This document discusses allergic diseases and their diagnosis. It notes that the incidence of allergic conditions like asthma and allergic rhinitis are rising. Atopy, the genetic predisposition to develop IgE antibodies, involves complex genetic and environmental factors. Allergic disorders are caused by type I hypersensitivity reactions and IgE-mediated immune responses. Diagnosis involves taking a thorough history, and may include nonspecific tests like CBC and IgE levels or more specific tests like skin prick tests and allergen-specific IgE blood tests to identify triggers.

1. Allergic
Diseases, Edited by H.A.Shakir

2. The incidence of asthma and allergic disease is rising.
However, primary care physicians
have dealt with allergic conditions far more often than they
may expect even before
the recent increase in
allergic conditions
. Some examples of immunological disease that
the primary care physician sees include asthma, allergic
rhinitis, and atopic dermatitis

3. Atopy, the genetic predisposition to thedevelopment ofantigen-specific
immunoglobulin
E (IgE) antibody formation, involves complex genetic and environmental influences
that are not fully understood. In other words, simple Mendelian inheritance patterns
not predict which individuals will develop allergies. Nevertheless,there appears to be
a higher incidence of allergies among children of allergic parents

4. ATOPIC AND ALLERGIC DISORDERS
Type I hypersensitivity reactions underlie all atopic and many allergic
disorders. The terms atopy and allergy are often used interchangeably but are
different:
•Atopy is an exaggerated IgE-mediated immune response; all atopic
disorders are type I hypersensitivity disorders.
•Allergy is any exaggerated immune response to a foreign antigen
regardless of mechanism.
Thus, all atopic disorders are considered allergic, but many allergic disorders
(eg, hypersensitivity pneumonitis) are not atopic. Allergic disorders are the
most common disorders among people.
Atopic disorders most commonly affect the nose, eyes, skin, and lungs. These
disorders include extrinsic atopic dermatitis, immune-mediated urticaria ,
immune-mediated angioedema, acute latex allergy , some allergic lung
disorders (eg, some cases of asthma, IgE-mediated components of allergic
bronchopulmonary aspergillosis), allergic rhinitis, and allergic reactions to
venomous stings.

5. One becomes “allergic” to a substance through a two-step process. The first step begins
with sensitization, During the initial stage of sensitization,
one develops significant amounts of IgE antibodies against an inhaled, ingested, or
injected substance. Memory B-cells appear that are capable of immediately producing
more specific IgE antibody when stimulated. The second stage involves adherence of this
newly formed IgE antibody to circulating blood basophils or to tissue mast cells located
in the mucosal surfaces of the skin, the gastrointestinal tract, and the respiratory system.
These tissue mast cells were previously coated with IgE antibodies directed specifically
against other potentially allergenic substances. The new exposure simply added to the
existing population

6. ASPECTS OF IgE PRODUCTION
The key intermediary in allergic conditions is IgE antibody.
it is the individual’s propensity to produce IgE in response to an “allergic antigen” (also
known as an allergen) that makes one atopic. The same allergen that stimulates B-cells
to produce IgG or IgMin a nonallergic person may stimulate IgE antibody production in
an atopic individual.
Why does the body respond to an allergen exposure by making IgE as opposed to other
classes of antibodies? Antibody molecules consist of a variable region responsible for
recognizing and binding the offending antigen and a constant region whose purpose is to
dictate the fate of the antigen–antibody complex. For example, a person may make both
IgA and IgG antibodies against a virus. Both are capable of binding to that virus, but the
IgA is found mainly in secretions (as in the nasal mucosa), whereas the IgG predominates
in the bloodstream. The mechanisms by which a particular antigen favors the production
of one class of antibody over another are not firmly established; nevertheless, several
factors that may favor IgE formation are worth discussing

7. All antigens initially elicit the production of IgM antibodies against an injected or
inhaled allergen. With repeated exposure, the antigen may stimulate an event known as
class switching, whereby the constant portion of the antibody will “switch” to another
class . The new antibody will still have the same antigen-recognition
region, but it will now be sitting on another constant region . IgE
production by B-cells as a result of class switching is regulated by T-cells and macrophages,
predominantly, and the cytokines they produce. Cytokines are small molecularweight molecules
that affect cell function at the local level. Two primary cytokines that
favor IgE class switching are interleukin (IL)-4 and IL-13. IL-4 and IL-13 are produced
by a subset of CD4+ T-cells, .
IL-4 is such an essential signal for IgE production that mice that have been genetically
engineered to be devoid of IL-4 (IL-4 knockout mice) are unable to synthesize IgE. In
contrast, the primary cytokine that inhibits IgE class switching is called interferon (IFN)-γ.
IFN-γ is produced by a subset of T-cells that have a T-helper 1 (TH1) cytokine profile. The
cytokines produced by TH1 and TH2 cells reciprocally inhibit the other’s development.. In atopic
individuals
the balance of TH1 and TH2 responses seems to favor the TH2 response and IgE production.
In nonatopic individuals, the balance between TH1 and TH2 favors a TH1 dominant
response.

9. THE MAST CELL
A medical student, named Paul Ehrlich, first described the mast cell in 1877. He chose
the name Mastzellen (well-fed cells) based on the cells’ characteristic cytoplasmic granules
(he incorrectly thought that the mast cells were phagocytes and that the granules were
ingested debris.
, where they mature, acquiring
both cytoplasmic granules and a coating of high-affinity IgE receptors (called FcεRI-α)
on their cell surface., it is now apparent that mast
cells are a heterogeneous cell population. Most pulmonary mast cells contain primarily
one neutral protease, tryptase. Skin mast cells, on the other hand, contain large amounts
of both tryptase and another protease, chymase (Mast cells in humans
are divided and named on the basis of this biochemical difference and are termed MCT
(for mast cells containing tryptase) or MCTC (for mast cells containing chymase). The
tissue distribution of these subtypes of mast cells is shown in. The relative
numbers of MCT or MCTC may change locally with tissue inflammation, fibrosis, or the
cytokine microenvironment. There are no accurate means of discerning from what tissue
an isolated mast cell population is derived, because mixtures of both MCT and MCTC cells

10. Diagnosis
Clinical evaluation
Sometimes CBC and occasionally serum IgE levels (nonspecific tests)
Often skin testing and allergen-specific serum IgE testing (specific tests)
Rarely provocative testing
A thorough history is generally more reliable than testing or screening. History should
include
Questions about frequency and duration of attacks and changes over time
Triggering factors if identifiable
Relation to seasonal or situational settings (eg, predictably occurring during pollen
seasons; after exposure to animals, hay, or dust; during exercise; or in particular
places)
Family history of similar symptoms or of atopic disorders
Responses to attempted treatments
Age at onset may be important in asthma because childhood asthma is likely to be
atopic and asthma beginning after age 30 is not. Health care workers may be unaware
that exposure to latex products could be causing their allergic reaction.

11. Nonspecific tests:
Certain tests can suggest but not confirm an allergic origin of symptoms.
CBC may be done to detect eosinophilia if patients are not taking corticosteroids,
which reduce the eosinophil count. However, CBC is of limited value because although
eosinophils may be increased in atopy or other conditions (eg, drug hypersensitivity,
cancer, some autoimmune disorders, parasitic infection), a normal eosinophil count
does not exclude allergy. Total WBC is usually normal. Anemia and thrombocytosis are
not typical of allergic responses and should prompt consideration of a systemic
inflammatory disorder.
Serum IgE levels are elevated in atopic disorders but are of little help in diagnosis
because they may also be elevated in parasitic infections, infectious mononucleosis,
autoimmune disorders, drug reactions, immunodeficiency disorders (hyper-IgE
syndrome—see Hyper-IgE Syndrome—and Wiskott-Aldrich syndrome—see Wiskott-
Aldrich Syndrome), and in some forms of multiple myeloma. IgE levels are probably
most helpful for following response to therapy in allergic bronchopulmonary
aspergillosis (seeAllergic Bronchopulmonary Aspergillosis (ABPA)).

12. Specific tests:
Skin testing uses standardized concentrations of antigen introduced directly into skin
and is indicated when a detailed history and physical examination do not identify the
cause and triggers for persistent or severe symptom
Two skin test techniques can be used:
Percutaneous (prick)
Intradermal
The prick test can detect most common allergies. The intradermal test is more
sensitive but less specific; it can be used to evaluate sensitivity to allergens when prick
test results are negative or equivocal.
For the prick test, a drop of antigen extract is placed on the skin, which is then tented
up and pricked or punctured through the extract with the tip of a 27-gauge needle
held at a 20° angle or with a commercially available prick device.
For the intradermal test, just enough extract to produce a 1- or 2-mm bleb (typically
0.02 mL) is injected intradermally with a 0.5- or 1-mL syringe and a 27-gauge short-bevel
needle.

13. Allergen-specific serum IgE tests use an enzyme-labeled anti-IgE antibody to
detect binding of serum IgE to a known allergen. They are done when
skin testing might be ineffective or risky—for example, when drugs that
interfere with test results cannot be temporarily stopped before testing
or when a skin disorder such as eczema or psoriasis would make skin
testing difficult. For allergen-specific serum IgE tests, the allergen is
immobilized on a synthetic surface. A substrate for the enzyme is then
added; the substrate provides colorimetric fluorescent or
chemiluminescent detection of binding. Allergen-specific IgE tests have
replaced radioallergosorbent testing (RAST), which used 125I-labeled
anti-IgE antibody. Although the allergen-specific serum IgE tests are not
radioactive, they are still sometimes referred to as RAST.

14. Provocative testing involves direct exposure of the mucosae to
allergen and is indicated for patients who must document their reaction
(eg, for occupational or disability claims) and sometimes for diagnosis of
food allergy. For example, patients may be asked to exercise to diagnose
exercise-induced asthma, or an ice cube may be placed on the skin for 4
min to diagnose cold-induced urticaria

15. Treatment
Removal or avoidance of allergic triggers
H1 blockers
Mast cell stabilizers
Anti-inflammatory corticosteroids and leukotriene inhibitors
Immunotherapy (desensitization)
Antihistamine solutions may be intranasal (azelastine or olopatadine
to treat rhinitis) or ocular
(azelastine, emedastine, ketotifen, levocabastine olopatadine
, or pemirolast
to treat conjunctivitis). Topical diphenhydramine
Anti-IgE antibody (omalizumab) is indicated for moderately persistent or
severe asthma refractory to standard treatment Some evidence suggests
that omalizumab is efficacious as treatment for chronic urticaria refractory
to antihistamine therapy.

16. Mast cell stabilizers:
These drugs block the release of mediators from mast cells; they are
used when other drugs (eg, antihistamines, topical corticosteroids) are
ineffective or not well-tolerated. These drugs may be given orally
(cromolyn), intranasally (eg, azelastine, cromolyn), or ocularly
(eg,azelastine, cromolyn
, lodoxamid, ketotifen, nedocromil, olopatadine, pemirolast). Several
ocular and nasal drugs are dual-acting mast cell
stabilizers/antihistamines

17. Immunotherapy:
Exposure to allergen in gradually increasing doses
(hyposensitization or desensitization) via injection or in high
doses sublingually can induce tolerance and is indicated
when allergen exposure cannot be avoided and drug
treatment is inadequate.
For full effect, injections must be given monthly. Dose
typically starts at 0.1 to 1.0 biologically active units (BAU),
depending on initial sensitivity, and is increased weekly or
biweekly by ≤ 2 times with each injection until reaching the
maximum tolerated dose (ie, the dose that begins to elicit
moderate adverse effects); patients should be observed for
about 30 min postinjection during dose escalation because
anaphylaxis may occur after injection. The maximum
tolerated dose should be given q 4 to 6 wk year-round;
year-round treatment is better than preseasonal or
coseasonal treatment, even for seasonal allergies.

18. Allergens used are those that typically cannot be avoided: pollens,
house dust mites, molds, and venom of stinging insects. Insect venoms
are standardized by weight; a typical starting dose is 0.01 mcg, and usual
maintenance dose is 100 to 200 mcg. Animal dander desensitization is
ordinarily limited to patients who cannot avoid exposure (eg,
veterinarians, laboratory workers), but there is little evidence that it is
useful. Desensitization for food allergens is under study. Desensitization
for penicillin and certain other drugs and for foreign (xenogeneic) serum
can be done

19. Asthma
Asthma Epidemiology: United States,
2001
31.3 million lifetime prevalence
20.3 million current sufferers
15.1 million adults (7.1%) with current
asthma
465,000 hospitalizations (year 2000)
14.5 million lost workdays
1.8 million emergency visits
~5000 deaths per year (14 people per day)
$14 billion costs
. In 2011, 235–300 million people globally have been diagnosed with asthma,[and it
caused 250,000 deaths

20. The word asthma was derived from the Greek word for
panting, or breathlessness, and
thus might be considered a description of the primary
symptom of this disease. Asthma
can be defined clinically as recurrent airflow obstruction
causing intermittent wheezing,
breathlessness, chest tightness, and sometimes cough with
sputum production. The
National Asthma Education Panel, developed in conjunction
with the National Heart,
Lung and Blood Institute, defined asthma as having three
components:
1. Airflow obstruction that is reversible (or nearly
completely so), either spontaneously or
in response to therapy
2. Airway inflammation
3. Increased airway responsiveness to a variety of stimuli

21. CAUSES OF
BRONCHIAL
ASTHMA
Allergic Asthma

22. About 90% of asthmatics between the ages of 2 and 16 yr are allergic, 70% less than
30 yr are allergic, and about 50% of patients older than 30 yr are concomitantly allergic
. One should suspect allergy as a
contributing factor when (1) there is a family history of allergic diseases, (2) the clinical
presentation includes seasonal exacerbations or exacerbations related to exposures to
recognized allergens, (3) there is concomitant allergic rhinitis or other allergic disease,
(4) a slight-to-moderate eosinophilia is present (300–1000/mm3) or eosinophilia in the
sputum is observed, or (5) the patient is less than 40 yr old
Conditions That Cause and Worsen Asthma
Conditions that cause asthma:
Chemical or drug ingestion
Allergic disease
Aspirin or other nonsteroidal anti-inflammatory
Allergic asthma
drugs
Allergic bronchopulmonary aspergillosis
Infections
Bronchiolitis
Upper respiratory tract infections
Bronchitis
Industrial–occupational or environmental exposure
Irritants
Allergens
Sulfiting agents
β-Adrenergic antagonists
Vasculitis (Churg and Straus allergic
granulomatosis)
Idiopathic (intrinsic)
Conditions that may worsen asthma:
Sinusitis
Gastroesophageal reflux
Pregnancy
Hyperthyroidism
Psychological stress

23. MAST CELLS AND ASTHMA
The essential components of allergic reactions include allergens, IgE
antibodies
directed at antigenic determinants on the allergen, and activated
mast cells, which
generate and release mediators and cytokines. In order to initiate
allergic responses,
exposure to an appropriate antigen and a genetically determined
capacity to respond with
IgE production are required. Antigen presentation requires access of
antigens to the
mucous membrane, uptake by antigen-presenting cells, antigen
processing, and stimulation
of local antibody production. IgE production occurs in the same
local environment
as antigen presentation, probably in the draining lymph nodes

24. MEDIATORS OF ANAPHYLAXIS
Three categories of mediators are released during the process of mast cell
degranulation:
preformed soluble molecules stored within the cytoplasmic granules, newly formed
lipid mediators, and cytokines (Table 3). The consequences of mediator release occur
within minutes (immediate hypersensitivity) or take hours to develop (late-phase
allergic
reactions). Research has revealed an expanding list of mediators whose actions may
contribute to the pathological changes seen in asthma
In addition to the granule-derived mediators, the process of degranulation leads to
transcription, synthesis, and secretion of potent cytokines over several hours, which
likely contribute to the late-phase allergic response. Thus, mast cells synthesize and
release interleukin (IL)-3, IL-4, IL-5, and IL-6 in addition to tumor necrosis factor and
other inflammatory cytokines. IL-4 helps regulate IgE production and mast cell
activation,
and release of IL-4 might actually upregulate IgE production

25. Pathological Changes in Asthma and the Putative Mediators Responsible
Pathological changes Mast cell mediators responsible
Bronchial smooth muscle contraction
Histamine
Leukotrienes C4, D4, E4
Prostaglandins and thromboxane A2
Bradykinin
Platelet-activating factor
Mucosal edema
Histamine
Leukotrienes C4, D4, E4
Prostaglandin E2
Bradykinin
Platelet-activating factor
Chymase
Reactive oxygen species
Mucosal inflammation
Inflammatory factors
Cytokines(IL-1, IL-6, TNF-α,etc.)
Eosinophil and neutrophil
Chemotactic factors
Leukotriene B4
Platelet-activating factor
Mucus secretion
Histamine
Prostaglandins
HETEs
Leukotrienes C4, D4,
E4
Chymase
Desquamation
Reactive oxygen
species
Proteolytic enzymes
Inflammatory factors
and cytokines

27. PATHOPHYSIOLOGY
Pathologically, the airflow obstruction of asthma is a result of combinations of bronchial
smooth-muscle contraction, mucosal edema and inflammation, and viscid mucus
secretion. The disease involves large and small airways but not alveoli. Pathological
examination of asthmatic lungs reveals that small bronchi and bronchioles are principally
involved, there is extensive airway denudation resulting from loss or thinning of the
epithelium, and the goblet cells are often markedly hyperplastic
. The basement membrane
is thickened because of the deposition of
subbasement membrane collagen, and
the
lamina propria is infiltrated with CD4+
lymphocytes, mast cells, eosinophils, and
neutrophils.
The smooth muscle is hyperplastic and
contracted. The submucosal glands are
hyperplastic and are actively secreting
mucus. The airway lumen is often filled
with
secretions containing mucus, edema
fluid, eosinophils, inspissated mucus
plugs, Charcot-
Leyden crystals, and Curschmann’s
spirals.

28. Immunological features
• Activation of mast cells leads to immediate and delayed mediator
release and synthesis of cytokines (IL-3, IL-4, IL-5: chemotactic for and
stimulatory to eosinophils).
• Lung eosinophilia may be marked, continuing the infl ammatory process
through the release of cytokines.
• Lymphocytes are recruited and activated, releasing Th2 cytokines and
stimulating further IgE production.
• The chronic phase may be considered to include a type IV reaction.

29. CLINICAL ASTHMA
Symptoms
The classic symptoms of asthma include intermittent, reversible episodes of airflow
obstruction manifested by cough, wheezing, chest tightness, and dyspnea (Table 10).
When the clinical situation permits, a detailed history should be taken that
includes the following:
(l) family and personal history of atopic disease;
(2) age of onset
of asthma, frequency and severity of attacks;
(3) times (including seasons) and places of occurrence of asthmatic attacks;
(4) known provocative stimuli and any previous correlating skin-test reactions;
(5) the severity of the disease as reflected in the wheezing
episodes per day, the number of missed school or work days per year, whether sleep is
interrupted, the necessity for emergency room visits, and the number of hospitalizations
for asthma; and (6) previous pharmacological or immunological therapy and its efficacy

30. Asthma Diagnosis: Episodic Symptoms of Airflow Obstruction
(Determine Frequency)
Wheezing
Shortness of breath (with or without exercise)
Chest tightness (below sternum)
Cough (throat vs chest, quantity and quality of sputum)
Nocturnal awakenings
Morning vs evening symptoms
Emergency room visits
Hospitalizations

31. Diagnosis
• The diagnosis depends on history and
examination. There is frequently
an atopic background and a family history
of atopic diseases. Wheeze
is less common in children, who tend to
cough instead.
• Serial peak fl ow measurements may
show the typical asthmatic
pattern. Chronic disease may show loss of
reversibility and be
diffi cult to distinguish from chronic
obstructive pulmonary disease
(COPD). Reactive airways may be
demonstrated with challenge tests
(methacholine—see Part 2).
• A high total IgE makes asthma more
likely but does not correlate well
with symptoms. A low IgE only excludes
IgE-mediated bronchospasm.
SPTs to common aero-allergens may pick
up positives, but the history
will indicate whether these are relevant
clinically.
• There may be an eosinophilia on full
blood count, although this is
rarely marked and is only present in
about 50% of asthmatics; sputum
eosinophilia is much more common

33. TREATMENT
Over the past decade, the treatment of asthma has changed remarkably,
largely because of our increased understanding of the pathophysiology of the disease,
with recognition of the importance of airway inflammation.

34. Specific treatments ( long-term controlling)
include the following:
• Allergy avoidance
• Allergy immunotherapy
• Inhaled CCS
• Cromolyn or nedocromil
• Oral CCS
• Leukotriene modifiers
• Combination of inhaled LABA and CCS
• Humanized monoclonal anti-IgE
(Omalizumab, Xolair)
Symptomatice treatments (short-term
relieving) include the following:
• β-agonists
• Theophylline
• Anticholinergics
• LABA

35. the basic concepts of asthma management include the following:
1. Daily use of specific treatments (long-term control
treatments), often used in combination.
Allergy management is superimposed on other treatment
modalities for long-term
control.
2. Symptomatic use of bronchodilators (quick-relief
medications) used only on an as-needed
basis.
3. Step therapy:
a. Use whatever dose or combination of therapies required
to totally control symptoms
and achieve a maximum (personal best) peak flow.
b. Once completely controlled, step down the treatment plan
while maintaining symptom
control and personal best peak flow to the lowest effective
doses of medication

37. When to Use an Inhaled Corticosteroid
1. For all asthmatics who:
a. wheeze more than 2 d/wk
b. use a bronchodilator on a frequent basis
c. have nocturnal awakenings with asthma (all
persistent asthmatics!)
2. Not indicated for the mild intermittent
asthmatic who wheezes less than 1-2 d/wk and
is otherwise asymptomatic

38. When to Use Cromolyn or Nedocromil
1. Most useful in younger, allergic asthmatics
2. Best if used for prophylaxis. Might add after patient is well
controlled with CCS, as a means
to reduce CCS dose
3. Try for coughing patient
4. Try prophylactically for exercise-induced asthma
5. Try larger doses if standard dose fails (more than two puffs at
a time)
6. Try nedocromil in the office. If taste is a problem, do not
prescribe
7. Use nebulized form for younger asthmatics

39. When to Use Leukotriene Modifiers
1. Leukotriene receptor antagonists: Zafirlukast (Accolate, 20 mg bid on empty
stomach) and
Montelukast(Singulair, 10 mg qhs)
2. Try in persistent asthmatics
3. Try in aspirin-sensitive patients and patients with sinusitis, polyposis,urticaria
4. Must adjust warfarin doses (Accolate)
5. Experience indicates that about 30-50% of patients will improve with each product,
some
dramatically
6. May allow reduced CCS requirement
When to Use a β-Agonist (Short-Acting)
1. With symptomatic disease, as needed
2. With exacerbations, at a peak flow 20% below
personal best
3. Prior to exercise
4. Do not use on a regular basis
Do not prescribe qid; Instead, use “as often as qid”

40. When to Add a Long-Acting β-Agonist
1. When patient requires multiple inhalations of short-acting β-
agonist per day despite appropriate
therapy
2. When patient is experiencing nocturnal wheezing despite
appropriate therapy
3. To prevent exercise-induced asthma when use of short-acting
β-agonist is inconvenient
4. When patient is intermittently exposed to irritants in the
environment (work exposures,
fumes) as prophylaxis
5. Consider as an inhaled CCS-sparing agent, especially
combined with an inhaled CCS
6. Not advisable to use without the concurrent use of inhaled
steroid in persistent asthmatics
7. Can enhance the effectiveness of inhaled CCS

41. When to Use Theophylline
1. When patients are not adequately controlled symptomatically with
short- or long-acting β-agonists plus inhaled cortocosteroid
2. With persistent nocturnal awakening
3. When a long-acting oral bronchodilator is preferred
4. Consider as an inhaled cortocosteroid-sparing agent
5. In pregnancy, when a safe long-acting bronchodilator is necessary
Anticholinergics
1. Most useful in the asthmatic with bronchitis to help reduce mucus production
2. Atrovent solution adds to β-agonist inhalation in emergency settings
3. Combivent (a metered-dose inhaler combining albuterol with ipratropium) may
be useful for
asthma and bronchitis (DuoNeb is one nebulized form)