12. Allergy and Clinical Immunology

A tick bite from the Lone Star tick can trigger a severe allergy to red meat.

This specific allergy is related to a carbohydrate called alpha-gal found in red meat. So do patients become allergic to themselves? No! Interestingly, the alpha-gal molecule is found in all mammals except apes, humans, and Old World monkeys.

12.1 Hypersensitivity Reactions

Types of hypersensitivity reactions

Timing of presentation after allergen exposure

Major mediators


Treatment (first step is to remove offending agents)

Type I—immediate

Occurs fast (within minutes to hours of exposure)

  • Initial exposure leads to antigen-specific immunoglobulin E (IgE) formation.a

  • Subsequent exposure leads to formation of antigen-IgE complexes that crosslink — mast cell degranulation — release of histamine and other mediators.

Urticaria: edema of epidermis and dermis

  • Mild to moderate urticaria: antihistamines

  • Severe urticaria or uncomplicated angioedema: antihistamines + oral steroids.

  • Severe angioedema or anaphylaxis (e.g., with respiratory distress): immediate parenteral epinephrine + oral steroids and antihistamines.


  • Edema of deep dermis, e.g., lip or eyelid swelling. Overlying skin may or may not have urticaria.

  • Edema of submucosal tissue may involve respiratory mucosa causing respiratory compromiseb

Anaphylaxis: involvement of respiratory (respiratory compromiseb) and/or circulatory system (vasodilatory shock)

  • Can present with or without urticaria or angioedema

Type II

Occurs 1 or more weeks after allergen exposure, but can also manifest much later

Antibody mediated

Presentation depends on the target of autoantibody:

  • Autoimmune thrombocytopenia

  • Autoimmune hemolytic anemia,

  • Pemphigus/pemphigoid disorders, etc.

For severe, persistent disease, treatment options include steroids and other immunosuppressants.
In acute severe cases, use plasmapheresis or IVIG.
Splenectomy can be done if chronic and refractory.

Type III

Primary damage is from immune complexes (antigen-antibody complexes).
Complement levels are typically low.

  • Serum sickness reaction

  • Various forms of vasculitis

  • Immune-complex glomerulonephritis

For severe persistent disease, can use steroids, azathioprine, methotrexate, mycophenolate mofetil, etc.

Type IV cell mediated

Delayed (>48 hours after allergen exposure; sometimes may take days or weeks to develop)

T-cell mediated

Poison ivy, Crohn’s disease, multiple sclerosis, morbilliform drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome, etc.


aCan be caused by anything: drugs, infection, foods, latex, bee sting, etc. Note that in a lot of cases history of sensitization might not be present.

bSevere angioedema and can overlap with early anaphylaxis.

Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms; IVIG, intravenous immunoglobulin.

12.1.1 Highly Allergenic Drugs

Theoretically, almost any drug can cause hypersensitivity reaction, but the most notorious ones are the following:

  • Sulfa drugs

    1 Sulfa drugs

    Most of the drugs that fall into this category have the word “sulf” in them:

    Sulfamethoxazole (antibiotic)

    Sulfasalazine (antiinflammatory drug)

    Sulfinpyrazone (uricosuric drug)

    Additionally, drugs which have the suffix “ide” (e.g., chlorpropamide —antidiabetic drug, diuretics—furosemide, acetazolamide, hydrochlorothiazide, bumetanide) have some sulfa component, but most are well tolerated and have very low cross-reactivity with other sulfonamides.

  • Penicillins and cephalosporins

  • Antiseizure medication (phenytoin, lamotrigine, valproic acid, carbamazepine, phenobarbital)

  • NSAIDs (nonsteroidal anti-inflammatory drugs)

These drugs can cause all four types of hypersensitivity (urticaria, anaphylaxis, autoimmune hemolytic anemia, serum sickness, allergic interstitial nephritis, maculopapular rash, toxic epidermal necrolysis, Stevens-Johnson syndrome, etc.). They will be called “highly allergenic drugs” for the purpose of this book.

These drugs are commonly implicated but any medication has the potential to cause allergic reaction in a genetically susceptible individual

  • Example: Allopurinol, various ACE inhibitors and proton-pump inhibitors are implicated in inciting all types of allergic reaction , but is less common than the highly allergenic drugs.

Clinical Case Scenarios

1. With diagnosis of otitis media, patient was started on amoxicillin more than a week ago. Patient now presents with new onset fever, rash, joint pain, and lymphadenopathy. ANA is negative. What is the likely dx?

An adult patient has hypotension and shortness of breath after a bee sting. Patient reports no hx of bee sting in the past. Exam reveals diffuse swelling of eyelids, lips, and bilateral extensive wheezing. He then develops hypotension.

2. Is this anaphylaxis?

3. What is the treatment?

12.1.2 Urticaria (Hives)

Pathophysiology: Edema of epidermis

2 Classic rash description: red or flesh-colored itchy bumps, with blanching erythema.

and dermis due to mast-cell degranulation, most commonly as a result of type I hypersensitivity. Antibody (type II), immune-complex, or T-cell-mediated urticaria can also occur.


Acute urticaria

Chronic urticaria


Urticaria of <6 weeks duration

Urticaria for >6 weeks


Most commonly due to allergic triggers

Mostly nonallergic

Likely etiology

Food (e.g., peanuts, shellfish, eggs), medications, insect bites, latex, infection, etc.

Physical urticariaa, or underlying systemic disorder (autoimmune, vasculitis, malignancy, etc.)


Antihistamines (H1– blockers)b
For moderate to severe disease, also add H2-blockers (e.g., ranitidine, famotidine)

Steroids can be used in significant cases not responding to above regimen.

In severe cases not responding to above regimen, use omalizumab (anti-IgE antibody). If not responding, use anti-inflammatory agents such as dapsone, sulfasalazine, hydroxychloroquine, or in more severe cases, immunosuppressives such as tacrolimus.

a Physical urticaria: Mast-cell degranulation due to physical factors such as exercise, sunlight, hot or cold temperatures, etc.

bFew notes on antihistamines (H1– blockers).

Antihistamines (H1– blockers) Side effects

Promethazine, diphenhydramine


Also blocks alpha-receptorsa and M-receptorsb


Less sedating (less blocking effect on alpha-receptors and M-receptors)

Newer generation antihistamines like loratadine, fexofenadine, cetirizine, etc.

Least sedating of antihistamines with minimal side effects, hence drug of choice for initial treatment of urticaria

aCan lead to orthostatic hypotension.

bDue to significant M-blocking effect, these can also be used for muscle spasms (e.g., for dystonia).

12.1.3 Angioedema

Definition: Edema of deep dermis, subcutaneous and/or submucosal tissue due to increased vascular permeability.

3Angioedema of lower lip Source: Localized Edema. In: Siegenthaler W, ed. Siegenthaler’s Differential Diagnosis in Internal Medicine: From Symptom to Diagnosis. 1st ed. Thieme; 2007.

Edema of

Clinical effect

Deep dermis and subcutaneous tissue

Puffy eyes, lips, face, genitals, etc.

Respiratory submucosa

Respiratory distress and arresta

Intestinal submucosa

Colicky abdominal pain
CT imaging may show bowel-wall thickening.

aIn a patient presenting with angioedema, the first step is to assess airway. If there is impending airway compromise, NSIM is intubation.


Histamine-mediated angioedema or mast-cell-mediated angioedema (allergic reaction)

Bradykinin-mediated angioedema

Etiology: Most commonly due to allergic triggers such as foods (e.g., peanuts, shellfish, eggs), pollen, medications (highly allergenic drugs), insect bites, rubber latex, contrast media, etc. This can also be due to physical factors such as exercise, sunlight, hot or cold temperatures, etc.
Presentation: Can present with urticaria or anaphylaxis (as this is an IgE-mediated reaction)a
Another rare cause is mast cell hyperactivity due to systemic mastocytosis (a mast cell malignancy).

There are two major types:

1. Bradykinin-mediated angioedema due to ACE-i: this is the most common form of bradykinin-mediated angioedema (it can occur any time after initiation)b

2. Bradykinin-mediated angioedema not related to ACE-i: This can be hereditary or acquired

  • Hereditary: Genetic mutation resulting in decreased production or loss of function of C1 inhibitor (normal levels of C1 inhibitor is seen in the latter).

  • Acquired: Autoimmune antibody against Cl-inhibitor due to autoimmune conditions like SLE or underlying myeloproliferative disorder that increases risks for autoimmunity (e.g., CLL)

Pathophysiology: Decreased activity of Cl inhibitor → increased C1 activity→increased activation and consumption of complement proteins (low C3, C4) →increased production of bradykinin and other edema mediators.

Urticaria is mostly present

Urticaria is absent, and usually not itchy.


  • Antihistamines (H1 and H2 blockers) and glucocorticoids

  • Add epinephrine, if having breathing issue or hypotension.

  • After one episode of anaphylaxis, patients must always carry epinephrine injection.

  • Desensitization can be done when the trigger cannot be avoidedd


  • Supportive

  • For significant bradykinin-mediated angioedema not related to ACE-i, C1 inhibitor concentrate or bradykinin inhibitor (icatibant or ecallantide) is given. Second-line treatment includes solvent-detergent treated plasma or fresh-frozen plasma (they contain multiple enzymes which degrade bradykinin)

  • For significant bradykinin-mediated angioedema due to ACE-i, icatibant, ecallantide, or FFP can be tried, but is not of proven benefit.

aAfter an anaphylaxis episode, the serum tryptase level increases (tryptase is a unique mast cell protein). This is useful for diagnosis in atypical cases, but the level needs to be drawn within few hours of symptom onset, as it rapidly falls to normal levels within few hours of the episode.

b Angiotensin-receptor blockers (ARBs), unlike ACE-i, do not decrease bradykinin metabolism. They act only by blocking angiotensin receptors. Hence ARBs can be given to patient with ACE-i-related angioedema.

cIf angioedema is idiopathic and does not fit into the above classification, treat as histamine-mediated angioedema.

dFor example, patient has anaphylaxis due to bee sting, but he is a bee farmer and would like to continue to work. Prior to desensitization any adrenergic blocking agents (such as B-blockers) must be stopped, because epinephrine might be required if the patient develops an anaphylactic reaction during the procedure.

Abbreviations: ACE-i, angiotensin-converting enzyme inhibitor; CLL, chronic lymphocytic leukemia; SLE, systemic lupus erythematosus.

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Dec 11, 2021 | Posted by in GENERAL SURGERY | Comments Off on 12. Allergy and Clinical Immunology
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