Anaphylaxis

ANAPHYLAXIS, the state of exaggerated susceptibility of an animal or man to a biologically foreign protein which may follow a first injection of that protein. Richet, who first used the term in 1893, found that after two properly spaced injections of an animal with eel serum, the second dose produced a toxic (often fatal) effect, much greater than did the first dose. He considered it to be the reverse of prophylaxis such as results from the use of bacterial vaccines. Theobald Smith, and later, Otto, extended these observations, using guinea-pigs and horse serum in their experiments.

The Anaphylactic Phenomenon.

If, for example, a guinea pig be injected intravenously, subcutaneously or intraperitone ally with horse serum in an amount ordinarily not harmful, it be comes "sensitized" to horse serum, so that, if after ten to 14 days it be again injected with horse serum (intoxicating dose), there promptly result striking symptoms. The animal appears depressed and nervous, scratches its nose, shows a rapidly increasing diffi culty in breathing, rapid pulse, and may die in a few minutes from respiratory failure. This symptom picture is called Anaphylactic shock. If the animal survive, it is for a time non-reactive to horse serum injections and is said to be antianaphylactic. After some weeks this refractory state wears off and the animal will again suffer shock if injected. Sensitivity may be transferred from one animal to another (passive anaphylaxis) and a similar passive transfer occurs from mother to offspring.

Anaphylactic sensitivity is strictly specific ; a guinea-pig hyper sensitive to horse serum is not shocked by sheep serum. One can even distinguish by an anaphylaxis experiment between two such closely related proteins as duck and hen egg-albumin. A single animal may be sensitized to a number of proteins. Animals vary widely in the ease with which they may be rendered sensitive; guinea-pigs are easiest to sensitize, o•000 ooigm. of horse serum at times sufficing as the sensitizing dose, and o•000 000 igm. as the intoxicating dose. Rats are most difficult to sensitize ; man is mod erately so. The symptoms of anaphylactic shock differ in various species but are always characteristic for that species. The basis of symptoms is in each instance the contraction of involuntary muscle and an increased permeability of the capillary blood vessel walls.

The Sensitizing Substances and Their Operation.—The substances to which animals may be sensitized (antigens) are pro. tein in nature, with a large molecule, and optically active in solu tion. If a protein be racemized (rendered optically inactive by heat or sodium hydroxide) it can no longer produce sensitization or shock.

The method whereby anaphylaxis occurs is probably as follows. The body normally protects itself against foreign protein in the intestinal tract where the digestive ferments break down the pro tein beyond the stage of intermediate (at times toxic) split-pro ducts. If an intact foreign protein reaches the blood in any way, the same digestion is carried out (rather slowly) by the ferments of the blood and tissues. But so abnormal is this, that the body's protective mechanism is stimulated to produce an excessive amount of a specific ferment (antibody) which can act on that particular protein. When a second dose of that protein gets into the blood, there is an intensely rapid combination of protein (antigen) and ferment (antibody) with the production, through partial digestion, of a poisonous substance (anaphylatoxin).

There are reasons to believe that the reaction occurs largely within the body cells. Thus, sensitized animals after perfusion with normal blood can still suffer shock, and a strip of uterus muscle from a sensitized guinea-pig, after being thoroughly washed so as to remove all traces of blood, still contracts when exposed to the protein. The intracellular site of the reaction probably ac counts for its intensity. The poisonous substance was at first supposed to be derived wholly from the second dose of foreign protein, but there is adequate evidence to show that much or all of it is derived from the proteins of the shocked animal.

Anaphylaxis in Man.

Typical anaphylactic shock is in rare instances seen in man. It has followed a second injection of horse serum (diphtheria or tetanus antitoxin, immune sera for treating scarlet fever, epidemic meningitis, pneumonia, etc.) given at a suitable interval after the initial dose. The symptoms are a feel ing of apprehension, sneezing, nettle-rash, tickling in the throat, swelling of the face or more generalized swellings, violent asthma, rapid weak pulse; occasionally convulsions; death may ensue in a few minutes or hours. Serum Sickness, the symptoms which often follow even the first injection of a foreign serum, is probably anaphylactic in nature.

The presence in an individual of hypersensitiveness to a sub stance, horse serum for example, may be determined by suitable tests (see below), and this hypersensitiveness can be temporarily lessened by frequently repeated injections of increasing amounts of serum, beginning with extremely small, non-toxic doses. The patient can then be given the needed diphtheria antitoxin or other type of serum treatment with safety. In the actual attack a hypo dermic injection of adrenalin may be life-saving.

Phenomena in Man Allied to Anaphylaxis.

Ten per cent of Caucasians are hypersensitive to a wide range of sub stances, usually protein in nature, that may be ingested (foods; e.g., egg, milk, shellfish, berries; drugs; e.g., quinine) or inhaled (pollens; animal emanations; e.g., feathers, hair, dandruff; dusts of organic origin; e.g., flour, wood dusts, house dust) . Even tiny amounts of these substances, in susceptible subjects, provoke a variety of diseases (q.v.) : asthma, hay fever, Urticaria, some forms of eczema, etc. Some of the phenomena of infections and parasitic infestations may be due to acquired hypersensitiveness to proteins of bacterial or parasitic origin (skin reactions to tuber culin and luetin, urticaria in Ascaris and Echinococcus infesta tions, etc.).

Hypersensitiveness of an individual to a protein may be dem onstrated by applying the protein to an abrasion in the skin or injecting it in solution into the skin : swelling and redness at the site of contact indicate sensitiveness to that substance. Such skin testing is used in the diagnosis of suspected hypersensitive ness. The treatment of human hypersensitiveness is (I) Avoid ance of the offending substance; e.g., omission of a food from the diet ; substituting a cotton pillow for the feathers to which the patient is sensitive; and (2) Creation of tolerance for the offend ing substance by repeated administration of increasing amounts of the substance, beginning with small non-toxic doses. Avoidance gives better results than does the second method.

Though human hypersensitiveness is probably closely allied to anaphylaxis, it differs therefrom by being usually a natural, not an acquired state ; it tends to be hereditary, following the Mende lian law ; it is not usually accompanied by presence of specific blood antibodies of the precipitin type (see IMMUNITY); it may exist towards non-protein as well as protein substances, etc.

The terminology of the entire subject is somewhat confusing. The term allergy was introduced by von Pirquet to include all manifestations of human hypersensitiveness. The term atopy has been applied by Coca to the natural (inherited) type of human hypersensitiveness. The term anaphylaxis is usually restricted to those instances of human hypersensitiveness which follow an in itial sensitizing dose, and conform in other respects to hypersen sitiveness as seen in laboratory animals.

Detailed discussions of the subject will be found in the stand ard text-books on immunology, pathology and internal medicine.

(R. A. KN.)