Part 11

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.