Rh incompatibility

URL of this page: http://www.nlm.nih.gov/medlineplus/ency/article/001600.htm

Rh incompatibility is a condition that develops when a pregnant woman has Rh-negative blood and the baby in her womb has Rh-
positive blood.

Causes

During pregnancy, red blood cells from the fetus can get into the mother's bloodstream as she nourishes her child through the placenta.

If the mother is Rh-negative, her immune system treats the Rh-positive fetal cells as if they were a foreign substance and makes
antibodies against the fetal blood cells. These anti-Rh antibodies may cross the placenta into the developing baby, where they destroy
the baby's circulating red blood cells.

When red blood cells are broken down, they make bilirubin, which causes an infant to become yellow (jaundiced). The level of
bilirubin in the infant's bloodstream may range from mild to dangerously high.

Firstborn infants are often not affected -- unless the mother has had previous miscarriages or abortions, which could have sensitized
her system -- as it takes time for the mother to develop antibodies against the fetal blood. However, second children who are also Rh-
positive may be harmed.

Rh incompatibility develops only when the mother is Rh-negative and the infant is Rh-positive. This problem has become uncommon
in the United States and other places that provide good prenatal care. Special immune globulins, called RhoGAM, are now used to
prevent RH incompatibility.

Symptoms

Rh incompatibility can cause symptoms ranging from very mild to deadly. In its mildest form, Rh incompatibility causes destruction
of red blood cells.

Symptoms may include:

• Low muscle tone (hypotonia)

• Developmental delay
• Increased amount of amniotic fluid (polyhydramnios)
• Yellowing of the skin and whites of the eyes (jaundice)

Exams and Tests

There may be:

• A positive direct Coombs test result

• Higher than normal levels of bilirubin in the baby's cord blood
• Signs of red blood cell destruction in the infant's blood

Treatment

Since Rh incompatibility is almost completely preventable with the use of RhoGAM, prevention remains the best treatment.
Treatment of the already affected infant depends on the severity of the condition.

Mild Rh incompatibility may be treated with:

• Aggressive hydration
• Phototherapy using bilirubin lights

Outlook (Prognosis)
Full recovery is expected for mild Rh incompatibility.

Possible Complications

Possible complications include:

• Hydrops fetalis (potentially deadly fluid buildup and swelling in the baby)
• Kernicterus (brain damage due to high levels of bilirubin)
• Neurological syndrome with mental deficiency, movement disorder, hearing loss, speech disorder, and seizures

When to Contact a Medical Professional

Call your health care provider if you think or know you are pregnant and have not yet seen a doctor.

Prevention

Rh incompatibility is almost completely preventable. Rh-negative mothers should be followed closely by their obstetricians during
pregnancy.

Special immune globulins, called RhoGAM, are now used to prevent RH incompatibility.

If the father of the infant is Rh-positive or if his blood type cannot be confirmed, the mother is given a mid-term injection of RhoGAM
and a second injection within a few days of delivery.

These injections prevent the development of antibodies against Rh-positive blood. However, women with Rh-negative blood type
must receive this injection:

• During every pregnancy

• If they have a miscarriage or abortion
• After prenatal tests such as amniocentesis and chorionic villus biopsy
• After injury to the abdomen during a pregnancy

Alternative Names

Rh-induced hemolytic disease of the newborn

References

Stoll BJ. Blood disorders. In: Kliegman RM, Behrman RE, Jenson HB, Stanton BF, eds. Nelson Textbook of Pediatrics. 18th ed.
Philadelphia, Pa: Saunders Elsevier; 2007:chap 103.

.
cytotoxic reaction

An immunologic (allergic) reaction in which noncytotropic IgG or IgM antibody combines with specific antigen on cell surfaces; the
resulting complex initiates the activation of complement which causes cell lysis or other damage, or which, in the absence of
complement, may lead to phagocytosis or may enhance T lymphocyte involvement.

(05 Mar 2000)

noun
An immunological reaction in which a noncytotropic antibody combines with a specific antigen on the surface of a cell and forms a
complex that initiates the activation of complement, leading to cell lysis or other damage.

ntroduction

Background

The immune system is an integral part of human protection against disease, but the normally protective immune mechanisms can
sometimes cause detrimental reactions in the host. Such reactions are known as hypersensitivity reactions, and the study of these is
termed immunopathology. The traditional classification for hypersensitivity reactions is that of Gell and Coombs and is currently the
most commonly known classification system.1 It divides the hypersensitivity reactions into the following 4 types:

• Type I reactions (ie, immediate hypersensitivity reactions) involve immunoglobulin E (IgE)–mediated release of histamine
and other mediators from mast cells and basophils.
• Type II reactions (ie, cytotoxic hypersensitivity reactions) involve immunoglobulin G or immunoglobulin M antibodies
bound to cell surface antigens, with subsequent complement fixation.
• Type III reactions (ie, immune-complex reactions) involve circulating antigen-antibody immune complexes that deposit in
postcapillary venules, with subsequent complement fixation.
• Type IV reactions (ie, delayed hypersensitivity reactions, cell-mediated immunity) are mediated by T cells rather than by
antibodies.

Some authors believe this classification system may be too general and favor a more recent classification system proposed by Sell et
al.2 This system divides immunopathologic responses into the following 7 categories:

• Inactivation/activation antibody reactions

• Cytotoxic or cytolytic antibody reactions
• Immune-complex reactions
• Allergic reactions
• T-cell cytotoxic reactions
• Delayed hypersensitivity reactions
• Granulomatous reactions

This system accounts for the fact that multiple components of the immune system can be involved in various types of hypersensitivity
reactions. For example, T cells play an important role in the pathophysiology of allergic reactions (see Pathophysiology). In addition,
the term immediate hypersensitivity is somewhat of a misnomer because it does not account for the late-phase reaction or for the
chronic allergic inflammation that often occurs with these types of reactions.

Allergic reactions manifest clinically as anaphylaxis, allergic asthma, urticaria, angioedema, allergic rhinitis, some types of drug
reactions, and atopic dermatitis. These reactions tend to be mediated by IgE, which differentiates them from anaphylactoid reactions
that involve IgE-independent mast cell and basophil degranulation. Such reactions can be caused by iodinated radiocontrast dye,
opiates, or vancomycin and appear similar clinically by resulting in urticaria or anaphylaxis.3

Patients prone to IgE-mediated allergic reactions are said to be atopic. Atopy is the genetic predisposition to make IgE antibodies in
response to allergen exposure.4

The focus of this article is allergic reactions in general. Although some of the clinical manifestations listed previously are briefly
mentioned, refer to the articles on these topics for more detail. For example, see Allergic and Environmental Asthma; Anaphylaxis;
Food Allergies; Rhinitis, Allergic; and Urticaria.
Pathophysiology
Immediate hypersensitivity reactions are mediated by IgE, but T and B cells play important roles in the development of these
antibodies. T helper (TH) cells, which are CD4+, have been divided into 2 broad classes based on the cytokines they produce: TH1
and TH2.5,6 Regulatory T cells (Tregs) are CD4+CD25+ and may also play a role.7

TH1 cells produce interferon gamma, interleukin (IL)–2, and tumor necrosis factor-beta and promote a cell-mediated immune
response (eg, delayed hypersensitivity reaction). TH2 cells, on the other hand, produce IL-4 and IL-13, which then act on B cells to
promote the production of antigen-specific IgE. Therefore, TH2 cells play an important role in the development of immediate
hypersensitivity reactions, and patients who are atopic are thought to have a higher TH2-to-TH1 cell ratio. Interestingly, the cytokines
produced by TH1 cells (specifically interferon gamma) seem to diminish the production of TH2 cells.8,5,6 Current evidence suggests
that Tregs may also actively inhibit TH2 responses to allergens.7

The allergic reaction first requires sensitization to a specific allergen and occurs in genetically predisposed individuals. The allergen is
either inhaled or ingested and is then processed by the dendritic cell, an antigen-presenting cell.9 The antigen-presenting cells then
migrate to lymph nodes, where they prime naive TH cells (TH0 cells) that bear receptors for the specific antigen.

TH0 cells are undifferentiated CD4 cells that release both TH1 and TH2 cytokines and can develop into either cell type. In the case of
allergen sensitization, the TH0 cells are thought to be exposed to IL-4 (from as yet unidentified sources, but including germinal-center
B cells) and possibly to histamine-primed dendritic cells, both of which cause them to develop into TH2 cells. These primed TH2 cells
then release more IL-4 and IL-13. IL-4 and IL-13 then act on B cells to promote production of antigen-specific IgE antibodies.

For this to occur, B cells must also bind to the allergen via allergen-specific receptors. They then internalize and process the antigen
and present peptides from it, bound to the major histocompatibility class II molecules found on B-cell surfaces, to the antigen
receptors on TH2 cells. The B cell must also bind to the TH2 cell and does so by binding the CD40 expressed on its surface to the
CD40 ligand on the surface of the TH2 cell. IL-4 and IL-13 released by the TH2 cells can then act on the B cell to promote class
switching from immunoglobulin M production to antigen-specific IgE production (see image below).

Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated allergic reaction.

[ CLOSE WINDOW ]

Immediate hypersensitivity reactions. Sensitization phase of an immunoglobulin E–mediated allergic reaction.

The antigen-specific IgE antibodies can then bind to high-affinity receptors located on the surfaces of mast cells and basophils.
Reexposure to the antigen can then result in the antigen binding to and cross-linking the bound IgE antibodies on the mast cells and
basophils. This causes the release and formation of chemical mediators from these cells. These mediators include preformed
mediators, newly synthesized mediators, and cytokines. The major mediators and their functions are described as follows:5,6

Preformed mediators

• Histamine: This mediator acts on histamine 1 (H1) and histamine 2 (H2) receptors to cause contraction of smooth muscles of
the airway and GI tract, increased vasopermeability and vasodilation, enhanced mucus production, pruritus, cutaneous
vasodilation, and gastric acid secretion.
• Tryptase: Tryptase is a major protease released by mast cells; its exact role is uncertain, but it can cleave C3 and C3a as well
as C5.10 Tryptase is found in all human mast cells but in few other cells and thus is a good marker of mast cell activation.
 • Proteoglycans: Proteoglycans include heparin and chondroitin sulfate. The role of the latter is unknown; heparin seems to be
important in storing the preformed proteases and may play a role in the production of alpha-tryptase.
• Chemotactic factors: An eosinophilic chemotactic factor of anaphylaxis causes eosinophil chemotaxis; an inflammatory
factor of anaphylaxis results in neutrophil chemotaxis. Eosinophils release major basic protein and, together with the activity
of neutrophils, can cause significant tissue damage in the later phases of allergic reactions.

Newly formed mediators

• Arachidonic acid metabolites

o Leukotrienes - Produced via the lipoxygenase pathway
 Leukotriene B4 - Neutrophil chemotaxis and activation, augmentation of vascular permeability
 Leukotrienes C4 and D4 - Potent bronchoconstrictors, increase vascular permeability, and cause arteriolar
constriction
 Leukotriene E4 - Enhances bronchial responsiveness and increases vascular permeability
 Leukotrienes C4, D4, and E4 - Comprise what was previously known as the slow-reacting substance of
anaphylaxis
o Cyclooxygenase products
 Prostaglandin D2 - Produced mainly by mast cells; bronchoconstrictor, peripheral vasodilator, coronary and
pulmonary artery vasoconstrictor, platelet aggregation inhibitor, neutrophil chemoattractant, and enhancer
of histamine release from basophils
 Prostaglandin F2-alpha - Bronchoconstrictor, peripheral vasodilator, coronary vasoconstrictor, and platelet
aggregation inhibitor
 Thromboxane A2 - Causes vasoconstriction, platelet aggregation, and bronchoconstriction
• Platelet-activating factor (PAF): PAF is synthesized from membrane phospholipids via a different pathway from arachidonic
acid. It aggregates platelets but is also a very potent mediator in allergic reactions. It increases vascular permeability, causes
bronchoconstriction, and causes chemotaxis and degranulation of eosinophils and neutrophils.
• Adenosine: This is a bronchoconstrictor that also potentiates IgE-induced mast cell mediator release.
• Bradykinin: Kininogenase released from the mast cell can act on plasma kininogens to produce bradykinin. An additional (or
alternative) route of kinin generation, involving activation of the contact system via factor XII by mast cell – released
heparin, has been described.11,12 Bradykinin increases vasopermeability, vasodilation, hypotension, smooth muscle
contraction, pain, and activation of arachidonic acid metabolites. However, its role in IgE-mediated allergic reactions has not
been clearly demonstrated.3

Cytokines

• IL-4: IL-4 stimulates and maintains TH2 cell proliferation and switches B cells to IgE synthesis.
• IL-5: This cytokine is key in the maturation, chemotaxis, activation, and survival of eosinophils. IL-5 primes basophils for
histamine and leukotriene release.
• IL-6: IL-6 promotes mucus production.
• IL-13: This cytokine has many of the same effects as IL-4.
• Tumor necrosis factor-alpha: This activates neutrophils, increases monocyte chemotaxis, and enhances production of other
cytokines by T cells.13

The actions of the above mediators can cause variable clinical responses depending on which organ systems are affected, as follows:

• Urticaria/angioedema: Release of the above mediators in the superficial layers of the skin can cause pruritic wheals with
surrounding erythema. If deeper layers of the dermis and subcutaneous tissues are involved, angioedema results. Angioedema
is swelling of the affected area; it tends to be painful rather than pruritic.
• Allergic rhinitis: Release of the above mediators in the upper respiratory tract can result in sneezing, itching, nasal
congestion, rhinorrhea, and itchy or watery eyes.
• Allergic asthma: Release of the above mediators in the lower respiratory tract can cause bronchoconstriction, mucus
production, and inflammation of the airways, resulting in chest tightness, shortness of breath, and wheezing.
• Anaphylaxis: Systemic release of the above mediators affects more than one system and is known as anaphylaxis. In addition
to the foregoing symptoms, the GI system can also be affected with nausea, abdominal cramping, bloating, and diarrhea.
Systemic vasodilation and vasopermeability can result in significant hypotension and is referred to as anaphylactic shock.
Anaphylactic shock is one of the two most common causes for death in anaphylaxis; the other is throat swelling and
asphyxiation.3,6
Allergic reactions can occur as immediate reactions, late-phase reactions, or chronic allergic inflammation. Immediate or acute-phase
reactions occur within seconds to minutes after allergen exposure. Some of the mediators released by mast cells and basophils cause
eosinophil and neutrophil chemotaxis. Attracted eosinophils and resident lymphocytes are activated by mast cell mediators.

These and other cells (eg, monocytes, T cells) are believed to cause the late-phase reactions that can occur hours after antigen
exposure and after the signs or symptoms of the acute-phase reaction have resolved. The signs and symptoms of the late-phase
reaction can include redness and swelling of the skin, nasal discharge, airway narrowing, sneezing, coughing, and wheezing. These
effects can last a few hours and usually resolve within 24-48 hours.

Finally, continuous or repeated exposure to an allergen (eg, a cat-owning patient who is allergic to cats) can result in chronic allergic
inflammation. Tissue from sites of chronic allergic inflammation contains eosinophils and T cells (particularly TH2 cells). Eosinophils
can release many mediators (eg, major basic protein), which can cause tissue damage and thus increase inflammation. This can result
in structural and functional changes to the affected tissue. Furthermore, a repeated allergen challenge can result in increased levels of
antigen-specific IgE, which ultimately can cause further release of IL-4 and IL-13, thus increasing the propensity for TH2 cell/IgE–
mediated responses.6

Frequency

United States

• The prevalence of atopic diseases had increased significantly in the 1980s and 1990s in industrialized societies.14
• Allergic rhinitis is the most prevalent allergic disease;4 it affects approximately 17-22% or more of the population.15
• Asthma is estimated to affect approximately 22.2 million people in the United States.16 Ninety percent of asthma cases in
children are estimated to be allergic, compared with 50-70% in adults.15
• Atopic dermatitis had also increased in prevalence in the 1980s and 1990s; prevalence in the United States is likely similar to
that in Europe (see international information below).5
• The prevalence of anaphylaxis is approximately 1-3% in industrialized countries.

International

• Approximately 300 million people worldwide are estimated to have asthma. Prevalence rates vary around the world and are
estimated to be from 3-38% in children17 and 2-12% in adults.18
• The International Study of Asthma and Allergies in Childhood (ISAAC) is an epidemiological research program that was
established in 1991 to evaluate asthma, eczema, and allergic rhinitis in children worldwide. The study is composed of 3
phases. Phase 1 used questionnaires designed to assess the prevalence and severity of asthma and allergic disease in defined
populations in centers around the world. Most of these data were collected in the mid 1990s. Phase 2 was designed to assess
possible etiological factors based on information gathered from Phase 1. Phase 3 is a repetition of Phase 1 to assess trends in
prevalence.19 Data from ISAAC show variations in the prevalence of allergic diseases between countries.
• ISAAC researchers found significant variability in the prevalence of allergic rhinoconjunctivitis in children from 56
countries. Rates varied from 1.4-39.7% and, although sites varied, a general trend of increasing prevalence of allergic
rhinoconjunctivitis was found over the 7 years between phases 1 and 3.20
• Similar to other allergic diseases, the prevalence in atopic dermatitis varies widely between countries. Prevalence varies from
1.4% in China to 21.8% in Morocco, and prevalence is generally increasing.20
• Asthma, as with other atopic diseases, was previously increasing in prevalence.21,22 Data from a study from England suggest
that the prevalence of asthma, allergic rhinitis, and atopic dermatitis may be stabilizing.23 Hospital admissions for
anaphylaxis, however, have increased by 600% over the past decade in England and by 400% for food allergy. Admission
rates for urticaria increased 100%, and admission rates for angioedema increased 20%, which suggests that these allergic
diseases may be increasing in prevalence.
• Studies in Africa and Europe have shown a greater prevalence of reversible bronchospasm in urban populations than in rural
populations. This was initially thought to be related to environmental pollution, but the results from studies of asthma
prevalence before and after the unification of Germany contradict this theory.14
o The prevalence of asthma in East Germany prior to 1990 was lower than in West Germany, despite the fact that East
Germany had more air pollution.
o Over the 10 years after unification, the prevalence of asthma in the former East Germany has increased and is now
comparable with that of former West Germany.14
o In addition, children placed in day care and with older siblings have a lower likelihood of developing atopic
disease.24
o These findings have led to the hygiene hypothesis, which proposes that early exposure to infectious agents or
endotoxins helps direct the immune system toward a TH1 cell–predominant response that, in turn, inhibits the
 production of TH2 cells. A TH1 response does not lead to allergies, while a cleaner, more hygienic environment
may lead to TH2 predominance and more allergies.25

Mortality/Morbidity

• Mortality from allergic diseases occurs primarily from anaphylaxis and asthma, although deaths from asthma are relatively
rare.6 In 1995, 5579 people died from asthma in the United States. Since 1999, the rate of death from asthma for individuals
between 5 and 34 years of age seems to have declined.26 Approximately 500 people die annually from anaphylaxis in the
United States.
• Allergic diseases are a significant cause of morbidity. In 1990, the economic impact of allergic diseases in the United States
was estimated to be $6.4 billion from health care costs and lost productivity. Children with untreated allergic rhinitis do
worse on aptitude tests than their nonatopic peers.

Race

• Differences in the prevalence of allergic diseases with respect to race were previously thought to be more related to
environmental factors than to true racial differences. For example, the prevalence of asthma is 2.5 times higher in African
Americans than in whites in the United States.4 Asthma is more prevalent in inner-city populations, and this was thought to
explain the difference. One study found a higher risk of asthma mortality in blacks than in other ethnic groups, however, and
this was independent of socioeconomic status. This suggests that a difference based on ethnicity alone could exist.27

Sex

• Some unexplained differences exist in the prevalence of allergic diseases between the sexes. Asthma is more prevalent in
boys during the first decade of life;4 after puberty, prevalence is higher in females.5 The male-to-female ratio of children who
have atopic disease is approximately 1.8:1.
• Skin test reactivity in women can fluctuate with the menstrual cycle, but this is not clinically significant.5

Age

• In general, allergic rhinitis symptoms (and skin test reactivity) tend to wane with increasing age.15
• Food allergies and subsequent anaphylaxis are more prevalent in children. Some children may outgrow their allergies to
certain foods, or their reactions may diminish over time. However, anaphylaxis from food and other triggers is still a threat in
adults. Some food allergies, such as allergy to peanuts, may last a lifetime.
• Childhood asthma is more prevalent in boys and can often resolve by adulthood. However, females tend to develop asthma
later in life (beginning in adolescence) and can also have asthma that is more severe.5

Clinical

History

History findings vary depending on which organ systems are affected.

• Anaphylaxis
o Patients may report skin itching, localized or diffuse pruritus, dizziness, faintness, and diaphoresis. Difficulty
breathing can result from angioedema of the pharyngeal tissue, from bronchoconstriction, or from both. Patients
may also report GI symptoms, including nausea, vomiting, diarrhea, and abdominal cramping. Patients may
experience uterine cramping or urinary urgency. Patients can have a sudden onset of respiratory and/or circulatory
collapse and go into anaphylactic shock.
o Symptoms usually begin within minutes of allergen exposure (eg, drug administration, insect sting, food ingestion,
allergen immunotherapy) but can recur hours after the initial exposure (late-phase reaction).
o Patients may not be able to identify the allergen either because they are unaware of the allergy (eg, first reaction to
insect sting) or because they were unaware of exposure to the allergen (eg, a patient who is allergic to peanuts who
eats a processed food containing hidden peanut protein).
o Particular attention should be given to new or recently changed medications. A history specific for insect stings or
new environmental exposures should be obtained. If applicable, a food history should also be obtained. Exercise-
induced anaphylaxis may be associated with prior ingestion of a food (eg, wheat, peanut, tree nuts, celery) or drug
(eg, NSAID) that does not produce symptoms when ingested without subsequent exercise.28
 • Allergic rhinoconjunctivitis
o Symptoms consist of congestion; sneezing; itchy, runny nose and eyes; and itching of the palate and inner ear.
Patients may also report postnasal drip, which can cause sore throat, coughing, or throat clearing.
o Rhinoconjunctivitis usually results from exposure to aeroallergens and can be seasonal or perennial. Airborne
allergens typically also cause ocular symptoms consisting of itchy eyes, tearing, swelling or redness of the eyes.
o Repeated exposure to the allergen can result in chronic allergic inflammation, which causes chronic nasal congestion
that can be further complicated by sinusitis.
• Allergic asthma
o Allergen exposure results in bronchoconstriction, and patients may report shortness of breath (eg, difficulty getting
air out), wheezing, cough, and/or chest tightness.
o Long-term allergen exposure can cause chronic changes of increased difficulty breathing and chest tightness, and the
patient may give a history of repeated rescue inhaler use or reduced peak flows.
• Urticaria/angioedema
o Diffuse hives or wheals may occur and cause significant pruritus; individual wheals resolve after minutes to hours,
but new wheals can continue to form.
o Acute urticaria (lasting <6 wk) can be caused by viral infections, foods, drugs, or contact allergens.
o Chronic urticaria lasts longer than 6 weeks. Although many causes are possible, often, a cause is not found. In many
cases, this is not due to antigen-IgE – mediated immediate hypersensitivity but to an autoantibody to the high
affinity IgE receptor or to IgE itself.
o Angioedema is localized tissue swelling that can occur in soft tissues throughout the body. Patients may report pain
at the site of swelling instead of pruritus, which occurs with urticaria.
o Angioedema of the laryngopharynx can obstruct the airway, and patients may report difficulty breathing. Stridor or
hoarseness may be present. Angioedema of the laryngopharynx can be life threatening.
• Atopic dermatitis
o This condition is an eczematous cutaneous eruption more common in children than in adults; it can be exacerbated
by allergen exposure, especially food allergies, in some patients.
o Patients report significant pruritus that causes scratching, which produces the lesions. Superinfection with
staphylococcal organisms can occur, particularly in severely excoriated or cracked lesions.
• GI allergies
o Patients may report nausea, vomiting, abdominal cramping, and diarrhea after ingestion of the offending food.
o Note that other mechanisms (eg, lactose intolerance) commonly cause these symptoms.
o Eosinophilic esophagitis and gastritis are newly recognized syndromes that may be allergic in nature.

Physical

Physical examination findings vary with the organ system involved.

• Anaphylaxis
o Vital signs should be monitored closely because patients can quickly progress to circulatory and/or respiratory
failure. Tachycardia may precede hypotension. Patients who are hypotensive may have reflex tachycardia, but
bradycardia can also occur in 5%.
o Patients may have urticaria, angioedema, or both. Angioedema of the airway and throat can result in respiratory
failure or asphyxiation; therefore, this dangerous occurrence must be closely monitored.
o Patients may be wheezing during the respiratory examination, which is secondary to bronchoconstriction.
o Confusion and alteration of mental status can occur.
• Allergic rhinoconjunctivitis
o Patients may sneeze, be congested, have a runny nose, or have frequent throat clearing and/or cough from postnasal
drip.
o Sclera may be injected, and patients may have dark rings under the eyes (ie, allergic shiners).
o Nasal mucosa can be boggy and pale, usually with clear drainage.
o The pharynx may have a cobblestone appearance reflecting lymphoid hyperplasia from postnasal mucus drainage.
o The patient may have frontal or maxillary sinus tenderness from chronic sinus congestion or infection.
• Allergic asthma
o Findings can vary depending on the patient and the severity of symptoms. Patients may be coughing or appear short
of breath. Wheezing may be present, but it might not be heard in patients with milder symptoms or, if the asthma is
very severe, patients may not move enough air to produce wheezing.
o Breaths may be shallow or the patient may have a prolonged expiratory phase.
o Cyanosis of the lips, fingers, or toes (caused by hypoxemia) may occur with severe asthma.
• Urticaria/angioedema
 o Urticaria is usually represented by wheals with surrounding erythema. Wheals from allergic causes usually last a
few minutes to a few hours. Wheals due to cutaneous vasculitis may last more than 24 hours and may leave
postinflammatory hyperpigmentation upon healing.
o Angioedema is localized swelling of the soft tissues that can occur anywhere but is particularly concerning if
pharyngeal or laryngeal tissues are involved.
• Atopic dermatitis
o The physical examination findings can vary with the severity of the disease. In less severe cases, skin can appear
normal, dry, or with erythematous papules. In more severe cases, patients can have extremely dry, lichenified,
cracked, and, sometimes, crusted lesions.
o In infants, the head and extensor surfaces are more involved, whereas in older children and adults, the flexural
surfaces tend to be affected.

Causes

Atopy is defined as the genetic predisposition to form IgE antibodies in response to exposure to allergens. Therefore, a genetic
predisposition exists for the development of atopic diseases. Mutations of specific alleles on the long arm of chromosome 5 have been
associated with higher levels of IL-4 and IgE and are known as IL-4 promoter polymorphisms.29 Impaired function of Treg cells may
also contribute to the development of atopic diseases.30

Environmental issues also play an important role, although the role that exposure at an early age to certain antigens might play in
either the progression to or the protection from the development of an allergic response remains unclear. Some studies have shown
that children in day care and those with older siblings may be less likely to develop allergic disease. The environment certainly can
help determine the allergens to which the patient will be exposed. For example, children in inner cities are more likely to be sensitized
to cockroaches than are children in suburban or rural areas. Similarly, dust mites, a potent allergen, are primarily found in humid
climates, and those who have never been exposed to such a climate are less likely to be allergic to mites.

• Allergic reactions
o Reactions can be elicited by various aeroallergens (eg, pollen, animal dander), drugs, or insect stings.
o Other possible causes are latex, drug, and food allergy.
• Allergens
o Allergens can be complete protein antigens or low–molecular-weight proteins capable of eliciting an IgE response.
o Pollen and animal dander represent complete protein antigens.
o Haptens are low–molecular-weight (inorganic) antigens that are not capable of eliciting an allergic response by
themselves. They must bind to serum or tissue proteins in order to elicit a response. This is a typical cause of drug
hypersensitivity reactions. Note that all drug hypersensitivity reactions are not mediated by IgE. In addition to
anaphylactoid reactions, drug reactions can be caused by cytotoxicity and immune-complex formation and by other
immunopathologic mechanisms.
• Foods
o The most common food allergens are peanuts, tree nuts, finned fish, shellfish, eggs, milk, soy, and wheat.
o Certain foods can cross-react with latex allergens. These foods include banana, kiwi, chestnut, avocado, pineapple,
passion fruit, apricot, and grape.
• Hymenoptera
o Bee, wasp, yellow jacket, hornet, and fire ant stings can cause IgE-mediated reactions.
o While anaphylaxis is the most serious reaction, localized swelling and inflammation can also occur and do not by
themselves indicate increased risk of a subsequent life-threatening reaction.
o At least 50 Americans die each year from anaphylaxis caused by a stinging insect.
• Anaphylactoid reactions
o Non–IgE-mediated mast cell and basophil degranulation can occur from a variety of substances. Although the
mechanisms are different, the clinical manifestations can appear the same.
o Causes can include radiocontrast dye, opiates, and vancomycin (eg, red man syndrome).
o Patients can be pretreated with glucocorticosteroids and both H1 and H2 antihistamines prior to exposure to
iodinated radiocontrast dye. This, together with the use of low-osmolal nonionic dye, reduces the risk of a repeat
reaction to approximately 1%.
o Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can also cause reactions by causing release of
leukotrienes via the 5-lipoxygenase pathway of arachidonic acid metabolism. Patients susceptible to this syndrome
can develop acute asthma exacerbation, nasal congestion, urticaria, or angioedema after ingestion. However, note
that in rare cases, patients can have what are thought to be true IgE-mediated anaphylactic reactions to a specific
NSAID. In these cases, no cross-reactivity occurs with other NSAIDs.