Allergic Rhinitis

610 PART IV | SINUS, RHINOLOGY, AND ALLERGY/IMMUNOLOGY
TABLE 38-2. Chemokines—Cont’d

Systematic Name Common Name(s)/Ligand(s) Target Cell(s)
CCL27 Cutaneous T-cell–activating chemokine/IL-11 receptor T cell
α-locus chemokine
CCL28 Mucosa-associated epithelial chemokine T cell, eosinophil
C Chemokines
XCL1 Lymphotactin/SCM-1β/activation-induced, chemokine- T cell, NK cell
related molecule
XCL2 SCM-1β
CXC3C Chemokine
CXC3CL1 Fracktalkine T cell, monocyte
CCL, CC ligand; CK, chemokine; CXCL, CXC ligand; GRO, growth-related oncogene; HCC, human CC chemokine; IFN, interferon; IL, interleukin;
MCP, monocyte chemoattractant protein; MGSA, melanoma growth stimulatory activity; MIP, macrophage inflammatory protein; MPIF, myeloid
progenitor inhibitory factor; NK, natural killer; SCM, single C motif.
damage self antigens in various tissues. One clinical example is significantly more likely—up to four to six times more likely—
known as penicillin-induced autoimmune hemolytic anemia. Type III to develop in individuals with asthma than in the general
reactions, immune complex–mediated reactions (IgG- or IgM- population.
complex–mediated), involve antibody-mediated inflammation,
whereby the antibody and its antigen form low-solubility
immune complexes, deposited in normal tissues; activate com- HYGIENE HYPOTHESIS AND FACTORS
plement; and set off an inflammatory response characterized THAT CONTRIBUTE TO THE INCREASE
primarily by neutrophil influx, which inflicts tissue injury.
Knowledge of this immunologic disease became widespread in
IN ATOPIC DISEASE
the early 1900s, when physicians began using immune animal Epidemiologic data provide strong evidence of a steady rise in
sera, usually equine sera, to treat bacterial infections, a practice the incidence of allergic diseases (asthma, rhinitis, atopic der-
that led to serious illness and even death of the treated subjects matitis)153-164 and autoimmune diseases (multiple sclerosis,165
from a disease known as serum sickness.142 Immune complex insulin-dependent diabetes mellitus,166 Crohn disease167) in
vasculitis in the skin can also occur in a series of clinical condi- developed countries since the beginning of the 1970s. Con-
tions, such as systemic lupus erythematosus, rheumatoid arthri- comitantly, the incidence of many infectious diseases in devel-
tis, drug reactions, and infections. Type IV reactions, delayed-type oped countries has decreased as a result of antibiotics,
hypersensitivity reactions (T-cell–mediated), are caused by vaccination, or improved hygiene. A hypothesis thus emerged
antibody-independent mechanisms that involve T cells or NK that the decrease in infectious diseases is causally linked to the
cells. These reactions are the pathologic variants of a normal increase in the incidence of allergic disease, the so-called
T-cell–mediated immune response, in which the T-cell response hygiene hypothesis. Strachan168 observed that the risk of aller-
to an environmental antigen becomes exaggerated. A clinical gic rhinitis was inversely linked to birth order and the size of
example of such a reaction, as previously described, is the cuta- the family. He proposed that infections within households in
neous reaction to challenge with the purified protein derivative early childhood have a role in preventing allergic rhinitis.
of M. tuberculosis in previously infected or vaccinated patients. The geographic distribution of allergic and autoimmune
diseases in the world also shows interesting patterns. The inci-
dence of disease decreases from north to south in the Northern
ALLERGIC RHINITIS Hemisphere and reciprocally from south to north in the South-
Allergic rhinitis is a clinical hypersensitivity of the nasal mucosa ern Hemisphere. Underdiagnosis of allergic and autoimmune
to foreign substances mediated through IgE antibodies. It has diseases in underdeveloped countries could explain these geo-
a prevalence of between 10% and 20% and affects 20 to 40 graphic differences, but it is not likely. Although this explana-
million individuals in the United States annually.143-148 The tion might be proposed for allergic rhinitis and atopic
prevalence of seasonal allergic rhinitis is higher in children and dermatitis, relatively benign diseases, it is not likely to apply to
adolescents than in adults,149 and in childhood, boys with aller- type I diabetes and multiple sclerosis, which lead to significant
gic rhinitis outnumber girls; the gender ratio becomes approxi- symptoms and are not likely to go undiagnosed. Environment
mately equal in adults, however, and may even favor women. seems to play an important role in this incidence gradient.
Because individuals require low-dose exposure to an offending In developed and industrialized countries, a higher preva-
allergen over many years before development of symptoms, lence of atopy and asthma is observed than in undeveloped and
seasonal rhinitis rarely occurs in children younger than 2 years. less affluent countries. In fact, a positive correlation has been
Most patients with allergic rhinitis have symptoms before age demonstrated between gross national product and the inci-
20 years.150,151 The severity of the disease remains relatively con- dence of asthma, diabetes, and multiple sclerosis in Europe.169
stant throughout childhood and early adulthood, usually Persons who have emigrated to countries in which allergies are
improves in middle age, and is seldom a problem in the elderly. prevalent have higher rates of allergies and asthma than persons
A family history of allergic rhinitis increases the odds that a who remain in their country of origin. This difference probably
child will have the disease. Atopy, the predisposition to respond involves exposure to a new set of pollutants and allergens and
to environmental allergens with the production of specific IgE several socioeconomic and cultural issues, such as housing con-
antibodies, occurs in only 13% of children for whom neither ditions, diet, and accessibility to medical services, all of which
parent is atopic but in 29% of children with one atopic parent are likely to affect migrants’ health. The increase in allergy and
or sibling and in 47% for whom both parents are atopic.152 A asthma is usually not related to ethnicity, but in certain popula-
history of asthma is also important because allergic rhinitis is tions, this may play an important role. Studies of migrants
38 | ALLERGY AND IMMUNOLOGY OF THE UPPER AIRWAY 611
support the notion that lifestyle and environmental factors in However, although endotoxin was inversely related to atopy
Western industrialized countries facilitate atopy and asthma.170 and related phenotypes, it was a risk factor for nonatopic
An obvious factor in the north-south gradient is socioeconomic asthma, increased airway hyperresponsiveness, and low lung
differences. Several studies have found a lower frequency of function.195,196 Although endotoxins were the earliest identified
immunologic diseases in populations with a low socioeconomic bacterial products considered to play an important protective
status. Some infections have been found to be distributed role for allergy and asthma, more recently, protective asso
according to a south-north gradient in European countries that ciations have been observed for muramic acid, a marker for
mirrors the gradient for autoimmune diseases. Low socioeco- gram-negative and gram-positive bacteria, and extracellular
nomic levels and high temperatures, two common features of polysaccharides and glucans, markers of fungal exposure not
southern countries, may predispose to infections in a number limited to children living on farms.197 Two independent popula-
of ways: less stringent control of microbial contamination of tion surveys have shed further light on these associations.
water and food, an increased risk of bacterial proliferation with In those studies, microbial exposure to bacteria was character-
higher ambient temperatures, and poorer housing conditions ized by analyzing mattress or settled dust samples by molecular
may all affect the risk of contamination. techniques; the association between bacterial diversity and
When infections are an incriminating factor, they often asthma was strong, and the protective effects were linked to
occur in childhood. Young children with older brothers and specific bacterial and fungal species determined by sequencing-
sisters at home and those who attend a day care center during identification techniques.198
the first 6 months of life subsequently have a lower incidence Animal studies support the preceding epidemiologic obser-
of asthma171 and type I diabetes172 than children who do not vations because autoimmune diseases in susceptible strains of
attend a day care center and have no older siblings. The admin- mice and rats develop earlier and at a higher rate among
istration of antibiotics to children has been suspected to raise animals bred in a specific pathogen-free environment than
the risk of asthma and allergy. Droste and colleagues173 observed among animals bred in a conventional environment. The same
that the use of antibiotics in the first year of life increased the has been observed in relation to allergic diseases: administra-
risk of asthma or other allergic diseases in children with a tion of Mycobacterium bovis and Mycobacterium vaccae can attenu-
genetic predisposition to atopy. Antibiotics might act by decreas- ate the late-phase response, airway hyperresponsiveness, and
ing the number of infections or by modifying intestinal flora. bronchoalveolar lavage eosinophilia in a mouse model of bron-
The increase in atopic diseases in the northern parts of the chial asthma.199
hemisphere, in comparison with the southern parts, has been Several mechanisms might explain these relationships. The
linked to sun exposure and levels of vitamin D. In addition to development of most autoimmune diseases depends on the
its traditional role in the endocrine system, vitamin D dimin- TH1 cytokines IL-2 and IFN-γ, whereas the development of
ishes the risk of many chronic illnesses, including cancer, auto- allergic diseases requires the TH2 cytokines IL-4 and IL-5.
immunity, infection, and cardiovascular disease.174 This vitamin Initial reports that suggested an inverse relationship between
has also been implicated in the development of atopic diseases the incidences of autoimmune diseases and allergic diseases200
such as asthma, allergic rhinitis, and anaphylaxis.175-177 In a later led to speculation that the reciprocal downregulation of TH1
study, our group demonstrated lower levels of vitamin D in a cytokines by TH2 cytokines and the reverse might account for
cohort of blacks with chronic rhinosinusitis than in same-race these observations. However, later evidence supports an associa-
controls.178 Anaphylaxis, measured in proxy on the basis of tion between the incidences of allergic and autoimmune dis-
prescription of EpiPens, varies with geographic latitude; the eases.201,202 These observations would fit with the concept of
finding of higher levels in areas with less sun exposure supports common mechanisms that underlie infection-mediated protec-
the preceding theory.179 The possible mechanisms by which tion against autoimmunity and allergy.
vitamin D might affect diseases characterized by chronic inflam- Another potential mechanism involves Tregs and cytokines.
mation could be related to its immunologic effects—including The decrease in antigenic stimulation related to the decreased
those on T cells, dendritic cells, and macrophages180,181—as well frequency of childhood infections has resulted in a decrease in
as to the ability to promote IL-10 production by Tregs.182 the levels of regulatory cytokines, specifically IL-10 and possibly
Differences in disease incidence between urban and subur- TGF-β. CD25+ T cells and other Tregs produce these two cyto-
ban dwellers have been observed, and factors other than air kines, which in turn act to downregulate both TH1- and TH2-
pollution have been implicated. In 1999, Braun-Fahrlander and mediated responses. Data from humans and animal models
colleagues183 found that children who lived on farms and whose tend to support the concept that infectious agents stimulate the
parents were farmers were less likely to become allergic than production of regulatory cells whose effects extend beyond the
children from the same rural region who were not raised on a responses to the invading microbe.203,204 IL-10 and TGF-β, which
farm. Since then, a large number of studies have documented may be produced by CD25+ and other Tregs,205 can inhibit both
that people raised on farms have a lower prevalence of hay TH1 and TH2 responses and thus are plausible candidates for
fever and atopic sensitization in childhood and in adulthood, mediators of the inverse relationship between infections on the
whereas effects on asthma are more consistent for the atopic one hand and allergic and autoimmune diseases on the other.
than the nonatopic phenotype.184-193 The timing of the expo- Another hypothesized mechanism relates to stimulation of the
sure played a crucial role because the protection was strongest innate immune system by viruses and bacteria and their com-
when the exposures occurred in the first years of life rather ponents. Pathogen-associated molecular patterns that are struc-
than in later years.184,194 One such study showed that allergies tural components of microbes are recognized by receptors of
were less frequent when the children were exposed early and the host’s innate immune system, the pattern-recognition recep-
for a prolonged period to farm animals and cow’s milk.184 In tors.206 Examples of pathogen-associated molecular patterns are
that study, a clear maternal effect was also seen, because the LPS, a component of endotoxin, and muramic acid, a compo-
mother’s exposure to animal sheds during her pregnancy had nent of peptidoglycan that is part of the cell wall of most bac-
a protective effect on the offspring.184 An inverse correlation teria. Examples of human pattern-recognition receptors are
between endotoxin levels in bedding and the incidence of CD14 and the human TLRs discussed previously. Strong indica-
atopic diseases among children living in rural areas was also tions exist that microbes and their components stimulate innate
found, which suggests that a subject’s environmental exposure immune receptors and thereby favor the generation of Tregs
to endotoxin may play a crucial role in the development of toler- that promote immunologic tolerance through complex signal-
ance to ubiquitous allergens found in natural environments.195 ing pathways of the immune system.207 The induction of Tregs
may be a critical characteristic of a healthy microbiota, which 35,757 U.S. households, the Pediatric Allergies in America
is protective against the development of aberrant immunologic survey, significant impairment in children’s well-being, sleep,
reactivity to potential allergens.208 Because of these observa- and productivity at home and at school was associated with
tions, administration of microbes to prevent the development having allergies.224 The Nasal Allergy Survey Assessing Limita-
of atopic diseases has been investigated. A review of 13 random- tions, a national survey that measured the burden of disease of
ized placebo-controlled trials concluded that certain, but not allergic rhinitis in the United States, compared the health status
all, microbes could have utility, particularly when administered of adults with current nasal allergies (n = 400) with a national
early in life.209 However, clinical data on the use of microbes in sample of adults without nasal allergies (n = 522).225 The results
the treatment of asthma and allergic rhinitis are conflicting. showed that compared with the nonallergic adults, respondents
Another interesting observation relates to the presence of pets with allergic rhinitis rated their overall health lower, were more
in the house and the risk of asthma. Farm animals have not likely to complain of sleep difficulties, and were more likely to
been common in big European and American cities, but domes- report that their health limited them from doing well at work;
tic pets are extremely common. They are a prolific source of their productivity was estimated to drop by around 20% on days
allergen, and sensitization to these allergens is strongly associ- when their symptoms were at their worst. In other adult surveys,
ated with asthma.210 Reports from Europe suggest that the pres- similar adverse effects on proper functioning ability led to an
ence of a cat in the home decreases the risk of sensitization to impairment in work ability and induced both work absenteeism
cat allergens.211 Because of studies that suggest that the same and a reduction in work productivity and presenteeism.226,227 In
effect occurs in countries where domestic animals are equally one study, the mean total productivity losses per employee per
common in the homes of families with a history of asthma as year were $593 for allergic rhinitis, which was more costly than
in the homes of families without such a history, the initially all other prevalent and chronic disorders, including migraine,
proposed explanation that this effect could be secondary to depression, respiratory infections, diabetes, asthma, and coro-
decisions by families with allergic disease not to have pets is nary artery disease.228
unlikely. Ownby and colleagues212 strengthened these initial For all these reasons, allergic rhinitis is a costly disease.
observations. They reported that children in a birth cohort Estimates of the annual health care costs have ranged from $2
raised in a house with two or more dogs or cats in the first year billion to $5 billion with the wide range related to the param-
of life not only have less allergic sensitization to dog and cat eters used to make these estimates.229
danders, as determined by skin-prick tests and allergen-specific
IgE levels, but also have less sensitization to allergens in general
at age 6 to 7 years. Because domestic animals can be a source
PATHOPHYSIOLOGY OF
of endotoxin, this finding suggests the possibility that the effects ALLERGIC RHINITIS
of pets, as these researchers described in the United States, SENSITIZATION AND IMMUNOGLOBULIN
could be comparable to those of cows and farm animals in
Europe. Mechanisms similar to those discussed earlier in this E PRODUCTION
chapter that involve Tregs and inhibitory cytokines are being During the initial stage of allergic rhinitis, low-dose exposure
investigated to explain these findings. leads to the production of specific IgE antibodies. Antigen that
The interesting relationships between infections and is deposited on the nasal mucosa is engulfed by APCs (macro-
immune-mediated diseases, such as allergic and autoimmune phages, dendritic cells, Langerhans cells) and is partially
diseases, and between early exposure to some allergens and the degraded within their phagolysosomes. Portions of the antigen
lowered risk of future allergic sensitization potentially create are then exteriorized on the surfaces of APCs and are recog-
new therapeutic strategies. The challenge will be to elucidate nized by helper T cells and class II MHC molecules. IL-1–acti-
the responsible immune mechanisms involved and to deter- vated helper T cells then secrete cytokines, which promote the
mine the extent of exposure that will ensure safety and the growth and differentiation of other cells involved in the
desired outcome—the development of healthy children with a immune response. TH2 CD4+ cells are important contributors
very low risk of allergic and autoimmune disease. to allergic reactions. They secrete the cytokines IL-4, IL-5, and
IL-13, which are all central to the production of IgE and to the
recruitment and survival of eosinophils at sites of allergic reac-
BURDEN OF DISEASE tions. Antigen-specific IgE then attaches to high-affinity recep-
Health-related quality of life is the component of overall quality tors on mast cells and basophils and to low-affinity receptors on
of life that is determined primarily by a person’s health and other cells, thereby sensitizing the nasal mucosa. On subse-
that can be influenced by clinical interventions. Using both quent exposure to the offending allergen, the IgE antibodies
generic and disease-specific tools, several investigations have on the surfaces of these cells serve as receptors for the antigen
documented a significant impairment of quality of life in molecules. Cross-linking of adjacent IgE molecules on mast
patients with allergic rhinitis.213-217 The disease-specific tools are cells leads to the release of inflammatory mediators that stimu-
more sensitive to change in the health-related quality of life late nerves, glands, and blood vessels to cause the clinical mani-
than the generic instruments. The most commonly used festations of the disease—namely, sneezing, pruritus, rhinorrhea,
disease-specific tool is the rhinoconjunctivitis quality-of-life and nasal obstruction. These events are known as the early
questionnaire developed and validated by Juniper and Guyatt.217 allergic response.
Modifications of this questionnaire are also validated and tested
for patients with perennial rhinitis, adolescents (12 to 17 years
old), and children (6 to 12 years old).
EARLY RESPONSE TO ANTIGEN
Poorly controlled allergic rhinitis has been shown to con- Within minutes after exposure of an allergic patient to antigen,
tribute to sleep loss or disturbance, and seasonal allergic rhini- an inflammatory response occurs. The patient first senses tin-
tis leads to increased daytime sleepiness.218-220 Allergic rhinitis gling and pruritus, followed by sneezing, rhinorrhea, and, lastly,
also contributes to children’s learning problems in school, nasal congestion. These subjective feelings correlate with physi-
either through direct interference or indirectly through its ologic changes measured after antigen provocation, such as
adverse effect on sleep.221 Treatment with sedating H1 antihis- increases in nasal secretions and nasal airway resistance.230 In
tamines aggravates these problems, and nonsedating antihista- addition to these physiologic changes, increases are noted in
mines only partially reverse this effect.222,223 In a survey of the levels of several mediators, including histamine,231 kinins,
tryptase,232 PGD2,233 leukotriene C4,234 leukotriene B4,235 MBP,236 mediated by these peptides amplify the inflammatory allergic
and platelet-activating factor.237 These mediators lead to the reaction.250-256
various symptoms of allergic rhinitis by their effects on end Mosimann and colleagues257 were able to demonstrate sig-
organs and nerves of the nasal mucosa. Histamine and tryptase nificant increases in the levels of substance P, CGRP, and vasoac-
are found in mast cell granules, and their detection in nasal tive intestinal peptide immediately after antigen challenge in
secretions after antigen provocation provides support for mast allergic individuals; in patients who experienced a late reaction,
cell degranulation during the nasal allergic reaction. PGD2 and only substance P increased slightly. These experiments suggest
the cysteinyl leukotrienes, newly synthesized mediators of the that neuropeptides are released in vivo in humans after allergen
arachidonic acid pathway, are also secreted by mast cells. challenge and might be partly responsible for symptoms of the
Further evidence for the role of nasal mast cells in the immedi- allergic reaction. Repetitive application of capsaicin, the essence
ate allergic reaction was provided by the demonstration of of chili peppers, releases substance P and CGRP from sensory
degranulated mast cells in nasal mucosal biopsies of allergic nerves and initiates both central and axonal reflexes.258 Capsa-
patients after allergen challenge.238 icin causes a burning sensation and profuse bilateral rhinorrhea
when applied to one side of the nasal cavity, and repeated
administration causes tachyphylaxis.259,260 The capsaicin-induced
NEURONAL CONTRIBUTION nasal secretory response in humans is glandular and is not
Sneezing and itching during the early response to allergen caused by increased vascular permeability.261 Furthermore, cap-
provocation involve the nervous system. Unilateral intranasal saicin desensitization reduces sneezing in response to antigen
antigen challenge experiments have supported the role of the and histamine challenges.262 All these findings point to the
nervous system in amplifying the allergic response, because importance of the participation of neurogenic elements to the
challenge leads not only to an increase in sneezes, rhinorrhea, allergic response, and more specific delineation of the role of
nasal secretions, histamine, nasal airway resistance,239 and each of these neuropeptides awaits the development of specific
PGD2240,241 on the side of challenge but also leads to an increase antagonists.
in rhinorrhea, secretion weights, and PGD2 contralateral to the Transient receptor potential (TRP) is one of a family of ion
challenge.241 The contralateral secretory response was rich in channels involved in transducing external stimuli to sensory
glandular markers240 and was inhibited by atropine, an anticho- neurons.263 Among those channels, TRP vanilloid 1 is capsaicin
linergic,239 which suggests that the efferent limb was cholinergi- sensitive and mediates the pungency of capsaicin, and TRP
cally mediated. It has also become clear that the nasal response ankyrin 1 mediates the effects of noxious stimuli such as cold
to allergen is accompanied by an ocular, a pulmonary, and even temperatures, pungent natural compounds, and environmen-
a sinus response that can, at least in part, be explained by a tal irritants.264 These channels are being recognized as increas-
neural reflex. Monitoring ocular symptoms and secretions after ingly important in mediating the nasal response to noxious
unilateral allergen challenge has shown an ocular symptomatic stimuli. Evidence that supports their contribution to allergic
and secretory response that is inhibited by pretreatment with rhinitis is emerging but is still scant. It is well known that the
an intranasal antihistamine, which suggests that histamine’s intranasal application of capsaicin produces more symptoms
action on nasal afferent nerves initiates this reflex.242 This nasal during the pollen season compared with prior to the season,
ocular reflex has also been shown to be potentiated by repeated which suggests that capsaicin generates nonspecific nasal
allergen challenges, which lead to priming, a process inhibited hyperreactivity during allergic inflammation.265,266 In a more
by pretreatment with intranasal steroids (INSs) because of their recent study, intranasal capsaicin—but not the stimulators of
antiinflammatory actions.243 Similar unilateral challenge studies TRP ankyrin 1 (mustard oil, cinnamaldehyde) or TRP member
with allergens have shown an influx of eosinophils into the 8 (menthol)—was shown to induce itching during the allergy
ipsilateral maxillary sinus hours after allergen provocation that season.267 Further support for the importance of these channels
parallels the increase in these cells seen in nasal secretions, comes from histologic findings that identify them in the epi-
albeit of a lesser magnitude.244 Seasonal studies have also shown thelial and subepithelial layers of the nasal mucosa and show
an influx of eosinophils into both nasal and maxillary sinus their expression to be higher, albeit not significantly higher, in
cavities during the peak of the allergy season.245 Similarly, chal- allergic patients compared with nonallergic controls.268 Unfor-
lenge of the nose with allergen has been shown to lead to tunately, a recent placebo-controlled clinical trial that used a
upregulation of inflammatory markers in bronchial biopsy TRP vanilloid 1 antagonist in allergic rhinitis, induced in a
specimens obtained 24 hours later.246 In a similar study, nasal challenge chamber, did not show evidence of efficacy when the
allergen challenge led to an increase in levels of leukotrienes agent was used either alone or in combination with an INS.269
and 8 isoprostane in exhaled-breath condensate 2 and 24 hours
after the challenge.247 Besides a reflex initiated in the nose,
another possible explanation of these findings has included the
LATE RESPONSE TO ANTIGEN
theory of systemic allergic inflammation, whereby an allergic The response to allergen exposure is not limited to the acute
reaction at one site generates an inflammatory response that events that occur minutes after exposure. Hours after antigen
reaches the systemic circulation and then leads to the involve- challenge, some patients experience a recurrence of symptoms,
ment of other predisposed end organs.248 most notably nasal congestion; this is termed the late response.
In addition to sympathetic and parasympathetic nerves and Several investigators have documented elevations in nasal
their transmitters, several neuropeptides are found in the nasal airway resistance 4 to 10 hours after antigen challenge, with a
mucosa. These neuropeptides are secreted by unmyelinated peak around 6 hours and resolution by 24 hours.270,271 After
nociceptive C fibers (tachykinins, calcitonin gene–related nasal challenge with antigen, the early response was followed
peptide [CGRP], neurokinin, gastrin-releasing peptide), para- by a recurrence of symptoms and increases in the levels of
sympathetic nerve endings (vasoactive intestinal peptide, histamine, tosyl-l-arginine methyl ester–esterase, and kinins,
peptide histidine methionine), and sympathetic nerve endings but not PGD2.272 Other mediators, including eosinophil prod-
(neuropeptide Y). Substance P, a member of the tachykinin ucts, have also been detected.236 These events are accompanied
family, is often found as a cotransmitter with neurokinin A and by an inflammatory cellular influx.
CGRP; it has been found in high density in arterial vessels and, In addition to the different preformed and newly generated
to some extent, in veins, gland acini, and epithelium.249 Several inflammatory mediators secreted by mast cells and other
studies support the concept that neuronal mechanisms inflammatory cells during the allergic reaction, cytokines have
been identified in the nasal mucosa and in nasal secretions of of TH2 cells and their cytokines in the allergic reaction. The
allergic patients during natural exposure and allergen provoca- effects of TH2 cytokines are all conducive to the promotion of
tion. In different allergen challenge experiments, increased allergic inflammation: IL-5 promotes the differentiation,286 vas-
levels of IL-1β, TNF-α, and GM-CSF were detected during the cular adhesion,287 and in vitro survival of eosinophils288 and
early hours after provocation, and levels of IL-5, IL-6, IL-8, enhances histamine release from basophils289; IL-4 is a mast cell
GM-CSF, TNF, and soluble intercellular adhesion molecule 1 growth factor290 that promotes the switching of B cells to the
(ICAM-1) were detected during the late-phase response.273-277 production of IgE291 and IL-13, independent from the other
Furthermore, significantly elevated baseline levels of IL-1β, two cytokines, and is necessary and sufficient to induce key
IL-6, and IL-8 were detected in nasal lavages of patients with features of inflammation such as eosinophil recruitment,
seasonal allergic rhinitis compared with those of healthy mucus hyperproduction, and airway hyperresponsiveness.292
subjects.275
Investigations relating to the role of cytokines in allergic
rhinitis have been performed using nasal biopsies during the
CELLULAR EVENTS
season or after challenge, looking either for protein expression Along with the physiologic changes and inflammatory mediator
using immunohistochemistry or mRNA using in situ hybridiza- production that occur hours after antigen provocation, inflam-
tion. Compared with healthy subjects, nasal biopsies from matory cellular influx occurs in the nasal mucosa and in recov-
patients with perennial allergic rhinitis show significantly more ered nasal secretions after experimental provocation and in
IL-4–positive cells, which seem to be primarily (78% to 100%) seasonally exposed patients. The sampling techniques in the
localized to mast cells as evidenced by positive staining of the various studies differ in that some target nasal secretions and
same cells on consecutive sections with an antibody against the superficial layers of the mucosa (lavage, scraping, brushing)
mast cell tryptase.278,279 Immunoreactivity for IL-5, IL-6, and IL-8 and others target the actual mucosa and submucosa (biopsy).
was present in most biopsy specimens from perennial rhinitis Studies suggest that these techniques yield different cellular
patients and healthy subjects, and no significant differences predilections for allergic inflammation; polymorphonuclear
were found between the two populations. Most IL-5–positive cells and eosinophils predominate in nasal secretions and
cells were mast cells, with some eosinophils. IL-6 also colocal- mononuclear cells predominate in the nasal mucosa, which
ized to mast cells, and IL-8 was localized to the cytoplasm of suggests that nasal secretions and the nasal mucosa are two
epithelial cells.278 No cytokine reactivity was localized to CD3− separate compartments with different inflammatory cellular
or CD4+ cells. These data suggest that IL-4, IL-5, and IL-6 pro- predominance during allergic inflammation.293
teins are localized to mast cells in the nasal mucosa of patients Typically, a slight initial increase in eosinophils in nasal
with perennial allergic rhinitis. The lack of localization of any secretions is observed within 1 to 2 hours of challenge and is
of the cytokines to T lymphocytes is attributed by the authors usually followed by a peak 6 to 8 hours later.294 MBP, a mediator
to the fact that cytokines generated by activated T cells are secreted by eosinophils, is also recovered in nasal lavages hours
rapidly transported from the cell and do not accumulate in after antigen provocation, and its levels correlate with the
sufficient concentrations to be detected by the techniques used. number of eosinophils, which suggests that these cells flow into
This work supports the role of mast cells in contributing to the nasal secretions and release inflammatory mediators.236 Baso-
cytokines released in the local milieu after exposure to aller- phils constitute 1% of the recovered cells; their number cor-
gen. The same investigators, studying seasonal allergic rhinitis, relates significantly with levels of histamine recovered in nasal
showed that pretreatment with intranasal corticosteroids sup- secretions during the late-phase response, which suggests that
pressed the increases in mucosal eosinophils and epithelial these cells are the source of the late rise in histamine.294
mast cells and also led to a significant suppression of IL-4–posi- Similar cellular changes have been observed during seasonal
tive cells in the nasal submucosa, without significant effects on exposure of allergic patients, which lends credibility to the
the number of IL-5 and IL-6 immunoreactive cells.280 observations after experimental allergen challenge. Nasal
Looking for mRNA for the different cytokines in nasal biopsy specimens collected from allergic patients during the
biopsy specimens after allergen challenge of allergic subjects, pollen season showed significant increases in total MBP and
Durham and others281 found significant increases in cells activated (EG2+) eosinophils in the submucosa compared with
bearing mRNA for IL-3, IL-4, IL-5, and GM-CSF—but not for preseasonal eosinophil numbers and with numbers in biopsy
IL-2 or IFN-γ—compared with biopsies obtained after a control specimens from nonallergic subjects.295 Basophilic cells were
challenge. Activated eosinophils (EG2+) increased significantly observed in nasal secretions during seasonal exposure of aller-
after allergen challenge and correlated positively with mRNA gic patients to pollen.296,297 In contrast to nasal secretions, exam-
expression for IL-5, IL-4, GM-CSF, IL-3, and IL-2 but not for ination of nasal mucosal scrapings298,299 or biopsy specimens,299,300
IFN-γ. Most IL-5 mRNA-positive cells were also shown to be which sample deeper layers, showed that most metachromatic
CD3+ (83%), and the rest were positive for tryptase (16.4%).282 cells in these compartments were mast cells. A seasonal increase
The same investigators demonstrated that pretreatment with in mast cells occurs on the surface of the nasal epithelium after
fluticasone propionate before allergen challenge resulted in 4 or 5 days of exposure to pollen, which seems to be the result
significant inhibition of an allergen-induced increase in acti- of migration of mast cells from the deeper layers of the lamina
vated eosinophils (EG2+) and cells that express mRNA for IL-4 propria to the surface.300 The consensus of most researchers is
but not for IL-5.283 In addition to inhibiting cellular influx into that basophils predominate in nasal secretions, whereas mast
the nasal mucosa, immunotherapy also induced a TH1 cell cells are more abundant in the epithelium and lamina propria
response, with a significant increase in cells expressing mRNA of allergic patients exposed to antigen either experimentally or
for IFN-γ.284 Other biopsy studies have also shown significant naturally.
increases in mRNA-positive cells for IL-10 and IL-13 after aller- Although eosinophils and mast cells are found in the nasal
gen challenge.285 submucosa, most cells in this location are mononuclear cells
These findings suggest that both T lymphocytes and mast (lymphocytes and monocytes). Numbers of CD4+ (helper T)
cells are contributors to cytokine production during the aller- lymphocytes and CD25+ cells are significantly higher after
gic reaction, and technical differences in detection probably antigen challenge than after sham challenge.301
account for the differences in the quantitative distribution of The preceding discussion of cytokines stresses that a signifi-
the cytokines between these two cell types. The cytokine profile cant source of cytokine production in the nasal mucosa in
observed after exposure to allergen emphasizes the importance allergic inflammation is the helper T cells of the TH2 subtype.
Freely Flattening
Expression Tissue
circulating Rolling and Transmigration
of receptors migration
cell adhesion
ICAM,
GM-CSF, Selectins VCAM
IL-3, IL-5,
PAF, LTB4
Integrins
FIGURE 38-5. Cellular adhesion and recruitment. An eosinophil is seen from the early stage of free circulation to rolling; adhesion to the vascular endothelium;
transendothelial migration; and, finally, tissue migration. In the case of the eosinophil, these events are regulated and mediated by multiple cytokines and
adhesion molecules. GM-CSF, granulocyte-macrophage colony-stimulating factor; ICAM, intercellular adhesion molecule; IL, interleukin; LTB4, leukotriene B4;
PAF, platelet-activating factor; VCAM, vascular cellular adhesion molecule. (From Mygind N, Dahl R, Pedersen S, Thestrup-Pedersen K, editors: Essential allergy,
ed 2, Oxford, 1996, Blackwell Scientific Publications.)
Another important cell type detected in the nasal mucosa of sialyl–Lewis X with E-selectin and P-selectin, and glycosylation-
allergic patients is the Langerhans cell, a large, mononuclear dependent cell adhesion molecule 1 for l-selectin.304,306
dendritic cell important in antigen presentation. Although the A series of events occurs during the migration of circulating
numbers of intraepithelial CD1+ (Langerhans) cells in healthy leukocytes into tissues (Fig. 38-5). The cells initially undergo
subjects and grass-allergic patients before and after the pollen reversible margination, and on intravital microscopy, they can
season are not different, the numbers of intraepithelial CD1+ be seen rolling along the endothelial surface.307 These changes
cells are significantly increased during the allergy season.302 In a are mediated by interactions between carbohydrates and selec-
study that involved patients with perennial allergic rhinitis, a tins. Leukocyte activation occurs next, presumably as a result of
significant decrease in numbers of Langerhans cells in the epi- exposure to chemoattractants or other activating factors released
thelium was seen after 3 months of treatment with fluticasone by endothelial cells or by nearby tissue-dwelling cells. Leukocyte
propionate.303 Thus Langerhans cells appear to be important in activation is associated with changes in affinity and expression of
the allergic reaction and seem to not be constitutively more adhesion molecules on the leukocyte surface. Leukocytes may
numerous in patients with allergic rhinitis but are more likely to also be activated directly by their interaction with adhesion mol-
be upregulated upon exposure to allergen. ecules on activated endothelial cells.308 Activated leukocytes
then attach to endothelial cells and migrate across the endothe-
ADHESION MOLECULES AND lium into the extravascular space. These events are mediated by
one or more members of the integrin, selectin, and immuno-
CELLULAR RECRUITMENT globulin families of adhesion molecules. Furthermore, it is
Cellular trafficking is integral to the human immune response, likely that the preferential recruitment of leukocytes involves
because it allows cells to be selectively recruited from the blood- multiple steps, such as leukocyte activation, vascular endothelial
stream into sites of tissue inflammation. Cellular recruitment cell expression of adhesion molecules, adhesion of leukocytes to
into sites of allergic reactions is an example of such trafficking. vascular endothelium, transendothelial migration, chemotaxis,
Numerous inflammatory cells are present in the nasal mucosa and localized survival within the tissues. Multiple cytokines and
and in nasal secretions of allergic patients during allergen expo- other factors are important in upregulating adhesion molecules
sure but are not present in healthy subjects. Mechanisms should on circulating leukocytes and vascular endothelium and are
therefore exist for the migration and accumulation of these crucial in chemotaxis and leukocyte survival within the tissues.
effector cells during allergic inflammation. Recruitment of cells Clear evidence shows that endothelial activation occurs
such as eosinophils and activated T lymphocytes is mediated in during allergic rhinitis in vivo. Enhanced expression of ICAM-1
part by interactions between adhesion molecules on the cells and VCAM-1, but not E-selectin, has been described in the
themselves and those on vascular endothelial cells, with cyto- mucosa of allergic patients.309 The expression of VCAM-1 was
kines playing various regulating roles in these interactions. found to be significantly upregulated in biopsy specimens
The molecules responsible for adhesion on leukocytes belong obtained from allergic patients 24 hours after antigen chal-
to different families, such as the integrin family, the very late lenge concomitant with a significant increase in the number of
antigen family, and the selectin adhesion molecule family.304-306 eosinophils.310 These studies of adhesion molecules in vivo
Adhesion molecules on the vascular endothelial cell surface suggest that these molecules, along with their counterligands
include ICAM-1 (CD54), ICAM-2, E-selectin, P-selectin (granule on circulating leukocytes, have an important role in cellular
membrane protein 140, CD62), and VCAM-1.307 Receptor- recruitment to allergic inflammatory sites. Further studies are
counterreceptor pairs for adhesion molecules include leuko- needed for better definition of the role of these adhesion
cyte function–associated antigen 1 with ICAM-1 and ICAM-2, mechanisms in allergic rhinitis and for determination of
the macrophage differentiation antigen Mac-1 with ICAM-1, whether interfering with the process of adhesion would modify
very late antigen 4 with VCAM-1, the carbohydrate structure the course and severity of the disease.
as histamine and the cholinergic agonist methacholine. Patients

HYPERRESPONSIVENESS who underwent an antigen challenge followed 24 hours later
One of the hallmarks of allergic rhinitis is the hyperresponsive- by a histamine challenge showed increased sensitivity to hista-
ness of allergic patients to specific stimuli such as antigen, a mine compared with those who underwent only a baseline
phenomenon known as priming, and to nonspecific stimuli. histamine challenge,313 and this response was inhibited by pre-
treatment with topical corticosteroids.314,315 The number of
Specific Hyperresponsiveness eosinophils in nasal secretions 24 hours after antigen challenge
Many allergic patients report worsening of symptoms as the correlated with the magnitude of reactivity to histamine, and
allergy season progresses despite unchanged or decreased inhibition by topical corticosteroids was accompanied by an
pollen counts. This phenomenon is probably caused by a shift inhibition of the increase in eosinophils.315 Similar studies
in the threshold of responsiveness. Connell311 found that the show nasal hyperresponsiveness to the cholinomimetic agonist
dose of pollen necessary to create symptoms decreased more methacholine.316-319 In allergic patients during the allergy
than fivefold by the fourth day of consecutive antigen chal- season, the hyperresponsiveness caused by nonspecific irritants
lenges. Consecutive nasal allergen challenges have also demon- probably reflects complex interactions among inflammatory
strated the priming phenomenon, in that patients challenged cellular influx, epithelial injury, and increased end-organ
24 hours after earlier exposure had significantly more sneezes responsiveness caused by exposure to antigen.
and a reduction in the threshold dose necessary to elicit the The pathophysiologic mechanisms in allergic rhinitis can be
response.312 Concomitant with the priming response observed synthesized (Fig. 38-6). In this scenario, sensitization of the
for sneezes, significantly higher levels of histamine and kinins nasal mucosa to a certain allergen entails multiple interactions
and an increase in the number of neutrophils, eosinophils, and among APCs, T lymphocytes, and B cells that lead to the pro-
basophils were observed in nasal lavage samples. These observa- duction of antigen-specific IgE antibodies, which then localize
tions suggest that mechanisms of priming involve cellular infil- to mast cells and basophils. Subsequent exposure leads to cross-
tration, increased mediator production, and possibly increased linking of specific IgE receptors on mast cells and their resultant
end-organ responsiveness. Inflowing inflammatory cells are degranulation, with the release of a host of inflammatory media-
hypothesized to alter the mucosal penetration of antigen and tors that are, in large part, responsible for allergic nasal symp-
to provide additional targets for antigen stimulation and toms. Other proinflammatory substances are also generated
increased generation of inflammatory mediators, which would after antigen exposure, the most prominent being eosinophil
in turn encounter more responsive end organs and would thus products and cytokines. Cytokines are thought to be generated
lead to the exaggerated response noted after repeated antigen in part by lymphocytes, which are abundant in resting and
exposure. stimulated nasal mucosa, and also by mast cells, which have an
important role in the storage, production, and secretion of
Nonspecific Hyperresponsiveness cytokines. Cytokines upregulate adhesion molecules on the vas-
Increased reactivity to irritant stimuli is often reported by aller- cular endothelium, and possibly on marginating leukocytes,
gic patients. This phenomenon has been studied by observation which leads to the migration of these inflammatory cells into
of the nasal response to nonantigenic nasal secretagogues, such the site of tissue inflammation. Various cytokines also promote
Phase 1 Phase 2
Sensitization Clinical Disease
Early Late
Antigen- Inflammation Inflammation
presenting cell
Allergen
Allergen
IgE antibodies Resolution

Late-phase
Cellular reaction
Processed
infiltration Hyper-
allergen
responsiveness Complications
Mast Eosinophils
CD4 Mediator cell Basophils
T cell release
Monocytes Priming ? Irreversible
B cell Nerves
Blood Lymphocytes disease
vessels
Glands
Sneezing
Rhinorrhea
Congestion
Plasma cell IgE antibodies
FIGURE 38-6. Pathophysiology of allergic rhinitis. The first stage of development of allergic rhinitis involves antigen processing and the production of specific
immunoglobulin E (IgE) antibodies, which attach to mast cells, basophils, and other inflammatory cells. On subsequent exposure to the same allergen, IgE
receptors on the surface of mast cells are cross-linked, which leads to the degranulation of these cells and to the release of preformed and newly synthesized
mediators responsible for symptoms of the disease. Recruitment of inflammatory cells to the nasal mucosa also occurs, as does a resultant state of chronic
inflammation with a heightened state of reactivity to specific and nonspecific stimuli—a hallmark of allergic nasal disease. In addition to the early and late
inflammatory responses, exposure to allergen leads to a secondary immune response with increased production of specific IgE and a perpetuation of the state
of susceptibility to allergen. (From Naclerio RM: Allergic rhinitis. N Engl J Med 1991;325:860.)
the chemotaxis and survival of these recruited inflammatory and for more than 4 consecutive weeks, with the realization that
cells, which leads to a secondary immune response by virtue of patients usually suffer almost every day. The severity is desig-
their capability to promote IgE synthesis by B cells. Also impor- nated as mild or moderate to severe. Mild implies that symp-
tant is the nervous system, which amplifies the allergic reaction toms are present but not troublesome; importantly, sleep
by central and peripheral reflexes that result in changes at sites disturbance and impairment of leisure/sport/school/work and
distant from those of antigen deposition, such as the eye, daily activities are absent. Moderate to severe implies the presence
sinuses, and lower airway. These inflammatory changes lower of one or more of the following: sleep disturbance; impairment
the threshold of mucosal responsiveness to various specific and of leisure/sport/school/work and daily activities; and trouble-
nonspecific stimuli, and this makes allergic patients more some symptoms. The ARIA classification is used to suggest a
responsive to stimuli to which they are exposed every day. treatment algorithm, whereas the traditional classification is
used to help define the offending antigens.
EVALUATION AND DIAGNOSIS More recently, a clinical phenotype has been described
whereby patients have the typical symptoms of allergic rhinitis
HISTORY but allergy testing results (skin or serologic) are negative.
The classic symptoms of seasonal allergic rhinitis are recurrent Whereas these patients were previously lumped into the diag-
episodes of sneezing, pruritus, rhinorrhea, nasal congestion, nostic subset of nonallergic rhinitis, positive nasal response to
and lacrimation that occur after exposure to the offending allergen challenge now places them in a category referred to
allergen. Itching is the symptom most suggestive of an allergic as local allergic rhinitis (LAR), characterized by a localized nasal
etiology and involves not only the nose but also the palate, allergic response in the absence of systemic atopy.322 Most of
throat, eyes, and ears. Rhinorrhea is usually clear and can be the data available on this entity have been generated in Euro-
anterior, resulting in sniffing and nose blowing, or posterior, pean centers, where prevalence data suggest that LAR may be
resulting in snorting, throat clearing, and postnasal drip. If the present in 47% to 62.5% of patients with perennial and sea-
rhinorrhea is purulent, the physician should consider other sonal symptoms who have negative skin-test responses and
etiologies, such as viral upper respiratory infections and bacte- undetectable specific IgE antibodies in serum.323-325 The aller-
rial rhinosinusitis. Nasal obstruction may be bilateral or could gens most commonly involved have been house dust mites,
manifest as exaggeration of the nasal cycle with alternating grass, and olive pollen.323-325 The pathophysiology is thought to
unilateral obstruction. If the obstruction is constant and fixed, involve the local nasal production of specific IgE, which has
the physician should think about coexisting mechanical causes been detected in 22% to 35% of the cases.323,324 Additionally, a
for the obstruction, such as septal deviation. If the congestion nasal TH2-IgE–mediated inflammatory response similar to that
is severe, it can be associated with a loss of smell secondary to in allergic rhinitis has been demonstrated in LAR with high
obstruction to airflow or to inflammation in the olfactory cleft numbers of eosinophils, basophils, mast cells, and CD4+ T cells
and usually manifests as a loss of taste. Ocular symptoms that in nasal lavages during natural exposure.323,324 Patients with
include itching, tearing, and conjunctival injection occur fre- LAR come to medical attention with nasal and eye symptoms
quently. Eustachian tube dysfunction, manifested as ear typical of allergic rhinitis and have a good clinical response to
popping and clicking, is an occasional manifestation. Systemic oral antihistamines and INSs.323,324,326 The disease often mani-
symptoms that may accompany allergic rhinitis include general fests later in life in a high proportion of patients. Diagnosis can
malaise, fatigue, irritability, snoring, and sleep problems.219,320 be confirmed by detection of nasal-specific IgE, or a positive
The history for rhinitis should also include query about family nasal provocation response, or both, in the absence of systemic
history of allergic diseases such as allergic rhinitis, asthma, and atopy. Whereas nasal provocation was traditionally done during
atopic dermatitis, because a positive family history for allergic several days to test different allergens, a multiple aeroallergen
diseases makes it more likely that the patient’s nasal symptoms provocation test has been recently described as a safe, time-
are secondary to allergic rhinitis. saving, and reliable diagnostic method.327 As mentioned above,
The traditional classification of allergic rhinitis is seasonal, LAR is described primarily by European investigators, and it
perennial, or episodic. Seasonal allergic rhinitis is defined by remains to be seen whether the prevalence and characteristics
symptoms that occur during exposure to seasonal allergens, of the disease are similar in the United States. One of the
such as ragweed, grasses, outdoor molds, and tree pollens. impediments to gathering information in the United States is
Perennial allergic rhinitis, defined as nasal symptoms for more the lack of availability of nasal provocation testing as a clinical
than 2 hours per day for more than 9 months of the year, occurs tool.
when allergies develop to house dust mites, indoor molds, It is important that the treating physician become familiar
animal dander, and cockroaches. Episodic rhinitis refers to symp- with the pattern of environmental allergens in the area of
toms on exposure to allergens not normally present in the practice. Once allergic symptoms are present, they may be
environment, such as a cat-allergic individual who becomes exacerbated by irritants such as strong odors or perfumes,
symptomatic upon entering the home of relatives who have a tobacco smoke, paint, newspaper ink, soap powders, and air
cat. pollutants. This exacerbation represents nonspecific hyperre-
During the Allergic Rhinitis and its Impact on Asthma sponsiveness. Several clinical entities should be considered in
(ARIA) World Health Organization workshop, and on the basis the differential diagnosis of the patient who comes in with nasal
of the facts that the preceding, more traditional classification obstruction and rhinorrhea; these are listed in Box 38-1.
did not always fit all disease presentations and that most patients
were polysensitized with both perennial and seasonal allergens,
a new classification was proposed.321 The new definition intro-
PHYSICAL EXAMINATION
duced the terms intermittent allergic rhinitis and persistent allergic A complete ear, nose, and throat examination is essential in the
rhinitis, with the emphasis that these terms were not synony- workup of every patient suspected of having allergic rhinitis,
mous with seasonal allergic rhinitis and perennial allergic rhinitis, and it is useful in identifying other problems rather than in
respectively. A degree of severity was also attached to this clas- confirming the diagnosis. The ear examination may show otitis
sification. Thus according to the ARIA classification, intermittent media with effusion, which is suggestive of nasopharyngeal
allergic rhinitis refers to symptoms present for less than 4 days a problems. Examination of the face may show periorbital cyano-
week or for less than 4 consecutive weeks, and persistent allergic sis and puffiness of the eyelids, usually the result of venous stasis
rhinitis refers to symptoms present for more than 4 days a week secondary to chronic nasal obstruction and often referred to as
For better examination of the nasal cavity, and in cases in

Box 38-1. DIFFERENTIAL DIAGNOSIS OF RHINORRHEA
which the existence of pathology not readily accessible to ante-
AND NASAL OBSTRUCTION
rior rhinoscopy is suspected, nasal endoscopy should be per-
Allergic Rhinitis formed. This procedure is usually done with the use of a flexible
Seasonal/perennial/episodic or intermittent/persistent or rigid fiberoptic instrument and is well tolerated by adults
Local Allergic Rhinitis and children older than 5 years. Nasal endoscopy allows visual-
Negative skin/radioallergosorbent testing but positive nasal allergen ization of the middle meatus to rule out the existence of puru-
challenge lent discharge or small polyps that originate in the sinuses.
When adenoidal hypertrophy or choanal atresia is suspected,
Nonallergic Rhinitis
endoscopy can help the clinician to visualize the nasopharynx.
Perennial (vasomotor): Constant symptoms of profuse, clear rhinorrhea
and nasal congestion without correlation to specific allergen
exposure or signs of atopy DIAGNOSTIC TESTS
Cold air–induced: Nasal congestion and rhinorrhea upon exposure to
cold, windy weather; occurs in both allergic and nonallergic individuals The two most common tests used to confirm the diagnosis of
Nonallergic Rhinitis with Eosinophilia Syndrome (NARES) allergic rhinitis are skin testing and in vitro testing for serum
levels of specific IgE antibodies. Skin testing is performed by
Most often seen in adults; characterized by eosinophilia on nasal
smears and with negative test results for specific allergens applying antigen extracts to the skin either epicutaneously
(puncture skin tests) or intradermally (intradermal tests). Intra-
Infectious Rhinitis
dermal testing is usually not required for the diagnosis of inhal-
Bacterial, viral, fungal ant allergy when standardized extracts are available328,329 and
Granulomatous Rhinitis may induce false-positive reactions. Testing is always accompa-
Sarcoidosis, Wegener granulomatosis nied by an introduction of the diluent for the allergen extract,
Drug-Induced Rhinitis used as a negative control; histamine or codeine, a mast cell
Oral contraceptives, reserpine derivatives, hydralazine hydrochloride, degranulating agent, is used as a positive control. A wheal and
topical decongestants (rhinitis medicamentosa), β-blockers (eyedrops) flare reaction is seen within 15 minutes of injection if a patient
Rhinitis from Mechanical Obstruction is sensitive to a specific antigen. A positive reaction indicates
the existence of specific IgE antibodies on intradermal mast
Septal deviation: Common; might exacerbate nasal obstruction in
allergic rhinitis cells and the reaction of the skin to released mediators.
Foreign body: Unilateral purulent nasal discharge is the usual Skin testing is rapid and inexpensive, but like all clinical
manifestation of a foreign body; resolves after removal tests, it has certain disadvantages: 1) skin reactivity may be
Choanal atresia or stenosis: Bilateral choanal atresia is usually diagnosed affected by previous ingestion of antihistamines or other drugs;
early in life, but unilateral choanal atresia or stenosis can go 2) children often do not tolerate multiple skin needle pricks;
unnoticed for several years; it is easily diagnosed by nasal endoscopy 3) prior or coexisting dermatologic conditions, such as eczema
and axial computed tomography of the midfacial skeleton or dermatographism, may preclude the performance of skin
Adenoid hypertrophy: Common cause of nasal obstruction in children tests; 4) the potency of antigen extracts needs to be maintained;
Others: Encephaloceles, lacrimal duct cysts, dermoids
and 5) systemic reactions may occur. Potentially interfering
Neoplastic Rhinitis medications must be discontinued prior to skin testing; mon-
Benign: Polyps, juvenile angiofibroma, inverted papilloma telukast does not appear to affect skin test reactivity, so it does
Malignant: Adenocarcinoma, squamous cell carcinoma, not need to be discontinued prior to skin testing.330 Most physi-
esthesioneuroblastoma, lymphoma, rhabdomyosarcoma cians test with a panel of allergens that are prevalent in their
areas in addition to allergens that seem relevant from the
history, such as cat, dog, and cockroach.
Both total and specific serum IgE levels can be measured in
“allergic shiners.” Other facial anomalies associated with long- vitro. Total IgE is elevated in 30% to 40% of patients with aller-
standing obstruction are elongated facies, open mouth, flat- gic rhinitis and can be elevated in patients with nonallergic
tened malar eminences, pinched nostrils, raised upper lips, conditions and in normal subjects; thus total IgE determination
high arched palate, and retracted jaws—a complex of signs is of limited use in the diagnosis of allergic rhinitis. The detec-
usually referred to as adenoid facies. Localized facial tenderness tion of specific IgE antibodies in the patient’s serum is useful
on palpation, especially in conjunction with purulent anterior in the diagnosis of allergic rhinitis. Although less sensitive than
or posterior nasal discharge, suggests rhinosinusitis. External skin testing, in vitro IgE measurements correlate well with the
nasal examination may show a gross deformity because of previ- results of skin testing and with the clinical picture. These tests
ous trauma or bony expansion by an underlying lesion. A supra- eliminate the need for multiple skin pricks but are more expen-
tip crease at the junction of the upper and lower lateral sive, and the results take longer to obtain than those of skin
cartilages is a result of frequent pushing upward of the nasal testing. It is important to obtain simultaneous total IgE levels,
tip, the “allergic salute.” because false-positive radioallergosorbent test results may occur
A nasal speculum or an otoscope fitted with the largest in sera with extremely high levels of IgE because of nonspecific
speculum is then used to inspect the inner aspect of the nasal binding. Other tools—such as nasal challenges and measure-
cavities. The anterior portion of the nose is examined for pos- ment of blood basophil histamine release, other peripheral
sible folliculitis and anterior septal deviations. The inferior blood activation markers, or eosinophils in nasal smears—are
turbinates are then inspected along the lateral nasal wall; these primarily utilized for research purposes.
structures are often described as being pale, bluish, and edema- The clinical history should guide the clinician to test the
tous and are coated with thin, clear secretions. It is important patient with a panel of the most relevant antigens. Testing with
to remember that no appearance of the nasal mucosa is pathog- the six most common antigens is effective in picking up 95%
nomonic for allergic rhinitis. A topical decongestant, such as of the allergens to which a patient is sensitive. It is always impor-
oxymetazoline, can be applied, and the nasal cavity can be tant to remember that a positive in vitro or skin-test result alone
examined a few minutes later; this step allows evaluation of the does not confirm the diagnosis of allergic rhinitis in the absence
reversibility of nasal congestion and facilitates inspection of the of a supporting clinical history, particularly because the last
area of the middle meatus. National Health and Nutrition Examination Survey study
showed that a prevalence of positive test results exceeded 50%, responsiveness, and reduction in soluble ICAM-1 levels in nasal
but full expression of allergic disease affected only 20% of the secretions.341-344 These additional properties, however, do not
study population. seem to translate into enhanced clinical efficacy; thus their
clinical importance is not clear.
The side effects of first-generation antihistamines can be
THERAPEUTIC OPTIONS bothersome. The most important of these is sedation, which is
reported in approximately 20% of patients. It is therefore
AVOIDANCE important to warn the patient receiving such a drug about its
Avoidance of the offending allergens is theoretically an effec potential effect on daily activities, such as driving or operating
tive treatment for allergic rhinitis. Multiple strategies for avoid- heavy machinery. The development of nonsedating antihista-
ance have been advocated over the years, including removing mines in the 1980s eliminated this problem. The newer, non-
a pet from the house, covering pillows and mattresses, washing sedating antihistamines have few effects on performance and a
bedding with hot water, and vacuuming mattresses and pillows. low reported incidence of sedation. The second-generation
These measures are targeted toward indoor allergens, especially antihistamines include loratadine, cetirizine, fexofenadine (all
dust mites. Unfortunately, a systematic review of many of these available over the counter), desloratadine, and levocetirizine
avoidance measures has shown that single measures are not (available by prescription). Both cetirizine and levocetirizine
effective in reducing symptoms in patients with allergic rhini- are labeled by the U.S. Food and Drug Administration (FDA)
tis.331 In a large study that investigated the effects of the use as sedating, but they cause less sedation than the first-generation
of allergen-impermeable bedding covers in the bedrooms of antihistamines.
patients with dust mite–associated perennial allergic rhinitis, H1 antihistamines are also available for intranasal adminis-
these covers reduced the concentrations of mattress Derma- tration. Azelastine, a phthalazinone derivative, is available in
tophagoides pteronyssinus by 30% of baseline but resulted in no the United States for the treatment of allergic rhinitis. It is
difference in the clinical symptoms of allergic rhinitis.332 Limited comparable in efficacy to other antihistamines, is usually given
evidence suggests that preventive measures such as removing twice daily, can cause somnolence, and may cause a sensation
carpeting, using tannic acid, washing bedding, or washing the of altered taste immediately after use.345 This agent has been
cat result in a reduction of levels of the allergen Fel d 1 in the shown to be effective in reducing itching, sneezing, runny nose,
house and a subsequent improvement of clinical symptoms of and nasal congestion.346,347 Olopatadine hydrochloride (0.6%)
allergic rhinitis because of cat allergy.333 Good evidence to has been shown to be safe and effective for the treatment of
support the use of high-efficiency particulate air filters is also seasonal allergic rhinitis and is usually administered as 2 puffs/
lacking.334 Outdoor allergens such as grasses, trees, and weeds nostril twice daily. The most commonly reported adverse reac-
are even more difficult to control, and some of the proposed tion to this drug is bitter taste, and the incidence of somnolence
measures that lack scientific evidence for efficacy include avoid- is minimally higher than that for the placebo vehicle.348 Onset
ing lawn mowing and driving with the car windows closed. The of action is within minutes.
lack of effectiveness of avoidance measures makes it less impor-
tant to define what specific allergens patients are sensitive to,
if pharmacotherapy is the planned treatment.
DECONGESTANTS
Both topical and systemic decongestants act by α-adrenergic
stimulation. They cause vascular constriction and a reduction
ANTIHISTAMINES of both the nasal blood supply and the volume of blood in the
H1 antihistamines act as inverse agonists that combine with and sinusoids. Topical decongestants can be either catecholamines,
stabilize the inactive conformation of the H1-receptor, shifting such as phenylephrine, or imidazoline derivatives, such as xylo-
the equilibrium toward the inactive state. They were earlier metazoline or oxymetazoline, and they have a rapid onset of
described as H1-receptor antagonists; however, this out-of-date action and are usually more efficacious than systemic deconges-
term does not accurately reflect the agent’s molecular mecha- tants. Topical decongestants do not have systemic side effects
nism of action.335 These medications are commonly used in the except in children, in whom seizures have been reported. Pro-
treatment of allergic rhinitis, and they include older, first- longed use leads to a progressively shorter duration of action,
generation drugs such as diphenhydramine; these drugs are until almost continuous application provides no relief—a con-
lipophilic and have varying degrees of anticholinergic and dition known as rebound. Further usage leads to mucosal inflam-
sedating side effects, whereas newer, second-generation antihis- mation, known as rhinitis medicamentosa. Therefore the use of
tamines such as loratadine, fexofenadine, and cetirizine have topical decongestants in allergic rhinitis should be limited to a
minimal or no sedative effect. The latter are less lipophilic, with short duration to 1) facilitate the penetration of INSs in patients
a reduced ability to cross the blood-brain barrier, and they have in whom severe congestion precludes it, 2) allow proper physi-
lower sedating and anticholinergic side effects. Oral H1 anti- cal examination, and 3) facilitate sleep during severe rhinitic
histamines are effective in controlling histamine-mediated exacerbations.
symptoms that include sneezing, itching, rhinorrhea, and eye Commonly used in the United States, oral decongestants do
symptoms such as itchy and watery eyes, but these drugs are not cause rhinitis medicamentosa but are not as effective as
minimally effective in alleviating nasal congestion.336 Further- their topical counterparts. Pseudoephedrine hydrochloride
more, several agents in this category improve quality of life as and phenylephrine are the most commonly used oral decon-
measured by generic and disease-specific tools.337-339 They are gestants. Phenylpropanolamine has been taken off the market
rapidly absorbed after oral administration and begin to provide in the United States because of the increased risk of hemor-
relief within 1 hour. Oral H1 antihistamines have been shown rhagic stroke in women associated with its use as an appetite
to be safe and effective in children, and many are available in suppressant.349 Products containing a pseudoephedrine decon-
liquid form.340 They are also safe when utilized for long-term gestant are now sold from behind the pharmacy counter in
treatment (years). the United States because of the potential for their conversion
In addition to antagonizing histamine at the H1 receptor, into methamphetamines. They are used most frequently in
some antihistamines have antiinflammatory properties that combination preparations with antihistamines (pseudoephed-
include inhibition of histamine release, reduction in leukotri- rine) or over the counter in cough and cold products in
ene production, inhibition of allergen-induced nonspecific combination with analgesics and antitussives. Phenylephrine is
another over-the-counter decongestant also used in combina- antiinflammatory effects of INSs, several placebo-controlled
tion products, but a 2007 meta-analysis showed lack of efficacy clinical trials that used a variety of these agents demonstrated
for this agent on both objective and subjective measures of their effectiveness in the reduction of all nasal symptoms in
nasal congestion in comparison with placebo.350 In addition to both seasonal357 and perennial358 allergic rhinitis. Studies have
nasal vasoconstriction, oral decongestants cause vasoconstric- also shown the efficacy of INSs in controlling ocular symp-
tion in other vascular beds, which accounts for their side effects, toms.359,360 In comparative studies, INSs have been shown to
the most common of which are insomnia and irritability, seen have superior efficacy to both H1 antihistamines361,362 and leu-
in as many as 25% of patients. An overdose of these agents kotriene receptor antagonists.363 Because of their safety and
causes hypertension, nervousness, renal failure, arrhythmias, superior efficacy, especially in controlling nasal congestion,
psychosis, strokes, and seizures. They should therefore be INSs are regarded as first-line treatment of allergic rhinitis
administered with caution to patients who have hypertension, except in the mildest forms of the disease.
heart disease, seizure disorders, hyperthyroidism, or prostatic Efficacy can start within a day of dosing,364 although
hypertrophy or those who are undergoing monoamine oxidase maximum efficacy requires days of INS administration. Prophy-
inhibitor therapy. lactic treatment with INSs is best initiated a week before the
pollen season in subjects with known seasonal allergic rhinitis.
Treatment should be started with the recommended dosage
ANTICHOLINERGICS with reevaluation of the patient in 2 weeks. During the reevalu-
Anticholinergic drugs are useful in the treatment of those sub- ation visit, the nose should be examined for signs of local irrita-
jects in whom clear anterior rhinorrhea is the predominant tion from the drug or mechanical trauma from the applicator
complaint. Ipratropium bromide has little or no systemic effect itself, and the patient’s response to treatment should be
when administered intranasally and has been shown to be effec- assessed. If a favorable clinical response is reported, the dose
tive in controlling watery nasal discharge in perennial allergic of INS can be lowered—keeping in mind the load of allergen
and nonallergic rhinitis.351 It has no effect on sneezing or nasal in the environment—with the aim of reaching the minimal
obstruction. This agent can be used in conjunction with other dose that provides symptomatic relief. Although continuous
modalities, such as antihistamines or INSs, for the satisfactory use of INSs is usually recommended, some studies have dem-
control of rhinorrhea. onstrated the superiority of the as-needed use of intranasal
fluticasone propionate over placebo.365,366
Some earlier INS preparations used a nonaqueous aerosol
CROMOLYN SODIUM formulation, but these were phased out in the United States by
Cromolyn sodium is available over the counter as a 4% solution 1996 after the call for discontinuation of products containing
for intranasal use and has been shown to be clinically effective chlorofluorocarbon by the Montreal Protocol.367 After that time,
in the treatment of allergic rhinitis. Like antihistamines, it is only aqueous INS preparations were available; in some patients,
more helpful for sneezing, itching, and rhinorrhea and less this resulted in undesirable side effects—primarily a sensation
effective in relieving nasal congestion. Its mode of action is of postnasal and anterior drip—that potentially contributed to
unclear, and it is most effective when started before the onset reduced compliance with treatment.368,369 To address this unmet
of symptoms. The dosage is four to six times daily, which can need, two intranasal nonaqueous preparations with hydrofluo-
cause compliance problems, but cromolyn sodium is very safe, roalkane aerosol are now approved for the treatment of allergic
especially in children and pregnant women. rhinitis in the United States. These include beclomethasone
dipropionate nasal aerosol and ciclesonide hydrofluoroalkane
nasal aerosol, both of which have been shown to be safe and
LEUKOTRIENE MODIFIERS effective in clinical trials and are approved by the FDA for
Because leukotrienes are generated in allergic rhinitis, the seasonal and perennial rhinitis in children and adults 12 years
effects of inhibitors of the 5-lipoxygenase pathway (zileuton) and older.370-373 A detailed list of available and approved prepara-
and leukotriene receptor antagonists (montelukast and zafirlu- tions of INSs is shown in Table 38-3.
kast) have been investigated. By far the most commonly used Local nasal irritation, the principal side effect of INSs, occurs
agent in this category is montelukast, which is approved for the in about 10% of patients. The incidence of epistaxis (specks of
treatment of seasonal and perennial allergic rhinitis in adults blood on a tissue) with different preparations ranges from 4%
and children. In placebo-controlled studies, montelukast has to 8% over a couple of weeks; higher incidences are found in
repeatedly been shown to be more effective than placebo and studies carried over a year, and septal perforations, although
equal in effectiveness to antihistamines for all ocular and nasal rare, have been reported. Biopsy specimens from the nasal
symptoms of allergic rhinitis, which includes congestion, rhi- mucosa of patients with perennial rhinitis who had been treated
norrhea, and sneezing.352-354 with fluticasone propionate or mometasone furoate continu-
ously for 1 year showed no evidence of atrophy374 and a higher
percentage of pseudostratified ciliated columnar epithelium
INTRANASAL STEROIDS after active treatment, which is suggestive of normalization of
Intranasal steroids (INSs) are the most potent drugs available the epithelium.356 Candida overgrowth in the nose with the use
for allergic rhinitis, a feature likely related to their diverse of INSs is rare. The long-term use of the newer INSs has been
antiinflammatory effects. In nasal allergen challenge models of shown to be free of the concerns associated with the use of
allergic rhinitis, pretreatment with INSs results in significant systemic steroids, such as growth retardation and interference
inhibition of mediator release during both the early-phase and with the hypothalamic-pituitary axis.375,376 It is recommended
late-phase reactions along with a significant inhibition of the that the growth of pediatric patients who receive INSs should
influx of basophils, eosinophils, neutrophils, and mononuclear be monitored regularly, every 3 to 6 months, with an accurate
cells in nasal secretions.294,355 These agents also lead to a reduc- instrument (stadiometer) by trained staff in a consistent way.
tion in the number of inflammatory cells and TH2-type cyto-
kines within the nasal mucosa of patients with allergic rhinitis.356
INSs also were found to reduce the antigen-induced hyperre-
SYSTEMIC GLUCOCORTICOSTEROIDS
sponsiveness of the nasal mucosa to subsequent antigen355 The role of systemic steroids in the treatment of allergic rhinitis
and histamine provocation.315 Coupled with these favorable is limited because of their adverse effects and the limited
TABLE 38-3. Commonly Used Intranasal Steroid Preparations

Dose/
Chemical Name Trade Name Formulation Actuation Recommended Dosage
Triamcinolone Nasacort Propellant, aqueous 55 µg 2 to 5 yrs: 1 spray/nostril qd (110 µg/day)
acetonide 6 to 11 yrs: 2 sprays/nostril qd (220 µg/day)
≥12 yrs: 2 sprays/nostril qd (220 µg/day)
Budesonide Rhinocort Propellant 32 µg ≥6 yrs: 2 sprays/nostril qd (128 µg/day)
>12 yrs: 2 sprays/nostril qd up to 4 sprays/nostril qd
(128-256 µg/day)
Flunisolide Nasalide 0.025% Solution 25 µg 6 to 14 yrs: 1 spray/nostril tid (150 µg/day)
Nasarel 2 sprays/nostril bid (200 µg/day)
≥14 yrs: 2 sprays/nostril bid-tid (200 to 300 µg/day)
Fluticasone Flonase 0.05% Nasal spray 50 µg 4 yrs to adolescence: 1 spray/nostril qd (100 µg/day)
propionate (aqueous) Adults: 2 sprays/nostril qd (200 µg/day)
Mometasone Nasonex Aqueous 50 µg 2 to 11 yrs: 1 spray/nostril qd (100 µg/day)
furoate ≥12 yrs: 2 sprays/nostril qd (200 µg daily)
Ciclesonide Omnaris Suspension 50 µg >6 yrs: 2 sprays/nostril qd (200 μg/day)
Fluticasone Veramyst Suspension 27.5 µg 2 to 11 yrs: 1 spray/nostril qd, can increase to 2 sprays/
furoate nostril qd (55 to 110 µg/day)
>11 yrs: 2 sprays/nostril qd (110 µg/day)
Beclomethasone Qnasl Nonaqueous aerosol 80 µg ≥12 yrs: 2 sprays/nostril qd (320 µg/day)
dipropionate
Ciclesonide Zetonna HFA-propelled aerosol 37 µg ≥12 yrs: 1 spray/nostril qd (74 µg/day)
HFA, hydrofluoroalkane.
morbidity of the disease. They are best reserved for patients mediators and causes a deviation toward a Treg response,
who come to medical attention in the middle of the pollen which leads to a normal immune response to allergens. Most
season with total nasal obstruction. Because oral decongestants, individuals express three T-cell subsets in different proportions,
with or without antihistamines, would not be effective in these depending on their state of health: TH1, TH2, and type 1 Treg
patients, and the INS preparations cannot be delivered because cells (TR1). In healthy subjects, IL-10–secreting TR1 or IL-10–
of nasal obstruction, a short course of systemic steroids is effec- Treg cells are usually the dominant subsets for common
tive in relieving nasal obstruction; it is also useful in reducing allergens, whereas in allergic subjects, allergen-specific IL-4–
the nasal obstruction associated with rhinitis medicamentosa, secreting T cells (TH2) exist at a higher frequency.378,379 There-
and it facilitates weaning of patients from topical deconges- fore a predominant IL-4–secreting T-cell status favors allergic
tants. Intramuscular injections of depo-steroids should not be disease, whereas a predominant IL-10–secreting T-cell status
used for the treatment of seasonal allergic rhinitis except in favors recovery. In addition to IL-10, other suppressive factors
extenuating circumstances, because a potential for decreased that mediate peripheral tolerance to allergens include TGF-β,
resistance to infection is always present during the 4 to 6 weeks T lymphocyte–associated antigen 4, and programmed cell
after the injection. Furthermore, depo-steroid injections have death 1.378 In subjects receiving AIT, the T cells that predomi-
long-term effects on bone density, cause systemic suppression nate during natural allergen exposure include TR1 or IL-10–
of the hypothalamic-pituitary axis, and have other systemic Treg cells within the CD4+/CD25+ cell population. Indeed,
effects associated with systemic steroids. during grass pollen immunotherapy, an increase is seen in
FoxP3/CD25+ Treg cells as well as in IL-10 mRNA expression
during late-phase responses and natural seasonal exposure,
IMMUNOTHERAPY respectively.380,381
Allergen-specific immunotherapy (AIT) involves the repeated In addition to the T-cell changes, AIT leads to a modification
administration of antigen extract, sublingually (sublingual in serum immunoglobulin profiles. Serum-specific IgE levels,
immunotherapy, SLIT) or subcutaneously (subcutaneous which often transiently increase after AIT is initiated, gradually
immunotherapy, SCIT), in an attempt to alter patients’ immu- decrease over months or years of continuous treatment.382
nologic responses and improve their symptoms. Immunother- Moreover, successful desensitization with AIT leads to inhibi-
apy is usually reserved for patients who have not experienced tion of the usual increase in serum-specific IgE levels observed
adequate responses to pharmacologic treatment. during the pollen season in untreated individuals.383 Further-
more, increases in specific IgG4 serum levels accompany clini-
Immunologic Changes After cal improvement with AIT.384 IgG4 is considered a blocking
Allergen-Specific Immunotherapy antibody and is thought to inhibit allergen and IgE-mediated
AIT induces significant modulation of the immune system and is proinflammatory effects. IL-10 and Treg cells play an important
the only known therapy to alter the natural course of the disease role in the suppression of both total and allergen-specific IgE
for continued efficacy after cessation of therapy. These changes and they lead to an increase in IgG4 production. Thus in addi-
have for the most part been shown to occur with both SCIT and tion to generating T-cell tolerance, IL-10 skews the specific
SLIT. An initial step in AIT therapy is desensitization of FcεRI- immunoglobulin response from an IgE- to an IgG4-dominated
bearing mast cells and basophils, possibly through the upregula- phenotype.385
tion of the histamine 2 receptor, a suppressor of basophil On top of their role in inducing a “healthy” T-cell status in
activation.377 This is followed by significant changes in T cells and allergic patients who receive AIT, IL-10 and Treg cells modulate
a T-cell–tolerant state. This allergen-specific peripheral T-cell the thresholds for mast cell and basophil activation and decrease
tolerance is mediated by IL-10, TGF-β, and other suppressive IgE-mediated histamine release.386 IL-10 also downregulates
eosinophil function and activity and suppresses IL-5 production

by human T cells.387 All these effects are supported by observa- Sublingual Immunotherapy
tions of decreased inflammation in the nasal mucosa of subjects Sublingual immunotherapy (SLIT), whereby extracts are
with allergic rhinitis taking AIT successfully. The ability of AIT administered under the tongue, was controversial for many
to alter the natural course of the disease and maintain benefi- years but has gained wide acceptance in European and other
cial antiinflammatory effects after discontinuation is inconsis- countries and is being investigated in the United States. In fact,
tent and seems to depend on the maintenance of some degree several preparations have recently been approved by the U.S.
of allergen exposure, and this sustained exposure likely aids in Food and Drug Administration. Meta-analyses have supported
maintaining tolerance.388 Finally, in addition to improving the safety and efficacy of SLIT in allergic rhinitis.405,406 SLIT
allergy symptoms, AIT appears to prevent progression of aller- significantly reduces allergic ocular symptoms and increases
gic rhinitis to asthma, and it prevents the development of new allergen tolerance in conjunctival challenges in patients with
allergic sensitization in monosensitized subjects.389 allergic conjunctivitis.407 Studies using grass tablets have also
shown efficacy and safety in allergic rhinitis.408,409 A meta-
Subcutaneous Immunotherapy analysis has also supported the efficacy of SLIT in children with
Since the introduction of SCIT in 1911, many studies have sup- allergic rhinitis410,411 and patients with asthma.412 Although most
ported its effectiveness in the treatment of pollen allergies. The of the studies with SLIT have evaluated grass tablets or extracts,
clinical efficacy of SCIT is well established for allergic rhinitis,390 data also support the use of SLIT for patients with house dust
and the therapy improves quality of life of patients with allergic mite and ragweed allergies. A meta-analysis reviewed evidence
rhinitis.391 The treatment offers relief, but the onset of action (published up to March, 2008) in support of the efficacy of
is slow: improvement starts within 12 weeks and increases over SLIT with house dust mite extracts in allergic rhinitis and aller-
a period of 1 to 2 years after treatment. Because the treatment gic asthma. In eight studies of allergic rhinitis patients with a
involves multiple visits, it requires a high degree of patient total of 382 subjects, a significant reduction in symptoms and
compliance; it also has significant adverse effects, such as death. rescue medication use was reported in patients receiving active
In addition, SCIT is highly specific and effective only for the SLIT compared with placebo.413 Further recent studies of house
allergens administered, and it takes months to achieve clinical dust mite SLIT have shown efficacy in elderly patients,414 an
improvement; therefore careful identification of all allergens onset of action as quick as 14 weeks,415 and equal efficacy in
responsible for the patient’s symptoms before initiation of monosensitized and polysensitized patients.416 Data also support
treatment is important. the potential of SLIT to alter the natural course of the
The duration of SCIT is usually 3 to 5 years. In a study to disease.417,418 A European trial of grass-allergen SLIT in adults
compare 3 versus 5 years of maintenance of SCIT to Dermatopha- with allergic rhinitis showed lasting benefits up to 2 years after
goides pteronyssinus, similar benefits were found in the control stopping a 3-year course of treatment.419 In seasonal disease, a
of rhinitis and asthma symptoms and quality of life, but the European study compared preseasonal and coseasonal treat-
5-year maintenance provided an additional 19% decrease in ment with grass SLIT and showed that preseasonal and cosea-
rhinitis symptom score.392 In a review of studies that compared sonal therapy can be as effective as year-round treatment with
SCIT with pharmacotherapies in seasonal allergic rhinitis, Mat- SLIT.420
ricardi and colleagues393 reviewed relevant meta-analyses and Two large, double-blind, placebo-controlled randomized
concluded that SCIT reduced symptoms similar to mometa- trials of timothy grass (Phleum pratense) allergy immunotherapy
sone and to a greater extent than montelukast or desloratadine. tablets in North America were reported in 2011, one in chil-
Several studies have shown persistence of benefit for various dren and adolescents and one in adults.421,422 The subjects in
periods of time after cessation of therapy, which supports the both studies were randomized to receive either a once-daily
conclusion that SCIT alters the natural course of allergic grass tablet treatment that contained 2800 bioequivalent units
rhinitis.394-396 In one such blinded, placebo-controlled study, (15 µg of Phl p 5) or placebo 16 weeks before the 2009 grass
Durham and colleagues396 showed that 3 to 4 years of immuno- pollen season and during the whole season. In 345 children
therapy with grass pollen extract resulted in prolonged clinical and adolescents, active treatment improved daily symptom
remission accompanied by a persistent alteration in immuno- scores and daily medication use by 25% to 81%, respectively.
logic reactivity as demonstrated by reduction in the late skin Similar improvements were noted in the adult study compared
response and associated CD3+ T-cell infiltration and IL-4 mRNA with placebo. In a multicenter, placebo-controlled study per-
expression 3 years after discontinuation of therapy. SCIT has formed in North America and Europe, 784 adults with ragweed
also been shown to prevent the development of new sensitiza- allergic rhinitis received either placebo or standardized short
tions in monosensitized children,397 and it may reduce the ragweed tablets at three different doses once daily for 52 weeks.
development of asthma in patients treated for rhinitis.398,399 The treatment was self-administered. The highest dose (12
Immunotherapy causes local and systemic adverse reactions. Amb a 1 U) was the most effective and provided consistent,
Lockey and Reid and their associates400,401 reported 46 fatalities superior, significant benefit over placebo in reducing daily
associated with immunotherapy and skin testing for the period symptom/medication scores when assessed during the peak as
1945 to 1985 and 17 fatalities associated with immunotherapy well as during the entire ragweed season. Treatment was well
for the years 1985 to 1989 in the United States. Analysis of these tolerated with no systemic side effects.423 A trial of SLIT for
data with special attention to risk factors suggested that house dust mite (Dermatophagoides farinae) allergy was also per-
although death from immunotherapy can occur, it is uncom- formed in the United States and compared placebo with either
mon (risk estimated at one fatality for every 2 million injec- high-dose (70 µg of Der f 1) or low-dose (1 µg of Der f 1) daily
tions). A more recent 3-year survey between 2007 and 2009 active maintenance therapy over 12 to 18 months in a small
included approximately 8 million injection visits per year and number of subjects with dust mite allergic rhinitis.424 Half the
showed an approximate reported rate of systemic reactions to subjects withdrew before the end of the study related to mild
SCIT to be 0.1% of injections with no fatalities reported.402,403 or moderate adverse effects, which rendered the evaluable
In this survey, the majority of systemic reactions (86%) occurred subject number small. Despite the small sample size, high-dose
within 30 minutes after SCIT administration. In view of the SLIT increased the bronchial threshold to allergen challenge
concerns about systemic reactions, practice guidelines recom- and increased serum D. farinae–specific IgG4 levels, whereas the
mend that patients receive SCIT in a supervised medical facility low dose had no effects when compared with placebo. No
and that they be monitored for 30 minutes after the improvement was noted in symptoms with either active
injection.404 treatment.
The obvious advantage of this treatment over SCIT is ease inguinal lymph nodes, is being investigated with promising
of administration, usefulness in children who dislike injections, results. The hypothesis is that its efficacy is similar to that of
and avoidance of the need to go to a doctor’s office to receive SCIT in a much shorter time frame. Proof-of-concept studies
the treatment; this is primarily related to the safety of SLIT, and were initially performed in mice and showed that direct intra-
safety has been demonstrated in multiple studies in adults and lymphatic injection, compared with subcutaneous or intramus-
children.425-427 Described local side effects have included itching cular injection, enhanced the efficiency of several peptide and
and swelling of the lips and sublingual oral mucosa that resolve DNA vaccines as well as protein allergens and adjuvants.440 This
without treatment. Systemic anaphylactic reactions have been was followed by clinical trials in larger animals, and finally, a
described, one with latex immunotherapy,428 one with an ill- randomized, open trial in subjects with allergic rhinitis to grass
defined multiallergen vaccine,429 and the last with a pollen mix pollen was done.441 In the trial, one group of subjects received
administered in conjunction with dust mite extract during the conventional SCIT that consisted of 54 injections over 3 years,
peak of the spring season in a child.430 Clear directions should and the group taking ILIT received three lymph node injec-
therefore be given to parents about what to do in the event of tions over 8 weeks with a much smaller dose than the SCIT
an adverse reaction, and the extracts should be kept in a safe group. Over the 3 years of follow-up, ILIT induced tolerance
place out of the reach of children. to a nasal allergen challenge significantly faster than SCIT (4
The comparative efficacy of SCIT versus SLIT is not well months vs. 1 year), resulted in significantly less rescue medica-
studied. In an effort to address this important issue, Dretzke tion intake during the first pollen season than SCIT, and led to
and colleagues431 performed a systematic review of double- an identical reduction in nasal symptom scores during the first
blind, randomized, controlled studies of SCIT and SLIT versus and third years of therapy compared with SCIT. Finally, ILIT
placebo and also of head-to-head studies that compared SLIT injections caused significantly fewer allergic adverse events
with SCIT in seasonal allergic rhinitis. Because only one head- than SCIT. The clinical efficacy of this new and promising
to-head study fulfilled the criteria for inclusion, they also ana- modality has since been confirmed in small clinical trials using
lyzed the relative comparative efficacy of these therapies with cat dander442 and birch or grass pollen.443
placebo. The analysis of the SLIT and SCIT studies confirmed
their reported efficacy relative to placebo. Both the head-to-
head comparison and the indirect comparisons of the relative
ANTI-IGE ANTIBODY
benefit compared with placebo did not yield conclusive results Recombinant, humanized, monoclonal anti-IgE antibody forms
in favor of either SLIT or SCIT based on symptom-medication complexes with free IgE and blocks its interaction with mast
scores or quality-of-life measures. However, a trend did favor cells and basophils. Anti-IgE has been shown to be beneficial
SCIT when symptom and medication scores were evaluated. and cost-effective in the treatment of moderate to severe
Despite being the only comparison, this evaluation suffers from asthma, for which it is currently indicated in the United
methodologic limitations; therefore direct head-to-head com- States.444,445 Although it has also been shown to be effective in
parisons of SCIT with SLIT are still needed. decreasing nasal symptoms and improving quality of life in
SCIT is probably best reserved for patients with severe sea- patients with allergic rhinitis, the lack of cost-effectiveness and
sonal rhinitis and perennial rhinitis, because they are symptom- the inconvenient route of administration (subcutaneous) make
atic all through the year and are willing to undergo prolonged this agent poorly suited to be the mainstay of treatment of
treatment. Medical treatment is probably more suitable for allergic rhinitis.446-448
patients with seasonal or episodic rhinitis who have symptoms
for much shorter periods of the year. SLIT is promising and TREATMENT OF EYE SYMPTOMS IN
has the advantage of self-administration with limited side effects.
ALLERGIC RHINOCONJUNCTIVITIS
Novel Approaches. Adding anti-IgE to SCIT has been shown Allergic rhinitis involves eye symptoms that are probably a com-
to improve its safety and tolerability during buildup, the likeli- bination of the direct effects of allergen deposition on the
hood of patients reaching maintenance dosage, and the overall conjunctiva and reflexes between the nose and the eye. Oral
effectiveness of therapy.432-434 Recombinant DNA technology H1 antihistamines and leukotriene receptor antagonists are
has allowed the production of allergens with improved purity, effective in controlling eye symptoms.336,352 Antihistamines
consistency, composition, and dosage. The use of such extracts given intraocularly have been shown to be effective for the
is being investigated for the immunotherapy of allergic rhinitis, control of allergic eye symptoms.449,450 They have a rapid onset
and initial results are promising.435 Peptide immunotherapy of action and are associated with lower rates of sedation and
uses synthetic peptides that consist of T-cell epitopes derived dry eye than first-generation oral H1 antihistamines.451 They
from major allergens and autoantigens to induce antigen- usually require twice-a-day dosing, although a newer prepara-
specific tolerance. Delivery of these epitopes intradermally is tion (olopatadine) is effective when used once daily.
thought to lead to the induction of T cells with a regulatory Interestingly, multiple studies have shown that the adminis-
phenotype and subsequent downregulation of the response to tration of INSs is effective in controlling ocular symptoms in
allergen. Such T-cell epitopes have been derived from cat aller- seasonal allergic rhinitis.452-455 Moreover, in a recent investiga-
gen Fel d 1 and have been used for desensitization.436 Repeated tional study, the addition of an intraocular antihistamine did
administration over a 3-month period has shown efficacy in the not add to the benefit of an INS in controlling eye symptoms
control of symptoms of allergic rhinitis induced by exposure to produced by nasal allergen challenge via the nasal-ocular
cat allergen in a chamber, and the treatment effect persisted 1 reflex.456 In a meta-analysis that compared H1 antihistamines
year later.437 Animal studies are also ongoing to test the efficacy with INSs, no difference was found in the efficacy of these two
of a mucoadhesive formulation of allergens that would enhance agent classes in the control of ocular symptoms, which suggests
adhesion of allergen extracts to the sublingual mucosal mem- that INSs were at least as effective as H1 antihistamines in the
brane and would thus augment treatment via the sublingual control of ocular symptoms in patients with allergic rhinitis.361
route.438 Innate immune response inducers, such as TLR ago- Furthermore, another meta-analysis to examine the findings
nists, can help skew the cytokine balance from a TH2 toward a from clinical trials that compared the effects of INSs and intra-
TH1 response, thereby reducing allergic disease. Ligands for nasal antihistamines on ocular symptoms in allergic rhinitis
TLR4 and TLR9 with and without allergen have been studied demonstrated no overall significant difference between the two
most in clinical trials.439 Intralymphatic immunotherapy (ILIT), treatment modalities.362 The mechanism of this favorable effect
whereby allergen is injected under ultrasound guidance into of INSs is speculated to be reduced intranasal inflammation,
which in turn inhibits the nasal-ocular reflex initiated by aller- with ARIA321,469,470 and the Global Allergy and Asthma European
gen contact with the nasal mucosa.243 Network.471 The interested reader is referred to these publica-
tions for more detail. We have tried to keep the discussion of
management simple and recommend the following general
COMBINATION TREATMENTS guidelines for the treatment of allergic rhinitis: if disease is
Combinations of drugs have been tested and proposed for the mild, we treat with as-needed (PRN) INSs; if it is moderate to
treatment of allergic rhinitis, because unmet needs remain. severe, we recommend the regular use of INSs; if patients are
The combination of montelukast and loratadine was found to not willing to use an intranasal medication or are bothered by
be superior to each agent alone in the treatment of seasonal local irritation, we recommend treatment with antihistamines.
allergic rhinitis in one study, although these results have not We generally reevaluate patients after 2 weeks to assess the
been duplicated consistently in subsequent investigations.457 response to therapy. If they have an excellent response, we
Ciebiada and colleagues458 conducted a placebo-controlled consider their anticipated exposure and treat accordingly. If
crossover study to evaluate the effect of montelukast, deslorata- response is partial, we identify residual complaints and add
dine, and levocetirizine alone or in combination in patients agents to target these symptoms. For residual eye symptoms, we
with persistent allergic rhinitis. These researchers showed that treat with intraocular antihistamines/mast cell stabilizers. If
all treatments were superior to placebo in the control of total there is significant redness of the eye, we refer the patient to
nasal symptoms and that the combination of either of the anti- an ophthalmologist. For residual nasal congestion, we consider
histamines with montelukast was more effective than each of the addition of an intranasal antihistamine. For residual rhinor-
the treatments used individually. A combination product that rhea, we consider adding ipratropium bromide. If the patient
contained loratadine and montelukast was not approved by does not improve after maximal medical therapy, we reconsider
the FDA. the diagnosis. If they have significant perennial disease and
The use of oral antihistamines with INSs has been investi- have no response to maximal medical treatment, we evaluate
gated and has shown variable results, with the majority showing the patient for immunotherapy. We do not routinely perform
no additional benefit over INS alone.459,460 Despite that fact, the allergy testing unless immunotherapy is planned, because
combination is frequently prescribed. The combination of an avoidance is great in theory but not proven in practice.
intranasal antihistamine with an intranasal steroid has shown We also consider special patient groups. In pregnant women,
clear additive benefit. Also, the addition of intranasal azelastine we use budesonide as the INS of choice and loratadine, cetiri-
to intranasal fluticasone propionate showed a synergistic effect zine, and levocetirizine as the antihistamines of choice, because
of the combination treatments in comparison with each agent these agents are all considered pregnancy category B agents by
alone in the control of nasal symptoms.461 When intranasal the FDA. In the elderly, we avoid sedating antihistamines
olopatadine was used in combination with intranasal flutica- because of the increased risks of falls in such patients. In com-
sone propionate, the efficacy in controlling symptoms of sea- petitive athletes, systemic decongestants are banned substances
sonal allergic rhinitis was similar to that of the combination of and are therefore avoided. In patients who take ritonavir, an
azelastine with the same INS,462 which suggests a class effect. inhibitor of human immunodeficiency virus protease and
Finally, because of the synergistic effect noted in the first study, potentially other protease inhibitors, we avoid INSs. Concomi-
a new intranasal formulation of azelastine hydrochloride and tant use of ritonavir and intranasal/inhaled fluticasone propio-
fluticasone propionate was developed and dosed twice daily; it nate may increase plasma concentrations of fluticasone and
was approved by the FDA and is available for use in the United may result in systemic corticosteroid effects and adrenal sup-
States. A study performed with this formulation duplicated the pression with reduced serum cortisol concentrations.472 In
initial results used with the combination and showed added patients who take protease inhibitors, safer options appear to
efficacy compared with placebo and the two active agents used be budesonide, triamcinolone, and flunisolide.472
alone in the treatment of seasonal allergic rhinitis.463 In an
ocular allergen challenge study, combining intranasal flutica- For a complete list of references, see expertconsult.com.
sone propionate and intraocular olopatadine produced signifi-
cantly greater improvements in ocular itching after challenge
than the combination of fluticasone and fexofenadine.464 An SUGGESTED READINGS
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Immunol 119:S61 [abstract 240], 2007. 2008.
39 Physiology of Olfaction
Donald A. Leopold | Eric H. Holbrook
Key Points
■ The olfactory epithelium is a pseudostratified columnar neuroepithelium that contains supporting
cells, bipolar olfactory receptor neurons, and dividing basal cells located in the superior cleft
between the middle and superior turbinates and the septum.
■ The axons that extend from the receptor neurons coalesce into bundles (cranial nerve I) that travel
through the cribriform plate to make primary synapses with the olfactory bulb.
■ As identified in rodents, an olfactory map exists in which individual odorant receptor types,
randomly distributed among zones within the olfactory mucosa, converge to form synapses in
specific glomeruli. This receptor map formation appears to extend to higher processing centers.
■ Multiple testing mechanisms for olfactory ability exist and are commercially available and accessible
for all physicians. Testing allows for an assessment of extent of olfactory loss and measures change
in ability over time.
■ The most common reasons for olfactory loss include chronic rhinosinusitis and polyps, upper
respiratory infection, head trauma, and aging. Patient history is extremely important in determining
etiology of olfactory disorders.
■ Patchy replacement of olfactory mucosa with respiratory epithelium appears to be common with
aging. Alzheimer disease is closely correlated with olfactory loss independent of aging.
■ Chronic rhinosinusitis can cause both a conductive loss of olfaction and a sensorineural loss. Nasal
endoscopy is extremely useful in assessing obstruction of the olfactory cleft.
■ Computed tomography scans are helpful in assessing conductive losses and chronic rhinosinusitis.
Magnetic resonance imaging can be helpful if neurologic signs suggest a mass, lesion, or
neurodegenerative disease.
■ Available therapies for olfactory disorders continue to be limited. Patient support and counseling of
hazards associated with the loss of smell are an important part of the patient visit.
T he perception of odors adds a quality to life that is difficult properties of any given odorant determine the particular “mix”
to express. Odors are part of our everyday life, from the plea- of these various inputs. Olfactory nerve (cranial nerve I) stimu-
sures of perfume, to the satisfactions of toast and coffee, to the lation, which is necessary for identification of most odorants,
warnings of skunks and fire. As the molecules of substances are depends on the odorant molecules reaching the olfactory
transported through the nose, the possibility of their being mucosa at the top of the nasal cavity. Although molecules can
perceived occurs. The quality and intensity of that perception reach the olfactory cleft by diffusion, essentially olfaction
depend on the anatomic state of the nasal epithelium and the requires some type of nasal airflow, usually as part of inhalation
status of the peripheral and central nervous systems. (orthonasal flow). During eating, a retronasal flow of odorant
This chapter explores the physiology of olfaction, noting molecules stimulates the olfactory receptors at the top of the
pertinent research data. The initial discussion focuses on the nose and contributes greatly to the flavor of the food.1,2 This
pathways and obstacles that odorant molecules must negotiate airflow can be very slight, such as that generated by the mouth
as they come in contact with the olfactory receptor cells. A and pharyngeal motion.3-5 Additional data from a large-scale
consideration of the neural processing of odorant stimulation model indicate that at physiologic airflow rates, approximately
and the pathways that project to the brain give some insight 50% of the total airflow passes through the middle meatus, and
into the mechanisms that underlie olfactory perception. Olfac- approximately 35% flows through the inferior meatus (Fig.
tory testing explores the assessment and method of this percep- 39-1). About 15% flows through the olfactory region.6
tion. The chapter ends with a section on clinical olfactory Mathematic models of the nose, created from digitized com-
problems in humans and includes suggestions for their diagno- puted tomography (CT) anatomy slices and predicted mass
sis and management. transport functions, can predict odor intensity for varying
amounts of olfactory epithelium, the character of the carrier
gas, and the solubility of the odorant molecules.7-9 These theo-
ANATOMY OF OLFACTORY retic results show agreement with human and animal experi-
STIMULATION mental data.
The effect of a rapid change in flow velocity, such as that
NASAL PASSAGEWAYS elicited with a sniff, on the in vivo airflow pattern remains
Experiencing an odor is a result of input from the olfactory, unknown. In their large-scale model studies, Scherer and col-
trigeminal, glossopharyngeal, and vagus nerves. Apparently, the leagues6 found that the percentage and velocity of airflow to
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610 PART IV | SINUS, RHINOLOGY, AND ALLERGY/IMMUNOLOGY

TABLE 38-2. Chemokines—Cont’d

as histamine and the cholinergic agonist methacholine. Patients

IgE antibodies Resolution

For better examination of the nasal cavity, and in cases in

TABLE 38-3. Commonly Used Intranasal Steroid Preparations

eosinophil function and activity and suppresses IL-5 production

multifunctional activities on mast cells. Curr Drug Targets Inflamm

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