Contents

CHAPTER V

Measles

Joseph Stokes, Jr., M. D.

HISTORICAL NOTE ¹

In periods of mobilization, measles has always been a problem among the armed services. This was true of the Civil War, the Spanish-American War, the Philippine Insurrection, and World War I. Recruit depots were recognized as the posts where the incidence of measles rose rapidly and accounted for relatively high morbidity rates.

In World War I, total Army admission and death rates, respectively, were 23.79 and 0.57 per 1,000 average strength per year among the total of the average annual strengths of approximately 4 million men, with a daily average noneffective ratio of 1.25 per 1,000 average strength. More than eight-tenths of the primary admissions were among troops serving in the United States and in Alaska. Of an average annual mean strength of over 2 million enlisted men in the United States, the average annual admission rate was about 40 with a death rate of 0.94, and a daily average noneffective ratio of 2.07 per 1,000 average strength.

Among 93,629 primary admissions of enlisted men in the United States and Europe during World War I, there were 22,809 complications, the most common of which were pneumonia, otitis media, and mumps. Other important complications were suppurative pleurisy, mastoiditis, and scarlet fever. Extensive studies were made of bacterial flora in a number of severe epidemics in Army posts. The hemolytic streptococcus was found more frequently than any other bacterium as the apparent etiologic factor in these complications.

REDUCTION OF THE MILITARY PROBLEM IN WORLD WAR II

Measles as a military problem changed to a great degree between World Wars I and II, apparently as a result of two major factors: (1) Reduction in the total number of susceptibles of draft age, as a result of sociological changes from 1919 to 1940 which helped to decrease the percentage of United States population that is both rural and isolated; and (2) lessening severity of the disease

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¹ The Medical Department of the United States Army in the World War.Communicable and Other Diseases. Washington: U. S. Government Printing Office, 1928, vol. IX, pp. 411, 414, 431.

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since 1936 as a result of sulfonamides and antibiotic agents, which have become increasingly useful in control of bacterial complications of measles.

Sociological changes.-The first factor is difficult to measure completely, although the decrease in percentage of rural population is obvious.It is well known that rural men of draft age in general have a higher percentage of susceptibles than urban draftees of the same age range, as indicated by experience in World War I. Such factors as the family automobile and the bus have greatly decreased isolation of the rural family, yet it is difficult to determine how much these changes have accomplished in lowering the age at which measles occurs.

Sulfonamides and antibiotics.-The second major factor, that of control of secondary bacterial complications, plays no part in decreasing actual incidence of measles but has a large role in reducing severity of measles and in thus diminishing its importance as a military problem. It has been realized for some time that such organisms as hemolytic streptococcus, pneumococcus, and staphylococcus had considerable effect on severity of the disease in World War I, and use of sulfonamides and antibiotics demonstrated more clearly the significance of those bacteria in relation to bronchopneumonia, otitis media, and other complications of measles.

Human-serum antibodies.-Also of increasing importance since World War I in control of sharp localized outbreaks of the disease, particularly as to its severity, was the availability of human-serum antibodies against measles in convenient and concentrated amounts which caused practically no discomfort and a rare local reaction in recipients. The first advance from the original use of convalescent serum by Nicolle and Conseil ² in 1918 and of adult serum by Reitschel ³ in 1921, was the production of a concentrated placental gamma globulin by McKhann and Chu ⁴ in 1933. Later, serum produced from fractionation methods by Cohn and his associates ⁵ in 1944 proved to be even more satisfactory, causing fewer reactions than placental gamma globulin. Now gamma globulin from pools of plasma may be considered a standard preparation for use intramuscularly, but not intravenously, in measles prophylaxis. Certain studies have been conducted to determine its value in therapy conducted in the early prodromal phase, but additional research is required.

Immunization.-Studies on methods of immunization were made by several researchers following World War I. Plotz ⁶ in 1938 investigated the cultivation of measles virus on tissue culture, and Rake and Shaffer ⁷ in 1939 made a similar investigation of the virus in the chorio-allantois of embryonated

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² Nicolle, C., and Conseil, E.: Pouvoir préventif du sérum d'un malade convalescent de rougeole. Bull. et mém. Soc. méd. d. hôp de Paris 42: 336-338, 1918.

³ Reitschel, P.: Zur Masernprophylaxe nach Degkewitz. Ztschr. f.Kinderh. 29: 127-132, June 1921.

⁴ McKhann, C. F., and Chu, F. T.: Use of Placental Extract in Prevention and Modification of Measles. Am. J. Dis. Child.45: 475-479, March 1933.

⁵ Cohn, E. J., Oncley, J. L., Strong, L. E., Hughes, W. L., Jr., and Armstrong, S. H., Jr.: Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. I. The Characterization of the Protein Fractions of Human Plasma.J. Clin. Investigation 23: 417-432, July 1944.

⁶ Plotz, H.: Culture "in vitro" du Virus de la Rougeole.Bull. Acad. de méd., Paris 119: 598-601, May 1938.

⁷ Rake, G., and Shaffer, M. F.: Propagation of the Agent of Measles in the Fertile Hen's Egg. Nature, London 144: 672-673, October 1939.

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hen's egg. It was shown by Shaffer and his associates ⁸ in 1941 that virus grown on the chick chorio-allantois sac, following several passages, will produce mild measles in Macaca mulatto monkeys and also in susceptible human beings. Monkeys and human beings thus infected demonstrated resistance to measles virus; the former apparently demonstrated a greater resistance than the latter. Later chorioallantois passages of virus produced fewer symptoms in man, but resistance appeared to be less than with earlier passage material. Difficulty in obtaining continued growth with fresh infective material on the chorio-allantois and in developing adequate serologic tests for susceptibility and resistance to measles has hampered further studies on possible production of active immunity in man by use of such passage material. Siim, in Copenhagen, has been able to repeat cultivation of the measles virus on the chorioallantois of embryonated hen's egg and has also been able to produce measles of a similar mild nature with Koplik spots in monkeys and human beings. With continued passage on the chorio-allantois, the Siim virus also decreased in virulence and activity.

Difficulties inherent in such studies were chiefly responsible for emphasis in World War II upon developing means of passive immunization for any sharp outbreaks in the armed services, in case an emergency occurred.

Gamma globulin.-Storage of convalescent measles plasma in a dried state was not considered practical for control of acute outbreaks of measles. Gamma globulin was available as a by product of fractionation of pooled Red Cross plasma for obtaining concentrated albumin for treatment of shock. Such gamma globulin was first tested by Enders ⁹ for antibodies against many viral and bacterial diseases, such as influenza A and B antibodies and diphtheria antitoxin. It was found to contain these antibodies in a stable form which was concentrated to approximately 25 times the amount present in original pools of Red Cross plasma.

Following the original suggestion by Col. Elliott, S. A. Robinson, MC, Chief, Laboratories Division, Preventive Medicine Service, Office of the Surgeon General, that gamma globulin be tested for its effect against measles, studies on prophylaxis were started. One study was conducted in Philadelphia by members of the Commission on Measles and Mumps, Army Epidemiological Board ¹⁰ Another study was conducted in Boston by Dr. Charles Janewav and his coworkers.¹¹ These studies were made to determine the efficacy of gamma globulin in prevention, attenuation, and treatment of

⁸ Shaffer, M. F., Rake, G., Stokes, J., Jr., and O'Neil, G. C.: Studies on Measles. II. Experimental Disease in Man and Monkey.J. Immunol. 41: 241-257, June 1941.
⁹ Enders, J. F.: Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. X. The Concentrations of Certain Antibodies in Globulin Fractions Derived from Human Plasma. J. Clin. Investigation 23: 510-530, July 1944.
¹⁰ Stokes, J., Jr., Maris, E. P., and Gellis, S. S.: Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation. XI. The Use of Concentrated Normal Human Serum Gamma Globulin (Human Immune Serum Globulin) in the Prophylaxis and Treatment of Measles. J. Clin. Investigation 23: 531-540, July 1944.
¹¹ Ordman, C. W., Jennings, C. G., Jr., and Janeway, C. A.: Chemical, Clinical, and Immunological Studies on the Products of Human Plasma Fractionation.XII. The Use of Concentrated Normal Human Serum Gamma Globulin (Human Immune Serum Globulin) in the Prevention and Attenuation of Measles.J. Clin. Investigation 23: 541-549, July 1944.

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measles in suitable groups of children in homes and hospitals. Conclusions fully established the value of gamma globulin in prevention and attenuation of measles. Some suggestion was also obtained in the Philadelphia studies that treatment of measles with large doses during the prodromal stages might result in modification of the disease, but findings were not sufficiently extensive to be conclusive. The very large dosage used for treatment, since it must be injected intramuscularly, caused such discomfort that it was impractical for routine use in either children or adults, unless the condition of exposed susceptibles warranted strenuous efforts for attenuation of measles.

Studies centering in Boston and Philadelphia also established that, while pools of Red Cross plasma from which the gamma globulin originated often produced serum hepatitis in a considerable percentage of the recipients, gamma globulin itself did not cause such hepatitis. In some cases, this may have been because of the infrequent presence of antibodies in the serum hepatitis virus. It appears more probable, however, from further studies conducted in Boston, that the virus may have an affinity for Fraction I of fractionated plasma rather than for Fraction II, since Fraction I is known to harbor the virus when it is present in plasma pools from which the fractions are obtained. It is also possible that the more rigorous handling of the gamma globulin fraction, as compared with other fractions, may inactivate the virus.

However, in view of safety, ready availability, small dosage resulting from concentration of antibodies, stability of antibodies, and lack of local or general reaction of gamma globulin, it appeared to be excellent material for storage in areas such as ports of embarkation in case emergency protection against measles was required. A number of emergencies which were not recorded are known to have existed during World War II. Two instances were reported, however. One occurred at an Army camp. Gamma globulin proved to be completely protective when injected in a dose of 10 ml., into each of 610 enlisted men who were exposed to measles.¹² In a similar situation, men in an Air Force unit, following exposure to measles, were injected just before embarkation and were completely protected by 5 ml. of gamma globulin.¹³

During the war, several thousand injections of gamma globulin in exposed susceptible children were administered by members of the Commission on Measles and Mumps, Army Epidemiological Board, for the purpose of deter mining proper dosage for attenuation and protection of personnel in the armed services. From a larger original dose of about .025 to .03 ml. per pound of

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¹² Letter, Col. T. G. Tousey, MC, Army Service Forces, New Fork Port of Embarkation, Camp Kilmer, N. J., to The Surgeon General, 10 June 1944, subject: Immune Serum Globulin for Prevention of Measles.

¹³Army Air Forces, Headquarters, I Troop Carrier Command, Stout Field, Ind., Preventive Medicine Bulletin No. 7, 20 Apr. 1945.

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body weight for attenuation of measles, the dose has been reduced to about .02 ml. per pound of body weight. Approximately four times this amount would be fully protective in most instances, although there is considerable variation in susceptible individuals. The use of ultraviolet light to prevent cross-infection in measles was a method not fully^, explored during World War II.

INCIDENCE OF MEASLES IN WORLD WAR II

In World War II, remarkable reduction in the military problem posed by measles is well illustrated by available statistical data. As was expected when induction started, morbidity from measles among Army personnel in the United States rose considerably, apparently as a result of an influx of susceptible men from states with large rural populations. Also, as was expected, when a relatively small number of men were inducted in 1944, the incidence rate, dropped considerably below that of the preceding 4 years. Incidence rates in the 4 years 1941-45 were 9.8 (enlisted men only and including Alaska), 4.5, 5.7, 2.7, and 0.9, respectively, as compared with an average during 1930-39 of 3.3 per 1,000. The morbidity rate for 1941 of 9.8 should be compared with the morbidity rate of 85.2 in 1917 inasmuch as both rates are for enlisted men only. The highest incidence rates for measles during the 3-,year period, 1942-44, were reported by the Seventh Service Command. During this period, rates were lowest in the First and Second Service Commands.

The case fatality rate for measles in World War II was approximately 40 times less than the rate for World War I, which was 2.4 per 100 admissions. Remarkable change in the severity of measles apparently resulted from three causes: (1) Better control of secondary bacterial invaders in measles itself, (2) better control of bacterial components in patients with respiratory infection who were exposed to measles, and (3) reduction by chemotherapy of the number of respiratory infectious cases who would otherwise have, been in hospital or barracks adding their bacterial population to already overpopulated areas.

Decrease in case fatality rates can best be explained by the control of pathogenic bacteria, although it is also probable that absence of pandemic influenza in World War II played some part in this reduction.

Table 24 shows annual incidence rates per 1,000 average strength for morbidity from measles, mumps, and scarlet fever from 19,30 to 1945, inclusive, for the Army in the continental United States.

Measles must still be regarded as a difficult problem for induction centers but probably need no longer be considered as a major military problem in the field of infectious diseases.

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TABLE 24.-Incidence rates for measles, mumps, and scarlet fever in the Army in the continental United States, 1930-45