2722 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

as well-circumscribed wheals with erythematous raised serpiginous

borders and blanched centers that may coalesce to become giant

wheals. Urticarial lesions last for <24 h, are intensely pruritic, frequently migrate around the body, and leave no bruising or scarring.

Angioedema is marked by dramatic swelling with more pain than

pruritus and minimal erythema, which may develop with a pruritic

prodrome and takes hours to days to resolve. Acute urticaria and/or

angioedema are episodes that occur for <6 weeks’ duration, whereas

attacks persisting for >6 weeks are designated chronic.

■ PREDISPOSING FACTORS AND ETIOLOGY

Acute or chronic urticaria and/or angioedema can occur at any point

in the life span with the third to fifth decades the most common for

chronic disease. Women are affected more often than men with a slight

predominance for those with a history of atopy. Acute urticaria is most

often the result of exposure to a food, environmental, or drug allergen

or viral infection, while chronic urticaria is often idiopathic. More

than two-thirds of new-onset urticaria cases are ultimately diagnosed

as acute.

The classification of urticaria-angioedema presented in Table 352-1

focuses on the different mechanisms for eliciting clinical disease and

can be useful for differential diagnosis.

Additional etiologies include physical stimuli such as cold, heat,

solar UV radiation, exercise, and mechanical irritation. The physical

urticarias can be distinguished by the precipitating event and other

aspects of the clinical presentation. Dermatographism, which occurs

in 2–5% of the population, is defined by the appearance of a linear

wheal with surrounding erythema at the site of a brisk stroke with a

firm object (Fig. 352-3). Dermatographism has a prevalence that peaks

in the second to third decades. It is not influenced by atopy and has a

duration generally of <5 years. Pressure urticaria, which often accompanies chronic idiopathic urticaria, presents in response to a sustained

stimulus such as a shoulder strap or belt, running (feet), or manual

labor (hands). Cholinergic urticaria is distinctive in that the pruritic

wheals are of small size (1–2 mm) and are surrounded by a large area

of erythema; attacks are precipitated by fever, a hot bath or shower, or

exercise and are presumptively attributed to a rise in core body temperature. Exercise-induced anaphylaxis can be precipitated by exertion

alone or can be dependent on food ingestion prior to exercise. There is

an association with the presence of IgE specific for α-5 gliadin, a component of wheat. The clinical presentation can be limited to flushing,

erythema, and pruritic urticaria but may progress to angioedema of the

face, oropharynx, larynx, or intestine and/or to vascular collapse; it is

distinguished from cholinergic urticaria by presenting with wheals of

conventional size and by not occurring with passive heating. Solar urticaria is subdivided into six groups by the response to specific portions

of the light spectrum. Cold urticaria is local at body areas exposed to

low ambient temperature or cold objects but can progress to vascular

collapse with immersion in cold water (swimming). Vibratory urticaria

and angioedema may occur after years of occupational exposure or

can be idiopathic; it may be accompanied by cholinergic urticaria. In

rare cases, variants of cold and vibratory urticaria are inherited and

syndromic conditions, with mutations in the NLRP3 component of

inflammasome leading to familial cold autoinflammatory syndrome,

and mutations in the mast cell mechanoreceptor ADGRE2 associated

with familial vibratory urticaria. Other rare forms of physical allergy,

always defined by stimulus-specific elicitation, include local heat urticaria, aquagenic urticaria from contact with water of any temperature

(sometimes associated with polycythemia vera), and contact urticaria

from direct interaction with some chemical substance (such as latex).

Isolated Angioedema Angioedema without urticaria can be

idiopathic or due to the generation of bradykinin in the setting of C1

inhibitor (C1INH) deficiency that may be inborn as an autosomal

dominant mutation or may be acquired through the appearance of an

autoantibody in the setting of malignancy or autoimmune disease. The

angiotensin-converting enzyme (ACE) inhibitors can provoke a similar

clinical presentation in 0.2–0.7% of exposed patients due to delayed

degradation of bradykinin. Black race, organ transplant, female gender,

smoking, and increasing age are known risk factors for ACE inhibitor–

related angioedema.

■ CLINICAL PRESENTATION AND

PATHOPHYSIOLOGY

Urticarial eruptions are distinctly pruritic, may involve any area of

the body from the scalp to the soles of the feet, and appear in crops of

12- to 36-h duration, with old lesions fading as new ones appear. Most

of the physical urticarias (cold, cholinergic, dermatographism) are an

exception, with individual lesions lasting <2 h. Neither urticaria nor

angioedema lesions are symmetric or dependent in distribution. The

most common sites for angioedema are often periorbital and perioral.

Angioedema of the upper respiratory tract may be life-threatening due

to transient laryngeal obstruction, whereas gastrointestinal involvement may present with abdominal colic, with or without nausea and

vomiting, and can result in unnecessary surgical intervention. No

residual scarring occurs with either urticaria or angioedema unless

there is an underlying vasculitic process.

The pathology is characterized by edema of the superficial dermis in urticaria and of the subcutaneous tissue and deep dermis in

angioedema. Collagen bundles in affected areas are widely separated,

and the venules are sometimes dilated. Any perivenular infiltrate consists of lymphocytes, monocytes, eosinophils, and neutrophils that are

present in varying combination and numbers.

The best evidence for IgE and mast cell involvement in urticaria

and angioedema is cold urticaria. Cryoglobulins or cold agglutinins

are present in up to 5% of these patients. Ice cube placement on the

TABLE 352-1 Classification of Urticaria and/or Angioedema

ACUTE CHRONIC

Drug reactions

 Including (but not limited to):

antimicrobials, nonsteroidal antiinflammatory drugs (NSAIDs),

contrast media, angiotensinconverting enzyme (ACE) inhibitors,

etc.

Food reactions

Inhalation or contact with

environmental allergens

Transfusion reactions

Stinging and biting insects

Toxin (scombroid)

Infections—viral, bacterial, parasitic

Idiopathic—subset with autoimmune

component

Collagen vascular disease—urticarial

vasculitis and other small vessel

vasculitis

Physical stimuli

Dermographism

Cholinergic urticaria

 Vibration, cold, pressure, water

(aquagenic)

Sun (solar)

Mastocytosis (cutaneous or systemic)

Hereditary

Hereditary angioedema (HAE)

C3b inhibitor deficiency

 CIAS1-associated periodic fever

syndromes (familial cold urticaria,

Muckle-Wells syndrome)

Schnitzler’s syndrome

Hypereosinophilic syndrome

Gleich’s syndrome

FIGURE 352-3 Dermographic urticarial lesion induced by stroking the forearm

lightly with the edge of a tongue blade. The photograph, taken after 10 min,

demonstrates a prominent wheal-and-flare reaction in the shape of a hashtag.

(Photograph provided by Katherine N. Cahill, MD, Harvard Medical School.)

Urticaria, Angioedema, and Allergic Rhinitis

2723CHAPTER 352

volar forearm precipitates urticaria or angioedema within minutes of

the challenge. Histologic studies reveal marked mast cell degranulation with associated edema of the dermis and subcutaneous tissues.

Elevated levels of histamine have been found in the plasma of venous

effluent and in the fluid of suction blisters at experimentally induced

lesional sites in patients with cold urticaria, dermographism, pressure

urticaria, vibratory angioedema, light urticaria, and heat urticaria. By

ultrastructural analysis, the pattern of mast cell degranulation in cold

urticaria resembles an IgE-mediated response with solubilization of

granule contents, fusion of the perigranular and cell membranes, and

discharge of granule contents, whereas in a dermatographic lesion,

there is additional superimposed zonal (piecemeal) degranulation.

Elevations of plasma histamine levels with biopsy-proven mast cell

degranulation have also been demonstrated with generalized attacks of

cholinergic urticaria.

Up to 45% of patients with chronic urticaria have an autoimmune

cause for their disease including autoantibodies to IgE or to the α

chain of FcεRI. In some patients, autologous serum injected into their

own skin can induce a wheal-and-flare reaction involving mast cell

activation. The presence of these antibodies can also be recognized by

their capacity to release histamine or induce activation markers such

as CD63 or CD203 on basophils. An association with antibodies to

microsomal peroxidase and/or thyroglobulin has been observed with

both clinically significant Hashimoto’s thyroiditis as well as a euthyroid

state.

The urticaria and angioedema associated with classic serum sickness or with hypocomplementemic cutaneous necrotizing angiitis

(urticarial vasculitis) are believed to be immune-complex-mediated

diseases.

Isolated Angioedema Hereditary angioedema (HAE) is a fully

penetrant, autosomal dominant disease due to a mutation in the

SERPING1 gene leading to a deficiency of C1INH (type 1) in ~85% of

patients or to a dysfunctional protein (type 2) in the remainder affecting 1:30,000–80,000 in the general population. A third, less common

type of HAE has been described in which C1INH function is normal,

and the causal lesion is a mutant form of factor XII, which leads to

generation of excessive bradykinin. C1INH deficiency can also develop

in a sporadic acquired form as a result of excessive consumption of

C1INH due either to formation of immune complexes or to the generation of an autoantibody directed to C1INH in the setting of lymphoproliferative or autoimmune disease. C1INH blocks the catalytic

function of activated factor XII (Hageman factor) and of kallikrein,

as well as the C1r/C1s components of C1, with the common result of

degrading bradykinin. During clinical attacks of angioedema, C1INH

function or levels fall, patients develop elevated plasma levels of bradykinin leading to angioedema, and excessive activation of C1 results

in a decline in C4 and C2 levels.

The use of ACE inhibitors results in impaired bradykinin degradation, which explains the idiosyncratic angioedema that can occur in

ACE inhibitor–exposed patients with a normal C1INH. Bradykininmediated angioedema, whether caused by ACE inhibitors or by C1INH

deficiency, is noteworthy for the conspicuous absence of concomitant

urticaria or pruritus, the frequent involvement of the gastrointestinal

tract, and the duration of symptoms >24 h.

■ DIAGNOSIS

The classification of urticaria and angioedema as presented in Table

352-1 in terms of duration can facilitate identification of possible

mechanisms. History alone of self-limited episodes can be sufficient

to make a diagnosis in the setting of acute disease triggered by drug,

environmental, or food allergen with history-directed confirmatory

skin testing or assay for serum allergen-specific IgE. Direct reproduction of the lesion in physical urticarias is particularly valuable because

it so often establishes the cause of the lesion. In chronic urticaria/

angioedema, initial diagnostic testing should be guided by history and

physical exam. Practice guidelines provide clinicians two options if

history and physical exam are unrevealing: no laboratory testing or limited testing, which includes complete blood count with assessment for

eosinophilia, erythrocyte sedimentation rate, and thyroid-stimulating

hormone level. The vast majority of chronic urticaria is associated with

no laboratory abnormality. Urticarial lesions that last longer than 36 h,

result in scarring, and are reported as painful and not pruritic warrant

biopsy to evaluate for cellular infiltration, nuclear debris, and fibrinoid

necrosis of the venules consistent with urticarial vasculitis. Chronic

angioedema without urticaria warrants assessment of complement

levels. Concomitant flushing and hyperpigmented papules that urticate

with stroking in the absence of angioedema raise the question of mastocytosis. An appropriate travel history should trigger an evaluation

for parasites.

The diagnosis of HAE is suggested not only by family history but

also by the lack of pruritus and of urticarial lesions, the prominence

of recurrent gastrointestinal attacks of colic, and episodes of laryngeal

edema. Laboratory diagnosis depends on demonstrating a deficiency

of C1INH antigen (type 1) or a nonfunctional protein (type 2) by a

catalytic inhibition assay. C4 and C2 are chronically depleted and fall

further during attacks due to the activation of additional C1. Patients

with the acquired forms of C1INH deficiency have the same clinical

manifestations but differ in the lack of a familial element. Furthermore,

their sera exhibit a reduction of C1 function and C1q protein as well as

C1INH, C4, and C2. Lastly, type 3 HAE is associated with normal levels

of complement proteins and a factor XII gene mutation.

TREATMENT

Urticaria and Angioedema

For most forms of urticaria, H1 antihistamines effectively attenuate

both urtication and pruritus; long-acting, nonsedating agents, such

as loratadine, desloratadine, and fexofenadine, or low-sedating

agents, such as cetirizine or levocetirizine, generally are used first

and can be increased to up to four times daily dosing. Earlier

generation antihistamines, such as chlorpheniramine or diphenhydramine, are sedating, and they induce psychomotor impairment,

including reduced eye-hand coordination and machine operating

skills. Their anticholinergic (muscarinic) effects include visual disturbance, urinary retention, and constipation. Clinical practice

guidelines indicate that the addition of an H2 antagonist such as

ranitidine or famotidine in conventional dosages and a CysLT1

receptor antagonist, such as montelukast 10 mg daily or zafirlukast 20 mg twice a day, may add benefit when H1 antihistamines

are inadequate. For chronic urticaria that has failed to respond to

the above combinations, monoclonal anti-IgE antibodies such as

omalizumab are now the next line of therapy. Older agents with

antihistamine properties such as doxepin, cyproheptadine, and

hydroxyzine have proven effective when H1 antihistamines fail but

are less effective than omalizumab and are sedating.

Topical glucocorticoids are of no value, and systemic glucocorticoids are generally avoided in idiopathic, allergen-induced,

or physical urticarias due to their long-term toxicity. Systemic

glucocorticoids are useful in the management of patients with

pressure urticaria, vasculitic urticaria (especially with eosinophil

prominence), idiopathic angioedema with or without urticaria, or

chronic urticaria that responds poorly to conventional treatment

and should be considered in any patient with debilitating disease.

With persistent vasculitic urticaria, hydroxychloroquine, dapsone,

or colchicine may be added to the regimen before or along with systemic glucocorticoids. Cyclosporine is efficacious for patients with

chronic idiopathic urticaria that is severe and poorly responsive to

other modalities and/or when glucocorticoids are a requirement.

BRADYKININ-MEDIATED ANGIOEDEMA

Infusion of plasma-derived C1INH protein and lanadelumab, a

monoclonal antiplasma kallikrein antibody, is approved for prophylaxis of HAE attacks. Administration of plasma-derived or

recombinant C1INH protein, a bradykinin 2 receptor antagonist

(icatibant), or a kallikrein inhibitor (ecallantide) may be used

for treatment of an acute attack of HAE. Older, less expensive

2724 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

preventative options include attenuated androgens, which stimulate production by the normal gene of an amount of functional

C1INH. The antifibrinolytic agent ε-aminocaproic acid may be

used for preoperative prophylaxis but is contraindicated in patients

with thrombotic tendencies or arterial atherosclerosis. Fresh frozen

plasma infusion can be used for acute attacks in a setting that lacks

access to newer modalities. Published studies are conflicting on the

efficacy of bradykinin 2 receptor antagonists and C1INH protein in

the treatment of ACE inhibitor–induced angioedema. Treatment of

the underlying autoimmune disease or malignancy is indicated for

acquired C1INH deficiency.

ALLERGIC RHINITIS

■ DEFINITION

Rhinitis is characterized by sneezing; rhinorrhea; obstruction of the

nasal passages; conjunctival, nasal, and pharyngeal itching; and lacrimation and can be classified as allergic or nonallergic. A clinical history

of rhinitis symptoms occurring in a temporal relationship to allergen

exposure and documentation of sensitization to an environmental

allergen are required for a diagnosis of allergic rhinitis. Although

commonly seasonal due to elicitation by airborne pollens, it can be

perennial in an environment of chronic exposure to house dust mites,

animal danders, or insect (cockroach) products. The overall prevalence

in North America has increased in the past 20 years and is 10–30%,

with the peak prevalence of >30% occurring in the fifth decade.

■ PREDISPOSING FACTORS AND ETIOLOGY

Allergic rhinitis generally occurs in atopic individuals, often in association with atopic dermatitis, food allergy, urticaria, and/or asthma

(Chap. 287). Up to 50% of patients with allergic rhinitis manifest

asthma, whereas 70–80% of individuals with asthma and 80% of

individuals with chronic bilateral sinusitis experience allergic rhinitis.

Female sex, particulate air pollution exposure, and maternal tobacco

smoking increase the risk of developing allergic rhinitis.

Wind-pollinated trees, grasses, and weeds produce sufficient quantities of pollen suitable for wide distribution by air currents to elicit

seasonal allergic rhinitis. The dates of pollination of these species

historically varied little from year to year in a particular locale but may

be quite different in another climate. In the temperate areas of North

America, trees typically pollinate from March through May, grasses

in June and early July, and weeds from mid-August to early October.

Molds, which are widespread in nature because they occur in soil or

decaying organic matter, propagate spores in a pattern that depends on

climatic conditions. Climate change is impacting these patterns with

early tree pollination and prolonged ragweed season with the delay of

the first frost. In laboratory studies, exposure to high carbon dioxide

concentrations increases pollen production in ragweed and timothy

grass. Perennial allergic rhinitis occurs in response to allergens that

are present throughout the year, including animal dander, cockroachderived proteins, mold spores, or dust mites such as Dermatophagoides

farinae and Dermatophagoides pteronyssinus. Dust mites are scavengers of human skin and excrete cysteine protease allergens in

their feces.

■ PATHOPHYSIOLOGY AND MANIFESTATIONS

Episodic rhinorrhea, sneezing, obstruction of the nasal passages with

lacrimation, and pruritus of the conjunctiva, nasal mucosa, and oropharynx are the hallmarks of allergic rhinitis. The nasal mucosa is pale

and boggy, the conjunctiva congested and edematous, and the pharynx generally unremarkable. Swelling of the turbinates and mucous

membranes with obstruction of the sinus ostia and eustachian tubes

precipitates secondary infections of the sinuses and middle ear, respectively. A growing number of patients with seasonal allergic rhinitis

demonstrate pollen-associated food allergen syndrome characterized

by oropharyngeal pruritus and/or mild swelling following the ingestion

of plant-based foods in the same plant family as a tree, grass, or weed,

which contain cross-reacting allergens.

The nose presents a large mucosal surface area through the folds

of the turbinates and serves to adjust the temperature and moisture

content of inhaled air and to filter out particulate materials >10 μm

in size by impingement in a mucous blanket; ciliary action moves the

entrapped particles toward the pharynx. Entrapment of pollen and

digestion of the outer coat by mucosal enzymes such as lysozymes

release protein allergens. The initial interaction occurs between the

allergen and intraepithelial mast cells and then proceeds to involve

deeper perivenular mast cells, both of which are sensitized with

specific IgE. During the symptomatic season when the mucosae are

already swollen and hyperemic, there is enhanced adverse reactivity

to the seasonal pollen as well as irritants such as tobacco smoke and

fragrances. Biopsy specimens of nasal mucosa during seasonal rhinitis

show submucosal edema with infiltration by eosinophils, along with

some basophils and neutrophils.

The mucosal surface fluid contains IgA and IgE, which apparently

arrives by diffusion from plasma cells in proximity to mucosal surfaces.

IgE fixes to mucosal and submucosal mast cells, and the intensity

of the clinical response to inhaled allergens is quantitatively related

to the naturally occurring pollen dose. In sensitive individuals, the

introduction of allergen into the nose is associated with sneezing,

nasal obstruction, and discharge, and the fluid contains histamine,

PGD2

, and leukotrienes. Thus, the mast cells of the nasal mucosa and

submucosa generate and release mediators through IgE-dependent

reactions that are capable of producing tissue edema and eosinophilic

infiltration.

■ DIAGNOSIS

The diagnosis of seasonal allergic rhinitis depends largely on an

accurate history of occurrence coincident with the pollination of the

offending weeds, grasses, or trees. The continuous character of perennial allergic rhinitis due to contamination of the home or place of work

makes historic analysis difficult, but there may be variability in symptoms that can be related to exposure to animal dander, dust mite and/

or cockroach allergens, fungal spores, or work-related allergens such as

latex. Patients with perennial rhinitis commonly develop the problem

in adult life and manifest nasal congestion and a postnasal discharge,

often associated with thickening of the sinus membranes demonstrated

by radiography. Perennial nonallergic rhinitis with eosinophilia syndrome (NARES) occurs in the middle decades of life and is characterized by nasal obstruction, anosmia, chronic sinusitis, and prominent

eosinophilic nasal discharge in the absence of allergen sensitization.

The term vasomotor rhinitis or perennial nonallergic rhinitis designates a condition of enhanced reactivity of the nasopharynx in which

a symptom complex resembling perennial allergic rhinitis occurs

with nonspecific stimuli, including chemical odors, temperature and

humidity variations, and position changes but occurs without tissue

eosinophilia or an allergic etiology. Other entities to be excluded are

structural abnormalities of the nasopharynx; exposure to irritants; gustatory rhinitis associated with cholinergic activation that occurs while

eating or ingesting alcohol; hypothyroidism; upper respiratory tract

infection; pregnancy with prominent nasal mucosal edema; prolonged

topical use of α-adrenergic agents in the form of nasal sprays (rhinitis

medicamentosa); and the use of certain systemic agents such as βadrenergic antagonists, ACE inhibitors, direct vasodilators (hydralazine), α1

-adrenergic receptor antagonists, estrogens, progesterone, nonsteroidal anti-inflammatory drugs, gabapentin, phosphodiesterase-5

inhibitors, and psychotropics (risperidone, chlorpromazine,

amitriptyline).

The nasal secretions of allergic patients are rich in eosinophils, and

a modest peripheral eosinophilia can be observed. Local or systemic

neutrophilia implies infection. Total serum IgE is frequently elevated,

but the demonstration of immunologic specificity for IgE is critical

to an etiologic diagnosis. A skin test by the intracutaneous route

(puncture or prick) with the allergens of interest provides a rapid and

reliable approach to identifying allergen-specific IgE that has sensitized cutaneous mast cells. A positive intracutaneous skin test with

1:10–1:20 weight/volume of extract has a high predictive value for the

presence of allergy. An intradermal test with a 1:500–1:1000 dilution of

Urticaria, Angioedema, and Allergic Rhinitis

2725CHAPTER 352

0.05 mL may follow if indicated by history when the intracutaneous

test is negative, but while more sensitive, it is less reliable due to the

reactivity of some asymptomatic individuals at the test dose.

Newer methodology for detecting total IgE, including the development of enzyme-linked immunosorbent assays (ELISAs) employing

anti-IgE bound to either a solid-phase or a liquid-phase particle,

provides rapid and cost-effective determinations. Measurements of

specific anti-IgE in serum are obtained by its binding to an allergen and

quantitation by subsequent uptake of labeled anti-IgE. As compared to

the skin test, the assay of specific IgE in serum is less sensitive but has

high specificity.

TREATMENT

Allergic Rhinitis

Although allergen avoidance is the most cost-effective means of

managing allergic rhinitis, only in the case of animal dander and

possibly dust mites is it feasible. Treatment with pharmacologic

agents represents the standard initial approach to seasonal or

perennial allergic rhinitis. Oral long-acting H1 antihistamines, such

as fexofenadine, loratadine, desloratadine, cetirizine, and levocetirizine, are effective for nasopharyngeal itching, sneezing, and

watery rhinorrhea and for such ocular manifestations as itching,

tearing, and erythema, but they are less efficacious for the nasal

congestion. They reduce nasal and ocular symptoms by about onethird. These antihistamines are less lipophilic and more H1 selective, thus minimizing their ability to cross the blood-brain barrier

and therefore diminishing their sedating and anticholinergic effect;

they do not differ appreciably in efficacy for relief of rhinitis and/or

sneezing.

Intranasal high-potency glucocorticoids are the most effective

drugs available for the relief of established rhinitis, seasonal or

perennial, and are effective in relieving nasal congestion as well as

ocular symptoms. They provide efficacy with substantially reduced

side effects as compared with this same class of agent administered

orally. Their most frequent side effect is local irritation, with fungal

overgrowth being a rare occurrence. The currently available intranasal glucocorticoids—beclomethasone, flunisolide, triamcinolone,

budesonide, fluticasone propionate, fluticasone furoate, ciclesonide,

and mometasone furoate—are equally effective for nasal symptom

relief, including nasal congestion; these agents all achieve up to 70%

overall symptom relief with some variation in the time period for

onset of benefit. The nasal antihistamines azelastine and olopatadine may benefit individuals with nonallergic vasomotor rhinitis

as well as have additive benefit to intranasal steroids in allergic

rhinitis, but they have an adverse effect of dysgeusia (taste perversion) in some patients. Alternative nasal decongestants include

α-adrenergic agents such as phenylephrine or oxymetazoline; however, the duration of their efficacy is limited because of rebound

rhinitis (i.e., 7- to 14-day use can lead to rhinitis medicamentosa)

and such systemic responses as hypertension. Oral α-adrenergic

agonist decongestants containing pseudoephedrine can improve

management of nasal congestion, generally in combination with

an antihistamine. These pseudoephedrine combination products

can cause insomnia and are precluded from use in patients with

narrow-angle glaucoma, urinary retention, severe hypertension,

marked coronary artery disease, or a first-trimester pregnancy.

The CysLT1 antagonist montelukast is approved for treatment of

both seasonal and perennial rhinitis. However, it is less effective

than H1 antihistamines and nasal glucocorticoids, and reports of

neuropsychiatric events have led to increased U.S. Food and Drug

Administration precautions. Cromolyn sodium nasal spray inhibits mast cell degranulation and can be used prophylactically on a

continuous basis during the season or as needed before a known

exposure. Topical ipratropium is an anticholinergic agent effective

in reducing rhinorrhea, including that of patients with perennial

nonallergic symptoms, and it can be additionally efficacious when

combined with intranasal glucocorticoids. For concomitant allergic

conjunctivitis, topical treatment with cromolyn sodium is effective

in treating mild allergic symptoms, and topical antihistamines such

as olopatadine, azelastine, ketotifen, or epinastine administered to

the eye provide rapid relief of itching and redness and are more

effective than oral antihistamines.

Immunotherapy Immunotherapy consists of repeated exposure

to the allergen(s) considered to be specifically responsible for the

symptom complex. Two forms of immunotherapy, subcutaneous

(SCIT) and sublingual (SLIT), are currently available. Randomized,

controlled studies of ragweed, grass, dust mite, and cat dander

allergens administered via SCIT for treatment of allergic rhinitis

have demonstrated significant improved symptom control over

medications alone with the advantage of providing a durable benefit, as well as a reduction in asthma symptoms, medication use,

and bronchial hyperreacticity in allergic asthma. Clinical practice

guidelines recommend a duration of SCIT is 3–5 years, with discontinuation being based on minimal symptoms over two consecutive

seasons of exposure to the allergen. Clinical benefit appears related

to the administration of a high dose of relevant allergen, gradually

uptitrating concentration and advancing from weekly to monthly

intervals. SCIT injections occur in a licensed treatment site; 2–3%

of SCIT patients experience a systemic reaction, including anaphylaxis, over a 12-month period. The majority of these reactions

occur soon after injection, and thus, patients should remain at the

treatment site for at least 30 min after allergen administration so

that any systemic reactions can be managed. Local reactions with

erythema and induration are not uncommon and may persist for

1–3 days. SLIT is prepared as a tablet to be dissolved under the

tongue at home after the first dose. The efficacy of SLIT is comparable to SCIT but only for the three allergen formulations currently

available: dust mite, timothy/northern grasses, and short ragweed.

Systemic reactions are less frequent with SLIT, but transient oral

pruritus is common. Immunotherapy is contraindicated in patients

with significant cardiovascular disease or unstable asthma. Severe

cases of anaphylaxis have occurred after allergen immunotherapy

when patients were taking a β-adrenergic blocking agent. Thus,

immunotherapy should be conducted with caution in any patient

requiring β-adrenergic blocking therapy due to the difficulty in

managing an anaphylactic complication.

Immunotherapy should be reserved for clearly documented

seasonal or perennial rhinitis that is clinically related to defined

allergen exposure with confirmation by the presence of allergenspecific IgE through skin or in vitro specific IgE testing. The

response to immunotherapy is associated with a complex of cellular

and humoral effects that includes a modulation in T lymphocyte

cytokine production and allergen-specific IgG4 expansion. Systemic

treatment with omalizumab, an anti-IgE monoclonal antibody, is

efficacious for allergic rhinitis and can be used with immunotherapy to enhance safety and efficacy. However, current approval is

only for treatment of patients with persistent allergic asthma not

controlled by inhaled glucocorticoid therapy or chronic idiopathic

urticaria not controlled by oral H1 antihistamines.

A sequence for the management of allergic or perennial rhinitis

based on an allergen-specific diagnosis and stepwise management

as required for symptom control would include the following: (1)

identification of the offending allergen(s) by history with confirmation of the presence of allergen-specific IgE by skin test and/

or serum assay; (2) avoidance of the offending allergen; and (3)

medical management in a stepwise fashion (Fig. 352-4). Mild intermittent symptoms of allergic rhinitis are treated with oral antihistamines, oral CysLT1 receptor antagonists, intranasal antihistamines,

or intranasal cromolyn. Moderate to more severe allergic rhinitis is

managed with intranasal glucocorticoids plus oral antihistamines,

oral CysLT1 receptor antagonists, or antihistamine-decongestant

combinations. Persistent or seasonal allergic rhinitis, rhinoconjunctivitis, or asthma that remains uncontrolled with maximal medical

therapy merit consideration of allergen-specific immunotherapy.

Immune-Mediated, Inflammatory, and Rheumatologic Disorders PART 11

2726

ENT evaluation

Intranasal ipratropium bromide

Intranasal glucocorticoids

Environmental

allergen control

Past history of

allergic rhinitis

Treat as allergic

rhinitis

Exclude foreign body

and anatomic defect

Non-allergic rhinitis

No specific allergen

identified

If negative

Topical intranasal antihistamines

or oral decongestants

No past history

of allergic rhinitis

Treat as infection

(viral vs bacterial)

Anatomic defects, polyps, foreign

body, and sinusitis

Exclude medication-induced rhinitis

Duration of symptoms

>4 weeks

Infectious symptoms

Present Absent Present

Present

Chronic

Absent

Acute

Absent

Treat medically

If chronic sinusitis,

consider immune

deficiency evaluation

Refer to ENT

Allergy evaluation

History/skin test or

blood test for

allergen-specific

IgE

Assess for asthma

Oral or intranasal

antihistamines,

decongestants, intranasal

cromolyn

Intranasal glucocorticoids

(+ antihistamines if required

and/or + CysLT1

receptor antagonist)

Consider nasal saline

Allergic rhinitis

Specific allergen

identified

Mild intermittent

symptoms

Severe intermittent

or mild/moderate

persistent symptoms

Moderate/severe

persistent

symptoms

Severe persistent

symptoms

Oral glucocorticoids

(brief: 3–7 days)

If associated with severe

asthma or chronic urticaria,

consider omalizumab

Intranasal ipratropium bromide

Immunotherapy

Subcutaneous

or sublingual

Persistent

rhinorrhea

If no response or moderate/severe symptoms

Add-on

therapy

If persistent rhinorrhea

If inadequate response

FIGURE 352-4 Algorithm for the diagnosis and management of rhinitis. Persistent is defined as >4 days per week for >4 weeks. Moderate/severe is defined as abnormal sleep, impaired daily activities (school, work, sport, leisure), and/or

troublesome symptoms. CysLT, cysteinyl leukotriene; ENT, ear, nose, and throat; IgE, immunoglobulin E.

Anaphylaxis

2727CHAPTER 353

■ FURTHER READING

Bernstein DI et al: Allergic rhinitis: Mechanisms and treatment.

Immunol Allergy Clin North Am 36:261, 2016.

Cho SH et al: Chronic rhinosinusitis without nasal polyps. J Allergy

Clin Immunol Pract 4:575, 2016.

Cicardi M et al: Classification, diagnosis, and approach to treatment

for angioedema: Consensus report from the Hereditary Angioedema

International Working Group. Allergy 69:602, 2014.

Corren J et al: Allergic and nonallergic rhinitis, in Middleton’s Allergy:

Principles and Practice, 8th ed. NF Adkinson et al (eds). Philadelphia,

Saunders, 2014, pp 664–685.

Jutel M et al: International consensus on allergen immunotherapy II:

Mechanisms, standardization, and pharmacoeconomics. J Allergy

Clin Immunol 137:358, 2016.

Maurer M et al: Omalizumab for the treatment of chronic idiopathic

or spontaneous urticaria. N Engl J Med 368:924, 2013.

Saini SS: Urticaria and angioedema, in Middleton’s Allergy: Principles

and Practice, 8th ed. NF Adkinson et al (eds). Philadelphia, Saunders,

2014, pp 575–587.

■ BACKGROUND

Anaphylaxis is a potentially life-threatening systemic allergic reaction

involving one or more organ systems that typically occurs within seconds to minutes of exposure to the anaphylactic trigger, most often

a drug, food, or Hymenoptera sting. The term anaphylaxis was first

described in 1902 by Charles Richet and Paul Portier who attempted

to immunize dogs against sea anemone toxin in the same way Pasteur

was able to vaccinate individuals against the smallpox virus. To their

surprise, repeated administration of small, sublethal doses of sea anemone toxin reliably induced acute-onset death when readministered

2–3 weeks after initial “vaccination” to the toxin. The phenomenon was

termed ana (anti)-phylaxis (“protection or guarding”) because vaccination with anemone toxin resulted in the opposite intended immune

effect. Charles Richet was awarded the Nobel Prize in Physiology or

Medicine in 1913 for this work, which led to further insights into

hypersensitivity and mast cell biology.

■ CLINICAL MANIFESTATIONS

While 80–90% of anaphylactic episodes are uniphasic, about 10–20%

of cases are biphasic, in which anaphylactic symptoms return about an

hour or longer after resolution of initial symptoms. Anaphylactic reactions are particularly dangerous when hypotension or hypoxia occurs,

leading potentially to cardiovascular collapse or respiratory failure,

respectively. There may be upper or lower airway obstruction or

both. Laryngeal edema may be experienced as a “lump” in the throat,

hoarseness, or stridor, whereas bronchial obstruction is associated with

a feeling of tightness in the chest and/or audible wheezing. Patients

with underlying asthma are predisposed to severe involvement of the

lower airways and increased mortality associated with anaphylaxis. In

fatal cases with clinical bronchial obstruction, the lungs show marked

hyperinflation on gross and microscopic examination. The microscopic findings in the bronchi, however, are limited to luminal secretions, peribronchial congestion, submucosal edema, and eosinophilic

infiltration, and the acute emphysema is attributed to intractable bronchospasm that subsides with death. Angioedema resulting in death by

mechanical obstruction occurs in the epiglottis and larynx; however,

the process also is evident in the hypopharynx and to some extent

in the trachea. On microscopic examination, there is wide separation

353 Anaphylaxis

David Hong, Joshua A. Boyce

of the collagen fibers and the glandular elements; vascular congestion

and eosinophilic infiltration also are present. Patients dying of vascular

collapse without antecedent hypoxia from respiratory insufficiency

have visceral congestion with a presumptive loss of intravascular fluid

volume. The associated electrocardiographic abnormalities, with or

without infarction, in some patients may reflect a primary cardiac

event mediated by mast cells (which are prominent near the coronary

vessels) or may be secondary to a critical reduction in blood volume.

Gastrointestinal manifestations represent another severe presentation of anaphylaxis and include nausea, vomiting, crampy abdominal

pain, and/or fecal incontinence. Angioedema of the bowel wall may

also cause sufficient intravascular volume depletion to precipitate cardiovascular collapse.

Cutaneous manifestations are among the most common presentations of anaphylaxis (>90% of cases). Symptoms include urticarial

eruptions, flushing with diffuse erythema, and/or a feeling of generalized warmth. Urticarial eruptions are intensely pruritic and may be

localized or disseminated. They may coalesce to form giant hives but

seldom persist beyond 48 h.

■ PATHOPHYSIOLOGY

Many of the important early mediators of anaphylaxis are derived from

mast cells, basophils, and eosinophils. Mast cells and basophils contain preformed granules composed of histamine, proteases (tryptase,

chymase), proteoglycans (heparin, chondroitin sulfate), and tumor

necrosis factor-α, which are rapidly released into surrounding tissue

upon cell activation, a process known as degranulation. Mast cells,

basophils, and eosinophils are also sources of arachidonic acid–derived

products, which include cysteinyl leukotrienes, prostaglandins, and

platelet-activating factor (PAF). Histamine release results in flushing,

urticaria, pruritus, and, in high concentrations, hypotension and tachycardia. Cysteinyl leukotrienes and prostaglandin D2 cause bronchoconstriction and increased microvascular permeability. Prostaglandin D2

causes cutaneous flushing and attracts eosinophils and basophils to the

site of mast cell activation. Serum PAF levels correlate with anaphylaxis

severity and are inversely proportional to the constitutive level of PAF

acetylhydrolase, which is necessary for PAF inactivation. Tryptase and

chymase can activate complement and coagulation pathways. Activation of these pathways results in production of the anaphylotoxins, C3a

and C5a, and activation of the kallikrein-kinin system, which regulates

blood pressure and vascular permeability. The actions of these anaphylactic mediators are likely additive or synergistic at the target tissues.

■ PREDISPOSING FACTORS AND MECHANISMS

Because the most dangerous manifestations of anaphylaxis involve

the cardiovascular and/or respiratory systems, preexisting asthma and

underlying cardiovascular disease could lead to more rapid decompensation from anaphylaxis. Atopy is not generally thought to be a risk

factor for anaphylaxis from drug reactions or Hymenoptera stings,

but it is associated with radiocontrast sensitivity, exercise-induced

anaphylaxis, idiopathic anaphylaxis, and allergy to foods or latex.

Severe Hymenoptera-induced anaphylaxis (generally with prominent

hypotension) can be a presenting feature of underlying systemic mastocytosis. Hymenoptera allergy is also more likely in patients whose

occupations (i.e., beekeepers, trash haulers, and landscape workers)

place them in regular proximity to stinging insects. Most commonly,

allergen-induced cross-linking of IgE-bound FcεRI receptors on mast

cells and basophils initiates the signal transduction events leading to

hypersensitivity syndromes, including anaphylaxis. The generation of

allergen-specific IgE is the end result of sensitization via the adaptive

immune system. While the mechanisms underlying sensitization

are beyond the scope of this chapter, environmental factors, innate

immune responses, and cytokines are among the many variables

leading to antigen-specific IgE production by B cells and plasma cells.

IgE-mediated drug allergies are most common with antibiotics and

certain chemotherapy drugs, though theoretically, they can occur with

almost any medication. As is the case with environmental allergies,

repeated exposure to the allergy-causing antigen is an important risk

factor to keep in mind when evaluating patients with anaphylaxis. In

2728 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

the case of allergy to carboplatin, the incidence of hypersensitivity is

27% in patients who have had ≥7 lifetime infusions and as high as 46%

in patients who have had ≥15 lifetime infusions. Similarly, patients with

cystic fibrosis have a relatively high incidence of allergic reactions to IV

antibiotics that they receive periodically for intermittent “clean-outs”

to maintain airway clearance. Drugs can also function as haptens that

form immunogenic conjugates with host proteins. The conjugating

hapten may be the parent compound, a nonenzymatically derived

storage product, or a metabolite formed in the host. Recombinant

biologics can also induce the formation of IgE against the proteins or

against glycosylated structures that serve as immunogens. Outbreaks of

anaphylaxis to the epidermal growth factor receptor (EGFR) antibody

cetuximab have been reported in association with elevated titers of

serum IgE to alpha-1,3-galactose (alpha-gal), an oligosaccharide found

in nonprimate mammals. Cetuximab is derived from a mouse cell line

expressing a transferase that tags the Fab′ portion of the cetuximab

heavy chain with alpha-gal. Interestingly, patients with a history of

multiple bites from Amblyomma americanum ticks commonly found

in the Carolinas, Arkansas, and Tennessee are more likely to have antialpha-gal IgE as compared with control patients living outside those

states. Some individuals who become sensitized to alpha-gal can develop

episodes of delayed-onset anaphylaxisto meat from beef, lamb, and pork.

Non-IgE-mediated mast cell activation secondary to certain drugs

is clinically indistinguishable from classical IgE-mediated hypersensitivity reactions, but it can occur with first known exposure since there

is no prior need for mast cell sensitization by IgE. MRGPRX2, a G

protein–coupled receptor that is highly expressed in skin mast cells,

has been shown in mouse models and in vitro studies using human

cells to induce mast cell activation and mediator release secondary to

neuromuscular blocking drugs (NMBDs), quinolones, and icatibant.

These findings are clinically significant since NMBDs are a relatively

common cause of perioperative anaphylaxis and in other settings

requiring endotracheal intubation and quinolones are a commonly

used antibiotic family. Icatibant, a bradykinin-2 receptor antagonist

administered by subcutaneous injection for the treatment of acute

attacks of hereditary angioedema, is known to frequently result in

local injection site reactions. Another example of non-IgE-mediated

anaphylaxis is demonstrated with paclitaxel, a chemotherapy agent

most commonly used in combination with carboplatin to treat ovarian

cancer. It is derived from yew tree bark and needles that require polyethoxylated castor oil (Cremophor) to be solubilized into aqueous solution. Cremophor has been shown in vitro to activate the complement

cascade, resulting in complement-dependent histamine release from

mast cells and basophils. A version of paclitaxel that is solubilized by

being bound to albumin nanoparticles, Abraxane, has a far lower rate

of hypersensitivity, especially for patients who have had infusion reactions to Cremophor-solubilized paclitaxel. Reactions to radiocontrast

and vancomycin are other examples of non-IgE-mediated hypersensitivity. Opiates and nonsteroidal anti-inflammatory drugs (NSAIDs) are

other drug categories that can have similar adverse reactions.

■ DIAGNOSIS

The diagnosis of an anaphylactic reaction depends primarily on a history revealing the onset of symptoms and signs within seconds to minutes after the putative trigger is encountered. An exception is delayed

anaphylaxis to meats in alpha-gal–sensitized patients. Every attempt to

identify the specific cause or causes should be made to minimize the

risk of recurrent anaphylaxis. If a particular drug or food is suspected,

skin or serum-specific IgE testing can be useful to confirm clinical

suspicions. If a specific trigger cannot be identified by history or testing, a workup of underlying baseline atopic diatheses may be useful to

identify risk factors that could play a potential contributory role. In the

acute setting, laboratory biomarkers of mast cell degranulation may be

useful to document the severity of an anaphylactic episode. The most

obvious serum biomarker to assay, histamine, has an extremely short

half-life with a measurable time-window that expires <1 h from the

onset of anaphylaxis. A more practical and useful biomarker is serum

tryptase, which peaks 60–90 min after the onset of anaphylaxis and

can be measured as long as 5 h after the onset of anaphylaxis. It may be

useful to follow-up an elevated tryptase measurement in the acute setting with another measurement when the patient is clinically stable to

establish a baseline reference. An elevated baseline tryptase level may

warrant further workup for mastocytosis, especially if the presenting

reaction occurred in the setting of Hymenoptera sting.

■ TREATMENT

Early recognition of an anaphylactic reaction and appropriate intervention are critically important because severe, even fatal, complications

can occur within minutes after symptoms first appear. The treatment

of first choice is intramuscular administration of 0.3–0.5 mL of 1:1000

(1 mg/mL) epinephrine, with repeated doses at 5- to 20-min intervals

as needed for a severe reaction. The failure to use epinephrine within

the first 20 min of symptoms is a risk factor for poor clinical outcomes

in various studies of anaphylaxis. Another important variable that may

affect anaphylaxis survival is body posture, as an upright or sitting

posture may lead to “empty ventricle syndrome” in which there is

insufficient venous return to the heart from sudden-onset hypotension

secondary to intravascular volume depletion. Epinephrine can further

accelerate empty ventricle syndrome due to its chronotropic effects.

For this reason, it is recommended that patients who suffer from anaphylaxis be placed in the supine position before receiving epinephrine.

IV fluids and vasopressor agents may be administered in the acute

medical setting if intractable hypotension occurs. Epinephrine provides both α- and β-adrenergic effects, resulting in vasoconstriction,

bronchial smooth-muscle relaxation, and attenuation of enhanced

venular permeability. Beta blockers may attenuate this response; therefore, an alternative antihypertensive may be considered in patients at

high risk of needing emergency epinephrine. Oxygen alone via a nasal

catheter or with nebulized albuterol may be helpful; however, either

endotracheal intubation or a tracheostomy is mandatory for oxygen

delivery if progressive hypoxia develops. Ancillary agents such as

antihistamines, glucocorticoids, and bronchodilators are also useful

therapeutics to treat urticaria/angioedema and bronchospasm once the

patient is hemodynamically stable.

■ PREVENTION

Avoidance The simplest, most straightforward approach to the

long-term management of a patient with a history of anaphylaxis is

strict avoidance of known anaphylactic triggers and education on acute

management, specifically, instructing the patient on proper use and

indications for use of self-administered epinephrine. Lifelong avoidance is not easy if the triggeris an occupational exposure, Hymenoptera

sting, a common food (i.e., peanut), or a drug representing the sole or

best therapeutic option for the patient. Special management options

may exist for these patients.

Venom Immunotherapy Patients with only large local reactions

to Hymenoptera stings are unlikely to have anaphylaxis with subsequent stings. However, patients of any age who have had documented

anaphylaxis should be formally evaluated and started on venom

immunotherapy (VIT) if skin or serologic IgE testing confirms the

history. Immunotherapy is a means of “tolerizing” patients to allergen

by means of serial subcutaneous administration of escalating doses of

extract containing relevant allergen until a target maintenance dose is

achieved. As in the case of Richet’s unfortunate dogs, anaphylaxis can

sometimes occur during the course of administering immunotherapy

extracts, so formulating extracts and administering them is typically

done under the care of a specialist familiar with this type of treatment.

In the case of Hymenoptera allergy, patients receive VIT extracts

containing actual Hymenoptera venom with a maintenance dose

equivalent to 2–5 stings. The recommended duration of treatment is

3–5 years; however, some patients who have experienced severe respiratory or cardiovascular anaphylaxis are put on lifelong therapy.

Preventative Tolerance Induction IgE sensitization to foods

occurs most frequently in infants and young children, especially those

Mastocytosis

2729CHAPTER 354

with atopic dermatitis, and is a risk factor for anaphylaxis (although

detection of specific IgE through skin or serum testing has relatively

poor predictive value). While most allergy to egg, milk, soy, and/or

wheat resolves spontaneously during childhood, ~80% of children with

peanut allergy remain sensitive for life. A sharp rise in the prevalence

of peanut allergy was also observed in the late 1990s to early 2000s,

especially in countries with Western diets where the average age of

peanut introduction was age ≥3 years. Curiously, in cultures where peanut was introduced much earlier into children’s diets, the prevalence

of peanut allergy remained low. The landmark Learning Early About

Peanut Allergy (LEAP) study demonstrated that early introduction

of peanut protein to the diet of high-risk infants (4–11 months of age

with atopic dermatitis and/or egg allergy) prevented the development

of most (80% or more) peanut allergy compared with children who

did not consume peanuts (avoidance group), even when IgE sensitization (based on positive skin test) had already developed at the time

of study entry. While the induction of tolerance at an early age seems

to be key to preventing clinical reactivity later in life, it is not yet clear

if this principle holds true for other foods commonly associated with

hypersensitivity reactions.

Desensitization For patients who have experienced anaphylaxis

from drug allergy and whose treatment regimen requires the administration of the offending drug, desensitization may be a short-term

treatment option to prevent reactions. Desensitization elicits a temporary state of tolerance to the drug in sensitized, clinically reactive

patients. While it has been a proven technique for penicillin-allergic

patients for decades, desensitization has more recently been proven to

be effective for certain chemotherapy agents, especially platin-based

chemotherapy agents that can induce IgE-mediated sensitization with

repeated exposures. The exact mechanisms underlying desensitization

are not fully understood; however, temporary tolerance can be achieved

through the serial administration of gradually escalating doses of drug,

starting from extremely low doses, over the course of hours. So long as

the patient continues to receive the drug in question at regular intervals based on drug half-life, a “desensitized” state can also be maintained until the drug is no longer needed. While drug desensitization

certainly works for IgE-mediated reactions, it has been performed in

cases of non-IgE-mediated anaphylaxis from Cremophor-solubilized

paclitaxel as described earlier in this chapter. Desensitization has

also been shown by multiple groups to prevent non-IgE-mediated

reactions from a variety of biologic agents, various chemotherapy

drugs, and NSAIDs. Given the complexity and variety of possible drug

reactions, the decision to desensitize, challenge, or avoid should be

made in conjunction with an allergy specialist for complete evaluation

and proper risk stratification of the different possible approaches to

take.

■ FURTHER READING

Brennan PJ et al: Hypersensitivity reactions to mAbs: 105 desensitizations in 23 patients, from evaluation to treatment. J Allergy Clin

Immunol 124:1259, 2009.

Castells MC et al: Hypersensitivity reactions to chemotherapy: Outcomes and safety of rapid desensitization in 413 cases. J Allergy Clin

Immunol 122:574, 2008.

Chung CH et al: Cetuximab-induced anaphylaxis and IgE specific for

galactose-alpha-1,3-galactose. N Engl J Med 358:1109, 2008.

Du Toit G et al: LEAP Study Team. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med 373:803,

2015.

Du Toit G et al: Immune Tolerance Network LEAP-On Study Team.

Effect of avoidance on peanut allergy after early peanut consumption.

N Engl J Med 374:1435, 2016.

Lieberman P et al: Anaphylaxis—A practice parameter update 2015.

Ann Allergy Asthma Immunol 115:341, 2015.

Mcneil BD et al: Identification of a mast cell-specific receptor crucial

for pseudoallergic drug reactions. Nature 519:237, 2015.

■ DEFINITION AND EPIDEMIOLOGY

Mastocytosis is defined by accumulation of clonally expanded mast

cells in tissues such as skin, bone marrow, liver, spleen, and gut. Diagnostically, mast cell expansion is most readily identified in skin and/or

bone marrow. Mastocytosis occurs at any age and has a slight preponderance in males. The prevalence of mastocytosis is estimated at ~1 in

10,000 people. Most forms of the disease are characterized by somatic

gain-of-function mutations in the stem cell factor receptor (KIT) gene.

Familial occurrence is rare, and atopy is not increased compared with

the general population.

■ CLASSIFICATION AND PATHOPHYSIOLOGY

A consensus classification for mastocytosis recognizes cutaneous mastocytosis with variants, five systemic forms, and the rarest variant, mast

cell sarcoma (Table 354-1).

Cutaneous mastocytosis is the most common diagnosis in children and indicates disease limited to skin with absence of pathologic

infiltrates in internal organs. It is usually diagnosed within the first

year of life with demonstration of fixed, maculopapular, polymorphic,

and hyperpigmented lesions (maculopapular cutaneous mastocytosis

[MPCM], formerly known as urticaria pigmentosa), mastocytoma(s),

or diffuse cutaneous mastocytosis. Although mast cell accumulation

is limited to the skin, children often have systemic symptoms. Systemic mastocytosis (SM) refers to involvement of a noncutaneous

site (usually bone marrow). There are five distinct variants of SM.

Indolent systemic mastocytosis (ISM) accounts for the majority of adult

patients. ISM is diagnosed when there is no evidence of an associated

hematologic disorder, mast cell leukemia, or organ dysfunction due to

mast cell infiltration. ISM is associated with a normal life expectancy.

Smoldering systemic mastocytosis (SSM) is characterized by high mast

cell burden as evidenced by a bone marrow infiltration of >30% and

a baseline serum tryptase >200 ng/mL (B findings), but absence of

systemic mastocytosis associated with clonal hematologic non–mast

cell lineage disease (SM-AHNMD) or aggressive systemic mastocytosis

(ASM) (Table 354-2). In SM-AHNMD, the prognosis is determined

by the nature of the associated disorder, which can range from dysmyelopoiesis to leukemias usually of myeloid origin. In ASM, mast cell

infiltration/proliferation occurs in multiple organs such as liver, spleen,

gut, bone, and bone marrow resulting in one or more C findings and

a poor prognosis (Table 354-2). Mast cell leukemia (MCL) is the rarest

form of SM and is invariably fatal at present; the peripheral blood

contains circulating, metachromatically staining, atypical mast cells.

An aleukemic form of MCL is recognized without circulating mast

cells when the percentage of high-grade immature mast cells in bone

354 Mastocytosis

Matthew P. Giannetti, Joshua A. Boyce

TABLE 354-1 Classification of Mastocytosis

Cutaneous mastocytosis (CM)

Maculopapular cutaneous mastocytosis (MPCM)

Solitary mastocytoma of skin

Diffuse cutaneous mastocytosis

Indolent systemic mastocytosis (ISM)

Smoldering systemic mastocytosis

Systemic mastocytosis with an associated clonal hematologic non–mast cell

lineage disease (SM-AHNMD)

Aggressive systemic mastocytosis (ASM)

Mast cell leukemia (MCL)

Mast cell sarcoma (MCS)

Source: Modified from H-P Horny et al: Mastocytosis. In: WHO Classification of

Tumours of Haematopoietic and Lymphoid Tissues, revised 4th ed. SH Swerdlow

et al (eds). Lyon, France, IARC Press, 2017, pp 61–69.

2730 PART 11 Immune-Mediated, Inflammatory, and Rheumatologic Disorders

marrow smears exceeds 20% in a nonspicular area. Mast cell sarcoma is

a rare solid mast cell tumor with malignant invasive features.

Somatic activating mutations in the KIT gene are characteristic of

mastocytosis. KIT D816V is most commonly observed, although other

mutations have been reported. KIT mutations are found in mast cells

and sometimes in multiple other cell lineages in patients with mastocytosis. KIT mutations are observed in patients with all forms of SM

but are also present in some children with cutaneous mastocytosis in

lesional skin, as might be anticipated because mast cells are of bone

marrow lineage. Additional mutations in genes such as TET2, SRSF2,

ASLX1, and RUNX1 known to be associated with other hematologic

neoplastic disorders can be detected in patients, usually with advanced

(non-ISM) forms of SM. The prognosis for patients with cutaneous

mastocytosis and for almost all patients with ISM is a normal life

expectancy, whereas that for patients with SM-AHNMD is determined by the non–mast cell component. ASM and MCL have a poor

prognosis, while patients with SSM have an intermediate prognosis.

Progression from ISM to a more advanced form is rare (~5% overall);

however, patients should be monitored for emergence of hematologic

disease and end-organ manifestations of ASM. In infants and children

with cutaneous manifestations, namely, maculopapular cutaneous

mastocytosis, mastocytoma(s), or bullous lesions, visceral involvement

is usually lacking, and spontaneous resolution is common prior to

adolescence. Polymorphic maculopapular cutaneous mastocytosis usually resolves spontaneously. Progression from cutaneous mastocytosis

(CM) to ISM may occur in ~10% of children, especially in those with

high mast cell burden (diffuse cutaneous mastocytosis) or hematologic

abnormalities and those who present with smaller uniform lesions with

diameters measuring <2 cm (monomorphic cutaneous mastocytosis).

■ CLINICAL MANIFESTATIONS

The clinical manifestations of SM are due to the release of bioactive

substances acting at both local and distal sites, tissue infiltration by

mast cells, and the tissue response to the cellular infiltrate. The pharmacologically induced manifestations are intermittent flushing, tachycardia and vascular collapse, gastric distress, crampy lower abdominal

pain, and diarrhea. The increased local mast cell burden in the skin

(MPCM), bone marrow, and gastrointestinal tract may be a direct

cause of pruritus, bone pain, and malabsorption, respectively. Mast

cell–mediated fibrotic changes may occur in liver, spleen, and bone

marrow but not in gastrointestinal tissue or skin.

The cutaneous lesions of MPCM are reddish-brown macules, papules, or plaques that respond to trauma with urtication and erythema

(Darier’s sign). Two distinct forms of MPCM are recognized: polymorphic MPCM and monomorphic MPCM. Children with CM may

present with MPCM, mastocytomas, or diffuse cutaneous mastocytosis

(DCM). Mastocytomas are generally solitary elevated lesions that are

yellow, brown, or red in color. Their size may vary from a few millimeters to several centimeters. Rubbing or irritation of the mastocytoma

lesion may lead to systemic symptoms such as flushing and urticaria.

Children with DCM present without distinct lesions, but rather a

generalized thickening of skin and “peau d’orange” appearance due

to diffuse mast cell infiltration. DCM may be associated with bullae

formation and more severe systemic symptoms, including upper

gastrointestinal irritation and vascular collapse in the first few years

of life. Maculopapular skin lesions of mastocytosis may be present in

patients with adult-onset systemic disease. The apparent incidence of

cutaneous lesions is ≥80% in patients with ISM and <50% in those with

SM-AHNMD or ASM. In the upper gastrointestinal tract, gastritis and

peptic ulcer are significant problems. In the lower intestinal tract, the

occurrence of diarrhea and abdominal pain is attributed to increased

motility due to mast cell mediators; this problem can be aggravated

by malabsorption, which can also cause secondary nutritional insufficiency and osteomalacia. The periportal fibrosis associated with mast

cell infiltration may lead to portal hypertension and ascites. In some

patients, anaphylaxis with rapid and life-threatening vascular collapse

may occur. Anaphylaxis is most commonly induced by Hymenoptera

stings, and patients often have evidence of venom-specific IgE. The

neuropsychiatric disturbances are clinically most evident as impaired

recent memory, decreased attention span, and “migraine-like” headaches. Patients may experience exacerbation of a specific clinical sign

or symptom variably with alcohol ingestion, temperature changes,

stress, use of mast cell–interactive opioids, or ingestion of nonsteroidal

anti-inflammatory drugs (NSAIDs).

■ DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

Cutaneous mastocytosis is diagnosed by observing the characteristic

lesions of MPCM or mastocytoma(s). A skin biopsy may be obtained

to confirm these subvariants of CM, whereas patients with suspected

DCM and bullous mastocytosis require a skin biopsy to confirm the

diagnosis. Although the diagnosis of SM is generally suspected based

on clinical history, physical examination findings, and laboratory procedures, it can only be confirmed with a tissue diagnosis. The diagnosis

of SM necessitates a bone marrow biopsy to meet the criteria of one

major plus one minor or three minor findings (Table 354-3). The major

criterion requires mast cell aggregates, often in paratrabecular and

perivascular locations with associated lymphocytes and eosinophils.

Minor criteria include abnormal “spindled” mast cell morphology,

aberrant mast cell membrane immunophenotype (CD25 and/or CD2),

or a codon 816 mutation in an extracutaneous tissue. A basal serum

total tryptase level is a noninvasive approach to consider before bone

marrow biopsy. The pro-β and α forms of tryptase are elevated in more

than one-half of patients with SM and provide a minor criterion; the

fully processed (“mature”) β form is increased in patients undergoing

an anaphylactic reaction. A rare histopathologic subvariant called

well-differentiated systemic mastocytosis (WDSM) is characterized by

clusters of mature-appearing, fully granulated and round mast cells,

lack of aberrant CD25 and CD2 expression, and lack of D816V KIT

mutation in most patients. These patients often have a history of

TABLE 354-2 B and C Findings for Diagnosis of SSM and ASM

B Findings (2 or more in the absence of any C findings are required for a

diagnosis of SSM):

1. MC infiltration in bone marrow biopsy of >30% and a basal serum tryptase

level >200 ng/mL

2. Hypercellular bone marrow with signs of dysmyelopoiesis but without

cytopenias meeting C criteria or WHO criteria for an MDS or MPN

3. Palpable hepatomegaly, palpable splenomegaly, or lymphadenopathy

(on CT or ultrasound: >2 cm) without impaired liver function or hypersplenism

C Findings (1 or more required for a diagnosis of ASM). C findings should be

reasonably attributable to high tissue mast cell infiltration.

1. Cytopenia(s): ANC <1000/μL or Hb <10 g/dL or PLT <100,000/μL

2. Hepatomegaly with ascites and impaired liver function

3. Palpable splenomegaly with associated hypersplenism

4. Malabsorption with hypoalbuminemia and weight loss

5. Skeletal lesions: large area(s) of osteolysis with pathologic fractures

(presence of osteoporosis alone without osteolytic lesions does not satisfy

this criterion)

Abbreviations: ANC, absolute neutrophil count; ASM, aggressive systemic

mastocytosis; CT, computed tomography; Hb, hemoglobin; MC, mast cells; MDS,

myelodysplastic syndromes; MPN, myeloproliferative disorders; PLT, platelets; SSM,

smoldering systemic mastocytosis; WHO, World Health Organization.

TABLE 354-3 Diagnostic Criteria for Systemic Mastocytosisa

Major:

 Multifocal dense infiltrates of mast cells (>15 mast cells per aggregate) in

bone marrow or other extracutaneous tissues

Minor:

 Abnormal mast cell morphology (spindle shape, bi- or multilobed or eccentric

nucleus, hypogranulated cytoplasm)

 Aberrant mast cell surface phenotype with expression of CD25 (IL-2 receptor

alpha chain) and/or CD2

 Detection of codon 816 mutation in peripheral blood cells, bone marrow cells,

or an extracutaneous lesional tissue

Total serum tryptase >20 ng/mL

a

Diagnosis requires either the major criterion and one minor criterion or three minor

criteria.

Autoimmunity and Autoimmune Diseases

2731CHAPTER 355

childhood-onset cutaneous disease, and their mast cells may display

aberrant CD30 expression and other markers of clonality such as atypical (non-D816V) KIT mutations. Additional studies directed by the

presentation include a bone densitometry, bone scan, or skeletal survey; computed tomography scan or endoscopy; and a neuropsychiatric

evaluation. Osteoporosis is increased in mastocytosis and may lead to

pathologic fractures.

Some patients presenting with recurrent mast cell activation symptoms (particularly anaphylaxis with hypotensive syncope) have been

found to have underlying mastocytosis. A subset of these patients may

be found to have evidence of a clonal hematologic process such as

the D816V KIT mutation or aberrant mast cells displaying CD25, but

lack other diagnostic criteria for SM. Such patients are termed to have

monoclonal mast cell activation syndrome.

The differential diagnosis requires the exclusion of other disorders.

A 24-h urine assessment of 5-hydroxy-indoleacetic acid and metanephrines should exclude a carcinoid tumor and pheochromocytoma,

respectively. Hereditary α-tryptasemia may be characterized by symptoms of mast cell activation in addition to multisystem involvement

and elevated baseline serum tryptase. These patients have autosomal

dominant inheritance of α-tryptase gene duplications at the TPSAB1

locus. Most patients with recurrent IgE-induced or idiopathic anaphylaxis present with urticaria, angioedema, and/or bronchospasm, which

are not typical manifestations of anaphylaxis in SM.

TREATMENT

Mastocytosis

The management of SM is symptom control using a stepwise

symptom/sign–directed approach. Medications include an H1 antihistamine for flushing and pruritus, an H2 antihistamine or proton

pump inhibitor for gastric acid hypersecretion, oral cromolyn

sodium for diarrhea and abdominal pain, and occasionally aspirin

(in those who are known to be tolerant of NSAIDs) for severe flushing to block biosynthesis of prostaglandin D2

. Systemic glucocorticoids appear to alleviate malabsorption. Mast cell cytoreductive

therapy consisting of midostaurin, avapritinib, IFN-α, or cladribine

is generally reserved for advanced, nonindolent variants of SM.

Midostaurin and avapritinib are small-molecule tyrosine kinase

inhibitors with activity against both mutated KIT D816V and wildtype KIT and should be considered as a first-line therapy for these

disease variants. The efficacy of cytoreductive therapy in mastocytosis is variable, perhaps because of side effects that limit dosages.

Imatinib is not effective in most cases as the D816V KIT mutation

mediates resistance. Combination chemotherapy is appropriate for

the frank leukemias. Stem cell transplantation has been shown to

be effective in a small subset of patients with advanced mastocytosis. A self-injectable epinephrine prescription is recommended for

most patients due to increased incidence of anaphylaxis. Patients

with a history of systemic Hymenoptera venom reaction should

be evaluated for venom-specific IgE and placed on lifelong venom

immunotherapy if positive.

■ FURTHER READING

Akin C: Mastocytosis: A Comprehensive Guide. New York, Springer

International Publishing, 2020.

Hartmann K et al: Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on

Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical

Immunology. J Allergy Clin Immunol 137:35, 2016.

Horny H-P et al: Mastocytosis (mast cell disease). In: WHO Classification of Tumours. Pathology & Genetics. Tumours of Haematopoietic

and Lymphoid Tissues. SH Swerdlow et al (eds). Lyon, France, IARC

Press, 2008, pp 54–63.

Theoharides TC et al: Mast cells, mastocytosis, and related disorders.

N Engl J Med 373:163, 2015.

Ustun C et al: Consensus opinion on allogeneic hematopoietic cell

transplantation in advanced systemic mastocytosis. Biol Blood Marrow Transplant 22:1348, 2016.

Valent P et al: European Competence Network on Mastocytosis. Proposed diagnostic algorithm for patients with suspected mastocytosis:

A proposal of the European Competence Network on Mastocytosis.

Allergy 69:1267, 2014.

Valent P et al: Mastocytosis: 2016 updated WHO classification and

novel emerging treatment concepts. Blood 11:1420, 2017.

One of the central features of the immune system is the capacity

to mount an inflammatory response to potentially harmful foreign

materials while avoiding damage to self-tissues. Whereas recognition

of self plays an important role in shaping the repertoires of immune

receptors on both T and B cells and in clearing apoptotic and other

tissue debris from sites throughout the body, the development of

potentially harmful immune responses to self-antigens is, in general,

prohibited. The essential feature of an autoimmune disease is that tissue

injury is caused by the immunologic reaction of the organism against

its own tissues. Autoimmunity, on the other hand, refers merely to the

presence of antibodies or T lymphocytes that react with self-antigens

and does not necessarily imply that the self-reactivity has pathogenic

consequences. Autoimmunity is present in all individuals and increases

with age; however, autoimmune disease occurs only in those individuals in whom the breakdown of one or more of the basic mechanisms

regulating immune tolerance results in self-reactivity that can cause

tissue damage.

Polyreactive autoantibodies that recognize many host antigens

are present throughout life. These antibodies are usually of the IgM

heavy chain isotype and are encoded by nonmutated germline immunoglobulin variable region genes. These antibodies are essential, as

they remove apoptotic debris through non-inflammatory pathways.

Expression of these autoantibodies may be increased after some inciting events. When autoimmunity is induced by an inciting event, such

as infection or tissue damage from trauma or ischemia, the autoreactivity is generally self-limited. When such autoimmunity does persist,

however, pathology may or may not result. Moreover, even in the presence of organ pathology, it may be difficult to determine whether the

damage is mediated by autoreactivity or an ongoing pathologic process

related to the inciting trigger. Individuals with autoimmune disease

may have numerous autoantibodies, only some or even none of which

may be pathogenic. For example, patients with systemic sclerosis may

have a wide array of antinuclear antibodies that are important in disease classification but are not clearly pathogenic; in contrast, patients

with pemphigus may also exhibit a wide array of autoantibodies, one

of which (antibody to desmoglein 1 and 3) is known to be pathogenic.

MECHANISMS OF AUTOIMMUNITY

Since Ehrlich first postulated the existence of mechanisms to prevent

the generation of self-reactivity in the early 1900s, there has been a

progressive increase in understanding of this prohibition in parallel

with a progressive increase in understanding of the immune system.

Burnet’s clonal selection theory included the idea that interaction of

lymphoid cells with their specific antigens during fetal or early postnatal life would lead to deletion of such “forbidden clones.” This idea

was refuted, however, when it was shown that autoimmune diseases

could be induced in experimental animals by simple immunization

355 Autoimmunity and

Autoimmune Diseases

Betty Diamond, Peter E. Lipsky