Part 9

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.