Chapter IV: Part 4

The second group, or those showing a leucopenia throughout their course, was by no means an unusual thing. This is a cardinal point—in fact, one of the most striking clinical features of the epidemic. The leucopenia here does not have the prognostic value that it seems to have in the group just referred to previously. We have observed cases go through a pneumonia with 4,000–5,000 white cells in a relatively easy manner. When, however, the leucocytes fall to 3,000 or under, one may be reasonably sure that the outcome is doubtful, even with the general condition of the patient at the time favorable. In the pneumonias of this group which died the leucocytes have always fallen to about 2,000 cells. We have a number of observations taken from one-half to four hours before death showing counts in the immediate neighborhood of 2,000, but never below this number. Where recovery has taken place the cells go forward to the normal, more or less keeping pace with the general clinical picture.

Of group three there is not much to say, except that on one hand it tends toward a leucocytosis, and on the other to a leucopenia. This group comprises a considerable number of the pneumonias. We are not in a position to say anything regarding the relative mortality of this group. The development of a leucopenia from these cases after a period of some stability in the leucocytic curve is of bad prognostic import. Not infrequently we have noticed rather wild abrupt rises to 20,000 in the leucocytes toward the late half of the disease. This curve was nearly always sustained until the end, which, as a rule, was recovery.

We do not need to consider at any length the effect on the leucocyte count of complications not of lung origin. Acute sinuses in head, otitis media and meningitis always produced a variable moderate leucocytosis. The change was not so marked in meningitis, as our cases were all preceded by a pneumonia which had independently invoked a slight leucocytic response. As a complication of the pneumonia we have noted an abrupt rise following an acute pleuritis with effusion, and similarly after the onset of an empyema. These complications seemed to be able to induce a leucocytosis with more certainty and ease than the more serious pneumonic condition. Possibly, as they occurred toward the end of the infection, the toxic factor of the epidemic influenza was more or less spent, and the secondary invader had a freer hand to act in its normal way.

Differential counts were made in 194 cases, including influenza, influenzal pneumonia and influenzal complications. We have taken the average percentage of each type of cell for the groups, which are purely numerical divisions based on the leucocytic count. No differentiation is made for the various clinical divisions of the epidemic in the following table:

LEUCOCYTES 2,000–8,000.
P. E. L.M. S.M. Trans.
Total counts 86 66% 1% 13% 17% 3%

LEUCOCYTES 8,000–10,000.
P. E. L.M. S.M. Trans.
Total counts 33 69% 1% 11% 16% 3%

LEUCOCYTES 10,000–20,000.
P. E. L.M. S.M. Trans.
Total counts 45 76% 2% 10% 19% 3%

LEUCOCYTES 20,000–30,000.
P. E. L.M. S.M. Trans.
Total counts 17 79% 2% 8% 7% 4%

LEUCOCYTES 30,000–40,000.
P. E. L.M. S.M. Trans.
Total counts 13 85% 1% 5% 6% 3%

The differential count in general indicates an increase in the polymorphonuclear leucocytes as the total leucocytic number increases. This is really what one would expect. There also seems to be an increase of the large mononuclear cells, with a slight diminution in the small mononuclear elements, particularly in the count below 10,000. Abnormal cells were encountered very seldom. One can hardly say that the epidemic has a characteristic differential blood picture, except, perhaps, that an increase of the large mononuclears is present in the low counts. This, however, may hold true for any leucopenia.

_Conclusions_

1. Epidemic influenza is often accompanied by a transient slight albuminuria with a few red blood cells and casts. Acute nephritis as a clinical entity does not appear to be other than a rare sequel.

2. Epidemic influenza tends to produce a leucopenia.

3. A leucocytosis in influenza, as a rule, indicates a secondary infection.

4. The pneumonia following influenza shows, as a rule, but a very moderate leucocytosis, while, on the other hand, the presence of a leucopenia is by no means infrequent.

We are greatly indebted to Miss R. Thompson, Messrs. Mock, Frost, Marshall and Scott for their assistance in this work at the Magee Hospital.

THE TREATMENT OF INFLUENZA

By W. W. G. MACLACHLAN, M. D.

One may frankly say there is no specific treatment for influenza. Possibly we are in error in introducing the discussion, particularly on treatment with such a definite and unsatisfactory conclusion. The same statement has been made after all the previous pandemics, and one wonders whether a like remark is going to apply to the next similar scourge. The past two or three months should bring to the medical profession a certain humility which should stimulate a keener sense of research, especially as we now have at our disposal highly organized laboratories where unsolved problems can be viewed from almost any angle. Yet we are really, save here and there, putting our forces together in the study of the disease. It is obvious that a fleeting epidemic makes a most difficult subject for study, especially during a time when there is a paucity of physicians. May we not hope, however, that some researches on the disease may be forthcoming, so that we may safely feel that at least preventive or protective measures will be possible?

There is no one who is able to say that this or that drug has not been thoroughly tried. The alkalies, salicylates, antipyretics, quinine and the sedatives have all been freely used in the last as well as the present epidemic. Each group of drugs has its following, although it appears to be a general rule in this epidemic to use the antipyretics (coal tar products) as little as possible. From the distant past we have numerous records of treatment. Willis (1658) emphasized the value of sweating and the use of diaphoretics, but at the same time he states that in mild cases the cure is left to nature; Sydenham (1675) claimed considerable value in fresh air. He also paid more attention to restricting the diet, and was not favorable to the use of anodynes. One certainly obtains the impression from the records of past epidemics that many of the general principles in treatment were similar to what are now in vogue. Medicinal remedies, of course, varied greatly, but to enumerate them would be merely giving a résumé of the progress of therapeutics. Sufficient is it to say that influenza has certainly, since the earliest days, given therapeutists an ample opportunity to test their wares.

The outstanding respiratory complication, pneumonia, has added a very undesirable phase to the disease. In fact, the greater part of the mortality was due to this serious sequela. Some interesting points have been brought out in serum and blood therapy for this type of pneumonia. The use of whole blood or serum from convalescent patients in cases of pneumonia opens up a new and not unlikely fruitful means of treatment. The method of treatment possibly may be applicable as an emergency measure in other diseases, as has been shown in the case of scarlet fever and poliomyelitis. We also have the anti-pneumococcic sera available for therapeutic use. The drugs and the general treatment of the pneumonia are virtually the same for the last two epidemics.

The protean manifestations of the 1890 epidemic, with its unusual nervous sequelæ, have not been seen to any extent, as far as we yet know. In fact, the present epidemic appears to be relatively free from complications other than those occurring in the lung during the acute course of the disease. Hence, in all likelihood, there will be less of the nervous after effects to be treated. It is, however, too early to hope that the nervous system is going to escape.

In another part of this volume the vaccine therapy is discussed in detail, so that we shall not repeat what has been brought out in that article. We would, however, emphasize the value of honest and accurate clinical reports of the use of vaccines, in order to establish their present status in epidemic influenza. Overestimation and commercialism are very likely to ruin a method of treatment, even when it may be of value in a certain phase of the disease. If we do not carefully weigh the pros and cons of the vaccine treatment in this epidemic from a purely scientific and coldly neutral attitude, we are simply doing the public and ourselves an injustice.

The treatment of influenza as the disease presented itself to us in this community will be considered under three divisions—acute influenza, pneumonia, and other complications.

_Acute Influenza_

There is one important thing to be done in the treatment of influenza, whether the infection be mild or severe. Have the patient go to bed as soon as possible. In most of the acute attacks the individual went to bed of his own accord; but there were, unfortunately, too many instances where the patient refused to surrender, trying, as we say, to fight the attack. Some appeared to be able to accomplish this feat. But how many of our cases of fatal pneumonia can be clearly linked up with this group of the mild or subacute preliminary course? No matter how light the attack may appear to be, the patient should be told of the necessity of remaining in bed until the pulse, respiration and temperature have returned to the normal and remained normal for at least five days. At the onset a hot bath, with care to avoid chilling, followed by a drink of hot lemonade and a Dover’s powder, gave considerable relief to the patient.

The value of good nursing cannot be overestimated. The nurse must see that the patient is always well covered and kept warm, not even permitting him to rise in bed to reach for a drink; also the regulation of the temperature of the room should be carefully watched. The main point is to have plenty of fresh air. We have noticed that the patient appeared more comfortable if the air was slightly warmed. Water should be given at regular intervals. Under no consideration should an acute influenza case be allowed to get up to go to the toilet.

At the onset, and while the febrile attack is still present, there is little desire for food—but one does not need to worry about the question of nourishment in such an acute illness. Milk, cream, cocoa, gruels and fruit juices may be given at first, and as the fever subsides the diet increased. We have found that the appetite returned to normal very readily. In view of the urinary findings indicating a slight transient nephritis, meat broths are to be avoided until the convalescent stage is reached. We have been very guarded in recommending cold sponging in acute influenza. As a rule, it was not necessary. The icebag to the head is often of great value in the intense headache, which is so frequent. It is our opinion that in the treatment of uncomplicated influenza what has just been mentioned constitutes the important part. Most physicians would agree with this. However, when we advance to drug therapy, we come into the personal realm of likes and dislikes of drugs and methods of usage.

We do not intend in any way to give our views in a dogmatic manner, nor to touch upon all of the remedies that have been advanced. At the onset of the disease a moderate calomel purge, followed by a saline, was given in all cases. We were practically free from the so-called intestinal type of influenza which was seen in some other communities, consequently we did not hesitate to use calomel. Castor oil or magnesium sulphate was given afterward, as was found necessary. Abdominal distention was rarely seen, and when it occurred a plain soapsuds enema with turpentine was administered.

Quinine sulphate (gr. iii-v, three times a day) combined with phenyl-salicylate (gr. v) was a routine measure. We often noticed deafness after a very few doses of quinine. It was then discontinued. Acetyl-salicylic acid (gr. v, three to six times a day) seemed to have a palliative effect on the severe headaches, although during the height of the disease the general muscular aching did not appear to be relieved by its use. It was not used routinely. These drugs possibly made the patients more comfortable, but we were very skeptical as to their influence on the general infection. The raising of the leucocyte count by quinine in influenza appears very unlikely. The use of alkaline salts has been a general procedure, particularly as we are now on the alkaline wave of therapeutics. Sodium bicarbonate was added to the drinking water of all patients (two drams to the quart). We gave this salt for its diuretic effect. In a few cases more active diuresis by the alkalines was readily and easily produced by the use of “imperial drink” three or four times a day. We felt that good kidney elimination was of considerable importance.

The use of tartrates and citrates, as in “imperial drink” in a condition where we know some kidney impairment is present, is possibly flying in the face of danger—especially in view of the fact that these salts are so available in the production of experimental nephritis. But we have only to see their application in the human in mercury bichloride poisoning, where an intense nephrosis usually develops, to fully realize that these salts may be given without danger to the kidney. We do not suggest that the kidney lesions of influenza and mercury bichloride poisoning are the same. We are merely bringing out this point of analogy in support of their use in certain desirable cases.

The respiratory symptoms gave us more concern than any other phase of the uncomplicated case. The irritating, distressing, non-productive cough suggested both a sedative and expectorant. Ammonium chloride (gr. iii-v, t. i. d.) was the usual expectorant. It seemed to increase in value with the more chronic type of case. It is our impression with those acute hacking coughs that the sedatives produced more gratifying results. Elixir terpin hydrate with heroin, codeine and occasionally morphine were preferred. When good results were noted sedatives were given liberally. Steam inhalations combined with tr. benzoin co., followed by spraying the throat with medicated liquid petroleum, gave some relief. The tendency to œdema, however, as we saw it in the cases complicated by pneumonia made us hesitate to use inhalations. Possibly the fear was groundless. Morphine (grs. ⅙) was given for sleeplessness, and it was repeated if necessary.

Cardiac stimulants were rarely needed. The tincture of digitalis was the choice, but in the uncomplicated cases was very seldom used.

At the beginning of the epidemic we prescribed whisky in almost every case. Our idea was that it would have a sedative action. At the present time we are very doubtful of its value. Toward the end of the epidemic we used it very moderately. The results obtained possibly depended for the most part upon the type of patient. Some of the soldiers asked to have it discontinued, not from any moral point of view, while others wished more frequent doses. The elderly patients seemed to appreciate this remedial agent to a fuller extent.

_Pneumonia_

The pneumonia following the original infection was, from the standpoint of physical diagnosis, often difficult of diagnosis in its early stages. The infection commencing as an influenza would at times pass imperceptibly into pneumonia, and obviously the points brought out in the previous paragraphs on treatment were applied until the diagnosis of pneumonia had been established. Some new factors were peculiar to the pneumonia and demanded further changes in the handling of the cases.

We would again emphasize the value of careful nursing to conserve the patients’ strength. They should be kept warm, well covered, with plenty of fresh air. Water should be given regularly and abundantly. The diet should be light, one depending a good deal upon the severity of the case. We believe it is safer to limit the diet to fluids while the infection is still pronounced, but as soon as the crisis has passed one may increase the diet freely and fairly rapidly.

Regular elimination from the bowel should be helped by the use of castor oil every other day, the dosage made to comply with the patient. We noticed much less abdominal distention in this form of pneumonia than one is accustomed to see in the ordinary lobar pneumonia. If distention were present, plain soap enemas with turpentine gave very satisfactory results. Turpentine stupes also are of considerable value. Rest at night is needed. When a hypnotic was necessary we gave morphine (gr. ⅙), and repeated if the desired results were not obtained.

The day is coming when we are going to isolate our pneumonia cases. This was almost an impossibility during the stress of the past epidemic, but we know that temporary and fairly satisfactory methods can be applied. Many hospitals provided for a type of isolation. In a pneumonia ward sheets stretched between the beds keep the fine spray which a heavy cough always produces from spreading over the next two or three beds. This method is simple and can be easily carried out. We feel almost certain of having seen convalescent influenza cases develop pneumonia from the adjacent pneumonia patients. As much as is physically possible, the uncomplicated influenza and the pneumonia cases should be separated. Further, it is to be kept in mind that reinfection by another group of pneumococcus is quite possible, even in a ward containing only pneumonia patients.

We did not observe any special effect of quinine, salol, salicylates after the pneumonia had developed and, therefore, these drugs were discontinued. Digitalis in the form of the tincture was at first made a routine measure, but toward the middle of the epidemic we stopped this routine usage and gave it only as it appeared to be indicated. Our impression was that the heart was not involved as it is in ordinary pneumonia. A slow, full pulse, as was so often the rule, did not seem to require digitalis. For more rapid action of the drug one of the hypodermic digitalis preparations or strophanthin was given.

Caffein sodium benzoate or salicylate seemed to be of considerable value given hypodermically every two or three hours, the last dose at 4 P. M. Its action as a respiratory stimulant and also as a diuretic was what we desired to obtain. The drug was used fairly early in the pneumonia, and although it was never prescribed routinely we gave it frequently.

Atropine was indicated whenever signs of œdema were evident. Its action was not always successful, but in certain severe cases we believe that large repeated doses of atropine saved a few lives. One-fiftieth (1/50 gr.) grain hypodermically, repeated every hour for several doses, was usually well borne. We noticed twice in each of two cases after using small doses (1/100 every four hours) a peculiar rapid cyanosis not associated with dyspnœa develop. This reaction remained, however, for only a short time, about 15 to 20 minutes, but it was rather alarming while it lasted.

The drug therapy is not very satisfactory in lobar pneumonia, and it is less so in the form of pneumonia which follows influenza. There is practically nothing essentially new in the drug and general treatment of this serious complication over what was shown in 1890, or even in the earlier epidemics, save that our nursing and hygienic measures are undoubtedly better.

The addition of an immune serum (anti-pneumococcus serum No. 1) to the treatment of pneumonia is a milestone in the history of the handling of this disease, but we must keep in mind that the pneumonia of the past epidemic was not the usual pneumococcic lobar pneumonia. That the pneumococcus was present in a great many cases is shown in another article of this series, but we also know that the B. influenzæ was present in many, and that it played an active part in the disease is evidenced by the constant low blood count or actual leucopenia. A leucopenia in true lobar pneumonia is most unusual in the United States. The rarity of Type I pneumococcus was noteworthy. We were practically unable to get any anti-pneumococcic serum which was known to be of value at the time of the epidemic, so naturally could not apply this method of treatment as was desired. About half a dozen 50 cc. bottles were in possession of the army medical officers here, but they unfortunately could get no further supply after this was used. We would have liked very much to have combined the anti-pneumococcic serum in Type I cases with the citrated convalescent blood, as was used by us during the epidemic. The anti-pneumococcic chicken serum of Kyes should also be considered. This serum has had but a very localized trial, but from competent observers who have given it to a considerable extent in some of the army camps we are led to believe that it has a very definite value. Major Lawrence Litchfield informed the writer that he had observed excellent results with Kyes chicken serum during the past epidemic in the treatment of pneumonia. This serum was not available for our use. It is to be hoped that further experience with Kyes serum will be favorable, because from the practical standpoint in the treatment of pneumonia it has many commendable features. Again, we desire to point out that the use of anti-pneumococcus sera in influenzal pneumonia may not be a fair test of their true value.

Very early in the epidemic we realized that the pneumonia was of unusual severity and most difficult to treat satisfactorily. We were at once impressed by our helplessness, particularly in those patients showing cyanosis. Nothing we did seemed to vary the course of the pneumonia after this sign was evident.

Our work in the epidemic began about October 10 on receiving a large batch of soldiers, about 100, from the Student Army Training Corps of the University of Pittsburgh. At the end of the first week several points were impressed on our mind. Firstly, in the severe cases of pneumonia; and in the early part of the epidemic most of the pneumonia was severe, the mortality was excessive, much higher than we have been accustomed to experience in Pittsburgh, where, as a rule, our hospital ward pneumonia is a very severe infection. Secondly, the wide variation in the severity of the epidemic as presented in the student soldiers coming from identical surroundings and conditions, the mildness on the one hand and the malignant character of the influenza on the other, was a very striking feature. This led to our adopting a form of treatment which was quite successful.

We worked purely on the hypothesis that those individuals recovering from a mild or moderate influenza infection developed a higher grade of immunity than those in whom the disease was more severe or fatal, and this immunity could be transferred to another. This, of course, was merely inference. If the mild cases did present a higher immunity, one would naturally think that immune bodies would be present in the blood, and that in transfusion from cases which had recovered one might have a measure of therapeutic value for this epidemic. Recently Spooner, Scott and Heath and others have demonstrated specific agglutins in the serum of patients convalescing from the epidemic. On October 17 we gave whole citrated blood from a convalescent case of uncomplicated influenza to an influenzal pneumonia patient. The result in this case was strikingly good, and for the following five or six weeks this method was frequently used. We decided to give the whole blood instead of the serum, as we were able to treat the cases more readily and rapidly in this way. Our method of transfusion was, fortunately, very simple.

We had treated but a few cases when the report of McGuire and Redden appeared. These observers working in the Naval Hospital at Chelsea, Mass., presented very excellent results in the use of immune serum from convalescent influenza cases in the treatment of pneumonia. They reported 30 recoveries out of 37 cases, with 1 death, and 6 cases still under treatment at the time of their report. This form of treatment began at Chelsea on September 28, 1919. In Texas, on October 15, Brown and Sweet gave two cases of influenzal pneumonia citrated blood from convalescent influenza patients. Their two cases recovered. Our published results, although not showing such excellent figures as from the Chelsea observers, agree very well with their work.

Since that time a number of confirmatory reports have been brought forward. Ross and Hund have shown that this method has been of value in their hands, and recently a further statement from McGuire and Redden tends to confirm their first views as to the value of immune serum from convalescent patients. Their last report giving a mortality of 6 in 151 cases of pneumonia cannot be other than positive proof of the value of this method of treatment.

As the technical side of the work has been given in several articles, we hardly think it necessary to again review it in detail. A few phases should, however, be recalled. It would seem that either serum or the whole citrated blood may be used. Solis-Cohen and his group of workers believe that whole blood has stronger bactericidal properties than defibrinated blood or the plasma. But yet one cannot complain, even on a theoretical basis, against the results obtained with serum by McGuire and Redden. The use of whole blood increases the detail of the procedure, in that the agglutination reactions must be estimated. Unfavorable results in this regard also naturally cut down the supply of available donors. In a military hospital a dearth of donors does not arise, but in civilian practice the problem is very different. In our work we never gave more than 100 cc. of whole blood; usually the amount varied between 50 cc. and 75 cc. On account of the small amount we felt that isoagglutination would not be a serious factor, and in more than 200 injections we failed to see any evidence of ill results from this source. Giving up to 500 cc., as was done by Ross and Hund, is probably a different affair, and accurate agglutination tests are essential. We feel that if the case is treated sufficiently early in the disease as much good can be shown to occur after 50 cc. as after 100 cc. of blood. We do believe, however, that the pooling of sera, where one is able to carry out this method, as it means a liberal supply of donors, is really the method of choice. Syphilis must be ruled out, both clinically and serologically.

As we emphasized previously, the problem presented in the army hospital and in civilian practice is a little different. We have had some experience with both sides. Fortunately, the greater part of our work was with the Student Army Training Corps, where army conditions were more or less carried out. There was never any difficulty in getting donors. In fact, the idea of giving blood appealed to these young fellows. In civilian life it is, in our experience, a more difficult problem. The usual personnel of the public ward has always its fair percentage of positive Wassermann reactors, and the type of individual is quite different from the young soldier. For a relative or friend we could easily get a donor, but this group would cover only a small percentage of the cases one wished to treat. The technique of giving blood can be reduced to a very simple procedure, and by no means should be regarded as a difficult surgical undertaking. Combining the receiving apparatus of Ross and Hund (J. A. M. A., 72, 1919, p. 642) with the syringe method for giving the blood which we suggested in our previous article makes an ideal arrangement.

The results depend upon the time of treatment. The earlier the pneumonia is recognized the better are the chances of recovery. It is our belief that the majority of influenza cases which kept a fairly high temperature for more than four days had a lung lesion, even if we could not make out definite consolidation. As the convalescent influenza serum may have value only for the influenza infection, it would, therefore, appear but logical that a late pneumonia which almost always has other organisms present would not react as favorably. We have seen very few of the deeply cyanotic type recover even with serum. The essential rule is to treat them before this stage develops.

We have observed little or no change in the leucocyte count, even after successful treatment, and taking our group as a whole we are rather surprised at this result. Other observers have noticed a marked increase in the leucocytes as the case reacted favorably to the injections. We agree with McGuire and Redden that the patients with counts below 10,000, as a rule, show the best results. This possibly indicates that the influenza infection is predominating, and that the usual secondary invaders (pneumococcus and streptococcus) are at this time playing but a little part. Hence the value of early treatment is apparent.

From the published results of different workers and our own experience, we feel that influenza immune serum or whole citrated blood given early in the pneumonia is of undoubted value—in fact, almost specific. If the epidemic reappears next year, unless some other better method is forthcoming, we would advise its more general use, and would suggest the collection of pooled serum as early as possible in the epidemic.

At the end of this article there is appended a series of our ward record charts of patients who developed pneumonia following the influenza. These charts are shown to indicate the results of giving immune convalescent citrated blood in pneumonia. The ones presented are from some of the group which recovered. We have, of course, the charts from the fatal cases, but as they do not bring out any special point, save that there was little or no change after treatment, we are omitting them. It is not our idea, however, to give the impression that we have had nothing but success with this method of treatment. It might be well to emphasize some of the salient points which are brought out.

(1) The regularity of the drop in temperature after the injection is almost generally demonstrated.

(2) The occasional chill following the injection seemed to have no untoward results.

(3) The leucocytes show, as a rule, little or no variation after transfusion. Our work agrees with McGuire and Redden’s statement that the cases with a leucocyte count under 10,000 give the best results with immune serum.

(4) The time of injection in many of the cases was by no means ideal, in that the disease was advanced; and again in many the injection should have been repeated sooner. This, however, is no fault of ours.

(5) One injection of 50 cc. of citrated blood from a good donor, if given early enough, may be all that is necessary. Several charts bear out this statement.

(6) The day of disease is dated from the onset of the influenza. The demonstrable signs of pneumonia correspond roughly to the initial rise in temperature following the influenza. The day of disease of the pneumonia is not indicated on the chart, as this information we have obtained from the daily notes.

_Complications_

The epidemic was well spent before we observed many complications, save those referable to the lung. Later various forms of sequelæ have been appearing. One must guard, however, against the danger of attributing all of our ills to the past epidemic. We are not going to give in detail the treatment of these various conditions, nor even mention all of the many complications. The main points, however, we desire to emphasize.

We have previously considered pneumonia, which is the principal complication with simple influenza, and the two are closely allied. As an end result of the pneumonia, non-resolution and fibrosis of the lung are of first importance. We cannot say very much on the treatment of this condition. The duration varied from a few to several weeks, and recovery was infrequent. Our treatment aimed at supplying as much nourishment as was possible to give, with, in addition, good nursing. The treatment otherwise was purely of a general hygienic type. Tepid sponging appeared to give considerable relief from the profuse sweating these patients so often had. Drugs were of value only for some local effect. We wonder if carefully handled vaccine therapy at the onset of such a complication might not prove of some value. The autogenous would be the one of choice.

Empyema was not found to be as prevalent as one would imagine. With so much non-resolution of lung following the pneumonia we were surprised to see so little empyema. All delayed resolutions we explored with the needle, so we feel that the condition, if present, would have been recognized. The treatment of empyema need not be given any special emphasis. It is, as of old, a surgical affair. One or two new points in the technique have been brought out in the way of drainage, but possibly they have not been sufficiently tried to lay any stress upon them at present. Dakin’s solution in certain chronic cases appeared of value. Our empyema cases did well.

Pleurisy with effusion was observed a number of times, although it has been our experience to find a very few large effusions. Pleural puncture often gave negative results, even when the signs did appear to indicate the condition. We aspirated the fluid when present. The end results were always good. In only one case did we have to repeat the aspiration for reaccumulation of fluid.

Chronic bronchitis, accompanied at times with considerable dyspnœa, has been seen on several occasions. There is very likely associated with this condition some fibrosis of lung, and probably some organization of small bronchioles themselves. Expectoration has been variable, profuse or scanty, mucoid or purulent. We consider rest in bed, with as full a diet as possible to build up the general condition of the patient, the best form of treatment. These cases had little or no temperature, and consequently at first absolute rest was not considered necessary, but we now regard it as the essential part of the treatment. Atropine and heroin are of value at certain times. We confess to have seen very little benefit from the expectorants. We are rather surprised that this sequela is not of more frequent occurrence.

Phlebitis, in our series usually of the formal vein, occurred about as often as it does in typhoid fever. The end result, however, is much better than in typhoid. We have seen only one case where “the milk leg” has resulted. Rest and elevation of the limb were all that we required. In the acute stage, if pain was present, a light, carefully applied icebag was added. It is important to rest the limb for at least two or three weeks, and to caution the patient against remaining on the feet too long for some weeks after recovery.

We saw a great deal of acute sinus infection, often occurring even while the attack of influenza was present, but, as a rule, this complication followed the attack. At times several weeks intervened. The ethmoidal sinuses are most susceptible, but a considerable number of acute frontal sinus infections were noted, the latter often immediately following or occurring during the acute period of the influenza attack. The majority of these infections appeared transient, and disappeared with a little local treatment. In fact, in frontal sinusitis cold applications seemed to be all that was necessary. With some of the more chronic infections nose and throat surgery has been followed by relief of symptoms. Acute suppurative otitis media, considering the number of influenza patients, was not common. Ear drum puncture was done if necessary. We saw one case of acute mastoiditis develop. The mastoid process was opened and drained.

Acute suppurative meningitis, following or associated with pneumonia, appeared on three occasions. The pneumococcus was cultured from the spinal fluid in all cases. Anti-pneumococcus sera intraspinally (Type I or the Kyes serum) should be given. The Type I serum is of value in a similar group infection. We have had no experience with this method, but some recoveries from pneumococcus meningitis have been reported after the early use of serum given into the spinal canal.

Following the 1890 epidemic cases complaining of blindness or partial loss of vision, with optic œdema or neuritis and a glycosuria, were occasionally observed. We have seen one of this type, and several transient glycosurias without eye signs or symptoms. The glycosuria may be of nervous origin. Our method of treatment was one of elimination and rest. The gastro-intestinal tract was emptied with calomel, and afterward a morning saline was given for a few days. Hot packs were administered, one a day for about two weeks. The patient was instructed to drink as much water as possible, and we eliminated sugar, bread and the 20 per cent. vegetables from the diet. The glycosuria lasted for three days, while the vision, although beginning to improve at once after treatment, took five weeks to return to normal. The patient was kept in bed for three weeks. How long the glycosuria had been present before admission to the hospital we do not know. The transient glycosuria group without the eye manifestations required very little treatment. They also showed a transient hyperglycemia. A carbohydrate free diet very rapidly cleared up these cases. After a time we decided to watch the course of this group on a non-restricted diet, even with sugar, and we found that they all returned to normal (blood and urine), in a few days clearly indicating their transient nature. We do not regard this process as a diabetes mellitus. We do not give the hot packs, although free elimination by bowel was attained in all. These cases were recognized only through routine urine examination.

Furunculosis with a high blood sugar, in one case 0.41, without glycosuria was a very interesting complication. We saw a great deal of furunculosis, always with the increased blood sugar from 0.2 to 0.3, but never with glycosuria. Reducing the carbohydrates, or even a fast day with good intestinal elimination, had excellent results.

Neuritis and general debility have often been associated with nasal or tonsilar infection, which when surgically corrected led to the disappearance of symptoms and improvement of health.

Finally, we wish to refer to an isolated case of acute osteomyelitis which was incised, and from the purulent fluid present in the bone B. influenzæ was grown in pure culture. This is a very unusual complication, and is of particular interest on account of the positive bacteriological finding. The patient made an uneventful recovery.

McGuire and Redden Jour. A. M. A., 1918; lxxi, p. 1311. McGuire and Redden Jour. A. M. A., 1919; lxxii, p. 709. Brown and Sweet Jour. A. M. A., 1918; lxxi, p. 1565. Ross and Hund Jour. A. M. A., 1919; lxxii, p. 640. Spooner, Scott and Jour. A. M. A., 1919; lxxii, p. 155. Heath Maclachlan and Fetter Jour. A. M. A., 1918; lxxi, p. 2053. Heist and Cohen Jour. Immunol., 1918; iii, p. 261. Kyes Jour. Med. Res., 1918; xxxviii, p. 495.

THE PREVENTION OF EPIDEMIC INFLUENZA WITH SPECIAL REFERENCE TO VACCINE
PROPHYLAXIS

By SAMUEL R. HAYTHORN, M. D.

INTRODUCTION

In developing practical measures for the prevention or control of influenza epidemics, preventive medicine faces one of the most difficult problems of modern times. By means of quarantine, protective vaccination and instructions in personal hygiene many of the diseases which formerly ravaged the world have been brought under control. At first glance it would seem to be a simple matter to apply the principles which we have found successful against these diseases to influenza and let it go at that, but in the recent epidemic many of the formerly successful measures were tried and found to be either inefficient, inapplicable, or at least of doubtful value.

During the pandemic there was little time to think collectedly, and no time to analyze procedures, and even now it is far from easy to determine what things were done wisely and what things were of no practical value. There exists the greatest difference of opinion as to what measures should again be used when the need arises, and what ones should be discarded. For instance, there are confirmed exponents of prophylactic vaccines, and equally able men who are convinced of their uselessness; enthusiastic advocates of the face mask, and almost as many objectors; those who would close schools, churches, theatres, etc., and those who claim that such measures serve only to prolong the epidemic. One naval officer is said to have stated that he had accumulated figures either to prove or to disprove the usefulness of any preventive measure yet recommended. There is, in short, a chaos of opinions with followers who vary from the one extreme of believing there is “virtue in all things” to those of the other extreme who state that every susceptible person develops the disease in the degree of his susceptibility, regardless of any and all preventive measures used. While there remain so many points on which definite, concrete knowledge is lacking, and so much controversy over the relative value of various measures, this paper can do little more than state the facts and discuss their bearing on prevention as impartially as possible.

Great progress has been made in controlling contagious diseases in recent years—a fact which can be easily verified by anyone who will compare the sick reports of the Great World War with those of any war previous to the beginning of the present century. The diseases which have been most easily controlled have been those against which prophylactic vaccines or prophylactic sera have been developed. Smallpox, dysentery and typhoid fever have lent themselves readily to control by protective vaccination, while reliable temporary immunity can be afforded by the administration of sera for protection against diphtheria and tetanus. These are by no means all, but are probably the most striking illustrations; and with such examples before us, the greatest hope for the prevention of influenza apparently lies in the development of a prophylactic vaccine against it.

_History of Prophylactic Vaccination in General_

The name vaccine came from “vacca,” or cow, and was originally applied by Jenner (1796) to the virus taken from cowpox pustules for prophylactic inoculation against smallpox. It has come to be loosely applied to all forms of preventive inoculations except sera. We have, therefore, a variety of vaccines which differ in their nature and method of preparation. Some are produced by growing the virus in insusceptible animals, some are composed of attenuated viruses, and most common of all are the bacterial vaccines, sometimes called “bacterins,” which are prepared from killed cultures of bacteria. Sera are used in prophylaxis, as well as treatment, and are made by bleeding and separating off the serum from animals which have been immunized against the cause of the disease in question. Sera and vaccines are wholly different products, and the distinction should be made in discussing them, although there is a common tendency, particularly among lay writers, to use the words interchangeably. Smallpox is the classical example of a disease which can be completely controlled by universal vaccination. The parasite causing smallpox has never been certainly demonstrated, but over a century ago Jenner showed that cowpox, a localized, non-fatal disease, protected against smallpox. Modern methods have proven that a cow inoculated with smallpox virus develops cowpox, and that thereafter the virus loses its power to produce smallpox when it is returned to man. Instead, it causes a local pustule, and confers immunity to smallpox over a considerable length of time. Rabies is another example in which the exact cause of the disease is still in doubt, and in which a protective vaccine has proven of great value. Rabies vaccine was developed by Pasteur, and is prepared by drying the spinal cords of rabbits that have been killed by a highly virulent rabies virus. Typhoid, dysentery, pneumonia and several other diseases of known etiology have been more or less controlled by the use of vaccines made from their respective bacterial causes. These vaccines are of the “killed bacteria” type of vaccines, and credit for their application to human disease belongs to Sir Almroth Wright (1896). The preparation of bacterial vaccines is very simple. Bacteria which are known to cause a certain disease are isolated in pure culture, grown on artificial media, killed either by chemicals or heat, standardized either by counting, or drying and weighing, and suspended in salt solution for subcutaneous injection. Salt suspension vaccines are usually given in three or four increasing doses, about one week apart. Le Moignic and Pinoy (58) first elaborated a lipovaccine for triple typhoid vaccination, which was used extensively in France during the war. Whitmore, Fennel and Peterson have recently also advised the drying of killed bacteria and the suspension of them in oil. This method makes it possible to give a single massive dose of bacteria which is sufficiently large to completely immunize the individual against the disease, and which prolongs the immunizing period by allowing slow absorption over a period of several weeks. These vaccines are called lipovaccines, have been adopted in the United States Army as the standard typhoid vaccine, and promise in time to supersede the salt suspensions entirely from a commercial standpoint. Many other modifications in the preparation of bacterial vaccines have been advised, notably the class known as sensitized vaccines. These are prepared by incubating bacterial vaccines for a time with the serum taken from animals already immunized against them. The serum apparently absorbs many of the toxic substances, and permits the injection of more efficient doses. Besredka advised the use of living cultures which had been incubated with immune sera, on the basis that vaccines so prepared were very active and non-toxic. The sensitizing treatment, however, does not stop the growing powers of the bacteria, and vaccines of the Besredka type are generally considered dangerous and so are little used. Sensitized killed bacterial vaccines, on the other hand, are quite popular.

When a sufficiently large dose of vaccine is given to an individual there is usually a transient rise in temperature for from 12 to 48 hours; the local focus of injection becomes sore and inflamed, and a white count often shows an actual increase in the number of polymorphonuclear leucocytes in the general circulation. A series of doses are usually given. If after a few days blood is withdrawn from the patient and immuniological tests made, it will generally be found that the patient’s leucocytes take up bacteria, and particularly the type of bacteria of which the vaccine was composed, more readily and in greater numbers than the leucocytes of the ordinary individual. Wright and Douglas (52) and Neufeld and Rimpau (53) have shown that this effect of increased phagocytosis is brought about by the vaccine through the production of substances which act specifically on the bacteria and render them more susceptible to inclusion within the white cells. These substances belong to the group of antibodies, and are known as “opsonins” or “bacteriotropins,” and are specific for any given bacteria. Moreover, the serum of the patient will, as a rule, be found to have developed the faculty of agglutinating and bacteriolysing suspensions of the specific organism injected and of fixing complement in the presence of an antigen prepared from that organism. In animal work it has been possible to go still farther, for it can be shown that the resistance of the animal can be raised until it is no longer possible to kill it with the same dose which is found to be fatal for the unimmunized animals. Not only has animal work made it possible to determine the protective powers of vaccines, but it has also served to show the specific nature of the protective power and the relative extent to which “group” or “crossed” protection can be conferred by vaccinating with closely allied organisms—as, for instance, paratyphoid bacilli in typhoid fever. The non-toxic nature of vaccines is also determined by animal experiment before such preparations are injected into humans.

The most successful prophylactic bacterial vaccine which has been developed so far is that for typhoid fever. A comparison of the occurrence of typhoid fever in the United States Army before and since the use of anti-typhoid vaccine is all that need be cited to convince one of its value. At the time of the Spanish War there was no vaccination against typhoid fever, and there were 20,738 cases, with 1,580 deaths, among 107,973 men who remained in the camps in the United States during the war (54).

During the summer of 1911, the maneuver division of the United States Army, having 12,801 men, all of whom had been vaccinated against typhoid fever, were stationed at San Antonio, Texas. Two cases of typhoid fever developed among them, and neither case died. Among the civilian population of the city, living under usual conditions during the same time, there were 49 cases of typhoid fever, with 19 deaths. Since 1912, typhoid vaccination has been compulsory in the United States Army, and the largest epidemic of typhoid fever which I have found reported so far during the late war was that at Camp Greene (55), Charlotte, N. C., where 18 cases developed. Only 12 of these men had received the complete series of immunizing doses. For a complete discussion of the value of typhoid vaccine the interested reader is referred to Gay’s Monograph (56) on typhoid fever.

_Prophylactic Vaccination Against Influenza_

The hope of finding an early solution to the vaccine problem in influenza appeared to be in the development of a prophylactic “bacterial vaccine” similar to that which proved so efficient for typhoid. In his discussion of the vaccine problem in pneumonia, Fennel pointed out that, theoretically, any disease of microbic origin in which spontaneous recovery is at all possible should yield to specific prophylactic measures. The difficulty, however, of preparing a bacterial vaccine for influenza comparable to that for typhoid fever is that the unquestioned cause of influenza has yet to be determined. The probable cause of influenza is the Pfeiffer bacillus, but its relationship has not been proven beyond question. On the other hand, the innocence has likewise not been proven, as Dr. Holman in his article of this series has ably shown. It is not my intention to go deeply into the question of etiology, but simply to bring out a few points which _a priori_ seemed to indicate that the reasonable solution of vaccine prophylaxis was in the preparation of a pure Pfeiffer bacillus suspension.

The experiments in man lead to very surprising results. Rosenau, Keegan, Goldberger and Lake, at Gallops Island, Boston, Mass., (1) inoculated volunteers with pure culture of B. Pfeiffer, with secretions of the upper air passages and with blood from typical cases of influenza. Sixteen men, of whom 13 were supposedly non-immune, had Pfeiffer bacilli installed into their nasal passages, and none of them developed the disease. Secretions filtered and unfiltered also gave negative results. Contact with well-developed early cases also failed. McCoy and Richey (1a) conducted similar experiments in San Francisco, with negative results. The men of the latter group had been vaccinated with a mixed streptococcic vaccine, which may have played some part. Had the experiments with the Pfeiffer bacillus been negative and the other experiments positive, they would have shown that the bacillus of Pfeiffer was not the cause of influenza; but since all attempts were negative, it merely brought out the fact that there had been a change, due probably to some immune factor, which seemed to have acted alike on the Pfeiffer bacillus and all other types of virus present, and to have made them all innocuous. These experiments still leave the cause of influenza in question.