Common Allergies and Management

A 12 year old girl presents with a chief complaint of year-round nasal stuffiness and
itching eyes for the last 2 years. Her complaints include eyes which are red, watery and
itchy; nasal drip (runny nose), congestion, itching, and a poor sense of smell; and
sneezing. Her nasal stuffiness bothers her most. Her symptoms disrupt her daily activities
and her sleep. Most of these symptoms improve slightly when she takes diphenhydramine
and when she is away from home. However, her nasal stuffiness does not change with
taking the medication. She has a cat which sleeps in her bed room.
Past history: As an infant she developed egg allergy and an eczematous rash on her face,
trunk and extremities. She has no history of asthma. Family history: Both her mother and
brother have asthma and hay fever.
Exam: VS are normal. Her height and weight are at the 50th percentile. She has bilateral
conjunctival inflammation (redness) with mild chemosis (edema), dusky discoloration of
the skin under the eyelids, marked pale swelling of the nasal mucosa which almost
completely occludes the nasal airways without evidence of nasal polyps or masses. Both
eyes and her nose have whitish clear exudates. Otoscopic examination shows fluid behind
both tympanic membranes. She has generalized dry skin with a scatter of hyperkeratotic
plaque on both extremities and pityriasis alba of her face.
She is diagnosed with severe persistent allergic rhinoconjunctivitis and otitis media with
effusion (OME) with a history of atopic dermatitis and egg allergy. She is treated with a
non-sedating antihistamine without significant improvement. Intranasal corticosteroids
are added next with minimal improvement. She is then referred to an allergist for
evaluation and further treatment. Her skin allergy test is positive to dust mite and cat
dander. Her family follows the allergist's recommendations which include: encasing the
mattress and pillows in a plastic bag wrap, removing the cat from the house, using an
antihistamine with mast cell stabilizing activity (olopatadine) eye drops and allergen
immunotherapy. All of her symptoms have gradually decreased with these
recommendations. She has currently discontinued all of her medications; except when she
exposes herself to cats or house dust (she may require antihistamines as needed).

Symptoms due to allergy commonly occur in children. Atopy refers to a tendency of

exaggerated IgE antibody production and is defined by the presence of specific IgE in
vivo (skin prick test) or in vitro (RAST test). Atopy represents a predisposition to atopic
or allergic diseases including allergic rhinitis, asthma, eczema and food allergy. Scientific
evidence of the systemic link between all of the atopic diseases has been increasing
recently.

The atopy march starts early in life and most believe that the fetal environment may
already be important for both the development of subsequent sensitization and disease
manifestation. Early events under the influence of a variety of environmental factors,
such as exposure to environmental endotoxin, allergens, infections, and variations in
nutrient intake, affect the expression of the atopy genotype. Age of onset of each atopic
disease is unique and may be influenced by the mentioned factors. Typically, both atopic
dermatitis and food allergy are commonly seen in young infants; while asthma usually
starts after 3 years of age, and allergic rhinitis develops in later childhood.
Allergic Rhinoconjunctivitis
By definition allergic rhinoconjunctivitis is a symptomatic disorder of the nose (allergic
rhinitis) and eyes (allergic conjunctivitis) resulting from an IgE-mediated immunological
reaction following exposure to allergens. Rhinoconjunctivitis is a combined term of
rhinitis and conjunctivitis because conjunctivitis is usually accompanied with rhinitis in
allergic conditions.
Allergic rhinitis (AR) is extremely common in the general population. The prevalence of
AR in the US is about 10-20%. An international study shows that the prevalence of
allergic rhinitis varies in different parts of the world from 1%-15% in the 6-7 year-olds
and 1%-40% in the 13-14 year-olds. Allergic conjunctivitis (AC), the most common form
of ocular allergies, is a self-limited, bilateral inflammation of the eyes.
The nose is a specialized structure with 5 important functions: smelling, resonating for
phonation, filtration, heating, and humidification of inhaled air. As a filter for inhaled
particles, the nose receives an allergen burden, which per square centimeter is
considerably higher than in the lower airways. Its function seems to be the price to be
paid for the higher prevalence of AR than other atopic diseases. When airborne allergens
come in contact with surface fluid on the nasal mucosa, allergenic molecules are removed
within seconds by mucociliary transport and only a small fraction of the allergen
molecules will penetrate the epithelial lining since proteins of this size are not easily
absorbed from the nasal mucosa. The allergens initiate an allergic reaction when they
bind with cell-attached IgE molecules. Mast cells, basophils and Langerhans cells are
responsible for the interaction and releasing inflammatory mediators.
Human conjunctiva consist of a nonkeratinized, stratified squamous cell epithelium. The
conjunctiva includes goblet cells within the epithelium and overlies the substantia
propria, which is composed of connective tissue with cellular elements including mast
cells, lymphocytes, macrophages and fibroblasts. One of the highest concentrations of
mast cells is at the limbus (the junction of the conjunctiva/sclera and the cornea). The
mast cells in the human conjunctiva tend to be centered just beneath the basal epithelial
cell layer and around blood vessels. AC is caused by direct exposure of the ocular
mucosal surfaces to environmental allergens. The allergic inflammation starts the same as
in the nose when allergens bind to the cell-attached IgE molecules and then mediators are
released from the cells. Histamine is the principal mediator involved in ocular allergy and

inflammation. Most of the allergic reactions are mediated through the effects of histamine
on H1 receptors which are found the conjunctiva, cornea, and ophthalmic arteries.
There are two phases of the allergic response in allergic rhinoconjunctivitis: the early
phase (minutes to hours) and late phase (6 hours to days). The early phase is induced by
mediators such as histamine, prostaglandin, neuropeptides and leukotrienes released by
the mast cells. Histamine directly stimulates sensory neurons, inducing pruritus and
sneezing, and in concert with the leukotrienes, stimulates the vascular endothelium,
inducing vasodilation and increased vascular permeability. Histamine also induces
cholinergically mediated reflex glandular secretions, which can be inhibited by atropine
or ipratropium. The early phase results in itchy eyes and nose, sneezing, watery eyes,
rhinorrhea, edematous conjunctiva and nasal mucosa. After several hours of allergen
exposure, other inflammatory cells including eosinophils, neutrophils and activated
lymphocytes are demonstrable in the last phase response. The late phase or cellular phase
leads to a recrudescence of nasal or eye symptoms associated with a second rise in
histamine occurring in some affected persons. Basophils are felt to be responsible for the
late-phase histamine peak. Eosinophil activation and accumulation with the release of
eosinophilic proteins and mediators are the cause of increasing nasal blockage and
hypersensitivity. It results in increasing sensitivity when repeatedly exposed to the same
allergens (called the priming phenomenon).
The major symptoms of AR are sneezing, rhinorrhea, nasal pruritus and nasal congestion.
There are two common presentations, seasonal and perennial allergic rhinitis. Seasonal
allergic rhinitis is characterized mainly by periodic symptoms of the nose, ears, and throat
with watery rhinorrhea, nasal congestion, sneezing, and pruritus occurring during the
pollination season of the plants (typically, trees in spring, grass in summer and weeds in
fall) to which the patient is sensitive. The sneezing, pruritus and rhinorrhea are a main
complaint in the seasonal type. Perennial allergic rhinitis is characterized by intermittent
or continuous nasal symptoms resulting from indoor allergen exposure (house dust mites,
animal fur) without seasonal variation. Nasal obstruction may be the major or sole
complaint of the perennial type, particularly in children, in whom the nasal passage is
relatively small. Lacrimation, sneezing, clear rhinorrhea and itching of the nose, ears and
throat may also occur. The symptoms are less severe than seasonal allergic rhinitis. The
decreased severity of the symptoms seen in these patients may lead them to interpret their
symptoms as resulting form "sinus trouble" or "frequent colds". In reality, the
differentiation of seasonal and perennial types may not be clearly defined. Physical
findings of AR often reveal changes in the eyes, nose, ears and throat. A horizontal nasal
crease, caused by upward rubbing of the nose due to itching (allergic salute), is usually
seen in children. The pale or bluish nasal mucosa with variable degrees of swelling and
nasal blockage, and clear watery or yellow nasal secretions may be seen. The appearance
of dark circles under the eyes (allergic shiners) is due to venous engorgement secondary
to nasal congestion. Periorbital eczema, erythematous conjunctiva with papillary
hypertrophy, and gelatinous secretions may appear. Posterior pharyngeal lymphoid
hyperplasia secondary to postnasal drip is also noted. Middle ear fluid (otitis media with
effusion or serous otitis media) is commonly noted. In some patients, however, the above

findings are absent. All of the symptoms may be associated with recurrent sinusitis,
asthma or eczema.
The symptoms of AC are watery, itchy, red, sore, swollen, stinging and burning eyes.
Corneal symptoms, including photophobia and blurring of vision, are reported in rare
cases. The ocular symptoms are frequently associated with nasal and/or pharyngeal
symptoms. AC is seldom followed by permanent visual impairment. The presentation can
be varied from mild to very severe and can be categorized into seasonal and perennial
type. Seasonal allergic conjunctivitis (SAC) is more common and more severe. The onset
of symptoms is seasonally related to specific circulating aeroallergens. Grass pollens are
more commonly thought to be associated with more ocular symptoms than other
aeroallergens. Ragweed is the most common cause of AC accompanying AR. Perennial
allergic conjunctivitis (PAC) has symptoms throughout the year. PAC patients may have
seasonal exacerbations. Dust mites, animal dander, and feathers are the most common
airborne allergens implicated in PAC, which is more likely than SAC to be associated
with perennial rhinitis. Both PAC and SAC patients are similar in distribution of age, sex,
and associated symptoms of AR, asthma or eczema. Clinical findings of AC include:
milky or pale pink conjunctiva with vascular congestion that may progress to conjunctiva
swelling (chemosis), a white exudate during the acute state that becomes stringy in the
chronic form. The conjunctiva surfaces are mildly injected with various degrees of
chemosis. Lid edema sometimes occurs, as well as papillary hypertrophy along the tarsal
conjunctival surface (the palpebral surface may appear bumpy). The clinical signs and
symptoms are usually bilateral, although the degree of involvement may not be
symmetrical.
The diagnosis of allergic rhinoconjunctivitis is based on a detailed history and physical
findings as mentioned. Many allergic patients do not report the ocular or nasal symptoms
unless they are asked directly about them during a medical examination. When evaluating
patients who present with significant nasal symptoms, the following questions should be
asked:
1. Is the nasal congestion or sneezing/itching/runny nose a main concern? Are there eye
symptoms?
2. Does an activity or allergen exposure or a specific environment contribute to the
symptoms? Seasonal or year-round symptoms? What are the clinically relevant allergens?
3. Are there other atopic diseases in the patient or the family?
4. Were any medications including topical OTC preparations (nasal and eye drops) used
in the past?
5. Do the symptoms cause a major impact on lifestyle such as school activity or sleeping?
Typically, patients with classic symptoms do not require any tests. Slightly elevated
serum IgE, mild peripheral blood eosinophils and eosinophilia of the nasal secretions are

common findings; but these results are not diagnostic. Allergy testing including skin
testing or radioallergosorbent test (RAST) may be required for the diagnosis and
guidance of environmental avoidance in some patients with uncontrollable disease or
atypical presentations. The allergy tests in young children are limited because positive
specific IgE or skin prick tests to inhaled allergens usually develop after the second year
of life.
Skin testing is the most common test for the diagnosis of allergy because of its simplicity,
high sensitivity, low cost and rapidity of the result. Prick testing is widely used by
allergists since the test is quick, not painful, inexpensive, highly specific with a low risk
of systemic reaction. Prick testing requires: 1) devices such as metal needles or lancets or
commercial test devices, 2) allergen extracts, 3) positive controls (histamine) and
negative controls (glycerin or saline). A physician and equipment for treating anaphylaxis
reaction should be readily available while performing the test. Patients should be
instructed to discontinue some medications inhibiting skin response for a period of time
including tricyclic antidepressants (5 days), hydroxyzine (3 days), astemizole (60 days),
and other antihistamines (3 days). Contraindications for skin tests are generalized skin
disease, inability to discontinue antihistamines, history of severe reactions or anaphylaxis
to previous skin testing, pregnancy, dermatographism, unstable angina and betaadrenergic receptor agent therapy (beta blockers, beta agonists or both). A response to an
allergen with a wheal size greater than 3 mm in diameter indicates a positive result and
having a specific IgE to the allergen. If the skin prick result is negative, an intradermal
skin test may be considered in a highly suspected patient since the intradermal skin test is
more sensitive.
RAST is an in vitro test for specific IgE antibodies based on the principle of
immunoabsorption . This in vitro test for allergy is a convenient allergy test for nonallergist physicians or for patients who have contraindications for skin testing. RAST is
not as sensitive as the skin test in most instances. Appropriate in vitro tests correlate up to
70-80% of the time with prick skin tests. CAP-RAST testing (a type of RAST test) is
preferred over other RAST tests because of better standardization.
The differential diagnosis of allergic rhinoconjunctivitis includes infectious
rhinoconjunctivitis, which includes the common cold, usually caused by rhinovirus, RSV,
parainfluenza virus, influenza virus and adenovirus. Fever, sore throat, thick purulent
rhinorrhea or eye discharge, erythematous nasal mucosa, and the presence of cervical
lymphadenopathy are helpful differential findings in infectious rhinitis. Common diseases
that may be confused with perennial allergic rhinitis are recurrent infectious rhinitis,
chronic sinusitis, and vasomotor rhinitis. Structural and mechanical conditions that may
mimic perennial allergic rhinitis include a deviated nasal septum, hypertrophic turbinates,
adenoid hypertrophy, foreign bodies and tumors. Inflammatory and immunologic
diseases such as Wegener's granulomatosis and sarcoidosis may present with rhinitis
symptoms. Nasal polyposis, an uncommon condition causing nasal congestion in
children, is usually associated with cystic fibrosis, asthma and aspirin intolerance and
predisposes to sinusitis.

Nonallergic rhinitis with eosinophilia (NARES) may be misdiagnosed as allergic rhinitis.

NARES is not IgE dependent and is not associated with high IgE levels or positive skin
tests. Symptoms in NARES are more likely to be induced by exposure to irritants, strong
odors, cold air, and cigarette smoke. Drug-induced rhinitis is associated with use of
various oral agents, especially certain classes of antihypertensive beta- blockers, oral
contraceptives, chlorpromazine, aspirin and overuse of topical (nasal drops and sprays)
sympathomimetics (rhinitis medicamentosa). Other less-common causes of rhinitis
include occupational exposure, hormones, food and alcohol.
Several eye diseases need to be differentiated in patients with allergy and ocular
symptoms. Irritative and chemical conjunctivitis is commonly confused with AC. The
main symptom caused by environmental pollutants and smoke is conjunctival hyperemia.
Atopic keratoconjunctivitis typically occurs in patients with atopic dermatitis. It is a
bilateral, sight-threatening disease and symptoms are much more severe than SAC and
PAC. The symptoms include significant itching, burning and redness, eventual fibrosis,
decreased keratinization of conjunctival surfaces, cataract formation and lid malposition.
Vernal keratoconjunctivitis is a chronic form of allergic conjunctivitis characterized by
large "cobblestone" papillae on the underside of the eyelid. The symptoms are intensely
pruritic and sight-threatening. Giant papillary conjunctivitis, a non-allergic condition,
may be confused with ocular allergy. Giant papillae on underside of eyelid and non
itching are distinguishing symptoms.
The management of allergic rhinoconjunctivitis in children includes allergen avoidance
and education, medications and allergen immunotherapy as in adults. Allergen avoidance
and environmental control are the main stay of treatment in all age groups.
Allergen avoidance and environmental control:
A wide range of allergens have been associated with allergic rhinoconjunctivitis, of which
house dust mites are clearly the most important. The single most effective strategy for
reduction of dust mite exposure involves bed-covering systems, which separate the mite
allergens from the allergic individual by encasing mattress, pillows and blankets with
mite allergen impermeable covers. Other recommendations for dust mite control are: 1)
Washing the blankets, bed linen or other washable material such as curtains and toys in
hot water over 55 degrees C regularly once a week. 2) Removing children's soft toys or
washing/freezing the toys once a week. 3) Removing and replacing carpet in the house
with vinyl or polished wooden floor boards. If it is impossible to remove the carpet, the
carpet can be completely covered by polyethylene sheeting. 4) Mite control (acaricide)
sprays have demonstrated some effects in reducing mite numbers and allergen levels.
However, the clinical efficacy demonstrates only reducing symptom scores but not
medication use. 5) High efficiency particulate air (HEPA) vacuum cleaners can reduce
allergen load but no trial has demonstrated that this will improve symptoms.
Cat and dog fur is one of major allergens implicated in causing the perennial type. The
allergens are not the dander itself but are contained in the saliva and in sebaceous
secretions, which can flake off in small particles and remain airborne for considerable

periods of time. This results in a ubiquitous allergen that can be found in many public
places, even in a cat-free or dog-free buildings and schools. It makes avoidance much
more difficult. The only effective measure for avoiding the allergens in the home is to
remove the pets, carefully vacuum and clean all carpets, mattresses and upholstered
furniture. Frequent washing of cats may reduce allergen exposure. However, clinical
studies have not shown a clear benefit from this procedure when carried out once a week.
A placebo-controlled trial of a HEPA air cleaner in the treatment of cat allergy did not
find a significant effect on rhinitis.
Indoor molds can be removed with a bleach solution and can be followed by measures to
reduce local moisture or humidity such as using a dehumidifier. Outdoor allergens, such
as pollens, grass and fungal spores, are difficult to avoid. Outdoor exercising in the
morning for sufferers with pollen allergy is recommended. These sufferers should be
reminded to keep their bedroom window closed during the daytime and open windows
only at night when the pollen count is low.
Medical treatment for allergic rhinitis:
It should be noted that there are only a few medications that have been tested in children
under the age of two years. In young children under the age of four, use of nasal saline
drops or spray can simply comfort them and help to clear their nose before eating or
sleeping. Several concerns of medical treatment in children have been raised. The most
important aspects are the antihistamine side effects on the cognitive functions of preschool and school children. The use of systemic corticosteroids such as oral or depotpreparations should be deferred due to their systemic adverse effects. Children with
allergic rhinitis who are athletes should be advised about the medications used since some
of these medications are prohibited by various sports organization. Alpha-adrenergic
agonists and systemic decongestants (both often combined with H1-antihistamines) are
often prohibited in organized youth sports since they have a central stimulant effect. For
intranasal corticosteroid use, a medical certificate documenting medical necessity should
be issued. However, the regulations vary between countries, so physicians treating the
athletes should be aware of these regulations.
All H1 antihistamines are competitive antagonists of histamine and are rapidly absorbed
from the gastrointestinal tract. Antihistamines are most effective for sneezing, pruritus
and rhinorrhea. They exert little effect on nasal congestion. Therefore, as a rule, they are
more effective in acute, seasonal allergic rhinitis than in the perennial form in which
congestion or stuffiness is usually more prominent. The use of H1-antihistamines is
important for the treatment of rhinitis in children. The response to different
antihistamines may differ from patient to patient, but it has been demonstrated that
children not responding to one antihistamine may respond to another.
Antihistamines have been classified into first and second generation families. Some of
the commonly used first generation antihistamines are triprolidine, diphenhydramine,
chlorpheniramine, azatadine and hydroxyzine. All of them except hydroxyzine are overthe-counter medications (OTC). The first-generation antihistamines cause drowsiness,

reducing one's ability to concentrate, blunting cognitive functions to some extent, and
have varying anti-muscarinic effects such as dry mouth, constipation, blurring of vision,
urinary retention. Their adverse effects limit their utility. Their use should be restricted to
two relatively uncommon situations: 1) Children with urticaria or atopic dermatitis whose
pruritus is so severe that the sedation produced by an old H1-antagonist, such as
diphenhydramine or hydroxyzine, is a benefit rather than a risk. 2) Children with
anaphylaxis who require intravenous diphenhydramine as adjunctive treatment to
epinephrine and other medications.
Second-generation antihistamines are recommended for seasonal AR. Currently available
forms include:
. . . . . azelastine (Astelin): nasal spray, BID.
. . . . . cetirizine (Zyrtec): low sedating, PO, once daily.
. . . . . loratadine (Claritin): non-sedating, PO, once daily.
. . . . . fexofenadine (Allegra): non-sedating, PO, BID.
. . . . . desloratadine (Clarinex): non-sedating, once daily.
Only cetirizine and desloratadine are approved by FDA for perennial allergic rhinitis.
Loratadine and fexofenadine are less sedating (minimal or no drowsiness). The above
oral antihistamines are available as a combination medication with pseudoephedrine
(Zyrtec-D, Claritin-D, Allegra-D) since antihistamines have little effect on congestion.
However, the use of an antihistamine with decongestant is limited to children older than
12 years. Desloratadine (Clarinex) is a non-racemic form of loratadine.
Intranasal corticosteroids ("steroids" for short) have proved to be the most effective class
of drugs in reducing the symptoms of allergic rhinitis. This clinical response reflects the
broad anti-inflammatory activity and multiple pharmacologic actions of corticosteroids.
They have demonstrated specific effects on decreasing the activity of inflammatory cells
such as mast cells, basophils, eosinophils, Langerhans' cells and decreasing the levels of
chemical mediators including histamine, Th2 cytokines, chemokine and adhesion
molecules. A single dose of intranasal steroid administration blocks the late-phase
response; whereas repeated dosing blocks both early and late response, as well as the
priming phenomenon. Intranasal steroids reduce the specific IgE production in seasonal
allergic rhinitis and decrease nasal hyperresponsiveness or the priming phenomenon.
Intranasal steroids have been considered as second line agents after antihistamines by
many physicians; however, first-line use of intranasal steroids is becoming increasingly
common, especially for patients with moderate to severe symptoms. Intranasal steroids
are more efficacious in chronic symptom relief than oral antihistamines, decongestants
and cromolyn except for eye symptoms. Regular use of intranasal steroids is more
effective than intermittent p.r.n. use, but p.r.n. use does have some efficacy in many
patients. Although no well controlled study of a combination use of steroids and other
medications is published, in clinical practice, intranasal steroids can be used in
combination with other therapies to achieve optimal improvement in overall symptoms.

Several intranasal steroids are available including beclomethasone (Beconase,

Vancenase), flunisolide (Nasarel), triamcinolone (Nasacort), budesonide (Rhinocort),
fluticasone (Flonase) and mometasone (Nasonex). After using the recommended dosage
for 2 weeks, the patient should be reevaluated, and the dosage can be adjusted based on
the clinical response. The goal of therapy should be to use the lowest dosage that
provides effective relief of symptoms. With proper use of intranasal steroids, 60-90% of
patients may have nearly complete relief of rhinitis symptoms.
The most frequently observed adverse effect with intranasal steroids is local irritation.
Approximately 10% of patients have some form of nasal irritation, nasal burning or
sneezing after administration. Bloody nasal discharge occurs in approximately 2% and a
few cases of septal perforation were reported due to improper techniques of
administration. Long-term use of intranasal steroids does not appear to cause a significant
risk of adverse morphologic effects on the nasal mucosa. Systemic side effects of
intranasal steroid are rare, such as growth suppression due to low systemic absorption.
Generally, the systemic absorption can occur through direct intranasal absorption or
through gastrointestinal absorption of the swallowed fraction of the administered dose. It
is likely that approximately 80% of the administered intranasal dose is swallowed
resulting in systemic absorption. Mild growth suppression may result from chronic use of
beclomethasone since it is metabolized to another active steroid compound.
Cromolyn sodium (Nasalcrom) has been one of the common drugs used for AR in
children. It inhibits mast cell mediator release, and may inhibit C-type sensory nerve fiber
transmission which modulates vascular and glandular responses. The drug is effective
only when applied topically to the mucosal surface of the allergic end organ. It cannot be
used orally for allergic disease. Cromolyn has been shown in numerous studies to be
effective for both types of AR. It has a greater benefit in seasonal type symptoms and in
highly allergic persons.
The major advantage of cromolyn is its safety, since there are no significant side effects
of this drug. Its major drawback is the Q.I.D dose. In addition, it must be used on a
regular basis to be effective, and ideally should be started before the onset of the
symptoms. In patients with the seasonal type, cromolyn is best initiated just before the
season starts at a dose of one spray in each nostril four times daily, and is continued
throughout the season. In patients with perennial type, it can be started at any time, but it
may take a few to several days to be effective. The recommended dose is one to two
sprays in each nostril four times daily. After a patient's symptoms have stabilized, the
dose may be decreased to three times daily, with increases to four times daily if
symptoms worsen. Patients who are allergic to known triggers, such as animals, can use
two sprays of cromolyn in each nostril 30 minutes before allergen exposure to prevent an
allergic reaction.
Montelukast (Singulair), a leukotriene receptor antagonist given orally, has a new
indication to be used for seasonal allergic rhinitis. Its efficacy might be equal to oral
antihistamines (more data are needed), but it is less effective than intranasal
corticosteroids and more expensive than both.

Nasal ipratropium (Atrovent), a topical anticholinergic nasal spray, is useful in patients

with both allergic and non allergic rhinitis who experience rhinorrhea from various other
triggers (e.g., cold air, eating spicy foods, and other irritants), by controlling rhinorrhea
induced by nonspecific activation of cholinergic receptors. Its effectiveness is limited in
patients with moderate to severe allergic rhinitis because ipratropium has little effect on
other symptoms, such as sneezing, pruritus, or congestion. It is commonly used as an
adjunct therapy if the rhinorrhea symptoms still persist with the antihistamine or
intranasal steroid treatment. It is recommended for use in children older than 6 years.
Common adverse effects are drying of the nasal mucosa and mild epistaxis.
Adrenergic nasal decongestants are available in both topical forms (e.g., oxymetazoline,
phenylephrine and propylhexedrine) and oral forms (e.g., pseudoephedrine,
phenylpropanolamine). The decongestants increase nasal patency by inducing
vasoconstriction and reducing tissue swelling and obstruction. Although the
decongestants have been used in children for years, there are very few studies in these
young patients. The decongestants can be useful initially, often coupled with an
antihistamine to control active allergic rhinitis symptoms. Once control is achieved,
further symptoms usually can be prevented by the judicious use of antihistamines alone
or with a nasal corticosteroid.
Decongestants should be deferred in small children and in patients who currently take
MAO inhibitors. The side effects of oral decongestants are nervousness, dizziness,
tachycardia, shakiness, urinary retention, insomnia. Its long-term round-the-clock use
may increase the risk for hypertension. There is an association of hemorrhagic stoke and
phenylpropanolamine (PPA) use in adults. Therefore, PPA was removed from the market
by the FDA in November 2000. The major concern of nasal decongestants is the
prolonged use which may induce rhinitis medicamentosa (especially with topical
decongestants), which is rebound mucosal swelling from withdrawal of the medication.
This discomfort may prompt the patient to use the medication frequently to avoid a sense
of smothering. Ultimately, this cycle can induce serious irreversible mucosal damage.
Therefore, topical preparations should be used for not more than 3 to 5 consecutive days
to prevent rhinitis medicamentosa.
A guideline of treatment for allergic rhinitis: Recently, an expert panel in association with
the World Health Organization (WHO) has recommended a guideline for the medical
treatment of AR based on clinical severity ("mild" or "moderate-severe"). The severity is
further subdivided into "intermittent" or "persistent" according to the duration of
symptoms. It is necessary to define the severity of the allergic individual, then the choices
of medications are based on the severity:
"Mild" means that none of the following items are present: sleep disturbance, impairment
of daily activities (leisure and/or sport), impairment of school or work, troublesome
symptoms. "Moderate-severe" means that one or more of the above items is present and a
disturbance or impairment exists which not found in "mild". "Intermittent" means that the
symptoms are present for less than 4 days a week or for less than 4 weeks. "Persistent"

means that the symptoms are present more than 4 days a week or for more than 4 weeks.
Treatment recommendations are as follows:
For mild intermittent disease: oral or intranasal H1 antihistamines or intranasal
decongestants (for less than 10 days and not to be repeated more than twice a month) or
decongestants (not recommended in children less than 12 years old).
For moderate-severe intermittent disease: oral or intranasal H1 antihistamines or oral H1antithistamines or decongestants or intranasal steroids or cromolyn sodium .
For mild persistent disease: Same medications as for moderate-severe intermittent above.
The patient should be reassessed after 2 to 4 weeks. A stepwise approach is advised. If the
patient has persistent mild symptoms and is on an H1-antihistamine or cromolyn
treatment, changing the medication to an intranasal steroid is suggested. The dosage of
intranasal steroids may be reduced by half if the patient responds well to the treatment. In
seasonal allergy, a shorter course of treatment is required depending on the pollen season.
However, long-term treatment may be needed especially in perennial allergy.
For moderate-severe persistent disease: Intranasal steroids are the first line treatment. The
patient should be reassessed after 2 to 4 weeks of the treatment. A stepwise approach is
advised. If the patient does not improve, consider other reasons for failure to respond to
the treatment including heavy persistent allergen exposure (e.g., cat on the bed),
inadequate medication compliance, nasal obstruction preventing drug delivery, other
additional nasal pathology such as nasal polyps, sinusitis or nasal septal deviation, and a
wrong diagnosis. If the major symptom is blockage, doubling the dose of the intranasal
steroid is suggested. Add an H1-antihistamine if the symptoms of sneezing, itching or
rhinorrhea still exist. Add ipratropium if rhinorrhea is not improved. If the patient's
symptoms are less, a step down approach should be used. However, the treatment should
last for at least three months or for the duration of the pollen season. In the step down
treatment, a low dose of intranasal steroid may be required as a maintenance treatment to
control symptoms. Referral to a specialist may be considered if the treatment is not fully
effective, or if the duration of the treatment is over 3 months and the medications are not
helpful.
Medical treatment of allergic conjunctivitis:
The primary goal of medical treatment is to alleviate the ocular symptoms and signs
which disrupt the patient's quality of life. Initial management with allergen avoidance,
cold compresses, and lubrication (artificial tears) should be tried before ocular agents are
tried. Cold compresses provide considerable symptomatic relief, especially from ocular
pruritus and swelling. In fact, all ocular medications provide additional subjective relief
when applied immediately after refrigeration. Tear substitutes consisting of saline
solution combined with a wetting and viscosity agent, such as methylcellulose or
polyvinyl alcohol, can be applied topically 2 to 4 times a day and as needed. It is a
soothing, effective, convenient and inexpensive option which directly removes and
dilutes allergens that may come in contact with the conjunctiva.

Oral antihistamines used for the treatment of systemic or nasal allergy can reduce but do
not eliminate the eye symptoms. However, treatment with oral antihistamines, especially
the first generation, may cause eye dryness which interferes with the ocular defense
mechanism and increases the potential for ocular irritation and sensitivity. The use of a
"topical" agent on the affected eyes is the easiest and most direct therapeutic method. An
important consideration for effective topical treatment is compliance. Treatments causing
ocular irritation are likely to diminish compliance and may lead to a chronic duration of
the condition, decreased patient satisfaction, and increased ocular sensitivity. Efficacy of
these agents varies from patient to patient, and the choice of agent used will depend on
the underlying health of the eye and other variables, such as drug cost, contact lens wear,
and compliance. Several topical agents are available for the treatment and the prophylaxis
of ocular allergies. These include vasoconstrictors, antihistamines, mast cell stabilizers,
and anti-inflammatory agents.
OTC topical antihistamines are widely used in combination with topical vasoconstrictors.
The combination is more effective than either agent alone or a systemic antihistamine.
Adverse effects of topical vasoconstrictors include burning and stinging on instillation,
mydriasis, rebound hyperemia or conjunctivitis medicamentosa with chronic use and
drug interaction with MAO inhibitors. Topical vasoconstrictors are contraindicated in
patients with narrow angle glaucoma.
Topical prescription antihistamines, including levocabastine, emedastine and azelastine,
are a good option for symptomatic relief of an ocular allergy. Since these agents do not
provide mast cell stabilization, they do not prevent or treat a significant cause of the
allergy. All of the topical antihistamines require dosing as frequently as every 4-6 hours,
except azelastine which requires only BID dosing, which may improve compliance.
Topical mast cell stabilizers include cromolyn, nedocromil, lodoxamide and pemirolast. It
should be noted that the medications require several days (3-5 days) to start providing
symptomatic relief of ocular allergy. The relief reported within 15 minutes probably
represents a "washout" effect immediately after contact with the eyes. Long term use of
these agents is necessary since they are preventive only. These agents require Q.I.D.
administration with the exception of nedocromil which is B.I.D. Topical dual action
antihistamine and mast cell stabilizers include ketotifen and olopatadine. Therefore, they
have rapid onset and prolonged duration of action. Both of them are approved for twice a
day dosing for treating AC in children 3 years and older. Topical ketorolac (a nonsteroidal
anti-inflammatory agent) is approved for use in children 12 years and older with acute
SAC. It inhibits allergen induced prostaglandin production which diminishes the ocular
itching and conjunctival hyperemia. Local administration of topical corticosteroids is
associated with localized ocular complications such as viral infection, elevated
intraocular pressure and cataract formation. Therefore, routine use is not recommended
and their use should be under the close supervision of an ophthalmologist.
Allergen immunotherapy (AIT) is a safe and effective treatment for long-term control of
allergic rhinoconjunctivitis. AIT is considered when environmental control is limited,
when medications are ineffective or not well tolerated, or when the symptoms are a

significant trigger for other chronic problems such as asthma or sinusitis. AIT results in
successful treatment of AR in 85%-90% of cases. It is also recommended as a treatment
for venom or insect hypersensitivity and selected cases of asthmatics. Patients with
chronic urticaria, atopic dermatitis, or food allergy do not benefit from AIT. AIT induces
immune tolerance to the specific allergens. In many cases, AIT can prevent clinical
progression of allergic disease and may minimize the development of sensitization to
multiple allergens in patients who are sensitized to a single allergen. The terms, "allergen
vaccination" and "allergen immunotherapy", can be used interchangeably.
Prior to considering AIT, the patient must have evidence of specific IgE sensitivity such
as a positive skin test or RAST test. Small doses of allergen extracts to which the patient
is sensitized, are administered subcutaneously. The injected dose can be gradually
increased as in a conventional AIT or rapidly increased as in a rush AIT until the
maintenance dose is reached. The goal is to blunt the immune response with an optimal
dose.
The efficacy of AIT for common allergens including house dust mite, cat, cockroach,
birch, grass, and ragweed pollens have been well-documented. The efficacy of AIT
depends on the quality of the allergen extract, the duration, the frequency of
administration, the relevant allergens and the allergen doses. The dose of specific protein
delivered in an allergen extract is crucial for induction of immune tolerance. If the extract
is highly diluted or there are too many allergens which result in reduction of the relevant
allergen dose, it will compromise the efficacy. In low doses, AIT is not effective in most
patients. Therefore, a high dose of allergen extract per injection must be achieved as a
maintenance dose to provide significant clinical benefit.
Allergic rhinoconjunctivitis causes substantial morbidity although the disease is not
associated with mortality. Many physicians do not pay attention to the disease because
they underestimate the impact of allergic rhinoconjunctivitis on other diseases, quality of
life and performance. AR is a common cause of asthma exacerbation or uncontrolled
persistent asthma. It is estimated that up to 90% of children with asthma have respiratory
allergies, especially to indoor allergens such as house dust mite, Alternaria species,
cockroach, or cat. All asthmatics should be evaluated for allergic rhinitis. Untreated or
undertreated allergic rhinitis is associated with the development of otitis media with
effusion (OME) and sinusitis. The OME may result in hearing impairment, which
worsens progressively as the symptoms continue. There is strong evidence that AR and
atopic dermatitis are more common in children with OME compared with normal
subjects. Therefore, children with OME should be assessed for allergic
rhinoconjunctivitis and children with allergic rhinoconjunctivitis should be assessed for
OME. Adverse effects of allergic rhinoconjunctivitis in children are school absences,
poor performance, poor concentration, headaches, malaise, and lethargy as a consequence
of sleep disturbance and therefore reduced ability to learn. Furthermore, many of the
antihistamines employed have some sedating effects, thereby aggravating the problem.
Although genetic factors contribute to the risk of allergic disease development, it is likely
that environmental factors are partially responsible for the increase in the prevalence of

atopic diseases. Therefore, changing the surrounding environment or other factors may
decrease or prevent the atopic diseases. The following measures are recommended:
1. Raising children in a smoke-free environment, starting in utero.
2. Breast feeding for 4-6 months, delaying the introduction of solid food until 6 months
of age, and withholding highly allergenic foods such as egg and peanut for 2 to 3 years,
especially in a highly allergic family.
3. Reducing exposure to environmental allergens, especially in patients who have already
developed respiratory allergies.
A hygiene hypothesis is supported by some studies. This hypothesis implies that
overcrowding and unhygienic contacts early in life may protect from atopic diseases. The
changes of human microbial flora, declining exposure to food-borne and orofecal
infections, to helminths and to environmental sources of endotoxin are putative
contributors to the rise of allergy cases among populations living with a western lifestyle.
Lifestyle or clinical recommendations based on this hygiene hypothesis still remain to be
proven.

References
1. Sly RM. Epidemiology of allergic rhinitis. Ann Allergy Asthma Immunol 2002;82:233248.
2. Bush RK. Diagnostic Tests in Allergy. In: Slavin RG, Reisman RE (eds). Expert Guide
to Allergy and Immunology. 1999, Philadelphia: American College of Physicians, pp. 122.
3. LaForce C. Use of nasal steroids in managing allergic rhinitis. J Allergy Clin Immunol
1999;103:S388-S394.
4. Nelson H. Mechanisms of intranasal steroids in the management of upper respiratory
allergic disease. J Allergy Clin Immunol 1999;104:S138-S143.
5. Caffarelli C, Savini E, Giordano S, et al. Atopy in children with otitis media with
effusion. Clin Exp Allergy 1997;28:591-596.
6. Simons FE. H1-antihistamines in children. Clin Allergy Immunol 2002;17:437-464.
7. Williams PV. Treatment of rhinitis, corticosteroids and cromolyn sodium. Immunol
Allergy Clin North Am 2000;20:369-381.

8. Gern JE, Lemanske RF. Pediatric Allergy: Can it be prevented? Immunol Allergy Clin
North Am 1999;19:233-252.
9. Bielory L. Allergic and immunologic disorders of the eye. Part II: ocular allergy. J
Allergy Clin Immunol 2000;106:1019-1032.

Corticosteroids

This is a 15 year old male with a PMH of steroid-dependent asthma who presents with a
chief complaint of "always feeling tired and weak". Since the age of 7 he has taken
inhaled bronchodilators, and for the last 4 years has used high doses of inhaled steroids.
During the last 10 months, he required hospitalized twice for status asthmaticus, during
which he was given IV and oral corticosteroid bursts. In addition, he has been taking
daily oral steroids for the last 5 months. Review of symptoms is significant for a weight
gain of 15 kg in the last 3 months, an increased incidence of recent "colds", and the
observation by his mother that he seems not to be growing as quickly as his siblings did
at this age. His mother also wants to know why, if her son is getting "steroids", he looks
as he does rather than "all the athletes on TV who are using steroids".
Exam: . Height is at the 10% percentile, and weight in the 50% percentile. His visual
fields are full. He has severe acne, truncal obesity and a "moon facies". His extremities
show several small bruises, muscle wasting with 4/5 weakness, but no areas of
hyperpigmentation were seen. There are two areas of poorly healing wounds on his left
arm from a fall 3 weeks ago.
Labs: CBC of 14,000 with 1% eosinophils, 2% monocytes, 68% neutrophils, and 29%
lymphocytes. Sodium 149, potassium 3.3, chloride 96, bicarbonate 28.5, glucose 110.
Cortisol levels were slightly elevated with no diurnal variation.
Given the patient's history, the diagnosis of iatrogenic Cushing's syndrome is made. The
patient is weaned off corticosteroid treatment over a period of 5 weeks. His Cushingoid
features resolve and his height approaches the 40th percentile. An ophthalmology referral
for a subsequent decrease in his vision identifies posterior subcapsular cataracts from his
corticosteroid treatment, which are stable but do not resolve.

Corticosteroids are four-ringed steroid hormones produced by the adrenal cortex, with
their common biochemical precursor being cholesterol. The corticosteroids are comprised

of two major physiological groups: the glucocorticoids and the mineralocorticoids.

However, the term "corticosteroids" is generally used to refer to glucocorticoids.
Mineralocorticoids, mainly aldosterone, influence electrolyte balance, and by
consequence, intravascular volume and blood pressure. Glucocorticoids are named for
their effect on carbohydrate metabolism, but they also have many other effects. One of
their most important uses clinically is their complex effect on the immune system.
Cortisol is the main physiologic glucocorticoid. Cortisol is called hydrocortisone when it
is used pharmacologically. Androgens of the adrenal cortex affect the growth spurt seen
in childhood and are responsible for secondary sexual characteristics. It is important to
remember that these compounds are chemically similar, and there are clinically important
areas of overlap seen in the effects of corticosteroids among these three groups; i.e., some
glucocorticoids will have some mineralocorticoid effects, and vice versa.
The adrenal cortex has three layers (GFR): zona glomerulosa, zona fasciculata, zona
reticularis, which are responsible for mineralocorticoids, cortisol, and androgenic steroids
(salt, sugar, sex), respectively. Cortisol is also produced to some degree in the zona
reticularis. Adrenal function is covered in the chapter on adrenal disorders. This chapter
will focus on glucocorticoid corticosteroids.
Once corticosteroids are released from the adrenal cortex or absorbed in the body, 90%
are bound to plasma proteins, the main two being corticosteroid-binding globulin (CBG)
and albumin (1). Once the glucocorticoid is freed from its binding in the plasma by
albumin or CBG, it crosses into the cytoplasm by simple diffusion to bind to the
glucocorticoid receptor. In the cytoplasm, a glucocorticoid receptor is found in its
inactive form bound to various heat-shock proteins. The heat-shock proteins dissociate,
and the glucocorticoid-receptor dimer enters the cell nucleus. Short DNA sequences,
called glucocorticoid response elements, interact with the glucocorticoid-receptor
complex, and this regulates gene transcription by RNA polymerase II and associated
transcription factors. The mRNA that is produced is ultimately exported to the cytoplasm
for protein production and the final cellular response. Enzyme activity increased by
cortisol results in an increase in providing carbon precursors (transaminases, etc.),
conversion of pyruvate to glycogen (pyruvate carboxylase, glycogen synthetase, etc.),
release of glucose (glucose-6-phosphatase) and disposal of ammonia liberated from urea
cycle amino acids (arginine synthetase, argininosuccinase, etc.) (2). This whole process
may take several hours for a response to be seen after corticosteroids are given.
In regards to the immune system, cortisol decreases the availability of arachidonic acid, a
precursor to many of the inflammatory immune mediators, such as leukotrienes,
prostaglandins, and thromboxanes. Cortisol has these effects by inducing the synthesis of
a phosphoprotein called lipocortin that inhibits the activity of phospholipase A2. This
decreases the synthesis of phosphatidyl choline to arachidonic acid. In addition, cortisol
decreases the expression of the gene for cyclooxygenase 2 (which is involved in the
production of leukotrienes and thromboxanes) and nitric oxide synthase (that decreases
the production of nitric oxide that limits vasodilatation) (2). Corticosteroids are

metabolized by the liver and made water soluble so that they may be excreted by the
kidneys (1).
The fetal adrenal cortex has two zones, an outer definitive zone that is mainly responsible
for glucocorticoid and mineralocorticoid synthesis, and a fetal zone which makes
androgenic precursors used by the placenta. At one year of age, the fetal zone has
involuted completely, and the definitive zone enlarges. The zona glomerulosa and zona
fasciculata are not fully differentiated until age 3, and the zona reticularis may not be
fully formed until age 15. At birth, the adrenal glands weigh 8-9 grams, which is twice
the size of adult adrenal glands (3). High levels of cortisol may be seen in the first few
hours of life, due to the high stress of birth and possibly due to increased levels crossing
the placenta. Cortisol changes the fetal digestive pattern to the digestive enzyme capacity
of an adult, allowing the newborn to use disaccharides present in milk (2). Cortisol
prepares the fetal lung for breathing air by accelerating the rate of alveolar development
and thinning of lung septa, and increasing pulmonary surfactant production by increasing
the activity of phosphatidyl acid phosphatase and choline phosphotransferase.
Betamethasone (a corticosteroid) is given clinically to mothers in premature labor to
accelerate fetal lung maturation to reduce the severity of neonatal respiratory distress
syndrome. Case reports of newborns with cleft palate, neonatal cataracts, growth
retardation, and adrenal suppression have been reported in maternal corticosteroid use
(4).
The use of inhaled corticosteroids at recommended doses in childhood does not have a
substantial measurable effect on bone mineral density, ocular toxicity, or suppression of
the HPA (hypothalamic pituitary adrenal) axis in childhood (5). Studies of inhaled
corticosteroids on vertical growth have produced conflicting results. Its effects from
childhood to adulthood are not known with certainty (4).
The various steroid compounds have differences in their glucocorticoid and
mineralocorticoid activity which are related to their chemical structures, altering their
affinities for the mineralocorticoids and glucocorticoids receptors. These structural
changes also affect metabolism of the hormones by the liver, fat, or other tissues, its
solubility and binding to plasma proteins, its ability to be absorbed, and its excretion.
Clinically, these affect the potency and duration of the corticosteroid. For example, if a
double bond is placed in the 1,2 position of ring A, then a four-fold increase in
glucocorticoid activity is seen with slower metabolism (longer duration) compared to
hydrocortisone. This is the case with prednisolone and prednisone. Another example is
fluorination at the 9-alpha position on ring B. This increases activity with the
glucocorticoid receptor 10-fold, but also increases the mineralocorticoid activity by 125fold, allowing these to be used as mineralocorticoids at small doses but with little to no
glucocorticoid activity at the small doses used. If substitutions are made at C16 on ring D
with the 9-alpha fluoro derivatives, then these compounds have marked glucocorticoid
activity and virtually no mineralocorticoid activity (triamcinolone, dexamethasone,
betamethasone) (1). Cortisone and prednisone are synthetic corticosteroids that require
enzymatic reduction by the liver before becoming biologically active. In cases of severe

hepatic failure, hydrocortisone and prednisolone should be used, since they do not require
this enzymatic activation.
Hydrocortisone, and its synthetic analogs, are effective when given by mouth. Esters of
hydrocortisone are more water-soluble and can be given intravenously for quicker and
higher concentrations in the body. Glucocorticoids applied topically over the skin can be
absorbed systemically with effects on the HPA axis if administration is prolonged or
when high potency corticosteroids are used topically over large areas of skin.
Besides being classified by their mineralocorticoid and glucocorticoid relative potencies,
corticosteroids can be classified by their duration of action. Short-acting glucocorticoids
include cortisol (hydrocortisone) and cortisone. Intermediate-duration glucocorticoids
include prednisone, prednisolone, triamcinolone, and methylprednisolone. Long-acting
glucocorticoids include dexamethasone and betamethasone. The latter have very high
glucocorticoid potencies and very little mineralocorticoid activity.
The table below summarizes glucocorticoid potency and duration. Substitutions and dose
equivalencies can be made based on these values.
Glucocorticoid potency equivalence (7):
Glucocorticoid
Plasma
Glucocorticoid Mineralocorticoid
equivalent dose
half-life
potency
potency
(mg)
(minutes)
Short-acting, low
potency
Cortisol

20

90

Cortisone

25

0.8

80-118

Prednisone

60

Prednisolone

115-200

Triamcinalone

30

Methylprednisolone

180

0.5

25-50

200

Intermediatepotency

Long-acting, high
potency
Dexamethasone

Betamethasone

0.65

25-50

300

When used pharmacologically (i.e., higher than physiologic levels), glucocorticoids have
profound effects on inflammation and the immune response of lymphocytes. These two
processes are linked because both involve leukocyte function. Glucocorticoids, as
mentioned above, inhibit phospholipase and cyclooxygenase, limiting the release and
production of prostaglandins, thromboxanes, and leukotrienes by mast cells, basophils,
and eosinophils. By inhibiting leukotrienes, neutrophil phagocytosis and bacterial
function are decreased. Glucocorticoids decrease extravasation of leukocytes and also
diminish the secretion of lipolytic and proteolytic enzymes, so that fibrosis is reduced (1).
In this way, glucocorticoids can be clinically used to modify (suppress) the inflammatory
response. These therapeutic effects have a physiologic basis. Many immune mediators,
such as IL-1, IL-6 and TNF-alpha, stimulate the HPA axis during times of stress,
increasing glucocorticoids and thus causing a decrease in the immune response.
Glucocorticoids are used in physiologic doses to treat adrenal insufficiency and in
pharmacological doses to treat inflammatory and autoimmune conditions. Given that
cortisol levels can rise 10-fold in times of stress, high-dose corticosteroids may have a
beneficial physiologic effect on the immune system. If the many immune mediators are
unopposed by corticosteroids in times of stress, decreased vascular tone and
cardiovascular collapse can occur. This important physiologic immune-modulating effect
protects the body from an unchecked and full-blown inflammatory response that can have
life-threatening consequences (1). Continued use of pharmacological doses can have
other adverse effects, such as increasing susceptibility to various bacterial, viral, and
fungal infections, permitting their dissemination. Corticosteroid use is contraindicated in
patients with tuberculosis, and they must be used with extreme caution with ophthalmic
herpes simplex infections. Hypertension, electrolyte and fluid abnormalities,
osteoporosis, fat redistribution, acne, hirsutism, and myopathy (among others) can all
develop with pharmacologic does of corticosteroids, especially when used over a long
period.
Giving a patient glucocorticoids, also affects the amount of different immune cells found
in the peripheral blood. The leukocyte count shows a polymorphonuclear leukocytosis
(increased WBC count due to increased neutrophils which can be greater than 11,000)
with lymphopenia (B and T cells), basopenia, a decreased monocyte count, and
eosinopenia in four to six hours after a single dose of hydrocortisone. Neutrophils are
increased due to demargination from vascular walls and increased release from the bone
marrow. Lymphocytes, basophils, monocytes, and eosinophils are redistributed away
from the periphery (1). Glucocorticoids can be used to treat various lymphoid
malignancies, either due to being directly toxic to these cells or by inducing apoptosis
(programmed cell death).
The acquired or adaptive immune system involves two main parts, cellular immunity and
humoral immunity. Cellular immunity is manifested by cytotoxic T cells and natural
killer cells involved in protection against intracellular bacteria, protozoa, fungi, and

certain viruses. Humoral immunity provides protection against parasites, extracellular

bacteria, soluble toxins and allergens, and certain viruses. It involves the production of
antibody by B cells. These two systems are controlled by different types of helper T cells.
Th1 cells, upon stimulation by IL-12, IFN-delta (among others) from antigen presenting
cells (APC), causes a cellular immune response. Th2 cells, upon stimulation by IL4,
cause a humoral response. These two systems are related, and an increase in IL-12, will
inhibit IL-4 production, shifting the immune response to a mainly Th1, and thus a cellular
immune response. Physiologic levels of glucocorticoids cause an increase in humoral
immunity, and a decrease in cellular immunity. This effect is mainly due to a
glucocorticoid-induced inhibition of IL-12 secretion by APC and IL-12 responsiveness in
Th1 cells. This inhibition of IL-12 frees IL-4 to have a more unopposed effect, triggering
an enhanced humoral response (6).
Clinically, this decrease in cellular immunity has many important effects. Stress, and the
subsequent physiologic increase in glucocorticoids and the Th2 shift, alters an
individual's response to infection and autoimmune diseases. Cellular immunity is
important in mycobacterial infections and HIV, correlating with the observation that these
two diseases may be accelerated with stress and an increase in cortisol. Autoimmune
diseases, although extremely complex in their pathophysiological mechanisms, can be
thought of as involving mainly Th1 and Th2 mechanisms. Rheumatoid arthritis, multiple
sclerosis, type I diabetes, and Crohn's disease are thought to be due to a hyperresponsive
Th1 response, with excess IL-12 and TNF-alpha production. Women in their third
trimester of pregnancy have increased levels of cortisol, which favors a Th2 response,
and a expected remission of these diseases are seen during this time of pregnancy. In
addition, decreased stress in the postpartum period or the stopping of glucocorticoid
therapy can cause a worsening of these conditions. Th2 driven diseases, such as systemic
lupus erythematous, can become worse during stress and pregnancy, when cortisol causes
an increased Th2 response (6).
Glucocorticoids induce gluconeogenesis and they have catabolic effects on the periphery
which supplies the liver with the amino acids and glycerol needed for gluconeogenesis.
Glucocorticoids also decrease glucose uptake in adipose tissue, most likely by moving
glucose transporters from the plasma membrane to an intracellular location. This can be
thought of as protecting glucose-dependent tissues such as the brain and the heart from
starvation during stress. Thus, under prolonged high levels of glucocorticoids, lymphoid
tissue, muscle, fat, bone, and skin undergo wasting. This can lead to Cushing's syndrome,
with a redistribution of fat from the periphery to the back of the neck (buffalo hump),
face (moon facies), and supraclavicular area with less fat in the periphery. One hypothesis
to this redistribution is that adipose cells in the neck, face, and supraclavicular area are
sensitive to insulin, so the glucocorticoid induced hypoglycemia leads to increased fat
deposition in these areas. The peripheral tissues are less sensitive to insulin and respond
mainly to the glucocorticoid-induced lipolysis.
Corticosteroids are required for permissive contraction of skeletal muscle. Patients with
Addison's disease frequently have fatigue and weakness as symptoms, which may be

partly due to vascular insufficiency. Chronic use of corticosteroids can cause skeletal
muscle wasting, called steroid myopathy.
Corticosteroids can have direct effects on a patient's mood and behavior. Patient's with
Addison's disease can show psychosis, apathy, depression, and irritability. Glucocorticoid
administration can have a stimulatory affect, with mood elation, euphoria, insomnia,
restlessness, and increased motor activity. These effects are thought to be due to
corticosteroids involvement in the regulation of neuronal activity (neurosteroids).
The most dangerous and life threatening complication of stopping corticosteroid therapy
is acute adrenal insufficiency due to the HPA axis being suppressed by exogenous
corticosteroids, disabling its ability to endogenously produce corticosteroids in sufficient
quantities. By withdrawing corticosteroids, the so-called corticosteroid withdrawal
syndrome can lead to cardiovascular collapse due to the loss of cardiovascular tone, with
hypotension, shock, and death. Other symptoms of this syndrome include malaise,
anorexia, headache, lethargy, nausea, and fever. Hypoglycemia and hyponatremia may be
present. This should be considered in patients who have been given supraphysiologic
(i.e., pharmacologic) doses of corticosteroids (e.g., a course of prednisone) in the
previous year. Patients taking glucocorticoid therapy for 7-10 days can safely be
discontinued abruptly. Those on longer therapy need to be tapered, with a 25% reduction
in the previous weekly level usually recommended, although patients need to be followed
clinically for signs of withdrawal (3). Once a physiological dose is achieved (8-10 mg per
square meter body surface area per day) and the patient is stable, the dosage can be
decreased to 4-5 mg per square meter per day for 4-6 weeks to allow the adrenal axis to
recover. Most patients recover their HPA axis within several weeks, although there is
wide variation and some may take a year or longer to recover fully, especially in the
physiological response of the HPA to stress. Stress doses of glucocorticoids, usually 3-10
times the physiological replacement, are recommended if a physiologically stressful
event (such as surgery) is encountered, for patients receiving chronic or long-term
glucocorticoid therapy or for those who have been recently withdrawn from
corticosteroids. A further problem of withdrawal can be a flare-up of the disease for
which the corticosteroids were originally given.
Other complications or corticosteroids include Cushing's syndrome, growth retardation,
the development of posterior subcapsular cataract formation, and advanced bone necrosis.
Complications are unlikely if given for less than 2 weeks with moderate doses. Most
side-effects of corticosteroids resolve with the exception of the formation of cataracts,
which are permanent.

Questions
1. Which of the following is not a corticosteroid:
. . . . . a. cortisol
. . . . . b. aldosterone

. . . . . c. adrenal androgens
. . . . . d. norepinephrine
2. Glucocorticoids that are intermediate-potency include
. . . . . a. prednisone
. . . . . b. prednisolone
. . . . . c. triamcinolone
. . . . . d. dexamethasone
. . . . . e. a, b, and c
3. Immune system cells that are increased in the peripheral circulation after corticosteroid
administration are
. . . . . a. neutrophils
. . . . . b. eosinophils
. . . . . c. lymphocytes
. . . . . d. monocytes
4. Safely tapering steroids in patient taking oral steroids for more than 10 days involves
. . . . . a. stopping steroid administration all at once
. . . . . b. changing a long-acting glucocorticoid to a short-acting glucocorticoid
. . . . . c. reducing previous weekly levels 10% with no clinical follow-up needed
. . . . . d. reducing previous weekly levels 25% with clinical follow-up
5. Glucocorticoids induce a Th2 shift by
. . . . . a. decreasing IL-12 production by antigen presenting cells, which allows an
increase in IL-4 effects and thus more humoral immunity
. . . . . b. increasing IL-12 production by antigen presenting cells, which allows for a
decrease in IL-4 and thus more humoral immunity
. . . . . c. glucocorticoids induce a Th1 shift
. . . . . d. none of the above
6. Glucocorticoids do NOT reduce inflammation by
. . . . . a. inhibiting phospholipase and production of arachidonic acid
. . . . . b. inhibiting cyclooxygenase and production of prostaglandins and thromboxanes
from arachidonic acid
. . . . . c. decreasing the levels of neutrophils in the peripheral blood
. . . . . d. inhibiting leukotriene action and thus neutrophil function
. . . . . e. decreasing production of nitric oxide by inhibiting nitric oxide synthase
7. A physician orders 40 mg of IV methylprednisolone for a 20 kg patient (2 mg/kg) with
status asthmaticus. The hospital pharmacy notifies the physician that IV
methylprednisolone is not currently available and is on back order. Utilizing
corticosteroid potencies, which of the following are approximate glucocorticoid
equivalents?
. . . . . a. Dexamethasone 4 mg (0.2 mg/kg)
. . . . . b. Hydrocortisone 200 mg (10 mg/kg)

. . . . . c. Prednisone 40 mg (2 mg/kg)
. . . . . d. Dexamethasone 400 mg (20 mg/kg)
8. Explain how corticosteroids could be beneficial in croup and status asthmaticus due to
a viral pneumonia. In both instances, a viral infection is causing the problem. Since
corticosteroids are potentially immunosuppressive agents, is there a net beneficial or
detrimental effect?

References
1. Schimmer BP, Parker KL. Chapter 60 - Adrenocorticotropic Hormone: Adrenocortical
Steroids and their Synthetic Analogs; Inhibitors of the Synthesis and Actions of
Adrenocortical Hormones. In: Hardman JG, Limbird LE, Gilman AG (eds). Goodman
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Answers to questions

1.d. Norepinephrine is a hormone of the adrenal medulla, not the adrenal cortex.
Corticosteroids are by definition hormones of the adrenal cortex.
2.d. Dexamethasone is a high-potency, long-acting glucocorticoid. Prednisone,
prednisolone, and triamcinolone are intermediate-potency glucocorticoids.
3.a. Eosinophils, lymphocytes, and monocytes are reduced in the peripheral circulation
after corticosteroid administration. Although neutrophil numbers are increased, their
bactericidal activity is decreased.
4.d. Safely tapering corticosteroids in a patient who has taken corticosteroids for more
than 10 days, involves reducing the previous week's levels by 25%, and the patient
should be monitored clinically for signs of corticosteroid withdrawal (malaise, anorexia,
headache, lethargy, nausea, fever, loss of cardiovascular tone, with hypotension, shock,
and death) and a worsening of the condition that the corticosteroids were originally given
for.
5.a. Th1 cells are stimulated by IL-12 from APC to cause a cellular immune response.
Th2 cells, upon stimulation by IL4, cause a humoral response. IL-12 will inhibit IL-4
production as well. Glucocorticoids cause a decrease in IL-12 secretion by APC and IL12 responsiveness in Th1 cells. This inhibition of IL-12 frees IL-4 to have a more
unopposed effect, triggering an enhanced humoral response.
6.c. Glucocorticoids inhibit production of arachidonic acid, prostaglandins,
thromboxanes, leukotrienes, and nitric oxide, all of which are involved in the
inflammatory response. Neutrophils are increased in the peripheral blood, not decreased.
7. a,b,c are correct. 0.2 mg/kg of dexamethasone would probably be the best answer,
although its duration is longer than that of methylprednisolone. This should not be a
problem for status asthmaticus. 10 mg/kg of hydrocortisone has equivalent glucocorticoid
activity, but it has unnecessary mineralocorticoid activity. 2 mg/kg of prednisone is
roughly the same as 2 mg/kg of methylprednisolone, but prednisone would have to be
given orally since it cannot be given IV. 20 mg/kg of dexamethasone is clearly an
overdose, which results from multiplying by 10 instead of dividing by 10. A good clue
would be that dexamethasone comes in 10 mg vials. A 400 mg dose would require 40
vials. This should clearly prompt questioning by pharmacy and nursing staff. Whenever a
pediatric dose requires more than one vial, the dose should be questioned.
8. The symptoms of croup and status asthmaticus are largely due to the inflammatory
response induced by the viral infection. The virus itself causes less of a problem
compared to the body's inflammatory response. Corticosteroids suppress the
inflammatory response resulting in less laryngeal and bronchial inflammation. It cannot
be assumed that this is true for all viral infections. For example, in viral pharyngitis, the
symptoms of a sore throat and nasal congestion may be suppressed with corticosteroids.
However, it may cause more harm than good. In the case of croup and status asthmaticus,
numerous studies have supported the net benefit of corticosteroids in these two

conditions. In bacterial meningitis due to H. flu, a similar benefit has been demonstrated,
but for bacterial meningitis due to other organisms and for viral meningitis, the benefit
has not been clearly demonstrated.