CHAPTER XIII
Infectious Mononucleosis
Alfred S. Evans, M.D., and John R. Paul, M.D.
Infectious mononucleosis was a common and usually benign disease during World War II, behaving, on the whole, as an endemic and sporadic illness with two possible exceptions. No sharp epidemics were recorded. Mortality due to this disease was very low but not unknown. The period of hospitalization was usually about 26 days, but in certain patients, especially those with liver or central nervous system involvement, it was much longer. The etiological agent and specific methods of prophylaxis and treatment remain unknown. Nevertheless, as this disease is one of young adulthood with its highest incidence in the 15- to 25-year age group, it has some significance for the Army medical officer.
HISTORICAL NOTE
At the outbreak of World War I, infectious mononucleosis, or glandular fever, as it then was called, was a poorly recognized disease and no specific hematological or serologic changes were known to be associated with it. Only a few accounts had appeared in the American literature up to this time, but notable among them was the report by West,1 in 1896, of an outbreak of the disease involving a large number of adults and children in an Ohio community. Later, others called attention to its occurrence in epidemic form in institutions.2
Little is recorded of the experience of U.S. Army troops with this condition during World War I. It is not mentioned in the official history of the Army Medical Department during that conflict, but some of the case reports recorded under the diagnosis of Vincent's infection are suggestive of infectious mononucleosis. The illness was better known in England where outbreaks of the disease were not infrequent in British Army camps and barracks, according to Burnford,3 although these outbreaks are not discussed in the official British history of the war. It seems possible that similar, though unrecognized, outbreaks may have occurred among U.S. troops and been recorded under some other disease.
1West, J. P.: An Epidemic of Glandular Fever. Arch. Pediat. 13: 889-900, January-December 1896.
2(1) Terflinger, F. W.: Epidemic of Glandular Fever. J.A.M.A. 50: 765, 1908. (2) Burns, J. E.: Glandular Fever: Report of an Epidemic in the Children's Ward of the Union Protestant Infirmary. Arch. Int. Med. 4: 118, 1909.
3Burnford, J. : A Note on Epidemics. Brit. 2 : 50-51, July 1918.
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DEVELOPMENTS BETWEEN WORLD WAR I AND WORLD WAR II
In the 20 years following World War I, two important discoveries were made relating to the diagnosis of infectious mononucleosis. The first of these was the recognition, in the early 1920's, of the characteristic blood picture associated with the disease;4 the second, the discovery by Paul and Bunnell,5 in 1932, of the development during convalescence of a high titer of sheep RBC (red blood count) agglutinins. The term "infectious mononucleosis" was introduced into this country soon after the end of World War I and is in general use today, although in England the older term "glandular fever" has remained popular. Reports of epidemics continued to appear from time to time. Among these are publications dealing with small outbreaks in nurseries6 and boarding schools7 and a larger outbreak involving 87 individuals in a community on the Falkland Islands.8 In 1935, Nolan discussed the occurrence of infectious mononucleosis in 220 individuals, including 115 children, at the U.S. Naval Base, Coronado, Calif.9 The disease has become of considerable importance among university populations in this country where it may account each year for an appreciable amount of illness among the students.
The etiological agent, method of spread, and specific treatment remained unknown.
HISTORY OF THE DISEASE, 1940-46
General Incidence
Before dealing with the occurrence of infectious mononucleosis in U.S. troops, some statements should be made concerning the data on which the tables are based. This disease was grossly underreported on weekly summary reports because reporting of it was not specifically required on the statistical health report. As a consequence, the hospital admission rates based on examination of individual medical records provide the only available source of information, and this must be regarded as provisional. From 1940
4(1) Sprunt, T. P., and Evans, F. A.: Mononuclear Leucocytosis in Reaction to Acute Infections (Infectious Mononucleosis). Bull. Johns Hopkins Hosp. 31 : 410, 1920. (2) Longcope, W. T.: Infectious Mononucleosis (Glandular Fever) With a Report of 10 Cases. Am. J.M. Sc. 164 : 781, 1922. (3) Downey, N., and McKinley, C. A. : Acute Lymphadenosis Compared With Acute Lymphatic Leukemia. Arch. Int. Med. 32 : 82, 1923.
5Paul, J. R., and Bunnell, W. W.: The Presence of Heterophile Antibodies in Infectious Mononucleosis. Am. J.M. Sc. 183: 90-104, January 1932.6Davis, C. M.: Acute Glandular Fever of Pfeiffer : Report of a Nursery Epidemic. J.A.M.A. 92: 1417-1418, April 1929.
7(1) Tidy, H. L., and Daniel, M. B.: Glandular Fever and Infectious Mononucleosis With an Account of an Epidemic. Lancet 2: 9, 1923. (2) Guthrie, C. C., and Pessel, J. F. : An Epidemic of "Glandular Fever" in a Preparatory School for Boys. Am. J. Dis. Child. 29 : 492, 1925.
8Moir, J. I. : Glandular Fever in the Falkland Islands. Brit. M.J. 2 : 822-823, November 1930.
9Nolan, R. A. : Report of So-Called Epidemic of Glandular Fever (Infectious Mononucleosis). U.S. Nav. M. Bull. 33: 479-483, October 1935.
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through 1943, the data also included patients with agranulocytosis since these two diseases were recorded under a similar heading. The effect on the total rate of the inclusion of agranulocytosis is probably small since in 1944 it accounted for only one-half of one percent of the combined incidence for both diseases. The increase in the number of admissions in 1943, however, may have been due in some measure to admission for Bullis fever.
The admission rates per thousand average strength per year in the U.S. Army as a whole, in troops stationed in the United States, and in troops in oversea areas for the years 1940 to 1946, inclusive, are indicated in table 34. As can be seen, the admission rate, both as a whole and for the subdivisions shown, rose gradually and steadily during these years. The incidence for the total Army for 1946 was over 16 times greater than that recorded in 1940. The rate for troops stationed in the United States declined in 1946. It will also be noted that the increase in troops in oversea areas lagged a year or so behind that of men stationed in the United States.
TABLE 34.-Admission rates for infectious mononucleosis in the U.S. Army by broad geographic area and year, 1940-461
Year | Total Army | United States | Overseas |
1940 | 0.09 | 0.11 | 0.05 |
1941 | .19 | .17 | .10 |
1942 | .28 | .29 | .23 |
1943 | .60 | .69 | .34 |
1944 | .83 | 1.22 | .41 |
1945 | 1.01 | 1.71 | .58 |
1946 | 1.57 | 1.52 | 1.64 |
1Rates for 1940 and 1941 are for enlisted men only; rates for 1940, 1941, 1942, and 1943 may include a few cases of agranulocytosis and for 1943 several hundred cases of Bullis fever.
Table 35 shows the admission rates per thousand per year in the U.S. Army in the various theaters and areas. From 1943 until 1946, the rate in troops stationed in the United States somewhat exceeded that recorded for troops in any other area with the exception of the 1943 rate in Europe. However, in 1946, three other areas had more hospital admissions diagnosed as infectious mononucleosis than had the Zone of Interior. These areas were: Mediterranean-Middle East, Japan-Korea, and Europe. Despite such differences during 1946 as well as in earlier years, it should be noted that there was no consistent, marked variation from area to area and that no single area appeared remarkable in this regard. A similar distribution of cases was observed in different Army sections of the United States (table 36).
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TABLE 35.-Admission rates for infectious mononucleosis in the U.S. Army by theater or area and year, 1942-46
Theater or area | 19421 | 19431 | 1944 | 1945 | 1946 |
Continental United States | 0.29 | 20.69 | 1.22 | 1.71 | 1.52 |
Overseas: |
|
|
|
|
|
| Europe | .43 | .72 | .59 | .78 | 2.20 |
| Mediterranean3 | .17 | .32 | .25 | .51 | --- |
| Middle East | .17 | .34 | .19 | .37 | --- |
| China-Burma-India | .46 | .61 | .18 | .27 | .56 |
| Southwest Pacific | .39 | .25 | .21 | .23 | .55 |
| Pacific Ocean | .23 | .22 | .28 | .59 | 1.08 |
| North America | .10 | .19 | .28 | .66 | .50 |
| Latin America | .18 | .36 | 1.20 | .34 | .94 |
| Japan and Korea | --- | --- | --- | --- | 2.31 |
1Data for 1942 and 1943 may include a few cases of agranulocytosis.
2May include several hundred cases of Bullis fever.
3Includes North Africa.
TABLE 36.-Admissions for infectious mononucleosis in the U.S. Army, by Army Area in the United States, 1945 and 1946
Army Area | 1945 | 1946 | ||
Number | Rate | Number | Rate | |
First | 390 | 1.33 | 230 | 1.49 |
Second1 | 510 | 1.23 | 445 | 1.74 |
Third | 1,075 | 1.56 | 265 | 1.23 |
Fourth | 1,235 | 1.93 | 355 | 1.76 |
Fifth | 1,125 | 2.64 | 265 | 1.59 |
Sixth | 665 | 1.32 | 255 | 1.23 |
| Total | 5,000 | 1.71 | 1,815 | 1.52 |
1Includes Military District of Washington.
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Individual Outbreaks
It would seem probable that an illness like infectious mononucleosis, which had the capacity to appear in epidemic form, would have done so under the circumstances of Army life. It appears remarkable, therefore, that only two reports10 can be found which suggest occurrence of the disease in epidemic form. The first of these was the publication of Vander Meer, Lutterloh, and Pilot from the station hospital at Camp McCoy, Wis.11 These authors observed 26 clinical and 340 subclinical cases of infectious mononucleosis from December 1943 to May 1944. The diagnosis of a subclinical attack was based on the results of a survey of 522 apparently healthy men in one training unit and 110 hospitalized patients with illnesses diagnosed as other illnesses. Atypical lymphocytes alone were found in the blood smears of 340 of the total number of men, and, in addition, an elevated heterophile antibody titer was demonstrated in 13. None of these men had a history of an acute illness suggestive of infectious mononucleosis in the 6 months preceding the survey.
The second account suggestive of the occurrence of an epidemic form of infectious mononucleosis is the extensively documented publication of Wechsler, Rosenblum, and Sills from the medical service, station hospital at Fort Bliss, Tex.12 These authors studied 556 patients with infectious mononucleosis from 1 January 1943 to 29 February 1944. An additional 131 cases had been admitted by July 1944, but clinical details on these patients were not included in their report. Unfortunately, neither the admission nor the incidence rates per 1,000 per year are recorded. Consequently, it is not possible to compare the incidence at Fort Bliss with that at other installations or with the incidence in the Army as a whole. The ages of the patients ranged from 18 to 47 years, but the greatest frequency
10A third outbreak of a disease with some of the features of infectious mononucleosis has been recorded. (Professional History of Internal Medicine in World War II, 1 Jan. 1940 to 1 Oct. 1945, the Panama Canal Department. Special Disease Problems, Various Diseases, vol. I, pp. 26-42. [Official record.] This occurred in the Canal Zone in the fall of 1944 during which time 91 cases were admitted to the 368th Station Hospital and the 262d General Hospital. High fever, generalized lymphadenopathy, splenomegaly, and lymphocytosis were present in the majority of the cases; atypical lymphocytes were found in some of the blood smears, and a few lymph nodes examined were said to be compatible with the diagnosis of infectious mononucleosis. A number of atypical features were noted, however. These included the occurrence of bronchopneumonia in 16.7 percent of the patients, a rash in 46.7 percent, and a normal or slightly elevated heterophile antibody titer in the serum of most of the patients. This titer never exceeded 1: 224 in any serum, and serum from only 16 patients had titers of 1: 112, or higher. Elevated Weil-Felix and cold-agglutinin titers and false-positive tests for syphilis were not infrequently encountered. Because of these unusual features, this outbreak has not been included as an unequivocal instance of an epidemic of infectious mononucleosis. Postwar experience has seemed to indicate that one or more "dengue-like diseases" exist in Panama, of which this may have been an example.
11Vander Meer, R., Lutterloh, C. H., and Pilot, J. : Infectious Mononucleosis. An Analysis of 26 Clinical and 340 Subclinical Cases. Am. J.M. Sc. 210: 765-774, December 1945.
12Wechsler, H. F., Rosenblum, A. H., and Sills, C. T. : Infectious Mononucleosis; Report of an Epidemic in an Army Post. Ann. Int. Med. 25 : 113, July 1946, and 236, August 1946.
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occurred in the 18- to 20-year group. Every organization present had one or more cases, and 21 organizations contributed 10 or more patients each. Epidemiological surveys were not carried out. This report detailed the many clinical forms that infectious mononucleosis may take and gave special emphasis to the hepatic, pneumonic, and meningitic symptoms which had not been widely appreciated before this study.
Military Significance
From the data available, it appears that infectious mononucleosis was a fairly common illness among U.S. troops in all theaters but that it rarely assumed epidemic proportions. Nevertheless, the possibility that it might produce widespread outbreaks at some time in the future should be borne in mind. Only nine deaths attributable to the disease or its complications were reported in U.S. soldiers.13 Although usually benign, the disease required hospitalization for an average of 26 days and occasionally for much longer, especially in the icteric forms of the disease.
Control Measures
No specific control measures were taken with respect to infectious mononucleosis, and the general experience with the disease suggests that none were necessary. Patients were often hospitalized on open wards without evidence of cross infections,14 and even aboard ships secondary cases were apparently very uncommon.15 In civilian colleges and universities also, infectious mononucleosis seems to have a low index of contagiousness.16
Research
Attempts to study the nature of the etiological agent of the disease by transmission to experimental animals have been unsuccessful. Experiments with human volunteers, in this country under the direction of the Commission on Virus and Rickettsial Diseases of the Army Epidemiological Board, and experiments conducted abroad have given only suggestive results.
The property of serum from some cases to agglutinate human red cells modified by treatment with Newcastle disease virus, an agent responsible for
13Custer, R. P., and Smith, E. B. : The Pathology of Infectious Mononucleosis. Blood 3 : 830?857, August 1948.
14Mitchell, R. H., and Zetzel, L. P. : Infectious Mononucleosis in the Army. War Med. 5 : 356-360, June 1941.
15Paul, O.: Mononucleosis on Board a Destroyer. U.S. Nav. M. Bull. 44 : 614-617, March 1945.
16(1) Houser, K. M. : Infectious Mononucleosis. Pennsylvania M.J. 46 : 1173-1174, August 1943. (2) Contratto, A. W. : Infectious Mononucleosis : A Study of One Hundred and Ninety-Six Cases. Arch. Int. Med. 73 : 449-459, June 1944. (3) Milne, J. : Infectious Mononucleosis. New England J. Med. 233: 727-731, December 1945. (4) Evans, A. S., and Robinson, E. D. : An Epidemiologic Study of Infectious Mononucleosis in a New England College. New England J. Med. 242: 492-496, March 1950.
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a disease in chickens, was discovered by Burnet and Anderson17 in Australia and later was confirmed in this country.18 Newcastle disease virus appears unrelated to the hypothetical agent of infectious mononucleosis. Wider appreciation of the clinical forms of infectious mononucleosis was gained during the war, especially through excellent studies like that of Wechsler, Rosenblum, and Sills. Splenic rupture was recognized as a rare but occasionally fatal complication. Involvement of the liver even in nonjaundiced cases was first reported by Cohn and Lidman from the Boca Raton Army Airfield, Fla.,19 and has been confirmed and reported by other investigators. Histological proof of such hepatic lesions in the jaundiced patients was reported by Kilham and Steigman20 from the Harvard unit in England, as well as by Bang and Wanscher.21 Similar, though less definite, involvement in the nonjaundiced cases was noted in punch biopsies studied by Van Beek and Haex,22 and by Davis, MacFee, Wright, and Allyn.23 The occasional occurrence of meningitic and encephalitic forms of infectious mononucleosis was emphasized in several reports appearing during, or shortly after, the war.24 The pathology of the disease was carefully investigated by Custer and Smith of the Armed Forces Institute of Pathology on the basis of nine fatal cases of infectious mononucleosis,25 which perhaps represent the largest series of fatal cases ever assembled in one group. It was emphasized that lymphocytic infiltrates may occur in almost any organ and may account for the widely different clinical patterns which occur. Penicillin, the sulfonamides, and streptomycin were found generally ineffective in the treatment of the disease, except in preventing and eradicating secondary bacterial invaders.
17Burnet, F. M., and Anderson, S. G.: Modification of Human Red Cells by Virus Action. II. Agglutinization of Modified Human Cells by Sera From Cases of Infectious Mononucleosis. Brit. J. Exper. Path. 27: 236-244, August 1946.
18(1) Evans, A. S., and Curnen, E. C.: Serological Studies on Infectious Mononucleosis and Other Conditions With Human Erythrocytes Modified by Newcastle Disease Virus. J. Immonol. 58: 323-335, March 1948. (2) Florman, A. L.: The Agglutination of Human Erythrocytes Modified by Treatment With Newcastle Disease and Influenza Virus. J. Bact. 57: 31-38, January 1949.
19Cohn, C., and Lidman, B. I.: Hepatitis Without Jaundice in Infectious Mononucleosis. J. Clin. Investigation 25: 145-151, January 1946.
20Kilham, L., and Steigman, A. J.: Infectious Mononucleosis. Lancet 2: 452-454, October 1942.
21Bang, J., and Wanscher, O.: The Histopathology of the Liver in Infectious Mononucleosis Complicated by Jaundice, Investigated by Aspiration-Biopsy. Acta med. scandinav. 120: 437-446, 1945.
22Van Beek, C., and Haex, A. J. C.: Aspiration-Biopsy of the Liver in Mononucleosis Infectiosa and in Besnier-Boeck-Schaumann's Disease. Acta med. scandinav. 113: 125-134, 1943.
23Davis, J. S., MacFee, W., Wright, M., and Allyn, R.: Rupture of the Spleen in Infectious Mononucleosis. Lancet 2: 72-73, July 1945.
24(1) Thelander, H. E., and Shaw, E. B.: Infectious Mononucleosis, With Special Reference to Cerebral Complications. Am. J. Dis. Child. 61: 1131-1145, June 1941. (2) Coogan, T. J., Martinson, D. L., and Mathews, W. H.: Neurological Symptoms of Infectious Mononucleosis. Illinois M. J. 87: 296-302, June 1945. (3) Peters, C. H., Widerman, A., Blumberg, A., and Ricker, W. A., Jr.: Neurologic Manifestations of Infectious Mononucleosis; With Special Reference to the Guillain-Barre Syndrome. Arch. Int. Med. 80: 366-373, September 1947. (4) Field, W. W.: Infectious Mononucleosis With Severe Central Nervous System Involvement. Am. J. Med. 4: 154-157, January 1948. (5) Dolgopol, V. B., and Husson, G. S.: Infectious Mononucleosis With Neurologic Complications: Report of a Fatal Case. Arch. Int. Med. 83: 179-196, February 1949.
25See footnote 13, p. 360.
