Penicillin Allergy
PKGhatak, MD
Penicillin was the first antibiotic that came into the medical field and it proved far superior to sulfonamides - the only antibacterial available during World War II.
Soon, Penicillin was prescribed on a wider scale for the public. Reports of allergic reactions and anaphylaxis began to surface made doctors take careful history of penicillin allergy before prescribing penicillin.
10 % of patients reported being allergic to penicillin G, penicillin related compounds and cyclosporins. At present, true penicillin allergy is seen in 3 % of users and the rest of the reactions are nonallergic minor symptoms.
Molecular basis of Penicillin allergy.
Penicillin is a Dipeptide. The structure of penicillin consists of a beta-lactam ring, a thiazolidine ring and a side chain of 6 amino acids. The allergenic property of penicillin lies within the Beta-lactam ring. Penicillin is a Hepten. It binds readily with plasma protein and becomes antigenic in susceptible individuals.
Why certain people develop Penicillin allergy:
The adaptive immune system produces IgM (Ig = immunoglobulin) and IgG classes of antibodies; IgA class antibodies in GI, Respiratory, and Genitourinary tracts. IgE( immunoglobulin E) antibody is produced in the regional lymph nodes draining location where the offending organism entered the body. However, the antigen must have these characteristics:
1. The antigen must be a small molecule and a protein, if the antigen is not a protein, then it must be a Hapten. A hapten binds readily with a protein and becomes an antigen.
2. The antigen must be soluble so that the Dendritic cells can pick up and recognize it as a foreign substance.
3. The amount of antigen must be small.
The plasma cells, in the lymph node genome center, switch IgE antibody production under the influence of CD4 and Th2 (thymic 2) cells. A low dose exposure of Penicillin on the Th2 cells produces Interleukin IL4 and IL13. Those two Interleukins are the molecular switch for IgM and IgG production. If penicillin exposure is large, then Th 1 cells are activated. Th 1 cells produce IFN gamma (interferon-gamma), IFN gamma acts as a break on Th2 cells, and Th2 cells stop producing IgM and IgG antibodies.
Penicillin induced Hypersensitivities are in Two categories. 1. Immediate, 2. Delayed. The reactions are also referred to as Type I to 4 Hypersensitive Reactions.
Immediate Reaction.
Type I. - Immunoglobulin E mediated immediate reaction, occurs minutes to hours after exposure to antigen.
Delayed Reaction.
Type II. - Immunoglobulins IgM and IgG mediated Cytotoxic reaction, occurs 72 hours after exposure.
Type III. - Immune Complex reaction occurs 10 to 12 days after exposure.
Type IV. - Cell mediated Delayed reaction, occurs 4 g days after exposure.
Special features of IgE.
IgE differs from other Ig class of antibody in being locally produced and most abundant in local tissue. IgE has a high affinity for the skin resident Mast cells FC e RI receptors. IgE also binds to some degree eosinophils and basophils. Repeat exposure to antigen the pre-formed Bradykinins, Histamine and other enzymes are released locally that produce allergic symptoms. In Anaphylaxis the mast cells and eosinophils and basophils all empty preformed enzymes producing swelling of mucosa of the tongue, pharynx, upper airway producing obstruction, and hypotension, hypoxemia and cardiovascular collapse.
Detecting IgE in Allergy and Anaphylaxis.
The tests are in two groups, namely - Skin Tests and Blood tests. The skin tests are the Scratch test, Intradermal test and Patch test. The first two tests are for detecting IgE antibody against Penicillin, and the Patch test is for detecting delayed reaction skin reaction to penicillin. The scratch test is performed on the forearm. A drop of a standard solution of penicilloyl-polylysine or undegraded penicillin is applied on the skin. A fine needle is used to lightly scratch the skin through the liquid. In 15 to 20 minutes a wheal should appear if the person is allergic to penicillin. The wheal is measured with a ruler. The degree of sensitivity is proportional to the diameter of the wheal.
The specificity and sensitivity of the scratch test can be improved by injecting the same penicillin solution in between the layers of the skin. And the resultant wheal is measured the same way the scratch test is done.
The patch test is described later under delayed hypersensitive reaction.
A skin test is generally considered a standard test for allergies. This test, however, has considerable risk. It may precipitate a severe allergic reaction or anaphylaxis.
That risk is totally eliminated by performing a blood test. A modified RAST (radio- allegro-sorbent test) blood test - CAP RAST or CAP FEIA (fluro enzyme immune test). Blood is collected from the patient. At the laboratory, tiny discs coated with penicillin are mixed with serum. After a certain time when the IgE antibodies binding with antigen is complete and the unbound IgE are washed away. The bound IgE is quantified by fluorescent enzyme immunoassay.
The blood test has a significant false positive result, but a negative result is confirmation of the absence of penicillin allergy.
Type II Penicillin Hypersensitivity.
Penicillin molecule at times binds with the normal cells' surface receptors. This new molecule is perceived by the immune cells as foreign. Antibodies of class IgM and IgG are generated and antibodies attack this penicillin bound normal tissue or the extracellular matrix. This triggers the activation of complement producing tissue and or matrix destruction and loss of function. Examples of type II hypersensitivity are acquired hemolytic anemia, Thrombocytopenia and Leukopenia.
Type III penicillin Hypersensitivity.
In type III hypersensitivity the IgG antibody is combined with penicillin. These antigen-antibody complexes are deposited in tissues. The immune cells are activated against this complex and the immune inflammatory reaction causes tissue damage and loss of function follows. Examples are Serum sickness (fever, arthralgia, urticaria, lymphadenopathy and glomerulonephritis) Vasculitis (multiple organ involvement – hepatitis, nephritis, pneumonitis, skin lesions, etc.). Interstitial nephritis.
Type IV penicillin Hypersensitivity.
Penicillin ointments, creams and drops were used to treat wounds. Penicillin sensitized the skin's immune cells. Sensitized immune cells produce inflammation in the skin area and the condition is called contact dermatitis. This exposure of penicillin to bacteria produced penicillin resistant bacteria. Now, this practice is abandoned, and contact dermatitis due to penicillin has greatly disappeared. Examples of delayed reactions are - Contact dermatitis, morbilliform skin eruptions, Steven Johnson Syndrome (SJS) and a more severe form of SJS, Toxic Epidermal Necrosis (TEN).
Footnote:
Skin test for Type IV reaction. A small piece of sterile dressing soaked with penicillin solution is applied on the back of the patient and kept in place by an occlusive dressing for 4 days. When the dressing is removed and the presence of skin lesions is noted.
Steven-Johnson Syndrome: Flue like symptoms, rapidly spreading skin lesions which quickly turn into blisters. Mouth, lips, and throat swell and become painful and bleed easily and fatigue. Shedding of layers of skin and rapid deterioration of the condition an emergency situation develops.
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