At present, there are only two cross-sectional studies that have investigated the link between
AD and endoparasites, one in Taiwanese schoolchildren with pinworm infection (Enterobius
vermicularis) and one in Ecuadorian children infested with soil-transmitted helminths. Both studies
found no significant associations ( Table 3 ).[54,55]
The decline in tuberculosis infection in Western industrialized countries over past decades has been
claimed to be one of the driving forces behind the recent epidemic of allergic disease. However, the
only study to date, an international ecological survey among 13-14-year-old schoolchildren, found no
association between AD and tuberculosis.[56] As for tuberculin responses, no inverse relationship
between AD and tuberculin responsiveness has been reported in three studies (one casecontrol, one
cross-sectional, one birth cohort)[57-59] following an initial cross-sectional report in Japanese children
who were all immunized with bacille CalmetteGurin (BCG). The latter indicated a 50% reduction in
AD risk at age 12-13 years in those with strong tuberculin responses (adjusted OR 050, 95% CI 033091).[44] In addition, the four studies (one ecological, two cross-sectional, one birth cohort) that have
investigated whether immunization with BCG can protect against AD found a reduction in AD risk but
results did not reach statistical significance ( Table 3 ).[33,60-62]
Two other factors that may profoundly affect the child's immune system in early life are childhood

vaccination programs and prescribing of antibiotics. Vaccinations expose infants and children to
antigens of infectious agents that may lead to Th2-dominated immune responses, as has been shown in
animal and clinical studies, and there is therefore concern that these might lead to an increase in
allergic disease.[63,64] Vaccines also contain adjuvants and stabilizers, which could conceivably
enhance allergenicity.[65] Antibiotics may lead to a reduction in microbial burden, but are also known
to alter the gut microflora and thus have an effect on the child's immune system at the level of the gut
mucosa (see Table 1 for a summary of the study results).[66]
cross-sectional study based on a U.K. general practice database indicated a slight increase in AD risk at
12 years of age in those who had received the combined diphtheria, pertussis and tetanus vaccine (OR
137, 95% CI 112-201).[49] Only univariate analysis results were presented and no significant
associations with other vaccines were found. A recent Danish population-based cross-sectional study,
assessing the risk of the measles, mumps and rubella vaccine, demonstrated an almost twofold increase
in AD risk in 3-15-year-old children (adjusted OR 186, 95% CI 125-279; Table 4 ).[46] However,
four other studies [one ecological, one cross-sectional, one birth cohort and one randomized controlled
trial (RCT)] found no significant association between childhood immunizations and AD.[33,61,67,68]
Frequent use of antibiotics has been identified as a risk factor for AD related to the 'hygiene
hypothesis', with six studies showing a consistent positive association, although two of these results
failed to reach conventional statistical significance (Fig. 2).[43,44,49,69-71] Where examined, a
doseresponse relationship was seen ( Table 4 ). The effect of antibiotics seems to extend into the
antenatal period.[42] A recent ecological study could not find an association between antibiotic sales
and AD risk at the population level.[72]

(Enlarge Image)
The postulated link between allergic disease and the gutmicroflora. Chronic stimulation of gutassociated lymphoid tissuethrough normal gut flora and other non pathogenic microbialantigens might
ensure the development of a T-helper 1- regulatoryT cell-dominated cytokine milieu and therefore
prevent clinicalexpression of allergic disease. Regulatory T cells may have a role in this through the
production of anti-inflammatory cytokines such asinterleukin (IL)-10 and transforming growth factor
(TGF)-b. DC,Dendritic cell; TH, T helper cell; rTc, regulatory T cell. Source:C.Flohr.
Forest plot of studies on antibiotics and risk of atopic dermatitis. CI, Confidence interval.
Lactobacillus GG supplementation has been reported to reduce both the risk of AD and AD severity.
Three RCTs, two from the same Finnish group and one from Denmark, conducted in infants with preexisting AD, showed a statistically significant reduction in SCORAD. In one study this effect was
confined to children who were also skin prick test and RAST positive to at least one environmental
allergen ( Table 5 ).[76-78] Lactobacillus GG supplementation also seems to work prophylactically.
The same RCT has been reported twice, at 2- and 4-year follow-up, and an almost 50% reduction in
AD frequency was maintained up to 4 years of age (rate ratio 057, 95% CI 033-097; Table 5 ).[79,80]
With regard to study quality, studies were small, one study was not blinded, and the double-blinded
RCTs failed to describe methods of treatment allocation and concealment adequately. Diagnostic
criteria used to identify AD cases were generally unclear and no intention-to-treat analysis was
performed.
Mycobacterium vaccae is one of many environmental saprophytic mycobacteria, and it is known to

suppress
in animal
models.[81]
Two recent
randomized
assessed
the
Althoughatopy
a consistent
association
between
a decreased
risk ofplacebo-controlled
AD and increasingtrials
number
of older
effect
ofinitially
a single led
intradermal
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in association
children with
moderate-to-severe
AD.exposure
Whereas to
a
siblings
to the hypothesis
thatvaccae
such an
might
be due to increased
significant
improvement
in
disease
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was
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in
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preliminary
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of
older
children
(age
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infections protecting against atopic disease, this review has not found any convincing evidence that
years),
there
no statistically
significant
AD severity
in some
a subsequent
smallevidence
RCT
exposure
to awas
specific
infection reduces
the difference
risk of AD.inInstead,
there is
high-quality
conducted
in
a
younger
age
group
(age
2-6
years).[82,83]
suggesting that certain infections in early infancy might be associated with an increased risk of AD
expression. The decreased risk of AD with increasing number of siblings persists after adjustment for
early infections, suggesting that early events, such as an alteration of the gut microflora, might be key
in programming subsequent AD.[22] This notion is further supported by the observation of increased
AD risk associated with antibiotic use, and intervention studies of probiotics, which are thought to act
through modification of the gut microflora. Likewise, the protective effect associated with endotoxin
exposure, day care during infancy, and being brought up with a dog during early life, could be mediated
through nonpathological microbial stimulation of the immune system that is chronic and/or recurrent in
nature. Such findings require further explanation and replication. In this context, it will be important in
future research to consider the degree of individual exposures.[84] It may be that an exposure at
moderate levels is protective against AD while high exposure levels could be harmful, or vice versa.
One study has found that AD risk increases modestly with increasing hygiene practices such as
frequent washing, although simple explanations such as increased irritation of the already dry atopic
skin barrier by increased soap usage may be responsible for such an observation, as opposed to reduced
infections.
Overall, study quality was moderate, with the majority of studies using unvalidated questionnaires
rather than physician diagnosis to identify AD cases. In addition, most studies had a cross-sectional or
retrospective design, which allows investigation of associations and not of causality. Such studies are
prone to recall bias of antecedent events based on the disease status of the study participant and prior
beliefs of possible causes. The few existing intervention studies of the potential therapeutic effect of
probiotics were generally promising but small and lacked clear diagnostic criteria and intention-to-treat
analysis.
Like any review that relies primarily on electronic searching, we may have missed important studies
not listed on Medline, although we made stringent efforts to identify these through searching through
the citations from retrieved reports. Some studies of asthma that have included results of AD in
appendices may have been missed by our searches that were based on AD. It is also possible that we
might have missed unpublished reports, and we invite readers to update the authors if this is the case.
The authors maintain their position that a meta-analysis was not possible in this review due to the
diversity in study designs, participants and quality of the retrieved studies. The authors have instead
described the results of studies in tabular form and commented on the strength of evidence, the
direction and magnitude of any risk associations, along with CIs (which in some cases were calculated
de novo from the data) to allow readers to judge whether the study was too small to have found a
potentially important association.
Overall, there now seems enough evidence against a protective effect of any particular childhood
infection on AD risk. The consistent protective effect of high numbers of older siblings on AD risk
must be due to another factor, which could well be nonpathogenic microbial exposure. Future research
should continue the quest to find factors that link AD, family size and socioeconomic status. These
should ideally meet three criteria: (i) variation with number of siblings, (ii) protection against AD, and
(iii) increasing prevalence over the past 40 years. An answer will most probably come from studies
using a combination of epidemiological and immunological tools, and which focus on the prenatal and
immediate postnatal environment of mother and offspring and on how such early exposures prime the
child's immune system towards an AD phenotype, possibly via the gut-associated lymphoid tissue.
Timing and different levels of exposure may be crucial and therefore birth cohort studies, using clear

diagnostic criteria for AD and sensitive exposure measurements, are needed.

Regarding clinical practice, caution should prevail in the prescribing of antibiotics early in life,
especially in children with a family history of atopic disease. Attempts to reduce AD risk and severity
with probiotics have been promising. Whereas there may be high public acceptability for such
treatments, some researchers have raised concerns about potential side-effects.[85,86] The authors of
this review suggest that probiotics, if used, should be prescribed with caution, only in fully
immunocompetent individuals and presently only as second- or third-line treatments, until results from
larger studies with clear diagnostic criteria become available.

Atopic dermatitis and the hygiene hypothesis: a

case-control study
1.
2.
3.
4.
5.
6.

Sam Gibbs1,
Heidi Surridge2,
Ruth Adamson3,
Bernard Cohen4,
Graham Bentham5 and
Richard Reading3

+ Author Affiliations
1. 1Ipswich Hospital NHS Trust, Ipswich IP1 3PP, UK
2. 2School of Nursing and Midwifery, University of Southampton, SO17 1BJ, UK
3. 3School of Medicine, Health Policy and Practice, University of East Anglia, Norwich NR4 7TJ,
UK
4. 4PHLS Central Public Health Laboratory, 61 Colindale Avenue, London NW9 5HT, UK
5. 5School of Environmental Sciences, University of East Anglia, Norwich NR4 7TJ, UK
1. Correspondence: Dr Richard Reading, School of Medicine, Health Policy and Practice,
University of East Anglia, Norwich NR4 7TJ, UK. E-mail r.reading@uea.ac.uk
Accepted June 20, 2003.
Next Section

Abstract
Background The notion that lack of exposure to infection in early life leads to development of atopic
disease has come to be known as the hygiene hypothesis. It has arisen from observations of the rapidly
rising prevalence of atopic diseases in recent decades and the lower prevalence of atopy with rising
birth order. Direct evidence for the hypothesis to date is inconsistent.

Methods A case-control study set in Norfolk, UK of 602 children aged 15 years. Cases and controls
were defined using the UK Diagnostic Criteria for atopic dermatitis (AD) and a range of direct and
indirect methods were used to measure exposure to infection during infancy. Odds ratios (OR) for the
effect of these measures were calculated using logistic regression with adjustment for possible
biological and social confounding factors.
Results Reduced odds of AD were associated with rising birth order (OR for one older sibling 0.59,
95% CI: 0.42, 0.84 and for 2 older siblings 0.49, 95% CI: 0.31, 0.77). None of the measures of
infection reduced the odds of AD significantly, either in the unadjusted or adjusted analyses. None of
the measures of infection explained the protective effect of older siblings.
Conclusions Increased exposure to infection does not explain the reduced risk of AD in second and
subsequent siblings. More generally, these data cast doubt on the hygiene hypothesis as a causal
explanation for AD in young children.

Key words

Atopic dermatitis
eczema
hygiene hypothesis
infection

Atopic dermatitis (AD) is a chronic, disabling disease of the skin that currently affects about 15% of
school-age children in industrialized societies.1,,2 There is compelling evidence that the true
prevalence of AD in these populations has increased 2- to 3-fold in the last four decades.36 This rate
of change is too rapid to be explained by genetic factors. Environmental changes must therefore be
responsible but despite a plethora of hypotheses and some tantalizing clues this puzzle remains largely
unsolved.7,,8
After initial observations in large UK cohorts on the effect of family size,9,,10 a number of studies
have shown an inverse relationship between birth order and the chances of developing symptomatic
atopic disease.11 In addition, a stepwise increase in the prevalence of AD with rising socioeconomic
status was observed in a cohort of UK children born in 195812 and similar findings have been reported
elsewhere.5,13,,14 These observations, together with evidence of a bias towards Th2 immune
responses in atopy, resulted in what has come to be known as the hygiene hypothesis.10 Expressed
simply, this suggests that a reduced exposure to microbial pathogens in early life, especially those that
result in a Th1 immune response, increases the chances of the expression of clinical atopic disease.
Epidemiological evidence supporting the hygiene hypothesis to date has been inconsistent15 and some
clinical and biological studies have suggested a more complex interaction between immunological
challenges in early life with programming of the immune system.1619 Despite this there is still a
widely held view that exposure to common infections in infancy protects against the manifestations of
atopic disease in later childhood and adulthood.
This case-control study was designed to rigorously test the hypothesis with respect to AD, a disease
that is perhaps more purely atopic than either asthma or hay fever, but that has received less attention
in epidemiological studies of this type. Our aim was to measure exposure to infection with validated
methods in a number of different ways and to analyse the effects of exposure on the risk of properly
defined AD in preschool children, controlling carefully for potential confounding variables.
Previous SectionNext Section

Methods
The study was approved by the local research ethics committee and parents gave informed consent
which included access to their child's general practice notes.
Sample size calculations suggested that 270 cases and controls each would be required to show (with
90% power to a significance level of 5%) that a 30% exposure rate to infection would reduce the odds
ratio (OR) of developing AD to 0.5. The exposure rate of 30% was derived from a local seroprevalence
study of antibodies to EpsteinBarr virus and cytomegalovirus in the 14 years age group and the
reduction in OR based on a review of the literature. We increased the sample size by around 10% to
account for missing data, so aimed to recruit around 300 cases and 300 controls.
Subjects were selected from patient lists of 12 general practices in and around Norwich, UK. Potential
cases and controls were identified according to whether or not topical steroids had been prescribed.
Roughly equal numbers of cases and controls at each age group between 1 and 4 years were selected
randomly from these lists using a computerized random number generator. Families were invited to
join by mail, with a telephone reminder. Willing families were then visited. Children were only
included as cases if they fulfilled all of the UK diagnostic criteria for AD20 including evidence of
current flexural dermatitis. Children were not included as controls if they met any of the UK diagnostic
criteria.
Exposure measures were collected from three sources:

Parent questionnaire
During home visits a questionnaire was administered to a parent (usually the mother) asking about
common infectious symptoms in infancy and of exposure to a series of specific infections such as
measles, chickenpox, pneumonia etc.

General practitioners' (GP) records

GP records of subjects during infancy were examined and all consultations coded using a predefined
algorithm to classify the reason for the consultation. Definite or likely infectious episodes were
recorded according to the type of infection. Particular care was taken to exclude possible atopic
conditions, so, for example, when the total number of infections were calculated, infective skin
conditions were excluded because these included a number of cases of infected eczema, and symptoms
of lower respiratory infections were excluded to avoid confusion with infantile asthma. The number of
antibiotic prescriptions was also recorded.

Salivary antibodies
Samples of saliva were collected from cases and controls using Oracol devices (Malvern Medical
Developments, Worcester, UK) and processed in the Central Public Health Laboratory, Colindale,
UK.21 IgG antibodies to EpsteinBarr virus and Varicella Zoster virus were measured by capture
ELISA and an indirect ELISA method respectively.22,,23 Positivity was determined by a comparison
of optical densities using mixture model analysis.24
These measures were chosen to provide a wide variety of markers of exposure to infections in infancy
and early childhood. The measures from parental recall were comprehensive but would suffer from
subjective interpretation and memory bias, the measures from general practice were more valid
medically and timed exposure to infancy but might be biased by parental healthcare usage. The viruses

were chosen as common infections in infancy and early childhood which would act as objective
markers for more general exposure to contagious infection. We hypothesized that the findings would be
strongest if there was a consistent pattern of results across all these different types of measure.
Possible confounding and sociodemographic factors were collected from the initial parent
questionnaire. These data included family structure, numbers of older and younger siblings, family
history of atopic conditions, method of infant feeding, income, attendance at child care and preschool
groups, number of house moves, crowding and room sharing in infancy, and a range of socioeconomic
factors both at the present and when the child was an infant. The computerized district immunization
records of each child were examined to provide information on age of uptake of routine childhood
immunizations.
Logistic regression was used with the presence of AD as the dependent variable. Unadjusted OR were
calculated for the effect of the various possible explanatory variables. From these results possible
confounding variables were identified and adjusted OR for the effect of the various measures of
exposure to infection were then calculated.

Role of the funding sources

Referees for the Eastern National Health Service executive made comments on the initial protocol
which resulted in small changes, otherwise neither of the funders had any further active involvement in
study design, data collection, analysis, or writing of the paper.
Previous SectionNext Section

Results
In all, 307 cases and 295 controls were recruited. Recruitment was lower among patients from the more
deprived urban practices but there were no obvious differences in the pattern of recruitment between
cases and controls. Table 1 shows the distribution of demographic, biological, and socioeconomic
variables between cases and controls. Cases and controls are well matched on most background factors.
There appears to be a higher proportion of parental atopy among controls than expected.
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Table 1
Distribution of biological, social, and family factors between cases and controls
We have calculated unadjusted OR for the effect of these variables on the occurrence of AD and, where
appropriate, we also show OR adjusted for the effect of numbers of older siblings and the number of
parents with a history of an atopic condition. The strongest effect is seen for the number of parents with
an atopic condition and the number of older siblings. There are inconsistent trends of effects of the
socioeconomic variables. Some of the measures of the socioeconomic environment in infancy such as
room sharing and crowding during the first year of life show a possible protective effect which is
reduced to insignificance when adjusted for the number of older siblings, while the number of house
moves in the first year shows a significant protective association after adjustment.
Table 2 shows the effect of the various measures of infection on the odds of AD. The first columns
show the unadjusted ratios and the second show the OR adjusted for number of older siblings, number

of parents with an atopic history, receipt of welfare benefits, room sharing in the first year, number of
house moves in the first year, and the number of cars owned by the family. The latter four adjustment
variables were chosen either because they had an effect on the outcome or because they identified
extremes of the social distribution that might potentially mask an effect of the infection variables. As an
intermediate step we adjusted only for parental atopy and number of older siblings. These results were
no different to the fully adjusted model and so are not shown.
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Table 2
Effects of different measures of exposure to infections on the odds of atopic dermatitis
None of the variables measuring exposure to infection showed a significant protective effect, either in
the unadjusted or in the adjusted analyses. The only measure suggesting a possible trend in this
direction is positive virology for EpsteinBarr virus but the effect is small with an OR of around 0.7 in
both adjusted and unadjusted analyses. In all other measures of infection exposure the OR are either
close to 1, or show a non-significant or barely significant trend for exposure to infection being
associated with increased odds of AD. Adjustment makes little difference to any of the OR.
In general, measures of exposure to infection that showed the largest positive association with AD were
subjective, such as parental report of minor infections and coughs and colds, and could have included
possible early manifestations of AD or other atopic conditions. Excluding possible atopic episodes from
the infective episode category (as described in Methods) did not alter this positive association, and it
persisted even for conditions that have no connection with atopy such as diarrhoea and vomiting.
We then looked to see whether any of the infection variables accounted for the protective effect of older
siblings. Table 3 shows the distribution of the infection measures according to the number of older
siblings among control children only. In order to account plausibly for the protective effect of older
siblings, at the very least we need to show a large increase in the proportion of infection among control
children with greater numbers of older siblings. The only measures which meet this test are exposure to
chickenpox, either serologically or by parental report, and frequency of minor infections by parental
report.
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Table 3
Measures of exposure to infection in control subjects only according to number of older siblings
To test whether these, or any of the other infection measures, account for all or part of the protective
effect of older siblings we carried out a series of regression analyses in which the unadjusted OR for
the effect of older siblings was sequentially adjusted for the various measures of infection. If the effect
of older siblings is mediated through increased exposure to infection, we would expect to see the
unadjusted odds of AD being reduced when the infection variables are introduced into the model. The
results of these are shown in Table 4. In none of these cases were the unadjusted OR for the effect of
older siblings on AD reduced by the measure of exposure to infection. In particular, no effect was
shown with EpsteinBarr virus or Varicella Zoster virus antibody status nor with chickenpox infection
or frequency of minor infections by parental report. Thus there is no evidence that exposure to any of

the infections we measured contributes to the protective effect of having older siblings.
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Table 4
Odds ratios for the effect of older siblings on atopic dermatitis risk, adjusted for a range of possible
infective factors
Previous SectionNext Section

Discussion
This study was designed to test the hygiene hypothesis as an explanation for the onset of AD in
children. In line with other studies we have found an apparent protective effect of larger sibship sizes
and have confirmed that this is due to the number of older siblings.11 No protective effect of exposure
to infection was demonstrated. Furthermore, adjusting for the various infection variables did not reduce
the effect of the number of older siblings on the odds of AD.
The strengths of this study were the clear and validated definition for both cases and controls and the
diverse measures of previous exposure to infection. Lack of clear case definition is a weakness of
previous studies of this type that have relied on parental report or historical diagnoses. The UK
diagnostic criteria require both a convincing history and current clinical evidence of active AD. Any
child not meeting these exacting criteria were excluded as cases regardless of history or previous
medical records, while any child who had a previous history suggestive of AD was excluded as a
control. We did not actively exclude children with other atopic conditions but because of the method of
selection, few control children had asthma or hay fever (3.4% and 2.7% respectively).
When considering previous exposure our intent was not to identify the effect of any specific infectious
agent but rather to include a wide range of indicators of exposure to infections in general. These ranged
from the objective measurement of salivary antibodies to two viruses, the GP records which enabled
timing of infectious symptoms to be restricted to infancy, and the more subjective information from
parental recall. All these methods have drawbacks, but our prior argument was that the findings would
be strengthened by a consistent pattern of results across all the measures and indeed this was the case.
The validity of the salivary antibody tests have been reported.22,,23 In addition, the salivary antibody
test for Varicella Zoster showed a high level of internal consistency with parental report of chickenpox
(213 of 244 children with a positive history tested positive, while 270 of 298 children with a negative
history tested negative). Data from GP medical records has been used to measure exposure to infections
in previous studies,2527 while Bruijnzeels and colleagues found greater consistency in data from
medical records than either diaries or interview.28 In order to minimize bias, an independent researcher
unaware of the case or control status of the children, and only vaguely aware of the hypothesis of the
study, scrutinized and coded the GP records. Different consulting patterns of parents for first children
and subsequent siblings may have introduced a bias, for example there was a small but significant
correlation between number of visits for non-atopic, non-infective conditions and number of older
siblings (r = 0.12, P = 0.003). Table 3 shows that children with 2 older siblings presented less
frequently to the GP with infectious symptoms, but this was not the case for children with one older
sibling. Thus, any possible bias from parents' consulting behaviour is likely to have been small and
restricted to the results from children with 2 older siblings. We made no attempt to validate the parent
questionnaire, although the wording of some of the infection questions followed the format developed

for the Warwick Child Health and Morbidity Profile29,,30 and there were positive associations between
the parents' replies and data from the GP records (e.g. ear infections, r = 0.43, P < 0.001, diarrhoea and
vomiting, r = 0.20, P < 0.001). Although the results from the parent questionnaire were considered to
provide the least robust evidence, such data can certainly be accurate, particularly in young children.31
Our sample sizes were large enough to reliably identify a reduction of the odds of AD by a half, which
is the size of effect reported in other studies.3235 We are therefore confident that we are not missing a
protective effect due to low power or residual confounding.
The consistent findings in the literature are the rising prevalence over the past 30 years and the reduced
risk of atopy in second and subsequent siblings. The hygiene hypothesis arose from these observations
but one of the subsequent challenges has been to identify any infectious, microbial, or toxic exposure
that varies markedly with birth order.
Support for the hypothesis that early infection protects against the subsequent development of atopic
disorders is largely indirect. Protective effects have been found for overcrowding,36 attendance at day
care nurseries,37,,38 and an anthroposophic lifestyle,39 while an increased risk has been shown for
consumption of antibiotics in infancy.27,40,,41 Our results also show a possible effect of the social
environment in infancy, for example the protective effect of room sharing, moderate crowding, and
frequency of house moves, but this is not explained by early infection, and we found no effect of
antibiotic prescriptions.
Studies using more direct measures of infection have shown inconsistent results, some appearing to
demonstrate the protective role of tuberculosis,33 BCG,42 measles,34 EpsteinBarr virus,43 hepatitis
A,32,,44 Toxoplasma,44 and respiratory infections,35 and others showing no effect, (or even a
potentiating effect) from BCG,45,,46 rubella and pertussis,47 measles, mumps, rubella, and Varicella
Zoster,44,47,,48 all infections in the first months of life,49 and early life respiratory infections.50,,51
We have only examined AD, but our results are in line with those studies that found no protective effect
on atopy of infection in early life. The consistent finding of protective effects of older siblings suggests
that programming of the immune system to be susceptible to allergic sensitization occurs in childhood
and our finding that the sibling effect is seen among very young children suggests it occurs very early
in life. Two possible explanations are the immunomodulatory effects of different patterns of neonatal
gut colonization17,,19 or factors acting on the immune response before birth.52,,53 Our results would
be consistent with either of these explanations.
In conclusion, this study has found no relationship between the manifestation of AD in young children
and infection in early life. The hygiene hypothesis may explain the rise in prevalence of AD over the
previous 30 years, but it does not explain why children born during the 1990s in a developed country
manifest the disease. There are now a number of well-designed studies that show no protective effect or
a small positive correlation between early life infection and subsequent atopic symptoms. Taken
together these cast doubt on the hygiene hypothesis as an explanation for AD.

KEY MESSAGES
The hygiene hypothesis was based on reduced prevalence of atopic disease in children with
large numbers of siblings and proposes that exposure to infections in infancy protects against
the subsequent manifestation of atopic disease.
This large case-control study of preschool children with atopic dermatitis has measured
exposure to infection in infancy using a variety of approaches.
No measure of infection showed a protective effect for atopic dermatitis.

 The protective effect of older siblings was confirmed.

Exposure to common infections in infancy does not protect against the manifestation of atopic
dermatitis, nor does it explain the sibling effect.
Previous SectionNext Section

Acknowledgments
We thank all the parents and children who collaborated in the study, staff at the general practices, Gill
Tanner for collecting the general practice data, Margaret Sillis and her team at the Public Health
Laboratory in Norwich for help with processing the saliva specimens, Bridget Coupland for help with
the immunization and birth data, and Hywel Williams for guidance with the UK Diagnostic Criteria for
atopic dermatitis. We thank the following staff at Central Public Health Laboratory: David Brown for
advice; Yamima Talukder for performing Varicella Zoster virus antibody assays; Carmen Sheppard and
Belinda Bickley for performing EpsteinBarr virus antibody assays and Nick Andrews of PHLS
Statistics Unit for performing mixture model and other analyses of antibody assay results. The study
was funded by the Eastern NHS executive and Children Nationwide.
IJE vol.33 no.1 International Epidemiological Association 2004; all rights reserved.
Previous Section

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