Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 579


proteolytically derived anaphylatoxins, are both essential for the to fungus-sensitized patients with asthma; and (iv) experimental
expression and regulation of asthma in experimental systems. validation that filamentous fungi are infectious for the mouse
C3a signaling through the C3a receptor C3aR is required for airway and readily produce allergic airway disease that is com-
robust Th2 responses, allergic inflammation, and AHR in response parable with asthma. Moreover, fungal airway infection can induce
to airway allergen challenge. In contrast, C5a, which can signal atopy to innocuous bystander antigens, suggesting that fungal
through two receptors, C5aR and C5L2, appears to inhibit Th2 infection could underlie both atopy and respiratory tract allergic
responses, perhaps acting as a physiological antagonist of the disease. However, not all patients with allergic airway disease
allergic disease-promoting activity of C3a. 30 demonstrate fungus-specific immunity; neither are antifungal
Lipid mediators of inflammation of importance to allergic agents effective in all such patients, especially those with CRS.
airway disease include the LTs and prostaglandins (PGs). The Thus fungal airway infections may be etiologically relevant to
cysteinyl leukotrienes (CysLTC4, -D4, and -E4) signal through only a subset of allergic disease patients. 33
at least two major receptors to mediate some of the same allergic Respiratory viruses and particulate matter are also prominently
disease features as IL-13, including airway inflammation and linked to allergic airway disease. Approximately 70–80% of
AHR. Full expression of experimental allergic disease, in fact, children and adults test positive for human rhinovirus (HRV)
appears to require the concomitant expression of both IL-13 during acute disease exacerbations. Other respiratory viruses
and the CysLTs. However, IL-13 appears to be the dominant are likely to contribute to allergic disease pathogenesis, although
34
allergic mediator, perhaps accounting, in part, for why LT the mechanisms remain obscure. Particulate matter in the form
antagonism alone is not as effective as inhaled steroids in asthma. of tobacco smoke, diesel exhaust particles, and other forms of
Noncysteinyl LTs, such as LTB4, also contribute to the expression smoke is strongly linked to asthma exacerbation and enhanced
of allergic airway inflammation by controlling the recruitment atopy, as is exposure to ozone (O 3 ). What links these various
of allergic effector cells, including Th2 cells. 31 forms of air pollution to allergic disease may be the induction
Similarly, PGD 2 is an important mediator of Th2 cell recruit- of oxidative stress, which ultimately leads to enhanced activation
ment and allergic airway inflammation in rodent models, most of nuclear factor kappa B (NF-κB), enhanced Th2 cytokine release,
likely acting cooperatively with LTB4 and chemokines. Most and increased allergic inflammation. 35
other PGs are thought to promote allergic airway disease, Research from experimental systems has shed additional light
especially in aspirin-sensitive rhinitis and asthma. An important on how allergens initiate allergic inflammation and disease.
exception to this is PGE 2 , which exhibits potent antiallergic Although the structural features of allergens do not determine
activity. Other lipid mediators likely contributing to the expression their allergic character, a common biochemical feature that is
of allergic inflammation and airway obstruction are the throm- strongly associated with allergenicity is protease activity. Proteases,
boxanes and lipoxins. Thromboxane A 2 is a potent proinflam- as single molecules, are as effective as any complex allergen or
matory lipid derived from platelets, whereas lipoxins have the fungal infection in inducing allergic airway inflammation and
opposite effect and are antiinflammatory. 32 AHR when administered to rodents or inhaled by humans.
Household proteases are derived largely from fungi, suggesting
Environmental Factors and Allergic Disease Initiation again that airway infection caused by these organisms, which
The earliest immunological events that initiate Th2 responses would result in in situ protease production, may be an important
and the environmental factors that trigger them are incompletely mechanism underlying allergic disease induction. Irritation of
understood. Currently, asthma and to a large extent RS and AR the airways through viral infection, ozone exposure, and other
are believed to represent aberrant immunological responses to mechanisms further increases endogenous airway protease activity,
innocuous inhaled antigens. The very strong association between especially through induction of thrombin activity. 36
asthma and atopy supports this concept, with many allergens Analyses of diverse allergenic proteases suggest that they initiate
being relatively innocuous proteins derived from organisms that a complex, airway epithelial-centered mechanism in which the
are not otherwise harmful or infectious, such as those from dust epithelial cytokines TSLP, IL-33, and IL-25 are induced and lead
mites, cats, dogs, and plants. Atopy is further thought to represent to robust allergic responses. In part, this sequence is initiated
a fundamental underlying condition that leads, in some cases, by the action of exogenous and endogenous proteinases on the
to overt allergic disease, but whether atopy represents primarily terminal coagulation protein fibrinogen, which is secreted by
a genetically or an environmentally controlled condition remains airway epithelial cells into the airway lumen. Cleavage of fibrino-
unclear. Extensive analysis of allergens has revealed no consistent gen by proteases yields fibrinogen-cleaved products (FCPs) that
structural features, suggesting that physical properties are highly signal through Toll-like receptor 4 (TLR4) to initiate both
relevant to atopy and allergic disease expression. antifungal responses and innate allergic inflammation, including
37
A major exception to the intrinsically innocuous nature of ILC2 responses. Proteolytic activation of complement proteins
allergens is, however, the role of filamentous fungi, such as (e.g., C3) is also a crucial early event in the evolution of allergic
30
Aspergillus spp., and other potentially infectious causes of allergic airway disease. Th2 responses arise, in part, through the action
disease. Fungal sensitization is not different from sensitization of proteases on pulmonary dendritic cells (Fig. 41.7).
to any other allergen ubiquitously present in human environments.
However, fungi differ from all other allergen sources in that they NONALLERGIC RESPIRATORY TRACT
are both ubiquitous and able to actively infect and grow within INFLAMMATORY SYNDROMES
the respiratory tract. 33
A fungal infectious basis for allergic disease is also suggested Although the majority of respiratory tract inflammatory disease
by (i) the high rate of isolation of filamentous fungi from the is allergic, additional pulmonary immune-related disorders exist
airways in CRS, especially AFRS, and ABPA; (ii) the universal that are nonallergic and are responsible for considerable morbidity.
presence of fungus-specific immunity in subjects with AFRS The immunological mechanisms, etiological environmental
and ABPA; (iii) the efficacy of antifungal antibiotics when given factors, and therapies for these diseases are distinct from common

580 ParT FIvE Allergic Diseases


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FIG 41.7 Mechanisms of Allergenic Protease-Dependent Induction of Allergic Airway Disease.
Inhaled proteases or protease sources (e.g., fungal spores) initiate a series of molecular events
in discrete lung compartments and involving distinct cell types that induce predominant airway
T-helper 2 (Th2) responses that coordinate both the allergic inflammation and physiological changes
that typify allergic respiratory tract disease. Initial innate immune responses induced by proteases
include induction of airway chemokines that favor recruitment of allergic effector cells including
Th2 cells (1). Likely airway cellular targets of proteinases include basophils, epithelial cells, smooth
muscle cells, and macrophages (2). Activation of these cells by cleavage of cell surface receptors,
such as PAR2 and CD23, potentially leads to activation of these cells to produce proallergic
cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and IL-25 that
promote Th2 responses. Allergenic proteinases also likely act on soluble substrates, such as
complement, especially C3 to generate C3a, the ligand for the C3aR, and fibrinogen, creating
fibrinogen cleaved products (FCPs) that signal through Toll-like receptor 4 (TLR4) to coordinate
antifungal immunity and promote Th2 responses. CD25 is another immune receptor present on
T cells that can be cleaved by proteinases, potentially to favor Th2 cytokine secretion. Finally,
proteinases act directly on antigen-presenting cells, such as dendritic cells (DCs), through an
unknown mechanism in secondary lymphoid organs, such as lymph nodes, to promote their
maturation in a manner that favors Th2 cell differentiation from naïve precursor (ThP) T cells (3).
(Modified from Porter PC, Yang T, Luong A, et al. Proteinases as molecular adjuvants in allergic
airway disease. Biochim Biophys Acta 2011;1810:1059–65.)




allergic disorders and hence warrant consideration in the dif-
ferential diagnosis of airway inflammatory disorders. Two of the Hypersensitivity Pneumonitis
most important nonallergic airway obstructive immune disorders Hypersensitivity pneumonitis (HP) is a non–IgE-mediated
are hypersensitivity pneumonitis and chronic obstructive pul- inflammatory lung disease that results from recurrent exposure
monary disease. to a wide variety of inhaled antigenic aerosols containing organic

CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 581


and possibly infectious matter. Pulmonary involvement is typically airway obstruction. Epidemiological studies have shown that
diffuse and consists predominantly of mononuclear inflammation lung cancer risk is strongly related to radiographic emphysema,
of the terminal bronchioles, interstitium, and alveoli, with little independent of air flow obstruction. In contrast, nonsmoking
involvement of the larger airways. Although the term “extrinsic patients with asthma have no greater risk of lung cancer than
allergic alveolitis” is commonly used for this disorder, low-grade the general nonsmoking population.
eosinophilia is only seen in 1–3% of BAL specimens and is not The Global Initiative for Chronic Obstructive Lung Disease
a consistent or characteristic feature of disease. Over time, this (GOLD) has in the past decade promoted the use of a fixed
pattern of inflammation leads to destruction of alveoli and to FEV 1 /forced vital capacity (FVC) ratio of <70% to diagnose
irreversible pulmonary fibrosis that may ultimately be fatal. COPD. This latter guideline is now widely used to classify smokers
The etiology of HP is usually idiopathic, but many cases can be with and without COPD, but it excludes up to 20% of smokers
traced to exposure to organic aerosols that contain thermophilic with emphysema who have normal lung function, and it under-
bacteria (e.g., Saccharopolyspora rectivirgula), filamentous fungi diagnoses and overdiagnoses COPD in young and old smokers,
(e.g., Aspergillus spp.), animal proteins and fecal matter (e.g., respectively. Recognizing different COPD phenotypes based on
pigeon breeder’s disease), and industrial chemicals, such as isocya- lung function, symptom severity, and exacerbation frequency,
nates. Symptoms, including chest tightness, chest pain, dyspnea, smokers are categorized into one of four stages: (A) fewer
and fever, appear 4–6 hours after exposure. Cessation of exposure symptoms, low risk; (B) more symptoms, low risk; (C) fewer
to the provoking antigen may prevent progression to chronic, symptoms, high risk; (D) more symptoms, high risk. Those in
irreversible disease. Other than oxygen therapy in the setting groups C and D are thought to benefit from inhaled corticosteroids
of profound hypoxemia, there is no defined medical therapy in addition to bronchodilators. 40
for HP; in particular, there is no role for glucocorticosteroids. Smokers with emphysema have enlarged alveoli that contain
The immunopathogenesis of HP is complex and not well increased numbers of macrophages containing nano-sized elemen-
understood. During the acute presentation, the histological picture tal carbon black (nCB). The key property underlying the initiation
is an immune complex–mediated interstitial injury with a of destructive lung inflammation with nCB inhalation appears to
predominant neutrophilic infiltrate. Subsequently, the disease be its chemical characteristics, namely, its insolubility and small
evolves into predominant mononuclear inflammatory infiltrates particle size that activate the inflammasome pathway and promote
consisting of lymphocytes, plasma cells, and foamy macrophages, differentiation of lung Th1 and Th17 cells. nCB can be readily
followed by granuloma formation. In advanced disease, the detected in lung phagocytic cells (e.g., DCs and macrophages) by
inflammatory infiltrates are replaced by fibrosis. using Raman spectroscopy and electron microscopy (Fig. 41.8). 41
Acutely, HP is thought to be initiated by an immune-complex The treatment of emphysema is largely supportive, comprising
mediated hypersensitivity (type III) with in situ immune complex bronchodilators and cholinergic antagonists, which suppress
deposition in the lung interstitium as a result of interaction of mucus production, and inhaled or systemic glucocorticosteroids,
the inhaled antigen and preexisting IgG antibodies in the alveolar
spaces. Complement activation occurs and most likely contributes
to the alveolitis and neutrophilia. However, many people with
precipitating antibodies to putative HP antigens (precipitins)
do not develop actual parenchymal or symptomatic disease.
Therefore it is believed type IV, delayed-type hypersensitivity
reactions involving Th1 and possibly Th17 cells also contribute
to disease expression. 38
Chronic Obstructive Pulmonary Disease
The disorder most frequently confused with asthma is chronic
obstructive pulmonary disease (COPD), which encompasses
chronic bronchitis with or without emphysema. COPD is currently
the fourth leading cause of death in the world but is expected
to reach third place by 2020. The most common cause of COPD
is active tobacco smoking, but chronic exposure to coal dust,
biomass fuels, second-hand smoke, and chronic respiratory
infections have been linked to COPD in nonsmokers. Because
not all smokers develop COPD, disease initiation is thought to
reflect interaction of genetic susceptibility and environmental
factors. Development of early-onset emphysema in highly sus-
ceptible smokers is sometimes caused by undetected mutations 1 µm
in the α 1 antitrypsin (A1AT) gene locus (e.g., ZZ, MZ, MS).
However, in the vast majority of individuals, the genetic factors
responsible for increased susceptibility to emphysema remain
unknown. Indeed, several large studies have shown that although
multiple genes contribute to increased risk of emphysema, each FIG 41.8 Nanoparticulate Carbon Black (nCB) Accumulation
individual gene shows only a modest and independent effect. 39 Within an Alveolar Macrophage. Electron micrograph of an
In addition to cough and sputum production, COPD often alveolar macrophage isolated from the peripheral lung of a ciga-
presents clinically with insidious onset of dyspnea and progressive rette smoker with emphysema. Arrow points to a vacuole contain-
and persistent exercise limitation, with minimal reversibility of ing nCB.

582 ParT FIvE Allergic Diseases


which suppress inflammation. Additional therapies for moderate production of matrix metalloproteinases (MMPs) and other
to severe disease include theophylline and the phosphodiesterase enzymes that degrade elastin (elastases), including MMP2, MMP9,
inhibitor roflumilast. During exacerbations of COPD, which MMP12, and neutrophil elastase (NE). The activity of most of
become increasingly frequent with advancing disease and are these enzymes is controlled by endogenous inhibitors, such as
often caused by bacterial and viral infections, tailored use of tissue inhibitors of metalloproteinases (TIMPs) and A1AT, the
antibiotics is frequently helpful. For severe disease with resting principal antagonist of elastases. Cigarette smoke exposure is
hypoxemia, continuous nasal oxygen can both extend life and sufficient to enhance elastase secretion from macrophages and
relieve dyspnea. Surgical interventions, such as lung volume neutrophils and to reduce the activity of elastase inhibitors. In
reduction surgery and lung transplantation, are reserved for addition to elastin, MMP12 specifically inhibits A1AT, leading
advanced disease. to unopposed NE activity. These biochemical events are critically
The immunological basis of COPD differs markedly from important to the expression of emphysema because elastin is an
asthma: smoking-related lung inflammation appears to be the important MMP that is partly responsible for both the structural
fundamental underlying cause of both airway obstruction and integrity of the lung and its stretchiness. In genetically susceptible
lung destruction (Fig. 41.9). In contrast to asthma, where Th2 individuals, elastin becomes the antigenic target of pathological
cells and other allergic effector cells are involved, the major Th1 and Th17 cells. Emphysema, therefore, is the clinical expres-
immune effector cells in COPD are Th1 and Th17 cells. Together sion of the autoimmune-based loss of lung integrity resulting
with macrophages and neutrophils, these innate and adaptive from enhanced expression of antielastin immunity that promotes
immune cells coordinate lung destruction in COPD by enhancing secretion of elastases. 42

Normal lung Emphysematous lung















































FIG 41.9 Lung Parenchymal Destruction in Smokers With Chronic Obstructive Pulmonary
Disease (COPD) and Emphysema. Representative computed tomography (CT) images show
lungs of a smoker without (A) and with (B) emphysema; arrows point to low attenuation dark
black areas devoid of lung tissue (emphysematous regions) within the diseased lung. Lower
panels show representative low- and high-magnification histology images from human lung in
each case including the focal collection of inflammatory mononuclear cells in emphysematous
lung.

CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 583


NOVEL PATHWAYS TO THERAPY IN Recent clinical studies have confirmed the importance of
INFLAMMATORY AIRWAY DISEASE Th2- and ILC-derived cytokines, including IL-5 and IL-13, to
the pathogenesis of human allergic disease. The anti–IL-5 antibody
Intensive research conducted over the past several decades has mepolizumab was recently approved by the US Food and Drug
markedly improved our understanding of the immune and Administration (FDA) for use in eosinophilic asthma; anti–IL-13
environmental basis of allergic and nonallergic airway diseases. (lebrikizumab) and anti–IL-4/IL-13 receptor (dupilumab)
Currently available therapies for these diseases have, however, antibodies are likely to be approved for similar indications.
failed to match this level of sophistication. It is now clear that In addition to defining disease populations that are most
allergic disease is immunologically complex and likely to involve likely to benefit from them, a major challenge with all biological
multiple hypersensitivity mechanisms operating in parallel. Recent agents is their prohibitive cost. Development of small, relatively
studies also show that factors other than allergens likely critically easily manufactured molecules that antagonize disease-related
influence the airway immune response to inhaled antigens and pathways is, in many ways, a more attractive approach with lower
particulate matter. These adjuvant factors include cell wall pharmaceutical costs. Small molecule agonists of peroxisome
products of bacteria and fungi, such as lipopolysaccharide (LPS); proliferator activated receptor-γ (PPAR-γ) are currently approved
secreted factors, such as proteases; and endogenous factors from for use in diabetes mellitus (pioglitazone, rosiglitazone) in the
cells damaged by exposure to allergens and smoke. There is United States, but they are also outstanding antagonists of Th17
44
increasing evidence that asthma and RS may be linked to respira- cells and can reverse experimental emphysema. Thus PPAR-γ
tory tract infections involving viruses, especially HRV, and fila- agonists are excellent candidates for future clinical trials in
mentous fungi. Future therapies are, therefore, likely to focus emphysema. Small molecule antagonists of IL-4/IL-13 signaling
on both endogenous factors that coordinate allergic inflammation that target STAT6 have also been discovered and are potentially
(e.g., cytokines) and etiological environmental factors (e.g., suitable for clinical trial and development. 45
proteases, fungi, and nCB). In future studies, it will be essential to clarify the role of
Once thought of as primarily a physical barrier, the respiratory chronic infections caused by viruses, bacteria, and fungi in asthma
epithelium is now recognized to actively coordinate immunity and RS. Although recent studies firmly implicate a central infec-
to allergens and other environmental challenges. Through release tious role for fungi in CRSwNP and asthma, it is a major challenge
of IL-33, IL-25 and/or TSLP, respiratory epithelial cells can initiate to design clinical trials that unequivocally demonstrate whether
and coordinate the innate and adaptive type 2 immune response antifungal antibiotics are useful in asthma and CRS. 9
(see Fig. 41.7). In addition, respiratory epithelial cells produce The central role played by proteases and the proteolytic
several chemokines in response to environmental triggers, activation of complement (e.g., C3) and coagulation-related
recruiting DCs, ILC2s, basophils, eosinophils, and mast cell inflammatory pathways (e.g., fibrinogen) in allergic diseases
43
progenitors. Several of the triggers listed above and also trauma suggest that antiproteases might be effective in the management
to airway cells can activate the release of these type 2 cytokines of these conditions. Broad-spectrum antiproteases are effective
and chemokines. in attenuating human and experimental asthma and are, thus,
37
The prototypical epithelial cell cytokines, IL-25, IL-33, and suitable for further therapeutic development. The major
TSLP, share many overlapping functions supporting a local type obstacles with these agents are discovering molecules with suf-
2 inflammatory response despite having unique receptors. As ficiently broad spectrum to inhibit the proteases of the many
expected, many of the type 2 cells, including eosinophils, DCs, fungi now linked to human allergic disease and overcoming
ILCs, and mast cells, express receptors to all three cytokines. potential safety issues related to their anticoagulant and immu-
Despite functional overlap, these cytokines also possess unique nosuppressive properties.
functions. For example, IL-33 and IL-25 activate different types
of ILCs, with IL-33 primarily activating ILC2 and IL-25 prefer- Please check your eBook at https://expertconsult.inkling.com/
entially stimulating a novel population of type 2 innate cells. for self-assessment questions. See inside cover for registration
TSLP is associated more with activation of the adaptive type 2 details.
inflammatory response via DCs. Also, TSLP uniquely supports
the hematopoiesis of basophils. Together, these epithelial cell
derived cytokines orchestrate a robust innate and adaptive type REFERENCES
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CHaPTEr 41 Immunological Mechanisms of Airway Diseases and Pathways to Therapy 584.e1


MULTIPLE-CHOICE QUESTIONS

1. What epithelial cell–derived cytokine contributes to the D. Autoimmune responses against elastin
pathophysiology of chronic rhinosinusitis (CRS) by serving E. Disease is linked to environmental exposures
as the primary driver of mucus production? 3. Which of the following factors is most clearly implicated as
A. Thymic stromal lymphopoietin (TSLP) via activation of an etiological environmental factor in human emphysema?
dendritic cells A. Molds (fungi)
B. Chemokine ligand 11 (CXCL11) via its chemotactic role B. Nanoparticulate carbon black (nCB)
for activated T cells C. Haemophilus influenzae
C. Interleukin-33 (IL-33) via activation of innate lymphoid D. Endotoxin (lipopolysaccharide; LPS)
cells E. Radon gas
D. IL-25 via increased expression of IL-4
4. Future therapies for asthma could target which of the
2. Which of the following characteristics MOST clearly distin-
guishes chronic obstructive pulmonary disease/emphysema following?
from asthma? A. IL-13
A. Airway obstruction B. IL-4 receptor
B. Lymphocytic inflammation C. IL-5
C. Disease exacerbations leading to disabling dyspnea D. Fungi
E. All of the above

42









Urticaria, Angioedema, and Anaphylaxis



Clive E.H. Grattan, Elena Borzova







Urticaria is a common skin disorder that can lead to severe GENETICS
impairment in quality of life. Recently, there has been substantial
progress in our knowledge and understanding of the pathophysiol- Although there is no indication of mendelian inheritance, the
ogy of the condition, offering new diagnostic and treatment frequency of chronic spontaneous urticaria (CSU) is higher in
4
approaches for many patients. first-degree relatives of patients. A link between CU and human
leukocyte antigen (HLA)-DRB1*04 (DR4) and its associated
DEFINITION allele, -DQB1*0302 (DQ8), was found in British patients with
CSU with evidence of functional autoantibodies compared with
5
1
Urticaria is characterized by itchy wheals, angioedema, or both. a control population. Strong associations with HLA-DRB1*1302
Urticarial lesions resulting from localized edema of the upper and DQB1*0609 alleles were found in aspirin-induced urticaria
dermis are called wheals (Fig. 42.1), whereas pronounced swelling in Korean patients. 6
of deeper dermal layers and subcutaneous and submucosal tissues
is known as angioedema (Fig. 42.2). CLINICAL PATTERNS
Urticaria is classified by the duration of continuous activity into
KEY CONCEPTS acute (<6 weeks), chronic (≥6 weeks), or episodic, where short
episodes occur repeatedly over a period, with short or long
Definition of Urticaria intervals. It may be spontaneous, inducible, or both. Inducible
urticarias may be triggered by mechanical, thermal, or other
• Urticaria is an illness characterized by wheals, angioedema, or both.
• Wheals are superficial swellings of the dermis of skin: they are pale stimuli. The differential diagnosis of urticaria includes urticarial
and itchy with surrounding redness when they appear and then become vasculitis, hereditary angioedema (HAE), and autoinflammatory
pink before fading. syndromes presenting with urticarial rash.
• Angioedema is a deep swelling below the skin or mucosa that usually
lasts longer than wheals and may be painful rather than itchy. ETIOPATHOGENESIS AND ETIOLOGICAL
• Wheals may occur with or without angioedema in urticaria.
• Acute urticaria lasts <6 weeks. It is common and often caused by CLASSIFICATION
viral infections. Urticaria caused by drugs and foods falls in this category,
but the diagnosis is usually clear from the history. Although many aspects of the pathophysiology of urticaria remain
• Chronic urticaria lasts ≥6 weeks with continuous disease activity. A unclear, our understanding has advanced considerably over
cause may not be found. Urticaria occurring intermittently over a the last two decades, allowing for an etiological classification
period of >6 weeks can be defined as episodic. (Table 42.1).
• When angioedema occurs without wheals, C1 esterase inhibitor
deficiency should be excluded. Mast Cell–Dependent Mechanisms
Skin mast cells are key players in the pathogenesis of urticaria.
They are predominantly located around the small blood vessels
EPIDEMIOLOGY and lymphatic vessels as well as around or within peripheral
nerves. The population density of mast cells is greatest at distal
7
Urticaria is common, and up to 25% of the general population body areas, including the face, hands, and feet. There is con-
experience some form of urticaria at least once over their lifetime, flicting evidence as to whether the number of cutaneous mast
whereas the lifetime prevalence of chronic urticaria (CU) is cells is increased in patients with urticaria, but it is accepted
2
0.1–3% of the general population. Acute urticaria mainly affects that these cells release mediators more readily compared with
2
young adults and has an obvious female preponderance, whereas normal cells.
CU is more common in adults, affecting mainly middle-aged Human skin mast cells contain preformed mediators in their
3
women, and is uncommon in children and adolescents. By granules, including histamine, proteases (tryptase, chymase), and
definition, acute urticaria resolves within 6 weeks, whereas CU heparin. They express many membrane receptors, including
may last for years. Rarely, CU may last >10 years. However, CU high-affinity immunoglobulin E (IgE) and low-affinity IgG
is almost always a self-limiting disorder, resolving spontaneously receptors. Unlike mast cells elsewhere (e.g., lung and gastro-
within 6 months of onset in 50% of patients. 3 intestinal [GI] tract), skin mast cells possess complement C5a
585

586 ParT fivE Allergic Diseases


Allergen



IgE
Substance P
Anti-FceRI
Stem cell factor

C5a

Codine
Anti-IgE
IgE

fiG 42.1 Spontaneous wheals in severe spontaneous urticaria
showing superficial pink swellings with pale edematous centers.
fiG 42.3 Schematic representation of a mast cell or basophil
illustrating activation of the immunoglobulin E (IgE) receptor by
cross-linking with immunological stimuli (allergen/specific IgE
binding, anti-IgE, or anti-FcεRI autoantibodies) or independent
activation by nonimmunological stimuli (substance P, stem cell
factor, codeine, or C5a) leading to degranulation.


8
D 2 [PGD 2 ]) and cytokines. In contrast, nonimmunological
stimulation of mast cells by neuropeptides, opiates, or C5a leads
to rapid release of histamine within 15–20 seconds, without
generation of eicosanoids and cytokines. Moreover, prolonged
and subthreshold immunological stimulation may result in a
state of receptor desensitization. For example, desensitization
of FcεRI may lead to basophil hyporesponsiveness to anti-IgE
9
fiG 42.2 Angioedema of the mouth in acquired C1 esterase in autoimmune CSU. However, desensitization of receptors by
inhibitor deficiency. immunological stimulation does not affect nonimmunological
release.

TABLE 42.1 Etiopathogenesis of Urticaria Allergic Urticaria
The classic example of immunological mast-cell activation via
acute high-affinity IgE receptors is IgE-mediated urticaria (often termed
Idiopathic allergic urticaria). Cross-linking of receptor-bound IgE leads to
Infection-related the release of diverse preformed mediators and newly synthesized
Allergic (mediated by specific IgE)
lipid mediators and cytokines, resulting in the early- and late-
Chronic phase IgE-mediated allergic inflammatory responses.
Idiopathic IgE-mediated mast-cell activation can present as acute urticaria
Autoimmune (IgG against IgE or FcεRI) in those individuals previously sensitized to exogenous aller-
Infection-related gens. IgE to autoantibodies are implicated in chronic wheeling.
Drug-induced Examples include some food- and drug-induced urticarias and
Diet-related latex-induced contact urticaria. Allergic urticaria to inhaled
allergens (e.g., latex, animal epithelia) is often accompanied by
respiratory symptoms. Generalized allergic urticaria may progress
receptors and activation sites for neuropeptides and basic to anaphylaxis. Allergic urticaria resolves rapidly on withdrawal
secretagogues. of allergen exposure and recurs with each reexposure to the
Skin mast cell activation is central to the pathophysiology of allergen or cross-reactive agents.
CU. Mast cells can be activated by a variety of immunological
and nonimmunological triggers (Fig. 42.3). Immunological and Autoimmune Urticaria
nonimmunological pathways of mast-cell activation are character- Functional autoantibodies directed against the extracellular α-
ized by distinct patterns of mediator release. Immunological chain of FcεRI on dermal mast cells or basophils or, less frequently,
activation of mast cells is triggered by cross-linking of high-affinity against receptor-bound IgE have been demonstrated in 25–50%
9,10
IgE receptors (FcεRI) by antigen bound to antigen-specific IgE, of adult and pediatric patients with CSU. The pathophysiology
by anti-FcεRIα, or by anti-IgE antibodies. Histamine release of autoimmune CU involves cross-linking of high-affinity IgE
peaks at 5–10 minutes, followed by de novo synthesis of lipid- receptors by autoantibodies leading to degranulation of mast
derived mediators (leukotriene C4 [LTC4] and prostaglandin cells and basophils. There is good evidence that activation of

CHaPTEr 42 Urticaria, Angioedema, and Anaphylaxis 587



Eosinophil






C5b-9
ICAM1
t-PA

TNF-α IL-8
Bronchi
E-selectin
Histamine C3a
C5a





Mast cell
fiG 42.4 Immune Complex-Mediated Urticaria Initiated by Lodging of Antigenic Complexes
in Small Blood Vessels Followed by C3a and C5a Generation. This results in mast cell
degranulation and cytokine upregulation of adhesion molecules (intercellular adhesion molecule
[ICAM]-1, E-selectin) by tumor necrosis factor-α (TNF-α) and interleukin-8 (IL-8), which leads to
tissue recruitment of neutrophils and eosinophils and activation of tissue plasminogen activator
(t-PA).

cutaneous mast cells by IgG derived from CSU sera in vitro is (hypocomplementemic urticarial vasculitis syndrome [HUVS]).
dependent on C5a, but not all histamine-releasing IgG derived Damage to postcapillary venules results from the deposition of
from CSU sera are complement dependent on basophil assays. immune complexes in the vessel wall. Immune complexes are
Most functional autoantibodies are IgG1 or IgG3, which are formed on exposure to external (drug or infections) or internal
known to fix complement. By contrast, nonfunctional anti-FcεRI (collagen-like region of C1q) antigens. Complement activation
autoantibodies demonstrated by Western blot or enzyme-linked via the classical pathway leads to neutrophil chemotaxis through
immunosorbent assay (ELISA) in other autoimmune diseases cytokine expression and adhesion molecule activation (Fig. 42.4).
(including systemic lupus erythematosus [SLE] and bullous Proteolytic enzymes released from neutrophils damage vessel
pemphigoid) are generally from the noncomplement-fixing walls, leading to wheal formation and red blood cell (RBC)
subclasses IgG2 and IgG4. 10 extravasation.
The low-affinity IgE receptor FcεRII/CD23 expressed on B
lymphocytes and eosinophils may be another target antigen for Nonimmunological Mast-Cell Activation
an autoimmune response in CSU. Anti-CD23 antibodies have Skin mast cells can be activated nonimmunologically by many
11
been detected in patients with CSU. The interaction between agents, including neuropeptides (substance P, neuropeptide Y,
anti-CD23 antibodies and CD23 on eosinophils may induce vasoactive intestinal peptide, or somatostatin), calcitonin gene-
release of major basic protein 1 (MBP-1), a potent IgE-independent related protein, compound 48/80, and natural polyamines. Drugs
histamine-releasing agent, resulting in activation of mast cells (e.g., opiates, muscle relaxants, radiocontrast media, polymyxin
and basophils. B) can also cause dose-dependent nonimmunological urticaria
by activating membrane-associated G-coupled proteins. A classic
Immune Complex–Mediated Urticarial Rash clinical example is codeine-induced acute urticaria.
Mast-cell activation can result from binding of circulating immune
complexes to FcγRIII, expressed on mast cells. In addition, cir- Mast-Cell and Basophil Releasability in Urticaria
culating immune complexes can activate complement, leading In patients with CSU, dermal mast cells show a decreased activa-
to C3a and C5a anaphylatoxin formation. Urticarial rash caused tion threshold. Although CSU basophils are often hyporesponsive
by immune complexes can occur acutely in serum sickness–like to anti-IgE, they are paradoxically hyperresponsive to an as yet
reactions, transfusion reactions, some drug-induced urticarias, unidentified factor in normal human serum. 10
and urticaria associated with infectious or autoimmune diseases.
Immune complex–mediated urticarial rashes usually develop Skin Response to Mast-Cell Activation in Chronic Urticaria
1–3 weeks after initial exposure to the antigen and disappear Despite the existence of different pathways for mast-cell activation,
several weeks after antigen discontinuation. Chronic wheeling the end result is degranulation with release or secretion of
mediated by immune-complex damage and associated with a mediators. Histamine is crucial for the development of cutaneous
histological evidence of leukocytoclastic vasculitis is known as manifestations of urticaria and is found in high concentrations
urticarial vasculitis (see below). In this condition, urticaria can in tissue fluid of wheals. It causes localized redness resulting
be associated with systemic symptoms, such as fever, arthritis, or from vasodilatation, wheal formation from increased vascular
nephritis, especially the uncommon hypocomplementemic variant permeability leading to plasma leakage, and a surrounding axon

588 ParT fivE Allergic Diseases


reflex-mediated flare-up. Histamine is also the main mediator Aspirin and NSAIDs can trigger acute urticaria as well as
of itch in urticaria. However, histamine-induced wheals are causing flare-ups of preexisting chronic spontaneous (but not
short-lived in contrast to urticarial lesions that may persist up physical) urticaria. Aspirin-induced exacerbations have been
13
to 24 hours, implying that other proinflammatory mediators reported in 20–40% of patients with CSU. In some patients,
and/or cellular infiltrates contribute to CSU pathogenesis. aspirin can act as a cofactor in food- or exercise-induced
anaphylaxis.
Mast Cell–Independent Mechanisms of Urticaria Urticaria can develop from a few minutes to 24 hours after
Pseudoallergy (Intolerance) aspirin ingestion but usually within 1–2 hours. Angioedema of
Pseudoallergy, or nonallergic hypersensitivity, mimics immediate- the lips and tongue, impaired swallowing, and laryngeal edema
type allergic reactions clinically without evidence of underlying develop occasionally. Aspirin-induced skin symptoms usually
12
immunological mechanisms. The most common triggers of subside 24–48 hours after discontinuing the drug. However, severe
pseudoallergic reactions are aspirin and other nonsteroidal exacerbations of CSU caused by aspirin and other NSAIDs can
antiinflammatory drugs (NSAIDs), as well as some food ingre- last from several days to several weeks after aspirin intake. 13
dients and additives, such as salicylates, benzoates, and tartrazine. There are no skin tests or reliable in vitro diagnostic techniques
These reactions do not involve IgE sensitization and can, therefore, for patients with aspirin-induced urticaria, and the diagnosis
occur on first exposure. Pseudoallergic reactions are dose- can only be established by challenge tests. Patients should avoid
dependent and usually occur with chemically nonrelated sub- aspirin and other NSAIDs, but COX-2 inhibitors (coxibs) are
stances. The diagnosis is difficult because skin tests and serology usually well tolerated and can probably be used safely.
are uninformative. Diagnosis of nonallergic hypersensitivity is
based on a distinctive clinical pattern, time course, clinical signs, Food-Induced Pseudoallergic Reactions in CSU
and response to elimination of the cause. In the appropriate Pseudoallergic food reactions appear to be important in some
clinical context, pseudoallergy can be confirmed with oral chal- patients with CSU. Pseudoallergic food triggers include natural
lenge tests. salicylates in fruit and vegetables and artificial food additives in
processed foods, such as benzoates and tartrazine. Low-molecular-
NSAIDs weight aromatic compounds in tomatoes, white wine, and herbs
14
Aspirin and other NSAIDs inhibit constitutive cyclooxygenase have also been implicated. Clinically, exacerbations of CSU
(COX-1) and inducible cyclooxygenase (COX-2), thereby diverting resulting from dietary pseudoallergens gradually subside within
arachidonic acid metabolism toward the 5-lipoxygenase pathway 10–14 days on an exclusion diet; in contrast, in 1–3 days in acute
in some cell types, notably eosinophils. This modulation of allergic urticaria. One study showed increased gastroduodenal
arachidonic acid metabolism results in overproduction of and intestinal permeability in patients with CU. Responders to
cysteinyl-leukotrienes LTC4, -D4, and -E4, leading to vasodilata- elimination of pseudoallergens in their diet demonstrated
tion and edema. Furthermore, reduction of PGE 2 formation by normalization of mucosal permeability and skin symptoms.
COX inhibition has two further effects that promote urticaria: Although the underlying mechanisms for pseudoallergic reactions
first, by reducing inhibition of cysteinyl leukotriene production in CU remain unproven, an impaired gastroduodenal barrier
and second, by reducing an inhibitory effect on immunologically- function may be a contributory factor. 14
mediated mast-cell degranulation (Fig. 42.5). Cross-sensitivity
occurs with other nonselective NSAIDs in susceptible individuals, Kinin-Mediated Angioedema
depending on their pharmacologic potency for COX inhibition The mediator of angioedema resulting from hereditary and
but not their chemical structure. acquired C1 esterase inhibitor (C1-INH) deficiency and
angiotensin-converting enzyme inhibitor (ACEI)–induced
angioedema is bradykinin rather than histamine or leukotrienes.
There is currently no evidence that kinins are involved in other
Arachidonic acid NSAIDs types of urticaria or angioedema. Bradykinergic angioedema is
COX-1
not considered a type of urticaria.
COX-2
LTA 4 PGH 2 CLINICAL CLASSIFICATION
COX-2i
CU may be spontaneous, inducible, or both.
LTB 4 LTC, D, E 4 PGE 2 PGD 2 Spontaneous Urticaria
PGI 2
TXA 2 Spontaneous urticaria is the most common presentation. The
term “spontaneous” makes no assumption about etiology, which
may include autoimmunity, allergy, pseudoallergy, or infection.
Those cases for which a cause cannot be ascertained with reason-
Mast cell able confidence are called idiopathic. In practice, this is the
majority of patients. Spontaneous urticaria can be further
fiG 42.5 Arachidonic acid pathways illustrating potential diversion classified by duration and frequency of attacks into acute, chronic,
from prostaglandin synthesis to cysteinyl leukotrienes (LTC4, and episodic urticaria.
-D4, -E4) by blocking cyclooxygenase (COX), leading to increased
vasopermeability. Reduction of prostaglandin E 2 also reduces Acute Spontaneous Urticaria
its direct inhibitory effect on leukotriene production and on Acute urticaria is defined as continuous disease lasting <6 weeks.
immunological mast cell degranulation. Individuals with an atopic predisposition are at higher risk of

CHaPTEr 42 Urticaria, Angioedema, and Anaphylaxis 589


acute urticaria; atopic diseases are found in about half the patients
3
with acute urticaria. Most acute urticaria resolves spontaneously
within 3 weeks, but in 10% of patients, it may progress to CSU.
Infections are the most common identifiable cause of acute
urticaria, with some cases resulting from foods or drugs. A specific
cause of acute urticaria will not be found in about 50% of patients.
Foods are the most common cause of acute urticaria in young
children but are rarely responsible for acute urticaria in adults.
In infancy, cow’s milk allergy may cause acute allergic urticaria.
Drug-induced urticaria is the most common presentation of
drug hypersensitivity, accounting for a quarter of all adverse
drug reactions, with penicillin and NSAIDs being the most
common causes of allergic and nonallergic drug-induced urticaria,
respectively. Drug-induced urticaria is more likely in older adults,
perhaps reflecting polypharmacy and age-related pharmacokinetic
changes, and in patients with human immunodeficiency virus fiG 42.6 Extensive induced dermographic whealing on the chest
(HIV) infection and those with renal or liver diseases. of a patient as a result of scratching.

Chronic Spontaneous Urticaria
CSU is characterized by daily or almost daily itchy wheals on
skin, with or without angioedema, for ≥6 weeks. In 30–50% of urticarias), which may lead to difficulty in diagnosis. With the
patients, CSU is caused by functional autoantibodies against the exception of DPU, inducible urticarias develop rapidly after
10
α chain of the high-affinity IgE receptor or against IgE itself. exposure to the relevant trigger and fade within an hour. 2
Functional abnormalities of basophils have also been described. The pathogenesis of inducible urticarias is unclear except in
However, in 50% of patients, the etiopathophysiology of the the case of allergic contact urticaria, which is caused by muco-
disease remains unknown and appears to be endogenous. cutaneous exposure to an allergen to which the individual has
Whatever the primary cause, CSU appears to be aggravated by already developed IgE sensitization. A diagnosis of physical
a variety of exogenous exposures, including acute infections urticaria is confirmed if the symptoms can be reproduced by
15
(most commonly viral upper respiratory tract infections), NSAIDs, challenge testing with the suspected stimulus. Challenge testing
dietary pseudoallergens, menses in women, tiredness, and stress. can be used for monitoring threshold changes during treatment.
The presence of these factors probably explains why the clinical In general, treatment of inducible urticarias involves avoidance
course is often erratic and unpredictable. of known triggers and taking antihistamines. Sometimes tolerance
CSU affects women twice as often as men. There is a common can be induced for cold and solar urticarias.
link between CSU and thyroid autoimmunity (present in about
14–25% of CU cases) as well as other autoimmune diseases, Mechanical Urticaria
including Graves disease, vitiligo, and insulin-dependent diabetes. Symptomatic Dermographism
CSU is often associated with inducible urticaria (e.g., delayed- Dermographism is the most common physical urticaria, mainly
pressure urticaria [DPU]). Around 50% of patients present with affecting young people. Typical red, itchy, linear wheals are evoked
both wheals and angioedema. CU can have a continuous or a within minutes of stroking, friction, rubbing, or scratching the
relapsing course. CU of all types, including CSU, can cause serious skin (Fig. 42.6). Overheating, stress, and anxiety usually aggravate
disability in patients, including loss of sleep and energy, social symptoms. The diagnosis of dermographism is confirmed by
isolation, altered emotional reactions, and difficulties in aspects stroking the skin with a blunt firm object or a calibrated instru-
of daily living similar in degree to patients with severe ischemic ment, such as a dermographometer (HTZ, Croydon, U.K.) or
heart disease. FricTest (Moxie, Berlin, Germany), usually on the upper back.

Episodic Spontaneous Urticaria Delayed Pressure Urticaria
The cause of episodic urticaria often remains unknown, but the Isolated DPU occurs in just 2% of all patients with urticaria,
possibility of an allergic or pseudoallergic cause needs to be but DPU coexists with CSU in up to 40% of patients. DPU is
considered. the most debilitating of the physical urticarias and is triggered
by sustained local pressure (e.g., wearing tight shoes, carrying
Inducible Urticarias heavy bags, long walks, sitting or leaning against firm objects,
Inducible urticarias are common, accounting for 25% of all cases climbing ladders, jogging, driving, or clapping hands). Deep and
of CU. These include physical urticarias, such as symptomatic painful swellings, clinically resembling angioedema, develop 30
dermographism, cold and heat urticarias, DPU, solar urticaria, minutes to 12 hours after pressure, and may be associated with
and vibratory angioedema, in which symptoms are triggered flu-like symptoms, fever, arthralgia, and fatigue. The most fre-
reproducibly by an external mechanical or thermal/ultraviolet quently affected sites are hands, soles, buttocks, shoulders, and
stimulus. The inducible group now also includes cholinergic, areas under straps and belts. DPU lesions last 12–48 hours and
adrenergic, aquagenic, and contact urticarias, in which the eliciting are usually painful rather than itchy, especially on the hands
stimuli for mast-cell degranulation are defined by a nonphysical and feet. Laboratory investigation reveals transitory leukocytosis
exposure. Inducible urticarias can coexist with CSU (e.g., DPU and elevated erythrocyte sedimentation rate (ESR). Hanging a
or dermographism), and more than one inducible urticaria can heavy weight suspended on a narrow band over the forearm or
occur in the same patient (e.g., dermographic and cholinergic thigh for 15 minutes may be used as a challenge test, but more

590 ParT fivE Allergic Diseases


reliable results can be obtained with a dermographometer applied urticaria presents some difficulty, as antihistamines are only of
2
at 100 g/mm for 70 seconds. The reaction should be assessed limited value.
after 2–6 hours. DPU is difficult to treat because it responds
poorly to antihistamines. Solar Urticaria
Solar urticaria affects about 1% of all patients with urticaria
Vibratory Angioedema and has a slight female predominance. It can be associated with
Vibratory angioedema is rare. Familial cases have been described. erythropoietic porphyria. Wheals are caused by electromagnetic
Local swelling develops several minutes to 6 hours after using wavelengths ranging from 290 to 760 nm (ultraviolet B [UVB],
vibrating machinery, lawn mowing, applauding, and jogging, UVA, and visible spectrum). It develops within minutes or hours
for instance. Systemic symptoms may occur (headache, chest after sun exposure and fades within 24 hours. Lesions are usually
tightness, diffuse flare). Placing the elbow or hand on a laboratory confined to sun-exposed skin, although they can also develop
vortex for 5–15 minutes is a useful challenge test. Avoidance of under clothing. The severity of solar urticaria depends on the
the trigger is the only helpful treatment strategy. wavelength, intensity, and duration of irradiation. Short exposures
induce flare and pruritus, whereas longer exposures cause wheal-
Thermal or Ultraviolet-Induced Urticaria ing. In patients sensitive to the visible spectrum, reactions may
Cold Urticaria occur through window glass.
16
Cold urticaria accounts for about 3% of physical urticarias. It Solar urticaria is diagnosed by phototesting. Patients are
occurs in both children and adults and is more common in cold advised to use creams with a high sun protection factor (SPF),
climates, in women, and in atopic patients. The majority of cases protective clothing, and protective window shields and to limit
are primary with no identifiable cause, but some cases are second- the time spent outdoors.
ary to internal disease. Clinical manifestations can be local or
generalized. Mucosal involvement may develop after drinking Other Patterns of Inducible Urticaria
cold beverages. Systemic symptoms may be respiratory (laryngeal Cholinergic Urticaria
angioedema, tongue or pharyngeal swelling, wheezing), vascular Cholinergic urticaria is the second most common physical
(hypotension, tachycardia), GI (hyperacidity, nausea, diarrhea), urticaria and occurs mainly in adolescents, young adults, and
or neurological (disorientation, headache). Cold-induced urticaria patients with atopy. Cholinergic urticaria usually follows a rise
can be evoked by low ambient temperature, contact with cold in core temperature resulting from physical exercise, fever, or
objects, food or beverages, or immersion in cold water. Wheals external passive heat (hot bath, shower, sauna) but may also be
develop during the cold exposure or, more commonly, on provoked by emotional stress and spicy food. The characteristic
rewarming. The severity of cold urticaria depends on the intensity lesions are highly pruritic pinpoint pale wheals of 1–3 mm
and duration of the cold stimulus. Cold urticaria is potentially surrounded by a red flare. The wheals may occur anywhere
life threatening, with a risk of anaphylaxis and death on exposure except the soles and palms. Lesions usually begin on the trunk
of large skin areas to cold, for example, jumping into cold water and the neck, extending outward to the face and limbs. As
and hypothermia in neurosurgical and cardiothoracic operations. lesions progress, confluent areas of whealing and redness may
Familial cold urticaria is caused by mutations in the cold-induced develop. Severely affected patients may develop angioedema and
autoinflammatory syndrome (NLRP-3) gene and is no longer even anaphylaxis. Most patients with mild disease do not seek
classified as an inducible urticaria. medical help. The rash is triggered by activation of cholinergic
In 1–5% of patients, cold urticaria is secondary to cryoproteins sympathetic innervation of sweat glands, but the mechanism of
(mainly cryoglobulins). These can be associated with infections activation remains unclear. Decreased blood protease inhibitor
(hepatitis C, infectious mononucleosis, syphilis, Mycoplasma levels have been reported, and this is the rationale for using
infection), autoimmune diseases, and lymphoreticular malignancy anabolic steroids to treat occasional severely affected individu-
(Waldenström macroglobulinemia, myeloma), but these are rare. als who are unresponsive to other measures. The prognosis is
Cold urticaria can precede these diseases by several years. Second- reasonably favorable, with spontaneous resolution within 8 years
ary cold urticaria can also be drug-related (penicillin, oral in most patients. However, 30% of patients are affected for over
contraceptives, ACEIs). 10 years.
The diagnosis of cold urticaria is confirmed by an ice cube Cholinergic urticaria can be confirmed by reproducing the
challenge or TempTest (Moxie, Berlin, Germany). Some atypical rash with exercise or passive heating in a hot bath at up to 42°C.
cold-induced urticarias have negative results in the ice cube test. Treatment is primarily with antihistamines, but beta-blockers,
The clinical workup in cold urticaria includes measurement danazol, ketotifen, and montelukast have also been used. The
of cryoproteins. Patients should be cautious about bathing or condition may be refractory for up to 24 hours, and this may
swimming in cold water and consuming cold food or drinks. enable patients to prevent attacks by taking daily exercise.
Antihistamine treatment is often helpful but does not prevent
anaphylaxis caused by swimming in cold water. In severe cold Aquagenic Urticaria
urticaria, tolerance induction may be attempted: this involves Aquagenic urticaria is very rare. It occurs in women more
depletion of mast-cell histamine by repeated cold exposure. often than in men and is triggered by water contact but not
after drinking water. Scattered small papular wheals, similar to
Heat Urticaria cholinergic urticaria but with a larger flare, appear within 10–20
Heat-induced urticaria is very rare. It is induced by local heating minutes of water contact and resolve in 30–60 minutes. Diagnosis
of the skin at 38–44°C. Challenge test is done by application of is made by using a challenge test in which a wet compress at
hot water in a tube or beaker at up to 44°C for 4–5 minutes body temperature is applied for up to 10 minutes on whichever
or TempTest (Moxie, Berlin, Germany). Symptoms develop part of the body is usually affected. Associations with HIV and
several minutes after exposure. Management of heat-induced hepatitis B infection have been described.

CHaPTEr 42 Urticaria, Angioedema, and Anaphylaxis 591



Angioedema




Without wheals With wheals




Low C4 Normal C4 Diagnose and manage
as for urticaria



Type I HAE Type II HAE AAE Idiopathic

↓ C1 inh Normal C1 inh Normal or low C1 inh Drug induced
↓ C1 inh functional ↓ C1 inh functional ↓ C1 inh functional e.g., ACEi
↓ C1q
Episodic angioedema
with eosinophilia

HAE: Hereditary angioedema HAE with normal C1
AAE: Acquired angioedema inhibitor (Type III HAE)
fiG 42.7 Diagnostic pathway for the differential diagnosis of angioedema.




Contact Urticaria Angioedema Without Wheals
Contact urticaria occurs locally after skin or mucosal contact Angioedema occurs in nearly half the patients with CSU; in
2,3
with the eliciting agent. Reactions usually develop within a these patients, the disease tends to be more severe and more
few minutes and resolve over 2 hours, although delayed-contact difficult to treat. Angioedema without wheals occurs in about
urticaria can occur with a latent period up to 48 hours. Contact 10% of patients with CSU but needs specific investigation because
urticaria can be caused by many organic and inorganic stimuli, it may be caused by C1 inhibitor deficiency or drugs, although
such as latex, animal danders and secretions, foods, plants, topical many cases remain unexplained (Fig. 42.7).
drugs, and cosmetics.
Allergic contact urticaria occurs mainly in atopic subjects. Angioedema Caused by C1 Inhibitor Deficiency
IgE sensitization can occur through skin, mucous membranes, The diagnosis and clinical presentation of hereditary and acquired
and the respiratory or GI tract. Foods are the most common C1-INH deficiency are covered in Chapter 21.
cause. In ≈15% of patients, contact with the allergen may induce
anaphylaxis. The severity of contact reactions depends on many Angioedema With Normal C1 Inhibitor
factors (area of exposure, duration of contact, amount and Histaminergic angioedema (without wheals)
concentration of substance, patient reactivity, comorbidity, and Idiopathic. Idiopathic angioedema is diagnosed when no
concomitant treatment). cause can be established. It is generally self-limiting but may
Nonallergic contact urticaria is commoner than allergic contact follow a prolonged course. Treatment of idiopathic angioedema
urticaria and is usually caused by low-molecular-weight chemicals. is as for spontaneous urticaria. Antihistamines are the mainstay
Contact urticaria to benzoic acid in food is thought to involve of therapy; corticosteroids (prednisolone 30–40 mg/day) are
generation of eicosanoids because it can be blocked by NSAIDs, useful for up to 3 days to cover more severe episodes, and epi-
but for other substances (e.g., polyvinylchloride, polyethylene nephrine is lifesaving in laryngeal angioedema. Tranexamic acid
glycol), the mechanism remains unknown. Nonallergic contact can help in idiopathic angioedema without wheals, but it is usually
urticaria may occur on first exposure and may depend on dose ineffective when angioedema occurs with urticarial wheals.
and concentration of the chemical. Drug-induced. Angioedema without wheals occasionally
occurs with NSAIDs, usually within several hours of intake.
DIFFERENTIAL DIAGNOSIS OF URTICARIA Bradykininergic angioedema
Hereditary. Some kindreds have been described with a
Urticarial Vasculitis dominant pattern of angioedema inheritance, mainly in women,
Urticarial vasculitis is characterized clinically by CU and histo- in whom a gain-of-function (GOF) mutation of the contact
17
logically by leukocytoclastic vasculitis on lesional skin biopsy. pathway of coagulation in F12 has been found in about 20% of
It is important to differentiate urticarial vasculitis from CSU affected families. This used to be called type III HAE, but the
in terms of prognosis, approach to diagnostic evaluation, term hereditary angioedema with normal C1 inhibitor is now
and therapy. preferred. 18

592 ParT fivE Allergic Diseases


Drug-induced. Angioedema develops in 0.1–2% of patients DIFFERENTIAL DIAGNOSIS
on ACEIs. Of these, up to 40% of patients present with life-
threatening angioedema of the upper airway. It is thought to Several dermatoses may present with urticarial lesions, including
result from inhibition of kininase II, which breaks down bra- erythema multiforme minor, bullous pemphigoid, and dermatitis
dykinin, as well as converting angiotensin I to angiotensin II in herpetiformis. These dermatoses can nearly always be distin-
the renin–aldosterone pathway. It usually presents with episodic guished clinically from urticaria on the basis of their polymorphic
and unpredictable swellings of the head and neck, especially of pattern, prolonged duration of individual lesions, lack of daily
the tongue and oropharynx. Although, in most cases, angioedema fluctuation, development of vesicles or blisters, and resistance
develops within the first week of treatment with ACEIs, symptom to conventional therapy for urticaria. Very occasionally, skin
onset may occur after several years on treatment. Management biopsy, with or without indirect immunofluorescence, may be
involves discontinuation of ACEI therapy. Angioedema often required to make the distinction.
recurs on reexposure to ACEIs. ACEIs may also precipitate Papular urticaria is an urticarial reaction to insect bites in
angioedema in patients with angioedema from other causes, sensitized individuals. The lesions are fixed rather than fluctuating,
including C1-INH deficiency. Rare instances of angioedema have may take days or weeks to resolve fully, and may leave pigmenta-
been reported with angiotensin II receptor antagonists. tion or scars. Bites often occur asymmetrically in groups or lines.
Although histamine is involved in the initial pruritic lesions,
Autoinflammatory Syndromes Presenting With oral antihistamines are usually unhelpful, and potent topical
Urticarial Rash steroids may be required to speed up natural resolution.
Acquired
Schnitzler syndrome. Schnitzler syndrome is a rare form of WORKUP IN PATIENTS WITH URTICARIA
CU with intermittent fever, bone pain, high ESR, and monoclonal
19
IgM, or, very rarely, IgG gammopathy. Clinically, patients present Evaluation of patients with urticaria requires a detailed history
21
with nonpruritic or mildly pruritic CU, mainly affecting the and a physical examination. The history is particularly important
trunk and limbs. The wheals are resistant to antihistamines, and in patients with urticaria and should include a thorough inquiry
angioedema is rare. Fever bouts may exceed 40°C, sometimes for all potential causes of the disorders, possible precipitating
with chills and nocturnal sweating. Patients often suffer from and aggravating factors, the timing of onset and duration of
bone pains, mainly in the pelvis or tibias, arthralgia, and some- individual wheals, associated symptoms as well as travel history,
times full-blown arthritis. Lymphadenopathy, hepatomegaly, and recent infection, occupational exposure, food and drug intake,
splenomegaly may be present. and comorbidity. Patients may be asked to keep a diary of attacks
1
Kappa light-chain monoclonal IgM and, less commonly, IgG and complete weekly urticarial activity scores for CSU. The
paraproteins are found on serum electrophoresis. The ESR is duration of individual lesions can be very helpful in distinguishing
persistently elevated at 60–100 mm/hour, with leukocytosis, the different clinical patterns of urticaria.
elevated platelet count, and anemia. Skin histology shows
neutrophilic urticaria with a tendency to localize around append-
ages in most cases; monoclonal IgM is deposited in the epidermis CLiNiCaL PEarLS
around the keratinocytes and along basement membranes on Diagnosis of Clinical Patterns of Urticaria
direct immunofluorescence. Bone examination may demonstrate
hyperostosis on radiography and hyperfixation on bone tech- • The duration of individual wheals can help define the pattern of
netium scanning. Bone marrow examination shows normal results urticaria.
in most patients, but nonspecific lymphocytic, plasmocytic, or • Wheals lasting ≤1 hour are usually triggered by a physical stimulus.
• Localized wheals lasting up to 2 hours may be caused by skin or
polyclonal infiltration is present in about 20%. mucosal contact with an allergen or a nonimmunological exposure.
The pathophysiology of Schnitzler syndrome is still unclear, • Wheals that take 1–24 hours to fade are usually a presentation of
and the severity of urticarial rash does not depend on the chronic spontaneous urticaria.
paraprotein level. Evidence of activation of interleukin-1 (IL-1), • Wheals lasting >24 hours may be caused by delayed pressure urticaria
increased IL-6, and granulocyte macrophage–colony-stimulating or urticarial vasculitis.
factor (GM-CSF) and anecdotal reports of complete clinical
responses to the IL-1 receptor antagonist anakinra suggest that
cytokines play a leading role in its pathogenesis. The prognosis Physical examination should focus on skin lesion morphology
is generally good. However, long-term follow-up is recommended and careful systemic evaluation for underlying disease or comor-
because patients may develop B-cell lymphomas 10–20 years bidities. If the patient is symptom-free at the time of evaluation,
after its onset. photographs taken when the symptoms occur are helpful. The
approximate duration of individual lesions can be assessed by
Hereditary (Cryopyrin-Associated) Periodic Syndromes outlining a particular lesion with a pen and observing it for a
Several hereditary autoinflammatory urticarial syndromes show day. The appearance and distribution of skin lesions may suggest
mutations of the NLRP-3 gene on chromosome 1q44. NLRP-3 a diagnosis (e.g., the pinpoint lesions with a large flare in cho-
encodes a protein called cryopyrin, which is involved in apoptosis linergic urticaria or lesions on sun-exposed areas in solar
and inflammation. These rare autosomal dominant disorders urticaria).
include familial cold autoinflammatory syndrome (FCAS), Further evaluation of patients with urticaria is guided by the
Muckle-Wells syndrome (MWS), and chronic infantile neurologi- patient history and clinical pattern of disease. However, it must
cal, cutaneous and articular (CINCA) syndrome, now grouped be remembered that there can be more than one cause for urticaria
under the inclusive term cryopyrin-associated autoinflammatory and that different clinical subtypes of urticaria can coexist in
syndrome (CAPS). 20 one patient.

CHaPTEr 42 Urticaria, Angioedema, and Anaphylaxis 593


to relevant antigens (FcεRIα or IgE) do not correlate well with
Workup in Acute Urticaria the results of functional assays. 10
When allergens are suspected as the cause there should be a
close temporal relationship to the time of exposure, usually MANAGEMENT OF URTICARIA
starting within minutes, a history of previous exposure causing
sensitization and prompt resolution on allergy withdrawal. IgE Finding effective treatment for urticaria can be challenging.
sensitization can be assessed by skin prick testing or fluoroen- Treatment should be tailored to the clinical pattern, duration,
zymatic immunoassay (FEIA) (also known as serum specific IgE and severity of the urticaria. Management should include
testing). nonpharmacological measures and drug therapy with a stepwise
approach. 1
Workup in Physical Urticarias
When physical urticaria is suspected, appropriate challenge testing
22
should be performed to confirm the diagnosis. Generally, there THEraPEUTiC PriNCiPLES
is no need for further investigation, except for cold urticaria, Management of Urticaria
where blood cryoglobulins should be assayed.
• Eliminate infectious, drug, or food causes.
Workup in Chronic and Episodic • Minimize nonspecific aggravators, including heat, stress, alcohol,
Spontaneous Urticarias nonsteroidal antiinflammatory drugs, and pressure.
No laboratory workup is recommended for patients with mild • Regular oral H1 antihistamines are the first line of therapy for all
spontaneous and inducible urticarias.
CSU that is easily controlled by antihistamines, unless the history • Second-line treatments, including short courses of oral corticosteroids,
points to an underlying disease. Studies have shown that random may be necessary for specific clinical situations.
laboratory testing very rarely yields evidence of unsuspected • Immunosuppressive therapies should be reserved for patients with
internal diseases as a cause of CSU, and this should therefore severe autoimmune urticaria or steroid-dependent urticaria that has
be discouraged. 21 not responded to other first- and second-line measures.
Screening laboratory evaluation can be considered in patients • Omalizumab (monoclonal anti-IgE) is effective in chronic spontaneous
urticaria refractory to H1 antihistamines
with poor response to first-line antihistamine treatment. A
complete blood count (CBC) with differential, ESR, thyroid-
stimulating hormone (TSH), thyroid antibodies, liver function
tests, and urinalysis will exclude most diseases associated with General Measures
urticaria. Causes, triggers, and aggravating factors should be avoided or
Other evaluations should be guided by abnormal findings minimized, whenever possible. Patients with CSU should minimize
in the history and physical examination in patients with CSU. exposure to nonspecific aggravating factors, such overheating,
Additional tests may include stool examination for ova and wearing tight clothes and shoes, stress, alcohol, dietary pseudoal-
parasites and Helicobacter pylori, antinuclear antibody titer, lergens, and some drugs. NSAIDs aggravate up to 30% of patients
hepatitis viral screening, and skin prick or blood tests for with CSU and are usually avoided. This does not apply to the
specific IgE in episodic urticaria if there is a story of intermit- physical urticarias, in particular DPU, where NSAIDs may be
tent allergen exposure. Tests for immediate hypersensitivities used as treatment. ACEIs are contraindicated in angioedema
should not be undertaken in chronic continuous urticaria unless without wheals that may be mediated by kinins but not in other
there are compelling reasons for doing so. Rarely, CSU can be patterns of urticaria. Although it is often recommended that
caused by a specific food additive, which should be confirmed patients with CSU avoid codeine and penicillin, clinical experience
by dietary exclusion and double-blind, placebo-controlled oral suggests that this is not necessary. Cooling lotions and creams,
challenge. such as 1% menthol in aqueous cream, may help relieve pruritus.
Some patients with spontaneous but not inducible CU appear
The Diagnosis of Autoimmune Chronic Urticaria to respond to a low-pseudoallergen diet. However, controlled
12
The diagnosis of autoimmune CU is not straightforward and clinical trials are lacking.
involves in vivo and in vitro approaches. Autologous serum skin
testing (ASST) is a simple and useful screening method for First-Line Therapy
autoreactivity in patients with CU. For skin testing, 0.05 mL of Antihistamines are the cornerstone of treatment for all types of
the patient’s own serum should be injected intradermally into histaminergic urticaria. Second-generation antihistamines offer
clinically uninvolved forearm skin, together with an equal volume several advantages over classic H1 antihistamines, including lack
of saline as a negative control. Histamine 10 mg/mL can be used of sedation and impairment of performance, longer duration
as a positive control. The reaction is considered positive if the of action, and absence of anticholinergic side effects. Meta-analysis
serum skin test forms a pink wheal at least 1.5 mm greater than indicates that antihistamines are effective in 40–90% of patients
the negative control at 30 minutes. The test is 80% specific and with CU. Second-generation antihistamines are inverse agonists
70% sensitive for autoimmune CU as defined by a positive of H1 receptors, which stabilize H1 receptors in the inactive
basophil histamine release assay. 23 conformation and are, therefore, most effective in CU when
The current diagnostic gold standard in autoimmune CSU taken regularly for prophylaxis. The timing of antihistamine
is a functional release assay using whole sera on healthy donor intake should be adjusted to suit the diurnal pattern of urticaria
basophils or mast cells, but these only give indirect evidence of for each individual. Although the evidence base for combining
functional autoantibodies. Being technically difficult, these assays H1 and H2 antihistamines is poor, this may be helpful. H2
are mainly confined to research centers. Nonfunctional immunoas- antihistamines also suppress the dyspepsia that often accompanies
says (Western blot, ELISA) based on binding of autoantibodies severe urticaria.

594 ParT fivE Allergic Diseases


Second-Line Therapy involved in the breakdown of bradykinin. Angiotensin II recep-
It has become common practice to increase second-generation tor agonist (ARA 2) are probably safe alternatives. Exogenous
antihistamines above their licensed doses up to fourfold when estrogen (oral contraceptives and hormone replacement therapies)
CU does not respond because clinical experience and updosing should be avoided in women, since it appears to activate kallikrein
studies show that this achieves better control in some patients. through activated factor XII. Lifestyle events that exacerbate HAE
When urticaria does not respond to first-line measures, systemic vary in their importance among individuals but may include local
corticosteroids are commonly used as short-term rescue therapy trauma (e.g., dental extraction), stress, tiredness, and intercurrent
for acute urticaria or severe exacerbations of CU. Long-term infections, possibly including Helicobacter pylori infection. Attacks
treatment with oral corticosteroids is not recommended because involving the extremities or abdomen are the most common. It is
of safety concerns. In corticosteroid-dependent patients, an estimated that over their lives, up to 50% of patients will experi-
alternate-day dosing schedule may be used, and steroid-sparing ence an attack of oropharyngeal swelling, with risk of asphyxiation,
drugs should also be considered. A wide variety of medications so treatment must be rapidly available for emergencies in all
have been reported to be of benefit for antihistamine-unresponsive patients as well as as a preventive measure. The intention of
urticaria when oral corticosteroids might otherwise have to be treatment is to reduce or curtail the severity of a swelling and to
considered, but they are invariably used off-label, and controlled reduce “downtime” if one occurs. Some patients with frequent
trials are usually lacking. Where possible, these should be targeted peripheral swellings prefer to treat themselves symptomatically
at specific subgroups of urticaria patients (e.g., the LT receptor with analgesics and wait for spontaneous resolution over 3–4
antagonist montelukast has been shown to be effective in aspirin- days, rather than have specific treatment, since no treatment is
sensitive patients with CSU, and there is limited evidence for a completely without risk of adverse effects, and there are potential
trial of thyroxine in biochemically euthyroid patients with CSU problems with cost and/or availability. The management of types
who have thyroid autoimmunity). I and II HAE is better defined than type III but follows similar
principles. 24
Third-Line Therapy
The recent approval of omalizumab (anti-IgE) as add-on therapy Treatment of the Acute Attack
for CSU not responding to antihistamines has transformed the The “gold standard” treatment for oropharyngeal or GI attacks
management of severe disease in many patients. The recom- in most countries (except the United States until recently) has
mended dose is 300 mg by monthly subcutaneous injection, been plasma-derived nanofiltered C1 esterase inhibitor (pd-
although clinical experience indicates that lower (and occasionally C1-INH) concentrate given by intravenous infusion. It has proven
higher) doses may be effective and the interval between treatments to be effective and safe. The recommended dose is 20 units/kg
can be extended in good responders. Clinical experience suggests body weight in adults and children, although smaller doses have
that when used off-label, it may also be effective for many patients been used in the past and may be effective. Up to 3 units of fresh
with inducible urticarias. The mechanism of action is still not frozen plasma (containing C1 inhibitor and its substrate, comple-
certain but probably involves reduction of high-affinity IgE ment) may be given as an alternative in an emergency when
receptors on mast cells and basophils as a consequence of a rapid pd-C1-INH is not available, but it will not have had the same
fall in circulating free IgE and a later reduction in IgE bound to stringent screening and production measures to eliminate the
mast cells, resulting in a stabilizing effect. Experience to date possibility of transmissible infection. Initial improvement in the
suggests that omalizumab is often highly effective for control of swelling may be seen within 30–60 minutes, and time to clearance
urticaria symptoms (including itch) but probably does not modify is usually in the order of 24 hours after pd-C1-INH. Self-
the natural history of the illness. administration can reduce the severity of attacks by allowing
Immunosuppressive therapy is mainly considered for auto- earliest treatment and should be encouraged. A recombinant
immune CSU. However, it may also benefit therapy-resistant C1-INH is licensed in Europe. Icatibant (a bradykinin 2 receptor
CSU without evidence of circulating antibodies. antagonist) is also highly effective for acute episodes of HAE.
The best-studied immunosuppressive therapy is cyclosporine, Ecallantide (a kallikrein antagonist) is currently licensed in the
shown to be effective initially at 4 mg/kg daily in patients with United States but not in Europe. Both are given by subcutaneous
CSU. Patients must be monitored carefully for renal impairment injection, which provides an easier route for administration than
and hypertension; treatment should normally be limited to 4 intravenous infusion. Ecallantide should be given under medical
months. Cyclosporine is contraindicated in patients with previous supervision, since there is a small risk of allergic reactions.
malignant disease except nonmelanoma skin cancer. There is Icatibant is licensed for self-administration, which provides a
some evidence for efficacy of plasmapheresis and immunoglobu- potential advantage. There have been no head-to-head studies
lins in chronic autoimmune urticaria, although these are expensive of pd-C1-INH, ecallantide, and icatibant, but experience suggests
options, and controlled clinical trials are needed. Methotrexate, that the effectiveness of these products is comparable. It should
mycophenolate mofetil, and azathioprine have also been used be noted that antihistamines and steroids have no place in the
alone or with corticosteroids. 14 management of HAE. Any improvement resulting from epineph-
rine’s effects on vasopermeability will be transient, and there is
MANAGEMENT OF HEREDITARY ANGIOEDEMA no evidence that it changes the overall course of an attack.
The swellings of HAE are mediated by kinins rather than hista- Short-Term Prophylaxis
mine, so the management of HAE is completely different from It has become common practice to give prophylactic treatment
mast cell–dependent urticaria. The primary aim of therapy is to with pd-C1-INH before procedures involving local trauma to the
replace the missing functional C1 esterase inhibitor or stabilize oropharynx, including dental extraction and intubation for general
the coagulation, fibrinolysis, complement, and kallikrein–kinin anesthesia. The dose for prophylaxis may be less than that needed
pathways. ACEIs should be avoided because ACE is a key enzyme for treatment of an acute attack. Common practice is to give at

CHaPTEr 42 Urticaria, Angioedema, and Anaphylaxis 595


least 500 units pd-C1-INH 1 hour before the procedure, with a of coronary and peripheral arteries, and vasodilation of venules,
further dose available in case a swelling develops. Other strate- thereby producing clinical symptoms of anaphylaxis. IgE-
gies include increasing the dose of prophylactic treatment with mediated reactions occur in presensitized patients (e.g., those
anabolic steroids (danazol or stanozolol) or plasmin inhibitors experiencing penicillin-, insulin-, latex-, or peanut-induced
(tranexamic acid or ε-aminocaproic acid) for at least 48 hours anaphylaxis). IgG- or IgM-related transfusion reactions should
before and after the procedure. Specific guidance on dosing for be classified as immunological, non–IgE-mediated anaphylaxis. In
adults and children can be found elsewhere. contrast, some substances, such as opioids, radiocontrast media,
vancomycin, and some muscle relaxants, are capable of direct
Long-Term Prophylaxis release of mediator (histamine) from basophils and mast cells
Anabolic steroids are the mainstay of long-term prophylaxis in without involvement of IgE. Although reactions to NSAIDs are
countries where they are licensed for use in the treatment of considered pharmacological rather than immunological (because
HAE. They increase the production of C1-INH by the liver in of the downstream effects of COX inhibition), an IgE-mediated
heterozygotes with a functioning allele. The dose should be titrated mechanism has been suspected in a few patients but is difficult
against the clinical response rather than blood levels of C1-INH to prove. Apart from IgE, other antibodies may be involved: In
to the lowest level that prevents or ameliorates the condition. murine models IgG-mediated FcγRIII-dependent anaphylaxis
Virilizing side effects can be problematic for women, and anabolic elicited by a high dose of allergen has been described. The key
steroids are avoided in children because of concerns about growth participating cells in this type of anaphylaxis are macrophages,
retardation. Monitoring of liver function and lipid profiles should with platelet-activating factor being the main mediator. 37
be undertaken periodically. Performing a liver ultrasound
examination every 3 years to screen for development of hepatoma Etiology of Anaphylaxis
is usually recommended in patients on long-term prophylaxis. Anaphylaxis is most commonly caused by foods, drugs, general
Plasmin inhibitors are generally less effective for prophylaxis anesthetic agents, insect stings, and latex. Rare causes include
compared with anabolic steroids but are preferred in children. vaccines, semen, and aeroallergen inhalation. Exercise can
pd-C1-INH infusions twice a week may be given as prophylaxis occasionally cause anaphylaxis either on its own (exercise-induced
during pregnancy and in rare situations when alternative therapies anaphylaxis) or after ingestion of a food to which the individual
are not appropriate. is presensitized (food- and exercise-induced anaphylaxis). Up
to 20% of patients with systemic mastocytosis present with
Anaphylaxis anaphylaxis during their lifetime. Anaphylaxis mostly occurs
38
Anaphylaxis is a severe, life-threatening, systemic reaction of in reaction to hymenoptera stings, NSAIDs, and opioids and in
39
sudden onset and involves respiratory compromise, cardiovascular the perioperative setting. Idiopathic anaphylaxis accounts for
collapse, or both. Its clinical features and management have been up to 60% of anaphylaxis cases in ambulatory adults and for
40
summarized in international guidelines. 25-28 10% of cases in children. It is increasingly recognized that some
anaphylactic cases are multifactorial. Cofactors are thought to
Epidemiology of Anaphylaxis lower the threshold for the induction of anaphylaxis and are
41
Estimates of the incidence of anaphylaxis in the general population implicated in about 30% of anaphylaxis cases in adults. The
in Europe and the United States vary from 50 to 103 cases per risk of severe anaphylaxis is increased in patients taking beta-
29
100 000 per annum. Lifetime personal risk estimate for ana- blockers or ACEIs, or both. 28
30
phylaxis in the general population is believed to be 0.05–2%. The most common routes of allergen exposure are oral and
The mortality rate in anaphylaxis is estimated to be below parenteral, although inhalation of allergens (e.g., fish or legume
31
0.001%. In the United Kingdom, anaphylaxis accounts for 20 allergens after cooking, latex particles in health care settings) or
32
deaths per year, which represents 1 death in 3 million people. percutaneous penetration after skin contact can induce anaphy-
According to the European Anaphylaxis Registry, a life-threatening laxis in highly sensitized patients.
or fatal anaphylaxis occurs in about 1 in 100 children experiencing
severe anaphylaxis. 33 Food-Induced Anaphylaxis
There was a sevenfold increase in anaphylaxis admissions in According to a meta-analysis of 34 studies, food-induced ana-
34
England and Wales in 1992–2002. Severe anaphylaxis was phylaxis was reported to occur with an incidence of 0.14 cases
diagnosed in 1–9 per 10 000 people attending emergency depart- per 100 000 person-years at all ages and up to 7 per 100 person-
35
42
ments in the United Kingdom, Australia, and the United States. years in children aged 0–4 years. According to the European
It is estimated that in a 12-month period, 1 in 12 patients with Anaphylaxis Registry, foods are a predominant cause of anaphy-
previous anaphylaxis will have a recurrence, and 1 in 50 will laxis in the first decade of life. Teenagers and young adults in
require hospitalization or treatment with epinephrine. 36 their second and third decades of life are known to be at the
highest risk of fatal food-induced anaphylaxis. 34
Pathophysiology of Anaphylaxis Peanuts, tree nuts, fish, and shellfish are the most frequent
Although anaphylaxis is often subdivided into immunological culprits in food-induced anaphylaxis, but almost any food can
and nonimmunological types, the clinical presentation is similar be implicated. Many cases of severe anaphylaxis are caused by
in both, and most authorities no longer make a distinction. unintended exposure to hidden food allergens. In addition,
Immunological anaphylaxis is further classified as IgE-mediated cofactors, such as alcohol, NSAIDs, and exercise, may increase
and non-IgE-mediated anaphylaxis. In IgE-mediated anaphylaxis, the severity of a food-induced allergic reaction. 27
allergen cross-links allergen-specific IgE on the surface of mast cells
and basophils, leading to their degranulation. Release of mediators Drug-Induced Anaphylaxis
causes bronchoconstriction, mucus secretion, diminished cardiac Drug-induced anaphylaxis is more common in hospitalized
contractility, increased vascular permeability, vasoconstriction patients than in the community. Any drug can cause anaphylaxis,

596 ParT fivE Allergic Diseases


but the prevalence varies: one study found 5–15 cases per 100 Other Rare Causes of Anaphylaxis
000 hospitalized patients for most analgesics and antibiotics, Anaphylaxis occurs during 1 in 20 000–47 000 transfusions of
whereas for dextran, penicillin, pentoxifylline, and streptoki- blood or blood products, especially in patients with IgA defi-
43
52
nase, the figure was over 30 cases per 100 000. Anaphylaxis ciency. IgA deficiency affects 1 in 500–700 Caucasians. One-third
has been reported after treatment with monoclonal antibod- of these patients have circulating anti-IgA antibodies, which are
ies (mAbs; basiliximab, rituximab, infliximab, omalizumab, associated with serious life-threatening anaphylactic reactions
52
44
etc.). IgE antibodies to galactose-α-1,3-galactose (α-gal) are to blood products containing IgA. Seminal fluid allergy is
thought to cause immediate anaphylaxis on first exposure to extremely rare, mostly affecting young women with atopy, with
cetuximab. 45 20% of cases developing life-threatening anaphylaxis. These
Drugs are known to be the leading cause of fatal anaphylaxis, reactions can be prevented with condom use or intravaginal
with the mortality rate in drug-induced anaphylaxis about one desensitization with seminal fluid. In cystic echinococcosis,
death per 50 000–100 000 treatment courses. 46 anaphylaxis can follow the rupture of a hydatid cyst during
All routes of administration can potentially be fatal, including surgery or as a result of trauma. 53
oral, intravenous, subcutaneous, intraarticular, intrauterine,
inhalational, rectal, or topical, but the risk is greatest after Anaphylaxis in Clonal Mast-Cell Disorders
parenteral administration. There is a link between unexplained anaphylaxis and clonal
mast-cell disease (systemic mastocytosis or monoclonal mast cell
Perioperative Anaphylaxis activation syndrome). In systemic mastocytosis, anaphylaxis may
54
Perioperative anaphylaxis occurs in up to 1 of 13 000 anesthesia occur to Hymenoptera stings and drugs (NSAIDs, opioids, and
28
administrations. The common causes of perioperative anaphy- drugs used in the perioperative setting). Patients with unexplained
laxis include neuromuscular-blocking agents, antibiotics, blood anaphylaxis should be evaluated for mast-cell clonality to exclude
28
and blood products, dyes, chlorhexidine, or natural rubber latex. systemic mastocytosis or mast-cell activation syndrome. 54
Reactions to neuromuscular-blocking agents mostly occur on
first exposure and have been associated with a 70% rate of Clinical Diversity of Anaphylaxis
cross-reactivity in this group; risk factors for fatal anaphylaxis In anaphylaxis, there is a remarkable range of clinical symptoms.
include male gender, history of cardiovascular disease, emergency Anaphylaxis can be preceded by prodromal symptoms, such as
47
setting, and use of beta-blockers. Latex remains an important tingling and redness of the palms and soles, anxiety, sense of
cause of intraoperative anaphylactic reactions. The antiseptic impending doom, and disorientation. Anaphylaxis most com-
chlorhexidine is increasingly recognized as a cause of IgE-mediated monly begins in skin and mucous membranes, is followed by
perioperative anaphylaxis. 48 involvement of the respiratory and GI tracts and the cardiovascular
system, and may finally proceed to cardiac and/or respiratory
Insect Sting–Induced Anaphylaxis arrest. Generalized urticaria and angioedema are the most
Following insect stings, life-threatening systemic reactions have common manifestations of anaphylaxis, observed in over 90%
49
been reported in 0.4–0.8% of children and up to 3% of adults. of cases, but may be absent. Respiratory symptoms may vary
Severe anaphylaxis from insect stings causes approximately 40 from rhinitis to laryngeal edema and airway obstruction, which
49
deaths annually in the United States and nearly 100 in Europe. are potentially life threatening. Cardiovascular manifestations
Occupational anaphylaxis caused by venom allergy can occur in anaphylaxis include hypotension and/or cardiac arrhythmias.
in bee keepers, gardeners, forestry or greenhouse workers, farmers, In adults, reduced blood pressure is regarded as systolic blood
50
truck drivers, and masons. The severity of reaction depends pressure of <90 mm Hg or >30% decrease from that person’s
27
on the type of insect, amount of venom, location of sting, the baseline values. Some patients present with only cardiovascular
patient’s sensitivity, older age, preexisting diseases, previous less collapse in the absence of other signs of anaphylaxis, especially
severe systemic reactions, concomitant treatment, mast-cell during general anesthesia. Anaphylaxis is usually associated with
51
disorder, and elevated baseline tryptase. Allergen-specific tachycardia caused by increased cardiac sympathetic drive in
immunotherapy with venom extracts has been shown to be safe response to a decreased effective vascular volume, but bradycardia
and effective in patients with Hymenoptera venom allergy, provid- may also occur. Anaphylaxis may result in up to 35% of intra-
ing some clinical protection within the first 8 weeks of treatment vascular fluid leaking into the extracellular space. A two-phase
and a long-lasting effect after 3–5 years of maintenance treatment reaction to the hypovolemia may present with tachycardia as
(Chapter 43). It is noteworthy that patients with systemic the first phase, followed by bradycardia when effective blood
mastocytosis are at risk of potentially fatal anaphylaxis to insect volume falls by 20–30%. 55
stings even if they are not presensitized to venom: this may be
attributed to venom components, such as phospholipase A2, CLiNiCaL PEarLS
acting as mast-cell liberators. 51 Diagnosis of Anaphylaxis
Latex-Induced Anaphylaxis • Anaphylaxis is characterized by extreme difficulty with breathing as
The prevalence of latex allergy has been estimated to be as a result of airway obstruction from angioedema/bronchoconstriction,
circulatory collapse, or both.
high as 1–6% in the general population, 8–17% in health • It is nearly always accompanied by tachycardia, usually by flushing,
31
care workers, and 67% in patients with spina bifida. urticaria, and panic, and sometimes by vomiting and diarrhea.
Latex-induced anaphylaxis has been reported in surgery and • Panic attacks do not involve airways obstruction, hypotension, or
dentistry and can be fatal. More than half the patients with urticaria but may be accompanied by faintness or tetany of the hands
latex allergy report allergic reactions to fruits, such as banana, as a result of hyperventilation.
avocado, kiwi fruit, chestnut, pear, pineapple, grape, and • Vasovagal attacks present with fainting, nausea, slow pulse, and pallor
without respiratory difficulty, diarrhea, or urticaria.
papaya.

CHaPTEr 42 Urticaria, Angioedema, and Anaphylaxis 597


Four clinical patterns of anaphylaxis have been described: parenterally induced. However, a normal tryptase result does
immediate, biphasic, protracted, and delayed. Anaphylaxis can not exclude anaphylaxis. Tryptase within the normal range during
occur within seconds after allergen exposure: The more rapid anaphylaxis is often observed in food-induced anaphylaxis. In
the onset of anaphylaxis after allergen exposure, the more severe infants, tryptase may not be elevated after anaphylaxis, although
59
and life-threatening is the reaction. Food-induced anaphylaxis the baseline levels may be increased. The diagnostic value of
takes slightly longer to develop than drug- or insect-induced other mast-cell products, such as histamine, platelet-activating
anaphylaxis. Some patients may have biphasic anaphylaxis, with factor, and proteases (carboxypeptidase A3), in anaphylaxis is
recurrence after 1–72 hours, but usually within 8–10 hours of under investigation.
28
the initial attack. According to a meta-analysis of 27 studies, In anaphylaxis, component-resolved diagnosis can be useful
60
patients with anaphylaxis presenting with hypotension or having to stratify risk in certain clinical scenarios. For example, patients
an unknown trigger may be at increased risk of biphasic ana- with wheat-dependent exercise-induced anaphylaxis should be
61
56
phylaxis. Some patients may develop protracted anaphylaxis, tested for omega-5-gliadin sensitization, whereas patients with
which sometimes lasts longer than 24 hours, may be extremely anaphylaxis to vegetables, fruits, nuts, and cereals may have IgE
severe, and is often resistant to treatment. Delayed onset of to nonspecific lipid transfer proteins (mostly Pru p 3 and Tri a
62
anaphylaxis has been reported anecdotally but is very rarely 14). In delayed anaphylaxis to mammalian meat or anaphylaxis
encountered in clinical practice. to cetuximab, tests for IgE against galactose-α-1,3-galactose
45
The diversity and severity of symptoms in anaphylaxis depend (α-gal) should be considered. Certain components are regarded
on the dose of allergen, the route of allergen exposure, the extent as risk factors for anaphylaxis; for example, Mal d 3 sensitivity
of allergen absorption, the degree of sensitization, individual carries a sevenfold greater risk of anaphylaxis to apple compared
allergen threshold for a reaction, target tissue sensitivity, cofac- with Bet v 1. 63
tor involvement, coexisting atopic diseases and their severity,
and concomitant treatment. “Summation anaphylaxis” has Management of Anaphylaxis
been recognized as occurring after simultaneous exposure to Early recognition of anaphylaxis facilitates removal of the cause
various stimuli (physical exercise, infection, stress, or concomitant and prompt institution of treatment. The patient with anaphylaxis
exposure to other allergens or treatment with NSAIDs, ACEIs, should lie down with the legs elevated to increase venous blood
or beta-blockers). return and maintain cardiac output, and intravenous fluids should
Fatal reactions to foods are usually characterized by respiratory be given. In drug-induced or insect-induced anaphylaxis a
symptoms (bronchospasm and hypoxia). In contrast, anaphylaxis tourniquet may be placed proximal to the site of the injection
induced by insect stings is more likely to lead to cardiovascular or insect sting to slow absorption of injected antigens. The
27
collapse. Asthma sufferers are at higher risk of fatal anaphylaxis. tourniquet should be released for 3 minutes at 5-minute intervals,
The risk of relapse in anaphylaxis depends on the type of allergen, with the total duration of application not exceeding 30 minutes.
individual allergen threshold, success of allergen avoidance, and Epinephrine should be administered by an intramuscular injection
the availability of immunotherapy. in the mid-outer thigh at the first sign of respiratory failure or
The most dangerous symptoms are laryngeal edema, respira- cardiovascular collapse and repeated after 5–15 minutes if the
25
tory failure, and circulatory collapse, which may lead to death. response to the first injection is suboptimal. Epinephrine
Deaths from acute asthma in anaphylaxis occur predominantly autoinjectors for self-administration are available, but a single
in patients with preexisting unstable asthma. Rapid fatal shock pen may be insufficient to reverse severe reactions. Use of these
often occurs without other symptoms, and laryngeal angioedema pens in anaphylaxis outside hospital can be lifesaving. Overall,
is the least common cause of fatality. Fatal anaphylaxis occurs prompt diagnosis of anaphylaxis, early administration of epi-
32
mostly within an hour of the onset of anaphylaxis. According nephrine, and fast transport to emergency rooms are crucial
to the UK Fatal Anaphylaxis Registry, the earliest arrest in fatal factors for successful management of anaphylaxis.
food anaphylaxis occurred within 25–35 minutes of exposure, Epinephrine is both an α and β adrenergic agonist with cyclic
slightly slower than with insect stings (10–15 minutes) or adenosine monophosphate (cAMP)–mediated pharmacological
drugs (≤5 minutes in hospital and 10–20 minutes outside effects on target organs. In patients with anaphylaxis, stimulation
hospital). 32 of α 1 adrenergic receptors increases peripheral vascular resistance,
thereby improving blood pressure and coronary perfusion,
Diagnosis of Anaphylaxis reversing peripheral vasodilation, and decreasing angioedema.
Measurement of blood tryptase is now widely used as a marker Activation of β 1 adrenergic receptors increases myocardial
of mast cell degranulation for in vitro confirmation of anaphylaxis. contractility (inotropy, chronotropy) while stimulation of β 2
Beta-tryptase is released from mast cells, but not from basophils, adrenoreceptors causes bronchodilation and decreases the release
and diffuses more slowly compared with histamine. The con- of inflammatory mediators from mast cells and basophils. 27
centration of tryptase peaks 1–2 hours after the onset of reaction, Current guidelines recommend the intramuscular route for
with a half-life of 1.5–2.5 hours. Samples for tryptase testing epinephrine administration because of faster absorption and
should be collected as soon as possible after emergency treatment higher plasma level of epinephrine after intramuscular injection
25
of the patients and within 1–2 hours (but not later than 4 hours) compared with subcutaneous injection. The appropriate dosage
of anaphylaxis onset, and again after 24 hours (baseline sample) of epinephrine is 0.01 mg/kg of a 1 : 1000 (1 mg/mL) solution,
27
57
to check that the value has returned to normal. Tryptase may to a maximum of 0.5 mg in adults. Epinephrine has a rapid
also be detected in postmortem specimens after death from but short action, so the dose may need to be repeated every 5–15
64
suspected anaphylaxis. 58 minutes until symptoms improve. More than one dose is
Normally, mature tryptase is below detection limits in the required in a third of patients. Intravenous administration of
serum of healthy subjects, whereas it is elevated in most cases epinephrine should be reserved for severe anaphylaxis with
of anaphylaxis with vascular compromise, especially if it is profound life-threatening hypotension that is refractory to other

598 ParT fivE Allergic Diseases


treatment because of a risk of potentially fatal cardiac arrhythmias Patients should be instructed how to avoid culprit allergens and
26
and myocardial infarction. The recommended dose is a 1 : 100 cross-reactive agents and should be advised on safe alternatives.
000 solution (i.e., 1 mg in 100 mL saline at initial infusion rate The education of patients, their families, and, in the case of
of 2–10 µg/min, titrated up or down, depending on the clinical children, caregivers and school staff about anaphylaxis, and
response or epinephrine side effects). availability of first-aid measures is of primary importance. Written
Common pharmacological adverse effects of epinephrine personalized emergency action plans should be provided to
include anxiety, fear, headache, pallor, tremor, dizziness, and patients at special risk, such as school children. Emergency
palpitation. In the event of an overdose, unwanted effects may medications, such as epinephrine autoinjectors, should be dis-
include increased Q–T interval on electrocardiography, ven- pensed, and patients should receive training on their correct
tricular arrhythmias, angina, myocardial infarction, increased use. Patients should be advised to carry an epinephrine autoinjec-
blood pressure, pulmonary edema, and intracranial hemorrhage. tor with them at all times. Immunotherapy is very effective for
Patients with cardiovascular diseases and thyrotoxicosis and prophylaxis of bee- and wasp venom–induced anaphylaxis in
cocaine users are particularly susceptible to the adverse effects of sensitized patients and can be lifesaving. Drug-induced anaphy-
epinephrine. laxis can be prevented by avoidance of culprit drugs and cross-
The efficacy of epinephrine can be decreased by concomitant reacting agents, by premedication (for radiocontrast media), and,
therapy with beta-blockers, which is associated with unopposed in some cases, by drug desensitization for antibiotics, chemo-
stimulation of α adrenoreceptors and reflex vagotonic effects, therapeutic agents, insulin, vaccines, biological agents, and so
leading to bradycardia, hypertension, coronary artery constriction, on. For food-induced anaphylaxis, avoidance of the culprit food
bronchoconstriction, and augmented mediator release. Anaphy- is essential; oral immunotherapy is available in some allergy
laxis in patients on beta-blockers can be severe, protracted, and centers. In idiopathic anaphylaxis, patients with frequent episodes
unresponsive to treatment. Patients treated with beta-blockers (>6 episodes per year or ≥2 episodes within 2 months) can be
67
may require fluid replacement and treatment with glucagon, treated with steroids to prevent further episodes. Omalizumab
68
which increases intracellular cAMP independently of β adrenergic and rituximab have been reported to be effective in preventing
receptors. Glucagon can be administered intravenously 1–5 mg idiopathic anaphylaxis. Prevention strategies for anaphylaxis
(20–30 mg/kg in children, maximum 1 mg) over 5 minutes, should also involve promoting public awareness and public health
26
followed by infusion at 5–15 mg/min titrated to clinical response. measures, such as appropriate food labeling, disclosure of food
Glucagon may improve hypotension in 1–5 minutes with maximal ingredients in restaurants, withdrawal of peanuts from in-flight
effect at 5–15 minutes. Side effects of glucagon include nausea refreshments, first-aid training in anaphylaxis for school staff,
and vomiting. and establishment of national anaphylaxis registries.
Corticosteroids are often administered in anaphylaxis to
minimize the risk of recurrent or protracted anaphylaxis. The TRANSLATIONAL RESEARCH OPPORTUNITIES
beneficial effects of corticosteroids develop 6–12 hours after
administration. Therefore their main role in anaphylaxis is likely
to be the prevention of relapse, but it is still unclear how they ON THE HOriZON
work. • Defining the role of functional autoantibodies and understanding the
If there is no response to epinephrine, life support measures mast-cell activation signals in chronic spontaneous urticaria should
should be instituted. The treatment choice depends on the clinical improve clinical assessment and management of patient subgroups.
presentation. In hypotension, large volumes of fluids should be • Development of new bradykinin and kallikrein inhibitors for patients
given rapidly using 1–2 L of 0.9% normal saline, infused rapidly with hereditary angioedema should further improve the acute manage-
(5–10 mL/kg within the first 5 minutes for an adult and up to ment of this rare but very important condition.
30 mL/kg in the first hour for children), to compensate for • Understanding the full clinical spectrum of patients with cryopyrin-
peripheral vasodilatation and for fluid loss into the extravascular associated periodic syndrome with NLRP-3 mutations should allow
earlier identification and treatment of these individuals with interleukin-1
26
space. According to a Cochrane review, crystalloid normal saline blockers to improve quality of life and prevent later complications.
65
should be preferred to colloids for intravenous fluid resuscitation.
Other vasopressors (dopamine, glucagon) may be needed to
reverse severe hypotension. Oxygen should also be administered Ongoing research into the importance of functional autoantibod-
in circulatory or respiratory failure. Bronchospasm should be ies in chronic urticaria and the cause or causes of mast-cell
treated with nebulized or inhaled β 2 agonists. If there is severe activation in patients with “idiopathic” disease should help to
laryngeal edema, endotracheal intubation and even emergency refine clinical assessment and management pathways.
tracheostomy may be needed to maintain the airway. Methylene The effectiveness of a bradykinin receptor antagonist and
blue, a selective nitric oxide cyclic guanosine monophosphate a kallikrein inhibitor for emergency treatment of HAE has
(cGMP) inhibitor, can prevent vasodilatation and has been illuminated the key role of the kallikrein–kininogen–kinin
66
reported to be effective in refractory anaphylaxis. Patients pathway in disease pathogenesis. Development of new inhibi-
presented with respiratory compromise should be observed in tors of this pathway may offer additional benefits to patients in
27
a hospital setting for at least 6–8 hours. In severe cases of the future.
hypotension, an observation period of 12–24 hours is Clarification of the phenotypic spectrum of patients with
advisable. 27 cryopyrin-associated periodic syndrome with NLRP-3 mutations
will facilitate early detection of affected individuals who present
Prevention of Anaphylaxis in childhood with persistent urticaria and would benefit from
The first step in prevention is to identify those at risk of ana- treatment with IL-1 blockers. Early treatment should improve
phylaxis. Therefore all patients with a history of anaphylaxis quality of life and may prevent the development of systemic
should be referred for assessment and undergo allergy evaluation. amyloidosis, nephropathy, and deafness in adulthood.

CHaPTEr 42 Urticaria, Angioedema, and Anaphylaxis 599


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parameter update 2015. Ann Allergy Asthma Immunol 2015;115:341–84.
27. Muraro A, Roberts G, Worm M, et al. EAACI Food Allergy and
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Immunol 2015;135:1125–31.

CHaPTEr 42 Urticaria, Angioedema, and Anaphylaxis 600.e1


MULT i PLE-CHO i CE QUEST i ONS

1. Urticaria is defined by: 4. The first-line treatment of anaphylaxis is:
A. Itchy wheals, angioedema, or both A. Subcutaneous epinephrine
B. Urticarial rash for >6 weeks B. Intramuscular epinephrine
C. An inducible elicitor C. Nonsedating H1 antihistamines
D. Spontaneous wheals D. Oral corticosteroids
E. Recurrent angioedema without wheals E. Parenteral corticosteroids
2. The main mediator of chronic spontaneous urticaria (CSU) 5. What is the treatment of choice for refractory anaphylaxis in
is: a patient who is taking beta-blockers?
A. Interleukin-1 A. Prednisolone
B. Bradykinin B. Glucagon
C. Tryptase C. Hydrocortisone
D. Histamine D. Loratadine
E. Cysteinyl leukotrienes E. Salbutamol
3. The first line of management of urticaria is:
A. Oral corticosteroids
B. Diet
C. Nonsedating H1 antihistamines
D. Omalizumab
E. Cyclosporin

43






Allergic Reactions to Stinging

and Biting Insects



Arthur Helbling, Ulrich R. Müller








Insects can induce allergic reactions by stinging and biting. They Vespula (V. germanica and V. vulgaris in Europe; V. maculifrons
sting humans to defend themselves; they bite to feed. With regard and V. germanica in the United States) are called wasps in Europe
to allergies, stings by insects of the order Hymenoptera (bees, and yellow jackets in the US. They breed in the ground, in attics,
wasps, or ants) are much more important than bites, which can or in shelters. The genus Vespula is, by far, the most aggressive.
be inflicted by various insects, such as mosquitoes, horseflies, Stings occur not only near the nests but also more often while
midges, fleas, and bed bugs. Hymenoptera stings can induce victims are eating outdoors.
acute systemic allergic reactions that kill several hundred patients Most species of Dolichovespula (D. media, D. sylvestris, D.
in Europe and America every year, whereas systemic allergic saxonica in Europe; D. maculata, D. arenaria in the United States)
reactions to bites are very rare. Both stings and bites can induce look very similar to Vespula, with black and yellow stripes on
local allergic or toxic reactions. Infections are only transmitted the abdomen and only a slightly larger size. They can be distin-
by bites. guished from Vespula by the larger distance between the eyes
and the mandibles. Only D. maculata, the bald-faced hornet in
ENTOMOLOGICAL ASPECTS 1-4 the United States, is easy to distinguish from other vespids by
its mostly black abdomen. Dolichovespula build their nests in
Stinging Hymenoptera all belong to the suborder Aculeatae (Fig. tree branches or under the roofs of houses. They sting almost
43.1) with the families Apideae, Vespidae, Formicidae, and exclusively in the vicinity of their nests.
Myrmicinae. Latin and popular names in English, which partly The genus Vespa (V. crabro, the European hornet[ Fig. 43.2E];
differ in Europe and the United States, are given in Table 43.1. V. orientalis) is easy to distinguish from other vespids by its
much larger size. The European hornet was brought to America
Apidae in the late nineteenth century, whereas the Asian hornet (V.
In this family, the honeybee (Apis mellifera) (Fig. 43.2A) is velutina) has recently (2005) been introduced to the South of
clinically the most important cause of allergies. Stings occur France. The oriental hornet is present in southeastern Europe,
either in the vicinity of beehives or when the insect feels threatened Asia, and Africa.
during human activities, such as cutting flowers or walking Nevertheless, hornet stings are rare and occur almost exclu-
barefoot in the grass. Because the whole beehive survives over sively in the vicinity of nests, which are usually in hollow tree
winter, stings can occur not only in spring and summer but trunks or bird nesting-boxes.
occasionally also on warm winter days. Honeybees are brown Polistinae (P. annularis, P. exclamans, P. fuscatus, “paper wasp”
and moderately hairy. In contrast to other Hymenoptera, they in the United States; P. dominulus, P. gallicus, P. nympha, “field
usually lose their barbed sting when stinging. wasp” in Europe) live mostly in the southern United States and
Bumblebees (e.g., Bombus terrestris) are increasingly used as in the Mediterranean area of Europe, but small colonies have
pollinators in greenhouses and occasionally cause allergic sting been observed all over Europe except in the British Isles. Their
2
reactions in greenhouse workers. Bumblebees are distinctly larger small nests consist only of one womb and are built in trees or
and more hairy compared with honeybees, and most species under roofs.
have distinct yellow or white bands on their abdomen (Fig. 43.2B).
Ants (Myrmicinae, Formicinae)
Vespidae In South and Central America, and in the southern states of the
The vespids are divided into the subfamilies Vespinae and United States, fire ants (Solenopsis invicta[see Fig. 43.3F]; S.
3
Polistinae, which differ morphologically in the junction between richteri) are responsible for many systemic allergic sting reactions.
thorax and abdomen (Figs. 43.2C, D). Vespids are almost hairless, Fire ants build their mounds in yards, playgrounds, and fields.
and in most species, the abdomen is striped black and yellow. Occasional allergic sting reactions to Pogonomyrmex, the North
Vespids do not usually lose their sting when stinging and may American harvester ant, have been described and extremely rarely
therefore sting several times, even the same victim. Because only to the European red ant, Formica rufa. In contrast, species of
the queen survives over winter, larger populations develop only Myrmicinae, especially Myrmecia pilosula, the “jack-jumper ant,”
in summer, and most stings occur in summer and fall. The are an important cause of allergic sting reactions in southern
4
subfamily Vespinae contains the three genera Vespula, Dolicho- Australia. Another group of aggressive ants are the ponerinae
vespula, and Vespa. of the genus Pachycondyla, including P. chinesis in the Far East
601

602 Part FIVE Allergic Diseases



Order +\PHQRSWHUD


Suborder $SRFULWD

Legion $FXOHDWD


Superfamily $SRLGHD 9HVSRLGHD 6FROLRLGHD


Family $SLGDH 9HVSLGDH 0\UPLFLQDH )RUPLFLGDH



Subfamily $SLQDH %RPELQDH 9HVSLQDH 3ROLVWLQDH 0\UPLFLQDH )RUPLFLQDH


Genus $SLV %RPEXV 9HVSXOD 'ROLFKRYHVSXOD 9HVSD 3ROLVWHV 0\UPHFLD 6ROHQRSVLV 3RJRQRP\UPH[ )RUPLFD


Species $SLV %RPEXV 9HVSXOD ' PHGLD 9 FUDEUR 3 GRPLQXOXV 0 SLORVXOD 6 LQYLFWD 3 UXJRVXV ) UXID
PHOOLIHUD WHUUHVWULV JHUPDQLFD ' VD[RQLFD 9 RULHQWDOLV 3 JDOOLFXV DQG RWKHUV DQG RWKHUV DQG RWKHUV DQG RWKHUV
DQG RWKHUV DQG RWKHUV YXOJDULV ' PDFXODWD 3 H[FODPDQV
PDFXOLIURQV ' DUHQDULD 3 IXVFDWXV
DQG RWKHUV ' V\OYHVWULV DQG RWKHUV
FIG 43.1 Taxonomy of Hymenoptera.



TABLE 43.1 Popular Names of the Most from S. invicta contains a 37-kDa allergen and a 24-kDa allergen,
Frequent Hymenoptera in Europe and in the with some sequence homology to phospholipase A1 and to antigen
3
United States 5 from vespid venom. In ant venom from M. pilosula, only
pilosulin 1 has been identified as a major allergen so far. The
Popular Name Popular Name in genes of many major venom allergens have been cloned, and
Latin Name in Europe the United States many of them have also been expressed as recombinant proteins
Apis mellifera Honeybee Honey bee comparable in allergenic activity and enzymatic function to their
6-9
Bombus Bumblebee Bumble bee natural counterparts (see Table 43.2). The amount of venom
Vespula ssp. Wasp Yellow jacket injected during a sting varies between and within species,
Dolichovespula maculata — Bald-faced hornet especially in vespids. Bees release 50–140 µg venom per sting
arenaria — Yellow hornet and vespids much less: between 2 and 17 µg. 2
media Median wasp —
Vespa crabro Hornet European hornet
Polistes spp. Field wasp Paper wasp CLINICAL PICTURE
Solenopsis invicta — Fire ant
CLINICaL rELEVaNCE

and P. senna arensis in the Middle East, which may also cause • Not every swelling after an insect sting is caused by allergy.
systemic allergic reactions. 3 • Hymenoptera venom allergy is generally caused by systemic IgE.
• Although Hymenoptera venom allergy is not as prevalent as respiratory
allergies, severe systemic reactions—even fatal—occur regularly
ALLERGENS IN HYMENOPTERA VENOMS worldwide.

All Hymenoptera venoms contain low-molecular-weight sub-
stances, such as biogenic amines, phospholipids, amino acids, Symptoms of venom hypersensitivity are most often caused by
and carbohydrates, as well as peptides, such as melittin, apamin, immunoglobulin E (IgE)-mediated immunological mechanisms,
and kinins, which contribute to the toxic effect but which—except but occasionally by non–IgE-mediated immunological mecha-
melittin—are probably irrelevant with regard to allergies. The nisms. Rarely, nonimmunological mechanisms of mediator release
allergens of the important stinging Hymenoptera are shown in play a role. The clinical presentation is classified into normal, large
Table 43.2. Most of them are glycoproteins of 10–50 kilodaltons local, systemic allergic, systemic toxic, and unusual reactions. 1,2
(kDa) and some, for example, dipeptidylpeptidases, are glyco-
5
proteins of up to 102 kDa. The major allergens in bee venom Normal Local Reactions
are phospholipase A2, hyaluronidase, and acid phosphatase; in The normal local reaction of a nonallergic subject to a Hyme-
vespid venoms, antigen 5 and phospholipase A1. Ant venom noptera sting consists of a painful, sometimes itchy, local wheal

CHaPtEr 43 Allergic Reactions to Stinging and Biting Insects 603



























A B

























C D



















E F
FIG 43.2 Common Hymenoptera. (A) Honeybee (Apis mellifera), (B) bumblebee (Bombus
terrestris), (C) wasp/yellow jacket (Vespula spp.), (D) field wasp (Polistes gallicus), (E) European
hornet (Vespa crabro), (F) fire ant (Solenopsis invicta). (Courtesy of US Department of Agriculture.)

604 Part FIVE Allergic Diseases



Order Diptera Hemiptera Siphonaptera

Family Culicidae Simuliidae Tabanidae etc Triatomidae Cimicidae Pulicidae


Species Mosquito Blackfly Horsefly, deer fly Kissing bug Bed bug Human flea
Example Aedes, culex, anopheles Simulium Tabanus Triatoma protracta Cimex lectularius Pulex irritans
FIG 43.3 Biting insects that may cause allergic reactions.

TABLE 43.2 allergens of Hymenoptera Venoms

allergen Molecular Weight (kDa) Glycosylation Major/Minor allergen a Expressed as recombinant
allergens in Bee Venom (Apis mellifera)
Phospholipase A2 16 Yes Major Yes
Api m1
Hyaluronidase 45 Yes Major Yes
Api m2
Acid phosphatase 49 Yes Major Yes
Api m3
Melittin 2.8 No Minor Yes
Api m4
Dipeptidylpeptidase 102 Yes Major Yes
Api m5
Trypsin inhibitor 8 No Minor Yes
Api m6
CUB serine protease 39 Yes Major? Yes
Api m7
Carboxylesterase 70 Yes Minor
Api m8
Carboxypeptidase 60 Yes Minor
Api m9
Icarapin 29 Yes Major Yes
Api m10
MRJP8 b 65 Yes ?
Api m11.0101 60 Yes
MRJP9
11.0201
Vitellogenin 200 Yes ?
Api m12
allergens of Wasp/Yellow Jacket (Vespula spp., Ves v) and ant (Solenosis invicta, Sol i), Myrmecia pilosula,
(Myr p) Venoms
Vespula Vulgaris
Phospholipase A1 34 No Major Yes
Ves v1
Hyaluronidase 45 Yes Minor Yes
Ves v2
Dipeptidylpeptidase 100 Yes ? Yes
Ves v3
Antigen 5 23 No Major Yes
Ves v5
Vitellogenin 200 Yes
Ves v6
Solenopsis Invicta
Phospholipase A1 37 Yes Major Yes
Sol i1
Sol i2 14 No Minor
Antigen 5 26 Yes Major Yes
Sol i3
Sol i4 12 No Minor
Myr p1 6.1 Minor
Myr p2 5.6 Major
Myr p3 8.2 Minor
a Major allergen: ≥50% of allergic patients have specific immunoglobulin E (IgE) against. Minor allergen: <50% of allergic patients have specific IgE against.
b MRJP, major royal jelly protein.

CHaPtEr 43 Allergic Reactions to Stinging and Biting Insects 605


and flare reaction, followed by a swelling of up to 5–10 cm in mechanisms are likely involved. The causal relation to the sting
diameter. Usually, local symptoms resolve within a few hours. event often remains uncertain. Serum sickness–like syndromes
The fire ant (S. invicta) attaches to the skin by means of its with fever, arthralgias, exanthema, and lymphadenopathy are
powerful mandibles and then stings, releasing venom that well documented. Less frequently reported complications of
produces a characteristic firelike pain. If not removed, it will Hymenoptera stings include diseases of the nervous system
continue to rotate in a pivotal fashion, repeatedly injecting further (peripheral neuropathy, polyradiculomyelitis, extrapyramidal
10
small amounts of venom. After the ant stings, a vesicle is left syndromes, acute disseminated encephalomyelitis), kidneys
behind, which later develops into a pustule that only heals after (glomerulonephritis, interstitial nephritis), or blood and blood
1–2 weeks. 3 vessels (hemolytic anemia, thrombocytopenia, Henoch-Schönlein
syndrome and other forms of vasculitis). In these situations, a
Large Local Reactions causal relation to the sting is less well documented.
Large local reactions (LLRs) are defined as swellings around the
sting site exceeding 10 cm in diameter, developing minutes to EPIDEMIOLOGICAL ASPECTS
1
hours after the sting and lasting more than 24 hours. LLRs may
cause significant discomfort, especially when they last for days Prevalence of Allergy to Stings by Flying Hymenoptera
or even weeks and involve a whole limb, eyelids, or lips. Sometimes
they are accompanied by lymphadenopathy or lymphangitis. KEY CONCEPtS
They may also be associated with nonspecific systemic inflam-
matory symptoms, such as malaise, fever, shivering, or headache. • Awareness of the most relevant insects, specifically Hymenoptera
and their entomological subdivisions, causing immunoglobulin E
However, the development of local infection, abscesses, or a (IgE)–mediated allergies
phlegmon at the sting site is inhibited by the bacteriostatic effect • Assessment of clinical symptoms and classification of Hymenoptera
of Hymenoptera venoms. In contrast, scratching after stings by venom allergy
the American fire ant or bites from blood-sucking insects, such • Evaluation of persons and circumstances at risk for Hymenoptera
as midges, can lead to skin infection. venom allergy
The pathogenesis of LLRs is thought to be based on IgE- • Knowledge of appropriate diagnosis of Hymenoptera venom allergy,
mediated and/or cell-mediated immune mechanisms, most likely potential diagnostic and therapeutic control test tools
a combination of both. 1,2
Cumulative lifetime sting rates of 61–95% have been reported
Systemic Reactions in people aged 16–65 years. Of course, this can vary considerably
Systemic reactions (SRs), including anaphylactic reactions, are in different regions of the world. Asymptomatic sensitization
usually mediated by IgE (Chapter 42). Affected organs include with the development of specific IgE to bee and wasp venoms
13
skin (pruritus, urticaria, flush, angioedema), the gastrointestinal is a frequent finding and has been reported in up to 40%.
(GI) tract (cramps, vomiting or diarrhea, dysphagia), the respira- Hymenoptera sting allergy can occur at any age. In general,
tory tract (laryngeal edema, bronchial obstruction, pulmonary because of their higher level of outdoor activities, men are more
edema), and the cardiovascular system (arterial hypotension, frequently stung compared with women, and children more often
shock, arrhythmias, loss of consciousness with incontinence). compared with adults. 14
The most commonly used classification of SRs was developed The reported cumulative lifetime prevalence of LLRs ranges
11
2
by Müeller. Symptoms appear most often within a few minutes from 2% to 26%, that of SRs from 0.3% to 5%. Among beekeep-
15
to 1 hour after the sting. The patient recovers usually within a ers, it varies between 14% and 43%. LLRs are not predictive
13
few hours. A protracted course over more than a day or a biphasic for SRs in the event of a subsequent Hymenoptera sting. In
course has been described but is rare. Europe and the United States, SRs are more frequently caused
Lasting morbidity, for example, myocardial or cerebrovascular by vespids than by honeybees. In the southern states of the United
infarction, as a consequence of SRs or even fatal reactions can States and in Australia, ants are important causes of SR.
occur, but these are rare (see “Epidemiological aspects”).
Risk Factors for Hymenoptera Allergy
Systemic Toxic Reactions The risk of developing a sting allergy increases with the number
Toxic reactions are dose dependent, and a clinically significant of stings, especially if two stings occur within a short period (up
16
toxic effect only needs to be considered after multiple stings— to 2 months). However, beekeepers stung less than 10 times a
1,2
usually 50 to several hundred. The main toxic effects develop year have a much higher risk for SRs compared with those stung
15
within hours to days and comprise rhabdomyolysis and intra- more than 200 times a year. Even after successful venom
vascular hemolysis leading to acute renal failure with tubular immunotherapy, the risk of recurrent SRs after Hymenoptera
17
necrosis. Myocardial damage, hepatic dysfunction, coagulation stings persists throughout life. Cardiovascular diseases and their
disorders, and brain edema and/or necrosis may occur. The treatment with β-blocking drugs and angiotensin-converting
number of stings needed to cause a fatal reaction in adults varies enzyme (ACE) inhibitors are associated with more severe sting
between 200 and 1000. In small children, however, fewer than reactions, sometimes also with lasting morbidity caused by cardiac
50 stings may be lethal. In most cases, death is not immediate or cerebrovascular infarction as a result of anaphylaxis. 1,18,19
but occurs after several days. However, β-blockers do not increase the overall risk of systemic
18
sting reactions. Systemic mastocytosis (indicated by elevated
Unusual Reactions baseline serum tryptase) is a risk factor for severe or even fatal
19
Various unusual sting reactions can occur: these are rare and systemic sting reactions. Atopy is not more frequent in patients
appear after hours to days. More than half of them follow with Hymenoptera sting allergy than in the general population.
immediate local or SRs. 1,12 Non–IgE-mediated immunological However, in patients with atopy and Hymenoptera venom allergy,

606 Part FIVE Allergic Diseases



TABLE 43.3 Natural History of Hymenoptera Venom allergy Based on Prospective Studies
With Sting reexposure in Patients Without Venom Immunotherapy

% WItH SYStEMIC rEaCtION tO rEEXPOSUrE BY
Previous reaction author, Year reexpo-sure by Bee or Vespid Bee Vespid ant
Large local reactions Müller, 1990 FS 6
Systemic reactions (SRs) van der Linden, 1994 CH 51 25
Mild SRs in children Schuberth, 1983 FS 16
Mild SRs adults Blaauw, 1985 CH 31 10
Severe SRs in adults Blaauw, 1985 CH 44 60 33
SR in controls of Hunt, 1978 CH 58
controlled studies Müller, 1979 FS 75
Brown, 2003 CH 72

Summarized in Rueff, Przybilla, Müller et al Allergy 1996;51:21-25. FS, field sting; CH, sting challenge.



SRs may be more severe and more often affect the respiratory circumstances of stings (e.g., environment, activities); kind and
tract. About 50% of beekeepers with venom allergy have atopy, severity of symptom; sting site; retained or removed stinger;
and they may become sensitized by inhaling dust containing interval to onset of symptoms; emergency treatment; risk factors
venom when working with beehives. 15 for a particularly severe reaction (e.g., comorbidity, drugs, elevated
baseline serum tryptase); tolerated stings after the first SR;
Mortality Caused by Hymenoptera Stings reduction of the quality of life ; and other allergies. In
1,2
24
Mortality resulting from Hymenoptera stings varies from 0.09 individuals with only LLRs, no further diagnostic tests are recom-
20
to 0.48 deaths per million persons per year. Over the past 40 mended. For those with SRs, diagnostic tests include skin tests,
years, the mean annual incidence of fatal Hymenoptera sting venom-specific serum IgE antibodies, and, in severe SRs, baseline
reactions in Switzerland has been 3.1; when extrapolated to the serum tryptase.
whole of Europe, this would be about 200. The vast majority of
fatal sting reactions occur in adults over 45 years of age. 2,20 Skin Tests
Additional risk factors include a positive history of sting allergy, Skin tests should not be performed until at least 3 weeks after
male gender, and stings on the head or neck. Autopsies have an SR, as false-negative results can occur (the refractory period).
20
documented preexisting cardiovascular disease in most cases. They are performed by intradermal or skin prick endpoint
2
Approximately half of the deaths occur in subjects with no known titration. Injection of 0.02 mL of venom solution is given
prior history of allergic sting reactions. intradermally in increasing concentrations—0.00001–1 µg/
mL—into the volar surface of the forearm. For skin prick tests,
Natural History of Hymenoptera Sting concentrations of 0.01–300 µg/mL are used. However, even at
Allergy (Table 43.3) 300 µg/mL, the sensitivity of skin prick is clearly lower than that
In prospective clinical studies, after an LLR, the risk of developing of the intradermal test. We therefore prefer the intradermal test.
an SR to the next sting is between 5% and 10%; after a mild SR,
the risk is between 15% and 30%; and after a severe SR, the risk Venom-Specific Serum IgE Antibodies
is between 50% and 75%. 13,21 The severity of an index sting Several different in vitro immunoassays for the detection of
reaction is an important factor determining the risk at reexposure. venom-specific serum IgE antibodies (sIgE) are commercially
1,22
Children are at lower risk of re-sting SR compared with adults. available (Chapter 95). Immediately after a sting, sIgE may be
The re-sting SR risk is definitely lower in patients with Vespula low or undetectable, but it usually increases within days or weeks
allergy than in those with bee venom allergy, probably because after an SR. If no sIgE is found in a patient with a clear history
of the smaller and more variable amount of venom injected. of venom allergy, the test should be repeated after 2–4 weeks. 2
Elevated sIgE levels after Hymenoptera stings that cause a
Epidemiological Aspects of Allergic Reactions normal sting reaction are not predictive for future development
to Ant Stings of an SR. sIgE can be determined against the whole venom or
13
Nearly 50% of inhabitants are stung each year in areas of the components of the venoms. Measuring sIgE to recombinant
United States that are fire ant endemic. 3,10 Many report LLRs, venom allergens has improved the precision of allergic diagnostic
but up to 1% of patients who are stung by imported fire ants tests. Tests are currently available for the species-specific, non-
develop anaphylaxis, and some deaths have been reported. In glycosylated major allergens Api m 1, Api m 10, Ves v 5, and Ves
Australia, more than 90% of ant venom anaphylaxis is caused v 1. Tests for Api m 2, Api 3, and Api m 5 will be available soon. 6,25
by M. pilosula. Age >35 years, annual sting rate, and allergy to
bee venom were predictive factors for more severe reactions. 23 Sensitivity and Specificity of Skin Tests and sIgE
The sensitivity of these tests is >90% in patients with a history
DIAGNOSIS of SR within the past year and decreases steadily thereafter with
or without venom immunotherapy but may stay positive for
History many years. However, their specificity is limited, since up to 20%
As in all forms of allergy, the clinical history is key to diagnosing of an unselected population have positive results, whereas only
1,2
Hymenoptera sting allergy. This includes the date, number, and 0.3–5% have a history of allergic sting reactions. As a rule, the

CHaPtEr 43 Allergic Reactions to Stinging and Biting Insects 607


intradermal test result remains positive longer than that of sIgE. commonly used expression marker is CD63. The sensitivity and
However, there is currently no reliable test that predicts the risk specificity of BAT seems to be superior to skin tests and venom-
of future SRs in untreated or treated patients. Despite a history specific sIgE. It may also have better predictive value. The test
of typical SRs to stings, a few patients have no detectable sIgE must, however, be performed with fresh blood; it is expensive
26
and have negative skin test results. This may be attributed to and not yet well standardized: there are few data on specificity
insufficient sensitivity of the available tests, a long interval between and predictive value in relation to a sting reexposure during or
the SR and testing with spontaneous decrease of sensitization, after venom immunotherapy.
or non–IgE-mediated pathogenesis.
Specificity may cause problems: more than 20% of people Allergen-Specific IgG
13
without a history of SR have a positive diagnostic test result. The presence of sIgG and IgG4 primarily reflects exposure to
Although it is difficult to exclude sensitization after a previous the respective venom. sIgG titers increase after a sting, irrespective
sting, this positivity may reflect cross-reactivity (see below). of the presence or absence of an allergic sting reaction. Venom
For skin testing and venom immunotherapy for fire ant (S. immunotherapy induces a rise in sIgG. However, there is no
invicta) stings, only whole-body extracts are currently available. close correlation between the concentration of sIgG or the sIgE/
These extracts have good sensitivity but low specificity. Therefore sIgG ratio and the clinical response to a resting during or after
1
they should only be used in patients with a history of systemic venom immunotherapy. Routine assessment of sIgG is therefore
10
sting reactions, at least 30 days after the SR. In contrast, venoms not recommended but may be helpful if the responsible insect
of M. pilosula have been shown to have excellent sensitivity and is unidentified.
specificity. 4
Baseline Serum Tryptase
Cross-Reactivity Because elevated baseline serum tryptase levels (>11.4 µg/L) are
Cross-reactivity between venom allergens is strong between species associated with severe, sometimes IgE-negative, systemic sting
within a family, for example, among Vespula, Dolichovespula, reactions and with cutaneous or systemic mastocytosis, this
and Vespa, but only limited between Vespinae and Polistinae or enzyme should be determined in all patients with a history of
19
6
between honeybees and bumblebees. There is some homology SRs. The commercially available fluorescence immunoassay
at the protein level between bee and vespid venoms, with ~50% measures total tryptase. α-Tryptase is secreted continuously and
sequence identity between the hyaluronidases and dipeptidyl- reflects whole-body mast cell load. Elevated values are seen in
peptidases of the two families, but double-positivity with cutaneous and systemic mastocytosis. β-Tryptase is released
diagnostic tests to both venoms is frequently observed. This may during mast cell activation and is a marker of anaphylaxis.
reflect true double-sensitization or cross-reactivity. Cross-reacting
carbohydrate determinants (CCDs) are present in many major Sting Challenge Tests
Hymenoptera venom allergens, such as hyaluronidase, acid Sting challenge with a live insect is not recommended as a
phosphatase, and phospholipase A2, but also in many plant diagnostic tool in untreated patients, but a sting challenge under
proteins (e.g., rapeseed pollen or bromelain). CCDs are certainly well-supervised clinical conditions may be helpful in evaluating
responsible for a significant proportion of the double-positivity the efficacy of venom immunotherapy. 21,29 However, a tolerated
of diagnostic tests to bee and vespid venoms. They may also sting challenge does not definitely exclude a reaction to future
explain why individuals with no history of SRs have positive test stings after immunotherapy, especially if these are repeated. 17
27
results. The CCDs are probably of no clinical relevance. The
radioallergosorbent test (RAST)for venoms and CCDs can help PREVENTION AND TREATMENT
distinguish between true double-sensitization and cross-reactivity
but is not always conclusive. Prevention
Assessing IgE antibodies to species-specific nonglycosylated, All patients with a history of SRs should receive detailed instruc-
recombinant major allergens (Api m1 [phospholipase A2] of tion on the avoidance of future stings and measures to take if
1
bee venom and Ves v5 [antigen 5] of Vespula venom) reduces stung. Bee stings occur most often when walking barefoot on
the rate of double-positivity very significantly and is helpful in grass, and wasp stings occur when eating outdoors, in orchards
choosing venoms for immunotherapy. 6,25,28 with fallen fruits, and near open waste-bins. The risk of a sting
Some cross-reactivity between allergens of vespid venoms is especially high near beehives or vespid nests. While gardening,
and those of S. invicta has also been documented. 3,6 wearing long trousers, shirts with long sleeves, and gloves are
recommended. Strongly scented perfumes, sun creams, or
Cellular Tests shampoos, as well as brightly colored garments, should be avoided.
If routine tests in patients with a history of SRs are negative,
cellular tests may be helpful to demonstrate sensitization. 2 Treatment of Large Local Reactions
In the basophil histamine release test peripheral blood leukocytes Oral antihistamines and cooling of the sting site (e.g., with ice
are incubated with venom allergens. The reaction with cell-bound cubes) reduces local swelling, pain, and itching. Antiinflam-
IgE antibodies leads to histamine release from basophils. In the matory ointments or topical corticosteroids may diminish the
cellular antigen stimulation test (CAST), leukocytes of patients local inflammatory process. In cases of severe swellings, oral
are prestimulated with interleukin-3 (IL-3) and exposed to venom corticosteroids together with antihistamines over several days
allergens. The released sulfidoleukotrienes are determined by are recommended. 10
using enzyme-linked immunosorbent assay (ELISA).
The basophil activation test (BAT) is based on flow-cytometric Systemic Allergic Reactions
demonstration of an altered membrane phenotype of basophils Sympathomimetics, antihistamines, and corticosteroids are the
stimulated by IL-3 and allergen exposure. At present, the most most effective drugs for symptomatic treatment of SRs. All patients

608 Part FIVE Allergic Diseases


experiencing SRs should seek medical advice and should be associated with a higher rate of side effects compared with
medically observed until the symptoms resolve and blood pressure conventional protocols. Most systemic side effects are mild; only
is stable. one-third of patients require medical treatment.
Mild reactions confined to the skin may be treated with Premedication with antihistamines reduces large local and
rapid-acting oral antihistamines alone. If respiratory or cardio- other cutaneous reactions, such as urticaria, but severe SRs may
vascular symptoms occur, intramuscular epinephrine must be not be suppressed. Some units routinely give antihistamines 2
given immediately, intravenous (IV) access should be established, hours before up-dosing injections until the maintenance dose
and antihistamines and corticosteroids given intravenously has been repeatedly well tolerated. In patients with recurrent
(Chapter 42). All patients with severe SRs should be hospitalized SRs during up-dosing, off-label use of anti-IgE (omalizumab)
and supervised until they recover completely. Patients with has made it possible to complete up-dosing and to continue
cardiovascular symptoms must be treated and transported in maintenance VIT. 31
the supine position, and IV volume replacement is indicated.
Subsequently, every patient who has experienced a systemic Efficacy of VIT
allergic sting reaction should be investigated with a view to In addition to three prospective controlled trials, the efficacy of
prevention measures and immunotherapy. 10 VIT has been confirmed by well-tolerated sting challenges during
1,10
VIT in several uncontrolled prospective studies. Full protection
Emergency Medication Kit is achieved in 80–85% of patients receiving bee venom and in
All patients with a history of SRs should carry an emergency kit 95–100% of patients receiving Vespula venom. The higher risk
30
for self-administration. After a sting, patients should immediately of treatment failure in bee venom allergy may relate to differences
take both antihistamines and corticosteroids, whether or not in venom compositions. Important allergens, such as Api m10
symptoms occur. In case of systemic symptoms, such as urticaria, or Api m 3, may be missing or present in low concentrations in
32
dyspnea, generalized weakness, or dizziness, epinephrine should some VIT products. It has therefore been suggested that patients
be administered intramuscularly via an autoinjector, such as the with a predominant sensitization to these allergens may not be
30
Epipen (dosage 0.3–0.5 mg of epinephrine). In children with properly protected by VIT. 33
body weight <25 kg, Epipen Junior (0.15 mg epinephrine) or The efficacy of immunotherapy with commercially available
an equivalent product should be administered, along with half whole-body extract of the ant Solenopsis has not been documented
the adult dose of antihistamines and corticosteroids. If any SR in controlled studies. However, excellent results, comparable with
occurs, medical care must be sought immediately. those of VIT with Vespula venom, were obtained in a double-blind
placebo-controlled study using M. pilosula venom. 4
Venom Immunotherapy 1,10
Indications Duration of VIT 17
Venom immunotherapy (VIT) is indicated in children and adults Lifelong treatment may be the safest recommendation, but in
with a history of severe SRs (grade III/IV), provided sensitization most allergy centers, VIT is given for up to 5 years. If VIT is
to the relevant venom has been demonstrated by skin and/or given for at least 3 years, >80% of both adults and children are
blood test. LLRs or unusual reactions do not require VIT. VIT still protected, when reassessed 1–7 years after discontinuation.
is also recommended for patients who experience repeated mild, Longer courses of treatment should be considered in high-risk
non–life-threatening reactions and are at high risk for reexposure, patients, such as those with very severe systemic sting reactions,
such as beekeepers or their family members. Concomitant coexisting cardiovascular or pulmonary disease, and systemic
cardiovascular disease, mastocytosis, and strongly impaired quality allergic reactions to VIT or stings during VIT and in subjects
of life because of the venom allergy are relative indications for with elevated basal serum tryptase levels. Lifelong VIT is advised
VIT in patients with non–life-threatening sting reactions. 19,24 for patients with cutaneous or systemic mastocytosis. 10
Contraindications for VIT are the same as for immunotherapy
with other allergens (Chapter 91). Risk Factors for Recurrence of SRs After Stopping VIT
A number of risk factors have been identified for relapse of
Dosage and Treatment Regimens Hymenoptera venom allergy after discontinuation of VIT : in
17
The recommended maintenance dose for both children and adults general, adults, especially older people, because of concomitant
is 100 µg of the venom. This maintenance dose is equivalent to diseases, have a less favorable prognosis compared with children.
approximately two bee stings or several vespid stings. A higher Patients with bee venom allergy have a higher relapse risk
dose (e.g., 200 µg) is recommended when SRs occur after compared with those allergic to Vespula venom. Patients with
29
reexposure to a field sting or a sting challenge. In highly exposed more severe pretreatment reactions and those with more SRs
subjects, such as beekeepers or professional gardeners, a main- during VIT (to injections or field stings) have a higher risk for
tenance dose of 200 µg is advised. recurrent SRs to Hymenoptera stings. The risk of relapse is lower
VIT may be initiated by a conventional or an ultra-rush after 5 years of VIT, compared with only 3 years of VIT.
protocol. During the first year, maintenance VIT is given every
4 weeks. Subsequently, the intervals may be extended to 6 weeks ALLERGIC REACTIONS TO BITING INSECTS
if VIT is well tolerated.
Biting insects may cause local allergic reactions as a result of
Adverse Reactions to VIT sensitization to their salivary proteins introduced during the
The overall incidence of systemic adverse reactions to VIT varies process of blood sucking. Systemic reactions are very rare. The
1,10
between 5% and 40%. VIT with bee venom causes side effects responsible insects belong to the orders Diptera, Hemiptera, and
29
more often than with Vespula venom. Ultra-rush protocols are Siphonaptera (Fig. 43.3). 34

CHaPtEr 43 Allergic Reactions to Stinging and Biting Insects 609


5. Ollert M, Blank S. Anaphylaxis to insect venom allergens: role of
Clinical Symptoms molecular diagnostics. Curr Allergy Asthma Rep 2015;15:26.
Local reactions to insect bites may be characterized by immediate 6. Müller U. Insect venoms. In: Ring J, editor. Anaphylaxis, chemical
wheal and flare, or may be delayed, with pruritic erythema and immunol allergy. Basel, Switzerland: Karger; 2010. p. 141–56.
papules developing after 12–24 hours and lasting for days to 7. King TP, Guralnick M. Hymenoptera allergens. In: Lockey R, Ledford D,
editors. Allergens and allergen immunotherapy, vol. 21. 4th ed. (Clinical
weeks; combined reactions can also occur. In delayed and Allergy and Immunology). Boca Raton, FL: Taylor & Francis; 2008. p.
combined reactions, vesicular, bullous, or even necrotic lesions 237–49.
may develop. SRs are much rarer than those to Hymenoptera 8. Grunwald T, Bockisch B, Spillner E, et al. Molecular cloning and
stings. They have, however, occasionally been described, especially expression in insect cells of honeybee venom allergen acid phosphatase
after bites by horseflies (Tabanus spp.) and the kissing bug (Api m 3). J Allergy Clin Immunol 2006;117:848–54.
(Triatoma protracta). 9. Seismann H, Blank S, Braren I, et al. Dissecting cross-reactivity in
Hymenoptera venom allergy by circumvention of a-1,3-core fucosylation.
Allergens Mol Immunol 2010;47:799–808.
The salivary proteins involved have either digestive (amylases, 10. Müller U, Golden DBK, Lockey RF. Byol S. Immunotherapy for
esterases) or hemostatic function (e.g., factor Xa inhibition). Hymenoptera venom hypersensitivity. In: Lockey R, Ledford D, editors.
Allergens and allergen immunotherapy, vol. 21. 4th ed. (Clinical Allergy
Numerous IgE-binding proteins with a molecular weight of and Immunology). Boca Raton, FL: Taylor & Francis; 2008. p. 377–92.
15–81 kDa have been described, especially in the saliva of 11. Mueller HL. Diagnosis and treatment of insect sensitivity. J Asthma Res
mosquitoes, and in horseflies and kissing bugs as well; some 1966;3:331–3.
of these proteins have been cloned. 35 12. Reisman RE. Unusual reactions to insect stings. Curr Opin Allergy Clin
Immunol 2005;5:355–8.
Prevention and Treatment 13. Sturm GJ, Kranzelbinder B, Schuster C, et al. Sensitization to
The application of insect repellents and prophylactic intake of Hymenoptera venoms is common, but systemic sting reactions are rare.
antihistamines can prevent or mitigate outdoor exposure. Screens J Allergy Clin Immunol 2014;133:1635–43.
on windows and doors and mosquito nets over the beds are 14. Graif Y, Confino-Cohen R, Goldberg A. Allergic reactions to insect stings:
effective in homes. Bedbug infestation should be eliminated by Results from a national survey of 10 000 junior high school children in
Israel. J Allergy Clin Immunol 2006;117:1435–9.
using appropriate pesticides; flea infestation of pet animals should 15. Müller U. Bee venom allergy in beekeepers and their family members.
be managed by a veterinarian. Local reactions may be treated Curr Opin Allergy Clin Immunol 2005;5:343–7.
with topical steroids or oral antihistamines. 16. Antonicelli A, Bilò MB, Bonifazi F. Epidemiology of Hymenoptera allergy.
Curr Opin Allergy Clin Immunol 2002;2:341–6.
17. Müller UR, Ring J. When can immunotherapy for insect sting allergy be
ON tHE HOrIZON stopped? J Allergy Clin Immunol Pract 2015;3:324–8.
18. Müller U, Haeberli G. Use of beta-blockers during immunotherapy for
The availability of recombinant venom allergens offers several promising
perspectives for diagnosis and immunotherapy. 5-9 Hymenoptera venom allergy. J Allergy Clin Immunol 2005;115:606–10.
• The specificity of these tests could be considerably improved by using 19. Ruëff F, Przybilla B, Bilò M, et al. Predictors of severe anaphylactic
recombinant cocktails with species-specific major allergens without reactions in patients with hymenoptera venom allergy: importance of
cross-reacting carbohydrate determinants (CCDs) for diagnosis instead baseline serum tryptase. J Allergy Clin Immunol 2009;124:1047–55.
of the whole venom. 20. Sasvary T, Müller U. Fatalities from insect stings in Switzerland 1978 to
• In patients with double-positive diagnostic tests to honeybee and 1987. Schweiz Med Wschr 1994;124:1887–94.
Vespula venom, recombinant species-specific nonglycosylated major 21. Ruëff F, Przybilla B, Müller U, et al. The sting challenge test in
allergens from honeybee and Vespula venom make it possible to dis- Hymenoptera venom allergy. Allergy 1996;51:216–25.
tinguish reliably between true double sensitization and cross-reactivity, 22. Golden DBK, Kagey-Sobotka A, Norman PS, et al. Outcomes of allergy to
an important issue for the choice of venoms for immunotherapy. insect stings in children, with and without venom immunotherapy. N
• Addition of such allergens to therapy solutions can increase the efficacy Engl J Med 2004;351:668–74.
of venom immunotherapy (VIT) with bee venom, as these are lacking 23. Brown SG. Cardiovascular aspects of anaphylaxis: implications for
or insufficiently represented in currently available preparations. treatment and diagnosis. Curr Opin Allergy Clin Immunol
• Allergic side effects of VIT might be reduced by using modified major 2005;5:359–64.
allergens with reduced immunoglobulin E (IgE) binding, but retained 24. Oude Elberink JN, Dubois AE. Quality of life in insect venom allergic
specific T-cell interaction. 36 patients. Curr Opin Allergy Clin Immunol 2003;3:287–93.
25. Frick M, Müller S, Bantleon F, et al. rApi m 3 and rApi m 10 improve
detection of honey bee sensitization in Hymenoptera venom-allergic
Please check your eBook at https://expertconsult.inkling.com/ patients with double sensitization to honey bee and yellow jacket venom.
for self-assessment questions. See inside cover for registration Allergy 2015;70:1665–8.
details. 26. Golden DBK, Kagey-Sobotka A, Norman PS, et al. Insect sting allergy
with negative venom skin test responses. J Allergy Clin Immunol
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27. Hemmer W, Focke M, Kolarich D, et al. Antibody binding to venom
1. Müller U. Insect sting allergy. Stuttgart, Germany: Gustav Fischer Verlag; carbohydrates is a frequent cause for double positivity to honey bee and
1990. yellow jacket venom in patients with stinging insect allergy. J Allergy Clin
2. Bilò MB, Ruëff F, Mosbech H, et al. Diagnosis of Hymenoptera venom Immunol 2001;108:1045–52.
allergy. Allergy 2005;60:1339–49. 28. Müller U, Johansen N, Petersen A, et al. Hymenoptera venom allergy:
3. Hoffmann DR. Ant venoms. Curr Opin Allergy Clin Immunol analysis of double positivity to honey bee and Vespula venom by
2010;10:342–6. estimation of species-specific major allergens Api m1 and Ves v5. Allergy
4. Brown SGA, Franks RW, Baldo BA, et al. Prevalence, severity, and natural 2009;64:543–8.
history of jack jumper ant venom allergy in Tasmania. J Allergy Clin 29. Ruëff F, Vos B, Elberink JO, et al. Predictors of clinical effectiveness of
Immunol 2003;111:187–92. Hymenoptera venom immunotherapy. Clin Exp Allergy 2014;44:736–46.

610 Part FIVE Allergic Diseases


30. Bilò MB, Cichocka-Jarisz E, Pumphrey R, et al. Self-medication of 34. Hoffman DR. Allergic reactions to biting insects. In: Levine MI, Lockey
anaphylactic reactions due to Hymenoptera stings – An EAACI Task RF, editors. Monograph on insect allergy. Pittsburgh, PA: Dave Lambert
Force Consensus Statement. Allergy 2016;71:931–43. Associates; 2003. p. 161–74.
31. Sokol KC, Ghazi A, Kelly BC, et al. Omalizumab as a desensitizing agent 35. Simons FER, Peng Z. Mosquito allergy. In: Levine MI, Lockey RF, editors.
and treatment in mastocytosis: a review of the literature and case report. Monograph on insect allergy. Pittsburgh, PA: Dave Lambert Associates;
J Allergy Clin Immunol Pract 2014;2:266–70. 2003. p. 175–203.
32. Blank S, Seismann H, Michel Y, et al. Api m 10, a genuine A. mellifera 36. Karamloo R, Schmid-Grendelmeier P, Kussebi F, et al. Prevention of
venom allergen, is clinically relevant but underrepresented in therapeutic allergy by a recombinant multi-allergen vaccine with reduced IgE binding
extracts. Allergy 2011;66:1322–9. and preserved T cell epitopes. Eur J Immunol 2005;35:3268–76.
33. Frick M, Pfützner W, Helbling A, et al. Predominant Api m 10
sensitization as risk factor for treatment failure in honey bee venom
immunotherapy. J Allergy Clin Immunol 2016;138:1663–71.

CHaPtEr 43 Allergic Reactions to Stinging and Biting Insects 610.e1


MUL t IPLE-CHOICE QUES t IONS

1. Which factor has NO influence on the severity of an allergic A. Api m 1
reaction as a result of a Hymenoptera sting? B. Api m 2
A. Elevated basal tryptase C. Api m 4
B. Treatment with β-blockers D. Api m 6
C. Two yellow jacket stings within 3 weeks E. Api m 10
D. Atopy 4. Concerning the duration of VIT with Hymenoptera venoms,
E. Previous repeated severe allergic sting reactions
which statement is correct?
2. The average amount of venom released by a single bee sting A. Once the maintenance dose of 100 µg can be given without
is approximately: any side effect, VIT can be discontinued.
A. 0.5 µg B. The recommended duration of VIT is 3–5 years.
B. 5 µg C. Most patients will need a lifelong VIT.
C. 50 µg D. Once the patient on VIT has tolerated a sting of the relevant
D. 0.5 mg insect, VIT can be stopped.
E. 0.5 g E. The duration of VIT—analogue to pollen immunotherapy—
is maximally 3 years.
3. Which important bee allergens are missing or found only in
small concentrations in some therapeutic products used for
venom immunotherapy (VIT)?

44









Atopic and Contact Dermatitis



Mark Boguniewicz, Luz Fonacier, Donald Y.M. Leung







Atopic dermatitis (AD) and contact dermatitis (CD) are common age, other diseases need to be considered in adults with new-onset
1,2
inflammatory skin diseases. The complex pathophysiology of dermatitis, especially in those without a history of childhood
AD involves both underlying skin barrier abnormalities and eczema, asthma, or allergic rhinitis (see Table 44.1, Differential
immune dysregulation. Its course is augmented by environmental Diagnosis). Although in some children, AD may progress to
influences, including stress, allergen exposure, and microbial milder forms of eczema, only in approximately one-third will
infection. Patients with AD experiencing a relapsing course benefit the disease be eliminated altogether. Severity and atopic sensitiza-
from a proactive approach with skin emollients and antiinflam- tion are major determinants of prognosis. A US registry of patients
matory therapy (e.g., intermittent use of a topical steroid or with mild-moderate AD showed that it was not until age 20
calcineurin inhibitor). The identification of new immune pathways years that 50% had experienced at least one 6-month period
associated with AD has resulted in the development of novel free of symptoms and treatments. 5
biologicals targeting patients with refractory AD.
CD is a skin disorder caused by contact with an exogenous Clinical Features
substance that elicits an allergic and/or irritant response. Allergic AD has no pathognomonic skin lesions or unique laboratory
contact dermatitis (ACD) accounts for 20%, whereas irritant parameters; the diagnosis is, therefore, based on the presence of
contact dermatitis (ICD) accounts for 80% of all cases of CD. major and associated clinical features (Table 44.2). The principal
ACD is a delayed-type, T cell–mediated immune response features include pruritus, a chronically relapsing course, typical
consisting of an afferent limb and an efferent limb. Irritants morphology and distribution of skin lesions, and a history of
cause direct activation of the innate immune system through atopic disease. Patients usually have dry xerotic skin, and those
hyperproduction of cytokines and chemokines. The management with mutations of the gene encoding the epidermal barrier protein
of ACD includes identification of the allergen, avoidance, filaggrin (FLG) typically have prominent scaling and hyperlinear
pharmacological intervention, and prevention. This chapter palms. Acute AD is characterized by pruritic, erythematous papules
reviews the clinical and mechanistic aspects of both AD and CD. associated with excoriations, vesiculations, and serous exudate.
Subacute AD is characterized by erythematous, excoriated, scaling
CLINICAL ASPECTS OF ATOPIC DERMATITIS papules, whereas chronic AD is characterized by lichenification
and fibrotic papules. During infancy, AD involves primarily the
Epidemiology face, scalp, and the extensor aspects of the extremities; the diaper
Prevalence of AD has been documented in up to 24% of children, region is typically spared, although some infants manifest the
with no apparent difference seen between urban and rural districts flexural involvement typical of older patients (Fig. 44.1).
or between the two sexes. Children from families with atopy
have a significantly higher risk of developing AD. Data from an Complicating Features
international study (ISAAC Phase 3) showed that prevalence of Ocular Problems
current eczema in children varies widely among countries, ranging Atopic keratoconjunctivitis is bilateral, with intense pruritus,
from 0.9% to 22.5%, and in adolescents, the prevalence ranges burning, tearing, and copious mucoid discharge. It is frequently
3
from 0.2% to 24.6%. These data point to the significance of associated with eyelid dermatitis and chronic blepharitis and
AD being a global health problem in both developed and develop- may result in visual impairment from corneal scarring. Patients
ing countries and suggest that the ultimate presentation of an may also develop keratoconus from persistent rubbing of the
atopic disease may depend on a complex interaction between eyes or anterior subcapsular cataracts.
environmental exposures and end-organ response in genetically
predisposed individuals. Prevalence of adult eczema from a Hand Dermatitis
nationally representative sample found that the 1-year prevalence Patients with AD may have a nonspecific irritant hand dermatitis
of eczema was 10.2% and that the 1-year prevalence of eczema aggravated by repeated wetting, especially in an occupational
with asthma and/or hay fever was 3.2%. 4 setting.
Natural History Infections
AD typically manifests in early childhood, with onset in the first Patients with AD have an increased susceptibility to infection
2
year occurring in >50% of patients and before 5 years of age in or colonization with a variety of organisms. Staphylococcus aureus
approximately 90% of patients. Although AD can present at any can be cultured from the skin of the majority of patients with
611

612 Part five Allergic Diseases



TABLE 44.1 Differential Diagnosis of TABLE 44.2 Clinical features of
atopic Dermatitis atopic Dermatitis
Congenital Disorders Major features
• Netherton syndrome • Pruritus
• Familial keratosis pilaris • Facial and extensor involvement in infants and children
• Flexural lichenification in adults
Chronic Dermatoses • Chronic or relapsing dermatitis
• Seborrheic dermatitis • Personal or family history of atopic disease
• Contact dermatitis (allergic or irritant)
• Nummular eczema Minor features
• Psoriasis • Xerosis
• Ichthyoses • Cutaneous infections
• Nonspecific dermatitis of the hands or feet
infections and infestations • Ichthyosis, palmar hyperlinearity, keratosis pilaris
• Scabies • Pityriasis alba
• Human immunodeficiency virus (HIV)–associated dermatitis • Nipple eczema
• Dermatophytosis • White dermatographism and delayed blanch response
• Anterior subcapsular cataracts
Malignancies • Elevated serum immunoglobulin E (IgE) levels
• Positive immediate-type allergy skin tests
• Cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome)
• Letterer-Siwe disease Modified from Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta
Derm Venereol (Stockh) 1980;92:44–7.
autoimmune Disorders
• Dermatitis herpetiformis
• Pemphigus foliaceus
• Graft-versus-host disease (GvHD) immune response to herpes simplex virus. In addition, genetic
• Dermatomyositis
variants in IFN-γ regulatory factor 2 (IFN-γR2) have been shown
immunodeficiencies to be associated with ADEH and may contribute to abnormal
• Wiskott-Aldrich syndrome (WAS) immune responses to herpes simplex virus.
• Severe combined immunodeficiency syndrome (SCID) Superimposed dermatophytosis may contribute to cutaneous
• Hyperimmunoglobulin E (IgE) syndrome (HIES) inflammation in AD. The opportunistic yeast Malassezia sym-
• Dedicator of cytokinesis 8 (DOCK8)–associated immunodeficiency podialis (previously Pityrosporum ovale) has been associated with
• Tyrosine kinase 2 (TYK2) deficiency a predominantly head and neck distribution of AD.
• Immune dysregulation, polyendocrinopathy, enteropathy X-linked
(IPEX) syndrome Systemic Complications
Metabolic Disorders A significant number of patients with AD do not outgrow their
• Zinc deficiency disease and can have systemic inflammation with increased risk
6
• Pyridoxine (vitamin B6) and niacin deficiency for systemic diseases, including cardiovascular disease, rheu-
7
• Multiple carboxylase deficiency matoid arthritis, and/or inflammatory bowel disease.
• Phenylketonuria
Psychosocial Implications
Patients with AD frequently respond to stress or frustration with
itching and scratching. Stimulation of the central nervous system
AD. Preferential adherence of this organism in AD may be related (CNS) may intensify cutaneous vasomotor and sweat responses
to expression of adhesins, such as fibronectin and fibrinogen, and contribute to the itch–scratch cycle. Scratching can be associ-
in inflamed skin. Recurrent pustulosis has become a significant ated with significant secondary gain or with a strong habitual
problem for a number of patients, especially with the emergence component. Severe disease can lead to problems with self-esteem
of methicillin-resistant S. aureus (MRSA) as an important and social interactions. Sleep abnormalities are common and
pathogen in AD. can contribute to impaired quality of life of patients and family
Viral infections in AD include herpes simplex, molluscum members, even when the skin disease appears to be in remission.
contagiosum, and human papillomavirus infections. Patients
who have atopic dermatitis with eczema herpeticum (ADEH) Differential Diagnosis
have more severe disease, increased body surface area affected, A number of diseases can be confused with AD (see Table 44.1).
and an increase in biomarkers, including circulating eosinophil Immunodeficiency with eczematous rash includes immune
counts, serum immunoglobulin E (IgE), thymus and activation- dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX)
regulated chemokine, and cutaneous T cell–attracting chemokine, syndrome. IPEX results from mutations of FOXP3, a gene located
compared with patients with AD who do not have a history of on the X chromosome that encodes a DNA-binding protein
EH. Patients with ADEH also have more cutaneous infections required for development of regulatory T cells (Tregs). Patients
caused by S. aureus or molluscum contagiosum virus and are may present with enteropathy, type 1 diabetes, thyroiditis,
more likely to have a history of asthma, as well as food and hemolytic anemia, and/or thrombocytopenia. Wiskott-Aldrich
inhalant allergies. Patients with ADEH have reduced interferon-γ syndrome (WAS) is an X-linked recessive disorder characterized
(IFN-γ) production. IFNγ and IFNγR1 SNPs are significantly by an eczematous rash, associated with thrombocytopenia along
associated with ADEH and may contribute to an impaired with variable abnormalities in humoral and cellular immunity

CHaPter 44 Atopic and Contact Dermatitis 613


and severe bacterial infections. Hyper-IgE syndrome (HIES) with immunity, interleukin-1 (IL-1) family signaling, Tregs, the vitamin
mutations in the signal transducer and activator of transcription D pathway, and the nerve growth factor pathway in the pathogenesis
9
3 gene (STAT3) is an autosomal dominant multisystem disorder of AD. Thus a combination of varied genetic factors may influence
characterized by recurrent deep-seated bacterial infections, a wide range of phenotypes of AD among individuals.
including cutaneous cold abscesses and pneumonias caused by
S. aureus. Patients with mutations in the gene encoding dedicator Immune Abnormalities in Atopic Dermatitis
of cytokinesis 8 protein (DOCK8) have an immunodeficiency Immunohistology
with eczema, recurrent viral infections, including some with On the basis of clinical appearance and duration of illness, AD
CNS involvement, and many have associated food allergies. skin can be characterized as nonlesional AD, acute AD lesions
Patients with tyrosine kinase 2 (TYK2) deficiency can also present (≤3 days after onset), and chronic skin lesions. Nonlesional AD
with an eczematous rash with high serum IgE and recurrent skin is not normal and is characterized by a sparse perivascular
cutaneous staphylococcal infections. Other diseases to consider T-cell infiltrate, suggesting the presence of minimal inflammation
in the differential diagnosis of AD include cutaneous T-cell at baseline. Langerhans cells (LCs) also exhibit surface-bound
lymphoma, especially in adults with no history of childhood IgE molecules, which have enhanced capacity to present allergen
eczema and without other atopic features, human immunode- to T cells. In acute lesions, there is epidermal spongiosis with
ficiency virus (HIV) infection, and CD (see section on ACD). an increased infiltration of activated memory T cells bearing
Contact allergy can also complicate AD, especially in patients the skin-homing cutaneous lymphocyte-associated antigen
+
whose AD does not respond to or worsens with therapy. (CLA ). Eosinophils, basophils, and neutrophils are rare. Mast
cells are seen in various stages of degranulation.
PATHOGENESIS OF ATOPIC DERMATITIS Chronic lichenified AD lesions are characterized by epidermal
hyperplasia, prominent hyperkeratosis, and an increased number
Genetics of dendritic cells (DCs) bearing surface IgE. Macrophages domi-
The genetics of AD are complex with key roles played by skin nate the dermal mononuclear cell infiltrate, but lymphocytes
barrier or epidermal differentiation genes and immune response remain prominent. Although intact eosinophils are rarely seen,
or host defense genes. eosinophil product deposition can be readily identified, suggesting
they contribute to allergic skin inflammation.
KeY CONCePtS Immune Pathways in Atopic Dermatitis
Pathogenesis of Atopic Dermatitis (AD) AD is associated with a combination of defective innate responses
to microbes and altered adaptive responses to environmental
• Patients with AD have abnormalities of skin barrier and immune allergens (reviewed in references 1,2,10 ). A key difference between
dysregulation. epidermal keratinocytes found in AD skin, compared with normal
• Some patients with AD have decreased filaggrin in the skin based on skin, is the presence of thymic stromal lymphopoietin (TSLP)
mutations in the gene encoding filaggrin (FLG), copy number variation
of FLG, or secondary to type 2–mediated cytokine (e.g., IL-4, IL-13) and IL-33 in the AD epidermis. TSLP and IL-33 are key cytokines
suppression of FLG. secreted by epithelial cells that induce DCs to drive T-helper 0
• FLG mutations are associated with early-onset, severe, persistent AD (Th0) cells into the Th2-cell differentiation pathway. Nonlesional
with increased risk for asthma and allergic sensitization. AD and acute AD skin lesions are predominantly associated with
• Normal-appearing skin in patients with AD is associated with immune expression of IL-4, IL-5, IL-13, IL-25, and IL-33. These type 2
activation and epidermal terminal differentiation abnormalities. cytokines are present in all stages of AD and can be secreted by
• Patients with AD are predisposed to Staphylococcus aureus colonization
or infection, and a small subset are prone to eczema herpeticum. multiple cell types, including innate lymphoid type 2 cells (ILCs),
• Patients with an “Asian phenotype” of AD have features of psoriasis mast cells, and basophils, which are present in AD skin lesions
with increased T-helper 17 (Th17) and Th22 along with increased Th2 and contribute to substantial redundancy in allergic inflammation.
skewing. As such, cytokine targeting, as opposed to cell targeting, is
considered a more effective approach in the treatment of AD.
It is noteworthy that experimental studies demonstrate pretreat-
Loss-of-function mutations of FLG are a major predisposing ment with IL-4 and IL-13 dampens responses to IFNs and IL-17,
factor for AD. Patients with FLG gene mutations have early-onset, suggesting that once the early AD lesion is exposed to IL-4 and
severe, and persistent AD and are at increased risk for developing IL-13, there is a long-lasting persistent effect.
8
asthma, as well as food and inhalant allergies. Other skin barrier Besides Th2, other cytokine pathways are also activated during
proteins implicated in AD include loricrin and involucrin, which the evolution of AD. The IL-22–IL-17 pathway is of particular
are both significantly decreased in lesional and nonlesional skin interest, since it, along with IL-4 and IL-13, can inhibit terminal
of patients with AD. Candidate gene approaches have also keratinocyte differentiation, including filaggrin expression. Since
implicated variants in the SPINK5 gene, and haplotype tagging DC-derived IL-23 enhances IL-22/IL-17 cell differentiation, all
of SNPs for the claudin-1 gene (CLDN1) has revealed associations of these cytokines are being closely examined for their potential
with AD. These observations have established a key role for role in AD. It is interesting that IL-4 and Il-13 can enhance IL-23
impaired skin barrier function in the pathogenesis of AD that production by DCs. Furthermore, blockade of the IL-4 and IL-13
allows increased transepidermal water loss and penetration of pathway, leading to improvement in AD, is also associated with
allergens, antigens, and chemicals from the environment, resulting reduced IL-23 and IL-17 expression in AD skin. When acute AD
in cutaneous inflammation. Additional genome-wide significant skin lesions become chronic, there is an increase in Th1 cytokines,
susceptibility loci identified through the genome-wide association such as IFN-γ, which potentiates AD skin inflammation. A recent
study (GWAS) and immunochip analysis continue to be reported birth cohort study, however, demonstrated that TSLP could be
and suggest a role for epidermal barrier function, innate-adaptive detected in at-risk infants before onset of AD, suggesting that

614 Part five Allergic Diseases


ICD ACD AD
Antigen Second exposure Antigen Disease alters threshold for
sensitization Elicitation ICD, ACD, and self-reactivity

1 Irritant 1 Allergen Antigen




IL-1α
IL-1α
KCs
2 IL-1α IL-1α Disturbed barrier
IL-1α IL-1α KCs KCs ( TEWL)
IL-1β
TNF-α 5
LC GM-CSF LC Further LC
IL-8 stimulation
3 2 of KCs iDEC LC
IL-1α
IL-1β
TNF-α
GM-CSF
dDC IL-8 dDC dDC Eotaxin
IL-18
dDC 3

TSLPR TSLP
Vasodilation dDC
Cellular Cellular recruitment
5 infiltration Infiltration OX40L
Lymph 4 OX40
3 node Th1 Lymph Th2 IL-4
IL-13
IFN-γ
TNF node IL-31
Lymphocyte
Th2 IL-4 Th1 IFN-γ
Th1 IL-5 T cell
IL-13
Neutrophil IL-17 LC
Th17 Th17 IL-22 Th22 IL-22
Naive Naive
T cell Th2 T cell
Treg IL-10 dDC Th17 IL-17
IL-22
Macrophage TGF-β
Th17 B cell
Mast TNF Th2 Mast TNF
Treg cell Histamine IL-4 cell Histamine

Endothelial Mast cell Hapten-specific IgE Class
cell T cell proliferation Eosino- MBP switchery Eosino- MBP
phil TNF-α phil TNF-α

3
ICAM E-selectin Treg Th2 Mast Eosino- T cell Mast

phil
Blood vessel 4 Vasodilation Th1 cell phil Treg cell Eosino-
Cellular recruitment
A B C

CHaPter 44 Atopic and Contact Dermatitis 615


fiG 44.1 (A) In patients with irritant contact dermatitis (ICD), exposure to an irritant exerts toxic effects on keratinocytes (KCs), activating
innate immunity with release of interleukin (IL)-1α, IL-1β, tumor necrosis factor (TNF)-α, granulocyte macrophage–colony-stimulating
factor (GM-CSF), and IL-8 from epidermal keratinocytes. In turn, these cytokines activate Langerhans cells (LCs), dermal dendritic
cells (DCs), and endothelial cells, all of which contribute to cellular recruitment to the site of keratinocyte damage. Infiltrating cells
include neutrophils, lymphocytes, macrophages, and mast cells, which further promote an inflammatory cascade. (B) In the sensitization
phase of allergic contact dermatitis (ACD), similar to ICD, allergens activate innate immunity through keratinocyte release of IL-1α,
IL-1β, TNF-α, GM-CSF, IL-8, and IL-18, inducing vasodilation, cellular recruitment, and infiltration. LCs and dermal DCs encounter
the allergen and migrate to the draining lymph nodes, where they activate hapten-specific T cells, which include T-helper cell-1 (Th1),
Th2, Th17, and regulatory T cells (Tregs). These T cells proliferate and enter the circulation and site of initial exposure, along with
mast cells and eosinophils (EOS). On re-encountering the allergen, the elicitation phase occurs, in which the hapten-specific T cells,
along with other inflammatory cells, enter the site of exposure and, through release of cytokines and consequent stimulation of
keratinocytes, induce an inflammatory cascade. (C) In patients with atopic dermatitis (AD), a disturbed epidermal barrier leads to
increased permeation of antigens, which encounter LCs, inflammatory dendritic epidermal cells (IDECs), and dermal DCs, activating
Th2 T cells to produce IL-4 and IL-13. DCs then travel to lymph nodes, where they activate effector T cells and induce immunoglobulin
E (IgE) class-switching. IL-4 and IL-13 stimulate keratinocytes to produce thymic stromal lymphopoietin (TSLP). TSLP activates OX40
ligand–expressing dermal DCs to induce inflammatory Th2 T cells. Cytokines and chemokines, such as IL-4, IL-5, IL-13, eotaxins,
CCL17, CCL18, and CCL22, produced by Th2 T cells and DCs stimulate skin infiltration by DCs, mast cells, and eosinophils. Th2 and
Th22 T cells predominate in patients with AD, but Th1 and Th17 T cells also contribute to its pathogenesis. The Th2 and Th22
cytokines (IL-4/IL-13 and IL-22, respectively) have been shown to inhibit terminal differentiation and contribute to the barrier defect
in patients with AD. Thus both the barrier defects and immune activation alter the threshold for ICD, ACD, and self-reactivity in
patients with AD. MBP, Major basic protein. (Figure adapted from Gittler JK, Krueger JG, Guttman-Yassky E. Atopic dermatitis results
in intrinsic and immune abnormalities: implications for contact dermatitis. J Allergy Clin Immunol 2013;131:300–13.)












the TSLP–Th2–ILC2 pathway plays a critical role in initiation tHeraPeUtiC PriNCiPLeS
of AD. 11
Atopic Dermatitis (AD)
Epidermal Barrier Dysfunction
• Fundamentals of skin care in AD include avoidance of irritants
The clinically dry skin and increased transepidermal water loss and proven allergens, along with proper skin hydration and use of
(TEWL) in AD reflects underlying skin barrier dysfunction and moisturizers.
loss of natural moisturizing factor that plays an important role • Patients and caregivers have concerns about topical steroids and
in the pathogenesis of AD. However, only a minority of patients calcineurin inhibitors and tend to underuse prescribed medications.
have FLG null mutations. Other genetic variants in the epidermal • If eczema cannot be cleared and the patients keep relapsing, they
may benefit from proactive intermittent antiinflammatory therapy.
differentiation complex (EDC) and tight junctions are even rarer. • The diagnosis of AD should be reconsidered in patients not responding
The majority of patients with AD likely have immune-mediated to conventional therapy, as the differential diagnosis includes a number
reduction in epidermal terminal differentiation, which leads to of immunodeficiencies with eczematous rash.
reduced generation of various epidermal structural proteins, • Systemic therapies should be reserved for patients with moderate-
filaggrin breakdown products, lipids, and antimicrobial peptides. to-severe AD that does not respond to conventional therapy.
TSLP, IL-4, and IL-13 are the most potent cytokines downregulat-
12
ing filaggrin expression by keratinocytes. IL-17, IL-22, IL-25,
and IL-33 can act synergistically with IL-4 and IL-13 to further
downregulate expression of epidermal proteins and lipids. This Identification and Elimination of Exacerbating Factors
combination of events, along with activation of proteases and Irritants
lipases, creates defective epidermal barrier function, alters epi- Patients with AD have a lowered threshold of irritant responsive-
dermal acidification, and leads to loss of moisturization in AD, ness. Recognition and avoidance of irritants is integral for
thereby contributing to enhanced allergen and microbial penetra- successful management of this disease.
tion met by the host immune response and clinical appearance
of AD. Allergens
Identification of clinically relevant allergens involves taking a
MANAGEMENT OF ATOPIC DERMATITIS careful history and doing selective testing, when appropriate.
Negative skin tests with proper controls have a high predictive
Recent guidelines address the management of AD. 13,14 Recognition value for ruling out a suspected allergen. Positive skin tests have
of skin barrier and immune abnormalities suggests the need for a lower correlation with clinical symptoms and may reflect
16
barrier repair and maintenance along with antiinflammatory sensitization. Patients with severe AD who are avoiding foods
measures. 15 based on in vitro testing results can tolerate many of the foods

616 Part five Allergic Diseases


previously avoided when they are introduced under supervision. applications of topical corticosteroid to areas that had previously
Environmental control measures aimed at reducing dust mite been involved but now appear normal, with fewer relapses and less
allergen can also improve AD in sensitized patients. need for topical corticosteroids compared with treating eczema
in a reactive manner.
Psychosocial Factors In addition to their anti-inflammatory properties, topical
Recognizing and addressing sleep disturbance in patients is corticosteroids can decrease S. aureus colonization in patients
critical in managing a chronic, relapsing disease such as AD. with AD. Failure to show clinical improvement with topical
Counseling together with relaxation, behavioral modification, corticosteroids may be due to inadequate potency or amount
and biofeedback may all be of benefit, especially for patients of medication used, superinfection, steroid allergy, steroid
with habitual scratching. resistance, or, more commonly, nonadherence with the treatment
regimen, emphasizing the need for both education and alternative
Patient Education therapies.
Patients and caregivers need to be educated regarding the chronic Systemic corticosteroids, including oral prednisone, should
relapsing nature of AD, its natural history, exacerbating factors, be avoided in the management of a chronic disorder such as
and treatment options. Recognizing that normal-appearing skin AD. 13,19 Improvement observed with systemic corticosteroids may
in patients with AD is, in fact, not normal is a difficult concept be associated with flaring of AD after discontinuation. If a short
to understand but has important therapeutic implications. Patients course of oral corticosteroids is given, topical skin care should be
should be counseled about prognosis and receive appropriate intensified during the taper to suppress rebound flaring of AD.
vocational counseling. Topical corticosteroid treatment in patients with AD was
recently shown to result in improvements of the AD genomic
Hydration signature. Cytokine levels (IL-12p40, IL-13, IL-22, CCL17, CCL18,
The skin of patients with AD shows enhanced TEWL and lipid peptidase inhibitor 3 [PI3]/elafin, and S100As) were consistently
abnormalities that result in reduced water-binding capacity, reduced, with corresponding improvements in epidermal disease
10
higher TEWL, and decreased water content. Skin hydration by markers (keratin 16 and loricrin) in lesional skin from responders.
soaking the affected area or bathing and applying an occlusive Even low-potency corticosteroids can affect a broad array of
15
agent to retain absorbed water can help restore barrier function. immune and barrier responses in patients with AD.
Bathing can also remove allergens, reduce S. aureus colonization,
and act as relaxation therapy. Topical Calcineurin Inhibitors
Tacrolimus ointment (0.03% and 0.1%) and pimecrolimus cream
Moisturizers and Occlusives (1%) are nonsteroidal topical calcineurin inhibitors (TCIs)
Use of moisturizer or occlusive, especially when combined with approved for the treatment of AD. 13,14 Both drugs have proven
hydration therapy, helps restore and preserve the skin barrier effective, with a good safety profile even when used over extended
and can result in decreased need for topical corticosteroids. periods, including in infants treated with pimecrolimus. Treatment
Twice-daily emollient application has been shown to improve with TCIs is not associated with skin atrophy and may also be
barrier function and protect the skin from S. aureus proliferation useful in treating patients with steroid insensitivity. A common
17
while preserving microflora biodiversity. Patients with AD have side effect with TCIs is burning or stinging sensation of skin.
been shown to have a ceramide deficiency of the stratum corneum; Ongoing surveillance and recent reports have not shown a trend
barrier repair may be accelerated by increasing the ratio of of increased frequency of viral infections or problems with
ceramides, cholesterol, and either the essential fatty acid linoleic response to childhood vaccinations. Although there is no evidence
acid or the nonessential palmitic or stearic fatty acids. of a causal link to cancer and the use of TCIs, the US Food and
Drug Administration (FDA) issued a “box warning” because of
Corticosteroids lack of long-term safety data. The labeling states that these drugs
Corticosteroids reduce inflammation and pruritus in acute and are recommended as second-line treatments and that their use
chronic AD, acting on multiple resident and infiltrating cells, in children under the age of 2 years is currently not recommended.
primarily through suppression of inflammatory genes. Topical However, a review of epidemiological and clinical data concluded
corticosteroids have been the mainstay of conventional therapy: that the published data did not demonstrate any causal relation-
when they are appropriately used, side effects are infrequent. ship between TCI use and malignancy or lymphoma risk.
Thinning of skin, telangiectasia, bruising, hypopigmentation, Studies of proactive treatment with tacrolimus ointment in
7
acne, striae, and secondary infections may occur. The face, adults and children have shown benefit. A systematic review
particularly the eyelids, and the intertriginous areas are especially and meta-analysis of randomized clinical trials comparing TCIs
sensitive to these adverse effects. If topical corticosteroids are with topical corticosteroids for AD found that both treatment
used on the face, this can lead to perioral dermatitis, characterized classes showed similar rates of improvement and treatment
by erythema, scaling, and follicular papules and pustules around success. 20
the mouth, in the alar creases, and sometimes on the upper
lateral eyelids. Antiinfective Therapy
An important concept with translational applications is the Systemic antibiotic therapy may be necessary when a secondary
2
recognition that nonlesional, normal-appearing skin in AD infection with S. aureus is present. Recolonization after a course
shows evidence of both immunological dysregulation and skin of anti-staphylococcal therapy occurs rapidly. Maintenance
18
barrier abnormalities. This observation provides a rationale antibiotic therapy should be avoided because it can result in
7
for the use of topical corticosteroids in a proactive manner. If colonization by MRSA. Bleach baths with dilute sodium hypo-
the eczema can be cleared or almost cleared but has a relapsing chlorite may reduce skin infections and improve eczema (based
course, long-term control can be maintained with twice-weekly on limited data). 13,14

CHaPter 44 Atopic and Contact Dermatitis 617


Patients with disseminated EH require treatment with a mofetil (a purine biosynthesis inhibitor), azathioprine (a systemic
2
systemic antiviral, such as acyclovir. Recurrent cutaneous herpetic immunosuppressive agent affecting purine nucleotide synthesis
21
infections can be treated with prophylactic oral acyclovir. and metabolism), and methotrexate (a folic acid antagonist that
Superficial dermatophytosis can be treated with topical or, rarely, interferes with purine and pyrimidine synthesis). 13,19 All of these
with systemic antifungals. drugs require careful monitoring of patients for potential serious
adverse effects.
Antipruritic Agents
Pruritus is the most common and least tolerated symptom in Phototherapy and Photochemotherapy
AD. Mediators other than histamine, including neuropeptides Ultraviolet (UV) light therapy can be a useful treatment for
19
and cytokines, especially IL-31, can contribute to pruritus, and chronic, recalcitrant AD. Potential long-term adverse effects
centrally acting agents, such as opioid receptor antagonists, have include premature skin aging and cutaneous malignancies. In
been shown to be effective against the itch of AD. Treatment patients with moderate-to-severe chronic AD treated with
with cyclosporine, which results in decreased transcription of a narrow-band UVB phototherapy, gene expression and immu-
number of proinflammatory cytokines, leads to rapid improve- nohistochemistry studies of both lesional and nonlesional skin
ment in pruritus in many AD patients. Monoclonal antibodies showed that Th2, Th22, and Th1 immune pathways were sup-
(mAbs) against IL-31 and its receptor are undergoing clinical pressed and that measures of epidermal hyperplasia and dif-
22
trials in patients with AD, and two phase three trials of a mAb ferentiation were normalized. Clinical improvement was associated
against IL-4 receptor alpha, inhibiting signaling by IL-4 and with decrease in Th2/Th22–associated cytokines and chemokines
IL-13 significantly reduced pruritus and enhanced quality of and, importantly, normalized expression of epidermal barrier
22a
life. Systemic antihistamines and anxiolytics may be most useful proteins. UVB phototherapy has also been shown to significantly
through sedative effects and should be used primarily at bedtime decrease levels of toxin-producing S. aureus on the skin of
to avoid daytime somnolence. Short-term use of a sedative to pediatric patients with AD.
allow adequate rest may be appropriate. Treatment with topical
antihistamines and topical anesthetics should be avoided because Allergen-Specific Immunotherapy
of the potential for allergic sensitization. Allergen-specific immunotherapy (AIT; Chapter 91) has been
administered to patients with AD for many years, although there
RECALCITRANT DISEASE is a paucity of controlled data on this treatment. Based on limited
evidence, the updated Practice Parameter for AD states that AIT
Hospitalization may be effective for a subset of patients with AD and aeroallergen
13
Patients who experience erythroderma, appear to have toxicity, sensitivity. A Cochrane review of randomized controlled trials
23
or fail on conventional therapies may require hospitalization. of AIT in AD found that the trials were confounded by high
25
Removing the patient from environmental allergens or stressors, loss to follow-up and lack of blinding. The authors were unable
intense education, and assurance of adherence with therapy to determine by subgroup analyses a particular allergen, age, or
usually result in marked clinical improvement. The patient can level of disease severity where AIT was more successful.
also undergo appropriately controlled provocative challenges to
identify potential triggering factors. Biologics and Investigational Therapies
Intravenous Gammaglobulin
Wet Wrap Therapy Because chronic inflammation and T-cell activation appear to play
Wet wrap therapy (WWT), in which a layer of wet clothing or a critical role in the pathogenesis of AD, high-dose intravenous
bandages is placed over topical corticosteroid with a dry layer immunoglobulin (IVIG; Chapter 84) could have immunomodula-
on top, can reduce inflammation and pruritus and acts as a tory effects in this disease. IVIG could also interact directly with
barrier to trauma associated with scratching. WWT can aid infectious organisms or toxins involved in the pathogenesis of
epidermal barrier recovery that persists even after this therapy AD. IVIG has been shown to contain high concentrations of
is discontinued, and clinical benefit can be demonstrated after staphylococcal toxin–specific antibodies that inhibit the in vitro
discontinuation. Overuse can result in chilling, maceration of activation of T cells by staphylococcal toxins. Treatment of severe
skin, or secondary infection. WWT should be employed for acute refractory AD with IVIG has yielded conflicting results. Studies
exacerbations of AD or for selective use in areas of resistant have not been controlled and have involved small numbers of
eczema, rather than as a maintenance treatment. The package patients. A systematic review of systemic therapies found that IVIG
inserts for topical calcineurin inhibitors recommend that they was not efficacious in the treatment of moderate-to-severe AD. 24
should not be used under occlusive dressings.
Omalizumab
Systemic Immunosuppressive Agents Treatment of patients with AD with omalizumab has mainly
Oral cyclosporine has been shown to be effective in placebo- been reported in case reports and case series, showing both
controlled studies in severe AD, although it is not approved for clinical improvement and lack of benefit. A placebo-controlled
treatment of AD in most countries. A systematic review of ran- trial of omalizumab given for 16 weeks did not show significant
domized controlled trials evaluating systemic immunomodulating clinical benefit. No specific markers have been identified that
treatments for moderate-to-severe AD found that, of 12 different define responders, although a recent study suggested that adult
interventions studied in 34 randomized controlled trials, strong patients with AD that responds to treatment have wild-type FLG
recommendations were only possible for the short-term use of mutations. In addition, patients receiving omalizumab have been
24
cyclosporine. Patients need to be appropriately monitored while shown to have decreased levels of TSLP, OX40L, thymus and
19
on this medication. Other systemic immunosuppressive drugs activation-regulated chemokine (TARC), and IL-9 and marked
that have been used to treat severe AD include mycophenolate increase in IL-10 compared with placebo.

618 Part five Allergic Diseases



Rituximab Recombinant Human Interferon-γ
Rituximab, a chimeric monoclonal anti-CD20 antibody has been Interferon-γ suppresses IgE synthesis and inhibits Th2 cell func-
given to patients with severe AD, with skin biopsies showing tion. In patients with AD, treatment with subcutaneous recom-
significant improvement in spongiosis and acanthosis and dermal binant human interferon-γ (rhIFN-γ) resulted in reduced clinical
13
13
T-cell and B-cell infiltrates decreased as well. Although total severity and decreased total circulating eosinophil counts.
serum IgE levels were reduced, allergen-specific IgE levels were rhIFN-γ may act primarily on the allergic inflammatory response
not affected. Treatment combining omalizumab and rituximab as opposed to IgE synthesis, and a subset of patients treated with
in patients with severe refractory AD was found to be effective, rhIFN-γ could respond to individualized titration of their treat-
suggesting that optimal therapy may require use of several ment dose. In a case series of pediatric patients with ADEH,
biologics. IFN-γ and IVIG were thought to be less likely to enhance the
cutaneous viral susceptibility of these patients compared with
Dupilumab systemic immunosuppressive therapies. 21
Dupilumab is a fully human mAb directed against the IL-4
receptor α subunit that blocks signaling of both IL-4 and IL-13. Phosphodiesterase-4 Inhibitors
Results from several randomized, double-blind, placebo-controlled Apremilast, an oral phosphodiesterase-4 inhibitor approved for the
trials involving adults with moderate-to-severe AD showed that treatment of psoriasis, was shown in a pilot study in adults with
treatment with dupilumab resulted in rapid and dose-dependent AD to reduce pruritus and improve the Dermatology Quality of
29
improvements in clinical indexes, biomarker levels, and disease Life Index (DLQI) and EASI scores. Gene ontological analyses
transcriptome. 22a,26 Of the patients in the dupilumab group, 85% comparing baseline samples with samples obtained during
had a 50% reduction in the Eczema Area and Severity Index treatment revealed alterations in immune response pathways,
(EASI) score compared with 35% in the placebo group (P <0.001); especially those related to cyclic adenosine monophosphate
40% of patients in the dupilumab group had an investigator’s (cAMP)–mediated signaling.
global assessment score of 0–1 (clear or almost clear) compared Crisaborole is a benzoxaborole phosphodiesterase 4 (PDE4)
with 7% in the placebo group (P <0.001); and pruritus scores inhibitor, which has been approved by the FDA as a 2% topical
30
decreased by 55.7% in the dupilumab group versus 15.1% in ointment in children and adults with mild to moderate AD.
the placebo group (P <0.001). In a combination study, 100% of The unique configuration of boron within the crisaborole
the patients in the dupilumab group had a 50% improvement in molecule enables selective targeting and inhibition of PDE4,
EASI (P = 0.002), compared with 50% of those in the placebo increasing cAMP levels and reducing inflammation. In addition,
group, even though the patients who received dupilumab used the boron molecule allowed for synthesis of a low-molecular-
less than half the amount of topical steroids compared with weight compound (251 daltons), thereby facilitating penetration
those in the placebo group (P = 0.16). Adverse events, such of crisaborole through human skin. In vitro experiments have
as skin infection, occurred more frequently with placebo; shown that crisaborole inhibits cytokine production by peripheral
nasopharyngitis and headache were the most frequent adverse blood mononuclear cells similar to other PDE4 inhibitors and
events with dupilumab. Of note, treatment with dupilumab distinct from corticosteroids. Randomized controlled clinical
monotherapy shifted the RNA expression profile of lesional skin trials have shown the efficacy and safety of crisaborole topical
to a more nonlesional signature. Dupilumab was well tolerated ointment 2% in children, adolescents, and adults with mild to
with no dose-limiting toxicity. Further dose ranging studies have moderate AD.
27
been reported, and studies in adolescents and children are
ongoing. Probiotics
Clinical trials in patients with AD show varying results. A meta-
Anti–IL-12/IL-23 analysis of randomized controlled trials that attempted to
Ustekinumab, an mAb used for treatment of psoriasis and overcome some of the limitations of prior reviews found a
psoriatic arthritis, binds to the common p40 subunit of IL-12/ reduction of approximately 20% in the incidence of AD and
IL-23. A recent study of Japanese and Korean patients with AD IgE-associated AD in infants and children with the use of probiot-
22
found overlapping features of both AD and psoriasis. The Asian ics. Although these results are encouraging, the use of probiotics
AD phenotype described presents a blended phenotype, including for the prevention of AD remains investigational.
increased hyperplasia, parakeratosis, higher Th17 activation, and
a strong Th2 component. Although these findings need to be PREVENTION
reproduced in a larger population of Asian patients, they do
suggest that ustekinumab may be of benefit in a subset of patients Two preliminary studies have suggested that emollient therapy
with similar features. started in early infancy in at-risk neonates can reduce the
incidence of AD. 31,32 Both studies were of relatively short-term
Other Biologics duration without follow-up off emollient therapy. It is noteworthy
A number of other biologics have been evaluated in preliminary that infants at risk for AD at 1 year of age could be identified
studies or are in early development in AD. 22,28 These include as early as day 2 of life by TEWL measurement, independent of
anti–IL-13 (lebrikizumab, tralokinumab), anti–IL-22, anti–IL-31, parental atopy or FLG mutation status. 33
and anti–IL-31-receptor, as well as anti-TSLP and anti–TSLP
receptor. New insights into AD phenotypes as well as better CONTACT DERMATITIS
understanding of underlying immunopathology will likely lead
to improved selection of appropriate patients for more targeted CD is a skin disorder caused by contact with an exogenous
therapies. substance that elicits an allergic and/or irritant response. The

CHaPter 44 Atopic and Contact Dermatitis 619


vast majority of cases of contact-induced skin reactions are The immune response of ACD requires completion of both an
attributable to CD. However, there are other less-well-defined afferent (sensitization) and an efferent (elicitation) phase.
contact reactions, including contact urticaria, contact urticaria In the afferent limb, the hapten enters the epidermis and
syndrome, and protein contact dermatitis. ACD affects approxi- activates keratinocytes to release inflammatory cytokines and che-
mately 7% of the general population, 13.3–24.5% of pediatric mokines, including tumor necrosis factor (TNF)-α, granulocyte
34
patients, and 33–64% of the elderly population. CD was macrophage–colony-stimulating factor (GM-CSF), IL-1α, IL-1β,
associated with more than 10.6 million physician office visits, IL-8, IL-10, IL18, and macrophage inflammatory protein-2 (MIP-
with annual direct costs estimated at $1.6 billion and indirect 2). The activation of LCs, other DCs, and endothelial cells can lead
costs at $566 million as a result of loss of work time, school to recruitment of even more DCs at the site of antigen contact.
35
time, and productivity. Numerous studies have reported an The release of IL-1β by epidermal LCs promotes their egress
36
increased frequency of ACD in patients with AD, likely as a from the epidermis. LCs process the antigen while migrating to
result of the increased exposure to products and chemicals used regional lymph nodes, where they present it to naïve T cells. This
to treat AD, the barrier defect, and immunological changes in phase is influenced by multiple factors. Defects in the integrity
AD, which predispose a patient to both ICD and ACD. 37 of the stratum corneum allow greater penetration of allergen
and increase the chances of activating antigen-presenting cells
PATHOGENESIS OF ALLERGIC (APCs) in skin. The availability and viability of APCs in skin,
CONTACT DERMATITIS as well as the presence or absence of cytokines produced by
keratinocytes, can promote or hinder APC–T-cell engagement.
The Genes In the draining lymph nodes, LCs present the peptides to T cells
ACD is a multifactorial condition in which genetic background and activate CD4 and CD8 antigen-specific T cells. An important
plays an important part, as shown by twin and family studies. property of LCs and DCs is their ability to present exogenous
An association has been demonstrated between loss of function antigens on both major histocompatibility complex (MHC) class
mutations R501x and 2282del4 in the filaggrin (FLG) gene and I and class II molecules. This cross-priming leads to the activation
contact sensitization against nickel II-sulfate, combined with of both CD4 and CD8 hapten-specific T cells. Although classic
an intolerance to fashion jewelry but not with other contact delayed-type hypersensitivity reactions are mediated primarily
38
allergens. FLG mutations have further been shown to lower by CD4 cells, CD to haptens is mediated primarily by CD8 cells
39
the age of onset of nickel sensitization. Thus FLG defects may with a Th1-type cytokine profile. LCs activate hapten-specific
40
be a risk factor for contact sensitization to allergens. T cells, which include Th1, Th2, Th17, and Treg subsets. This
preexisting mix of T-cell subtypes specific for the antigen influence
The Allergens the outcome of this process. The higher the frequency of cells
Most contact allergens are haptens, that is, simple chemicals that of an effector subtype, the higher the likelihood that dermatitis
bind to carrier proteins present in skin to form a complete antigen will result, whereas a higher frequency of cells of a regulatory
(Chapter 6). To be allergenic, the chemical must be able to subtype may limit or prevent the development of dermatitis.
penetrate the principal barrier in skin (stratum corneum) and The efferent phase of ACD occurs on subsequent contact of
reach the living cells of the epidermis. Only molecules with skin with the hapten. Antigen-specific memory T cells and other
molecular mass of <500 daltons (Da) are capable of penetrating inflammatory cells leave vessels and enter skin through sequential
the stratum corneum. Lipid solubility promotes transit through activation of a number of adhesion molecules by cytokines.
the stratum corneum. Thus most contact allergens are small, Memory T cells constitutively express CLA. E-selectin, the ligand
lipophilic molecules. Once in the epidermis, the nature of the for CLA, is induced on vascular endothelium by inflammatory
protein carrier for the hapten is very important because if the mediators, such as IL-1 and TNF-α. This interaction causes
contact sensitizer is complexed to nonimmunogenic carriers, memory T cells to slow down and roll along the endothelial surface
this may induce tolerance rather than sensitization. 38 as a prelude to migration to sites of inflammation. Firm adhesion
and migration of leukocytes to the endothelium are mediated by
The Immune Response T-cell very late antigen-4 (VLA-4)/leukocyte function–associated
antigen-1 (LFA-1) and endothelial cell vascular cell adhesion mol-
KeY CONCePtS ecule-1 (VCAM-1)/intercellular adhesion molecule 1 (ICAM-1),
Pathogenesis of Contact Dermatitis respectively (Chapter 11). Subsequently, LFA-1β T cells migrate
toward ICAM-1β epidermal cells.
• Allergic contact dermatitis (ACD) is a delayed-type, T cell–mediated Mast cells can also participate in the elicitation phase. In mice,
response with an afferent limb or sensitization phase and an efferent mast cells can be activated by a T-cell–derived antigen-binding
or elicitation phase. factor that induces release of serotonin, producing swelling 2
• Irritant contact dermatitis (ICD) is caused by irritants exerting toxic hours after challenge. In addition, mast cells contain preformed
effects on keratinocytes, causing a direct activation of the innate TNF-α, which may regulate the adhesion molecules involved
immune system through hyperproduction of cytokines and chemokines in the early recruitment of Th cells. The net result is an influx
and inducing an inflammatory skin reaction.
• Patients with ICD are more susceptible to the development of ACD, of sensitized T cells homing to the hapten-provoked skin site,
indicating that the activation of innate immunity by irritants likely releasing their inflammatory mediators, IL-2 and IFN-γ, and this
reduces the threshold for development of ACD. results in an enhanced immune response through activation and
• There is an increased frequency of ACD in patients with AD likely recruitment of more inflammatory cells, producing spongiosis
because of the disturbed skin barrier allowing increased allergen and the inflammatory dermal infiltrate characteristic of ACD.
penetration on an already amplified adaptive response in AD. Although Th1 cells have been classically considered the primary
• Although ACD, ICD, and AD are independently defined diseases, they
frequently interact and coexist. effector cells of ACD (responses to haptens, such as nickel, were
dominated by IFN-γ–producing cells), recent studies have

620 Part five Allergic Diseases


indicated that Th2 cells also participate in the development of abrade or irritate skin. After exposure to skin irritants, perturba-
contact hypersensitivity. 41 tion of the skin barrier and disorganization of the lipid bilayers
46
Recently, both murine models and human studies have sug- with lamellar body lipid extrusion in the epidermis is seen,
gested the potential role of Th17 cells in the immunopathogenesis with an associated increase in TEWL.
of ACD. Increased levels of cytokines favoring a Th17 response Irritants cause direct activation of the innate immune system
42
(i.e., IL-6) and allergen-specific IL-17–producing T cells were through hyperproduction of cytokines and chemokines, such
found in sensitized mice. In addition, IL-17–deficient mice showed as IL-1α, IL-1β, IL-6, IL-8, and TNF-α, which further induce a
decreased secretion of cytokines and chemokines, diminished cytokine cascade and inflammatory reaction with infiltration of
hapten-specific CD4 T-cell responses, and reduced ear swelling. inflammatory cells. Epidermal keratinocytes have been identified
In patients with ACD, Th17-associated mediators, such as IL-17A, as key effector cells in the initiation and propagation of contact
IL-17F, IL-22, IL-23, chemokine receptor 6 (CCR6), IL-22 receptor, irritancy. Keratinocytes can release both preformed and newly
and the Th17 transcription factor retinoic acid–related orphan synthesized cytokines, and can upregulate MHC class II molecules
40
receptor γ, were shown to be produced by nickel-specific T cells and induce adhesion molecules in response to irritants. These
and were upregulated in ACD lesional skin and positive patch mediators can cause direct tissue damage, activating LCs, dermal
43
test biopsy specimens. Nickel exposure was reported to induce DCs, and endothelial cells, which contribute to further cellular
production of IL-23 by keratinocytes, promoting a Th17-mediated recruitment, including neutrophils, lymphocytes, macrophages,
response, as detected by the presence of IL-17–producing T cells and mast cells, which also contribute to the inflammatory cascade.
44
in peripheral blood from patients with nickel allergy. The The “final” cellular damage results from inflammatory mediators
role of IL-17 in ACD lesions includes induction of keratinocyte released by activated nonsensitized T cells.
release of cytokines and chemokines (i.e., IL-8 and IL-6) and Application of sodium lauryl sulfate (SLS) exerts direct toxic
promotion of T cell–induced apoptosis of keratinocytes. The effects on keratinocytes (an experimental model of ICD) and has
significance of IL-17 in ACD is emphasized by the correlation been demonstrated to induce LC mobilization and consequent
between the increase in IL-17–producing cells with the clinical migration to the draining lymph nodes. Other irritants have
manifestations of ACD, as well as by their significant percentage been shown to cause direct activation of the innate immune
(20%) among skin-infiltrating CD4 and CD8 T cells in contrast system through a set of membranous and intercellular receptors
to their minor representation (only 1.5%) in the regional lymph called Toll-like receptor 7 (TLR-7) and nucleotide-binding oligo-
nodes of allergen-primed mice. 43 merization domain (NOD)–like receptors (NLRs) that activate
A particular role for IL-22 (produced by Th22 and Th17 T the inflammasome and nuclear factor-κB (NF-κB) pathways,
45
cells) has been suggested in ACD. Significantly higher levels of inducing release of many cytokines and chemokines.
IL-22 were detected in the serum of patients with ACD to nickel Although few immunohistopathological differences have been
compared with those seen in control subjects. IL-22 cytokine noted between ICD and ACD, ICD does not require prior
levels have also been shown to be upregulated in inflamed skin sensitization, and immunological memory is not involved. The
44
of patients challenged with nickel allergy, although its specific cellular infiltrate includes CD4 T cells with a Th1-type profile.
contribution to ACD reactions is not yet known. Irritant reactions predispose to allergic reactions, making patients
The skin of patients with AD is at increased risk for the with ICD more susceptible to the development of ACD. Animal
development of ACD, and this may be attributed to multiple models in which skin was preirritated with 5% SLS showed an
factors. First, AD skin is exposed to chemicals used to treat AD, increase in skin sensitization rate to paraphenylenediamine from
47
including moisturizers, topical corticosteroids, and TCIs. Second, 38% to 78% and enhanced T-cell proliferative responses to
the disturbed barrier system allows increased permeation of 2,4-dinitrochlorobenzene (DNCB). The DNCB-primed ICD
allergens. Third, AD skin has a heightened immunological status reaction conditioned the development and severity of the ACD
with existing activation of innate immunity, increased access of response. Similarly, in human studies, when patch test sites were
surface antigens to LCs, and selective upregulation of the Th2 pretreated with SLS, the threshold elicitation concentrations of
adaptive immune response. In patients with AD, cutaneous contact contact allergens, such as cobalt, nickel, and colophony, were
with irritants and allergens leads to amplification of innate significantly decreased, indicating that the activation of innate
immunity and enhanced adaptive immune responses, including immunity by irritants likely reduces the threshold for the develop-
Th2 and Th17 in patients with acute AD and Th22 and Th1 in ment of ACD.
patients with chronic disease. Just as innate immune activation In summary, although ACD, ICD, and AD are independently
stimulated by an irritant permits a lower threshold of ACD defined diseases, they interact and frequently occur in combina-
elicitation, the amplified adaptive responses in lesional and tion. In patients with AD, if the activation of an innate immune
nonlesional skin promote increased expression of ACD and ICD response is preceded by exposure to irritants and allergens, there
in patients with AD. is altered permeation of contact allergens, which are introduced
into an already activated innate immune system, resulting in
PATHOGENESIS OF IRRITANT CONTACT DERMATITIS amplification of innate immunity and enhanced adaptive immune
responses. The amplified adaptive responses in AD promote
ICD accounts for 80% of cases of CD. The clinical presentation increased ACD and ICD. Conversely, the innate immune activation
of ICD is usually restricted to skin that is directly in contact with stimulated by an irritant permits a lower threshold of ACD
the offending agent, with little or no extension beyond the site of elicitation (Fig. 44.2).
contact. The inflammatory response is dose- and time-dependent.
Any impairment to the epidermal barrier layer (e.g., fissuring, CLINICAL MANIFESTATIONS OF
overhydration) renders skin more susceptible to an irritant effect. CONTACT DERMATITIS
Contact with agents, such as detergents, solvents, alcohol, creams,
lotions, ointments and powders, and environmental factors, such The clinical and histological findings of ACD are characteristic,
as wetting, drying, perspiration, and temperature extremes, can but not diagnostic. ACD should be suspected in patients with

CHaPter 44 Atopic and Contact Dermatitis 621

























fiG 44.4 Allergic contact dermatitis of the face caused by
fragrance.




fiG 44.2 Acute allergic contact dermatitis.
















fiG 44.3 Allergic contact dermatitis of the eyelid.


acute and chronic eczematous or noneczematous dermatitis and fiG 44.5 Allergic contact dermatitis of the hand caused by rubber
is diagnosed on the basis of the clinical appearance of the lesions, accelerators.
the distribution of the dermatitis, the presence of pruritus, and
the absence of other etiologies. Acute CD is characterized by
erythematous papules, vesicles, oozing, and crusted lesions (Fig. is a diffuse eruption involving flexural and intertriginous areas
44.3). Recurrence and persistence of the dermatitis may lead to following oral, intravenous, or transcutaneous exposure to the
subacute and chronic lesions. Subacute CD manifests as erythema, allergen in a contact-sensitized individual. The most common
scaling, fissuring, or a parched, scalded appearance and chronic causes of SCD are (i) metals, such as mercury, nickel, and gold;
inflammation may have more skin thickening, hardening, scaling, (ii) medications, including aminoglycoside antibacterials, topical
fissuring, and lichenification. corticosteroids, and aminophylline; and (iii) plants and herbal
Although the location of the dermatitis serves as an important products, including Compositae and Anacardiaceae families and
clue to the source of the offending chemical, multiple factors Balsam of Peru (also known as Myroxylon pereirae resin).
contribute to the distribution of ACD. Spread from the principal Histologically, CD demonstrates intercellular edema of the
site of exposure can involve distant sites, either by inadvertent epidermis (spongiosis) with varying degrees of acanthosis
contact or by autosensitization. Areas of the scalp, palms, and (thickening of the epidermal stratum basale and stratum spi-
soles have thicker skin, whereas the eyelid, face, and genital areas nosum) and superficial perivascular, lymphohistiocytic infiltrates.
have thinner skin that is more sensitive to contact allergens (Figs. It is often difficult to distinguish ACD (Fig. 44.5) from ICD (Fig.
44.4 and 44.5). A geographical approach can be very helpful 44.6) on the basis of physical examination or histological
in identifying the causal allergen, but dermatitis with scattered findings.
generalized distribution, which lacks the characteristic distribution
that gives a clue as to the possible etiology of ACD, is actually MANAGEMENT OF ALLERGIC
the most common pattern of dermatitis in both children and CONTACT DERMATITIS
adults, as reported by the North American Contact Dermatitis
48
Group in 2013, followed by hands and then the face. Systemic The management of ACD includes identification of the allergen,
contact dermatitis (SCD), specifically the “baboon syndrome,” avoidance, pharmacological intervention, and prevention.

622 Part five Allergic Diseases



Symptomatic Therapy
In addition to avoidance of exposure, appropriate adjunct medical
treatment can be prescribed. First-line therapy is with topical
corticosteroids, and second-line treatment includes phototherapy,
oral retinoids, and immunosuppressant agents. The age of the
patient and the severity, location, and acuteness of the dermatitis
affect the selection of topical corticosteroids, which may be
sufficient for localized lesions. Patients with dermatitis that is
acute, extensive (particularly if involving >10% of total body
surface), or severe may benefit from systemic therapy.
Contact sensitization to the corticosteroid itself, the vehicle,
or other ingredients in the topical corticosteroid should be
suspected if symptoms worsen, initially improve but then worsen
fiG 44.6 Irritant contact dermatitis. with continued treatment, or do not respond to treatment at
all. Several topical T-cell selective inhibitors (tacrolimus and
pimecrolimus) have been used successfully in the treatment of
51
AD, but their efficacy in ACD or ICD has not been established.
tHeraPeUtiC PriNCiPLeS Other treatments, including cyclosporine, azathioprine, oral
retinoids, and phototherapy, have been used for steroid-resistant
Contact Dermatitis ACD, such as chronic hand dermatitis.
• Patch testing is the procedure of choice to confirm the diagnosis of
allergic contact dermatitis (ACD) and to identify offending contact PERSPECTIVES IN ATOPIC DERMATITIS AND
allergens.
• The interpretation of patch tests requires both experience and judgment ALLERGIC CONTACT DERMATITIS
on its relevance.
• Once identified, the key to management of ACD is prevention by Looking into the future, as we define the immune pathways that
avoiding substances containing the allergens or irritants that have cause AD, novel biologicals currently in clinical trials may provide
been identified. more targeted therapy in AD.
• Medical treatments such as topical and/or systemic corticosteroids
can be used to relieve ongoing dermatitis.
ON tHe HOriZON

• Novel biologicals currently in clinical trials may provide more targeted
Identification of the Allergen therapy in atopic dermatitis (AD).
The most widely acceptable and available method for confirming • Characterization of unique clinical phenotypes of AD may lead to a
the diagnosis of ACD is patch testing. Nickel remains the most better understanding of AD pathophysiology and a precision-medicine
approach to treatment.
common contact sensitizer and is more common in women than • Identification of “at risk” patients will facilitate preventative strategies.
in men, likely because of greater exposure to nickel in jewelry • A large number of chemicals are in everyday usage: new, rare,
and body piercing practices. In cosmetic products, fragrances, and emerging allergens should be considered in the assessment
preservatives, and emulsifiers are the most common causative of suspected ACD. Patch testing to these allergens has yet to be
allergens. In addition, paraphenylenediamine (in hair dye), standardized and irritant and elicitation concentration to patch testing
cocamidopropyl betaine (in shampoos and soaps), and medica- determined.
tions (e.g., neomycin, benzocaine, corticosteroids) are commonly • Data about contact allergen sensitization in children with AD are limited
and are continually expanding. Frequency and patterns of CD in children
reported allergens in personal hygiene and medical products. with AD and results of patch testing have yet to be determined.
The results of patch tests must be interpreted in the context of
the patient’s experience; exposure and relevance should be
established. 49
Identification of the endotypes involved in the pathogenesis
Allergen Avoidance of unique clinical phenotypes of AD will be required for a
Once the allergen or irritant has been identified, avoiding further precision-medicine approach to treatment. In the absence of a
contact with the offending agent would provide improvement low-cost cure for AD, biomarkers to identify “at-risk” patients
of the dermatitis. This requires extensive patient education on could facilitate preventative strategies.
what they are allergic to, including synonyms and cross-reactivity, In the area of ACD, a large number of chemicals are being
products they must avoid, and, most importantly, products that evaluated for their role, and new, rare, and emerging allergens
may be safe for them to use. The dimethylglyoxime test (nickel should be considered in the assessment of suspected ACD. Patch
spot test) and the cobalt spot test (based on disodium-1-nitroso- testing to these allergens has yet to be standardized; irritant and
2-naphthol-3,6-disulfonate) can be used to detect nickel or cobalt elicitation concentrations to patch testing need to be determined.
released from metal objects and dermal exposure, thus aiding Data about contact allergen sensitization in children with AD
in avoidance of contact in sensitized patients. Use of appropriate are limited but are continually expanding. Frequency and patterns
skin protection (i.e., gloves) may help with avoidance of exposure, of CD in children with AD and the results of patch testing have
especially in the occupational setting. 50 yet to be determined.

CHaPter 44 Atopic and Contact Dermatitis 623


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CHaPter 44 Atopic and Contact Dermatitis 624.e1


MUL ti PL e -CHO i C e QU e S ti ONS

1. Immunodeficiencies with eczematous rash that may be 3. Which of the following is a TRUE statement regarding atopic
misdiagnosed as atopic dermatitis include all of the following dermatitis?
EXCEPT: A. Downregulation of a number of antimicrobial peptide
A. Wiskott-Aldrich syndrome (WAS) genes caused by local upregulation of Th2-type cytokines
B. Properdin deficiency could explain the increased susceptibility of patients with
C. Immunodeficiency with mutations in dedicator of cyto- atopic dermatitis (AD) to cutaneous infections.
kinesis 8 (DOCK8) B. Serum levels of thymus and activation-regulated chemokine
D. Immune dysregulation, polyendocrinopathy, enteropathy (TARC) rise with successful treatment.
X-linked (IPEX) syndrome C. Patients whose AD has been in remission for >5 years are
no longer at increased risk for eczema vaccinatum from
2. The TRUE statement regarding filaggrin is:
A. Mutations in the gene encoding filaggrin (FLG) occur only smallpox vaccine.
in patients of European Caucasian descent. D. Langerhans cells are the primary source of antimicrobial
B. Filaggrin is an enzyme that regulates breakdown of the peptides in skin.
epidermal barrier. 4. Which of the following is the MOST common contact
C. T-helper 2 (Th2) cytokines interleukin-4 (IL-4) and IL-13 allergen?
can downregulate FLG gene expression. A. Neomycin
D. Abnormal filaggrin expression in bronchial epithelium B. Nickel
leads to increased risk of asthma. C. Paraphenylenediamine
D. Cocamidopropyl betaine