Clinical Immunology_ Principles and Practice ( PDFDrive )

45









Food Allergy



J. Andrew Bird, Stacie Jones, Wesley Burks






Adverse reactions to foods may be mediated by immunological soy (~0.4%), tree nuts (e.g., cashew and walnut) (0.2%), fish
mechanisms (food allergy) and nonimmunological mechanisms (0.1%), and shellfish (0.1%). Prevalent allergens vary in different
(food intolerance). Immune-mediated reactions to foods most cultural groups, with milk, egg, peanut, and tree nut allergens
commonly involve immunoglobulin E (IgE), an antibody that topping the lists in the Americas, Australia, and Western Europe,
4
binds to mast cells and basophils. Upon exposure to allergen, whereas fish and shellfish allergies are more common in Asia.
they release inflammatory mediators, such as histamine, prost- Most food allergies are typically outgrown; however, allergies to
aglandins, and leukotrienes, resulting in symptoms ranging from some foods, such as peanut, tree nuts, fish, and shellfish, are
localized oral itching to anaphylaxis, a potentially fatal systemic often more persistent, and these are the food allergens most
reaction. Non–IgE-mediated immune reactions to foods include commonly reported in adults. Food allergy commonly co-occurs
such diseases as celiac disease and food protein–induced entero- with other atopic diseases, such as atopic dermatitis (AD), asthma,
colitis syndrome (FPIES), while other diseases, such as eosinophilic and allergic rhinitis. 5
esophagitis (EoE) and eosinophilic gastroenteritis (EGE), involve
both IgE-mediated and non–IgE-mediated mechanisms. Food SPECTRUM OF DISEASE
allergy has a significant negative effect on quality of life, and the
burden on the health system amounts to approximately $25 IgE-Mediated Food Allergies
1
billion US dollars annually. Current management of food allergy Immediate reactions to foods compose the largest proportion
relies on avoidance, but ongoing research into treatment for of food-induced allergic diseases. IgE-mediated food allergy
food allergy should provide options for the majority of affected occurs when allergenic proteins cross-link allergen-specific IgE
persons in the near future. This chapter will review the basics bound to mast cells or basophils, leading to release of histamine
of food allergy diagnosis, management, and natural history, with and other inflammatory mediators. Symptoms of IgE-mediated
a specific focus on IgE-mediated food allergies. food allergy usually occur within minutes after ingestion of the
provoking food allergen, and do not start >2 hours later except
KEY CONCEPTS in very rare circumstances (e.g., delayed anaphylaxis related to
red meat ingestion).
Common Characteristics of Most Frequently Symptoms may be severe (e.g., anaphylaxis) or localized (e.g.,.
Encountered Food Allergens pollen-food allergy syndrome). Characteristic signs of an immedi-
ate allergic reaction manifest through skin and subcutaneous
A relatively small molecular weight (<70 kDa)
Abundant source of the relevant allergen tissues (e.g., urticaria and/or angioedema), the respiratory system
Glycosylation residues (e.g., bronchospasm), the gastrointestinal system (e.g., vomiting
Water solubility and/or diarrhea), and/or the cardiovascular system (e.g., increased
Most are resistant to heat and digestion vascular permeability leading to hypotension). Anaphylaxis is
the most severe symptom of food allergy and may result in death
(Chapter 42).
PREVALENCE Pollen-food allergy syndrome (PFAS, or oral allergy syndrome)
symptoms are restricted to the lips, throat, and mouth and are
The true prevalence of food allergy is difficult to establish. This most commonly elicited due to fruit and vegetable proteins
is probably because (i) studies have focused on only the most cross-reacting with antibodies against pollen proteins in individu-
common food allergens; (ii) the incidence and prevalence of als with pollen allergy. Affected individuals will typically complain
food allergy may be increasing and changing with time, with of pruritus and/or tingling of the lips, tongue, roof of the mouth,
studies showing an increasing prevalence over the past 10–20 and throat with or without swelling. PFAS reactions are unlikely
years; and (iii) studies of prevalence are difficult to compare to progress to a systemic reaction.
2
because of inconsistencies and deficiencies in study design. Best More than 170 foods have been reported to be allergenic, but
estimates suggest a self-reported prevalence of food allergy of most of the food-induced allergic reactions are caused by eight
5
12% and 13% for children and adults, respectively, with confirmed food groups. Cow’s milk, hen’s egg, and peanut are the most
food allergy in approximately 3% of adults and children when commonly identified food allergens in the United States, followed
6
3
assessed by double-blind placebo-controlled food challenge. The by tree nuts, wheat, soy, fish, and crustacean shellfish. There is
most common foods to trigger reactions in children are cow’s variability across the world and cultural groups with regard to
milk (2.5%), hen’s egg (1.3%), peanut (0.8%), wheat (~0.4%), which allergens are the most common, but cows’ milk and hen’s
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626 ParT FIVE Allergic Diseases



TABLE 45.1 Food allergens by Family
Food allergen Family Foods Containing allergen Description
Tropomyosins Crustacean shellfish (e.g., shrimp, Invertebrate tropomyosins are a family of muscle proteins that share homology across
lobster, crab), mollusks (e.g., invertebrate species and therefore may act as panallergens. They do not share
oyster, scallop, squid) homology with vertebrate tropomyosins. They are generally heat stable and highly
cross-reactive.
Parvalbumins/EF-hand Vertebrate fish and frogs Muscle proteins that possess a calcium-binding domain referred to as an EF-hand
proteins motif. This is the second-largest family of allergens, and these allergens are
considered highly cross-reactive panallergens.
Casein Mammalian milk Function to bind calcium and stabilize it in micellar form. There is high sequence
homology between cow’s milk and other mammalian milks, such as goat’s milk and
sheep’s milk. Other animal milks such as human milk, horse’s milk, donkey’s milk,
and camel’s milk have caseins with approximately 60% homology, which may
account for less allergenicity than seen with cow’s milk.
Prolamin superfamily Seeds, tree nuts, legumes This family contains the highest number of plant food allergens and is characterized
(including peanut), fruits, by rich disulfide bonds and a core of eight conserved cysteine residues, providing
vegetables, wheat, corn, rice stability and resistance to digestion. Families within this superfamily include 2S
albumin seed storage proteins, nonspecific lipid transfer proteins, and α-amylase/
trypsin inhibitors.
Cupin superfamily Legumes, nuts, seeds A large and functionally diverse superfamily of proteins termed seed storage globulins
that share a β-barrel structural core domain. Seed storage globulins may be grouped
into two families: vicilins and legumins.
Bet v 1 superfamily Apple, pear, stone fruits, celery, Bet v 1 is the major birch pollen allergen and is a member of the pathogenesis-related
carrot, soybean, peanut protein 10 family within this superfamily. Symptoms of Bet v 1 hypersensitivity
typically present with pollen food allergy syndrome (also known as oral allergy
syndrome), which is caused by IgE cross-reactivity between Bet v 1 and
homologous allergens from plant foods.
From Sampson HA, Aceves S, Bock SA, et al. Food allergy: a practice parameter update-2014. J Allergy Clin Immunol 2014;134:1016–25 e1043.


egg tend to be the most common allergens across varying (Chapter 46). The most common food proteins involved in
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geographical locations and cultural groups. The most common these diseases include milk, egg, wheat, and soy. Celiac disease
food and plant allergens are listed in Table 45.1. is a non–IgE-mediated food allergy triggered by ingestion of
Because of protein similarities between allergens, cross- gluten-containing grains (e.g., wheat, barley, and rye). Human
reactivity occurs. Patients allergic to certain foods should be leukocyte antigen (HLA) DQ2- or DQ8-restricted CD4 T cells,
counseled to avoid cross-reactive food proteins. It is common which recognize gluten selectively in affected persons, are critical
to find cross-reactivity among tree nuts; in particular, cashew to the pathogenesis of celiac disease.
and pistachio share common allergen binding sites, as do walnut EoE is a clinicopathological diagnosis, based on symptoms of
and pecan. Between 25% and 50% of patients with peanut allergy esophageal dysfunction (including dysphagia, vomiting, feeding
are also allergic to tree nuts, with particular cross-reactivity noted disorders, and abdominal pain) together with pathological find-
between peanut allergens and tree nut allergens in almond, walnut, ings of at least 15 eosinophils per high-power field on light
9
pecan, hazelnut, and Brazil nut. Tropomyosins found in crustacean microscopy. The precise role of food allergy in EoE is not well
5
shellfish are a panallergen, and approximately 75% of individuals defined; IgE-mediated and non–IgE-mediated mechanisms may
allergic to one crustacean (e.g., shrimp) are likely to also react be involved in the pathogenesis. The most common food allergens
8
to another crustacean (e.g., lobster and/or crab). Parvalbumins implicated in the pathogenesis include milk, egg, wheat, and soy.
found in vertebrate fish are commonly cross-reactive on testing, Numerous other foods have been implicated in the pathogenesis of
but clinical relevance of cross-reactivity varies. Studies have shown EoE, and a common approach to treatment is initial elimination
that an individual allergic to one fish species has approximately of milk, egg, wheat, soy, peanut, tree nuts, fish and shellfish.
a 50% likelihood of reacting to another species of fish. If dietary elimination is not successful or not feasible for the
Although most reactions occur immediately after ingestion, patient, then topical (swallowed aerosol) inhaled steroids (e.g.
some individuals may experience delayed anaphylaxis following fluticasone or budesonide) may be swallowed rather than inhaled
5
ingestion of mammalian meat. Delayed allergy to mammalian to treat the inflammation.
meats has been linked to the production of IgE to α-gal in EGE is less common than EoE and, like EoE, it is believed
susceptible subjects. α-Gal is an immunogenic oligosaccharide, that its pathogenesis involves both IgE-mediated and non-IgE-
and sensitization is believed to occur via a tick bite. Symptoms mediated mechanisms. Common symptoms of EGE include
of urticaria, angioedema, and anaphylaxis can occur 3–6 hours vomiting, abdominal pain, diarrhea, and failure to thrive/weight
after eating beef, pork, lamb, and venison. The mechanism(s) loss. Multiple food allergens are often implicated, although
underlying the delayed reaction is poorly understood. response to dietary elimination of the most common food
allergens (milk, egg, wheat, soy, peanut, tree nuts, fish, and
Mixed IgE/Non-IgE– and Non–IgE-Mediated shellfish) is typically less successful than dietary elimination
reported in patients with EoE. Topical (swallowed aerosol) inhaled
Food Allergies steroids (e.g. fluticasone and budesonide) may provide some
Delayed gastrointestinal (GI) reactions to foods include such benefit; however, systemic steroids are often necessary for disease
diseases as EoE, EGE, FPIES, and eosinophilic proctocolitis control.

CHaPTEr 45 Food Allergy 627


FPIES is a non–IgE-mediated disease usually occurring in KEY CONCEPTS
10
infants. Characteristic symptoms of FPIES manifest as repetitive
emesis with or without diarrhea accompanied by lethargy occur- Risk Factors for Fatal Food-Induced
ring 2–4 hours after ingestion of the offending food protein. Allergic Reactions
The risk of abrupt volume loss, hypotension, and potential for Peanut and/or tree nut allergy
bowel perforation makes this a medical emergency. Treatment Delay in administration of autoinjectable epinephrine
is reliant on rehydration. Ondansetron may be helpful in managing Preexisting and/or poorly controlled asthma
acute FPIES reactions. Milk and soy are most commonly impli- Concomitant use of beta-blocker medications
cated, along with less common food allergens, such as rice, oats, Teen and young adult age groups
fruits, or vegetables. FPIES is outgrown in the majority of affected
children by 3 years of age but may be protracted for many years of the relevant allergen; (iii) glycosylation residues; (iv) water
in a smaller subset of patients. solubility; and (v) resistance to heat and digestion. These char-
Celiac disease is an immune-based reaction to gluten, a storage acteristics allow the proteins to stay intact until reaching the
protein for wheat, barley, and rye. The small intestine is typically small intestine, where they initiate a T-helper cell-2 (Th2) response
affected in genetically predisposed individuals, and symptoms that results in production of specific IgE and eventual allergic
resolve with gluten avoidance. Symptoms of celiac disease are disease. Glycosylation refers to the reaction by which carbohydrates
variable and may include diarrhea, steatorrhea, weight loss, are attached to molecules: in food allergens, the carbohydrate
bloating, flatulence, abdominal pain, and also non-GI symptoms, is most often attached to a protein. Carbohydrate residues sur-
such as abnormal results on liver function tests, iron deficiency rounding proteins may be important in initiating the immune
anemia, bone disease, and skin disorders. Celiac disease is detected response. For example, interaction with DC-specific intercellular
with serological testing of celiac-specific antibodies and confirmed adhesion molecule–grabbing nonintegrin (DC-SIGN), a c-type
by duodenal mucosal biopsy, both of which should be performed lectin expressed on APCs that identifies conserved carbohydrate
while the patient is on a gluten-containing diet. 11 residues, has been shown to mediate recognition of the major
peanut protein, Ara h 1. This interaction allows DC activation
PATHOPHYSIOLOGY and Th2 skewing of naïve human T cells.
Once the Th2 response is initiated, it is strengthened through
Food allergy results from a breakdown of oral tolerance (or the induction of interleukin-4 (IL-4) signaling. IL-4 signals B
failure to develop it); foods which are ordinarily harmless may cells to undergo class-switch recombination and begin producing
then trigger an immune response that results in harmful adverse IgE. Basophils have been implicated as a likely contributor of
symptoms upon exposure. Maintaining tolerance requires a early IL-4 production and may play an important role in priming
delicate balanced effort from multiple arms of the immune system. the T-cell response to allergens.
Deviation from the protective response may result in the develop-
ment of an allergic response. The Allergic Response
Allergenic food proteins that survive the initial stages of digestion
PROPERTIES OF FOOD ALLERGENS are taken up by the APCs in MALT. Mucosal DCs may encounter
antigen through (i) extending dendrites through the paracellular
An intact GI mucosal barrier is required to maintain tolerance. space between epithelial cells to sample luminal contents; (ii)
The first line of defense against the mucosal immune system is directly interacting with the epithelial cells; and (iii) taking up
a hydrophobic layer of mucin oligosaccharides, which serve to antigen in the Peyer patch. Once contact with the antigen is
12
trap antigen. Secretory IgA is also a part of the outer layer of established, the antigen is processed and loaded onto major
intestinal defense against dietary antigens. Dietary antigens must histocompatibility complex (MHC) class II molecules on the
then penetrate the intestinal epithelium, which is maintained cell surface, costimulatory molecules necessary for T-cell activation
by epithelial junction complexes (adherens junctions) and tight are upregulated, and chemotaxis to the draining lymph node
junctions. Intestinal epithelial barrier dysfunction may play a occurs. Once a DC encounters a T-cell receptor with the same
role in food allergen sensitization. Alterations in the integrity of specificity as the peptide antigen, an immune response ensues.
junctional complexes may be induced by calcineurin inhibitors, In the presence of cytokines, such as IL-4, IL-5, and IL-13, the
and this can result in food allergen sensitization. Genetic defects, responding T cell is programmed to be a Th2 cell. The Th2 cell
such as those in individuals with filaggrin mutations, a protein that will then signal B cells to generate IgE antibodies.
binds to keratin and is important for epithelial cell integrity, may Soluble IgE that is produced by B cells circulates and binds to
predispose individuals to increased risk of EoE. Other factors that the surface of mast cells and basophils. Mast cells are found in
have been shown to affect intestinal permeability include viruses, skin, the gut, and the respiratory tract and are located adjacent
alcohol, and nonsteroidal anti-inflammatory drugs (NSAIDs). to nerves and blood vessels. When an allergen is encountered and
These environmental exposures may alter intestinal epithelial recognized by cell-bound IgE, calcium influx ensues, activating
integrity, thus allowing antigen to interact with the next layer of the mast cell. Once activated, the mast cell degranulates and
defense, mucosa associated lymphoid tissue (MALT; Chapter 20). releases vasoactive compounds and proteases, including histamine,
MALT is composed of lymphocytes, antigen-presenting cells platelet-activating factor, tryptase, chymase, carboxypeptidase, and
(APCs), stromal cells, and other immune cells in the lamina heparin, resulting in the characteristic symptoms of an allergic
propria. It is within MALT that dendritic cells (DCs) interact reaction: urticaria, angioedema, flushing, nausea, vomiting,
with dietary antigens. abdominal pain, diarrhea, wheezing, coughing/bronchospasm,
There are several common characteristics among the most rhinorrhea, and hypotension/syncope. Symptoms may occur
commonly allergenic foods: (i) relatively small molecular weight, alone or in combination and typically appear within minutes
generally less than 70 kilodaltons (kDa); (ii) an abundant source of ingestion.

628 ParT FIVE Allergic Diseases


Natural History Allergy persistence has also been associated with the rate of
The majority of food allergies are outgrown. Allergies to peanut, change of food-specific IgE levels or SPT wheal sizes. In clinical
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tree nuts, fish, and shellfish are more likely to persist. Clinical practice, food-specific IgE levels are typically checked yearly
characteristics and laboratory measures may help predict which except in patients whose specific IgE levels remain high and
food allergies will be outgrown and which are more likely to be unchanged over several years.
lifelong.
DIAGNOSIS
CLINICaL PEarLS
Important Diagnostic Considerations The diagnosis of food allergy begins with obtaining a detailed
6
medical history. Food-induced allergic reactions result in
The patient’s history should support a diagnosis of immunoglobulin E reproducible characteristic symptoms, as described above. Vali-
(IgE) –mediated food allergy before performing either serum-specific dated testing modalities are only available for IgE-mediated food
IgE testing or the skin prick test. allergies and celiac disease. If the clinical history does not support
95% predictive probability cutoffs have been established for only a few either diagnosis, then food allergy serum or skin testing should
foods, including cow’s milk, hen’s egg, and peanut. not be done, since there is a risk of finding sensitization to
Even with negative specific IgE serum testing or skin testing, the patient
could be allergic if he or she has a convincing history. In this case a allergens which are not clinically relevant and multiple studies
physician-supervised oral food challenge may be required to confirm have shown the dangers of unnecessary dietary avoidance. When
the presence or absence of an IgE-mediated food allergy. the clinical history does support a diagnosis of food allergy, this
Testing for food allergies should be limited to the food(s) in question, can be confirmed by SPTs and detection of specific IgE in serum.
since positive IgE tests are not always clinically relevant. Unnecessary SPTs to food allergens can be performed in the office setting
avoidance of foods may lead to nutritional deficiencies. and are both safe and effective, with results being available within
minutes. A positive result of the SPT reflects the presence of
Cow’s milk is typically one of the first foods introduced to specific IgE bound to the surface of cutaneous mast cells, but
infants in the form of infant formula: it is present in diets across as with serum IgE testing, a positive test result does not always
cultural groups and is one of the most common allergens globally. indicate clinical reactivity. A positive test result is generally
Fortunately, cow’s milk allergy is typically outgrown without interpreted as 3 mm larger than the negative SPT control, and
intervention. Studies of natural resolution vary but about 50% the larger the SPT mean wheal diameter, the more likely it is
of children with milk allergy develop tolerance between 5 and indicative of a clinically relevant response. Negative SPT results
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10 years of age. High levels of milk-specific IgE generally indicate have been associated with a high negative predictive value and
a higher likelihood of persistent disease, but as many as 60% of may lead the physician either to offer an observed challenge or
children whose milk-specific IgE level peaks at over 50 kU/L will to counsel the patient on dietary reintroduction, depending on
achieve natural tolerance by age 18 years. Up to 75% of children the clinical history and circumstances.
with reactions to uncooked milk can tolerate baked milk products. Serum-specific IgE testing is useful in providing an objective
Consumption of heated milk products has been associated with measure of food-specific IgE antibody, especially if the patient
accelerated acquisition of tolerance. 14 cannot stop antihistamine therapy or has extensive skin disease
Hen’s egg allergy is another common food allergen across making it impossible to perform the SPT, and may be helpful
cultural groups. Most of the allergenic proteins in hen’s egg are in counseling patients on the natural history of their food allergy.
in the egg white. Allergy typically develops in the first year of Predictive values have been established for a limited number of
life, while in some children, especially those with atopic dermatitis, foods. Higher specific IgE levels are more likely to be associated
13
it may develop before 4 months of age. Similar to cow’s milk with clinical reactivity, but the predictive value of specific IgE
allergy, egg allergy usually resolves during childhood without levels varies across patient populations and is affected by such
intervention. Roughly 50% of individuals with egg allergy in factors as the patient’s age, ethnicity, and time since last ingestion
infancy develop natural tolerance between 6 and 9 years of age. of allergen. Specific IgE levels may also help physicians decide
Baked egg is tolerated by approximately 70% of children with when an oral food challenge is or is not appropriate.
15
egg allergy. Individuals who can tolerate baked egg are likely The component-resolved diagnostic (CRD) test uses allergenic
to develop tolerance to lightly cooked egg sooner compared with proteins derived from recombinant DNA technology or purifica-
individuals unable to tolerate baked egg. 16 tion from natural sources to identify the patient’s specific IgE
Although the majority of individuals allergic to peanut will reactivity to individual allergenic proteins rather than to the
remain reactive throughout life, approximately 20% of individuals whole allergen. Diagnostic accuracy can be enhanced in specific
18
with peanut allergy may develop natural tolerance. Favorable circumstances (e.g., for peanut and hazelnut). However, CRD
prognostic factors include low levels of peanut-specific IgE is not routinely used for diagnosis and has not been shown to
antibodies in the first 2 years of life and decreasing levels of IgE provide significant additional clinical information for most
sensitization by 3 years. Those with peanut-specific IgE ≥3 kU/L allergens. CRD for peanut provides additional diagnostic informa-
and skin prick test (SPT) wheal diameter >6 mm before 2 years tion that is helpful to the clinician, but standardized decision-
of age are more likely to have persistent peanut allergy. 17 making cutoffs have not yet been established.
Allergy persistence, regardless of the food allergen, has been The basophil activation test (BAT) uses flow cytometry to
associated with the following factors: (i) earlier age at diagnosis; detect upregulation of cell-surface molecules, such as CD63 and
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(ii) concomitant presence of other allergic diseases (e.g., allergic CD203c, after stimulation with allergen. BAT has been reported
rhinitis, asthma, and eczema); (iii) severity of those allergic to be superior to the SPT, the CRD test, and the whole-allergen-
diseases; (iv) symptom severity after ingestion; and (v) lower specific IgE test for diagnosis of peanut allergy; however, testing
threshold dose required to elicit a reaction. The higher the food- has not been standardized. Further research is needed to standard-
specific IgE level, the more likely it is that the allergy will persist. ize the BAT and validate results with various food allergens.

CHaPTEr 45 Food Allergy 629


The oral food challenge (OFC) remains the gold standard for beta-blocker medications; there is increased mortality in teen
20
the diagnosis of food allergy. OFCs can be conducted in an open and young adult age groups. Intramuscular autoinjectable
manner; with a placebo control, where the patient is blinded to epinephrine must be readily available to patients with IgE-
the product being given; or in a double-blinded manner, with mediated food allergies and is the first-line treatment for a
both the physician and patient blinded to the food being given food-induced allergic reaction. Patients with food allergies are
to the patient. An open OFC is most commonly performed in encouraged to have a written emergency action plan that lists
clinical practice, while the double-blind, placebo-controlled food the signs and symptoms of an allergic reaction and details treat-
challenge is considered the diagnostic standard typically reserved ment of those symptoms.
for research studies. During the OFC, a standard serving size
of the allergen is divided into 4–7 servings and administered PREVENTION OF FOOD ALLERGY
over 60–90 minutes, with each dose being given 15–20 minutes
apart. The initial amount fed to the patient is typically a very Exposure to antigen early in life is likely very important for
small proportion of the total serving, and each successive shaping the appropriate immune response to foods. Primary
dose administers a larger amount of protein. At the first sign exposure through the oral route is believed to predispose to the
of an objective reaction, the OFC is stopped and appropriate development of a tolerogenic response, whereas primary exposure
21
treatment administered. In cases where anxiety or subjective through skin may result in sensitization. Support for the theory
symptoms may affect the interpretability of the OFC, a single- of prevention through primary oral exposure has been strongly
blind or double-blind placebo-controlled food challenge may be supported through epidemiological studies showing that some
preferred. cultural groups that introduce peanuts to their children in the
22
first year of life have a lower incidence of peanut allergy. This
MANAGEMENT theory has been strengthened through recent evidence demon-
strating that children identified as being at high risk of developing
The patient with a food allergy must maintain strict avoidance peanut allergy (severe atopic dermatitis and/or egg allergy) are
of the food allergen to prevent an allergic reaction. Avoidance substantially protected against the development of peanut allergy
requires constant vigilance. Accidental ingestion is common, with if they regularly ingest peanut, from between 4 and 11 months
reports showing that as many as 50% of children with a peanut of age through 60 months of age, compared with matched controls
allergy may experience an adverse reaction in a 2-year period who avoid peanut. 23
6
and up to 75% over 10 years. Individuals with food allergies Evidence in favor of a compromised skin barrier as the primary
and their caregivers must read ingredient labels closely, prevent site of sensitization was shown in the Avon Longitudinal Study
cross-contact, communicate with restaurant staff when eating of Parents and Children birth cohort study, which reported that
outside of the home, and be prepared to treat a reaction, when infants who had peanut allergy were more likely to have had
necessary. severe AD in the first 6 months of life and also to have been
24
Food allergy labeling laws in the United States require that treated with application of peanut oil to the skin. In children
the presence of the most common allergens (milk, egg, peanut, with AD, the outermost layer of skin (stratum corneum) con-
tree nuts, wheat, soy, fish, and crustacean shellfish) must be tributes to skin barrier function. Patients with AD have increased
declared in simple English on the ingredient labels of all packaged transepidermal water loss (TEWL). Increased TEWL not only
foods. Individuals allergic to foods other than the eight most allows water loss through skin but also facilitates allergen penetra-
common allergens may have more difficulty with interpretation tion and resultant sensitization. Further work is required to
of ingredient labels. Ingredient labels may report “spices” or understand whether emollient use may reduce the risk of AD
“natural flavors,” which could include a multitude of foods or development and possibly reduce the risk of developing food
food products not covered by food allergy labeling laws. State- allergy.
ments such as “may contain [allergen]” and “manufactured on The role of the microbiome is an intense area of study with
shared equipment with [allergen]” are voluntary and not regulated. regard to food allergy development. Microbial products in the
Allergen content in such products is unknown, and it is typically gut flora interact with innate immune receptors, such as Toll-like
recommended that individuals with allergies avoid products with receptors (TLRs) and relay signals implicated in the activation
“may contain” labeling. of regulatory T cells (Tregs), which are important in the promo-
Children with milk allergy or with two or more food allergies tion of tolerance. Activation of a specific TLR using nonpathogenic
have been shown to be at particular risk of growth deficiency. bacteria (probiotics) could conceivably prevent allergic disease.
Nutritional counseling with a registered dietitian is encouraged Unfortunately, studies investigating the role of probiotics in
for these patients. A registered dietitian will help educate the preventing allergic disease have not shown promise, probably
patient and his or her family on avoidance of food allergens, in because of the difficulty in identifying which specific strains of
addition to providing guidance on nutrient supplementation to gut bacteria are beneficial. Encouragingly, new techniques, such
avoid potential dietary deficiencies. as deep-sequencing technologies, are allowing better characteriza-
tion of the gut flora. As techniques improve and our understanding
TREATMENT OF A REACTION deepens, there is hope that new therapeutic targets will emerge
for food allergy prevention.
An acute reaction must be recognized and treated expeditiously.
Food-induced fatalities are most commonly reported from EXPERIMENTAL INTERVENTIONAL THERAPIES
ingestion of peanut and tree nuts, but any food allergen can
induce a severe reaction. Fatalities have been associated with The standard of care for IgE-mediated food allergy is avoidance
delay in administration of autoinjectable epinephrine, preexisting of the potentially triggering allergen, treatment of a reaction
and/or poorly controlled asthma, and concomitant use of with autoinjectable epinephrine, and dietary supplementation

630 ParT FIVE Allergic Diseases


of potentially deficient nutrients in the diet of the patient with Few studies have compared SLIT with OIT; current evidence
a food allergy. Allergen-specific immunotherapies are currently indicates that SLIT has fewer side effects compared with OIT,
under investigation utilizing the oral, sublingual, and epicutaneous but SLIT does not appear to induce a similar level of desensitiza-
routes for the application of the allergen. Although currently no tion or achieve SU as often as OIT. Ongoing compliance with
therapies have been approved by the US Food and Drug Admin- SLIT has also been reported as challenging. Additional studies
istration for the treatment of food allergy, several of those being are needed to reveal whether adjuvant therapy with SLIT increases
investigated are promising. efficacy and to understand whether SLIT could be combined
with OIT to improve its safety.
Oral Immunotherapy
Oral immunotherapy (OIT) is accomplished by mixing the THEraPEUTIC PrINCIPLES
allergenic food into a vehicle food, initially giving doses below avoidance
the level that would trigger reactions in an allergic individual Read ingredient labels closely. The eight most common food allergens
and gradually increasing the amount of protein ingested over are required to be disclosed on ingredient labels of foods manufactured
time. The buildup phase of therapy typically lasts several months; and sold in the United States.
once a maintenance dose of allergen is achieved, the patient Minimize cross-contact with food allergens during meal preparation.
has to ingest the allergen for a certain period (typically ≥1 years, Use utensils, cutting boards, and pans that have been thoroughly
washed with soap and water.
possibly indefinitely) to maintain a protected, desensitized state. If you are preparing several foods, make the allergy-safe food first.
Most studies have focused on achievement of desensitization, Wash hands with soap and water before touching anything else if
which refers to a temporary increase in the threshold of allergen you have handled a food allergen.
required to elicit a reaction and is dependent on regular exposure Wash counters and table with soap and water after making meals.
to the allergen. When eating at a restaurant, inform the waiter and cooking staff about
OIT will induce significant desensitization in most patients food allergens.
who are able to tolerate therapy. However, sustained protection Avoid buffets.
against an allergic reaction independent of ongoing allergen Treatment
exposure (sustained unresponsiveness [SU]) has not been Advise patients at risk of anaphylaxis to carry two autoinjectable epi-
adequately measured; only a minority of individuals achieved nephrine devices at all times.
25
SU in the few studies measuring this outcome. Most indi- Recommend a medical identification bracelet.
viduals undergoing OIT will experience adverse reactions. Oral Provide an anaphylaxis emergency plan, and review indications for
pruritus and transient abdominal pain are the most common administration of autoinjectable epinephrine.
problems; reactions are typically mild and do not require any Demonstrate the appropriate use of autoinjectable epinephrine with a
treatment. Severe reactions, such as anaphylaxis, may develop trainer device at the physician’s clinic visits.
during therapy; predisposing factors include infection, exercise,
and allergen coexposure. GI symptoms are the most common Epicutaneous Immunotherapy
reason for participants withdrawing from OIT trials, and EoE Epicutaneous immunotherapy (EPIT) delivers allergen to the
has occasionally been documented. Further work is needed to skin through application of an allergen-containing patch.
determine which patients are most likely to develop SU, who Langerhans cells in the skin are activated and effector cell
will tolerate OIT with few dose-limiting adverse events, and responses are downregulated. Peer-reviewed published data are
the mechanisms underlying the development of desensitization currently lacking, but preclinical studies have demonstrated
and SU. potential for clinical efficacy. The only published trial utilizing
The initial immune response detected in desensitization EPIT has reported an increased threshold of reactivity after 3
26
includes an increase in food-specific IgG4, decreased basophil months of therapy in children with milk allergy. Anaphylaxis
and mast cell responsiveness, and an initial increase in allergen- has not been reported with EPIT; the most common side effect
specific IgE. Allergen-specific IgE then decreases gradually over appears to be an eczematous response at the site of patch
time. After 6–12 months of therapy there appears to be a shift application.
away from Th2 cytokine production in response to allergen
toward a Th1 profile. Treg upregulation occurs later in the course CONCLUSIONS
of OIT, with studies showing increased function of antigen-specific
+
+
+
CD4 CD25 FOXP3 Tregs. Epitope mapping typically changes
over time indicating different antigen-specific responsiveness. ON THE HOrIZON
Unfortunately, there are no biomarkers that consistently predict Allergen-specific desensitization therapies are currently investigational
successful desensitization or sustained unresponsiveness. but may be available for clinical use in the near future.
Oral immunotherapy (OIT) exposes the allergic patient to progressively
Sublingual Immunotherapy larger doses of ingested allergen in an effort to induce a desensitized
state. Gram quantities of allergen are typically administered.
Sublingual immunotherapy (SLIT) utilizes a food protein dis- Epicutaneous immunotherapy (EPIT) applies microgram amounts of
solved in a liquid medium and delivered beneath the tongue. allergen directly to the allergic patient’s skin, resulting in an effort
The oral mucosa contains tolerogenic APCs: SLIT is thought to to increase the threshold of reactivity. EPIT patch is typically kept
rely on these cells to induce a desensitized state. SLIT dosing on skin for up to 24 hours at a time, and a new patch is applied
utilizes microgram to milligram quantities of protein, whereas daily. Few published studies to date have reported its efficacy.
OIT protocols utilize gram quantities of protein. Increasing Sublingual immunotherapy (SLIT) involves sublingual administration
the amount of allergen given is limited by the concentration of milligram quantities of allergen solubilized in a liquid formulation.
of available extracts and the volume of liquid that can be held Systemic reactions are rare; however, studies to date have not
consistently shown benefit in tested subjects.
sublingually.

CHaPTEr 45 Food Allergy 631


Diagnosis of food allergy is reliant on an understanding of its 10. Nowak-Wegrzyn A. Food protein-induced enterocolitis syndrome and
pathogenesis and proper application of available diagnostic tools. allergic proctocolitis. Allergy Asthma Proc 2015;36:172–84.
Management of food allergy requires education about avoidance 11. Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis
of the allergenic food(s), dietary supplementation of missing and management of celiac disease. Am J Gastroenterol 2013;108:656–76,
quiz 677.
nutrients, and recognition and early treatment of any allergic 12. Vickery BP, Chin S, Burks AW. Pathophysiology of food allergy. Pediatr
reactions. Although food allergy has increased in prevalence over Clin North Am 2011;58:363–76, ix-x.
the past two decades, preventive strategies, including early 13. Savage J, Sicherer S, Wood R. The natural history of food allergy. J Allergy
introduction of allergenic solids, may help curb this as yet Clin Immunol Pract 2016;4:196–203, quiz 204.
unexplained epidemic. As our knowledge of food allergy grows, 14. Kim JS, Nowak-Wegrzyn A, Sicherer SH, et al. Dietary baked milk
we can expect significant changes in our approach to the treatment accelerates the resolution of cow’s milk allergy in children. J Allergy Clin
of those affected in the years to come. Immunol 2011;128:125–31.e122.
15. Leonard SA, Caubet JC, Kim JS, et al. Baked milk- and egg-containing
Please check your eBook at https://expertconsult.inkling.com/ diet in the management of milk and egg allergy. J Allergy Clin Immunol
for self-assessment questions. See inside cover for registration Pract 2015;3:13–23, quiz 24.
details. 16. Leonard SA, Sampson HA, Sicherer SH, et al. Dietary baked egg
accelerates resolution of egg allergy in children. J Allergy Clin Immunol
2012;130:473–80.e471.
REFERENCES 17. Ho MH, Wong WH, Heine RG, et al. Early clinical predictors of
remission of peanut allergy in children. J Allergy Clin Immunol
1. Gupta R, Holdford D, Bilaver L, et al. The economic impact of 2008;121:731–6.
childhood food allergy in the United States. JAMA Pediatr 2013;167: 18. Grabenhenrich L, Lange L, Hartl M, et al. The component-specific to
1026–31. total IgE ratios do not improve peanut and hazelnut allergy diagnoses.
2. Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and J Allergy Clin Immunol 2016;137:1751–60.e1758.
management of food allergy in the United States: summary of the 19. Santos AF, Lack G. Basophil activation test: food challenge in a test tube
NIAID-sponsored expert panel report. J Allergy Clin Immunol or specialist research tool? Clin Transl Allergy 2016;6:10.
2010;126:1105–18. 20. Nowak-Wegrzyn A, Assa’ad AH, Bahna SL, et al. Work Group report: oral
3. Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and food challenge testing. J Allergy Clin Immunol 2009;123:S365–83.
distribution of childhood food allergy in the United States. Pediatrics 21. du Toit G, Tsakok T, Lack S, et al. Prevention of food allergy. J Allergy
2011;128:e9–17. Clin Immunol 2016;137:998–1010.
4. Koplin JJ, Mills EN, Allen KJ. Epidemiology of food allergy and 22. Du Toit G, Katz Y, Sasieni P, et al. Early consumption of peanuts in
food-induced anaphylaxis: is there really a Western world epidemic? Curr infancy is associated with a low prevalence of peanut allergy. J Allergy
Opin Allergy Clin Immunol 2015;15:409–16. Clin Immunol 2008;122:984–91.
5. Sampson HA, Aceves S, Bock SA, et al. Food allergy: a practice 23. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut
parameter update-2014. J Allergy Clin Immunol 2014;134: consumption in infants at risk for peanut allergy. N Engl J Med
1016–25.e1043. 2015;372:803–13.
6. Bird JA, Lack G, Perry TT. Clinical management of food allergy. J Allergy 24. Lack G, Fox D, Northstone K, et al. Factors associated with the
Clin Immunol Pract 2015;3:1–11, quiz 12. development of peanut allergy in childhood. N Engl J Med 2003;348:
7. Fiocchi A, Brozek J, Schunemann H, et al. World Allergy Organization 977–85.
(WAO) Diagnosis and Rationale for Action against Cow’s Milk Allergy 25. Wood RA. Food allergen immunotherapy: current status and prospects
(DRACMA) guidelines. Pediatr Allergy Immunol 2010;21:1–125. for the future. J Allergy Clin Immunol 2016;137:973–82.
8. Sicherer SH. Clinical implications of cross-reactive food allergens. 26. Dupont C, Kalach N, Soulaines P, et al. Cow’s milk epicutaneous
J Allergy Clin Immunol 2001;108:881–90. immunotherapy in children: a pilot trial of safety, acceptability, and
9. Dellon ES, Liacouras CA. Advances in clinical management of impact on allergic reactivity. J Allergy Clin Immunol 2010;125:1165–7.
eosinophilic esophagitis. Gastroenterology 2014;147:1238–54.

CHaPTEr 45 Food Allergy 631.e1


MULTIPLE-CHOICE QUESTIONS

1. A 3-year-old boy is seen in his primary care physician’s office A. Egg
after having a reaction at a recent birthday party. His mother B. Peanut
states that she noticed lip swelling and coughing within minutes C. Cashew
after eating off a plate containing a variety of foods. The meal D. Tilapia
consisted of a hamburger with mustard, lettuce, onion, and E. Shrimp
pickles; potato chips; fruit punch juice; and a piece of candy 3. An 11-year-old male has recently been diagnosed with
containing chocolate, pecans, and caramel. Which of these eosinophilic esophagitis (EoE). Which of the following is an
foods the child ate most likely contributed to his reaction? appropriate long-term treatment option for him?
A. Mustard A. Daily oral prednisone
B. Red dye #5 in the fruit punch B. Avoidance of milk, egg, wheat, soy, nuts, and seafood
C. Chocolate C. Monthly injections of omalizumab
D. Pecan D. Daily montelukast
E. Onion
E. Oral desensitization to milk, egg, and wheat
2. A 14-year-old boy with a diagnosis of atopic dermatitis and
multiple food allergies is seen in his primary care physician’s 4. A new mother brings her 5-month-old child with severe atopic
office for his yearly well-child physical. His mother reports dermatitis into your office for evaluation. Is there anything
that he has been avoiding eggs, peanuts, tree nuts, fish, and you could tell her to decrease the likelihood of the child
shellfish since he was 2 years old. He has a history of ana- developing a food allergy?
phylaxis to peanuts, and documented sensitivity to eggs that A. Introduce egg products after 2 years of age.
resulted in worsening of his atopic dermatitis as an infant. B. Introduce wheat products after 2 years of age.
Which of the following allergens is most likely to be tolerated C. Introduce sweet potatoes at 6 months of age.
in this child who is now 14 years old? D. Introduce peanut products at 5 months of age.
E. Introduce shrimp at 3 years of age.

46






Eosinophil-Associated

Gastrointestinal Disorders



Alex Straumann







The human gastrointestinal (GI) tract is the largest host- eosinophil-predominant tissue infiltration. Moreover, it is likely
environment interface of the body, where the epithelial surface that eosinophils play a crucial role in the pathogenesis of these
is exposed to an overwhelming load of diverse microorganisms disorders. However, each of these conditions has different proper-
as well as to dietary products. Commensal microorganisms, the ties and probably has its own pathogenesis; to subsume them
so-called “intestinal microbiota,” are currently regarded as an into one single category is quite arbitrary and based exclusively
integrated part of the body involved in the regulation of several on descriptive features. EoE is definitely an esophageal-restricted
4
physiological functions (Chapter 14). In contrast, potentially disease with a benign long-term prognosis. In patients with
pathogenic microorganisms of the luminal content must be EGE, the inflammatory process can involve several segments of
recognized and, if possible, eliminated by the mucosal immune the GI tract; nevertheless, in clinical terms this chronic inflam-
5
system. Several mechanisms are involved in maintaining a physical mation is also a benign disorder. In contrast, HES is a multisystem
and functional barrier to stabilize body homeostasis. Besides the disorder that may involve several organ systems, including the
6
physical barriers, the mucosal immune system is of particular digestive tract, sometimes with a fatal outcome. Despite these
importance, with the evolutionarily ancient “innate” and the differences, all three conditions share the common features of
more specific and more diverse “adaptive” immunity (Chapter being idiopathic, chronic, and eosinophilic, and although our
20). Its task is to initiate an inflammatory response against understanding of the underlying mechanisms remains fragmen-
invading microorganisms while maintaining a state of nonre- tary, we may take the liberty of classifying them into one single
sponsiveness or tolerance to innocuous substances such as category.
commensal bacteria or food antigens. EoE is by far the most common eosinophil gastrointestinal
Each system of immunity relies on different cell types and disorder (EGID). Because of its clinical relevance, EoE is discussed
gene products with characteristic modes of action. Eosinophils— in greater depth here than the other two eosinophil-associated
part of the innate immune system—are present in the peripheral disorders.
blood of healthy individuals and account for approximately 1–3%
of peripheral leukocytes with an upper limit of the normal range EOSINOPHILIC ESOPHAGITIS
1
of 350 cells per cubic millimeter of blood. Tissue-dwelling
eosinophils reside in the hematopoietic and lymphatic organs, Definition
such as the bone marrow, spleen, lymph nodes, and thymus. In the latest consensus recommendations, the following conceptual
However, based on a comprehensive analysis of normal human definition was published: EoE represents a chronic, immune/
tissues from almost all body organs, we know that the GI tract antigen-mediated esophageal disease, characterized clinically by
is the only nonhematopoietic organ showing significant numbers symptoms related to esophageal dysfunction and histologically
2
4
of tissue-dwelling eosinophils under healthy conditions. The by an eosinophil-predominant inflammation. This definition
distribution of eosinophils is not homogeneous throughout the shows that the diagnosis of EoE is based on clinical and on
digestive tract, with the highest density of cells in the cecal and histopathological findings.
2
appendiceal region. Under physiological conditions, the esopha-
gus is the only segment of the digestive tract that lacks tissue- Epidemiology
2,3
dwelling eosinophils. Besides the resident eosinophils, a marked Epidemiological information is essential to determine the clinical
accumulation of eosinophils in the digestive tract can be seen and socioeconomic impact of a disease. Therefore knowledge
under inflammatory conditions. Because eosinophils are non- of the epidemiological parameters of a disease is crucial for
specific late-phase inflammatory cells, infiltration can occur in identifying risk factors as well as pathogenetic mechanisms, for
the context of any type of inflammation—e.g., bacterial and planning preventive measures, and for determining optimal
parasitic infections, celiac disease, Crohn disease, and ulcerative treatment approaches.
colitis—independently of its cause. 1
This chapter focuses on three idiopathic eosinophil-associated Demographic Cornerstones
GI disorders, in particular idiopathic eosinophilic esophagitis Cases of EoE have been reported worldwide and identified in
(EoE), idiopathic eosinophilic gastroenteritis (EGE), and idio- those with a variety of ethnic backgrounds, including Caucasians,
pathic hypereosinophilic syndromes (HESs) with GI manifestation African Americans, Hispanics, and Asians. However, as there are
(Table 46.1). The term “eosinophil-associated” denotes that the no controlled data about geographical variations of prevalence,
histological inflammatory response is characterized by an it remains unclear whether EoE is associated with any particular

633

634 Part five Allergic Diseases



TABLE 46.1 eosinophil-associated incidence and prevalence of EoE in the adult population during
7-9
Gastrointestinal Disorders recent years.
Probably the most conclusive epidemiological data originate
Eosinophilic esophagitis (EoE) from the geographically confined district of Olten, Switzerland,
Eosinophilic gastroenteritis (EGE) where a prospective population-based assessment strategy has
Hypereosinophilic syndromes (HESs)
been used with consistent diagnostic and enrollment procedures
for evaluation of EoE. Between 1989 and 2009, EoE was diagnosed
in 46 patients (76% males; mean age 41 ± 16 years). An average
CLiNiCaL PearLS annual incidence rate of 2.45/100,000 was calculated. In the face
Eosinophil-Associated Gastrointestinal of a constant diagnostic delay and the lack of EoE awareness
Disorders (EGID) programs, significantly more EoE cases were diagnosed from
2000–2009 compared with 1989–1999. Because EoE is clinically
• All more common in males a benign disease affecting mainly younger individuals, the
cumulative EoE prevalence rose to 42.8/100,000 in 2009. Extrapo-
eosinophilic esophagitis (eoe) lating from this study, in North America and in Europe there is
• Persistent solid food dysphagia/impaction, often with coexisting allergic one patient with diagnosed EoE among every 2–3000 inhabitants.
diseases Current prevalence and incidence data of EoE are comparable
• Structural changes may be present at endoscopy with those of other chronic inflammatory diseases of the GI
• Diagnosis confirmed by histology tract, for instance Crohn disease.
• Treatment includes:
• Corticosteroids (swallowed or systemic)
• Allergen-specific diets KeY CONCePtS
• Dilatation treatment for strictures
Differential Diagnosis of Eosinophilic Esophagitis
eosinophilic Gastroenteritis (eGe)
• Nonspecific gastrointestinal symptoms due to eosinophilic infiltration • Gastroesophageal reflux disease (GERD)
of segments of GI tract; can affect all layers of the intestinal wall • Infectious esophagitis (Herpes, Candida)
• Diagnosis based on histology and exclusion of other causes of intestinal • Parasitic infection
eosinophilia • Drug-induced esophagitis
• Treatment of serosal EGE is with systemic steroids; optimal treatment • Autoimmune disease (vascular and connective tissue diseases)
for other forms not yet defined • Eosinophilic gastroenteritis with involvement of the esophagus
• Hypereosinophilic syndrome with involvement of the esophagus
• Crohn disease with involvement of the esophagus
Hypereosinophilic Syndromes (HeSs)
• Persistent peripheral blood eosinophilia >6 months
• Eosinophilic infiltration of several organ systems with related
symptoms Pathophysiology
• Gut and cardiac involvement associated with a poor prognosis Eosinophils’ Natural Lifecycle
• Treatment strategies for patients with HESs include:
• Corticosteroids Eosinophils reside predominantly in three anatomical compart-
• Cytotoxic agents ments: the bone marrow, blood vessels, and organs with mucosal
• Interferon-α surfaces. Eosinophils originate in the bone marrow from plu-
• Imatinib mesylate (for PDGFRA-associated HESs) ripotent stem cells. Their differentiation process is orchestrated
mainly under the influence of three cytokines: interleukin (IL)-3,
IL-5, and granulocyte macrophage–colony-stimulating factor
ethnic or racial groups, especially as most of the published studies (GM-CSF), leading to a fully granulated state before they migrate
1
have analyzed data from primarily Caucasian patients. EoE can to the vascular space. In particular, IL-5 is very specific for the
be found in all age groups, but most studies report an average eosinophil lineage; it stimulates the release of eosinophils from
age between 34 and 42 years with a male-to-female risk ratio of the bone marrow and extends their survival once they are in
7,8
3 : 1. EoE therefore affects mainly middle-aged male individuals target tissue. Mice lacking IL-5 show a significant reduction in
with an atopic background. tissue eosinophilia, whereas mice overexpressing IL-5 show
10
Interestingly, age at diagnosis does not correlate with onset markedly increased peripheral eosinophilia. A multistep process
of EoE-attributed symptoms, which can be considered as the mediated by adhesion molecules on endothelial cells and cor-
onset of disease. Several studies report a substantial time lag responding ligands on eosinophils (P-selectin and β-1 and β-2
between onset of symptoms and time of diagnosis (diagnostic integrins) enables migration from the vascular space into tissues.
delay), which in some cases can be attributed to unawareness This is orchestrated by T-helper cell-2 (Th2) cytokines (IL-4
of sentinel features at endoscopy (doctors’ delay). Often patients and IL-13) that induce expression of cell surface ligands of the
develop specific eating strategies, with careful chewing and β-integrin family, such as very late antigen (VLA)-4 (β-1 integrin)
avoidance of dry and rough food; despite a substantial impairment on the surface of eosinophils and their counterligands on
of quality of life, they bypass medical care (patient delay). An endothelial cells including vascular cell adhesion molecule
9
average diagnostic delay of 5 to 6 years has been reported from (VCAM)-1. Various chemoattractants—released within local
both North America and Europe. 7-9 mucosal environments—provoke eosinophil migration, including
leukotriene B 4 , platelet activating factor, chemokines, and bacterial
Incidence and Prevalence of Eosinophilic Esophagitis products. 9,11 Eotaxin is important, as it binds the chemokine
Although considered a rare disease, several epidemiological studies receptor CCR-3 on eosinophils. Eosinophils are absent from the
from geographically confined regions indicate an increasing gastrointestinal tract in mice lacking eotaxin-1. 12

CHaPter 46 Eosinophil-Associated Gastrointestinal Disorders 635


Environment Genes
The Role of IgE in Eosinophilic Esophagitis Food and aero TSLP
In up to 70% of EoE patients, there is a history of concomitant allergens Eotaxin-3
atopic diseases such as allergic rhinitis, bronchial asthma, and
atopic dermatitis; elevated total serum immunoglobulin E (IgE) Epithelial cell Eotaxin-3
7-9
levels are found in about 70% of EoE patients. Therefore both IL-13
food and airborne allergens have been implicated as factors in Th 2 cell
13
inducing and maintaining the eosinophilic inflammation. IL-5
Children with esophageal eosinophilia not responding to phar-
macological and/or surgical antireflux therapy showed marked IL-4 Eosinophil Fibrosis
7-9
improvements after being given elemental formulas. This APC IL-13 TGF-β remodeling
observation suggests that EoE could represent an IgE-mediated IL-5
allergic disease in which food proteins play an important role.
On the other hand, clinical trials of targeted food elimination B cell IgE
diets, or treatment with IgE-blocking agents, have failed to show Mast cell
7-9
an IgE-mediated mechanism. Moreover, the identification of
causative foods based on empiric elimination diets correlated fiG 46.1 Immunopathogenesis of Eosinophilic Esophagitis.
poorly with the findings of IgE-sensitization patterns to food The current understanding of cellular and molecular mechanisms
allergens as determined by skin prick tests (SPTs) and/or blood in the pathogenesis of eosinophilic esophagitis (EoE) involves
tests for food-specific IgE. a complex interaction of genetic and environmental factors. EoE
In summary, the current understanding is that IgE plays at disease susceptibility is linked to single nucleotide polymorphisms
most a subsidiary role in the pathogenesis of EoE and that neither (SNPs) in the eotaxin-3 and thymic stromal lymphopoietin (TSLP)
IgE-based diagnostic tools nor IgE-targeted treatment is helpful. 13 gene. A sensitization to food and aeroallergens has been noted.
Two possible pathways can lead to accumulation of eosinophils
Th2-Mediated Immune Response in the esophageal wall. First, allergens can be recognized by
EoE is characterized by infiltration with cells having a charac- antigen-presenting cells (APCs), such as dendritic cells, and can
14
teristic Th2-type inflammatory pattern (Fig. 46.1) (Chapter 16). activate a type 2 helper T-lymphocyte (Th2) immune response
In esophageal biopsy specimens of EoE patients, increased to induce the release of eosinophil-specific cytokines such as
numbers of lymphocytes (T cells and B cells) and mast cells are interleukin (IL)-5 and IL-13 and subsequently the production of
found as well as increased expression of the cytokines IL-5 and eotaxin-3, which is a potent chemoattractant for eosinophils.
14
IL-13. The crucial role of IL-5 and IL-13 in the pathogenesis Second, allergen exposure can result in the cross-linking of
15
of EoE has been demonstrated in various experimental models. immunoglobulin E (IgE) receptors on mast cells, leading to release
As a proof-of-concept study of aeroallergen-induced esophageal of specific inflammatory mediators, which boost directly or
eosinophilia, intranasal allergen challenge with Aspergillus through stimulation of epithelial cells’ accumulation of eosinophils
fumigatus resulted in an infiltration of eosinophils in both the in the esophageal layers. Both eosinophils and mast cells produce
esophagus and the bronchi, whereas tissue eosinophilia did not transforming growth factor (TGF)-β, a potent cytokine involved
develop in IL-5–deficient mice. Direct delivery of IL-13—the in fibrosis and smooth muscle contraction that promotes tissue
other important cytokine of the Th2 immune response—into remodeling, leading to loss of elasticity of the esophageal wall
the pulmonary tree induced esophageal eosinophilia, which can and luminal narrowing.
15
be blocked by antihuman IL-13 antibody. Interestingly, esopha-
geal epithelial cells produce the important eosinophil chemoat- remodeling and has been described in clinical studies as well as
tractant eotaxin-3 after IL-13 stimulation, through a transcriptional in animal models. 8,16,17 Although the exact mechanism is not
10
mechanism dependent on STAT6. Esophageal eotaxin-3 strongly known, eosinophils and subepithelial mast cells expressing tryptase
correlates with tissue eosinophilia, and eotaxin-3 is one of the are critically involved in this process via secretion of TGF-β1.
12
most induced genes in patients with EoE. Moreover, a single TGF-β1 appears to be involved in numerous processes relevant
nucleotide polymorphism in the eotaxin-3 gene (SNP 2496 T→G) to allergic inflammation, including regulation of profibrotic
is linked to increased disease susceptibility for EoE. 12 processes and modulation of smooth muscle contraction with
Accumulation and activation of eosinophils in the esophagus increased contractility, thereby potentially contributing to clinical
is followed by release of various granule proteins and cytokines. symptoms such as dysphagia and bolus obstruction in EoE
These mediators can exert cytotoxic effects (e.g., major basic patients. Furthermore, there is growing evidence in murine models
protein [MBP], eosinophil-derived neurotoxin [EDN], eosinophil that IL-5 and IL-13, the two crucial cytokines involved in tissue
peroxidase [EPO]), or they can contribute to perpetuation of eosinophilia, also induce esophageal remodeling. 17
the inflammatory response through activation of a wide range Application of the topical corticosteroid budesonide markedly
of other inflammatory cytokines, such as IL-1, IL-3, IL-4, IL-5, decreased expression of fibrosis-related markers such as TGF-β1
IL-13, IL-15, GM-CSF, TNF-α, RANTES, MIP1-α, and transform- and tenascin C in esophageal tissue, suggesting that antiinflam-
ing growth factor (TGF)-β, highlighting the complexity of the matory treatment might interrupt or even reverse remodeling
pathophysiological mechanisms. 8,9 of the esophagus. 7

Esophageal Remodeling Clinical Manifestation of Eosinophilic Esophagitis
Unbridled eosinophilic inflammation leads to fibrosis and The predominant symptom of adult EoE is dysphagia for solids,
angiogenesis with an ensuing loss of elasticity of the esophageal often leading to long-lasting food impaction requiring endoscopic
wall and luminal narrowing. This phenomenon is called tissue bolus removal. Because EoE patients rapidly develop specific

636 Part five Allergic Diseases























A B





















C D
fiG 46.2 Endoscopic Findings in Eosinophilic Esophagitis (EoE). Representative endoscopic
pictures of active eosinophilic esophagitis showing loss of vascularity and red furrows (A), whitish
exudates (B), corrugated rings (C), and a long-distance stricture with a deep laceration after
dilatation (D).





eating strategies, a careful evaluation of changes in eating habits TABLE 46.2 Symptoms of eosinophilic
18
is required. EoE patients tend to chew carefully and avoid dry esophagitis
or rough food. Dysphagia and food impaction are reported
increasingly with age. A minority of patients report symptoms adults Children
akin to gastroesophageal reflux disease (GERD) swallowing- Dysphagia Food aversion/food refusal
unrelated chest pain, and upper abdominal pain. In contrast, Bolus obstruction Vomiting/regurgitation
food refusal and failure to thrive may be observed in children, Nonswallowing-related chest pain Abdominal pain
as dysphagia is less easily expressed in this age group. Children Failure to thrive
often report GERD-like symptoms such as heartburn and reflux, Dysphagia
Heartburn/reflux
vomiting, and abdominal pain; less frequently, they report diarrhea Bolus obstruction
(Table 46.2). 7 Diarrhea
Endoscopy and Histology
Endoscopy shows a heterogeneous mix of abnormalities: subtle
reddish, longitudinal furrows and white exudates may occur, instrument that should be used for the structured assessment
19
reflecting local edema and acute inflammation, respectively. of endoscopic activity. Of note, because endoscopic features
Transient or fixed corrugated rings as well as crêpe paper mucosa may be minimal in EoE, histological examination is recommended
7,8
may be observed due to loss of mucosal elasticity and, most in every patient presenting with dysphagia. The diagnosis of
likely, chronic eosinophilic inflammation (Fig. 46.2A–D). EoE is based on typical esophageal symptoms and characteristic
The five major endoscopic signs of EoE are summarized in an histological findings (≥15 eosinophils/high power field [×400]),
EoE Endoscopic Reference Score (EREFS), a validated scoring after exclusion of other esophageal diseases associated with an

CHaPter 46 Eosinophil-Associated Gastrointestinal Disorders 637


4
eosinophilic infiltrate of the mucosa (e.g., GERD). Several biopsies
should be taken in EoE: tissue eosinophils can be patchily dis- Drugs
tributed in EoE, whereas eosinophils appear superficially along Acid suppression with proton pump inhibitors (PPI) is not usually
4
the luminal surface. Because white exudates correspond to effective in relieving symptoms and resolving eosinophilic
eosinophil aggregations and microabscesses (Fig. 46.3), biopsies inflammation in patients with EoE. However, patients with
should preferably be taken from these areas. concomitant GERD, and a subgroup of EoE patients with “PPI-
responsive” EoE, may respond to treatment with PPI. Therefore
Treatment PPI therapy should not be considered as first-line treatment but
As a result of recent advances in the understanding of the natural instead used as cotherapy in patients with secondary or coexisting
course of the disease, at least three reasons have been determined GERD. 4,8
to treat EoE: (a) improvement of quality of life after resolution Systemic and topical corticosteroids show comparable effective-
of the swallowing disturbances; (b) reduction of the risk of severe ness in resolving signs and symptoms of active EoE in both
8
esophageal injury by preventing long-lasting food impactions; children and adults. As topical steroids have fewer side effects,
8
and (c) prevention of esophageal remodeling. The current they are recommended as first-line therapy. Short-term use of
treatment options can be summarized as the three D’s (Drugs, systemic corticosteroids may be limited to emergent cases, such
Diet, and Dilatation) and are presented in Table 46.3. as dysphagia requiring hospitalization, patients with dehydration
due to swallowing difficulties, or patients with symptoms refrac-
tory to topical steroids. Discontinuation of topical and systemic
corticosteroids is usually followed by recurrence of the disease
TABLE 46.3 Current treatment Options within a few weeks. 8
for eosinophilic esophagitis: the three D’s Antiallergic drugs have been found largely ineffective in EoE
(Drugs, Diet, and Dilatation) treatment. Cromolyn sodium has no apparent therapeutic effect,
and although leukotriene receptor antagonists have been shown
tHeraPeUtiC OPtiONS to induce symptomatic relief, they do not affect esophageal
Drugs eosinophilia.
• Swallowed topical corticosteroids (budesonide, fluticasone) Only limited data are available for targeted therapy with novel
• Systemic corticosteroids (prednisone)
• Biologicals (monoclonal antibodies against interleukin [IL]-13, IL-5) biological agents or immunosuppressants. The most impressive
• Immunosuppressants (azathioprine, 6-mercaptopurine) effect on symptoms, inflammation, and molecular abnormalities
• Antiallergic agents (CRTH2 blockers) has been demonstrated with QAX576, a monoclonal anti-IL-13
antibody. Mepolizumab (anti-IL-5) significantly reduced esopha-
Diets geal eosinophils in adult EoE patients with only minimal effects
7,8
• Targeted elimination diets (individualized based on results of allergic on clinical improvement. Treatment of EoE patients with the
testing) anti-TNF-α antibody infliximab did not reduce eosinophilic
• Empiric “6-Food” elimination diet (milk, soy, wheat, nuts, eggs, tissue infiltration or improve symptoms, even though massive
seafood)
• Elemental diet (protein-free formulas) expression of TNF-α has been shown in the squamous epithelium
of the esophagus in active EoE. The immunosuppressants aza-
Dilatation thioprine and 6-mercaptopurine were effective in inducing and
• For strictures maintaining remission in three corticosteroid-refractory EoE
patients. However, further evaluation of these alternatives for
corticosteroid-refractory EoE is needed before they can be
implemented into daily clinical practice.

Diet
Several prospective uncontrolled trials have been conducted to
assess the potential of three different diets in treating EoE.
Individually tailored so-called targeted elimination diets, empirical
six-food elimination diets (removal of the six most common
allergenic foods such as dairy, eggs, wheat, soy, peanuts, fish/
shellfish), and a protein-free elemental diet have all shown efficacy
7-9
in active EoE. The choice of a specific dietary therapy requires
that the patient’s lifestyle and family resources be considered.
So far, dietary treatment has been more effective in children
than in adults. Overall, the value and the feasibility of dietary
therapy require further evaluation.
Dilatation
Esophageal dilatation leads to long-lasting symptom relief but
does not influence the underlying inflammation. It should
fiG 46.3 Histopathological Findings in Eosinophilic Esopha- therefore be reserved for patients who present with functional
gitis (EoE). Representative histological pictures of active eosino- esophageal narrowing (strictures, stenosis) that is refractory to
philic esophagitis showing a dense infiltration of the squamous drug therapy. Endoscopic dilatation should be performed with
epithelium with eosinophils forming microabscesses. caution, as it carries a risk of esophageal injury, although recently

638 Part five Allergic Diseases


published large series suggest this risk is not as great as originally responses to a variety of agents, including corticosteroids, PPIs,
thought. 7,8 mast cell stabilizers, antihistamines, and leukotriene antagonists
as well as surgical resection of strictured segments. 5,20
IDIOPATHIC EOSINOPHILIC GASTROENTERITIS Patients with the serosal type typically respond to steroid
therapy; however, optimal treatment is not yet defined for other
Definition and Classification forms of EGE. Based on these limited data, initial treatment
EGE is a rare, heterogeneous, and poorly defined condition. It should be with PPIs, with a switch to systemic corticosteroids
is characterized by chronic-recurrent tissue infiltration of the in the case of nonresponse. Unfortunately, the relapsing nature
5
GI tract with eosinophils. The diagnosis is based on the following of the disease means long-term treatment may be needed with
three criteria: 1) nonspecific GI symptoms; 2) eosinophilic infiltration oral corticosteroids, with the inevitable risk of side effects.
of one or more areas of the GI tract; and 3) exclusion of other Leukotriene inhibitors should be evaluated in patients with
5
causes for the intestinal eosinophilia. No consensus has yet been frequent flare-ups.
reached regarding the histological criteria for diagnosing EGE.
This may be related to the fact that healthy gastric and intestinal
mucosa harbors eosinophils under physiological conditions and HYPEREOSINOPHILIC SYNDROMES WITH
so it is difficult to establish “normal” cell numbers. GASTROINTESTINAL INVOLVEMENT
EGE can be subclassified either according to the segments of
the GI tract affected by the process or according to the depth Definition and Classification
5
of the eosinophilic infiltration. The latter (or Klein) classification The HESs are a heterogeneous group of rare disorders character-
system distinguishes between mucosal, muscular, and serosal ized by 1) persistent peripheral blood eosinophilia with more
5
3
forms of EGE. Parasitic infections, inflammatory bowel disease, than 1500 cells/mm for a period of >6 months; 2) no known
connective tissue diseases, side effects of drugs, and lympho- cause of eosinophilia; and 3) signs and symptoms of organ
6,21
proliferative malignancies must be ruled out before a diagnosis involvement. Recent efforts have led to reclassification of these
of EGE can be established. 5 disorders according to the recognition of several clinical subtypes
and new biomarkers. Currently recognized subtypes include
Epidemiology and Natural History fip1-like1/platelet-derived growth factor receptor α (FIP1L1-
EGE predominantly affects male children and adults. In contrast PDGFRA)-associated HESs, lymphocytic variant HESs, chronic
to EoE, EGE is a very rare disease. During the 70 years since it eosinophilic leukemia, and familial eosinophilia. 22,23 Independent
19a
was first described by Kaijser in 1937, approximately 200 cases of this subclassification, the eosinophilic infiltration can affect
have been reported in the literature. Although EGE is likely a the cardiovascular system (90%), the peripheral and central
chronic disorder, its natural course is still poorly defined. nervous systems (90%) including the retina, the coagulation
system (80%), the skin (55%), the respiratory system (50%), the
Clinical Presentation liver and spleen (35%), and the GI tract (25%).
The clinical manifestation of EGE depends on its location within
the GI tract and on its depth of infiltration of the intestinal wall. Epidemiology and Natural History
Mucosal involvement is typically associated with vomiting, HESs, similar to the other idiopathic eosinophilic disorders,
diarrhea, abdominal pain, weight loss, failure to thrive, and either predominantly affect middle-aged males, with a male-to-female
occult or frank bleeding. Involvement of the muscular layers ratio of 3 : 1. Onset of the disease is commonly between 20 and
may lead to signs and symptoms of intestinal obstruction, whereas 50 years of age. Data about its prevalence or incidence are not
patients with serosal involvement typically complain of bloating available. 6,21
and can present with ascites. Peripheral blood eosinophilia is
observed in approximately two-thirds of EGE patients. 5 Clinical Presentation
HES has a gradual onset, presenting initially with general
Diagnostic Measures symptoms such as anorexia, fatigue, weight loss, fever, abdominal
The mucosal form of the disease can be visualized by endoscopy. pain, and night sweats. Throughout the course of the disease,
The findings are usually not spectacular and include thickening the clinical manifestations vary according to which organs are
of the intestinal folds with deformation of the luminal configura- involved. With GI involvement, abdominal pain and diarrhea
tion, diminished peristalsis, and an erythematous and friable with malabsorption have been reported, but the leading sign is
mucosa. Moreover, endoscopy enables representative biopsy samples hepatosplenomegaly, either due to eosinophilic infiltration or
5
to be taken for histological confirmation of the diagnosis. Patients secondary to congestive heart failure. During its long-term course,
with suspected serosal disease should be evaluated by laparoscopy; extraintestinal manifestations or lymphoproliferative conditions
findings for this form of EGE include ascites, whitish nodules, may occur and facilitate the definite diagnosis. The ultimate
and thickening of the parietal and visceral peritoneum. 5 prognosis depends on the extent of end organ damage. Intestinal
The muscular form of EGE can be detected by CT scan or manifestations and cardiac involvement are associated with poor
conventional radiological examinations. Diagnostic confirmation prognosis and risk of fatal outcome, whereas patients with skin
is hampered by the difficulty in obtaining histological samples. Most disease generally have a milder course. 6,21
reported cases of muscular EGE have been diagnosed after surgical
resection of an intestinal obstruction or suspected malignancy. Immunopathogenesis
HESs encompass several disease processes with different patho-
Treatment genic mechanisms. One form is characterized by a significant
EGE is an uncommon disease, and therefore no therapeutic trials elevation of the eosinophilopoietic cytokine IL-5 in serum.
have been done. Case reports and small case series have reported Recently an IL-5–independent form of HES has been described

CHaPter 46 Eosinophil-Associated Gastrointestinal Disorders 639


in which a tyrosine kinase is overexpressed due to gene fusion. 22,24 HESs are a heterogeneous group of rare disorders, characterized
Notwithstanding the heterogeneity of underlying mechanisms, by persistent peripheral blood eosinophilia with more than 1500
3
the clinical manifestation of HES is similar, with eosinophil- cells/mm for longer than 6 months, no known cause of eosino-
mediated end organ tissue damage. philia, and signs and symptoms of organ involvement. Prognosis
depends on the degree and location of the eosinophil-mediated
Treatment end-organ tissue damage.
Like EGE, HES is a rare disorder, and no prospective treatment
studies have been carried out to date. Treatment strategies for Please check your eBook at https://expertconsult.inkling.com/
patients with HESs aim to lower the eosinophil tissue infiltration. for self-assessment questions. See inside cover for registration
Corticosteroids have been used for decades to treat HESs and details.
remain first-line therapy, except for PDGFRA-associated HESs.
Cytotoxic agents, such as hydroxyurea, vincristine, and chlor- REFERENCES
ambucil, have been successfully used in corticosteroid-refractory
patients. Interferon-α is reported to be useful in patients with 1. Rothenberg ME. Eosinophilia. N Engl J Med 1998;338:1592–600.
23
mucosal ulcerations. The tyrosine kinase inhibitor imatinib 2. Kato M, Kephart GM, Talley NJ, et al. Eosinophil infiltration and
mesylate has been shown to induce prolonged remissions in degranulation in normal human tissue. Anat Rec 1998;252:418–25.
patients with PDGFRA-associated HESs. Future studies will show 3. Straumann A, Simon HU. The physiological and pathophysiological roles
of eosinophils in the gastrointestinal tract. Allergy 2004;59:15–25.
whether monoclonal antibodies against IL-5 could prove to be 4. Liacouras CA, Furuta GT, Hirano I, et al. Eosinophilic esophagitis:
a valuable approach, given that patients with HESs often have updated consensus recommendations for children and adults. J Allergy
high levels of IL-5. 25 Clin Immunol 2011;128:3–20.
5. Talley NJ, Shorter RG, Phillips SF, et al. Eosinophilic gastroenteritis: a
SUMMARY clinicopathological study of patients with disease of the mucosa, muscle
layer, and subserosal tissues. Gut 1990;31:54–8.
6. Fauci AS, Harley JB, Roberts WC, et al. NIH conference. The idiopathic
ON tHe HOriZON hypereosinophilic syndrome. Clinical, pathophysiologic, and therapeutic
considerations. Ann Intern Med 1982;97:78–92.
• Clinical research is needed to:
• Improve diagnostic criteria 7. Straumann A, Aceves SS, Blanchard C, et al. Pediatric and adult
• Implement new diagnostic tools eosinophilic esophagitis: similarities and differences. Allergy
• Achieve early diagnosis 2012;67:477–90.
• Goals of clinical research are early treatment to improve quality of life 8. Furuta GT, Katzka DA. Eosinophilic esophagitis. N Engl J Med
and avoid tissue remodeling in patients with eosinophilic esophagitis 2015;373:1640–8.
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• Multicenter clinical studies are needed to evaluate alternative treatment features of eosinophilic esophagitis. J Allergy Clin Immunol
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EoE. 10. Mishra A, Rothenberg ME. Intratracheal IL-13 induces eosinophilic
• Translational medicine will help to identify cellular and molecular factors esophagitis by an IL-5, eotaxin-1, and STAT6-dependent mechanism.
involved in fibrosis of the esophageal wall to understand the molecular Gastroenterology 2003;125:1419–27.
mechanisms of tissue remodeling. 11. Blanchard C, Stucke EM, Rodriguez-Jimenez B, et al. A striking local
esophageal cytokine expression profile in eosinophilic esophagitis.
J Allergy Clin Immunol 2011;127:208–17.
Much ground still remains to be covered in diagnosing and 12. Blanchard C, Wang N, Stringer KF, et al. Eotaxin-3 and a uniquely
treating patients suffering from the three eosinophil-associated conserved gene-expression profile in eosinophilic esophagitis. J Clin
GI disorders: Invest 2006;116:536–47.
EoE is a common disease but challenging to diagnose due to 13. Simon D, Cianferoni A, Spergel JM, et al. Eosinophilic esophagitis is
its confusing endoscopic features. Patients, usually males, present characterized by a non-IgE-mediated food hypersensitivity. Allergy
with recurrent dysphagia and food impaction as well as coexisting 2016;71:611–20.
allergic airway diseases. Untreated EoE can induce structural 14. Straumann A, Bauer M, Fischer B, et al. Idiopathic eosinophilic
changes of the esophagus, eventually leading to an extremely esophagitis is associated with a T(H)2-type allergic inflammatory
response. J Allergy Clin Immunol 2001;108:954–61.
fragile and rigid esophageal wall structure with increased risk 15. Blanchard C, Mingler MK, Vicario M, et al. IL-13 involvement in
for complications, including perforation. Effective treatments eosinophilic esophagitis: transcriptome analysis and reversibility with
for adult patients with EoE include swallowed topical (or, seldom, glucocorticoids. J Allergy Clin Immunol 2007;120:1292–300.
systemic) corticosteroids, hypoallergenic diets, and esophageal 16. Straumann A, Spichtin HP, Grize L, et al. Natural history of primary
dilatation. Though quality of life is substantially diminished in eosinophilic esophagitis: a follow-up of 30 adult patients for up to 11.5
this chronic disorder, life expectancy is not affected. years. Gastroenterology 2003;125:1660–9.
EGE, a rather rare disorder affecting predominantly males, 17. Aceves SS, Newbury RO, Dohil R, et al. Esophageal remodeling in pediatric
may involve the entire GI tract, or it may be restricted to isolated eosinophilic esophagitis. J Allergy Clin Immunol 2007;119:206–12.
segments and affect mucosal, muscular, and serosal layers of the 18. Schoepfer AM, Straumann A, Panczak R, et al. Development and
intestinal wall. Clinical manifestations depend on location and validation of a symptom-based activity index for adults with eosinophilic
esophagitis. Gastroenterology 2014;147:1255–66.
depth of the infiltration. Mucosal involvement, the most frequent 19. Hirano I, Moy N, Heckman MG, et al. Endoscopic assessment of the
subtype, is typically associated with vomiting, diarrhea, abdominal oesophageal features of eosinophilic oesophagitis: validation of a novel
pain, and weight loss. The muscular form may mimic intestinal classification and grading system. Gut 2013;62:489–95.
obstruction or acute abdomen. Patients with the serosal form 19a. Kaijser R. Zur Kenntnis der allegischen Affektioner desima
complain mainly of bloating and ascites and usually respond Verdauungskanal von Standpunkt desima Chirurgen aus. Arch Klin Chir
dramatically to corticosteroids. 1937;188:36–64.

640 Part five Allergic Diseases


20. Neustrom MR, Friesen C. Treatment of eosinophilic gastroenteritis with 24. Simon HU, Rothenberg ME, Bochner BS, et al. Refining the
montelukast. J Allergy Clin Immunol 1999;104:506. definition of hypereosinophilic syndrome. J Allergy Clin Immunol
21. Hardy WR, Anderson RE. The hypereosinophilic syndromes. Ann Intern 2010;126:45–9.
Med 1968;68:1220–9. 25. Plotz SG, Simon HU, Darsow U, et al. Use of an anti-interleukin-5
22. Owen WF, Rothenberg ME, Petersen J, et al. Interleukin 5 and antibody in the hypereosinophilic syndrome with eosinophilic dermatitis.
phenotypically altered eosinophils in the blood of patients with the N Engl J Med 2003;349:2334–9.
idiopathic hypereosinophilic syndrome. J Exp Med 1989;170:343–8.
23. Klion AD, Bochner BS, Gleich GJ, et al. Approaches to the treatment of
hypereosinophilic syndromes: a workshop summary report. J Allergy Clin
Immunol 2006;117:1292–302.

CHaPter 46 Eosinophil-Associated Gastrointestinal Disorders 640.e1


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

1. Eosinophilic esophagitis: 3. Eosinophilic gastroenteritis:
A. Is the most common entity among the eosinophil A. Is a rare disease with unclear pathogenesis
gastrointestinal disorders (EGIDs) B. Can be diagnosed only after exclusion of infections and
B. During the natural course of the disease, often involves intestinal allergies
stomach and small bowel C. Can involve each segment of the gastrointestinal tract
C. Is mainly triggered and driven by food-antigens D. Swallowed topical steroids are currently considered as
D. Immunoglobulin E (IgE)-based testing plays a crucial role first-line drugs
in the identification of causative foods
4. Hypereosinophilic syndromes:
2. Eosinophilic esophagitis: A. Have an unforeseeable and sometimes even fatal natural
A. Must be treated only when a patient’s quality of life is course
markedly impaired B. Involve mainly the gastrointestinal tract and seldom other
B. Can be treated with drugs, diet, or dilatation organ systems
C. Dilatation is regarded as first-line treatment due to the C. Encompass a group of entities with different immune
rapid symptom resolution pathogeneses
D. Swallowed topical steroids and elimination diet have a D. Require a comprehensive hematological and multisystem
comparable efficiency examination

47









Allergic Disorders of the Eye



Virginia L. Calder, Amirah Mohd-Zaki, Valerie Saw







Allergic disorders of the eye range from the mild conditions of to open the lids and a ballooning out of the conjunctiva termed
seasonal and perennial allergic conjunctivitis (SAC, PAC), due chemosis, particularly after exposure to high aeroallergen con-
to immunoglobulin E (IgE)–mediated mast cell and histamine- centrations or after rubbing of the eye. Eversion of the lids to
related inflammation, to the clinically more severe diseases reveal the tarsal conjunctiva demonstrates some hyperemia and
associated with T cell–mediated chronic inflammation, vernal mild infiltration (loss of transparency and thickening) of the
and atopic keratoconjunctivitis (VKC, AKC). The ocular allergic conjunctiva with diffuse small inflammatory excrescences known
responses in SAC and PAC are confined to the conjunctival tissues, as papillae. Because there is no serious limbal disease or con-
whereas in both VKC and AKC the cornea also can become junctival scarring and the cornea is not involved, the visual acuity
involved, potentially leading to impaired vision. Research to remains normal. Outside the pollen season, the eye examination
identify the inflammatory cells and molecules involved in allergic is normal.
responses at the ocular surface and their role in the pathogenesis
of allergic eye diseases has increased in the past few years. Extensive Conjunctival Immunostaining in SAC
immunohistochemical studies have identified distinct expression SAC involves an immediate, rapid early-phase hypersensitivity
profiles of adhesion molecules, chemokine receptors, cytokines, response due to allergens binding and cross-linking IgE molecules
and immune cell types for each subtype of allergic conjunctivitis, attached to tissue mast cells. The acute response is rapid, usually
while immune pathways are being studied via novel experimental taking place within 30 min. The late-phase response occurs 6–12 h
models. This chapter reviews recent advances in our understanding after antigen exposure and involves the infiltration of inflam-
of the cellular and molecular processes occurring in ocular allergy. matory cells, primarily mast cells, and some eosinophils and
1
neutrophils (Fig. 47.1). Primarily mast cells and their degranula-
tion products (histamine, proteases, leukotrienes, chemokines,
KEY CONCEPTS and cytokines) orchestrate the inflammatory response in SAC,
Predominating Cell Types in the although neutrophils and eosinophils also secrete a wide range
Conjunctival Tissues of proinflammatory mediators that amplify the inflammation.
Immunohistochemical studies of tarsal and bulbar conjunctival
In seasonal and perennial allergic conjunctivitis: mast cells biopsy specimens demonstrated increased expression of intercel-
In vernal keratoconjunctivitis: eosinophils, T cells, neutrophils, mast cells lular adhesion molecule (ICAM)-1 and E-selectin adhesion
In atopic keratoconjunctivitis: T cells, eosinophils, neutrophils molecules in SAC in comparison with controls, but only inseason,
2
and expression returns to baseline outside the pollen season.
This pattern of expression is correlated with the degree of
SEASONAL ALLERGIC CONJUNCTIVITIS neutrophil or eosinophil infiltration in the bulbar tissue, sug-
gesting a mast-cell–mediated cell recruitment process.
Ocular allergy, principally SAC, is the commonest ocular disorder
seen in primary care. SAC is a recurrent conjunctivitis apparent Therapy
only during the pollen season; the timing (spring, summer, or General measures may provide effective relief, particularly when
autumn) is dependent on which particular pollen or mold is the disease is not severe. Limiting pollen exposure by keeping
allergenic for that individual. The disorder can occur at any age windows shut and remaining indoors, especially on high-pollen-
but is more frequently seen in children and young adults and count days, is common sense. Cold compresses and ocular
tends to lessen in severity in the older age groups. lubricants (artificial tears) relieve symptoms, particularly itching.
Patients present with seasonally recurring itching, watering, Numerous classes of agents, both systemic and topical, have
redness, and swelling of the eyes and lids, and there may be been used to manage the signs and symptoms of allergic con-
3
increased conjunctival discharge. An associated rhinitis is junctivitis. Topical mast cell inhibitors, the prototype being
common. A personal or family history of atopy very often can sodium cromoglycate, are the most useful drugs for non-sight-
be elicited. During the allergen season, the ocular signs range threatening ocular allergy. Sodium cromoglycate eye drops are
from mild to dramatic and are usually bilateral and symmetrical. available over the counter. They have a number of effects
Edema of the lids and conjunctiva may be mild and often (inhibition of other leukocytes, direct mediator antagonism) in
outweighs the degree of hyperemia, giving a milky or pink addition to inhibiting mast cell degranulation (one of the earliest
appearance to the eye, but the swelling may be gross, with inability mechanisms of the acute ocular allergic response), which accounts

641

642 ParT fivE Allergic Diseases


Normal conjunctiva Seasonal allergic conjunctivitis Histamine, LTs,
cytokines

Intraepithelial Mast cell
Mast cells lymphocytes ↑Neutrophils degranulation
Tear film
Epithelium

Blood
vessel Blood vessel

Stroma





Endothelium



Vernal keratoconjunctivitis Atopic keratoconjunctivitis
Secrete eotaxin to ECP, EDN,
↑TH 2 attract eosinophils EPO, ↑ TH 2 ↑TH 1
Thickened Uneven
epithelial layer T cells Mast cells ↑Eosinophils T cells Eosinophils
Tear film epithelial layer

Epithelium





Stroma




Endothelium
fiG 47.1 A schematic diagram of a cross-section of conjunctival tissue, showing the cell processes
involved in normal vs. SAC- vs. VKC- vs. AKC-affected tissues. AKC, atopic keratoconjunctivitis;
ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase;
SAC, seasonal allergic conjunctivitis; VKC, vernal keratoconjunctivitis.




for their potency and their ability to offer a preventative action Anti-H1/H2 histamine drugs, both oral and topical, are used
if used early and continued throughout the allergen season. One widely and provide rapid symptom reduction; however, they are
limitation is the slower onset of symptom relief compared with not preventative and have limited potency, as they address only
5
antihistamines, although this is less of an issue with the newer, one arm of the inflammatory mediator response. Oral antihis-
high-potency preparations (lodoxamide, nedocromil). They are tamines also treat any rhinitis, but the onset of ocular action
extremely safe. is slower, the local effective concentration is less than for
If topical mast cell inhibitors do not provide sufficient relief, topical therapy, and they expose the patient to the risk of
dual-acting topical antiallergic compounds (olopatadine, epi- unwanted effects. They often are used for children when drop
nastine, and ketotifen) combine antihistaminic properties (H1 use can be difficult, plus at night any sedative effect can be
and/or H2 receptor antagonism) with mast cell stabilization. advantageous. Long-term use of oral antihistamines leads to
They offer the advantage of rapid onset of action with the chronic dry eye. Topical antihistamines are available as
preventative and long-term effect of inhibiting mast cell mediator higher-potency antihistamine-only preparations (e.g., levoca-
release. Olopatadine and epinastine in particular offer a clinical bastine, emedastine, azelastine), which provide rapid onset of
advantage over oral and topical antihistamines and compare symptom relief and more prolonged action after drop instillation.
well with mast cell inhibitors in allergen challenge models and, Lower-potency topical antihistamines in combination with a
at least in some studies, in SAC. 4 vasoconstrictor (e.g., antazoline-naphazoline) are generally not

CHaPTEr 47 Allergic Disorders of the Eye 643


recommended, especially for long-term use, due to rebound that several cell-mediated processes are involved and contribute
vasodilatation of the conjunctival vessels with long-term vaso- to the chronic inflammation found in PAC. 7
constrictor use. They can cause contact allergic conjunctivitis,
sedation, or excitability, and they are slower and shorter-acting Therapy
than high-potency topical antihistamines. In the case of house dust mite sensitivity, advice should be
provided on mite reduction; allergy support groups can be helpful
for this and for accessing equipment. Potential mite reduction
CLiNiCaL PEarLS measures include removing soft furnishings (e.g., carpet, curtains)
Seasonal Allergic Conjunctivitis from the bedroom; using special vacuum cleaner filters; intensive
and regular vacuuming of bedrooms, including the curtains and
• Seasonal response to allergen (e.g., pollen) mattress; using a mite-impermeable mattress and pillow covers;
• Mast cell–mediated washing bed linen and curtains at mitocidal temperatures (>131
• Antihistamines, mast cell inhibitors
°F or >55 °C); and using mitocidal chemicals. For mold sensitivity,
dehumidifying devices and mold-killing chemicals may help.
Of the several topical nonsteroidal antiinflammatory drugs The drug therapy of PAC is essentially as recommended for
(NSAIDs) assessed in ocular allergy, ketorolac is the only one SAC (see above), but as the disease is usually prolonged, the
approved for ocular allergy. NSAIDs are not used as first-line continuing use of mast cell inhibitors assumes more importance,
therapy for ocular allergy. They offer the advantage of safety, whereas antihistamines tend to be used intermittently for flare-ups
but their efficacy is not well proven against other established of inflammation.
remedies, and cost is a concern, as is discomfort upon instillation Allergen-specific immunotherapy (AIT) can be effective for
and potentially reduced patient adherence. The use of NSAIDs patients with severe allergic rhinoconjunctivitis who have specific
is more common outside the United Kingdom. IgE antibodies to allergens (Chapter 91). Increasing doses of the
Topical steroids have a minimal role in SAC because of allergen are administered by subcutaneous immunotherapy
their potential for ocular adverse effects (see below). They (SCIT) or sublingual immunotherapy to achieve hyposensitization
occasionally are used short-term for severe disease to gain control mediated by production of interleukin (IL)-10 and transforming
of inflammation, but their use must be supervised by an growth factor (TGF)-β1. Side effects, including anaphylaxis, are
ophthalmologist. known to occur with this form of therapy. SIT requires a long-term
commitment from the patient and/or caregiver in terms of time
PERENNIAL ALLERGIC CONJUNCTIVITIS (SCIT requires monthly injections for 3 years) and expense. This
may not be practical for the SAC or PAC patient who does not
PAC is the second most common ocular allergy. It bears many suffer from other comorbidities. 8
similarities to SAC, but because the allergens in PAC are present
for most or all of the year, the time course of the disease is not Experimental Models of Allergic Conjunctivitis
seasonal. The disorder is again most severe and most frequently Conjunctival Allergen Challenge
seen in children and young adults. House dust mite (Derma- This model involves challenging the ocular surface with an allergen
tophagoides pteronyssinus) is the most common sensitizing allergen, to artificially provoke an ocular allergic response in sensitized
9
but animal hair and dander, molds, and other antigens may be individuals. Symptoms are similar to those seen in SAC, and
responsible. so the model is useful for investigating the early- and late-phase
The symptoms are perennial ocular itch, discomfort, watering, allergic responses at the ocular surface. During the early-phase
redness, and some discharge. Patients may be able to correlate response (20 mins post challenge), increased levels of histamine
symptomatology with exposure to, for example, pets or a par- and tryptase can be detected in tears, suggesting that the active
ticular location. House dust mite allergy sufferers may give a cell population is predominantly mast cells. At 6 hours, histamine
history of symptoms worse in the morning. Approximately and eosinophil cationic protein levels are increased, but not
one-third have an associated rhinitis, and a family and/or personal tryptase, suggesting that basophils and eosinophils are infiltrating
10
atopic history is very common. The clinical appearance is of and active during the late phase. T cells are also increased and
mild conjunctival inflammation, and clinical signs may be very can be seen in bulbar biopsy specimens. The allergen challenge
slight. The bulbar conjunctiva (on the eye globe) may be slightly model is often used for testing the efficacy of eye drops.
red and edematous, and the tarsal conjunctiva shows mild to
moderate hyperemia, infiltration, and fine papillae. Lid edema Experimental Allergic Conjunctivitis
11
is usually mild. As with SAC, there is neither conjunctival scarring A mouse model of experimental allergic conjunctivitis (EAC)
nor corneal or serious limbal involvement, so normal visual was established by an initial footpad sensitization with short
acuity is maintained. ragweed pollen (SRW), followed 7–10 days later by conjunctival
SRW challenge. An infiltration of mast cells, neutrophils, and
Immunohistological Studies in PAC eosinophils occurs, as well as increased conjunctival chemosis
As with SAC, PAC involves an immediate-type hypersensitivity and lid edema. Interestingly, although there is no significant
response, but because the allergens are present continuously, the infiltration of T cells, expression of the model is attenuated in
resultant inflammation is more chronic. Therefore the immu- IL-12 knock-out mice. In BALB/c mice, SRW-induced EAC was
nopathology of PAC differs slightly from that of SAC. Increased interferon (IFN)-γ–dependent and could not be induced in IFN-γ
12
numbers of mast cells are detected in both the tarsal conjunctival knock-out mice, supporting a role for Th1 pathways. A role
epithelium and the substantia propria, with both mucosal and for thymic stromal lymphopoietin (TSLP) has also been dem-
2
connective-tissue-type mast cell phenotypes. In addition, mast onstrated in EAC, with TSLP expression upregulated in allergen-
cells, eosinophils, neutrophils, and T cells are present, suggesting challenged corneal and conjunctival epithelium. 13

644 ParT fivE Allergic Diseases



VERNAL KERATOCONJUNCTIVITIS
VKC is a serious ocular allergy of childhood, comprising 0.1–0.5%
of ocular disease in the developed world but more common and
much more severe in hot, dry countries, especially the Middle
East, West Africa, and the Mediterranean. In the United Kingdom,
VKC is an unusual, self-limiting, often seasonal ocular allergy
that affects children and young adults, especially males (85%)
many of whom have a personal or family history of atopy. The
link with atopy and seasonality is less clearly defined in cooler
climates. Showing
The symptoms are worse in the spring and summer but last corneal plaque
all year in severe disease. Patients complain of marked itching, A
discomfort or pain, photophobia, stringy discharge, blurred
vision, and difficulty opening the eyes in the morning. The ocular
signs may be very asymmetrical. Conjunctival signs are maximal
in the superior tarsal conjunctiva and limbus, and the heavily
inflamed lid may droop (ptosis). The conjunctival surfaces are
hyperemic, edematous, and infiltrated, and a stringy mucoid
discharge is present. The tarsal conjunctiva is densely infiltrated,
with papillae that are often giant (>1 mm in diameter, also known
as cobblestone papillae). The limbus may show discrete swellings Showing corneal
or, less often, diffuse hyperemia and infiltration. The presence vascularization
of small white-chalky deposits (Trantas’ dots) is typical of vernal and mucus thread
limbitis. In the later stages, fine reticular white scarring may be
seen or, in some cases, sclerosing VKC with sclerosis of the upper B
limbus over 90–120° of arc (from ~10–2 o’clock). fiG 47.2 Two clinical pictures showing features of (A) vernal
Visual acuity can be affected by involvement of the cornea keratoconjunctivitis, corneal plaque formation, formation of giant
(keratopathy), which is most marked in the upper third of the papillae; (B) atopic keratoconjunctivitis, mucus thread, corneal
cornea due to greater exposure to toxic inflammatory mediators, vascularization.
not mechanical rubbing by the papillae. At its mildest, there is
a punctate disturbance of the epithelium, which may coalesce
to form a discrete epithelial defect (macroerosion). Deposition VKC tear fluids were found to have increased levels of IL-4, IL-10,
of mucus, fibrin, and inflammatory debris can then result in IFNγ, eotaxin, and tumor necrosis factor (TNF)-α compared
18
the formation of a shallow oval plaque (or shield) ulcer, which with controls. Compared with controls, conjunctival biopsy
repels the hydrophilic tears and the epithelial healing response specimens from VKC patients showed increased expression of
(Fig. 47. 2A). Herpetic and bacterial (staphylococcal) corneal infec- RANTES, eotaxin, monocyte chemotactic protein (MCP)-1, and
19
tion may occur as a result of impaired cell-mediated immunity MCP-3, reflecting the range of inflammatory cells present.
in these patients. In the later stages, scarring of the cornea can Tissue remodeling, giant cobblestone papillae formation,
lead to permanent visual reduction. Complications related to limbal stem cell deficiency, and various degrees of superficial
steroid treatment, along with (because of the young age group) corneal opacification are further consequences of the chronic
sensory-deprivation amblyopia, can contribute to the potential inflammation typical of VKC. Factors that promote fibroblast
for long-term visual loss. proliferation include Th2 cytokines, growth factors such as TGF-β,
20
bFGF, PDGF, and also histamine. These growth factors also
Immunological Studies in VKC increase integrin expression, which in turn promotes cellular
Several studies have identified innate and adaptive immune cells infiltration and proliferation in VKC. Dendritic cells activating
to be activated during VKC. T lymphocytes and eosinophils profibrotic T lymphocytes also may be relevant. 21
predominate, with mast cells, neutrophils, and other cell types
infiltrating the conjunctival epithelium and stroma (Fig. 47.1). Management of VKC
Studies of tarsal conjunctival tissue specimens have found The treatment goals of VKC are to obtain adequate symptom
increased numbers of activated CD4 T cells, mainly localized control and to prevent complications of disease and treatment
to the subepithelial layer of the affected tissue, and increased that might permanently reduce visual acuity; one must bear in
14
HLA-DR expression compared with normal subjects. There is mind that the disease is likely to remit spontaneously before
evidence that dendritic cells migrate to the lymph node to activate adulthood. In cases where there appears to be pollen sensitivity,
15
T cells using a CCR7-mediated process. Increased numbers of advice on pollen avoidance should be given, similar to that for
+
Langerhans cells and activated macrophages (CD68 ) have also SAC (see above). Simple measures such as cold compresses,
been observed. Conjunctival T cells, cloned from VKC tissues, ocular lubricants, and mucolytic drops may help. Oral and topical
have been functionally characterized as T-helper cell-2 (Th2) type, antihistamines have a very limited role in the disease.
whereas in situ hybridization staining demonstrated upregulation Topical mast cell inhibitors are effective in VKC and should
of IL-3, IL-4, and IL-5 messenger ribonucleic acids (mRNAs) in be maintained throughout the time of active inflammation, two
VKC in areas of maximum T-cell infiltration, consistent with Th2 to four times daily, depending on the severity of disease and
16
17
cell involvement. Th1 and Th17 cells also can be involved. which preparation is used. Olopatadine twice daily is effective

CHaPTEr 47 Allergic Disorders of the Eye 645


and safe to use in VKC. Lodoxamide and nedocromil are more
potent than sodium cromoglycate and are worth trying if Experimental Model of VKC
olopatadine does not appear to control symptoms. Those with In genetically susceptible rats and mice, experimental blepharo-
mild disease may be able to discontinue therapy during the winter conjunctivitis (EBC) is inducible by subcutaneous immunization
months. It is important to emphasize to patients and parents with SRW followed by conjunctival allergen challenge at day 10.
that mast cell inhibitors are safe and must be continued when In this model a significant eosinophilia is found 24 hours after
using steroids to minimize the dose of steroids required and the challenge, and EBC has therefore been used as a model for
risk of steroid complications. studying eosinophil infiltration as found in VKC. It also can be
induced by adoptively transferring Th2, but not Th1, T cells,
CLiNiCaL PEarLS consistent with our understanding that eosinophil infiltration
23
Vernal Keratoconjunctivitis is Th2-mediated.
• Chronic conjunctival inflammation with seasonal exacerbations ATOPIC KERATOCONJUNCTIVITIS
• Eosinophils and T-helper 2 (Th2) cells infiltrate the conjunctival tissues
• Usually affects young males AKC is the least common but most serious of the ocular allergies.
• Cornea can be affected It is a life-long condition that affects adults who have systemic
• Increased expression of Th2 cytokines, adhesion molecules, eotaxin atopic disease, particularly atopic dermatitis. It usually starts in
• Often requires steroids and topical cyclosporine
the late teens, but unlike VKC, the disease is persistent and
may be relentlessly progressive; occasionally the disease can
Steroids are highly potent controllers of multiple features of begin in childhood. AKC is a highly symptomatic disorder with
allergic inflammation and are frequently required in VKC. severe itching, pain, watering, stickiness, and redness of the eyelids
Unfortunately they carry a significant risk of ocular adverse and eye. 24
effects, including ocular hypertension, glaucoma, and cataract,
and they can worsen infective keratitis. This is a particular concern
in children, where examination to detect these complications CLiNiCaL PEarLS
can be difficult (e.g., tonometry for intraocular pressure) and Atopic Keratoconjunctivitis
also where iatrogenic adverse effects may have long-term visual
consequences beyond the time when the disease has spontaneously • The most severe form of allergic eye disease
regressed. To minimize the risk of adverse effects, topical cyclo- • Affects adults with atopic dermatitis or asthma
• Predominant infiltration of T cells expressing interferon (IFN)γ in severe
sporine should be used, and then steroids can be prescribed in cases
short, sharp, rapidly tapering doses during episodes of high • Cornea can be affected, often due to secondary infections
disease activity or significant keratopathy. In addition, the use • Requires steroids and cyclosporine
of surface-acting preparations with a reduced intraocular action
(e.g., fluorometholone, rimexolone, loteprednol) is advisable,
although they are not available in preservative-free formulations There is usually facial atopic dermatitis involving the eyelids.
that are preferred for high-frequency use. Systemic steroids also The lid margins show severe blepharitis (chronic inflammation
are sometimes used but expose the patient to numerous potential of the lash follicles and Meibomian glands) and are thickened
adverse effects. Supratarsal injections of steroids, either long-acting and hyperemic, posteriorly rounded, and sometimes keratinized;
(triamcinolone) or short-acting (e.g., dexamethasone), may also the lid anatomy may be distorted with ectropion (outwardly
be used to great effect, but these are not surface-acting agents turning eyelid), entropion (inwardly turning eyelid), trichiasis
and therefore do carry significant risk of local side effects; unlike (in-turning lashes), loss of lashes, and notching. The whole
drops, neither the treatment effect nor any adverse effects can conjunctiva is affected and shows intense infiltration, papillae
be terminated suddenly if problems arise. (which may be giant), and sometimes scarring with linear and
Cyclosporine is a specific T-cell inhibitor but also has a number reticular white scar tissue, lid-to-conjunctiva adhesions (sym-
of other inhibitory effects (e.g., on eosinophils, mast cells) that blepharon), shrinkage or loss of the conjunctival sac, and second-
are likely to contribute to its effectiveness in ocular allergic therapy. ary lid distortion. Marked limbal inflammation can develop,
Topical cyclosporine 2% dissolved in oil (usually corn) has been and Trantas’ dots may occur. The disease may not affect the
used to great effect in VKC and is particularly effective in treating cornea at all, in which case it is sometimes called atopic blepha-
22
corneal complications and in acting as a steroid-sparing agent. roconjunctivitis (ABC); in this situation, the overall inflammation
It has no systemic adverse effects and none of the serious ocular is generally less severe.
complications of steroids, so generally it can be used safely The cornea may be affected directly during inflammation, or
long-term. Commercially available topical cyclosporine 0.1% in it may be damaged secondarily after extensive changes to the
a cationic emulsion (Ikervis in UK; Restasis in US) has recently protective ocular surface by continual mechanical trauma, reduced
been licensed for use in dry eye. A randomized study in Europe lid protection, or severe loss of conjunctival tear production.
evaluating 4×/day topical cyclosporine 0.1% in children with Significant visual acuity reduction due to corneal involvement
VKC is ongoing. occurs in 40–70% of cases. Keratopathy may consist of punctate
Surgical interventions are sometimes required in VKC for the and macroscopic epithelial defects, filamentary keratitis, plaque
corneal manifestations; surgical or excimer laser superficial ulcer, progressive scarring, neovascularization (with or without
keratectomy may be used in conjunction with medical therapy lipid deposition), thinning, and secondary corneal infections
for plaque ulcer; rarely, corneal grafting may be required for (herpetic, bacterial, and fungal) (Fig. 47.2B). There are recognized
scarring. Surgical removal of giant papillae or conjunctival associations between AKC and eye rubbing, keratoconus, atopic
reconstruction is not generally recommended. cataract, and retinal detachment.

646 ParT fivE Allergic Diseases


keratitis, which is more common and severe in AKC, can be
Immunological Studies in AKC potentiated by topical steroids. Topical tacrolimus is more potent
26
In AKC the predominant cell types infiltrating the conjunctival than topical cyclosporine and well tolerated. Facial and lid
tissues are T cells, eosinophils, and neutrophils (Fig. 47.1). As dermatitis should be actively managed, if necessary in conjunction
observed in VKC, increased numbers of activated CD4 T cells, with a dermatologist, whereas lid margin inflammation (blepha-
HLA-DR expression, and cells of the monocyte/macrophage ritis) should be treated with hot compresses followed by lid
14
lineage are found in conjunctival biopsy specimens in AKC, hygiene, topical antibiotic, and/or steroid preparations and
as well as mRNA expression of IL-3, IL-4, and IL-5 in the stroma. systemic low-dose antibiotics (especially tetracyclines), all of
However, in AKC there is a significant increase in the expression of which will lessen the need for antiinflammatory and immunosup-
IL-2 mRNA and in the numbers of IFN-γ–expressing T cells, sug- pressive therapy.
16
gesting a Th1-mediated inflammation in this disease. Collagen Systemic therapy can be necessary in severe cases, particularly
deposition and conjunctival tissue remodeling are considerable in when surgical therapy is undertaken, and includes steroids,
VKC and AKC, so the production of proinflammatory cytokines cyclosporine, and sometimes other immunosuppressive agents
by infiltrating cells may be the mechanism whereby tissue-resident such as mycophenolate mofetil. All of these carry risks of serious
cells such as conjunctival fibroblasts become involved. side effects and also affect the general atopic picture, so consulta-
tion with the patient’s physician is advisable.
Experimental Model of AKC A significant number of patients require ocular surgery, either
To investigate the immunopathogenic mechanisms involved as a consequence of the disease or because of associated kera-
during AKC, a new clinically more severe model of EAC has toconus. Surgery for AKC includes both elective procedures and
25
been developed. In this model, EAC was induced in C57BL/6 emergency interventions and may consist of corneal gluing, patch
mice by systemic immunization and topical daily challenge grafts, corneal transplants (partial or full thickness), conjunctival
with ovalbumin (OVA). OVA-challenged mice exhibited more reconstruction, amniotic membrane grafts, and limbal trans-
severe clinical symptoms compared with other mouse models plantation. These are generally high-risk procedures and often
described above, with chemosis and hyperemia. Because this require support with systemic immunosuppression.
model demonstrated clinical symptoms similar to AKC, it has In summary, allergic disorders of the eye range in severity
been used to show that mast cell, CD4 T cell, and dendritic and duration. Recent studies have increased our understanding
cell numbers are increased during disease, while IL-9, a growth of the molecular mechanisms involved. VKC and AKC require
factor for mast cells, was also upregulated (Mohd Zaki et al, immunosuppressive therapy, which can have serious side effects.
submitted; Fig. 47.3). Although the therapeutic options for treating mast cell–mediated
forms of allergic conjunctivitis have improved, there is still a
Therapy need to find alternative, safer therapies for the more severe and
Therapy for AKC not only aims to control symptoms but also chronic forms.
attempts to modify and reduce serious sight-threatening sequelae;
therefore it should be aggressive. The topical treatment of the Please check your eBook at https://expertconsult.inkling.com/
ocular surface is similar to VKC in that some general therapy for self-assessment questions. See inside cover for registration
may help, antihistamines are not useful, mast cell inhibitors are details.
continued long-term, and steroid and cyclosporine drops are
often required. However, the disease is generally less episodic REFERENCES
than VKC, so long-term steroid use is often needed, and steroid-
related complications are more problematic. In particular, herpetic 1. Anderson DF, MacLeod JD, Baddeley SM, et al. Seasonal allergic
conjunctivitis is accompanied by increased mast cell numbers in the
absence of leucocyte infiltration. Clin Exp Allergy 1997;27(9):1060–6.
Allergens 2. Bacon AS, McGill JI, Anderson DF, et al. Adhesion molecules and
relationship to leukocyte levels in allergic eye disease. Invest Ophthalmol
Vis Sci 1998;39(2):322–30.
3. Castillo M, Scott NW, Mustafa MZ, et al. Topical antihistamines and mast
cell stabilisers for treating seasonal and perennial allergic conjunctivitis.
Conjunctival
epithelium Cochrane Database Syst Rev 2015;(6):CD009566.
4. Bilkhu PS, Wolffsohn JS, Naroo SA. A review of non-pharmacological
and pharmacological management of seasonal and perennial allergic
conjunctivitis. Cont Lens Anterior Eye 2012;35(1):9–16.
5. del Cuvillo A, Sastre J, Montoro J, et al. Allergic conjunctivitis and H1
Fc RI
IL-9 antihistamines. J Investig Allergol Clin Immunol 2009;19(Suppl. 1):11–18.
6. Dart JK, Buckley RJ, Monnickendan M, et al. Perennial allergic
conjunctivitis: definition, clinical characteristics and prevalence. A
comparison with seasonal allergic conjunctivitis. Trans Ophthalmol Soc
IL-9R
Mast cell IL-4 U K 1986;105(Pt 5):513–20.
IL-5 7. Leonardi A, De Dominicis C, Motterle L. Immunopathogenesis of ocular
IL-13 allergy: a schematic approach to different clinical entities. Curr Opin
Allergy Clin Immunol 2007;7(5):429–35.
Mucus production 8. Kari O, Saari KM. Updates in the treatment of ocular allergies. J Asthma
Scarring Allergy 2010;3:149–58.
fiG 47.3 Hypothesis of a role for interleukin-9 in allergic 9. Friedlaender MH. Objective measurement of allergic reactions in the eye.
conjunctivitis. Curr Opin Allergy Clin Immunol 2004;4(5):447–53.

CHaPTEr 47 Allergic Disorders of the Eye 647


10. Bacon AS, Ahluwalia P, Irani AM, et al. Tear and conjunctival changes 19. Abu El-Asrar AM, Struyf S, Al-Kharashi SA, et al. Chemokines in the
during the allergen-induced early- and late-phase responses. J Allergy limbal form of vernal keratoconjunctivitis. Br J Ophthalmol
Clin Immunol 2000;106(5):948–54. 2000;84(12):1360–6.
11. Magone MT, Whitcup SM, Fukushima A, et al. The role of 20. Vichyanond P, Pacharn P, Pleyer U, et al. Vernal keratoconjunctivitis: a
IL-12 in the induction of late-phase cellular infiltration in a severe allergic eye disease with remodeling changes. Pediatr Allergy
murine model of allergic conjunctivitis. J Allergy Clin Immunol Immunol 2014;25(4):314–22.
2000;105(2 Pt 1):299–308. 21. Dale SB, Saban DR. Linking immune responses with fibrosis in allergic
12. Stern ME, Siemasko K, Gao J, et al. Role of interferon-gamma in a mouse eye disease. Curr Opin Allergy Clin Immunol 2015;15(5):467–75.
model of allergic conjunctivitis. Invest Ophthalmol Vis Sci 22. Gonzalez-Lopez JJ, Lopez-Alcalde J, Morcillo Laiz R, et al. Topical
2005;46(9):3239–46. cyclosporine for atopic keratoconjunctivitis. Cochrane Database Syst Rev
13. Zheng X, Ma P, de Paiva CS, et al. TSLP and downstream molecules in 2012;(9):CD009078.
experimental mouse allergic conjunctivitis. Invest Ophthalmol Vis Sci 23. Fukushima A, Ozaki A, Jian Z, et al. Dissection of antigen-specific
2010;51(6):3076–82. humoral and cellular immune responses for the development of
14. Metz DP, Bacon AS, Holgate S, et al. Phenotypic characterization of T experimental immune-mediated blepharoconjunctivitis in C57BL/6 mice.
cells infiltrating the conjunctiva in chronic allergic eye disease. J Allergy Curr Eye Res 2005;30(4):241–8.
Clin Immunol 1996;98(3):686–96. 24. Foster CS, Calonge M. Atopic keratoconjunctivitis. Ophthalmology
15. Saban DR. The chemokine receptor CCR7 expressed by dendritic cells: a 1990;97(8):992–1000.
key player in corneal and ocular surface inflammation. Ocul Surf 25. Schlereth S, Lee HS, Khandelwal P, et al. Blocking CCR7 at the ocular
2014;12(2):87–99. surface impairs the pathogenic contribution of dendritic cells in allergic
16. Metz DP, Hingorani M, Calder VL, et al. T-cell cytokines in chronic conjunctivitis. Am J Pathol 2012;180(6):2351–60.
allergic eye disease. J Allergy Clin Immunol 1997;100(6 Pt 1):817–24. 26. Erdinest N, Solomon A. Topical immunomodulators in the management
17. Reyes NJ, Saban DR. T helper subsets in allergic eye disease. Curr Opin of allergic eye diseases. Curr Opin Allergy Clin Immunol
Allergy Clin Immunol 2014;14(5):477–84. 2014;14(5):457–63.
18. Leonardi A, Curnow SJ, Zhan H, et al. Multiple cytokines in human tear
specimens in seasonal and chronic allergic eye disease and in conjunctival
fibroblast cultures. Clin Exp Allergy 2006;36(6):777–84.

CHaPTEr 47 Allergic Disorders of the Eye 647.e1


MULT i PLE-CHO i CE QUEST i ONS

1. Which patient with ocular allergy would you treat with specific C. VKC
immunotherapy? D. AKC
A. Seasonal allergic conjunctivitis (SAC) 3. Are topical cyclosporine and/or tacrolimus indicated in ocular
B. Perennial allergic conjunctivitis (PAC) allergy?
C. Vernal keratoconjunctivitis (VKC) A. Yes
D. Atopic keratoconjunctivitis (AKC)
B. No
2. Anti-IgE is indicated in which forms of ocular allergy? C. Unknown
A. SAC
B. PAC

48









Drug Hypersensitivity



Mariana Castells, Rafael Bonamichi-Santos







Reactions to drugs are an important source of morbidity and KEY CONCEPT
mortality and constitute a major hazard in the practice of
medicine. We have an incomplete understanding of the mecha- Main Presentations of Drug Hypersensitivity
nisms of the reactions, few tools for their diagnosis and/or 1. Type I reactions with the involvement of mast cells and basophil
1,2
prevention, and limited treatment options. With the introduc- triggering by IgE and/or non-IgE mechanisms and ranging from urticaria
tion of new and better medications to treat cancer, chronic to anaphylaxis
inflammatory diseases, and infections, there has been a parallel 2. Type IV delayed hypersensitivity reaction presenting as delayed rash;
increase in instances of drug allergy and hypersensitivity. Although drug-specific T cell–specific clones may be identifiable
these new, targeted therapies offer increased survival and quality 3. Severe cutaneous reactions, including Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN), drug-induced reactions with
of life, repeated exposures to small molecules and monoclonal eosinophilia and systemic symptoms (DRESS), and acute generalized
antibodies (mAbs) with immunogenic and allergenic capacity exanthematous pustulosis (AGEP), in which HLA genotypes and viral
have increased the rate of sensitizations and reactions. Drug infections play major roles
hypersensitivity prevents patients from receiving first-line therapy,
and doctors have few guidelines on how to diagnose and address
these potentially life-threatening reactions. 3,4
11
Identifying drug-hypersensitive patients protects them from antiepileptics are among the most frequent causes. The risk
reexposure to culprit medications and permits access to desen- of sensitization and of a reaction depends on the drug chemistry
sitization procedures when needed and indicated. Identifying and structure, the host immune system, the dose, the route,
patients who are not in fact hypersensitive means they can avoid the duration of treatment, the patient’s gender and specific
receiving second-line therapies with their associated increased HLA alleles. In a study from Brazil, >50% of the anaphylactic
5
costs and resource requirements. The vast majority of patients reactions treated in the emergency department were induced
with a history of penicillin allergy have negative results on skin by nonsteroidal anti-inflammatory drugs (NSAIDs), the most
12
testing and do not react during a challenge or during further frequently implicated medications. A recent US study of drug-
6
courses of penicillin, but there is a lack of standardized reagents induced anaphylaxis found that most patients were female, few
approved by the US Food and Drug Administration (FDA) for received appropriate treatment with epinephrine, and 29% had
the diagnosis of allergy to the majority of antibiotics and other concomitant asthma and allergic rhinitis. A high proportion
drugs. Central to the evaluation of patients with drug hyper- of these patients were receiving antidepressants, angiotensin-
sensitivity is an understanding of the pathophysiology of the converting enzyme (ACE) inhibitors and/or angiotensin II
reactions. Genotype studies of patients with severe hypersensitivity blockers, confirming the association of these medications with
reactions, including drug-induced reactions with eosinophilia severe reactions. 13
and systemic symptoms (DRESS), Stevens-Johnson syndrome
(SJS), toxic epidermal necrolysis (TEN), have uncovered predis- IMMUNE DRUG RECOGNITION AND GENETIC
posing specific HLA alleles permitting identification of targeted BASIS OF DRUG HYPERSENSITIVITY
7
populations and protection against these reactions. Systematic
utilization of available markers of immune cell activation, such Drugs are recognized by the immune system and initiate immune
as tryptase (the major mast cell protease release during anaphy- responses, depending on their structure, size, and multimeric/
lactic IgE- and non-IgE–mediated reactions) can provide useful multivalent presentation. Most drugs are small molecules, which
diagnostic information and help guide the treatment and require haptenization, or binding to carrier proteins, to interact
management of drug reactions. 8 with antigen-presenting cells (APCs), including B cells. Once B
cells are activated, epitope-specific antibodies are made, including
14
EPIDEMIOLOGY OF DRUG HYPERSENSITIVITY IgE if interleukin-4 (IL-4) is present. Beta-lactam antibiotics,
such as penicillin and cephalosporins, are haptens with unstable
Drug hypersensitivity has a spectrum of presentations and beta-lactam rings that acylate lysine residues in proteins, forming
9
can be fatal : the most common presentation is skin rashes, covalent bonds and leading to the major penicilloyl epitope
observed in about 2–3% of hospitalized patients. 10,11 Any drug responsible for urticarial reactions. Carboxyl and thiol groups
can elicit hypersensitivity reactions: antibiotics, chemotherapy in beta-lactams can also haptenate. These hapten–carrier
drugs, mAbs, antihypertensives, radio contrast media, and complexes are called minor allergens because they are found

649

650 ParT FivE Allergic diseases


in only a small proportion of cases; they have been implicated for processing and generating haptenated peptides recognized
15
in anaphylactic IgE-mediated reactions to penicillin. Large by T cells as neoantigens. In the p-I model, small drug molecules
molecules, such as succinylcholine, which has quaternary bind directly to the HLA molecule or T-cell receptor (TCR) in
ammonium epitopes, can act as complete allergens. Epitope- a noncovalent manner and stimulate T cells. In the altered
specific antibodies can elicit type I, II, and III hypersensitivity repertoire model, small molecules bind directly to the MHC-
reactions (see below). Type IV (T cell–mediated) reactions can binding cleft to alter the specificity of peptide binding. This
occur through several mechanisms. Currently at least three models results in the presentation of novel peptide ligands that elicit an
are proposed—the hapten/prohapten model, the p-I model, and immune response. Fig. 48.1C shows the altered repertoire model
16
the altered peptide repertoire model (Fig. 48.1). Drugs or their in the case of abacavir (green), which binds to HLA-B*57:01
reactive metabolites undergo intracellular processing to generate (gray). The neoepitopes generated by abacavir are thought to
a pool of peptides, which then are presented in the context of be responsible for T-cell activation and the symptoms of
MHC as foreign peptides at the surface of the APC and elicit a hypersensitivity.
T-cell response (see Fig. 48.1A). The three current models for At least 24 HLA alleles have been identified in association
T-cell interactions with small drugs are shown in Fig. 48.1B. The with drug hypersensitivity, providing an insight into both the
prohapten/hapten model is based on the drug binding to a protein complexity of the immune response to drugs and our incomplete






Peptide A Peptide B T cell membrane
T cell receptor


Peptide A Peptide A
MHC MHC MHC

A APC membrane APC membrane APC membrane



T cell membrane T cell membrane
T cell receptor T cell receptor
T cell membrane
T cell receptor


Peptide A Peptide A Peptide B
MHC MHC MHC
APC membrane APC membrane APC membrane
B Hapten/prohapten model p-i model Altered peptide repertoire model


P9 (Val)
α1 α1


90˚
Pep-V Pep-V S116
V
Pe Pe Pe P P P Pep-V
p
V
V
D11 1 4 4 4 4 4
D114
D114
D11
β2MG I124 4 4 4
12 12 124
2
α2 Abacavir α2
C
FiG 48.1 Models of T-cell activation by small molecules. (A) Peptide selection and presentation
by MHC. (B) Mechanisms of T-cell activation by small molecules. (C) The abacavir–HLA-B*57:01
interaction demonstrates the altered peptide repertoire model. (From White KD, et al. Evolving
models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens,
and drug response. J Allergy Clin Immunol. 2015; 136: 219–34.)

CHaPTEr 48 Drug Hypersensitivity 651


17
understanding of the pathogenesis of these reactions. Although Heterologous responses to viral infections, in the context of
different organ systems are affected, typically the targets are the specific HLA alleles, have been implicated in severe skin reactions.
liver and skin; other organs, such as muscles (statin-induced T cell–mediated immunity can be modified by heterologous
myopathy) and neutrophils (clozapine-induced agranulocytosis), immune responses that are induced by pathogen-specific
can be affected, indicating a heterogeneity determined not just by T-effector-memory cells. Microbial pathogens, such as human
the associated HLA allele but also by the expression of homing herpes virus (HHV) and cytomegalovirus (CMV), among others,
16
receptors and T-cell clonotypes. Striking ethnic variations, such can establish lifelong infections and cellular latency. From time
as the high prevalence of HLA-B*15:02 in carbamazepine-induced to time, latent virus can activate transcriptional programs,
SJS/ TEN have been uncovered in Han Chinese, Thai, and Malay resulting in viral proteins that stimulate virus-specific T-cell
populations, but not in Japanese, Korean, or Northern Europeans memory.
(Table 48.1). Some HLA alleles are associated with reactions to The induction of this type of drug hypersensitivity requires
unrelated compounds, such as B*57:01, which has been linked an HLA risk allele, a primary infection with HHV or other viruses
to reactions to abacavir and flucloxacillin, with different organ in the context of that HLA risk allele, polyclonal expansion of
target effects. In contrast, specific HLA alleles may predispose to a CD8 T cells, and the induction of memory T cells. Upon exposure
particular type of organ injury regardless of the drug involved in to the drug, the interaction with HLA induces neoantigens, and
the reaction, as seen with HLA-DRB1*15:01–associated liver injury the peptide–MHC complex is recognized by the TCR, triggering
with lumiracoxib and co-amoxiclav. Although HLA-associated activation of T cells (Fig. 48.2). 16
reactions occur within hours to days of drug exposure, additional About 25% of women who are treated with carboplatin for
factors must influence these interactions because rechallenge gynecological cancers become sensitized after several exposures
with the drug may not reproduce the symptoms, and time lags and then have type I IgE-mediated reactions, most of which
have been observed. Such factors can be influenced by the dose. are anaphylactic. Although carboplatin triggers cell death at the
High doses of phenytoin can increase the rate of cutaneous erup- cancer tissue level, it can also bind to proteins as a hapten and
tions, which suggests that genetic polymorphisms influence drug then be presented to T cells, inducing sensitization and expansion
metabolic pathways leading to a potential increase in the risk for of B cells producing IgE that recognizes the hapten. Because
idiosyncratic reactions. A recent genome-wide association study women with BRCA1 and BRCA2 mutations seem more prone
23
has linked phenytoin reactions to allelic variations of cytochrome to carboplatin reactions after fewer exposures, it is possible
P450 isoform CYP2D9*3, with resulting decreased detoxification that these genetic mutations facilitate T-cell presentation. The
18
activity of CYP2C9. Evidence for the association of specific HLA presence of IgE antibodies in carboplatin-sensitized women can
alleles in penicillin/beta-lactam or sulfonamide reactions is less be detected in blood and by skin test. The IgE levels may be
clear, perhaps because these medications are metabolized into transient, being lost within 6–12 months of exposure. However,
several antigenic and allergenic components that interact with memory T and B cells remain active in these patients, allow-
multiple HLA types. The recently reported association between ing clonal expansion upon reexposure months to years later.
penicillin-induced type I reactions and HLA-DRA indicates the Patients with connective tissue disorders have an increased rate
24
need for strong phenotype association with the culprit drug and of reactivity to mAbs. Similarly, women exposed to endog-
19
adequate sample size. The strength of the association between enous and exogenous progesterone can develop progesterone
HLA alleles and certain drug reactions can be very strong, as hypersensitivity. 25
seen with abacavir and HLA-B*57:01. Patients expressing the
relevant allele can be patch tested before exposure to the drug. CLASSIFICATION OF DRUG
Prospective DNA screening has a 100% negative predictive value, HYPERSENSITIVITY REACTIONS
eliminating all potential reactors.
Drug reactions can be classified according to whether they occur
RISK FACTOR FOR DRUG ALLERGY: HOST, as a result of the mode of action (on target) or in some other way
16
PATHOGENS, AND DRUG RESPONSE (off target) (Fig. 48.3). Type A (on-target) reactions account for
over 80% of drug reactions. These are predictable, dose dependent,
Females are at higher risk for drug reactions, but the basis of and mirror the pharmacological action of the drug. Type B (off-
20
this propensity has not been studied. Quaternary ammonium target) reactions comprise 20% of drug reactions. These are not
compounds present in cosmetics are thought to be cross- predictable and may be immunological or nonimmunological.
reactive with neuromuscular-blocking agents and may increase Immunological reactions include B cell–dependent reactions,
the risk of drug reactions during general anesthesia. Patients such as antibody-mediated immediate and immune complex
with cystic fibrosis and those with multiple exposures to latex reactions (Gell and Coombs types I and III) and T cell–mediated
during surgery were found to have latex IgE sensitization and reactions (type IV). Nonimmunological hypersensitivity reactions
presented severe reactions, including asthma and anaphylaxis. include idiosyncratic reactions caused by individual predisposition
Decrease in aerosolized latex particles has effectively decreased (e.g., enzymatic defect) and activation of effector cells through
21
reactions. Because patients with cystic fibrosis have recurrent off-target receptors, such as the MRGPRX2 mast-cell receptor,
infections, these patients have an increased exposure to antibiot- a transmembrane G-coupled protein that can be activated by
22
ics and an increased rate of type I IgE-mediated reactions, quinolone medications, such as icatibant, and neuromuscular
including anaphylaxis. Increased rates of drug reaction have blocking agents, such as atracurium. 26
been observed in patients with human immunodeficiency virus Drug hypersensitivity can cause a spectrum of hypersensitivity
(HIV) infection, especially to trimethoprim-sulfamethoxazole. diseases. These were originally classified by Gell and Coombs
Low CD4 T cell counts as well as active immune suppression as into four types: antibody-dependent type I, II and III reactions
a result of antiretroviral therapy are thought to increase the risk and T cell–mediated type IV reactions. More recently, in the
of reactions. light of developments in T-cell biology and to take account of

652 ParT FivE Allergic diseases



TABLE 48.1 HLa–associated Drug Hypersensitivity reactions
adverse Drug Positive Predictive Negative
Drug reaction associated HLa alleles value Predictive value Populations
Abacavir HSS B*57:01 55% 100% European, African
Carbamazepine SJS/TEN B*15:02 3% 100% Han Chinese, Thai,
Malaysian, Indian
B*15:11 Korean, Japanese
B*15:18, B*59:01, C*07:04 Japanese
A*31:01 Japanese, Northern
European, Korean
DRESS 8.1 AH (HLA A*01:01, Cw*07:01, White
B*08:01, DRB1*03:01,
DQA1*05:01, DQB1*02:01)
A*31:01 0.89% 99.98% European
A*31:01 0.59% 99.97% Chinese
A*31:01 Northern European,
Japanese, Korean
A*11 and B*51 (weak) Japanese
MPE A*31:01 34.9% 96.7%
Allopurinol SJS/TEN, DRESS B*58:01 (or B*58 haplotype) 3% 100% in Han Han Chinese, Thai,
Chinese European, Italian,
Korean
Oxcarbazepine SJS/TEN B*15:02 and B*15:18 Han Chinese, Taiwanese
Lamotrigine SJS/TEN B*15:02 (positive), B*15:02 (no Han Chinese
association)
Phenytoin SJS/TEN B*15:02 (weak), Cw*08:01, Han Chinese
DRB1*16:02, CYP2C9*3
DRESS/MPE B*13:01 (weak), B*5101 (weak), Han Chinese
CYP2C9*3
Nevirapine SJS/TEN C*04:01 Malawian
DRESS DRB1*01:01 and DRB1*01:02 18% 96% Australian, European,
(hepatitis and low CD41) and South African
Cw*8 or Cw*8-B*14 haplotype Italian and Japanese
Cw*4 Black, Asian, White, and
Han Chinese
B*35, B*35:01, B*35:05 16% 97% Asian
Delayed rash DRB1*01 French
Cw*04 African, Asian,
European, and Thai
B*35:05, rs1576*G Thai
CCHCR1 status
Dapsone HSS B*13:01 7.8% 99.8%
Efavirenz Delayed rash DRB1*01 French
Sulfamethoxazole SJS/TEN B*38 European
Amoxicillin-clavulanate DILI DRB1*15:01, DRB107 (protective), European
A*02:01, DQB1*06:02, and
rs3135388, a tag SNP of
DRB1*15:01-DQB1*06:02
Lumiracoxib DILI DRB1*15:01-DQB1*06:02- International, multicenter
DRB5*01:01- DQA1*01:02
haplotype
Ximelagatran DILI DRB1*07 and DQA1*02 Swedish
Diclofenac DILI HLA-B11, C-24T, UGT2B7*2, IL-4 European
C-590-A
Flucloxacilin DILI B*57:01, DRB1*01:07- 0.12% 99.99% European
DQB1*01:03
Lapatinib DILI DRB1*07:01-DQA2*02:01- International, multicenter
DQA1*02:01

DILI, drug-induced liver injury; DRESS, drug-induced reactions with eosinophilia and systemic symptoms; HSS, hypersensitivity syndrome; MPE, maculopapular eruption; SJS,
Stevens-Johnson syndrome; SNP, single nucleotide polymorphism; TEN, toxic epidermal necrolysis.
(From White KD, et al. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J Allergy Clin Immunol. 2015;
136: 219–34.)

CHaPTEr 48 Drug Hypersensitivity 653



Autologous HLA T cell
risk allele
1 2


3
Primary HHV
infection


T EM cells persist
in tissue
Patient is exposed
to drug
Model of Effector
heterologous Immunity memory T cell
4




Cross-reactive HHV or other Endogenous
TCR pathogen peptide
HHV peptide Drug 5


HHV-specific T cells
EM
recognize endogonous peptide
presented in context of HLA +
drug to elicit T cell response

T EM cell
A


Antiviral sensitization phase Antiviral T cell proliferation Antiviral effector phase
T cell membrane Effector T cell Virus specific memory T cell
T cell receptor T cell receptor T cell receptor


Viral peptide Viral peptide
MHC MHC
Virus specific memory T cell
APC membrane Infected cell
T cell receptor






T cell membrane
T cell receptor
T cell membrane T cell membrane
T cell receptor T cell receptor


Self peptide Self peptide Self peptide
MHC MHC MHC
APC membrane APC membrane APC membrane
Hapten/prohapten and heterologous p-i model and Altered peptide repertoire model and
B immunity model heterologous immunity model heterologous immunity
FiG 48.2 Generation of heterologous immune responses that contribute to the pathogenesis of T cell–mediated adverse drug
reactions (ADRs). (A) Timeline of the generation of ADRs. (B) Integration of the models of T-cell activation by small molecules and
heterologous immunity. (From White KD, et al. Evolving models of the immunopathogenesis of T cell-mediated drug allergy: the
role of host, pathogens, and drug response. J Allergy Clin Immunol. 2015; 136: 219–34.)

654 ParT FivE Allergic diseases


Adverse drug reactions
On-target Off-target
(Type A; >80% ADRs) (Type B; <20% ADRs)

Dose-dependent
phenotype is Pure T-cell Antibody or non-
Mechanisms predictable based on Non-immunologic (HLA risk allele present) (with or without T-cell help)
mediated
antibody mediated
pharmacologic action
activation of off-
(Type I-III)
(Type IV)
(ADME genes, drug
target receptor
transporters, receptors)
Phenotype Pharmacologically Pharmacological Immunologically
and
immunological
contributors
mediated
mediated
FiG 48.3 Adverse drug reactions can result from either on-target or off-target interactions between
the drug and cellular components. (From White KD, et al. Evolving models of the immunopatho-
genesis of T cell-mediated drug allergy: the role of host, pathogens, and drug response. J Allergy
Clin Immunol. 2015; 136: 219–34.)



28
the varied presentation and heterogeneity of T cell–mediated inhibitory mechanisms. In this type of reaction, symptoms
reactions, type IV reactions have been divided into four pheno- occur within seconds of parenteral drug administration and
27
types: types IV a, b, c, and d. Because the maturation of B cells within minutes of oral administration; both depend on the
and expansion to plasma cells producing Igs depend on the mediators released from mast cell and basophil granules. Pre-
interaction of B cells with T cells in the presence of cytokines formed mediators, such as histamine, tryptase and tumor necrosis
and costimulatory molecules, drugs can induce IgE and IgG factor-α (TNF-α) are released first, prostaglandins (PGs) and
antibodies and induce type I and type IV reactions in the same leukotrienes (LTs) are generated from membrane arachidonic
patient (Fig. 48.4). Type I reactions result from the release of acid within minutes, and newly generated cytokines are released
inflammatory mediators from mast cells and basophils and often within hours of the initiation of the reaction. Pruritus, urticaria,
present with urticarial (see Fig. 48.4A) and systemic reactions, and angioedema are followed by gastrointestinal (GI) symptoms,
such as anaphylaxis. such as nausea, vomiting, and diarrhea; hoarseness; shortness
of breath and wheezing; and dizziness, which can occur in rapid
ANTIBODY-MEDIATED DRUG succession. In highly sensitized individuals, systemic reactions
29
HYPERSENSITIVITY REACTIONS can occur within minutes after intravenous exposure; hypotension,
laryngeal edema, and death have occurred following administra-
Type I IgE-Mediated Hypersensitivity tion of antibiotics and chemotherapeutic agents as a result of
Drugs with hapten-like features bind to soluble and cell-bound cardiovascular collapse or asphyxia. Although skin is the organ
proteins, inducing a humoral response, which can lead to IgE most commonly involved, and itching is a typical sign of the
antibodies. Chimeric antibodies bearing foreign determinants initial reaction, ≈60% of anaphylaxis-related deaths are due to
can also elicit IgE responses. During the sensitization phase at asphyxia. Anaphylaxis is diagnosed when two or more organs
the initial drug exposure, IgE antibodies are generated; these are affected, when there is a sudden drop of blood pressure after
bind to FcεRIα on mucosal and connective tissue mast cells and exposure to a known drug allergen, or when there is laryngeal
30
blood basophils. B cells mature into IgE-secreting cells when edema (Table 48.2). Atypical symptoms include pain, which
activated by T cells in the presence of IL-4/IL13 and CD40/ has been reported in patients with anaphylactic reactions to
31
CD40L. The sensitization phase typically requires several days taxanes, oxaliplatin, and mAbs, such as rituximab. The mediators
and patients do not develop reactions during the first exposure. responsible for pain have not been identified within mast cells
Upon re-exposure, crosslinking of FcεRIα receptors on sensitized or basophils. It has been suggested that activation of the kinin
31
mast cells and basophils by polyvalent haptenated drug allergens pathway generating bradykinins may be responsible. The severity
causes cell activation and degranulation and the release of of the reactions is graded according to the extent of the symptoms.
inflammatory mediators that are responsible for the clinical Reactions confined to the skin or one organ are considered mild
symptoms. Although IgE is produced in small amounts compared and do not require epinephrine treatment. Reactions that involve
with IgG, most IgE is found on tissue mast cells in different two organs or are associated with vital sign changes are considered
organs, including blood vessel walls, accounting for the systemic moderate and severe, respectively, and treatment with epinephrine
32
nature of reactions when mast cells are activated. Small amounts is recommended. Elevated tryptase levels in blood are found
of drug can induce severe systemic reactions, including anaphy- in patients with grade 2 and 3 reactions, indicating the involve-
laxis, depending on the patient’s sensitization and the amount ment of mast cells. Depending on the magnitude of the reaction,
of specific IgE directed against the drug. The relationship between tryptase levels return to baseline, usually within days, but
8
the amount of IgE and the dose of drug allergen can determine sometimes remain elevated for a few weeks after the reaction.
the induction of either cell activation or desensitization, activating Patients with severe anaphylactic reactions induced by drugs

CHaPTEr 48 Drug Hypersensitivity 655





















A B




















C D
FiG 48.4 Examples of hypersensitivity reactions. (A) Type I: Urticaria. (B) Type IVc: maculopapular
rash. (C) Type IVc: erythema multiforme. (D) Type IVc: mucosal involvement (Stevens-Johnson
syndrome [SJS])



TABLE 48.2 Severity Grading System of reactions on first exposure to cephalosporins because these
immediate Type i Hypersensitivity reactions antibiotics share epitopes that can bind beta-lactam–specific IgE.
Patients with cancer who are exposed to one platin, such as
Grade Severity Description carboplatin, can react on first exposure to another platin, likely
34
1 Mild Symptoms are limited to the skin (e.g., as a result of shared cross-reactive epitopes. Not all patients
flushing) or involve a single organ/system reacting with symptoms of type I hypersensitivity to taxanes,
and are mild (e.g., mild back pain). such as paclitaxel, have evidence of IgE sensitization. Reactions
2 Moderate Symptoms involve at least two organs/ to cremophor, the diluent of paclitaxel, have been implicated in
systems (e.g., flushing and dyspnea), but some reactions. 35
there is no significant decrease in blood
pressure or oxygen saturation. Non–IgE-Mediated Type I Hypersensitivity Reactions
3 Severe Symptoms typically involve at least two
organs/systems, and there is a significant The definition of type I hypersensitivity reactions has been
decrease in blood pressure (systolic expanded to include reactions with similar symptoms without
≤90 mm Hg and/or syncope) and/or evidence of IgE. These are caused by the presence of multiple
oxygen saturation (≤92%). activating receptors on mast cells and basophils. Examples include
(Adapted from Brown SGA, et al. Clinical features and severity grading of anaphylaxis. muscle relaxants and quinolones, which can induce anaphylactic
J Allergy Clin Immunol. 2004; 114: 371–376.) reactions with release of mast cell mediators, including tryptase,
36
without evidence of IgE sensitization, indicating that mecha-
should be evaluated for mastocytosis if their tryptase levels do nisms other than IgE-mediated degranulation can trigger these
not normalize after the reaction. Common causes of IgE-mediated effector cells. One candidate for the receptor involved is the
26
allergic drug reactions include: beta-lactam antibiotics (penicillins G-coupled receptor MRGPRX2. These reactions were previously
and cephalosporins); chemotherapeutic agents, such as carbo- called “pseudoallergic reactions.” The symptoms are identical to
platin, cisplatin, and oxaliplatin; and both chimeric and non- IgE-mediated reactions and include hives, angioedema, respiratory
33
chimeric mAbs. Cross-reactivity occurs with beta-lactam distress, GI symptoms, and hypotension; epinephrine is required
medications; patients sensitized to penicillins can be subject to if the reactions are moderate or severe. Vancomycin can induce

656 ParT FivE Allergic diseases


histamine release from mast cells without IgE involvement, in heparin and PF4. These immune complexes activate platelets,
a dose-dependent fashion. releasing PF4 and causing platelet destruction. Mild throm-
bocytopenia can occur in up to 5% of patients treated with
heparin, and 10% develop paradoxical thrombosis, which can be
CLiNiCaL PEarLS life-threatening.
Vancomycin Red Man Syndrome Type III Reactions
• Presents as erythema, flushing, rarely hypotension Immune complexes form during normal immune responses
• Histamine elevated in urine and blood without any clinical consequences. Immune complexes can also
• Direct mast cell activation and release of histamine be formed during treatment with drugs that form hapten–carrier
• Can be potentiated by mast cell activation agents (e.g., opioids) complexes or with chimeric or humanized proteins, such as mAbs.
• Treatment: slow infusion, dose reduction, and antihistamines
These immune complexes are typically cleared by binding to
the FcγRI or complement receptor CR1 on reticuloendothelial
cells. Decreased clearance because of high levels complement
Type II Reactions: IgG-Mediated Cytotoxic Reactions defects or aberrant FcγRI function can lead to type III reac-
Type II and type III reactions result from the formation of tions. Recently a low copy number of FcγRIII was shown to
complement-fixing IgG antibodies, typically of the IgG1 and be associated with glomerulonephritis. Type III reactions can
IgG3 subclasses, which bind to Fcγ receptors (FcγRI, IIa, and present as small vessel vasculitis and/or serum sickness. Serum
IIIa) on macrophages, natural killer (NK) cells, granulocytes, sickness was first described when heterologous serum or foreign
and platelets, or form immune complexes and interact with serum was used for passive immunization. Antibodies appear
complement receptors on these cells. In type II reactions, the in 4–10 days and react with drug antigens, forming soluble
antibody is directed against antigens on the cell membrane, or circulating immune complexes. These immune complexes capture
immune complex activation occurs on the cell surface. Both complement and are deposited in postcapillary venules, attract-
events can lead to cell destruction or sequestration; affected cells ing leukocytes by interacting with FcγRIII, eventually inducing
include erythrocytes, leukocytes, platelets, and bone marrow the release of proteolytic enzymes and tissue damage. Non-
precursor cells. The development of type II reactions requires protein drugs, such as cefaclor, trimethoprim-sulfamethoxazole,
an IgG immune response to a drug hapten–carrier complex after cephalexin, amoxicillin, NSAIDs, and diuretics, are the most
high-dose and prolonged treatment, as is seen in penicillin and commonly implicated drugs, but these reactions can also occur
cephalosporin reactions, where the reaction is caused by comple- with protein drugs, such as mAbs.
ment fixation. IgM antibodies are sometimes implicated, as well The incidence of hypersensitivity vasculitis is 10–30 cases
as autoantibodies reactive to the carrier molecule. These immune per million per year. The presentation can include fever, skin
reactions can persist after cessation of the drug. Another type rash, myalgia, arthralgia, and lymphadenopathy. Palpable
of type II reaction occurs when the drug or its metabolites adhere purpura may be present in legs, with lesions that can coalesce
to the erythrocyte or platelet surface, creating a new antigenic and ulcerate. The GI tract, kidneys, and joints can be affected:
complex with the cell membrane. Quinine-induced thrombo- the prognosis depends on the extent of systemic involvement.
cytopenia occurs when IgG or IgM antibodies react with Patients taking systemic steroids may present with a milder form
membrane epitopes, such as GPIIb/IIIa (fibrinogen receptor) or of reaction, with fewer manifestations. Renal biopsy reveals
GPIb/IX (von Willebrand factor receptor); this only happens IgA-containing immune complexes, similar to those found in
37
when the drug in present in soluble form. This interaction IgA nephropathy.
results in platelet destruction and thrombocytopenia. Similar
reactions occur with sulfonamides and quinidine. The antibody- Type IV Reactions
coated cells can be sequestered in the liver and spleen by Fcγ or Cell-mediated reactions are now subdivided on the basis of the
complement receptor binding. Rarely, intravascular destruction cytokines produced by T cells and the type of effector immune
occurs via complement-mediated lysis. cells induced by these cytokines, such as eosinophils and
Penicillin, cephalosporins, levodopa, methyldopa, quinidine, neutrophils.
and some antiinflammatory drugs can induce hemolytic anemia, Type IVa reactions correspond to classic T helper 1 (Th1)–type
which presents with fatigue, pallor, shortness of breath, tachy- immune reactions, in which Th1 cells activate macrophages by
38
cardia, and dark urine. Direct and indirect Coombs tests are secreting interferon-γ (IFN-γ) and other cytokines (TNF-α,
positive, unconjugated levels of bilirubin are elevated, haptoglobin IL-12). These Th1 cells drive the production of the complement-
is decreased, and hemoglobinuria is present. Thrombocytopenia fixing antibodies involved in types II and III reactions and are
can occur with quinine, quinidine, sulfonamide antibiotics, and costimulators of pro-inflammatory responses, and CD8 T-cell
39
mAbs. Drug-induced thrombocytopenia usually occurs after responses. Examples of type IVa reactions include tuberculin
5–8 days of exposure but may occur after a single exposure reactions, contact dermatitis (with activated CD8 cells) and
in a sensitized patient. The typical presentation is petechial sarcoidosis (with granuloma formation and monocyte
hemorrhages in skin and mucosal bleeding, sometimes associated activation).
with GI and urinary bleeding. Intracranial bleeding is rare, and Type IVb reactions correspond to type 2 immune responses
the platelet count returns to normal 3–5 days after the drug is with IL-4, IL-13, and IL-5 cytokines, which promote IgE- and
discontinued. In heparin-induced thrombocytopenia, FcγRIIa IgG4-producing B cells, mast cells, and eosinophils. IL-5 produc-
receptors on platelets bind IgG and IgM immune complexes tion leads to eosinophilic inflammation, which is seen in many
of heparin and platelet factor 4 (PF4), a CXC chemokine drug-induced hypersensitivity reactions, including DRESS. Type
usually stored in platelet α-granules. About 50% of patients I reactions are linked to these reactions since IgE is produced
treated for >7 days with heparin develop antibodies against as a result of IL-4 and IL-13 secretion by Th2 cells. Maculopapular

CHaPTEr 48 Drug Hypersensitivity 657




Keratinocyte




ICAM-1 MCH II
Keratinocyte
cell necrosis
Perforin

Hydropic
degeneration
LFA-1 TCR Granzyme B
Eosinophils

Mononuclear
cell infiltrate
A B Drug-specific CD4 + T cell
FiG 48.5 (A) Typical histology of a maculopapular exanthema (MPE). Note the focal keratinocyte
necrosis, often in close apposition of T cells (which have cytotoxic potential and are perforin-
positive). (B) Schematic representation of CD4-mediated killing of activated keratinocytes, which
express MHC class II and intercellular adhesion molecule 1 (ICAM1). (Modified from Pichler WJ.
Delayed drug hypersensitivity reactions. Ann Intern Med. 2003; 139: 683–693.)




exanthema (MPE) (Fig. 48.5), infections with nematodes, asthma, KEY CONCEPT
and rhinitis are considered part of this group of reactions.
Stevens-Johnson Syndrome (SJS) and Toxic
KEY CONCEPT Epidermal Necrolysis (TEN)
Drug-Induced Reactions With Eosinophilia and SJS
Systemic Symptoms (DRESS) Syndrome • Detachment <10% of body surface area (BSA), plus
• Widespread macules or flat atypical target lesions
• Drug-induced
• Anticonvulsants, antidepressants, non-antimicrobial sulfones/sul- Overlap SJS-TEN
fonamides, nonsteroidal antiinflammatory drugs (NSAIDs), angio- • Detachment 10–30% of BSA, plus
tensin-converting enzyme (ACE) inhibitors, beta-blockers, and • Widespread macules or flat atypical target lesions
antibiotics
• Systemic disorder TEN
• Hematological abnormalities (eosinophilia, atypical lymphocytes)
• Multiorgan involvement • Detachment of >30% of BSA, plus
• kidney, liver, heart, lung, thyroid • Widespread macules or flat atypical target lesions
• Hypogammaglobulinemia • Detachment >10% of BSA with large epidermal sheets and without
• Lymphadenopathy any macules or target lesions
• Skin involvement

Type IVc reactions result from T-cell migration to tissues and DIAGNOSIS OF DRUG HYPERSENSITIVITY:
direct damage or killing of tissue cells, such as hepatocytes, CLINICAL SYMPTOMS AND HISTORY
through perforin-, granzyme B– and Fas-ligand–dependent
mechanisms, with the recruitment of other inflammatory cells, A detailed history is the most important element in the diagnosis
such as monocytes, eosinophils, and neutrophil polymorpho- of all drug reactions; it is necessary to determine the type of
nuclear leukocytes. These reactions present as delayed hyper- reaction and the test required to confirm the diagnosis and to
sensitivity reactions, such as SJS, TEN, and contact dermatitis establish management and treatment plans. Type I IgE- and
(Fig. 48.4B, C and D). non–IgE-mediated reactions occur with a rapid onset, within
Type IVd reactions occur when T cells activate sterile neu- minutes of drug exposure, which can present as pure skin
trophilic inflammation, as in acute generalized exanthematous manifestations or as involvement of other organs. Sudden onset
pustulosis (AGEP). T cells producing CXCL8 and granulocyte of hypotension can be the first manifestation during anesthesia
macrophage–colony-stimulating factor (GM-CSF) recruit leu- or when infusing high doses of chemotherapy drugs, such as
kocytes, and the cytokines then prevent their apoptosis. Behçet taxanes. Tryptase levels help determine the mechanism of the
disease, linear IgA bullous dermatosis, and pustular psoriasis reaction and its extent. The basophil activation test (BAT) has
are examples of type IVd reactions (Fig. 48.6). been performed for several drugs yielding different results;

658 ParT FivE Allergic diseases



A



















C















B

FiG 48.6 Clinical pictures and immunohistologies of drug-induced exanthema. (A) Pustular drug
eruption (acute generalized exanthematous pustulosis [AGEP]). (B) Intraepidermal, nonfollicular
pustules. (C) A patch test reaction leading to a pustular reaction. (From Schaerli P, Britschgi M,
Keller M, et al. Characterization of human T cells that regulate neutrophilic skin inflammation. J
Immunol. 2004; 173: 2151–8.)


Tryptase
the test is limited by the patient’s number of basophils and
premedications because basophils undergo apoptosis in the Activation of mast cells during type I IgE and non-IgE reactions
presence of steroids. BAT seems to be a promising test for leads to release of granule mediators, including tryptase, which
diagnosis of platin hypersensitivity. can be measured in serum. After secretion from tissue mast cells,
Delayed-type IV reactions are characterized by skin rashes. tryptase requires 30 minutes to reach peripheral blood. Its levels
The differential diagnosis includes viral exanthema, other infec- peak in 2–4 hours after an anaphylactic event, but in patients
tions, food allergy, and graft-versus-host reactions. Severe reactions, with marked elevations above the normal range (11.4 ng/mL),
such as DRESS, SJS, and TEN, are associated with blood eosino- the levels may remain elevated for >6–8 hours and in extreme
philia, leukocytosis, and biochemical changes, such as elevated cases for several days.
liver enzymes. Evidence of systemic involvement should be
determined with whole-body skin evaluation, and the presence Skin Testing, Specific IgE, and Challenges
of fever, lymphadenopathy, and organomegaly should be noted. Skin testing for penicillin has been available for several
Nikolsky sign should be elicited because its presence can indicate years and its predictive value is >97%, meaning that patients
a severe bullous condition. Danger signs without skin involvement, with negative skin tests are not at risk for anaphylaxis.
such as malaise, fever, photophobia, abdominal pain, and alterations Patients sensitive to minor determinants may not be identified
in GI and urinary function, can be early signs of severe drug- by current reagents in the United States because none of the
induced syndromes. Type 1 reactions occur within an hour of tests for minor determinants has been approved. Skin testing
exposure, but in patients receiving premedication with antihis- for cephalosporin sensitivity has not been standardized but
tamines and steroids, onset of urticaria or hypotension may take non-irritant concentrations are available for some of them
several hours. Type IV reactions are typically delayed and appear (Table 48.3) as well as for other antibiotics. The sensitivity and
several hours after drug exposure. However, in highly sensitized specificity of these tests have geographical differences, possibly
individuals, symptoms can occur within 1–2 hours. because of different rates of exposure. Skin testing to chemo-
Diagnostic tools to identify the culprit drug are limited. They therapy and mAbs can be done when an IgE-mediated reaction
include skin testing and patch testing, but these tests are not is suspected, ideally 2–4 weeks after the reaction to minimize
standardized and have variable reliability. false-negative results caused by natural desensitization. The

CHaPTEr 48 Drug Hypersensitivity 659



TABLE 48.3 Nonirritating Concentrations SPECIFIC DRUG HYPERSENSITIVITY
for 15 Commonly Used antibiotics
NiC (as KEY CONCEPT
Dilution From No. of Drug Allergy
antimicrobial Full-Strength Full-Strength Patients
Drug Concentration Concentration) Tested General Evaluation of Drug allergy
Cefotaxime 100 mg/mL 10 −1 25 • History: Indication for drug use, association with viral/bacterial
infection
Cefuroxime 100 mg/mL 10 −1 25 • Physical examination
Cefazolin 330 mg/mL 10 −1 25
Ceftazidime 100 mg/mL 10 −1 25 • Blood count/differential, Liver function tests
• Serum tryptase
Ceftriaxone 100 mg/mL 10 −1 30
Tobramycin 40 mg/mL 10 −1 25 • Skin testing
• Patch testing/Delayed reading of skin test
Ticarcillin 200 mg/mL 10 −1 25
Clindamycin 150 mg/mL 10 −1 25 • Specific igE, basophil activation test
• Genotyping
Gentamicin 40 mg/mL 10 −1 30
Cotrimoxazole 80 mg/mL 10 −2 25
Levofloxacin 25 mg/mL 10 −3 25 Specific Evaluation of Drug allergy
Erythromycin 50 mg/mL 10 −3 25 • Name of the drug, ingredients, preservatives
Azithromycin 100 mg/mL 10 −4 30 • First exposure
Nafcillin 250 mg/mL 10 −4 25 • How long ago did the reaction occur?
• re-exposure: Has the patient been exposed to the drug or a related
(From Empedrad R, et al. Nonirritating intradermal skin test concentrations for drug?
commonly prescribed antibiotics. J Allergy Clin Immunol. 2003; 112: 629–630.) • Other drugs administered at the same time
• associated narcotics
• Symptoms and signs of the reaction
negative predictive value (NPV) for carboplatin is very high • Timing of symptoms relative to the drug exposure
with recent exposure, and patients with negative skin test results
24
do not develop anaphylaxis, but the NPV is not known for Underlying Condition for which the Drug was Prescribed
most mAbs. In a study of patients who needed to be desensitized • Similar symptoms unrelated to the drug exposure (urticaria)
to trastuzumab, infliximab, or rituximab, only 13 of 23 patients • Treatment and response to treatment (epinephrine)
had positive skin test results. 40 • Timing of resolution
Drug challenges are considered the gold standard for type I
reactions and should be performed to confirm tolerance in all
patients with negative skin test results. Such challenges can trigger Beta-Lactams
mild, acute, and/or delayed reactions but are considered extremely Penicillins, aminopenicillins, and cephalosporins can induce type
safe. Cofactors, such as viral infections, can influence these tests, I, II, III, and IV reactions and are the medications most often
and a patient with negative results of the skin test and challenge implicated in drug hypersensitivity. These drugs are small chemical
can present a recurrent skin rash if he or she takes the same compounds with a common beta-lactam core and different side
drug during a viral infection. Patients with a history of mild- chains (Fig. 48.7). Drug antigens are created through hydrolysis
to-moderate reactions and a remote history of drug allergy, who when in contact with blood or other proteins. Penicilloyl is the
have negative skin test results, can be safely challenged without dominant (or major) drug allergen responsible for most type I
an increased risk of anaphylaxis. 41 reactions. Minor components include penilloate and penicilloate,
which have been implicated in severe anaphylactic reactions.
Patch Testing, Delayed Intradermal Reading, and Patients with a history of suspected penicillin allergy can be
Lymphocyte Transformation Tests evaluated by skin testing with major and minor determinants.
Skin testing with percutaneous and intradermal drug injections Over 90% of individuals with a history of penicillin allergy have
can provoke a maculopapular reaction at the site of injection in no evidence of IgE sensitization and can safely be reexposed to
24–96 hours, mimicking the systemic reaction induced by the beta-lactams with a very low rate of adverse reaction upon
drug. These tests have been used to determine which drugs induce reexposure. This contrasts with chemotherapy drugs, such as
34
42
the various type IV reactions, such as MPE. Patch testing, with carboplatin. Once a patient has experienced a reaction, subse-
application of the drug allergens to stripped skin after absorption quent reexposure typically induces a reaction. Although both
of superficial T cells and other effector cells, is used to identify medications are haptens and probably trigger T-cell activation
drugs responsible for contact dermatitis and other type IV and B-cell expansion to produce IgE antibodies in a similar
reactions. Commercial reagents are available for common contact fashion, there are some important differences. The route of
allergens and provide high specificity for metal allergies, such administration of chemotherapy drugs is typically intravenous,
as nickel allergy. However, for some diseases, such as MPE, DRESS, the doses are high, and the interval times are short, with repetitive
and AGEP, the sensitivity is considered low. The lymphocyte doses administered over few weeks to months. In contrast,
transformation test relies on the activation and proliferation of beta-lactam antibiotics are used for short periods during acute
T cells cultured in the presence of drug allergens. Reactivity is infections, so memory T and B cells may not be reactivated during
3
measured by H-thymidine incorporation after several days in reexposure. If taken orally, repeated exposure to beta-lactams
43
culture, or by enzyme-linked immunospot (ELISPOT), 5(6)-car- may generate tolerance instead of allergy. Patients who have a
boxyfluorescein N-hydroxysuccinimidyl ester (CSFE) staining, history of penicillin allergy and are admitted to hospital have
or CD69 upregulation. These tests may prove valuable in the increased risks of complications from use of second-line antibiot-
5
future but have not yet been standardized. ics, with increased days of hospitalization and health care costs.

660 ParT FivE Allergic diseases



H H
ROCHN S ROCHN S R H H H
N N N S
O O X O N
CO 2 H CO H O
2
Penicillins Cephalosporins CO Na
2
NH 2
O OH Carrier
R 1 S protein
R N
N O Hydrolysis
O CO 2 H
CO 2 H
Clavulanic acid
Penems (an oxapenem)
H H H S
R N
H RHN N CO Na
HO O H 2
R HN O Penicilloyl
N N –
O O SO 3 Carrier
CO 2 H
Carbapenems Monobactams protein
FiG 48.7 Drug antigens: beta-lactams.


The incidence of allergy to specific side-chain epitopes in beta- TABLE 48.4 Local anesthetics
lactam compounds has increased in the last 20 years as a result
of increased use of aminopenicillins and cephalosporins. 44 Benzoic acid Esters amides and Other
Benzocaine Bupivacaine
Radio Contrast Media Butamben picrate Dibucane
Reactions to iodinated and noniodinated contrast media are Chloroprocaine Duclonine
relatively rare, and their mechanisms are not well understood, Procaine Etiodocaine
although premedication can protect affected patients. Some of Proparacaine Levobupivacaine
Tetracaine
Lidocaine
these reactions are thought to be caused by activation of the Cocaine Mepivacaine
complement pathway with generation of the anaphylatoxins C3a Prilocaine
and C5a, which can bind to complement receptors on mast cells Ropivacaine
and induce mediator release. The newer nonionic, low-osmolality
contrast media products can also be involved in type I reactions;
in a few cases, positive skin test results suggest an IgE-dependent
mechanism. 45 range from benign maculopapular rashes to SJS/TEN.
47
Patients with HIV and cystic fibrosis are at high risk. Sulfa-
Perioperative Anaphylaxis methoxazole metabolism and protein adduct formation stimulates
Patients who have anaphylactic reactions during surgery are at T cells and induces delayed reactions. Nonantibiotic sulfonamides
risk for reactions during future operations. Evaluating the drug have a similar chemical structure, but their stoichiometry
responsible for these reactions is complex because multiple drugs is different because of a shared arylamine group being in a
48
are used in patients undergoing surgery. Having an accurate different position. In practice, patients with sulfonamide
account of the initial symptoms of the reaction and changes in antibiotic hypersensitivity can be safely exposed to non-antibiotic
vital signs and blood pressure in relation to the timing of each sulfonamides. 49
drug used is key to an accurate diagnosis. Neuromuscular-blocking
agents, antibiotics, and latex are the most common causes of Aspirin
reactions, with cephalosporins often being implicated. In most Reactions to NSAIDs can induce respiratory and skin reactions
cases, skin testing will identify the culprit drug, allowing safe as well as anaphylaxis. Up to 10% patients with asthma may
drugs to be chosen for future procedures. 47 have aspirin-exacerbated respiratory disease and react to aspirin
and other NSAIDs. They typically have nasal polyps, anosmia,
Local Anesthetics and severe asthma. The pathophysiology of these reactions involves
Reactions to local anesthetics are rare, and most are not IgE- decreased production of PGE 2 and increased production of LTs,
mediated. Idiosyncratic reactions include the proarrhythmic which are found in urine and other secretions at baseline and
effects of lidocaine and other amide drugs. There is no cross- after aspirin challenge. Aggregates of leukocytes and platelets
reactivity between benzoic ester and amide drugs, so patients are observed in the peripheral blood of these patients. It is
who have reacted to one group generally tolerate drugs from possible that platelets contribute to the pathogenesis of the
the other group (Table 48.4). syndrome. Patients with aspirin-exacerbated respiratory disease
(AERD) cannot tolerate any COX-1 inhibitor but can tolerate
Sulfonamides COX-2 inhibitors indicating a common mechanism of action
50
Delayed reactions to sulfonamide antibiotics are common, but for all NSAIDs (Fig. 48.9). Urticaria and angioedema can
all types of reactions have been seen (Fig. 48.8A). Delayed reactions be induced by aspirin and NSAIDs; patients can also present

CHaPTEr 48 Drug Hypersensitivity 661


Sulfonamide antibiotics reactions Sulfonamide antibiotics structure
Arylamine group
O O N O CH 3 O O N N CH O CH 3
S CH 3 N S 3 N SO NH
Serum sickness H N N H H N SO NH N H N N H S H 2 2 N CH 3
2
2
Immediate Rash/fever 2 Sulfamethoxazole Sulfamerazine 2 Sulfamethizole Sulfamoxole
hypersensitivity +systemic CH 3 O
Urticaria/ symptoms H N SO 2 NH N NH 2 SO NH N H N SO NH S
2
2
2
2
anaphylaxis DRESS N CH 3 CH 3 CH 3 N
Sulfamethazine Sulfisoxazole Sulfapyridine
Non-antibiotic sulfonamides structure
O Cl
Delayed Sulfonamide Furosemide O Celecoxib
maculopapular antibiotics SJS/TEN Hydrochlorothiazide HN S O Acetazolamide
rash Sulfasalazine NH 2 Sumatriptan
O Glyburide
OH
A B
FiG 48.8 Reactions to and structures of sulfonamide antibiotics (A). Structures of sulfonamide
antibiotics (B). (Adapted from Tilles, SA, Slatore, CG. Hypersensitivity reactions to non-beta-lactam
antibiotics. Clin Rev Allergy Immunol. 2003; 24: 221–8.)



ASPIRIN-TOLERANT AERD


• Platelets not adherent to leukocytes • Platelets adherent to leukocytes
• Leukocyte adhesion receptors upregulated


• Few eosinophils in tissue or blood • Increased eosinophil numbers in tissue and blood



• Few mast cells in tissue • Increased mast cell numbers in tissue




• PGE (signaling through EP ) blocks 5-LO • Less blockade of 5-LO by PGE (due to less EP )
2
2
2
2
Very little LTA produced Leukocytes LTA is produced, passed to adherent platelets
4
4
Baseline • Platelet-derived TXA downregulates LTC S Platelets • Platelet-derived TXA downregulates LTC S
4
2
4
2
Very little LTA converted to cysLTs
Some LTA converted to cysLTs by adherent platelets
4
4
Low baseline cysLT levels OUTCOME High baseline cysLT levels
• PGE level stays constant through COX-2 Leukocytes • PGE 2 production decreases in absence of COX-2
2
EP signaling keeps 5-LO inactive
PGE + less EP signaling = 5-LO is activated
Following COX-1 inhibition • TXA2 levels Platelets • TXA levels
2
2
2
Very little LTA produced
LTA is produced
4
4
2
LTC S is upregulated
LTC S is upregulated
4
4
production still low and few adherent
• LTA converted to cysLTs by eosinophils, mast cells, or
• LTA 4
4
platelets to convert it to cysLTs
cysLT levels stay constant OUTCOME adherent platelets
cysLT levels rise; respiratory reaction occurs
FiG 48.9 Summary of the pathogenesis of aspirin-exacerbated respiratory disease (AERD) at
baseline and after cyclooxygenase 1 (COX-1) inhibition. PGE 2 , prostaglandin E2; 5-LO, 5-lipoxygenase;
LTA 4 , leukotriene A4; LTC 4 S, leukotriene C4 synthase; cysLTs, cysteinyl leukotrienes; COX-2,
cyclo-oxygenase-2; TXA 2 , thromboxane A2; EP 2 , prostaglandin E2 receptor 2. (From Laidlaw TM,
Boyce JA. Pathogenesis of aspirin-exacerbated respiratory disease and reactions. Immunol Allergy
Clin North Am. 2013; 33: 195–210.)

662 ParT FivE Allergic diseases


with exacerbation of chronic urticaria. Anaphylaxis can occur such as with rituximab. Infusion-related reactions to mAbs
to a single NSAID with tolerance to all others, but usually present as cytokine storm-like reactions, with such symptoms
there is complete cross-reactivity. Desensitization protocols are as nausea, chills, fever, and malaise. These are thought to be
available for AERD to ameliorate nasal polyps and increase the caused by release of proinflammatory cytokines (e.g., IL-1, IL-6,
sense of smell. Desensitization has also been tried for urticarial and TNF-α) and respond to NSAIDs and steroids. Hypersensitivity
reactions. reactions to cetuximab on first exposure have been attributed
to sensitization to the galactose-α-1,3-galactose epitope caused
Biological Agents and Monoclonal Antibodies by exposure to the lone star tick (Amblyomma americanum).
The use of mAbs to target cancer and chronic inflammatory The carbohydrate galactose-α-1,3-galactose is expressed on
diseases has become widespread over the past decade. Inevitably nonprimate mammalian proteins and also on the cetuximab
this has led to adverse reactions, which sometimes prevent the heavy chain.
use of first-line therapies. Some of the most frequently used HSRs to mAbs can also be caused by IgE against antibody
mAbs are presented in Table 48.5, including their targets, moieties, as in some patients sensitized to rituximab. Both
incidence of overall injection/infusion site reactions, and rates immediate and delayed hypersensitivity reactions (skin lesions
51
of severe immediate hypersensitivity reactions (HSRs). The with CD4 T cells and eosinophilic infiltrates) can occur with
immunogenicity of mAbs varies, depending on whether they tocilizumab.
are chimeric mouse–human, humanized, or fully human mAbs given subcutaneously can elicit injection-site reactions,
mAbs, such as adalimumab and ofatumumab. Reactions to with symptoms including local redness, warmth, burning,
mAbs can occur during the first exposure, as has been reported stinging, itching, urticaria, pain, and induration. Such reactions
with cetuximab and trastuzumab or after multiple exposures, can start within 1 hour of the injection and usually resolve
over a few days, but large and persistent reactions can lead to
discontinuation of the mAb; desensitization protocols have been
developed for patients who have no alternative medications
(see Table 48.5).
TABLE 48.5 Biological agents:
actions, incidence, and Hypersensitivity Chemotherapy
Drug reactions Most cancer chemotherapy drugs can induce hypersensitivity
reactions. Platins are the agents most able to induce IgE responses.
Overall Platin-induced reactions typically occur after several exposures;
Drug Target reactions HSr the incidence of carboplatin allergy is about 27% after seven
Rituximab CD20 77% (first 5–10%* lifetime exposures and up to 46% in patients who have had
(Rituxan) IV infusion) 15 or more doses. Patients carrying the BRCA1 and BRCA2
Ofatumumab CD20 44 % (first 2%* mutations are at increased risk for carboplatin hypersensitivity
(Arzerra) IV infusion) reactions. Most HSRs to platins occur during the infusion, with
67% (combination
therapy) symptoms consistent with type I reactions, including anaphylaxis
Obinutuzumab CD20 66% * (i.e., flushing, hives, wheezing, hypotension). They are gener-
(Gazyva) IV ally amenable to desensitization. Positive immediate skin test
Trastuzumab HER-2 40% (mild; first 0.6-5%* results to platins have a positive predictive value (PPV) of up
(Herceptin) IV infusion) to 86% for patients exposed to ≥6 courses of carboplatin, but
Cetuximab EGFR 15–21% 1.1–5% 50% patients with reactions to oxaliplatin may have negative
(Erbitux) IV 14–27%
(Southern skin test results, indicating that non-IgE mechanisms may be
USA)* involved, such as direct activation of mast cells/basophils or a
Tocilizumab IL-6 7–8% 0.1-0.7%* different cell target because some reactions are associated with
(Actemra) IV receptor cytokine storm–like reaction with fever and chills, suggesting IL-6
Infliximab TNF-α 5- 18% 1%* release. Repeated skin testing before each chemotherapy exposure
(Remicade) IV has been suggested in patients with mild reactions to uncover
Etanercept TNF-α 15- 37% <2%* sensitization before the patient reacts. Adriamycin, cyclophos-
52
(Enbrel) SC
Adalimumab TNF-α 20% 1%* phamide, methotrexate, topotecan, and other chemotherapies
(Humira) SC can induce type I reactions, which are also amenable to rapid
Golimumab TNF-α 4–20% Not reported desensitization.
(Simponi) SC
Certolizumab TNF-α 0.8–4.5% Not reported Taxanes Hypersensitivity
(Cimzia) SC Taxanes include paclitaxel, docetaxel, cabazitaxel, and abraxane.
Brentuximab CD30 12% *
(Adcetris) IV Cremophor is used to solubilize paclitaxel molecules, and
Bevacizumab VEGF-A <3% * polysorbate 80 is used to solubilize docetaxel (Fig. 48.10). These
(Avastin) IV solvents can cause complement activation, leading to generation
Omalizumab IgE 45% 00.9–0.2%* of anaphylatoxins and mast cell activation. Initially, the side
(Xolair) SC effects of paclitaxel were attributed to cremophor; these responded
to premedication with antihistamines and high-dose corticoster-
*Case reports of anaphylaxis.
(Modified from Galvão VR, et al. Hypersensitivity to biological agents-updated oids. Despite using premedication, HSRs occur in up to 10% of
diagnosis, management, and treatment. J Allergy Clin Immunol Pract. 2015 Apr; 3(2): patients treated with paclitaxel, and in 1% the reactions can be
175–185; quiz 186.)
severe, necessitating discontinuation of the medication. Reactions

CHaPTEr 48 Drug Hypersensitivity 663


TAXANES HYPERSENSITIVITY
Taxus baccata Solvents and excipients
Taxane moiety
Paclitaxel Solvent
Docetaxel Cremophor EL
Cabazitaxel Polysorbate 80

IgG



C3a
C5a
IgE
Direct action


Mediators
LTC4
PGD2
Histamine
Tryptase
Mast cell/basophil
FiG 48.10 Taxanes: Plant origin, solvents, and excipients.







typically occur during the first or second lifetime exposure with For type I IgE- and non–IgE-mediated reactions, desensitiza-
such symptoms as throat tightness, flushing, hypotension, and tion is now the state-of-the-art management option in patients
dyspnea. However, some patients also report severe chest, back, who still require the offending drug as first-line therapy. Desen-
and/or pelvic pain. sitization has been successfully achieved for chemotherapy drugs,
IgE-mediated HSRs to taxane molecules have been reported, mAbs, antibiotics, and other medications in both adults and
leading to skin test evaluations for patients with taxane reactions. children. Although drug reactions are less common in children
When skin testing was performed in 145 patients with taxane- than in adults, perhaps because of fewer exposures, patients with
related HSRs, 103 (71%) had positive results. Thirty-six (22%) cystic fibrosis have an average 30% sensitization rate to antibiotics;
patients with negative skin test results eventually resumed regular they can be successfully desensitized with first-line antibiotics,
infusions. 53 even during lung transplantation. The mechanism of desensitiza-
tion for IgE-mediated reactions has been studied in vitro and
MANAGEMENT OF DRUG HYPERSENSITIVITY in rodents. Although antigen induces membrane changes leading
AND DESENSITIZATION to internalization of the antigen, IgE and FcεRI, when cells are
repeatedly exposed to increasing suboptimal drug concentrations,
Stopping a drug suspected of inducing a reaction has therapeutic this prevents these membrane events and blocks calcium entry
and diagnostic implications. If the symptoms are alleviated upon and the release of inflammatory mediators (Fig. 48.11). Other
cessation, it is likely, but not certain, that the drug was responsible mechanisms that may be relevant to human desensitization have
for the reaction. Although most type I symptoms are readily also been implicated (Fig. 48.12). Further research is needed to
reversible, death has occurred in patients on concomitant beta- better understand these.
blockers or ACE inhibitors when epinephrine did not reverse Application of the principles of desensitization has been
cardiovascular collapse. Patients with severe anaphylactic drug remarkably successful, and thousands of patients have been safely
reactions, as seen with chemotherapy and platins, may develop desensitized, including patients suffering severe anaphylactic
posttraumatic stress disorders. Severe reactions, such as DRESS, reactions. Indications for desensitization include type I IgE- and
SJS, and TEN, do not have specific therapies and require intensive non–IgE-mediated reactions. The risk/benefit ratio needs careful
and aggressive treatments, including steroids and/or immuno- consideration because desensitization can sometimes induce
globulin infusion at high doses, to accelerate the resolution of severe reactions. If there is a good alternative drug, desensitization
inflammatory events and facilitate recovery. Recurrence of these should not be attempted. Desensitization protocols generally
reactions upon inadvertent exposure can be lethal, and those involve diluting the drug up to 1/1000 of its normal concentration,
surviving can suffer life-debilitating consequences, such as followed by doubling doses at short intervals. A 12-step protocol
depression and increased suicides. Blindness, permanent hair for carboplatin desensitization is shown in Table 48.6. For patients
and nail loss, mucosal dryness, and fibrosis can dramatically with high risk, four bags and 16 steps may be used as shown in
decrease the quality of life in patients with SJS and TEN, and Table 48.7 for ofatumumab. For patients with local and systemic
patients with DRESS can have persistent hepatitis and/or reactions to subcutaneous injections, desensitization has been
eosinophilic cardiac complications. successfully achieved by the subcutaneous route.

664 ParT FivE Allergic diseases






1 1 2 2 3 3



Ca 2+ Ca 2+ Ca 2+


Resting mast cell Sensitization Antigen addition







ACTIVATION
(one antigen/IgE/FcεRI complex is shown)
4 4

Extracellular
Ca 2+ calcium
Ca 2+ flux
Ca 2+



5 5 5
DESENSITIZATION
(11 step protocol)
Degranulation
Ca 2+ (pre-formed
Ca 2+ mediators)



Ca 2+ Ca 2+
6 6

Ca 2+ Newly generated
Arachidonic lipid mediators
acid (minutes)
Ca 2+ Membrane
rearrangement
of receptors

7 7

Cytokine and
Ca 2+ Ca 2+ chemokine FcεRI receptor Pre-formed mediators
Nuclear production
transduction (hours) IgE Newly generated lipid mediators
Multivalent antigen Cytokines and chemokines


FiG 48.11 Simplified cartoon comparing activation and desensitization outcomes as well as a
possible explanation of how rapid desensitization works and the rearrangement of the FcεRI
receptors at the cell membrane. (From Castells et al. Hypersensitivity to antineoplastic agents:
mechanisms and treatment with rapid desensitization. Cancer Immunol Immunother. 2012; 61:
1575–84.)

CHaPTEr 48 Drug Hypersensitivity 665



TABLE 48.6 Example of 12-Step Desensitization Protocol for Carboplatin
Target dose (mg) 300
Standard volume per bag (mL) 250
Final rate of infusion (mL/h) 80
Calculated target concentration (mg/mL) 1.2
Standard time of infusion (minutes) 187.5
Concentration amount
volume (mg/mL) Total mg per Bag infused (mL)
Solution 1 250 mL of 0.012 mg/mL 3 9.38
Solution 2 250 mL of 0.120 mg/mL 30 18.75
Solution 3 250 mL of 1.190 mg/mL 297.638 250
***NB*** The total volume and dose dispensed are more than the final dose given to patient because many of the
solutions are not completely infused.
volume infused Dose administered Cumulative
Step Solution rate (mL/h) Time (min) Per Step (mL) With This Step (mg) Dose (mg)
1 1 2.5 15 0.63 0.0075 0.0075
2 1 5 15 1.25 0.015 0.0225
3 1 10 15 2.5 0.03 0.0525
4 1 20 15 5 0.06 0.1125
5 2 5 15 1.25 0.15 0.2625
6 2 10 15 2.5 0.3 0.5625
7 2 20 15 5 0.6 1.1625
8 2 40 15 10 1.2 2.3625
9 3 10 15 2.5 2.98 5.3389
10 3 20 15 5 5.95 11.2916
11 3 40 15 10 11.91 23.1971
12 3 80 174.375 232.5 276.8 300
Total time: 5.66 hours




TABLE 48.7 Example of a Four-Bag 16-Step High-risk Desensitization to Ofatuzumab
Bag volume per Bag (mL) Concentration (mg/mL) Total Dose per Bag (mg) amount of Bag infused (mL)
1 250 0.002 0.500 9.38
2 250 0.040 10.000 9.38
3 250 0.400 100.000 18.75
4 250 3.968 992.106 250.00
**NB** The total volume and dose dispensed are more than the final dose given to patient because many of the solutions are not completely
infused.
volume Dose
Cumulative infused per administered With Cumulative Fold increase
Step Bag rate (mL/h) Time (min) Time(min) Step(mL) This Step (mg) Dose (mg) per Step
1 1 2.5 15 15 0.625 0.001 0.001
2 1 5 15 30 1.25 0.003 0.004 2
3 1 10 15 45 2.5 0.005 0.009 2
4 1 20 15 60 5 0.010 0.019 2
5 2 2.5 15 75 0.625 0.025 0.044 2.5
6 2 5 15 90 1.25 0.050 0.094 2
7 2 10 15 105 2.5 0.100 0.194 2
8 2 20 15 120 5 0.200 0.394 2
9 3 5 15 135 1.25 0.500 0.894 2.5
10 3 10 15 150 2.5 1.000 1.894 2
11 3 20 15 165 5 2.000 3.894 2
12 3 40 15 180 10 4.000 7.894 2
13 4 10 15 195 2.5 9.921 17.815 2.5
14 4 20 15 210 5 19.842 37.657 2
15 4 40 15 225 10 39.684 77.341 2
16 4 80 174.375 399.375 232,5 922.659 1,000.000
Total infusion time: 6.6 hours
Standard volume per bag: 250 mL
Final rate of infusion: 80 mL/h (as patient now deemed tolerant)
Number of bags: 4; time per step: 15 minutes; total number of steps: 16; total dose: 1000 mg.

666 ParT FivE Allergic diseases



ON THE HOriZON
Drug Monomeric/low drug allergen
allergen decreased cross-linking • There is a need for a new mechanistic approach and categorization
Subclinical of delayed hypersensitivity reactions, better diagnostic tools, and a
Inhibitory mediator IgE standardized approach to desensitization protocols.
receptors release • Modulation and treatment of hypersensitivity reactions will include
LILRB4 FcεRI the use of anti–IgE and other mAbs as well as small molecules to
inhibit signal transduction.
• Prevention of hypersensitivity reactions will include the identification
ITIM ITAM ITAM ITAM ITAM of patients at risk by HLA genotyping.
P P P P
Syk • Drug desensitization should be more widely available. Patients with
Degranulation Syk degradation allergies can then be treated with first-line therapies, which will improve
SHP-1 quality of life and reduce both costs and risks.
Internalization of
antigen/IgE/FcεRla

11. Bigby M, Jick S, Jick H, et al. Drug-induced cutaneous reactions. A report
Cumulative drug concentration Threshold for anaphylaxis 12. Aun MV, Blanca M, Garro LS, et al. Nonsteroidal anti-inflammatory
Target
from the Boston Collaborative Drug Surveillance Program on 15,438
dose
consecutive inpatients, 1975 to 1982. JAMA 1986;256:3358–63.
drugs are major causes of drug-induced anaphylaxis. J Allergy Clin
Immunol Pract 2014;2:414–20.
Desensitization
13. Banerji A, Rudders S, Clark S, et al. Retrospective study of drug-induced
anaphylaxis treated in the emergency department or hospital: patient
characteristics, management, and 1-year follow-up. J Allergy Clin
Immunol Pract 2014;2:46–51.
cytokine signals and the functions of epsilon germline transcripts. Curr
Dose 14. Oettgen HC. Regulation of the IgE isotype switch: new insights on
Opin Immunol 2000;12:618–23.
FiG 48.12 Proposed mechanism for drug allergens/IgE desen- 15. Gorevic PD, Levine BB. Desensitization of anaphylactic hypersensitivity
sitization. (Courtesy of Sancho-Serra MC and Bonamichi-Santos specific for the penicilloate minor determinant of penicillin and
R.) carbenicillin. J Allergy Clin Immunol 1981;68:267–72.
16. White KD, Chung WH, Hung SI, et al. Evolving models of the
Please check your eBook at https://expertconsult.inkling.com/ immunopathogenesis of T cell-mediated drug allergy: the role of
for self-assessment questions. See inside cover for registration host, pathogens, and drug response. J Allergy Clin Immunol
details. 2015;136:219–34.
17. Pirmohamed M, Ostrov DA, Park BK. New genetic findings lead the way
to a better understanding of fundamental mechanisms of drug
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CHaPTEr 48 Drug Hypersensitivity 667.e1


MULT i PLE-CHO i CE QUEST i ONS

1. Human herpesvirus 6/7 reactivation during an adverse drug 4. Patients with sulfonamide antibiotic allergy:
reaction is frequently seen in: A. Typically present with IgE-mediated reactions
A. Stevens Johnson syndrome B. Can use nonantibiotic sulfonamides
B. Toxic epidermal necrolysis C. Are not at risk for reactions to other antibiotics
C. Maculopapular exanthema D. Cannot be desensitized
D. Drug reaction with eosinophilia and systemic symptoms
5. Drug desensitizations:
2. Screening for which human leukocyte antigen (HLA) alleles A. Are limited to type I, IgE-mediated reactions
should be done in a patients with carbamazepine-induced B. Are not performed in patients with anaphylaxis
Stevens-Johnson syndrome/toxic epidermal necrosis (SJS/ C. Can induce drug tolerance
TEN)? D. Require specific protocols based on the dose, initial reaction,
A. HLA-B* 57:01 and patient risk
B. HLA-B* 15:02
C. HLA-B* 13:01 6. Serum markers of drug hypersensitivity and mast cell activation
D. HLA-B* 58:01 include:
A. Histamine
3. The most important risk factor associated with allergic reactions B. Complement CH50
to carboplatin in women with ovarian cancer include: C. Tryptase
A. High cancer burden with metastatic disease D. Bradykinins
B. BRCA1 and BRCA2 mutations
C. Food allergy
D. Asthma

49









Occupational Respiratory Allergies



Catherine Lemière, James G. Martin







Occupational asthma (OA) is a unique phenotype of asthma, Once antigen has been taken up, the DC migrates to regional
which provides us with an opportunity to understand the origins lymph nodes, undergoes maturation, and expresses antigenic
not only of OA but also of asthma in general. In the vast majority peptide on its surface in conjunction with major histocompat-
of cases, the onset of OA occurs in adulthood, in response to a ibility complex (MHC) type II molecules. In this location, they
specific exposure at work. As such, it opens a unique window encounter circulating CD4 T lymphocytes that stochastically
4
on the natural history of asthma and the risk factors associated sample the DC surface. The DC eventually interacts with CD4
with the risk of development of the disease. This chapter will T cells expressing high affinity receptors for the antigen−MHC
review the mechanisms of occupational sensitization, the evalu- II complex. The T cells expand and exit the lymph node, and
ation of the disease from exposure to the manifestation of the T-helper-2 (Th2) cells will eventually resettle in the airways,
disease clinically, and the main steps in diagnosis and management attracted by chemokine gradients, in particular, the macrophage-
of sensitizer-induced OA. derived chemokine (MDC) CCL22 and the thymus and activation-
regulated chemokine (TARC) CCL17, which are secreted by
KEY CONCEPTS epithelial cells and act on their cognate receptor CCR4 on the
T cells. In the airways, CD4 T cells may react to antigen presenta-
5
• Occupational sensitizers induce sensitization through different tion locally on future exposures, synthesizing interleukin (IL)-4,
mechanisms, depending on their nature (proteins vs chemicals). IL-5, and IL-13. Certain characteristics of antigens, such as
• Atopy, rhinitis, and genetic markers are host risk factors predisposing protease activity or endogenous nicotinamide adenine dinucleo-
to develop occupational asthma (OA).
• The level of exposure to the causal agent is the main environmental tide phosphate (NADPH) oxidase activity, have been associated
risk factor predisposing to development of OA. with allergenicity, likely through the effects of these stimuli on
• Experimental models support roles for a diverse range of lymphocytes epithelial cells, which, in turn, secrete cytokines that not only
in airway hyperresponsiveness (AHR) and inflammation induced by favor the development of Th2 cells but also activate novel innate
allergens and nonallergenic stimuli. lymphoid cells that themselves produce type 2 cytokines. Th2
• Objective confirmation of a diagnosis of OA is crucial because of cells provide key help to B cells to undergo isotype switching
socioeconomic implications for affected workers.
and produce IgE. The binding of IgE to both high- and low-affinity
receptors on a number of cells and its subsequent interaction
MECHANISMS OF OCCUPATIONAL SENSITIZATION with antigen not only result in mediator release from mast cells
and basophils but also have effects on the functions of other
More than 400 distinct agents have been documented as causing cells, such as neutrophils and smooth muscle cells. 6
1
OA. The type of agents to which the subjects are exposed drives A few LMW occupational agents also induce specific IgE
different pathophysiological mechanisms. The agents responsible antibodies, but they do so by acting as haptens and binding with
for OA are usually considered according to their molecular proteins to form functional antigens. Specific IgE to isocyanates
weights. High-molecular-weight (HMW) agents (>10 kilodaltons and plicatic acid (western red cedar, Thuja plicata) have been
[kDa]) include proteins of animal and vegetable origin and identified. However, the significance of finding specific IgE to
microorganisms, whereas low-molecular-weight (LMW) agents isocyanates or plicatic acid is not so straightforward to interpret.
include wood dust, drugs, metals, and chemicals. Exposure to In contrast, OA caused by platinum salts or acid anhydrides is
HMW agents usually induces the production of allergen-specific clearly IgE mediated, and so the presence of specific IgE to those
immunoglobulin E (IgE), whereas only a few LMW agents have agents is a useful additional tool for making a diagnosis of OA
been associated with the production of specific IgE. 2 to those agents.
IgE-Mediated Non–IgE-Mediated
HMW agents are proteins and in general bear similarities to the Cell-mediated reactions are likely to play an important role in
aeroallergens triggering usual allergic asthma. They act as complete OA because of LMW agents. Although the predominant immune
antigens provoking the production of specific IgE antibodies. response to chemical respiratory allergens may be of the Th2
Sensitization involves the uptake of antigen by immature dendritic type, other cells may play important support or regulatory roles.
cells (DCs) residing in the subepithelial space within the airway CD4 as well as CD8 T cells and different cytokines, such as IL-1,
3
walls. DCs extend cellular projections between the epithelial IL-4, IL-5, IL-6, and IL-15, have been found in the biopsy material,
cells and are believed to sample the airway microenvironment. bronchoalveolar lavage (BAL), and sputum of patients with
669

670 ParT fivE Allergic Diseases



TABLE 49.1 Summary of the Most frequently Encountered Occupational agents Causing
Occupational asthma (Oa)
agents Occupation/industry
High-Molecular-Weight agents
Immunoglobulin E (IgE)–Dependent Causes
Cereals, flour Flour mills, bakers, pastry makers
Animal-derived allergens: laboratory animals Laboratory workers, farmers
Enzymes: α-amylase, maxatase, alcalase, papain, bromelain, Baking product production, bakers, detergent production, pharmaceutical
pancreatin industry, food industry
Seafood Seafood processing
Latex Health care workers, laboratory technicians
Low-Molecular-Weight agents
IgE-Dependent Causes
Acid anhydrides, phthalic, trimellitic, tetrachlorophthalic anhydrides Epoxy resin workers
Platinum salts Platinum refining
Other Potential immunological Mechanisms
Diisocyanates: toluene diisocyanate (TDI), methylene diphenyl- Polyurethane production, plastic industry, insulation, molding, spray painting
diisocyanate (MDI), hexamethylene diisocyanate (HDI)
Wood dusts: western red cedar, iroko, obeche, oak, and others Sawmill workers, carpenters, cabinet and furniture makers
Amines and epoxy resins Rubber industry, cosmetics, hair dye manufacturing, fur industry, rubber
additives
Colophony Electronic industry (flux)
Acrylates: cyanoacrylates, methacrylates, di- and triacrylates Adhesives, dental and orthopedic materials, sculptured fingernails, printing
inks, paints and coatings
Pharmaceutical products Pharmaceutical industry
Formaldehyde, glutaraldehyde, biocides Health care workers, cleaners
Persulfate salts: hair bleach Hairdressers
Reactive dyes: reactive black 5, pyrazolone derivatives, vinyl sulfones, Textile workers, food industry workers
carmine
Metals: chromium, nickel, cobalt Metal refinery, metal alloy production, electroplating, welding



isocyanate-induced asthma. Murine models of toluene diisocya- inhibitory factor [MIF], monocyte chemoattractant protein-1
nate “asthma” have shown a dependence of airway hyperrespon- [MCP-1]). Furthermore, repetitive antigenic stimulation of
siveness (AHR) and Th2-type inflammation on both CD4 and peripheral blood mononuclear cells from patients with diiso-
CD8 cells, but primarily the former. IL-4 and IL-13 are major cyanate asthma induced the synthesis of tumor necrosis factor
determinants of the pathobiology. Recent studies have suggested (TNF)-α and MCP-1, but not IL-4 or IL-5. The bioactive lipid
a role for innate lymphoid (lineage negative) cells to contribute lysophosphatidic acid is released from lung epithelial cells by
to type 2 cytokine production in the airways in response to allergen or isocyanate and has the potential to contribute to the
nonallergenic stimuli. Although few in number, these type 2 pathogenesis of asthma through a number of biological effects.
innate lymphoid cells can produce significant quantities of IL-5 Table 49.1 summarizes the most frequent agents responsible
and IL-13. IL-13 is a pleiotropic cytokine affecting the epithelium, for occupational asthma.
smooth muscle, and immune cells and possibly drives asthma
that is induced by allergens or irritants. The potent oxidant ozone
induces AHR in the mouse through activation of inducible natural NATURAL HISTORY OF OCCUPATIONAL ASTHMA
killer (NK) cells, so similar mechanisms may apply in human AND RISK FACTORS
subjects exposed to molecules that cause oxidative stress.
Neutrophils are also likely to be involved in isocyanate-induced Natural History of the Development of the Disease
asthma, as shown by an increase in myeloperoxidase and IL-8 Studies performed in apprentices shed light on the natural history
after exposure to toluene diisocyanate (TDI). A mixed Th1/Th2 of occupational asthma and risk factors for developing occupa-
pattern of cytokine production has been observed in subjects tional asthma. Epidemiological studies give some indication of
with red cedar–induced asthma. Furthermore, a specific inha- the course of the disease. Atopy and exposure levels have been
lational challenge test induced a mixed Th1/Th2 response in shown to predict sensitization to laboratory animals; sensitization
which CD8 T cells were the main producers of interferon (IFN)-γ. has been shown to precede the occurrence of rhinitis and asthma
However, histopathological changes in the airways in isocyanate- at the workplace. 7
induced asthma are similar to those found in atopic asthma that
is not associated with occupational sensitization. Risk Factors
There is evidence that isocyanates can stimulate human innate The occurrence of OA is the result of an interaction
immune responses by upregulating immune pattern recognition between environmental and host factors (Fig. 49.1). Several host
receptors on monocytes and increasing the chemokines that factors have been shown to increase the risk of developing OA
regulate monocyte/macrophage trafficking (macrophage migration (Table 49.2).

CHaPTEr 49 Occupational Respiratory Allergies 671


Therefore, and not surprisingly, atopy is also a risk factor for
developing OA to HMW agents, since subjects who develop OA
Level of exposure to occupational agents need to be sensitized to a specific agent to develop an asthmatic
reaction on exposure. Atopy has been associated with OA to
several different HMW agents, including OA caused by flour,
laboratory animals, latex, snow crab, detergent enzymes, and
Smoking α-amylase. It seems that the sensitization to specific allergen
Genetic predisposition occurs mainly in the first 1–2 years after the beginning of
8
Atopy exposure. However, atopy does not seem to influence the timing
Occupational rhinitis of onset of OA symptoms. 9
Pathophysiology. The predisposition to atopy has increased
Airway hyperresponsiveness markedly in recent years. The explanation for the increase is
considered to be largely environmental but has not been fully
identified, although airborne particulates have been shown to
have adjuvant effects and may, therefore, play a part. The hygiene
hypothesis has led to evidence of protective effects of certain
environments, such as the farm. A fundamental question remains
as to why T-cell differentiation into Th2 cells occurs in the airways.
Multiple stimuli within the airway environment have been shown
to promote a Th2 phenotype when interacting with DCs, including
Occupational asthma IL-4, thymic stromal lymphopoietin (TSLP), eosinophil-derived
neurotoxin, and cysteinyl leukotrienes. Interaction of antigens
fiG 49.1 Environmental and host factor favoring the occurrence directly with airway epithelial cells releases alarmins, such as
of occupational asthma. IL-33, and TSLP, which condition DCs such that their interactions
with CD4 T cells direct them to produce Th2 type cytokines.
These epithelial-derived cytokines also direct innate lymphoid
TABLE 49.2 risk factors associated With cells to produce type II cytokines.
the Occurrence of Occupational asthma (Oa) Certain characteristics of antigens, such as protease activity
risk factor Mechanisms or endogenous NADPH oxidase activity, have been associ-
ated with allergenicity. 10,11 Binding of IgE to B cells and DCs
Environmental factors facilitates the process of antigen presentation and provides a
High level of exposure Activation of airway epithelium and potential explanation for the predisposition, once sensitization
Cigarette smoking sensory nerves through Toll-like
receptors (TLRs) and transient to one allergen has occurred, to develop allergy to unrelated
6
receptor potential (TRP) channels. antigens.
Rhinitis and airway hyperresponsiveness
Host-related factors Clinical evidence. The presence of AHR and rhinitis before
Atopy Promotion of a T-helper-2 (Th2) entering a workplace is an independent risk factor for subsequent
phenotype by multiple environmental IgE sensitization to allergens present at the workplace. The
stimuli when interacting with dendritic development of occupational rhinitis during exposure often
cells (DCs), including interleukin-4 precedes the occurrence of OA. However, the predictive value
(IL-4), thymic stromal lymphopoietin
(TSLP), eosinophil-derived neurotoxin of work-related nasal symptoms is only 11.4% for the subsequent
(EDN), and cysteinyl leukotrienes. development of OA in workers exposed to laboratory animals,
Facilitation of antigen presentation by over a follow-up period of 30–42 months. 2
immunoglobulin E (IgE) binding to B Pathophysiology. The onset of allergic rhinitis before asthma
cells and DCs suggests that additional pathophysiological factors are required
Genetic markers The genetic polymorphisms identified for the expression of lower airway disease. The inflammation
do not yet lead to clear explanations
of the known pathophysiological affecting the upper airway is generally felt to be representative
processes. of that present concurrently in the lower airway. However, the
Preexisting nonspecific Airway remodeling may be necessary clinical expression of lower airway disease requires that the airways
bronchial before asthma becomes manifest in become reactive to the mediators of bronchoconstriction and
hyperresponsiveness subjects with rhinitis. mucus secretion, such as cysteinyl leukotrienes. The mechanism(s)
and work-related rhinitis of the increase in airway responsiveness remains uncertain but
may involve growth of airway smooth muscle and/or changes
in airway smooth muscle contractility through increase in
Host Factors expression of smooth muscle proteins. Other possible contributory
Atopy changes include altered matrix deposition, an increase in mucous
Clinical evidence. Atopy is clearly associated with increased glands, and goblet cell hyperplasia, all of which are forms of
risk of sensitization to HMW agents. For example, atopy has airway remodeling that may be required before asthma becomes
been identified as one of the determinants for sensitization to clinically manifest.
7
rodents in apprentices working in animal facilities. Furthermore, Genetic predisposition
the vast majority of apprentices who become sensitized to HMW Clinical evidence. There has been a tremendous effort
7
agents have atopy, in contrast to those who do not get sensitized. to identify genetic predisposition for subjects developing

672 ParT fivE Allergic Diseases


occupational asthma. Certain human leukocyte antigen (HLA) dependence of allergic sensitization on concomitant TLR4
class II molecules (i.e., HLA-DR, HLA-DQ, and HLA-DP alleles) activation by endotoxin, although in high concentrations Th2-cell
were found to be factors that either placed subjects at risk of inflammation is inhibited. In addition, TRPA1 is activated by
OA or were protective against OA caused by various LMW and stimuli, such as cigarette smoke, chlorine, aldehydes, scents, and
HMW agents. Genes associated with Th2-cell differentiation may endogenous products of oxidative stress, and has been shown
14
also play a role in the development of OA. Increased risks of to be essential for allergic “asthma” in a murine model. Con-
developing isocyanate-induced asthma may be associated with firmation of such mechanisms in humans is required.
genetic variations in transforming growth factor (TNF)-α,
TGF-β1, PTGS1(cyclooxygenase-1), and PTGS2 (cyclooxygenase-2) DIAGNOSIS AND MANAGEMENT OF
genes, as well as genes involved in the protection against oxidative OCCUPATIONAL ASTHMA
stress, such as glutathione-S-transferase and N-acetyltransferase.
Genome-wide association studies have identified genetic poly- Diagnosis of Occupational Asthma
morphisms in catenin α-3, α-T catenin (CTNNA3) associated Sensitizer-induced OA should be suspected in every worker
with isocyanate-induced asthma. Although some genetic markers exposed to potential sensitizers with new-onset asthma or with
seem to indicate susceptibility or a protective effect for developing asthma that has become difficult to control. The diagnosis of
OA, we are not yet ready to use these in clinical practice. 12 OA should not be discarded only on the basis of the time between
Pathophysiology. As is frequently the case, the genetic onset of asthma and the beginning of the occupational exposure,
polymorphisms identified do not lead to clear explanations of since approximately 20% of subjects with OA report having
the known pathophysiological processes but often appear to be childhood asthma or asthma onset before entering the workforce.
peripheral to the issue of excessive airway narrowing. Although Although some of them had a remission of their asthma before
genes associated with inflammatory processes and oxidative stress entering the workforce, many of them still experience asthma
are expressed in association with OA driven by HMW or LMW symptoms when entering the workforce. 15,16
agents, the precise mechanistic links await elucidation. Catenins The respiratory symptoms (e.g., dyspnea, chest tightness,
are linked to epithelial cell adhesion processes and differentiation wheezing, cough, and sputum production) are similar to those
and, as such, may affect epithelial responses to injury or inflam- encountered in non–work-related asthma, but in OA, their
mation. Allergens that trigger neutrophilic inflammation will occurrence is usually modulated by the work exposure. The
necessarily cause oxidative stress, as neutrophils are a rich source symptoms can start at the beginning of the work shift, toward
of reactive oxygen species and produce hypochlorite in high its end, or even after working hours, with remission or improve-
concentrations within the airway lumen. Prostaglandin synthesis ment during weekends and holidays. Rhinitis often precedes the
may also result in proinflammatory effects, vasodilation, and occurrence of the respiratory symptoms, especially with HMW
airway smooth muscle constriction. agents. A thorough clinical and occupational history must be
carefully recorded, but the diagnosis of OA cannot be made only
Environmental Factors on the basis of a compatible history, which has a low positive
Level of exposure. The level of exposure to sensitizers has predictive value. A comprehensive investigation should be
1
been well established as a strong predictor of the occurrence of performed to accurately diagnose OA. Fig. 49.2 summarizes the
OA and appears as the most important environmental risk factor different steps leading to a diagnosis of OA.
for developing OA. A dose–response relationship has been The investigation of OA should start as soon as the diagnosis
identified between the level of exposure to HMW agents and is suspected, as a long duration of exposure after the occurrence
the occurrence of IgE-mediated sensitization and OA. Such a of respiratory symptoms is associated with a poor prognosis.
dose–response relationship has also been documented for some Immunological assessment is particularly important for the
LMW agents, such as platinum salts, acid anhydrides, and diagnosis of HMW agents. Skin prick tests or serological assess-
isocyanates. 2 ment of specific IgE have a high sensitivity but a relatively poor
Tobacco smoke and irritants. Cigarette smoking may increase specificity, since they indicate sensitization, which is necessary
the risk of IgE-mediated sensitization to some HMW and but not sufficient for the disease. Unfortunately, immunological
LMW agents, although the association between smoking and tests are limited by the lack of standardized commercially available
the occurrence of OA is weak. The role of other environmental reagents for skin and in vitro tests for allergens implicated
cofactors, such as nonrespiratory routes of exposure and in OA.
concomitant exposure to endotoxin and pollutants at work, In any case, the diagnosis of asthma needs to be confirmed
remains largely uncertain. Exposure to pollutants augments in a worker who has a clinical and occupational history compatible
13
the response to allergens. It is also possible that exposure to with OA, by documenting reversible airflow limitation and/or
17
irritants in the workplace modifies the immunological response to AHR. Although the lack of AHR does not exclude the diagnosis
sensitizers. of OA in subjects who have been removed from exposure, in
Pathophysiology. Exposures in the workplace may be complex subjects that are still working a negative methacholine challenge
and do not only involve sensitizing substances. It is increasingly has a 95% negative predictive value for excluding the diagnosis
18
recognized that nonimmunological stimuli, such as endotoxin, of OA. The work-relatedness of asthma should be assessed
cold, and irritants, activate the airway epithelium and sensory through serial measurements of peak expiratory flow (PEF) and/
nerves through Toll-like receptors (TLRs) and transient receptor or AHR at work and off work and/or specific inhalation challenges
potential (TRP) channels. The release of proinflammatory in the laboratory or at the workplace.
mediators may be predicted to evoke neutrophilic inflammation Specific inhalation challenge tests involve exposing the subject
directly but also favors eosinophilic inflammation by the release to the putative cause of OA in the laboratory and/or at the
19
of mediators favoring Th2-cell differentiation or type II innate workplace. Although these tests are considered reference tests
lymphoid cell stimulation. Experimental models have shown a for diagnosing OA, they are only available in a small number of

CHaPTEr 49 Occupational Respiratory Allergies 673



Work and clinical history compatible with OA the suspected occupational agent has a specificity of 97% for a
20
diagnosis of OA. Although fractional concentration of expired
nitric oxide (FeNO) levels are correlated with eosinophilic airway
Confirmation of asthma diagnosis inflammation, the sensitivity of FeNO measured 24 hours after
(Reversible airflowlimitation and/or airway hyperresponsiveness) exposure appears to be too low (37%) to be useful in clinical
practice. 21

MANAGEMENT OF OCCUPATIONAL ASTHMA
No evidence of asthma Asthma
Diagnosis of OA highly unlikely, if Workers with sensitizer-induced OA who continue to be exposed
patient still working. to their causal agent are at a high risk of deterioration of asthma
symptoms, airway obstruction, and nonspecific AHR. Complete
and definitive avoidance of exposure to the causal agent is the
Assessment of the relationship between asthma and work optimal treatment for immunological OA. However, complete
Skin-prick tests to the suspected agent (if possible) elimination of exposure or reassignment of affected workers to jobs
that avoid exposure is not always possible. Reduction of exposure
to the agent causing OA has been assessed as an alternative option
to total avoidance. Unfortunately, this option is associated with
Patient off work Patient at work a lower likelihood of asthma improvement and a higher risk
of worsening. Therefore this management approach should
be restricted to selected patients and requires careful medical
monitoring to ensure early identification of asthma worsening.
Consider return to work
Small uncontrolled studies suggest that immunotherapy
may be effective in some cases of OA caused by HMW agents.
However, some safety concerns remain. Further studies need to
be conducted before immunotherapy can be recommended for
Impossible Possible OA to HMW agents.
Anti-IgE (omalizumab) may improve asthma control in
subjects with flour-induced OA who remain exposed to the
SIC in the laboratory if Serial monitoring of PEF ± methacholine work environment, although further prospective investigations
available challenge ±, sputum eosinophil counts at are required in subjects who choose to remain in an environment
and off from work and/or SIC in the of exposure.
laboratory and/or at the workplace if
available Even in spite of complete removal from exposure to the
offending agent, asthma symptoms and AHR to methacholine
persist in approximately 70% of the patients with OA several
years after removal from the offending environment. Besides
environmental interventions, pharmacological treatment of OA
Negative Positive Negative should follow standard clinical practice guidelines for asthma.


Occupational Non-work-related
asthma asthma ON THE HOriZON
• Identification of new genetic markers may allow the identification of
Sensitizer-induced OA unlikely subgroups with high or low risks of developing occupational asthma
(OA).
fiG 49.2 Stepwise approach for diagnosing occupational asthma. • Identification of new biomarkers may improve the diagnosis of OA.
• Identification of different OA phenotypes and endotypes that may
improve the management of the disease.



centers worldwide. Specific challenge tests are especially useful Our understanding of how and why OA develops in a given
when (i) the diagnosis of OA remains uncertain after measure- individual has improved within the last 20 years, but many aspects
ment of serial PEF or monitoring of airway responsiveness; remain obscure. Awareness that the level of exposure plays a
(ii) a patient clearly has OA, but the causal agent needs to be pivotal role in the occurrence of sensitization has helped improve
identified; (iii) a new agent is suspected of causing OA; and (iv) primary prevention of the disease. Although several markers of
the patient cannot be returned to the incriminated workplace. A genetic predisposition have been identified, these findings have
false-negative response can occur if the wrong agent is used or not yet been translated into biomarkers that can be used in
if the exposure conditions are not comparable with those in the clinical practice. Once OA is present, there is no reliable and
workplace. effective medication to cure it. Instead, a thorough and timely
Eosinophilic inflammation has been shown to increase after investigation needs to be performed to diagnose it with certainty
exposure to the causal agent(s) in the majority of subjects with and then remove the patient from exposure to ensure the best
OA. An increase in sputum cell count >3% after exposure to possible prognosis.