Uric acid is a substance about which more has been written and less understood than many others in medicine and that is saying a great deal. As a basis of the suboxidation theory of Bence Jones' day, as the cause of gout with Garrod, as a step in our knowledge of metabolism and as a popular fad, uric acid in its time has played many parts.
Uric Acid in Hay Fever.In 1893, Dr. Seth Bishop announced before the American Medical Association that "excess of uric acid in the blood causes hay fever and nervous catarrh;" and advised elimination and control of the uric acid as the principle of treatment. The article may be found in theJournal of the American Medical Association, 1893, and abstracted with an interesting discussion on the treatment of hay fever, in thePhiladelphia Medical News, 1894. This position, of course, is also thatof Haig (Uric Acid, seventh edition, page 386) and his followers.
Now, in 1893, the theory of uric acid poisoning flourished like a green bay tree and all sorts of queer and misunderstood pathological processes came and roosted in its branches. Patients came to our offices, not complaining of headache or lumbago or cough, but asking for "something for that uric acid." As patients will, they had already made the diagnosis from the newspapers and wished our advice only for the remedy.
As the basis of hay fever, this theory of uric acid poisoning has apparently made as little impression as de Mussy's theory of gout on the nose and throat specialists of this country and Great Britain; for I find no mention of it in their books, except the brief reference of Professor Grayson quoted in the preceding chapter. In theVirginia Medical Monthly, however, I find an interesting paper by Dr. John Dunn, Professor of Diseases of the Nose and Throat in the University Medical College of Richmond, Virginia. Following the suggestions of Dr. Bishop, Dr. Dunn treated his patients withdiet and alkalies according to the uric acid theory and reports excellent results.
It may be pointed out that the successful results of the treatment by no means prove that the condition was due to uric acid; for the diet may be doing many other things besides controlling the movements of the uric acid and it is probable that the effect of an alkali in the blood is not a simple neutralizing of an acid but that it sets in motion a train of chemical changes of great complexity. None the less, Dr. Dunn's paper is well worth reading by every physician for its practical suggestions in the treatment of hay fever.
The cardinal error made by the advocates of theuric acid poisoningis that theyname the poison. If the theory were stated that an unknown poison or poisons circulate in the blood and cause many symptoms of disease, as headache, gouty pains, bilious vomiting, and so on, we would all agree that this is so. Call it the X-poison, if you will, as Roentgen did with his unknown ray. But when you name the poisonuric acid, you challenge the chemist and the physiologist to test your doctrine by chemicalanalysis, and when the uric acid doctrine is tested in this way it is found sadly wanting.
It is true that uric acid in the form of urates is found in the blood in varying quantities, but there is no proof that it does any harm there. In fact, there is good evidence that it does not. In the disease, leukæmia, there is an enormous amount of uric acid in the blood, far more than was ever demonstrated in gout or the so-called uric-acid disorders; yet, in leukæmia, there are no symptoms of gout or any other symptoms that have been attributed to uric acid poisoning.
A second error of the uric acid advocates, flowing from their first error of naming the poison, is to pour their acids and alkalies into the blood with the childlike faith that, like good children, the acids and alkalies will go in there and do just what they were told to do, neutralize the uric acid, and get out. They assume that the chemistry of the acids and alkalies is as simple inside of the body as it is outside of it and that the blood is simply a passive mixture of chemicals.
A third error of the uricacidites is to talkso glibly of the chemistry of the blood and the influence of this or that food or medicine on its chemical changes. The chemistry of blood! A subject of which the ablest physiological chemists have but touched the fringe,—is that a knot to be unloosed familiar as his garter by an amateur with a watch-glass and a thread?
In hisLehrbuch der Organischen Chemie für Mediciner, Leipzig, 1906, Bunge observes slyly that he had "sometimes had occasion to remark in private that the less a physiologist knew about chemistry, the more irresistible was his impulse to undertake the most difficult subjects."
When the uric acid amateur chemist comes to study the real poisons of the blood, he will be confronted with a problem even more intricate than uric acid, though that one is intricate enough and still unsolved. For there are "poisons in the blood," though it is improbable that uric acid is one of them. These poisons are the blood-proteins, so many that the physiologist has never counted them, so minute in quantity that no chemist has ever isolated them, so complex in structure that the ablest chemists of the worldstand appalled before a molecule that contains sixty atoms of carbon,[1]so powerful that an undetermined fraction smaller than one-third of a grain will kill ten thousand guinea pigs or one hundred thousand mice, and so perfectly under control that they circulate harmlessly in the normal blood. The marvel is that any animal remains alive; and no animal would remain alive were it not for a system of protection by which these poisons are rendered harmless, usually by a slight rearrangement of the atoms in their molecule which is one of the wonders of organic chemistry.
We are far from knowing just what happens when we pour acids and alkalies and foods into this witches' cauldron of blood. Rather than impudently announcing the changes that are about to take place in the blood when we administer a certain food or medicine, we should stand in reverent awe before one of the most intricate and marvelouspuzzles with which nature ever challenged the chemist and the physiologist.
Shall we therefore stop using acids and alkalies as medicines because we do not know each step in their mode of action? By no means. We do not know each step in the mode of action of any medicine or of our foods, either, for that matter; but we do not for that reason stop eating. We should still use the acids and alkalies for their effect on the patient as far as we can see it just as we shall still go on eating food because it nourishes us; but we shall be wise to stop talking so glibly about what we cannot see and do not yet know, the effect of those acids and alkalies on the chemistry of the blood.
Uricacidæmia and Gout.Now, why do I speak with respect of de Mussy's theory of gout as a cause of hay fever and so disrespectfully of the uric acid doctrine? Are not gout and uric acid poisoning the same thing? No. They are not; though the two ideas are usually confused by medical men since Garrod's time and his demonstration of the increase and decrease of uric acid in the blood of gouty patients. Goutis something more than a simple accumulation of uric acid in the blood because of its imperfect elimination by the kidneys. What that something is, we do not know; but gout is, at least, a clinical entity, a definite group of symptoms known since Hippocrates' time. Take away the uric acid theory and you still have the disease, gout, that any of us can recognize, as the Greeks and Romans recognized it when the word uric acid was unknown. It is on these symptoms of gout, the clinical picture of disease, not on any hypothetical uric acid, that de Mussy based his theory and thus far he is on solid ground. On the other hand,uric acid poisoningis largely a figment of the imagination. Take away the uric acid, which has never been satisfactorily proved to be there, and there is nothing left. In not one one-hundredth part of the cases of so-called uric acid poisoning is it proved that uric acid has anything to do with the case.
The Deposits of Uric Acid in Gout.The deposit of uric acid in the form of urates in the gouty joint has always been a strong argument for the theory that gout,at least, is due to an excess of uric acid (urates) in the blood. At one time, in a humble way, I was a pathologist, and this theory of a blood overloaded with uric acid as the only thinkable cause of its deposition in the joints never impressed me as pathologically sound. I often compared these deposits of urates in the joints with the deposits of lime salts so often found at autopsies in caseous glands or small necrotic areas. The superficial observer says:
"See what an excess of lime salts there must have been in the blood." He is thinking of laboratory glassware and the ground around a mineral spring that becomes encrusted with salts as the solutions evaporate. But, in animal pathology, this is a false conclusion. The animal body is not a test-tube and, in it, the laws of physics are modified by those of physiology. Lime salts are deposited in the caseous gland or tubercle not because they are in excess in the blood but because lime salts are attracted to all caseous material from normal blood. Whether or not this calcification is an intentional provision of nature to protect the body, to petrify the necrotic materialand make it harmless, is not the question here, though the calcification has this effect. The point here is that calcification of caseous glands or necrotic areas does not presuppose an excess of lime salts in the blood. The first step is not an excess of lime in the blood but a necrosis, after which the lime salts will be deposited from normal blood.
So, it has seemed to me that the deposit of urates in and around a joint is no proof of their excess in the blood. Just as in calcification, so in gout, the first step may be a minute area of necrosis or other local degeneration that attracts the urates that are always present in normal blood; or the secret of the gouty inflammation, like that of urticaria and hay fever, may at last be found in Anaphylaxis, as described in the next chapter.
FOOTNOTES:[1]Wenn mehr als 60 Atome Kohlenstoff im Molekül sind, dann ueberlasse ich das Object zu andern. Bunge, page 262, quoting "einen hervorragenden Forscher auf dem Gebiete der organischen Chemie." See Bunge for authority of these statements.
[1]Wenn mehr als 60 Atome Kohlenstoff im Molekül sind, dann ueberlasse ich das Object zu andern. Bunge, page 262, quoting "einen hervorragenden Forscher auf dem Gebiete der organischen Chemie." See Bunge for authority of these statements.
[1]Wenn mehr als 60 Atome Kohlenstoff im Molekül sind, dann ueberlasse ich das Object zu andern. Bunge, page 262, quoting "einen hervorragenden Forscher auf dem Gebiete der organischen Chemie." See Bunge for authority of these statements.
Fifty years ago de Mussy pointed to the resemblance between hay fever and gout and claimed hay fever as a manifestation of the gouty diathesis. As related in Chapter VII, he based his theory on the resemblance between the history and symptoms of hay fever patients with those of gouty patients. In his day he found both hay fever and gout confined to the Anglo-Saxon race, both hereditary and familial, both exhibiting urticaria, eczema, and asthma, and he recognized that the lesion in the eyes and nose of the hay fever patient was not a true catarrh but an urticaria.
On the other hand, Wolff-Eisner declared that hay fever is an anaphylaxis and this idea has been developed and confirmed by Koessler and others so fully that we must accept it as proven. Let us examine this matter of anaphylaxis to determine whetherafter all there is any essential difference between the two views of hay fever.
Anaphylaxis.The conceptionanaphylaxisorlack of protectionbegins with the discovery that a harmless protein injected into a dog will so sensitize him that, after ten days or so, another injection of the same protein will kill him. The point is that the change has occurred in the animal, not in the protein injected. The protein is the same as before and can be injected once into any number of dogs without harm. In this way we explain the cases in which drugs and foods that are harmless to most people may be virulent poisons to those who happen to have been sensitized by a former overdose. The widespread use of antitoxin in diphtheria gave abundant opportunity to study the phenomena of sensitizing a human being with one dose and killing him with another dose of the same thing.
The symptoms of anaphylaxis first observed were urticaria, arthritis, and dyspnœa. Then Bruck showed that what we used to callidiosyncrasyto drugs and foods that are harmless to most people is really an anaphylaxis, attributable to a former overdoseof the same thing. Next, it was learned that anaphylaxis may persist through life and be transmitted to the offspring of rabbits and guinea-pigs, illustrating the cases in human families where sensitiveness to a certain food or drug runs down through several generations. Then the dermatologist brought in a list of skin eruptions, urticaria in the lead, as examples of anaphylaxis to certain foods or to poisons generated within the body, especially in the intestines. Then asthma was included among the anaphylactic reactions and, finally, Wolff-Eisner pointed out that the lesion of hay fever is an anaphylaxis. I may add here that this view of hay fever confirms my observation that the lesion is not a catarrhal inflammation but an urticaria.
So we have a picture of anaphylaxis as a sensitiveness to bacterial poisons or to foods or drugs that are harmless to most people expressing itself as an urticaria, an arthritis, an asthma or hay fever. But this is the very group of symptoms on which de Mussy based his theory of gout. When we add that this sensitiveness or anaphylaxis is hereditary and that it is aggravatedby foods, drugs, or pollens that are harmless to most people, I submit that we have a pretty picture of the gouty diathesis; for the gouty diathesis, too, is a susceptibility to arthritis, to urticaria, and to asthma from causes that do not trouble other people, and in gout, too, this weakness is hereditary. One thinks of the gouty patient who cannot take iron or digitalis because it aggravates the gouty pain and of the attack of gout that is brought on by a glass of champagne or a piece of beef or a few strawberries that the majority of mankind can take freely without harm. Now, if urticaria, eczema, arthritis, asthma and hay fever form a picture of anaphylaxis, and if these symptoms also form the picture of the gouty diathesis, is it not probable that one of these pictures can be explained in the terms of the other? If the anaphylaxis to the diphtheria antitoxin, horse serum, can develop arthritis, is it not probable that the most striking feature of gout, the inflammation of the joint, is also an anaphylaxis to poisons yet unknown to us but the same poisons that make the gouty urticaria and asthma?
What if gout should prove to be a sensitizationor anaphylaxis to uric acid that does not exist in the non-gouty? This would explain the puzzle of one patient full of gouty pains with very little uric acid in his blood while another patient, like the leukæmic, has a blood full of uric acid that does not trouble him.
The Mechanism of Anaphylaxis in Hay Fever.The anaphylaxis theory of hay fever is based on the observation that the epithelial cells of the mucous membranes of the eyes, nose, and throat have not lost their primitive power of digesting foreign protein.
Ages ago, when we were amœbæ or little drops of protoplasm, we had no eyes or nose or separate stomach for digesting food. The one little cell body did everything. One of the most important powers of that cell body was its power of digesting and assimilating food, and its most important food was the nitrogenous food or protein from which it built up its own body substance. Now, foreign or food protein cannot be simply absorbed as such. Foreign protein is a poison and never tolerated in the blood. The foreign protein used as food must firstbe changed into the special kind of protein that the body can use. The foreign protein is changed by splitting its molecule into its simplest parts and then recombining them in the desired form. The complex protein molecule, containing those sixty atoms of carbon that gave the Schrecklichkeit to the German professor of chemistry as related on page 71, is split up again and again into simpler forms. The end products are harmless, but the early splittings produce both poisonous and non-poisonous products. The end-results of these successive splittings, the splinters, as it were, are then combined by the amœba to form its own kind of protein or body substance.
As we rose in the animal scale, instead of being an amœba of a single cell, we became constructed of millions of tiny cells and began to set aside certain groups of cells to do special work, the eyes for seeing, the ears for hearing, the lungs for breathing, the digestive organs to prepare our food and a sheath of harder cells over the outside of the body that we call our skin and mucous membranes. Specialized as those cells have been for many generations,they have never forgotten that a foreign protein is a food or, perhaps, an enemy, to be split up and decomposed at sight. So, the epithelial cells of the mucous membrane of the nose and eyes, though they have no longer anything to do with digesting our food, secrete a ferment or enzyme that can split up any protein that may happen along. This process is calledparenteral digestionor digestion outside of the intestines; and this theory of the parenteral digestion of protein is the foundation of the anaphylaxis theory of hay fever.
During the growing months of the year the air is full of pollen that is blown in everybody's eyes and nose. In that pollen is a proteid that is digested by the secretion of those mucous membranes, proceeding exactly as food is digested in the stomach and intestines, splitting up the complex proteid molecule into simpler groups, and forming both poisonous and non-poisonous substances. In the normal eyes and nose this splitting of the protein proceeds slowly, forming only minute amounts of poison. As absorption from the eyes and nose is slight, no unpleasant effects are produced.
The first step in the development of hay fever is supposed to be a disturbance in this digestion of protein in the eyes and nose, by which larger amounts of poison are formed and absorbed by the mucous membrane, producing the first poisoning, which, like the first injection into the dog, sensitizes the mucous membrane to other doses of the same poison. It is supposed that disturbance in the protein digestion may be caused by stoppage of the nasal passages, with excessive accumulation of proteid, inhalation of excessive amounts of pollen, forming excessive amounts of poison, or, perhaps, insufficient secretion, so that the splitting-up process is not hastened to its conclusion of harmless products. The anaphylaxis theory halts a little at this point and is not exactly clear about the mechanism of that first poisoning.
After the first poisoning, the epithelia are permanently injured and remain more permeable to protein. They also develop the power of making large amounts of the digesting enzyme, which is absorbed into the blood and is supplied to all the tissues of the body, so that all tissues, including theskin, can decompose the pollen protein. Advantage is taken of this distribution of the protective enzyme in the skin reaction, in which a small area of skin denuded of its superficial epithelia reacts in the form of a hive-like swelling when the pollen that originally affected the patient is brought in contact with it.
The next time that the pollen reaches the eyes and nose the mucous membrane is ready for it with an abundant secretion of enzymes to destroy it. In this intense digestion of the proteid, quantities of the poisonous substances are formed which irritate the eyes and nose worse than before, explaining why hay fever becomes worse with successive attacks.
The inherited form of hay fever is explained by the well-known transmission of anaphylaxis to the offspring. The first case in the line of descent must start with a severe poisoning that lays the foundation of the anaphylactic inheritance.
I would submit to the enthusiastic immunologist that this first sensitization which he takes for granted but cannot prove is the weak spot in his hypothesis. This isthe point where he needs help, and it is at just this point that de Mussy's neglected theory of gout completes the picture. The immunologist has not explained why I, a boy growing up with other boys, inhaling the same amounts of pollen as they, catching no more colds than they, and never having any serious illness, became sensitive to pollen while the others did not. There is no recollection of any "first poisoning" by pollen that might have started the anaphylaxis. But, says the immunologist, it was your parents who were sensitized and you inherited the anaphylaxis. Now, my parents lived to old age and had no sign of hay fever, though my brother had it and my children are beginning to sneeze and rub their eyes suspiciously in June and August. But if you associate hay fever with the gouty diathesis, as the clinical histories seem to justify, you enlarge immensely your opportunity to prove ancestral sensitization to whatever unknown poison originally produced the gouty sensitization. This view does not restrict you to ancestral hay fever, but extends it to gout or to any equivalent of gout.
The best work in English on hay fever asan anaphylaxis is the monograph of Karl K. Koessler in Forchheimer'sTherapeusis of Internal Disease, 1914, Volume 5, page 671, to which the reader is referred for a full discussion of the subject. The same author gives an abstract of his work in theIllinois Medical Journal, 1914, page 120. This article in Forchheimer is the most complete that has been written since Sticker's time and covers the ground from Sticker, who knew not anaphylaxis, to Wolff-Eisner, who is not available in English.
I was gratified to find in Koessler a sympathetic soul. He thinks, as I did, that the monograph of Sticker in Nothnagel is the best review of hay fever that we have. He calls it "a remarkable monograph and the standard work on the subject." But why, oh why, K. K. K., in your own masterly article in Forchheimer, did you follow Sticker all through his historical chapter but leave out all that he says of de Mussy's theory of gout or arthritism as the constitutional basis of hay fever and also leave de Mussy and every reference to his work out of your list ofLiterature? The German books are more liberal. While most ofthem ignore de Mussy and his theory in their text, they all list his writings in theLiteratur. Has the microbe of bacteriology and the laboratory bitten you so virulently that you can find no place for the gouty diathesis even in an index?
I know that the gouty diathesis is out of date. In fact, all diatheses are out of fashion. Nobody speaks of them now. They went out with the medical philosophies of the eighteenth century. Cellular pathology with its wonderful revelation of the anatomical seat of disease and bacteriology, with its still more wonderful revelation of the external cause of disease, so dazzled the eye and the mind that we forgot that the sensitive animal body behind the attacking microbe had its changes, too, its changes in body chemistry that could not be stated in terms of cells and bacteria. The pendulum is swinging back now to a consideration of the constitution of the body on which the microbe or poison acts, itsresistanceorimmunity, itsanaphylaxisorallergie. With these holiday and lady terms, are we not trying to describe what our ancestors knew asdiathesis? For what is the old conceptionof diathesis but just such a hereditary weakness or lack of defense or tendency to disease that our ancestors recognized clinically but could not demonstrate, elusive, difficult to detect, but nevertheless there; like the dog who has been sensitized to an otherwise harmless proteid, who seems well and is well in everything except his susceptibility to that one special cause of disease?
Bacteriology, which first took away the idea of diathesis, is now giving it back. The discovery of the tubercle bacillus as the cause of tuberculosis banished thetubercular diathesisapparently forever; but, step by step, through bacteria and then toxins and antitoxins and now through anaphylaxis and allergie, bacteriology is bringing back the old conception of an inherited or acquired susceptibility to attack. Call the old tubercular diathesis asensitizationand you have made it the most modern of modern discoveries. So, also, step by step, through bacteriology with its toxins and antitoxins and now with anaphylaxis, from the philosophic ash-heap on which we thought to have thrown it for good and all, likean old family cat that we thought was dead, comes creeping back that old conception of a gouty diathesis or arthritism, not as dead as we thought it, to complete the explanation of the existence of hay fever.
I am far from saying that calling hay fever a form of gout ends the subject. I say only that bringing such a common and puzzling disorder as hay fever in line with such a common and puzzling disorder as gout brings us a long step nearer to solving the puzzle that lies behind both of them; and I say also that, in the records of this work, the name of Gueneau de Mussy, who first recognized this relation clinically, deserves a place.
Gout as an anaphylaxis, hay fever as an external expression of gout, what a vista of therapeutic possibilities is opened up by these simple experiments with pollen extracts and foods. The subject ramifies in every direction, touching the gouty form of Bright's disease, gouty heart disease, endocarditis and pericarditis, the popular "hardening of the arteries," which may prove after all not to be due to meat in all cases or alcohol in all cases but certain foods incertain cases, the increase in deaths from heart disease and kidney disease in the fifth decade of life. The correlation of these gouty problems with this work in the prevention and cure of hay fever anaphylaxis awaits a Lister or a Pasteur or a Koch who will have an eye to see and a patient industry to search and find.
When you have established hay fever as anaphylaxis or lowered resistance to a specific proteid, you may be sure that the immunologist will seize the patient as his own, carry him off to the laboratory, and there attempt to raise his resistance or develop immunity to the attacking proteid by giving minute doses of the poison gradually increased. The success of this procedure will be related in the next chapter.
The idea of preventing disease and poisoning by preparing the body with minute doses of that poison, gradually increasing until the body is immune, is an ancient one. The practice is Ur-alt, as my favorite German history books say; for it has been found among savages and primitive peoples and is practised in a crude way by every boy who accustoms himself to that noxious weed, tobacco. Then, there are the Psylli, whom Lucan tells of, who were by heredity immune to snake poison and who could make the favored stranger immune by inoculating him with small doses (Pharsalia, Book ix); and old King Mithridates, of Pontus, who believed in preparedness and kept himself prepared for the attentions of his faithful subjects by taking small doses of poison every day, keeping himself immune should by any accident some poison slip into his porridge (Pliny, Book xxv). Old King Mithridates was a good immunologist. He knew the transient nature ofimmunity and kept the treatment up. He knew that, if he stopped taking the poison for a week or so, he would go into a state of anaphylaxis and the next dose would kill him; so he kept himself in a state of anti-anaphylaxis by not permitting too long a time to elapse between doses, after the most approved rules of modern immunology. That patient whom Goodale immunized against horse-asthma who objected to a treatment that had to be taken for the rest of her life, should learn of old King Mithridates the true practice of immunity.
This is still the weak point of artificial immunity; it does not last very long. You can immunize a guinea-pig or a patient to almost anything now-a-days by giving him minute doses gradually increased but the immunity passes off quite rapidly when the treatment is stopped. We have still something to learn from Nature in this respect. Nature can give us one dose of yellow-fever or scarlet-fever or small-pox or measles and make us immune for life but your artificially produced immunity may last for a few weeks or months only. Our closest imitation of natural immunity is vaccinationagainst small-pox. Here we produce an actual disease, cow-pox; yet, even here, we are not at all sure how long immunity lasts. Even in Jenner's time, the original belief in protection for life came down to seven years and our modern health boards would vaccinate every two years or, in the presence of an epidemic, more frequently.
However, Nature is a wasteful worker, wasteful of her material, and she kills a great many of her children with measles and scarlet-fever and small-pox and yellow-fever while immunizing the lucky ones. A Health Board that would kill so many people while immunizing the rest would be a public scandal. Yet it is probable that Nature's way is the most effective and that the best immunizer is the disease itself, as Koch found with tuberculosis among his guinea-pigs that the best protection against tuberculosis was inoculation with living tubercle bacilli, not with dead ones; and the autopsies show that the majority of the human race that grow up at all have been successfully immunized against tuberculosis by a mild local attack of the disease.
As yet, no one has had the boldness toinoculate human brings with living bacteria and to imitate Nature in her manner of killing off all the sensitive subjects in order to preserve the rest. This was formerly done by inoculation with small-pox but the unfortunate results of the practice compelled its abandonment among civilized people. Even Nature's immunity is not perfect in all diseases, as many a patient with his sixth attack of grippe or third pneumonia or fortieth year of hay fever has learned most feelingly; and this irregularity of natural immunity bears directly on the proposal to immunize patients against hay fever by small and increasing doses of the offending pollen. If the natural disease does not confer lasting immunity, you will have some difficulty in conferring lasting immunity artificially, as the immunologist is just now discovering. His immunity passes off so rapidly that he is now searching for a method of immunizing that can be carried on for many years without tying the patient to a laboratory for life. It is right here that I believe that homœopathy has valuable methods that can be applied to the situation.
But we must not jump to conclusions. Because we can immunize successfully against one disease, it does not follow that the same methods will immunize against another disease. Each disease is a problem in itself and may require its own methods. Nor because we can immunize the guinea-pig in the laboratory, does it follow that the same methods are applicable in the human patient. The only proof that we can immunize against hay fever is to immunize against hay fever. So, to the subject!
Passive Immunity.The first man to attempt to apply the methods of modern immunity to hay fever was Dunbar, of Hamburg, in 1903, with thispollantin. He attempted to duplicate in hay fever the triumph of antitoxin in diphtheria by injecting a horse with increasing doses of pollen until the horse became immune to large doses of pollen and his blood full of antibodies. Dunbar expected to confer passive immunity on the hay fever patient by transferring to him this horse serum with its antibodies. There is no better example of the rule that each disease requires its own methods of immunity. Whilediphtheria antitoxin is harmless to the diphtheria patient, the serum of the pollen-immunized horse nearly killed the first patient Dunbar tried it on, who happened to be his assistant, a sufferer from hay fever. It is probable that pollantin is based on the wrong principle, that hay fever is not, like diphtheria, a poisoning by a toxin to be antidoted by an antitoxin. However, to Dunbar belongs the credit of first attempting to put the treatment of hay fever on a scientific basis and he introduced the method of testing the patient that has been followed by all later workers, dropping the pollen extract in the eye.
In theCentralblatt für Bakteriologie, Referate, xxxvi, s. 453, there is an account of a most unseemly quarrel between Dunbar and Weichardt, the latter claiming that before leaving Hamburg, he suggested the idea of pollantin to Dunbar. Weichardt has since put on the market another hay fever specific, calledgraminol, which is the blood-serum of cattle that have fed on the offending grasses during the hay fever season. The theory is that the blood of the cow contains antibodies to those grassesand that passive immunity can be conferred on the hay fever patient by transferring those antibodies to his blood.
This is the old, old experiment that has been tried so many times in many diseases and has so often failed. It reminds us of the many attempts to confer on the tuberculosis patient the natural immunity possessed by the jackass by injecting the patient with the blood serum of that friend of man. The result of these experiments left some doubt as to who merited most the name of jackass, the doctor, the patient or the patient beast. Both pollantin and graminol have been praised highly in Germany but neither of them have succeeded so well in this country. Perhaps a shrewd advertising campaign had something to do with it; for the combination of a German scientist and his manufacturer can give points to any Yankee in exploiting the public with sure cures for the sick.
Active Immunity.In active immunization, the real pioneers, after Mithridates, were the homœopaths, who, for many years, have given small doses of poison ivy to prevent ivy poisoning and smalldoses of the poisons of infectious diseases to prevent and cure those diseases; but the homœopath did not realize the transient nature of immunity and the necessity for continuing the treatment for many months or years, nor did he adopt the principle of increasing the dose to the point of toleration.
The first to attempt active immunization and cure of hay fever by injecting extracts of the pollen that causes the disease appears to have been Noon, working in Wright's laboratory in London. The work was continued by Freeman, their work being reported in theLancet, 1911, i, page 1572 and ii, page 814. They found the English spring form of hay fever due to the pollen of grasses. By dropping extracts of various pollens into the patient's eye, after the manner of Dunbar, they concluded that their patients were most sensitive to timothy grass and they used timothy extract exclusively in the treatment. Freeman states explicitly that a patient immunized against timothy grass is immune to all other grasses of that season; that it is unnecessary to immunizehim to each particular grass, thus differing from some of our American observers who use the skin reaction to determine the particular pollens to which the patient is sensitive and inject every one of those pollens in the treatment.
Independently of these British observers, Karl Koessler, of Chicago, in 1910, attempted to immunize patients against hay fever by injecting pollen extracts. Like Noon and Freeman, he used the eye reaction to test his patients and found them most sensitive to rag weed. Just as the Englishmen had used only timothy grass in their cases, Koessler used rag weed exclusively. His work is reported in his article on Hay Fever in Forchheimer'sTherapeusis, Volume V and also in theIllinois Medical Journal, 1914, page 120.
Selecting the Pollen. The Skin Reaction.The next step in the development of the pollen treatment was to substitute the skin reaction for the eye reaction in testing the patient's sensitiveness to various pollens. The advantage of the skin reaction over the eye reaction is that it permits testing many pollens at the same time anddoes not distress the patient as does a sharp eye reaction.
While Noon and Freeman selected the one typical pollen of spring, the timothy grass pollen, and Koessler selected the typical fall pollen of the American hay fever, rag weed, for all cases of that season, later workers, using the skin reaction, go to the extreme of injecting the patient with each and every pollen to which his skin reacts. Oppenheimer and Gottlieb carry this individualization to the point of attempting to discriminate by the skin test the patient's varying resistance to his different pollens at each treatment. This resistance may rise for some and fall for other pollens so that six or eight different pollens in different doses must be injected separately at each treatment. This is individualizing the case with a vengeance and requires an expenditure of time and skill (I almost saidskin) that must be rather expensive for the patient.
A series of light scratches are made on the skin of the forearm or the inner side of the arm where the skin is delicate. The scratch must be only superficial and notdraw blood. Really the best method is to make a round denuded spot by twirling a small brad-awl. A drop of extract of different pollens or a speck of the pure pollen protein is rubbed into each scratch and the result awaited for fifteen minutes. Within that time, a redness and swelling, like a hive or a bite, will appear at some of the scratches.
This swelling is the skin reaction to that pollen. Its appearance indicates the presence in the skin of reaction bodies to that pollen. It is argued, and partially proved by practice, that the pollens to which the skin reacts are the pollens to which that patient has been sensitized and these pollens are selected for administration.
The Dose.The first dose of pollen extract is the danger dose and differs for each patient according to his susceptibility for a given pollen. It is determined by dropping the pollen extract into the eye or rubbing it on the skin. To avoid anaphylactic shock, this dose must be incredibly small. Noon and Freeman's first dose was one-third c. c. of the weakest dilution of which one drop in the eye would cause hyperaemia.This was usually four drops of a millionfold dilution in water. Later doses were never more than 1 c. c. of a 1 to 100,000 dilution "to avoid unpleasant reactions."
Goodale begins with five drops of that dilution that just fails to cause a skin reaction. Later, to avoid the risk of shock, he advises one-tenth of this dose.
Koessler's theoretical initial dose of rag weed extract is one drop of the weakest dilution that will just redden the conjunctiva. As he finds rag weed more toxic than the English timothy, his actual first dose is one-half of this theoretical dose. The actual first dose will vary from one drop of a 1 to 1,000,000 to one drop of a 1 to 20,000 dilution, the smaller of which he estimates to contain of pollen protein one one-hundredth part of a millionth of a gramme or .000,000,01 gramme.
Shade of Samuel Hahnemann, the first and greatest homœopath! And they drove you out of Leipzig into poverty and exile for teaching that in using drugs that are similar to the disease there is serious danger of aggravating the disease; that the dose must be extremely small; and that diseaseso sensitized the patient that a dose so small as to be inappreciable in health becomes active in disease!
The smaller doses of pollen extract are given every three or four days and increased as rapidly as possible, judging the increasing tolerance or resistance by a diminishing eye or skin reaction. With larger doses, the interval is longer, a week or ten days. The pioneer, Noon, and all workers since, warn against increasing the dose too fast, for the reactive power of the patient is easily exhausted, his resistance lowered and he may be left more sensitive than before.
Dangers of Pollen Injections.Treatment by pollen injection is beset with dangers for the unlucky patient. It has been noted how Dunbar nearly killed his first patient by injecting the serum of the horse that had been immunized to pollen. All experimenters, without exception, say that the injection of pollen extract is attended with danger to the patient, danger of anaphylactic shock, and warn against the use of any but the most infinitesimal doses. The hay fever patient is a human being who, in some way, has been sensitizedto pollen. He is in a state of exquisite anaphylaxis and a dose of pollen injected into his blood may kill him in twenty minutes. Goodale reports shock (faintness, nausea, vomiting) in two patients following the mere rubbing of a drop of pollen extract into a scratch on the skin. Evidently the scratch was too deep and the pollen poison was absorbed rapidly into the blood instead of being stopped by the deep epithelia. I have seen a similar absorption and general reaction in children after a skin test with tuberculin, when the tuberculin entered the blood through too deep a scratch.
Another danger lies in the instability of the pollen extracts. Koessler expressly warns against commercial preparations of pollen protein because of the danger of decomposition. His extracts do not keep more than three weeks and are dangerous to use after that time. On the other hand, Goodale, making his extracts with 15% alcohol, reports them as active and fit for use after more than one year. Oppenheimer and Gottlieb object to commercial preparations on different grounds. The commercial preparations contain many differentpollens so as to be sure to include those to which the patient is sensitive. They point out that in these mixtures, the dose of the individual pollens cannot be adjusted to the changing conditions of the patient and, in addition, injecting into the blood of the patient pollens to which he is not already sensitive may sensitize him to these pollens also and leave him worse than before.
There is the lesser danger that the patient will not be immunized by the injections but become more sensitive to his old pollens than he was before, as Noon pointed out in his first paper; for artificial immunity is a difficult thing to control and is by no means as easy as it looks in the book. Nor is it as easy to immunize a human being over many years of life, subject to so many conflicting influences, as it is to immunize a guinea-pig living in a cage.
To lessen the dangers and enable the patient to keep up his immunization for many months and years, Goodale borrowed an idea from Schloss, who fed his egg-oat-meal-almond anaphylaxis patient minute doses of these foods until he so raised his resistance that he was able to eat them inordinary quantities without harm. Such artificial resistance must be kept up by eating a small quantity of the food each day or it will be lost (old King Mithridates again). As most of the pollens are not edible and as patients react to botanically allied plants, Goodale tried feeding the patient over long periods of time with vegetables and edible plants that were allied to the offending pollens, expecting that, as in Schloss's patient, some minute part of the protein would pass unto the blood unchanged and maintain the protection. So far, these feeding experiments have failed. Trial with homœopathically potentized pollens over long periods of time has not been made.
Conclusions on Pollen Extracts.My conclusions on the pollen treatment are that it is in line with our best practice of immunity but that it is still in an experimental stage, the pollens are possibly dangerous even in the hands of a skilled immunologist. In a disease that is usually so easily controlled by rosin-weed, faradism and ichthyol, I would not expose a hay fever patient to the very real danger of anaphylacticshock. The conditions governing immunity stated in the beginning of this chapter still hold good. It is transient. Already some of the early workers have discontinued the practice. The despair of Goodale has been quoted. Scheppegrell, probably the first in this country to use the pollens, has given them up and advises the patient to keep away from his irritant and to have the weeds cut in all cities as the best treatment obtainable (Journal of the A. M. A., March 4, 1916, page 710). The most hopeful aspect of the pollen extracts seems to me to be their administration all around the year in high dilutions,more homœopathico, and to this practice I believe the immunologist will eventually come.
Pollen Extracts not Vaccines.Some manufacturers and all British writers speak of pollen extracts asvaccinesand of immunizing the patient asvaccination. This seems an unnecessary confusion. We have two kinds of vaccines already, the cow-pox vaccine and the killed cultures of bacteria introduced by Wright. For an account of the use of these vaccines in hay fever, we will pass to the next chapter.
In his paper inThe Lancet, the pioneer in the use of pollen extracts, Freeman, observed that "many cases of supposed hay fever" were simply acute bacterial catarrhs. He excluded hay fever by the lack of any reaction when timothy extract was dropped into the eye. The bacterial infection was proved by culture from the eyes and nose, usually yielding the staphylococcus. The final proof was the cure of the patient by an autogenous vaccine made of the offending microbe. In the past few years, this observation has been confirmed and many cases of cure of "hay fever" by bacterial vaccines have been reported in the journals. The bacteria were chiefly staphylococci, rarely the pneumococcus or the micrococcus catarrhalis.
Oppenheimer and Gottlieb report cases of mixed hay fever where the skin reacts to pollen but the pollen extract failed to cure. In these cases, they found a bacterial catarrh of the eyes and nose. Theysuppose a vicious circle, the catarrhal inflammation and the hay fever sensitiveness mutually interfering with each other's recovery and they succeeded in curing the patient by using the appropriate pollen extract and the bacterial vaccine at the same time, believing that while the pollen extract was raising resistance to the pollen poisoning, the bacterial vaccine was raising resistance to the bacterial catarrh.
While hay fever is not strictly a catarrhal inflammation, the cure of hay fever by curing a coexisting catarrhal rhinitis or conjunctivitis seems easily possible. The surgeons taught us long ago that some cases of "hay fever" need nothing but good drainage of the nose, which they secured by freeing the nose from obstruction. Every physician sees mild cases of hay fever recover on various popular catarrh treatments. The tablets sold by homœopathic pharmacies, containing iodide of arsenic, naphthalin and quillaya, cure many cases of hay fever and these are the same drugs that cure catarrhal rhinitis. It is easily possible that my old inheritance, rosin weed, cures hay fever by curing the coexisting catarrh; for it was afamous remedy among the eclectics for catarrhal inflammation of the nose, throat and bronchial tubes.
If, then, operations or remedies that cure catarrhal rhinitis cure also some cases of hay fever, there is nothing inherently improbable in expecting the bacterial vaccines to cure some cases of hay fever, for the vaccines have made many cures of catarrhal inflammation. However, the physician using them should understand that they are not specific drugs against the pollen anaphylaxis but against a supposed catarrh or bacterial infection. He will be well advised to control the treatment by taking cultures from the nose to make sure that the bacteria are there, determine the variety present and, if possible, have an autogenous vaccine made up for treatment.
I have no personal experience with the vaccines in the treatment of hay fever, though I know their value in ordinary catarrhal conditions. As remarked in the chapter on Pollens, I have succeeded with the milder methods of rosin-weed, faradism and ichthyol. However, bacterial vaccines are much safer than pollen extracts, thetechnique of their use is not as complicated and they are well worthy of trial in refractory cases if bacteria are demonstrated in the eyes and nose. I might remark here that this demonstration will seldom fail; for you can get a culture of the staphylococcus from almost any nose.
The Word Vaccine.Used in connection with the treatment of hay fever, the wordvaccineis confusing, for it has been applied to two totally different kinds of medicine, the bacterial vaccines and the pollen extracts. Physicians intending to usevaccinesin the treatment of hay fever should make sure which they are using; for the methods and dosage of the one are quite different from those of the other. Sir Almroth Wright, to whom the whole world is indebted for his work in preventive medicine, started the trouble by calling his killed bacteriavaccines, having in mind the prevention of bacterial diseases as the familiar vaccine prevented small-pox. Now,vaccais Latin for cow,vacciniais properly cow-pox and the virus of cow-pox that we use in vaccination against small-pox is properly calledvaccine. With a paucityof vocabulary unexpected in an Irishman, Wright called his killed bacteriavaccinesbecause he used them to prevent disease, using the word as synonymous withpreventive. As cow-pox vaccine is the greatest preventive we know, the wordvaccinemight be justified when applied to the bacterial cultures or to the pollens or to any preventative of disease. But when you leave pure prevention and apply these remedies to thecureof disease, the wordvaccineloses even this shadow of justification and the present confusion results. One American house makes a laudable attempt at a more exact terminology by calling the killed cultures of bacteriabacterins. Still, the wordvaccinefor killed bacterial cultures has been advertised so deeply into the medical mind that it is firmly rooted there and not likely to be disturbed by mere considerations of etymology. As for the pollen extracts, they are yet young and impressionable. It would be better to leave off the wordvaccineas applied to them and call them what they are,pollen extracts.
Until recently, diet in hay fever was a matter of avoiding meat and strawberries and the result was usually unsatisfactory. With the conception of hay fever as an anaphylaxis and the recent studies in food anaphylaxis, the subject of diet in hay fever assumes a new and inviting aspect.
This new view of diet in hay fever begins with Schloss's masterly study of a case of food anaphylaxis reported in theAmerican Journal on Diseases of Children, 1912, No. 6. A good review of the subject with references to the literature will be found in the special Hay Fever and Anaphylaxis number of theBoston Medical and Surgical Journal, August 10, 1916, especially the article by Talbot.
Some physicians have long insisted that they could relieve hay fever by diet. For instance, I once asked a physician of large general practice what he did for hay fever. He smiled in an incredulous way that I have noticed before among people who never had hay fever and replied, "I find thatif people will stop eating strawberries and not eat too much meat, they soon get rid of their hay fever." This answer surprised me for I knew that in his long practice, he must have seen many cases of hay fever and my experience had been that diet had no influence on the symptoms.
Then, there is Professor Dunn, already quoted in Chapter IX, who believes in the uric acid theory and says that, in his opinion, "hay fever is the result of improper eating and living." He has been able to prevent the annual attacks by using cold baths and excluding meat, tea, coffee and alcohol from the diet.
Any patient who can get rid of the annoying symptoms of hay fever by such simple means of diet and bathing should be urged to try it, whether he believes or disbelieves in the "uric acid poisoning" on which the treatment is based. My own experience leads me to believe that most hay fever patients require something more than dietary regulation to control the disease. For instance, in my own case, the disease appeared at an age when I had never taken tea, coffee or alcohol, during the summervacation when I was living a hygienic out-door life, playing ball, cycling and swimming every day in the salt water. I remember one summer in camp by a lake among the pines, in which I lived Dr. Dunn's hygienic life for many weeks, drinking no tea, coffee or alcohol, eating chiefly fresh fish and green vegetables and swimming daily. My experience can be paralleled by many hay fever patients that as long as I remained among the pines, I was in perfect health but on going down into the valley, one breath of fragrant wind blowing over the fields would cause instant itching and swelling of eyes and nose and all the previous hygienic life up at the lake was no protection against the disorder. I have seen the hereditary form develop in three children of one family while they were at the seashore, bathing daily in salt water and living a care-free, active, out-door life, never taking tea, coffee or alcohol and not much meat.
So, I concluded long ago that there must be two kinds of hay fever, one kind curable by diet, bathing and exercise and another kind in which habits of living and eatingmade no difference; and I had seen mostly the other kind.
Now, there may well be cases of hay fever as there are known to be cases of that other anaphylaxis, asthma, that are pure examples of food anaphylaxis. In such a case, detecting the irritating food and removing it from the diet is the proper path to cure. The error in our former practice was to divide foods into good and bad for certain diseases. We should rather think of foods as good or bad for a particular patient.
The plain people long ago crystallized their experience in diet in the maxim that what is one man's meat is another man's poison, but your scientist will never believe anything until he sees it in a test-tube and physicians have kept on a few centuries behind the rest of the world prescribingdietfor all cases of the same disease irrespective of whether or not it agreed with the patient. Witness the rigiddietsfor tuberculosis and Bright's disease. So, inevitably, there had to be adietfor hay fever and equally inevitably, the same diet did not agree with everybody.
Scientific men are fond of stating in scientific terms what everybody else knows already. While we have known for a long time that some foods did not agree with everybody, science is just now demonstrating that one man's meat is literally another man's poison by testing the different food proteins on the skin and calling the conditionfood anaphylaxisorfood allergie.
As the patient reader of the chapter on Pollens will remember, the anaphylaxis or sensitiveness of the patient to particular pollens is tested by rubbing a speck of different pollens into scratches on the skin. This skin reaction as a test of anaphylaxis was used by Schloss with different foods before it was adopted in hay fever; and it has been taken up by the dermatologist also. The dermatologist has long suspected that certain skin diseases, as urticaria, and eczema, are aggravated or produced by certain foods but he has been unable to demonstrate just what foods were at fault. The problem was confused by the fact that he had found no guiding principle. Food that one patient could eat with impunity brought out a beautiful eczema or urticariaon another patient. The uric acid theory was one effort to solve this problem but it was not comprehensive enough and it was not true. Forbiddingnitrogenous foodshas been a favorite formula with some and they straightway advised milk, which is highly nitrogenous. The recent recognition that food sensitiveness is an anaphylaxis and the detection of the foods at fault by the skin reaction may supply the missing guiding principle that was needed to adjust a diet to the individual needs.
The poisonous element in food is the protein. The food itself will serve for the skin test but it is better to use the pure food protein, which gives clearer reactions and avoids contamination. Proteins of all our common foods are now obtainable in the drug trade put up in tiny capsules ready for the test.
The skin is cleansed with soap and water and dried. A number of little spots are denuded of their superficial epithelia by twirling a small brad-awl, which should not scrape deeply enough to draw blood. Most workers speak of scratching the skin but the brad-awl scrapes to the proper depthmore quickly and easily. The spots are marked with the names of the foods to be tested, as milk, beef, potato, oats, etc., and a drop of a five per cent solution in water of the respective proteins is rubbed into the spots. One spot is left as a control, into which normal saline or 3% solution of milk sugar is rubbed, as the proteins of commerce are made up with milk sugar. Within five or ten minutes, there appears a redness and swelling, as with the pollens. As with the pollens, a patient who at any time has been poisoned or, as we now say,sensitizedby any of these foods, still has circulating in his blood or fixed in his skin the reactive bodies to that food. These reaction bodies react to that food on the skin by redness and swelling. Food proteins that cause no redness and swelling are thought harmless for that patient. Foods that cause the reaction are thought to be those to which the patient has been sensitized and to which he has not developed or maintained an efficient defence. There is a contradiction here; for the reaction merely shows the presence of defense bodies in the blood and does not tell us whether that defence is oris not efficient. However, even if the argument limps, the results reported are encouraging. Some striking cures have been reported by simply excluding these foods from the diet. The test is simple and harmless if the scratch is not too deep andif the protein is not injected beneath the skin. If injected beneath the skin or rubbed into a deep scratch, the food proteins, like the pollen proteins, may be dangerous. If they are absorbed rapidly into the circulation of a patient who happens to have been sensitized to any of them, there is serious danger of anaphylactic shock.
If these observations prove reliable, here is a method of selecting a diet for the individual patient that surpasses in accuracy anything that we have ever known. If hay fever is ever a food anaphylaxis, this method of testing the food sensitiveness of the individual patient promises much; but these observations are still too new and unconfirmed and the skin reaction too uncertain to rely on it implicitly yet. There was a time, back in 1908 to 1910, when the skin reaction for tuberculosis too was highly valued. Enthusiasts proposed to test allthe school children and all the soldiers and all the factory workers and segregate the tubercular by the skin test. The diagnosis of tuberculosis was to be put in words of one syllable.
That dream is over. Tuberculin skin reactions have now been made by the million and we know that a positive reaction means nothing but that, at some time, the patient has been infected with tuberculosis. The skin test does not tell us whether he has recovered long ago and built up a good defense or whether he is still sick with tuberculosis and will die of it. It reacts equally well in the healthy, vigorous subject who at one time has had a mild tuberculosis and recovered, in the patient with early phthisis and in the advanced case. In Kraus and Levaditi'sHandbuch der Technik und Methodik der Immunitätslehre, 1911, page 205, von Pirquet himself, the grandfather of all the skin tests, says, "A positive skin reaction indicates with certainty that the organism has been infected with tuberculosis. Of the localization, extent and prognosis of tubercular infection, a positive skin reaction gives no conclusion."Yet hundreds of physicians to-day are making diagnoses of tuberculosis by the skin test; for if there is one thing more difficult than to get a new idea into a doctor's head, it is getting it out again when the idea proves fallacious. So, I view these skin reactions for food and pollens with some suspicion of their real value in diagnosis and prognosis and as guides to treatment. Still, Talbot says, "Experience has shown that when a positive skin test is obtained for a food and that food is then excluded from the diet, the general condition of the patient almost invariably improves and in many instances a cure results." May his words prove true.