Part 13

Most of the vaccine was distributed within a radius of 200 miles of Rochester, Minn., but samples were furnished to physicians all over the country, who agreed to return statistics on its use. No evidence was found that this vaccine caused a temporary break in the resistance of the user. Out of a total of 20,972 persons vaccinated, 14.6 cases of influenza, 1.8 cases of pneumonia, with 1.8 mortality, occurred per thousand in the six weeks following vaccination. As controls, he took “such persons in institutions, colleges, factories and communities where vaccine was used, and included only those reports which contained accurate data as to the incidence and mortality among them.” Among 61,753 such controls he found 229 cases of influenza, 15.7 cases of pneumonia and 3.4 deaths per thousand. He concluded from his results that “it appears possible to afford a definite degree of immunity by prophylactic inoculations to persons against the more serious respiratory infections during the present epidemic.” It is quite difficult to agree with Rosenow in his interpretation of the figures as presented by him, inasmuch as he made no allowance for the stage of the epidemic at which vaccination was carried out, either among the vaccinated or the non-vaccinated. Such a comparison would be well nigh impossible where the vaccine was sent in varying quantities to such a large number of places.

4. League Island Report (22). Vaccines were used as a preventive in 50 persons, most of whom were hospital apprentices and in the wards 12 to 15 hours a day. Other precautions were used, such as masks, but not a single case developed in the group. The vaccine was used as a curative agent in 50 uncomplicated cases; none of the patients injected early developed pneumonia.

5. Puget Sound Navy Yards Report (23). The vaccine used at this station was made from hæmolytic streptococci, no other organisms being used; 4,212 men were vaccinated, and not one died from influenza. Among 111 Philippinos isolated and vaccinated there occurred only 2 cases. Among 361 marines vaccinated early there occurred 2 cases. Among 62 marines at the ammunition depot who were vaccinated early there occurred 3 cases, only 1 of which occurred after completion of vaccination. Among 662 bluejackets at Seattle Training Camp only 10 men developed the disease. Among 83 at the aviation corps there were 32 cases—31 of them developed the disease within a few hours after the first injection. There were no deaths in any of the above groups. The period of observation was closed on October 21, and so few cases of influenza appeared subsequent to that date that it seemed that the epidemic was practically over at the time the data was obtained.

6. Kitano (24) used a vaccine for prophylaxis containing 0.2 m.g. of Pfeiffer bacilli per c.c. on 10,300 persons with encouraging results. He used vaccine for treatment on 87 patients, without any deaths. In the same group were 270 cases treated in the usual way, with 23 per cent. mortality. The vaccine lessened the severity, shortened the period of illness, and lowered the mortality.

7. Wynn (25) used mixed vaccines in the treatment of influenza, and believed they aborted the disease if given early.

8. Norman White (26) states that vaccination in India would be impractical, because the disease is so brief and severe that it would be over before innumerable doctors could complete inoculations.

9. Whitingham and Sims (27) reported the use of a mixed vaccine in an institution where 156 were inoculated and 149 were not. The case incidence was 5 per cent. among the vaccinated and 12 per cent. among the controls. No statement of the stage of the epidemic at which vaccination was done is mentioned in the report.

10. Cadham (28) reported on inoculations in a military hospital and in the civilian population near Winnipeg. Of 282 vaccinated soldiers admitted to the hospital, 17 had pneumonia and 5 died. Of 238 not vaccinated, 41 had pneumonia and 17 died. Among 24,184 civilians given two doses, 9.7 per cent. had influenza and 0.5 per cent. had pneumonia and 0.09 per cent. died. Among 85,941 controls, 24.8 per cent. had influenza, 2.2 per cent. pneumonia and 0.66 per cent. died. Cadham states that most of the inoculations were made early in the epidemic, but no accurate statistics were kept on the point.

11. A conference was held at the British War Office on October 14, 1918 (30), to discuss prophylactic vaccination and vaccines for treatment of influenza. Elaborate plans regarding dosage and gathering of statistics were made.

NOTANDA.—For reasons already given, the reports in Series III fail to give very reliable data on which to base a knowledge of the value of preventive vaccination against epidemic influenza.

_The Attempt to Prevent Pneumonia as a Complication of Influenza Through the Use of Lipovaccine_

Whitmore, Fennel and Peterson (31) developed a method of preparing an oily suspension of killed bacteria which they called “lipovaccine.” The method was used at first in making typhoid and dysentery vaccines. The advantages of lipovaccines (32) over salt suspensions are: the prevention of autolysis of the bacteria, thus increasing the length of time during which the vaccine remains active; the slow absorption of the dose, allowing the patient to continue to absorb immunity-producing substances over a period of days or weeks; the administration of a single massive dose, which does away with the three doses necessary when salt suspensions are used; and perhaps, also, the direct reduction in the toxicity of the dose by the lipoid material.

Based upon the classification of pneumococci by Dochez and Gillespie (33) in this country, and by Lister (34), (35), (36) in South Africa, and upon the latter’s successful use of anti-pneumonia vaccine on the Rand, an anti-pneumonia lipovaccine was prepared at the Army Medical School which contained approximately 10,000,000,000 each of types I, II and III pneumococci. The vaccine was made by growing the pneumococci in dextrose broth, centrifuging them out of the broth with a sharpless milk centrifuge, drying the sediment at 55° C., weighing it out so that each cubic centimeter of the finished vaccine contains 0.83 m.g. of each type, and making a suspension of them in olive oil. More recently cotton-seed oil has been used.

The result of the use of a salt suspension pneumococcus vaccine at Camp Upton was published by Cecil and Austin (37). A study of the agglutination and protective power of the serum of 42 persons vaccinated against pneumococcus types I, II and III demonstrated that a definite immune response could be secured to types I and II but not to type III. Twelve thousand five hundred and nineteen men were vaccinated at the camp, and most of the men received three or four inoculations at intervals of from five to seven days. The men were under observation for ten weeks, and during that time no cases of pneumonia of the three fixed types occurred among those who had received two or more injections. In a control of approximately 20,000 men there were 26 cases of pneumonia of types I, II and III. The incidence of pneumococcus type IV pneumonia was less among the vaccinated than among the unvaccinated groups. There were, however, 17 cases of pneumonia among the vaccinated men, compared to 173 cases of pneumonia among the controls. The annual pneumonia death rate for vaccinated groups in the army was 0.83 per one thousand, and for unvaccinated groups was 12.8.

Fennell reported the use of pneumo-lipovaccine in Washington during the influenza epidemic, but the number of cases cited by him were too small to permit of definite conclusions. His results appeared favorable.

Cecil and Vaughan (37a) reported on the results of vaccination with pneumo-lipovaccine at Camp Wheeler; 13,460 men, comprising 80 per cent. of the camp, were inoculated. Most of these men were under observation for 2 or 3 months after vaccination, and there occurred among them 32 cases of pneumococcus types I, II and III pneumonia. In one-fifth of the camp which was not vaccinated there occurred 43 cases of pneumonia. They observed that influenza caused a marked reduction in the resistance to pneumonia among vaccinated as well as non-vaccinated men. Of 155 cases of pneumonia of all types, which developed one week or more after vaccination, 133 were secondary to influenza. The death rate among vaccinated men one week or more after vaccination was 12.2 per cent., whereas the death rate for 327 cases of all types of pneumonia which occurred among unvaccinated groups was 22.3 per cent. The death rate for primary pneumonia among vaccinated groups was 11.9 per cent., and among unvaccinated 31.8 per cent. It was found that protective bodies do not begin to appear in the serum after lipovaccines are given until the eighth day after the injection. Twenty-four cases of pneumonia occurred in the first week after vaccination. In their conclusions Cecil and Vaughan state that there was no evidence whatever that pneumococcus vaccine predisposed the individual, even temporarily, toward either pneumococcus or streptococcus pneumonia. Most of the reactions after vaccination were mild, but one disagreeable feature was that in a certain percentage there persisted a small fluctuating mass at the site of the injection. Lacy saw a number of these cysts aspirated, and the contents were found to be a sterile, oily fluid, with many leucocytes present. In one instance the primary reaction disappeared within a few days after vaccination, but recurred after four months and persisted for several weeks.

NOTANDA.—The army lipovaccine apparently offers a certain definite amount of protection against pneumonia, which was the most dangerous complication of influenza. The protective substances do not appear in the serum until eight days have elapsed after the vaccination, and while no definite evidence has appeared to show that there is a temporary increase in susceptibility immediately after vaccination, the best results would undoubtedly be obtained where the dose is given something more than eight days before the appearance of the epidemic. The indications are that the vaccine will not protect against influenza, but that the complication of pneumonia is less likely to occur in the vaccinated than in the unvaccinated individual.

_Summary_

Records of attempts to confer immunity to influenza by the use of vaccines have been separated into related groups and studied. Those where pure Pfeiffer strains were used have been considered in one group. Those where mixed vaccines were used have been analyzed in three sub-groups or series, depending on the relation between the times of vaccination and of the advent of the epidemic, upon whether or not a week-by-week comparison of the occurrence of influenza among vaccinated and unvaccinated groups was made, and upon whether or not statistics for total comparison alone were available. The third group included the reports of the use of army pneumo-lipovaccines for the prevention of the secondary pneumonia complications of influenza.

_Conclusions_

From our statistics we conclude that:

1. There is as yet no evidence that vaccines composed purely of strains of Pfeiffer bacilli will confer immunity to epidemic influenza.

2. The only data which can be used as a basis for estimating the value of mixed vaccines as a preventive for epidemic influenza must be obtained from experiments in which vaccination was either completed before the epidemic appeared, or in which week-by-week comparisons between the number of cases occurring in the vaccinated and unvaccinated groups can be made.

3. Data obtained from experiments conducted under the above qualifications is inconclusive, but presents little evidence of the value of mixed vaccines in protecting against influenza. There is, however, an indication that mixed vaccines used prior to the arrival of the epidemic will lessen the number and the severity of secondary pneumonias, and will probably lower the death rate to a small degree.

4. The army pneumo-lipovaccine apparently offers some protection against primary infections with types I, II and III pneumococci, and a somewhat lesser amount of protection against secondary pneumococcic infections with these strains following influenza.

5. While it is impossible to say that the large number of influenza cases developing almost immediately after vaccination would not have occurred anyway, it is at least suggestive that a temporary break occurs in the resistance after the inoculation, and that unusual care should be taken by persons who have been recently vaccinated, particularly when they are in the midst of an epidemic disease.

PART II. GENERAL PROPHYLACTIC MEASURES

One of the most remarkable things about the 1918 pandemic was the great rapidity with which it spread to all parts of the world. From the report of the first cases which landed in Boston until the epidemic arrived in San Francisco the time consumed was less than two months, and the peaks of the two epidemics were just about one month apart. Apparently no part of the world escaped. Asia, Europe, Africa, North and South America, and some of the remote islands of the Pacific, all reported large epidemics, with high mortality and great suffering. The deplorable failure of precautionary measures in controlling the spread, or at least in limiting the disease, may be offset in a measure by the unusual conditions under which almost everybody had been living. Vast numbers from all over the world were gathered together because of the war. Thousands of men were housed together in army camps or in training cantonments. Other thousands were doing relief work or engaged in the manufacture of munitions. Most of those at home were doing double duty, and were on a severe nervous strain. Everyone everywhere was working to the limit and was consequently fatigued. The necessities of war had cut down the amounts of food generally, and sugar and fat rations particularly. Traffic, both between nations and at home, had never been so great nor accommodations so insufficient. So that it is likely that all of these and many more changes in the daily routine of individuals led to a condition of lowered resistance, and at the same time increased their chances of exposure. One point, at least, stands out prominently, and that is that “influenza as it occurred clinically during the first great wave was different from those cases which appeared later.” This was seen in the acuteness of the onset, in the severity of symptoms, and in the high mortality rate. Therefore, any measure which afforded protection, if only for the time being, is worthy of retrial.

In view of the fact that recurrences have followed closely in the wake of all former influenza epidemics, and with the hope of stimulating concerted investigation of preventive measures, the American Public Health Association (57), at its meeting in Chicago in December, 1918, appointed a committee to outline “a provisional working formula, based on the facts and opinions brought out at the meeting.” A summary of the opinions as taken from the report of the committee is given here. They reported that the disease was probably due to some micro-organism or virus as not yet identified; that while it was known as “influenza,” it was not known to be identical with the disease generally known under that name; that there was no known laboratory method of differentiating it from ordinary colds, bronchitis, etc.; that there was no known laboratory method of determining when a patient ceased to be infective; and that the deaths from influenza were due to secondary pneumonia resulting from an invasion by one or more forms of streptococci, or by one or more forms of pneumococci, or by the so-called influenza bacillus or bacillus of Pfeiffer. Because of the clear and concise manner in which this report brings out the opinions held, at the time, by a majority of the medical profession a portion of the report is given here _verbatim_.

“Evidence seems conclusive that the infective micro-organisms or virus of influenza is given off from the noses and mouths of infected persons. It seems equally conclusive that it is taken in through the mouth or nose of the person who contracts the disease, and in no other way except as a bare possibility through the eyes by way of the conjunctivæ or tear ducts.

“If it be admitted that influenza is spread solely through discharges from the nose and throats of infected persons, finding their way into the noses and throats of other persons susceptible to the disease, then, no matter what the causative organism or virus may ultimately be determined to be, preventive action logically follows the principles named below, and, therefore, it is not necessary to wait for the discovery of the specific micro-organism or virus before taking such action.

“1. Break the channels of communication by which the infective agent passes from one person to another.

“2. Render persons exposed to infection immune, or at least more resistant, by the use of vaccines.

“3. Increase the natural resistance of persons exposed to the disease by augmented healthfulness.”

The ways and means of carrying out these principles are many and varied, and it is merely the intention of this paper to put together a sort of digest of some of the more important arguments for and against some of the seemingly more important measures proposed.

_Methods Proposed for Breaking the Channels of Communication_

(a) Rigid quarantine for all persons suffering from the disease and all contacts. During the epidemic quarantine was advocated by many people. It was pointed out that the disease spread most rapidly in camps, in ships, and in quarters generally where large numbers of persons were closely associated; that it was quite as contagious and more rapidly fatal than most diseases which are regularly quarantined; that while it was admitted that there is no laboratory method to make certain the diagnosis, and no method of telling how long convalescents are capable of transmitting the disease, as there is, for instance, in diphtheria, still there is no question of the value of the arbitrary quarantine used in measles, scarlet fever and smallpox, all of which are diseases in which the parasitic causes are not known. Further, the opinion was expressed that complete isolation and quarantine would not only protect the community from influenza, but that it would also in a measure protect the patient from contact with numerous outside strains of pneumococci and streptococci, and so lessen secondary infection and reduce the general mortality.

There are many reasons why quarantine is not applicable in epidemic influenza. Most important of all is probably the inability to make certain the diagnosis, especially during the early stages in light cases. This would work detrimentally in several ways. Really ill patients would delay calling a physician until late, for fear of unnecessary quarantine. Many needless and unjust quarantines would result when the diagnosis was uncertain and the physician anxious to carry out quarantine measures efficiently. Many patients would have contacts running about and infecting their neighborhoods while a delayed diagnosis was being made. Influenza was so contagious during the epidemic that it would have necessitated general quarantine not only of all infected persons but also of all contacts to have obtained any favorable results, and since nearly everyone was either a patient or a contact, all lines of business would literally have been paralyzed by the procedure. If it is true that the infected person is most dangerous to others before he has developed symptoms himself, he is a carrier impossible of detection and control. Points in favor of the hypothesis that infected persons spread the disease before they develop symptoms are found in the following facts. As the disease passed from community to community officials became alert for the appearance of the first case. In army barracks and in large institutions it was often possible to determine the first case at its development. The case was, in many instances, removed at once and isolated, but I have seen no instance in which such a measure was successful in curbing the disease. As subsequent cases appeared they were likewise immediately removed, but the cases continued to spread just the same. Bloomfield (38) cited the incident of a student who spent a few hours visiting his sister in a part of the country where there had been no influenza. He appeared well at the time, but six hours after his return to school he developed influenza. Two days after the contact the sister came down with the disease. On the other hand, he told of a student who did not contract the disease, though he slept for two nights in the same bed with his roommate, who had returned to school with a well-developed case of influenza. The unsuccessful attempts to transmit influenza in the experiments of Rosenau (37), McCoy (37a) and others already cited would indicate that the cases from whom the material was taken were no longer infectious, although some of them had been showing symptoms for only about 12 hours. Bloomfield observed that the general use of face masks in the wards did not alter the course of the epidemic, and stated that if face masks are protective, infection from early unisolated cases must be assumed.

Provided influenza is generally transmitted during the period of incubation, a theory which seems consistent with the facts, rigid quarantine for epidemic influenza is impracticable and probably useless.

_Partial Isolation by Means of the Cubicle System_

The so-called cubicle system consists in the dividing of rooms, or more particularly of wards, into small compartments by means of suspending sheets from wires so that each bed is separated from its neighbor. Capps (39) reported favorably on the method as used at Camp Grant, where sheets or halves of tents were suspended from wires or from the mosquito netting frames which were a part of the standard beds. Doctors, nurses and attendants were forced to wear masks in the wards, and patients were not allowed out of the cubicles without them. In discussing this paper Thayer emphasized the value of screening, masking and the wearing of gowns, and also recommended thorough washing of the hands between the examination of each two patients; and Emerson called attention to the fact that the first demonstration of the cubicle system as an adequate means of preventing acute respiratory diseases was made at the Pasteur Institute of Paris, where it had been in operation for 10 years. The latter stated that the system had been used in various hospitals in America and was essential for the care of diphtheria, measles and scarlet fever. He further indicated that if the technique of personal cleanliness of nurses, doctors and attendants could be perfected, it was probable that the height of the cubicle partition could be reduced to that of a “red string.” The method certainly seems worthy of consideration and trial, particularly in large general hospitals and public institutions.

_The Use of the Face Mask_