Serum disease, as this is called, is a man-made malady. If we had no curative serums and if there were no such thing as a hypodermic syringe with which to introduce the material under the skin, there would be no serum disease.
The most devastating allergic reaction is that which may follow the injection of curative serum. Fortunately it is rare. When it does occur one is again reminded of the strangeness of a disease which may be caused by a curative medicine. A friend, depended upon in time of need, turns out to be a vicious enemy.
Mr Black had had a sore throat for a day or two. When he discovered that he had a fever and was really ill he called his doctor. The doctor promptly found the telltale grayish membrane of diphtheria. He swabbed the throat with a small wisp of sterile cotton, obtaining material for laboratory examination and, since there was no doubt of the diagnosis, injected diphtheria antitoxin. Within three minutes Mr Black was unconscious, apparently about to die. The doctor, recognizing the condition as allergic shock, promptly gave his patient several injections of adrenalin, saving his life.
Another patient similarly affected called his physician, who realized the possibility and dangers of sensitization and therefore gave an extremely small dose of antitoxin in order to make sure that no unpleasant symptoms would develop.' He injected one one hundredth of a cubic centimeter into the skin. The amount corresponds to about one seventh of a drop. Surely this was so little that it could not possibly cause trouble. Five minutes later his patient was dead from allergic shock. Even the seventh of a drop had been too poisonous.
A child was ill with diphtheria. The doctor considered it wise to give prophylactic or preventive injections of antitoxin to all members of the family. The child’s father, who was still quite well, dropped dead shortly after receiving his injection.
One of the most pathetic of these unusual experiences occurred in a doctor’s family. Since the cook had diphtheria the doctor wished to give prophylactic injections to his twin daughters. One had suffered from hives. Realizing that she might be allergic, he hesitated to give serum. To the other twin with no allergic history he gave 1500 units, the regular
dose of diphtheria antitoxin. Within five minutes she was
Severe or fatal reactions from curative serums are rare, although probably not as rare as the reports in the medical literature would lead one to believe. Dr Robert Lamson found only forty-four cases of fatal allergic shock described between 1893 and 1929. Between 1924 and 1936 Dr Pipes and I found sixty-nine reports of severe shock or death. Although the majority were deaths from serum, other allergens were responsible in some instances. When one realizes the tremendous number of preventive and curative hypodermic injections given every day the number of reactions is very small. The late Dr WTilliam H. Parks, analyzing a series of 350,000 serum injections, concluded that there might be a fatal reaction once in every 50,000 and a severe but nonfatal reaction once in every 20,000 treatments. The method of giving the serum plays some part. When it is injected directly into the vein reactions occur about once in every seven hundred treatments. These are not necessarily fatal.
Serum disease, as this is called, is a man-made malady. If we had no curative serums and if there were no such thing as a hypodermic syringe with which to introduce the material under the skin, there would be no serum disease. Instead multitudes would still be dying from diphtheria and lockjaw and several other infections. Thus we find ourselves in somewhat of a dilemma, faced with the necessity for choosing the lesser of two potential evils. Fortunately, with an adequate understanding of allergy and with improvements in methods of purifying serums, the risk today has been reduced almost to the vanishing point.
Before 1893 there was no such medicine as diphtheria antitoxin. Curative horse serum was not being injected into people. Consequently there was no such malady as serum disease. Serum sickness interests us not only because it is an expression of the allergic state but also because it was the first disease recognized as being allergic.
Extrinsic and Intrinsic Allergens
Until now we have discussed responses to allergens originating outside the body. We must also consider factors acting from within. Bacterial infection and, occasionally, disturbances of the glands of internal secretion are in this category.
We speak of extrinsic allergy and intrinsic allergy. In the former the excitant is normally outside the body, causing trouble only after penetration. If its entry into the body can be prevented, reactive symptoms subside. If, as in the case of pollen, its penetration cannot be prevented, there is still the possibility of successful treatment by desensitization. It is not an easy matter to eradicate bacterial infection, the chief factor in intrinsic allergy. As a consequence treatment is not always successful.
In many cases both extrinsic and intrinsic factors play a part. Asthma may be caused by sensitization to house dust. Avoidance and desensitization may give some relief, but infection hidden in the sinuses may interfere with completely satisfactory results. The obvious precedure in such cases is to try to eradicate the infection too.
One need not be sensitized to the infecting bacteria. The existence of infection may itself suffice to cause symptoms.
It should not surprise us that persons may become sensitized to bacteria, since the Ehrlich side-chain theory was developed as an explanation of bacterial immunity and its application to allergy was predicated upon an identical mechanism. Much of the early investigative work on experimental anaphylaxis was done with bacterial protein as the antigen. Guinea pigs were sensitized against typhoid-bacillus protein injected through the skin as a vaccine. After ten days or more, reinjection of the same vaccine in suitable dosage caused death from anaphylactic shock.
Prophylaxis vs. Anaphylaxis
You may ask how this fact can be reconciled with the injection of typhoid vaccine to protect people against typhoid fever. The answer is not difficult.
Man receives three injections of protective typhoid vaccine at weekly intervals. Seven days is too short for the development of clear-cut sensitization. By the injections the cells are taught to produce free, protective antibodies.
During the second injection (after ten days) of typhoid vaccine into the sensitized guinea pig, typhoid protein combines with free antibody. Its attraction toward the living body cells is thus neutralized, just as it should be for protection. But the guinea pig is a very small animal, and we have given him a tremendous dose as compared with what we use when vaccinating human beings. There is too much typhoid protein in the second injection. There are not enough free antibodies to completely neutralize it. That which remains becomes attached to the tissue cells, thereby causing injury. It is primarily a matter of the quantity of antigen administered.
A human being vaccinated against typhoid drinks contaminated water containing a few living typhoid bacilli. In an unprotected person these few bacilli will grow in the blood in great abundance. But when the same few enter an immunized vaccinated person they combine with free antibody and are thus destroyed. They might even combine with attached antibody but are numerically so few that the damage is negligible.
The combination of typhoid protein with human protein through the antibody as a connecting link injures the latter as well as the former. The process works both ways. The typhoid cell is injured and cannot grow. If only a few body cells are injured at the same time, there will be no symptoms, and since the germs are destroyed in the same reciprocal reaction, immunity results.
If very large quantities of antigen are injected, large numbers of body cells are damaged in the process of destroying the antigen. The result is anaphylaxis.
How do we know that persons may become sensitized to bacteria? First we have the experimental proof of sensitization in animals, just discussed. Second, many allergic persons give positive skin reactions when tested with bacterial vaccines. Third, they sometimes respond satisfactorily to desensitizing treatment with vaccines. Fourth, once in a while a person will react to an extremely small dose of vaccine in such a violent manner that it can only be explained as due to allergic shock.
As an example, a man was being skin tested with a streptococcus vaccine. Scratch test was negative. An intracutaneous test was then made, the material being injected from a hypodermic syringe directly into the skin. This test is roughly one hundred times more reactive than the scratch test. Much less than a drop was injected. Within sixty seconds the man broke out with hives over the entire skin and developed asthma so severe that ten times the ordinary dose of adrenalin had to be given before he was relieved. Such severe reactions to bacterial vaccines are very rare.
There is abundant evidence that certain forms of arthritis, rheumatism involving the joints, are associated with sensitization to bacteria, especially the streptococcus.
There is also evidence that bacteria can sensitize only after combination with a hapten. Bacteria do not combine with blood protein to produce a hapten combination as drugs do. Instead they combine with a carbohydrate, a form of sugar, which is built into and becomes a part of the bacterial cellular molecule. In this hapten-protein combination the carbohydrate is the hapten, corresponding to the drug in drug allergy, while the bacterial protein corresponds to human blood protein. This hapten combination has been shown to exist for the pneumococcus, the cause of lobar pneumonia, and possibly exists also for other bacteria.
There are many gaps in our understanding of bacterial allergy.