CHAPTER V
Measles
Joseph Stokes, Jr., M. D.
HISTORICAL NOTE 1
In periods ofmobilization, measles has always been a problem among the armedservices. Thiswas true of the Civil War, the Spanish-American War, the PhilippineInsurrection, and WorldWar I. Recruit depots were recognized as the posts where the incidenceof measles rose rapidlyand 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 93,629primary admissions of enlisted men in the United States and EuropeduringWorld War I, there were 22,809 complications, the most common of whichwere pneumonia,otitis media, and mumps. Other important complications were suppurativepleurisy, mastoiditis,and scarlet fever. Extensive studies were made of bacterial flora in anumber of severeepidemics in Army posts. The hemolytic streptococcus was found morefrequently than anyother 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 greatdegree between World Wars I and II,apparently as a result of two major factors: (1) Reduction in the totalnumber of susceptibles ofdraft age, as a result of sociological changes from 1919 to 1940 whichhelped to decrease thepercentage of United States population that is both rural and isolated;and (2) lessening severityof the disease
1 The MedicalDepartment of the United States Army in the World War.Communicable andOther Diseases.Washington: U. S. Government Printing Office, 1928, vol. IX, pp. 411,414, 431.
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since 1936 as a result ofsulfonamides and antibiotic agents, which have become increasinglyuseful 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 ofcontrol of secondary bacterialcomplications, plays no part in decreasing actual incidence of measlesbut has a large role inreducing severity of measles and in thus diminishing its importance asa military problem. It hasbeen realized for some time that such organisms as hemolyticstreptococcus, pneumococcus, andstaphylococcus had considerable effect on severity of the disease inWorld War I, and use ofsulfonamides and antibiotics demonstrated more clearly the significanceof those bacteria inrelation to bronchopneumonia, otitis media, and other complications ofmeasles.
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 byseveral researchersfollowing World War I. Plotz 6 in 1938 investigated thecultivation of measles virus on tissueculture, and Rake and Shaffer 7 in 1939made a similar investigation of the virus in the chorio-allantois ofembryonated
2 Nicolle,C., and Conseil, E.: Pouvoir préventif du sérum d'unmaladeconvalescent derougeole. Bull. et mém. Soc. méd. d. hôp de Paris 42:336-338, 1918.
3Reitschel,P.: Zur Masernprophylaxenach Degkewitz. Ztschr. f.Kinderh. 29: 127-132,June1921.
4 McKhann,C.F., and Chu, F. T.: Useof Placental Extract in Prevention and Modification ofMeasles. Am. J. Dis. Child.45: 475-479, March1933.
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 ofHumanPlasma Fractionation. I. The Characterization of the Protein Fractionsof Human Plasma.J. Clin. Investigation 23: 417-432, July 1944.
6Plotz, H.: Culture"in vitro" duVirus de la Rougeole.Bull. Acad. de méd., Paris 119:598-601,May 1938.
7 Rake, G., andShaffer, M. F.:Propagation of the Agent of Measles in the Fertile Hen'sEgg. Nature, London 144: 672-673, October 1939.
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hen's egg. It was shown by Shafferand his associates 8 in 1941 that virus grown on the chickchorio-allantois sac, following several passages, will produce mildmeasles in Macaca mulattomonkeys and also in susceptible human beings. Monkeys and humanbeings thus infecteddemonstrated resistance to measles virus; the former apparentlydemonstrated a greaterresistance than the latter. Later chorioallantois passages of virusproduced fewer symptoms inman, but resistance appeared to be less than with earlier passagematerial. Difficulty inobtaining continued growth with fresh infective material on thechorio-allantois and indeveloping adequate serologic tests for susceptibility and resistanceto measles has hamperedfurther studies on possible production of active immunity in man by useof such passagematerial. Siim, in Copenhagen, has been able to repeatcultivation ofthe measles virus on thechorioallantois of embryonated hen's egg and has also been able toproduce measles of a similarmild nature with Koplik spots in monkeys and human beings. Withcontinued passage on thechorio-allantois, the Siim virus also decreased in virulence andactivity.
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 byCol. Elliott, S. A. Robinson, MC, Chief, LaboratoriesDivision, Preventive Medicine Service, Office of the Surgeon General,that gamma globulin betested for its effect against measles, studies on prophylaxis werestarted. One study wasconducted in Philadelphia by members of the Commission on Measles andMumps, ArmyEpidemiological Board 10 Anotherstudy was conducted in Boston by Dr.Charles Janewav andhis coworkers.11 These studies weremade to determine the efficacy ofgamma globulin inprevention, 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 ofchildren in homes and hospitals. Conclusions fully established thevalue of gamma globulin in prevention and attenuation of measles. Somesuggestion was alsoobtained in the Philadelphia studies that treatment of measles withlarge doses during theprodromal stages might result in modification of the disease, butfindings were not sufficientlyextensive to be conclusive. The very large dosage used for treatment,since it must be injectedintramuscularly, caused such discomfort that it was impractical forroutine use in either childrenor adults, unless the condition of exposed susceptibles warrantedstrenuous efforts forattenuation 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 viewof safety, readyavailability, small dosage resulting from concentration ofantibodies, stability of antibodies, and lack of local or generalreaction of gamma globulin, itappeared to be excellent material for storage in areas such as ports ofembarkation in caseemergency protection against measles was required. A number ofemergencies which were notrecorded are known to have existed during World War II. Two instanceswere reported,however. One occurred at an Army camp. Gamma globulin proved to becompletely protectivewhen injected in a dose of 10 ml., into each of 610 enlisted men whowere exposed to measles.12In a similar situation, men in an Air Force unit, following exposure tomeasles, were injected justbefore embarkation and were completely protected by 5 ml. of gammaglobulin.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
12 Letter, Col. T. G. Tousey, MC, Army ServiceForces, New Fork Port of Embarkation, Camp Kilmer, N. J., to TheSurgeon General, 10 June 1944, subject: Immune Serum Globulin forPrevention of Measles.
13Army Air Forces,Headquarters, I Troop Carrier Command, Stout Field, Ind., PreventiveMedicine Bulletin No. 7,20 Apr. 1945.
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body weight for attenuation ofmeasles, the dose has been reduced to about .02 ml. per pound ofbody weight. Approximately four times this amount would be fullyprotective in most instances,although there is considerable variation in susceptible individuals.The use of ultraviolet light toprevent cross-infection in measles was a method not fully,explored during World War II.
INCIDENCEOF MEASLES IN WORLD WAR II
In World War II,remarkable reductionin the military problem posed by measles is wellillustrated by available statistical data. As was expected wheninduction started, morbidity frommeasles among Army personnel in the United States rose considerably,apparently as a result ofan 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, theincidence rate, droppedconsiderably below that of the preceding 4 years. Incidence rates inthe 4 years 1941-45 were9.8 (enlisted men only and including Alaska), 4.5, 5.7, 2.7, and 0.9,respectively, as comparedwith an average during 1930-39 of 3.3 per 1,000. The morbidity rate for1941 of 9.8 should becompared with the morbidity rate of 85.2 in 1917 inasmuch as both ratesare for enlisted menonly. The highest incidence rates for measles during the 3-,yearperiod, 1942-44, were reportedby the Seventh Service Command. During this period, rates were lowestin the First and SecondService 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 casefatality rates canbest be explained by the control of pathogenic bacteria,although it is also probable that absence of pandemic influenza inWorld War II played somepart 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 stillbe regarded as adifficult problem for induction centers but probably need nolonger be considered as a major military problem in the field ofinfectious diseases.
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