Naturally the pre-eminent position in the list of remedies comprehended by the term, serum therapy, must be assigned to antidiphtheric serum or diphtheric antitoxin, which, of all the serums thus far evolved for application in the human being, has earned the distinction of being an absolute and certain specific. In truth, of the multitude of serums for other microbic diseases which have been produced and tested since the epoch in therapeutics inaugurated by Behring's and Roux's discovery, antidiphtheric serum has alone wholly fulfilled the expectations of those who believed a new era in the conquest of man's maladies had been inaugurated. But all the problems relating to this important biologic agent have not yet been solved. Take, for instance, the weighty matter of dosage. Here after some fluctuations caused by the occasional success in obtaining a very high potency serum in the uncommon horse, and the consequent stress laid upon the small dose of serum very high in unitary value, we find the current tending towards larger doses, or, in other words, more massive doses, irrespective of the potency. In several quar

*Read before the Wayne County Medical Society, November 5, 1906.

ters, and more particularly in the splendid results obtained in the Boston City Hospital, the importance of using larger quantities of serum has been demonstrated. It appears, indeed, that for the practical end in view, namely, the cure of diphtheria, a large dose of low potency serum is actually more effective than a small dose of one strongly impregnated with antitoxic power, and there are those who believe that these favorable consequences are due to the presence in antidiphtheric serum of some substance besides the specific antibody of diphtheria which, acting as a complement or otherwise, assists the specific antitoxin in overcoming the disease. My personal observation which began with an experience in producing antidiphtheric serum in the early days of its introduction and which has continued in private and institution practice, inclines me strongly to this view.

"Refined and Concentrated" Antitoxin.

Allied to this question of dosage comes a consideration of antidiphtheric globulin solution, or as it is called in commerce, "refined and concentrated" diphtheric antitoxin, the chief merit of which is said. to be its small dose and a reduction in

frequency of serum reactions. This product which has been known in the experimental laboratory for several years is obtained by treating ordinary antidiphtheric serum after the process devised by Pick, Seng, Atkinson and others, and modified by Gibson. Essentially the procedure is to precipitate with ammonium sulphate, the proteids of antidiphtheric serum. These proteids are collected, dissolved, reprecipitated, then dissolved in saturated common salt solution. Here a separation of proteids ensues, certain globulins, including those carrying the antitoxin, being dissolved in the salt solution from which they are precipitated once more by ammonium sulphate or weak acetic acid. The final globulin precipitate is then subjected to dialysis by which the salts are removed and its solution follows. This solution of the globulins which is reduced in bulk as compared with the original serum. volume, and which contains the antitoxin minus a certain amount lost in the manipulations, after bacterial filtration and the addition of a preservative, is the finished product, and in its smaller volume represents a concentration of the original antitoxic content of the serum. By this treatment one leaves behind serum albumin, the globulins insoluble in saturated chloride solution, the salts and extractives of the serum, and the finished product is a most attractive looking, clear fluid, which, in guinea-pig essays, neutralizes the test toxin just as does the antidiphtheric horse's serum.

Waiving the matter of volume in dosage which, after all, is of little significance to the physician skilled in serum injections, comes the vital questiondoes this this solution solution of antidiphtheric globulins represent all the curative substances residing in the native horse's serum and essential for combating diphtheria in man in all its clinical manifestations, including the various forms of mixed infection. Or, to put it otherwise,

will globulin antitoxin endure the test of time and usage in an enormous number of cases which antidiphtheric serum has so splendidly withstood? If so, and if by its use, the frequency of serum sequels can be somewhat reduced, it should ultimately replace the whole serum as now employed.

Antitetanic Serum.

As for antitetanic serum, it must be reluctantly confessed that the beguiling promises of the laboratory have not been upheld at the bedside of the patient afflicted with lockjaw. The specificity of this serum as tested on laboratory animals is demonstrable by the same beautiful accuracy as obtains with antidiphtheric serum, but when man is infected by the tetanus bacillus to a point at which symptoms show, his organism is apparently overwhelmed by the deadly tetanus toxin to an extent prohibiting neutralization by antitetanic serum how

ever

administered, and by however heroic a dosage. Offsetting its therapeutic failure, however, is the certainty of its success as a prophylactic, and the vast importance of using subcutaneous immunizing doses of this serum in cases of suspicious wounds, and of dusting the dry powdered serum locally cannot be overstated.

To American physicians who have felt the desirability of some uniform measure of value of commercial antitetanic serum, it will not be unwelcome news to learn that the Hygienic Laboratory of the U. S. Public Health and Marine Hospital Service is about to establish a standard, which will be for tetanus serum the same guarantee of uniformity that their official or Standard Unit is for all antidiphtheric serums admitted to interstate commerce.

Utility of Antistreptococcic Serums. Antistreptococcic serums, of which several are found in commerce both in the United States and in Europe, cannot be said to have fulfilled the original ex

pectations of their therapeutic efficacy. Furthermore, there is much variation in the different brands found on the market, both in their behavior in laboratory tests and in their use at the bedside. I cannot here discuss the very inviting subject of animal tests of antistreptococcic serums, or point out what in my estimation is the absurd futility of attempting to gage the therapeutic value. of these serums in human infections by mouse, rabbit or guinea-pig experiments. But appraised by the supreme trial of any therapeutic agent's serviceablenessthe results of its clinical application one must admit that for certain at least of the products now found on the market, evidence is strongly in favor of their usefulness in various streptococcus infections whether primary or secondary. From what I have individually seen during the last year in the trial of a certain antistreptococcic serum, and from what has come to my personal notice of the written or verbal testimony of competent medical men, I cannot escape a conviction as to its therapeutic value in such affections as scarlet fever, acute and chronic rheumatism, various local or regional streptococcic infections including acute otitis media and mastoiditis.

In

the streptococcus mixed-infection of phthisis, a curious contradiction exists in the extreme enthusiasm of one group of reporters and the unqualified dissent of another. A similar incompatibility is found in recent German literature concerning the value of antistreptococcic serum as a prophylactic against infection in extensive surgical operations, either in conditions in which pre-existing infections are likely to be aroused to further activity or where the extent of operative mutilation predisposes to infection.

But with what we know of our helplessness in the fact of many infections with the streptococcus, and since biologic therapy has not yet offered, at

least for acute streptococcic diseases any remedy except antistreptococcic serum, physicians should, I believe, allow themselves to be swayed by the clinical testimony thus far adduced, and give their patients the benefit of such doubt as may exist, administering antistreptococcic serum in sufficient doses to permit a fair trial.

Serum Therapy of Pneumonia.

Of antipneumococcic serum it may be said that the status is one of uncertainty much more pronounced than regards the antistreptococcic serums. That this should be the case must cause profound regret on the part of every physician who realizes that croupous pneumonia heads the list of fatal acute infections

during the cold season in our north temperate zone, and that it chooses indiscriminately young and middle-aged robust adults in all walks of life. Today one hears little or nothing about several serums for pneumonia proclaimed in Europe on the basis of laboratory experimentations and a limited trial in hospital and private practice. Perhaps the same fate may await a report which I possibly may make in due time of an antipneumococcic serum which has been produced under my direction, and which was given preliminary clinical trial last spring in Detroit through the kind cooperations of several operations of several local physicians, and in three of the leading hospitals of Chicago.

My own verdict on these tests of the new serum for pneumonia is-satisfactory but not conclusive. Satisfactory is a justifiable report in that no untoward or harmful effects were noted, though considerable amounts of serum were used in several cases, intravenous injection being practiced in the most urgent ones, and, further, some astonishing and rapid recoveries, quite out of accord with what one might expect to see in the ordinary course of cases of pneu