Chapter 6
Other Viral Diseases
Jay P. Sanford, M.D., and Colonel Adolf E. Rahm, Jr., MC, USA
Section I. Acute Respiratory Disease
Jay P. Sanford, M.D.
Acute infections of the respiratory tract constitute a major health problem not only for civilians and military recruits but also for seasoned troops, even in areas of the world where hygienic and climatic conditions predispose the troops to other illnesses such as gastrointestinal disorders and skin diseases. Such was the USARV (U.S. Army, Vietnam) experience, where rates for respiratory infections (based on soldiers reporting on sick call and confined to quarters or admitted to medical care facilities) varied between 315 and 617 cases per 1,000 troop strength per annum (USARV-CHR 1970).
In the past 20 years, virologists have made major advances in defining the etiologic agents of common respiratory diseases. More than 100 agents of human respiratory disease are now recognized (Ward 1973). The goals of this presentation are to review the current knowledge of the etiology and epidemiology of acute respiratory illness with special reference to military populations, to summarize observations in U.S. Army personnel in Vietnam, and to recommend types of data which are useful in developing methods for surveillance and control.
HISTORICAL PERSPECTIVE
As a result of the recognition of "primary atypical pneumonia, etiology unknown" at Camp Claiborne, La., in the winter of 1941-42, the Commission on Acute Respiratory Diseases was established by The Surgeon General of the Army. The objectives of the commission were to classify the acute respiratory diseases occurring among military personnel and to investigate their epidemiology. Fort Bragg, N.C., was selected for study because of its large size and because both relatively stable military units and recruits could be observed. The commission laboratory opened at Fort Bragg in October 1942. The epidemiological data were published in 1968 by Dr. John H. Dingle, commission director, and Dr. Alexander D. Langmuir, a member of the commission (1968). Despite a 25-year delay in publication the observations are brilliant, and they are directly pertinent to the problem of acute respiratory diseases in Vietnam. Furthermore, because specimens collected from 1942 to 1946 were stored well, recently developed laboratory techniques could be applied to them, enabling some of the epidemiological observations to be clarified.
110
The terminology and diagnostic criteria for classifying data were as follows: For the entire post:
(1) Respiratory admissions: Daily admissions to the hospital with a diagnosis of some type of respiratory disease.
(2) Common respiratory diseases: Weekly admissions for respiratory disease as reported by the hospital`s registrar. Similar reports from all Army posts in the continental United States were combined in the Office of the Surgeon General and were compared with the Fort Bragg data.
(3) Primary atypical pneumonia: The figures for this category were based on routine chest roentgenograms taken at the time of admission and on discharge diagnosis.
For the special studies:
(1) Acute undifferentiated respiratory diseases (also termed acute respiratory disease [ARD] of recruits): Acute illnesses, usually febrile, with respiratory or generalized constitutional symptoms, or both, ordinarily of less than 2 weeks` duration. Patients having exudative tonsillitis or pharyngitis, specific contagious diseases, antibody responses to influenza viruses A or B or to streptolysin 0, or pulmonary infiltration demonstrable radiographically were excluded.
(2) Nonstreptococcal exudative tonsillitis or pharyngitis: Respiratory illnesses characterized by exudative lesions on the tonsils, palate, or oropharynx without either beta-hemolytic streptococci or an increase in titer of antistreptolysin antibodies during convalescence.
(3) Primary atypical pneumonia: Respiratory illnesses accompanied by roentgenographic evidence of pulmonary infiltration but not by clinical and laboratory evidence of bacterial pneumonia, bronchiectasis, or other causes of pulmonary consolidation.
(4) Hemolytic streptococcal infection: Diagnosed only when the illness was clinically compatible with such an infection and when beta-hemolytic streptococci were isolated from the throat and a significant rise in antistreptolysin titer was demonstrable during convalescence.
(5) Other illnesses: A small number of patients admitted with tentative diagnoses of respiratory disease proved to be suffering from other types of illness, such as immunization reactions, contagious exanthemas, meningococcal infection, or acute or chronic allergic disease. They were excluded from further consideration in this study.
The criteria employed in USARV Command Health Reports were essentially the same as those listed above except that CRD (common respiratory diseases) and acute undifferentiated respiratory diseases were interchangeable in Vietnam.
The first year of investigation at Fort Bragg led to a series of important observations. The most important respiratory disease, accounting for about 80 to 90 percent of hospital admissions, was ARD of recruits, so named because it was confined to newly inducted men. This disease occurred epidemically among both inductees in training centers and new recruits assigned to units composed of seasoned troops.
111
The epidemics began in the fall, usually in an irregular fashion. In midwinter, they were sharp, distinct, and self-limited in newly arrived units, usually occurring within the first 4 or 5 weeks of training and not recurring in those units. In the spring, the epidemics were less severe; they were barely discernible or absent in summer. Units arriving in late summer, whose training period extended into the fall or winter, frequently experienced an epidemic at the end of their training period.
Susceptibility to ARD usually correlated inversely with length of military service. Geographic origin and age did not appear to be important factors. In general, the acute respiratory diseases occurred in association with primary atypical pneumonia in a ratio of approximately 10 to 1, regardless of season or length of service.
ARD OVERVIEW
Temperate Areas
Virtually all of the etiological and epidemiological studies of ARD which might serve as background upon which to assess the USARV experience are of troops based in temperate climates. The general pattern of occurrence of respiratory diseases in these areas is summarized, by specific agents, in table 19. The difficulty of extrapolating from such data is reflected in the following example. In the late summer and fall of 1968, an outbreak of coxsackievirus A21 occurred among marine trainees at Camp Lejeune, N.C., accounting for 60 to 86 percent of viral isolations; however, between February 1969 and February 1971, no isolations of this organism were made (Wenzel et al. 1971).
In addition to rates of occurrence, the severity and duration of illness are important considerations. For instance, while 89 percent of a group of Navy and marine recruits shed rhinoviruses on at least one occasion during 4 weeks of study in November 1965 and only 1 to 2 percent of them did not have symptoms
112
of a common cold, these illnesses did not require loss of time from duty, although efficiency was undoubtedly impaired (Rosenbaum et al. 1971). In contrast, the average duration of hospitalization for ARD caused by adenovirus 4 or 7 was about 9 days, and for Mycoplasma pneumoniae illness the average was 20 days (Wenzel et al. 1971). While criteria for hospitalization and assignment to quarters probably differed, during an outbreak of influenza caused by A2/Hong Kong, the average time lost from duty was 2.6 days(Smith et al. 1970).Specific duties of afflicted personnel must also be considered. For example, a rhinovirus infection or otitis externa may be totally incapacitating in airborne personnel in whom aerotitis or aero sinusitis may occur, while these same entities merely decrease efficiency in ground support personnel.
Tropical Areas
The seasonal change of weather is one of the factors that influence the spread of respiratory viruses through a population. Several studies demonstrating this have been performed in tropical areas; however, these have primarily involved children, and applying the data to adults is difficult (Monto and Johnson 1967; Chanock, Chambon, et al. 1967; Bell et al. 1959).
In a study designed to define the etiology of severe viral respiratory infections in children, particularly in tropical areas, paired serums were collected from 528 children up to 5 years old admitted to hospitals in 10 countries (Chanock, Chambon, et al. 1967). The areas surveyed included Hong Kong, Singapore, and New Delhi. The findings indicated that the pattern of severe respiratory disease in tropical areas is similar to that which has been defined in temperate areas.
In a serological survey of both children and adults in Paraiso, Canal Zone (Panama), between May 1963 and January 1964, 41 individuals between the ages of 15 and 39 were included (Monto and Johnson 1967). Significant increases in antibody titer were noted in seven (17 percent): two in the parainfluenza 1 group, three in the parainfluenza 3 group, one in the respiratory syncytial virus group, and one in the adenovirus group; there were none in the parainfluenza 2 and Mycoplasma pneumoniae groups. No differences in antibody content were demonstrated when comparisons were made with serums obtained from a group of American adults. Respiratory disease accounted for more than two-thirds of the illnesses seen in Paraiso, with rates as high as 160 per 1,000 per month, so that lack of a winter season did not prevent dissemination of pathogens. An increase in illness was usually seen at the start of the rainy season, which coincided with the start of the school year.
These observations reflect a similarity between tropical and temperate climates. In contrast, in a study of adenoviruses isolated from conjunctival specimens in eastern Saudi Arabia, adenovirus types 1, 2, and 5, which are com mon in the United States, were never isolated; types 15, 16, 17, and several new types which were common in Arabia have not yet been reported in the United States (Bell et al. 1959).
113
Olson and associates (1973), in Thailand, observed that periods when specific agents were prevalent were independent of season, the only relevant weather variable being the presence or absence of rainfall. (The one possible exception was the 2-year period when coxsackievirus B2 was recovered only during January and February, months corresponding to the drier season.) Influenza A outbreaks were recognized in Hong Kong in April 1957 and July 1968 (Sanford 1969).
Thus, from the limited data available one could expect the patterns of seasonal occurrence in temperature climates to be absent or altered in tropical climates, where other factors would dominate the epidemiology. Furthermore, although viral respiratory diseases are widespread, the relative frequencies given for various pathogens in temperate climates only reflect observations in urban groups. In addition, differing serotypes may be encountered in different areas of the world, as with adenoviruses and possibly rhinoviruses.
ARD IN VIETNAM
Technical Considerations
Most of the data presented here, obtained from monthly USARV Command Health Reports (USARV-CHR) and from reports of selected units, have been reviewed not only for rates but also for the preventive medicine officers` comments. In these reports, rates are defined as follows:
rate = new cases x 1,000 x days in year
average morbidity strength x days in month
The terminology used includes:
ARD - acute respiratory disease; cases requiring hospitalization or assigned to quarters.
CRD - common respiratory disease; used interchangeably with ARD.
URI - upper respiratory infection; includes outpatients with symptoms of upper respiratory infection as well as individuals requiring hospitalization or assignment to quarters, except for patients with pneumonia, influenza, and streptococcal sore throat.
Pneumonia - a separate category; a requirement for radiographic change was not defined.
Unfortunately, laboratory support for identification of respiratory disease agents was essentially limited to the detection of cold hemagglutinins. The 9th Medical Laboratory Activities Report for 1968 (ML9-AR, p.19) stated that expanded studies of known agents of respiratory disease were projected and that attempts would be made to isolate antigenic variants of the principal groups being studied.
____________
Materials reviewed for the statistics in this section include monthly reports from the unit surgeons of the 1stCavalry Division (Airmobile), the 173d Airborne Brigade (Separate), and the 9th Infantry Division, to the USARV Surgeon, 1965-70 (CD1-HR; AB173-HR; ID9-HR). The data from these reports were used in the USARV surgeon`s monthly reports to the USARV commander. Other sources are noted where appropriate.
114
Observations
The rates for URI varied markedly among units; for example, in March 1969 the rate in the 1st Infantry Division was reported as 2.2 cases per 1,000 average strength per year, while that of the 11th Armored Cavalry Regiment was 167 per 1,000 per year. Such discrepancies almost certainly reflect differences in reporting. Overall U.S. Army URI rates for 1968-70 fall in the range of 350 to 600 per 1,000 per year, which is remarkably close to the lowest rate from Fort Bragg in June and July 1944-520 per 1,000 per year (Dingle and Langmuir 1968).
The ARD rates vary less and may reflect more accurately the total respiratory disease problem, although only 6.5 to 12 percent of all individuals with respiratory diseases were assigned to quarters or admitted to hospitals. Rates for USARV for 1965 through 1970 are plotted in chart 5. These rates (15 to about 105 per 1,000 per year) are comparable to the rates observed for the Army in the continental United States during 1944-45 (50 to 200 per 1,000 per year) (chart 6), especially since these latter rates included a proportion of recruits. The reason for the higher rates in USARV in 1965 is unknown.
A role of weather changes in the frequency of URI (and possibly ARD) was suggested by comments in the health reports of various units. An increase in URI between December 1968 and January 1969 in XXIV Corps tactical area, I CTZ (Corps Tactical Zone), was associated with the occurrence of rain and cooler weather, especially at night. A similar increase at Long Binh in April 1969 was associated with the monsoon. To better document these impressions, ARD rates for 1967 for the 9th Infantry Division at Dong Tam, in IV CTZ in the Mekong Delta, were compared with the rates for the 1st Cavalry Division (Airmobile) at An Khe and the 173d Airborne Brigade at Dak To, both in II CTZ in the Central Highlands (chart 7). The 9th Infantry Division was exposed to the summer monsoons and temperatures often exceeding 100° F at midday, while the 1st Air Cavalry Division (AM) and 173d Airborne Brigade were in the area of the winter monsoons (October to April), with temperatures in the 70`s. No correlation could be made between ARD rates and season (dry or monsoon) or temperature differences associated with altitude. An isolated rate of 276.4 cases per 1,000 in the 9th Infantry Division in January is unexplained.
Rates for pneumonia were 8 to 10 percent of the ARD rates, varying between 1.3 to 6.8 per 1,000 per year, except for a rate of 10.5 per 1,000 per year in November 1967.
Confirmation of the specific etiologies which were responsible for ARD has not been possible. The occurrence of influenza A2/H3 N2/Hong Kong in the late summer and fall of 1968 is suggested by individual reports. In August, classical symptoms of an influenzal syndrome were noted in various units, including the 11th Armored Cavalry Regiment near Xuan Loc. In this regiment, rates for ARD increased from 98.8 per 1,000 in July to 386.1 per 1,000 in August. In December 1968, an increase in influenzal illness was reported in the Americal Division (23d Infantry Division).
115
CHART 5.- Reported incidence of acute (common) respiratory diseases in USARV, 1965-701
116
117
These observations coincide with those reported by Smith and associates (1970) at the Korat Royal Thai Air Force Base, Thailand, where the initial peak of Hong Kong influenza occurred during the week of 19 August and the outbreak lasted through October. The duration of illness varied between 1 and 14 days (average 3.8 days), with an average of 2.6 days lost from duty. The attack rate was 8 percent based upon number of individuals off duty and 12.2 percent based upon a serological survey. The spread was slow, with no more than 1.5 percent of troops sick at any one time, and the outbreak subsided while a large segment of the population was still susceptible; thus, it was only slightly disruptive of activities. The relatively minor increase in ARD reported in Vietnam during the
118
fall of 1968 (see chart 5) may have been caused by the same virus, especially since the A2/Hong Kong influenza vaccine was not received until late 1968 or early 1969.
In a study of FUO (fever of undetermined origin) in Special Forces troops in 1963, Legters, Buescher, and Coppage* observed that infection with a respiratory agent, demonstrated by serologic evidence, was the most common etiology (table 20). Of particular interest in this study is the proportion of adenovirus group infections. One can only speculate that despite the fact that these men were seasoned troops they encountered adenovirus types with which they had not had previous contact; in view of the differences in adenovirus types encountered by civilians and the military in the United States and military groups elsewhere in the world, this seems plausible.
TABLE 20.- Review of 553 Special Forces troops with fever of undetermined origin, Vietnam, 1963 1
The occurrence of RS (respiratory syncytial) virus in this group is also of considerable interest since almost all adults have RS antibody. RS virus primarily causes respiratory disease in infants and children (Chanock, Chambon, et al. 1967; Reilly et al. 1961), although a common cold like syndrome can be produced in adult volunteers and acute lower respiratory illness has been observed in elderly patients (Kravetz et al. 1961; Fransen et al. 1967).
An unpublished study of a group of hospitalized patients by Arnold and associates** provides additional insight into the etiologic basis for pneumonia. Sixty-eight patients admitted consecutively to the 3d Field Hospital in Saigon between November 1969 and February 1970 with a diagnosis of pneumonia were studied. Bacteriological and virological isolation techniques (monkey kidney cells and WI-38 human diploid cells) and serological procedures (cold agglutinins, psittacosis, Mycoplasma pneumonia, respiratory syncytial, adenovirus group, influenza A, influenza B, parainfluenza 1 and 3, and melioidosis tests)were used.
____________
*R. L. Coppage: Personal communication, based on data gathered by L. J. Legters, E. L. Buescher, and R. L. Coppage.
* *K. Arnold: Personal communication.
119
Of the 68 patients, 59 were U.S. military personnel stationed within 50 miles of Saigon. Acute and convalescent serum specimens were obtained from 58 patients. Of these, 24 (42 percent) had significant increases in the complement fixation test for M. pneumoniae. (Cold aggutinins were elevated in eight patients, six of whom had a positive complement fixation text for M. pneumoniae.) Analysis of clinical features revealed no differences distinguishing the patients with M. pneumoniae infections from the others.
Among the infectious diseases diagnosed in 1969 in consultation with the 9th Medical Laboratory (ML9-AR 1969, p. 17) were 22 cases of primary atypical pneumonia. The following list of cases (incomplete for November and December) shows the facilities where probable and confirmed cases were seen:
3d Field Hospital - 5
6th Clearing - 2
24th Evacuation Hospital- 5
3d Surgical - 2
67th Evacuation Hospital- 1
91st Evacuation Hospital- 2
93d Evacuation Hospital- 2
95th Evacuation Hospital- 1
Other - 2
These diagnoses were based solely upon positive cold agglutinins; hence, they grossly underestimate the actual occurrence of M. pneumoniae infections. However, they do indicate that cases were encountered throughout Vietnam. These observations can be compared with observations in the United States, where M. pneumoniae is responsible for 20 to 44 percent of pneumonia hospitalizations (Chanock, Fox, et al. 1967; Griffin and Crawford 1969; Mogabgab 1968).
LESSONS LEARNED
Conclusions about ARD in USARV personnel in 1965-73 can be summarized as follows:
Upper respiratory disease was a major illness among U.S. Army personnel, ranking approximately equally with diarrheal disease as a cause of hospitalization or assignment to quarters.
The specific causal agents responsible for the acute respiratory disease syndrome in Vietnam were not defined. Limited studies suggest the occurrence of members of the adenovirus group as well as respiratory syncytial viruses. During the fall of 1968, influenza of the A2/H3 N2/Hong Kong strain was widespread but was not associated with marked increases in hospitalization or mortality. Mycoplasma pneumoniae was the most common demonstrable causative agent in soldiers admitted to hospitals with pneumonia.
The following recommendations are made:
Standardized diagnostic and reporting criteria should be developed to improve surveillance.
Because of the prevalence of acute respiratory disease among even seasoned troops and the potential for developing means of immunoprophylaxis and chemoprophylaxis, clinical and laboratory support should be provided early to enable definition of specific disease problems.
120
Data on time lost from duty and reduction of unit effectiveness because of specific disease entities should be collected so that priorities may be established in the development of control measures.
Section II. Infectious Mononucleosis
Jay P. Sanford, M.D.
Infectious mononucleosis is a clinical syndrome which has been defined by clinical features, typical hematologic findings, and the presence of heterophil antibodies. The diagnostic criteria of Col. Robert J. Hoagland, MC (1967), have made possible more uniform diagnoses of the syndrome and have facilitated some astute observations on its epidemiology. Patients with clinically similar syndromes, in whom heterophil antibodies were absent, have been reported, resulting in the designation of a "heterophil-negative mononucleosis."
Henle, Henle, and Diehl (1968) reported the association of the EBV (Epstein Barr virus), a herpes-like virus, with infectious mononucleosis. Subsequently persuasive evidence that EBV is causally related to heterophil-positive infectious mononucleosis was accumulated (Henle and Henle 1973). Studies based on serological evidence of infection with EBV have confirmed many earlier postulates, clarified aspects of the epidemiology, and modified some traditional clinical considerations. The experiences of the U.S. Army Medical Department in Vietnam will be reviewed and interpreted in light of this new knowledge.
ETIOLOGY
Since its earliest comprehensive descriptions, infectious mononucleosis has been strongly suspected of having a viral etiology, on the basis of clinical and epidemiological patterns and heterophil antibody responses. Hoagland (1967, p.3) summarized the salient features of the syndrome: occurrence in young adults, usually between 15 and 23 years of age; a low degree of communicability, reflected by infrequent occurrence among roommates; prolonged duration of fever; sore throat, splenomegaly, and posterior cervical adenopathy; absolute and relative lymphocytosis, including the presence of atypical lymphocytes in the peripheral blood; and agglutinins for sheep erythrocytes (positive heterophil) which are not absorbed by guinea pig kidney extract.?
The following observations support a causal association between EBV and heterophil-positive infectious mononucleosis. Infectious mononucleosis has been found to develop only in individuals whose serums lacked EBV antibody (Evans, Niederman, and McCollum 1968). EBV antibody has been absent in pre-illness serums of patients with infectious mononucleosis and has appeared during illness. The presence of EBV antibody has been regularly demonstrated in heterophil antibody-positive cases (Niederman et al. 1968; Evans, Niederman, and McCollum 1968; Smith and Bausher 1972). EBV is recoverable from washed leukocytes of patients with infectious mononucleosis (Diehl et al. 1968), which
121
may be transmitted by transfusion of whole blood or various blood components (Hoagland 1967, p. 25; Gerber et al. 1969; Blacklow et al. 1971; Turner, MacDonald, and Cooper 1972).
Throat washings from patients with infectious mononucleosis usually contain a filterable agent which is capable of transforming human umbilical cord leukocytes into lymphoblasts (Gerber et al. 1972; Miller, Niederman, and Andrews 1973; Golden et al. 1973) or converting an indicator lymphoid cell from negative to positive for EBV antigen (Golden et al. 1971). The transformed cells contain EBV-specific complement fixing antigens and EBV DNA (Gerber et al. 1972). The transforming capacity is neutralized by serums with EBV antibody (Miller, Niederman, and Andrews 1973).
EBV-specific IgM antibody responses suggesting primary infection have been demonstrated by special immunofluorescence techniques (Hampar, Hsu, and Martos 1971; Banatvala, Best, and Waller 1972; Schmitz and Scherer 1972). The inoculation of EBV-transformed autologous lymphoblasts in squirrel monkeys has induced both heterophil and EBV-specific antibodies (Shope and Miller 1973). Even though the last of the Koch postulates-the induction of infectious mononucleosis by the administration of EBV to susceptible volunteers -has not been fulfilled, the evidence for causal association between EBV and infectious mononucleosis appears convincing.
Some patients manifest many of the clinical features and hematologic signs of infectious mononucleosis but have negative heterophil agglutinations. Heterophil-negative mononucleosis syndromes have been associated with infections caused by Toxoplasmagondii (Remington et al. 1962; Beverley and Beattie 1958), adenoviruses, and cytomegaloviruses (Klemola et al. 1969).
In Western Europe and England, toxoplasmosis was estimated to account for 3 to 7 percent of heterophil-negative glandular fever (Beverley and Beattie 1958). In the United States, Remington and associates studied a group of 154 college students hospitalized with suspected infectious mononucleosis and found that, of the 85 students in whom other illnesses were not subsequently diagnosed, 34 had negative heterophil titers. Paired serums were obtained from 92 students; significant rises in toxoplasma dye inhibition titers or hemagglutination titers were demonstrated in 3 (Remington et al. 1962). Thus, toxoplasmosis may occasionally present as heterophil-negative infectious mononucleosis.
Infection with CMV (cytomegalovirus) can cause an illness hematologically resembling infectious mononucleosis but not associated with heterphil antibodies and often not associated with tonsillitis or cervical lymphadenopathy. Klemola and associates (1969) found that among 275 patients with infectious mononucleosis or a similar syndrome, 60 (22 percent) had negative heterophil titers. Recently, evidence for the occurrence of CMV and EBV was studied in 44 of these patients (Klemola et al. 1970). In 19 of the 44 cases, none of which involved tonsillitis or cervical lymphadenitis, CMV was implicated. Eight of the remaining 25 patients had high EBV antibody titers indicating current or recent infection, and 12 had titers compatible with either current or past infection. EBV and CMV seem to be the principal etiologic agents of heterophil antibody-
122
negative mononucleosis, but a proportion of cases is caused by as yet unidentified agents.
VIETNAM EXPERIENCES
Technical Considerations
The laboratory diagnosis of infectious mononucleosis during the later years of the Vietnam conflict was based upon the screening monospot or rapid slide test, using formalized horse erythrocytes. The correlation of this test with the Davidsohn differential test (used as the arbitrary definition of infectious mononucleosis) is 98.5 percent. Its sensitivity corresponds to that of sheep erythrocyte agglutination tests (Hoff and Bauer 1965). Some specimens diagnosed by the monospot test were forwarded to the 9th Medical Laboratory for confirmation by the Paul-Bunnell sheep erythrocyte agglutination and Davidsohn differential tests. The change from the traditional Paul-Bunnell technique to the monospot test apparently did not significantly modify diagnostic results.
Because infectious mononucleosis was not reported as a separate item in monthly USARV Command Health Reports, incidence figures are not available for the entire command. The major sources of data for this review were the Army Medical Service Activities Reports submitted by the 9th Medical Laboratory and its components, the 946th, 528th, and 406th Mobile Medical Laboratories (ML9-AR). However, the 9th Medical Laboratory data do not accurately reflect the number of cases of infectious mononucleosis in Vietnam since hospital laboratories and the mobile medical laboratories directly supported most of the hospitals and merely referred specimens to the 9th Medical Laboratory. The 9th Medical Laboratory did provide direct support to the 36th Evacuation Hospital near Vung Tau; hence, its data are mixed.
Observations
The data from the 9th Medical Laboratory are summarized in table 21. The proportion of positive tests to tests ordered ranges from 10 to 22 percent. Applying these figures, the estimated number of cases for 1968 is between 240 and 520. In 1967, approximately 480 serums at the 528th Mobile Medical Laboratory, Qui Nhon, had positive titers of heterophil antibodies if 10 percent of those tested were positive. Assuming U.S. Army troop strength at approximately 300,000 men during 1967 and applying the rate of hospitalization for infectious mononucleosis of U.S. marines in Vietnam-2.1 per 1,000 per year (Lehane 1970) - this figure reasonably approximates the anticipated incidence of infectious mononucleosis. Using the same rate and assuming the U.S. Army troop strength to be approximately 400,000 during 1968 and early 1969, the incidence of infectious mononucleosis is approximately two to four times the number of cases recorded in table 21.
In the FUO studies summarized by Col. John J. Deller, Jr., MC, in chapter 4, infectious mononucleosis was not a significant diagnosis; among 892 patients in
123
five studies, 6 had heterophil-positive infectious mononucleosis: 4 from I CTZ, 1 from Nha Trang in II CTZ, and 1 from Dong Tam in IV CTZ.
The increased frequency of requests for serological tests for infectious mononucleosis which occurred during the third and fourth quarters of 1968 is striking; it may be related to the allowance of leave following the January 1968 Tet offensive. Many cases of infectious mononucleosis occurred following leave to the United States and the disease was relatively frequent among soldiers about to be reassigned to Vietnam at the end of their home leave.
Lehane estimated the rate of seroconversion to EBV among susceptible Marine Corps recruits (14.3 percent of those studied) to be 166 per 1,000; the overall rate was 23.8 per 1,000 during a 13-month tour in Vietnam. This latter rate, contrasted with the hospital discharge rate of 2.1 per 1,000, suggests that the ratio of inapparent to apparent infection is approximately 10:1 (Lehane 1970). The application of these figures to U.S. Army personnel suggests a much higher EBV infection rate than is reflected in the available data. The ratio of inapparent to apparent infection among college students is much lower than the military figure, varying between zero and 1:2 (Sawyer et al. 1971; Niederman et al. 1970). A similar discrepancy between civilian adults and military population has been observed in another infectious disease, rubella, in which the ratio of inapparent to apparent disease is 1:1 or 2:1 for civilians but as high as 6.5:1 for military recruits (Horstman, Pajot, and Liebhaber 1969; Buescher 1965).
LESSONS LEARNED
Infectious mononucleosis must be anticipated whenever health plans include young adults. However, U.S. Army Medical Department data suggest that
124
the incidence of clinically apparent infectious mononucleosis in Vietnam was perhaps less than that encountered in military hospitals in the United States, that is, 3 to 4 cases per 100 admissions. It is unlikely that "heterophil-negative" mononucleosis is important in accounting for the difference. Bender (1959) discussed the relative lack of infectious mononucleosis in the Southwest Pacific Area during World War II. He attributed at least a portion of the decrease to the absence of women, but this was probably not the only factor.
Observations on EBV clearly demonstrate that persons of lower socioeconomic status acquire it at an early age as an asymptomatic or undifferentiated illness. Shedding of the virus in pharyngeal secretions may occur for considerable intervals but appears to become less common as the time since acquisition of infection increases. Thus, while the American soldier in Vietnam may have had considerable contact with women under circumstances conducive to the spread of EBV, most of his contacts probably had acquired it at so early an age that by puberty they only infrequently shed the virus in oral pharyngeal secretions. However, the susceptible soldier is at high risk and may acquire EBV while home on temporary leave or reassignment. Since almost all soldiers received leave and many were in the United States, including Hawaii, where they were probably exposed to infectious mononucleosis, this might account for the overall infection rate of 29.9 per 1,000 in susceptible (EBV antibody-negative) marines in Vietnam in comparison with a rate of 11.1 per 1,000 for susceptible college students (Lehane 1970). The apparent high rate of acquisition of EBV antibodies by susceptible individuals stationed in Vietnam may reflect not only experience in Vietnam but also greater opportunity for exposure during brief intervals out of country. Accepting this hypothesis, the problem that infectious mononucleosis poses to military effectiveness will be determined to a major extent by the socioeconomic conditions of the area in which troops are stationed. It is unlikely that epidemics will occur or that the disease will interfere with combat unit effectiveness as do many other infectious diseases in the Tropics.
Section III. Rabies
Colonel Adolf E. Rahm, Jr., MC, USA
Any warmblooded animal can carry rabies, a fact which fosters a serious problem whenever American troops are deployed overseas. Even in the United States, where most pets are immunized, some 30,000 Americans received vaccinations because of actual or possible exposure to rabies in 1967 (Plotkin and Clark 1971).
In a country like Vietnam where pets were not routinely immunized, the risk of exposure to rabies was much greater. In 1969, there were reports of 2,967 animal exposures; 1,628 individuals were treated prophylactically for rabies, and 76 were also given immune serum (USARV-CHR 1969). In 1970, 1,905 exposures were reported, 1,039 individuals were immunized, and 125 received serum (USARV-CHR
125
TABLE 22.-Animal bite cases and antirabies treament, USARV, 1969 and 1970
1970). Table 22 shows the monthly breakdown of animal bite cases and antirabies treatment in USARV in 1969 and 1970.
An average of 352,755 individuals in 1969 and 289,964 in 1970 were eligible for primary medical care through Army Medical Department resources in Vietnam.* Contact with hostile forces during those years was more or less average and many troops who were not in direct combat activity had numerous opportunities to acquire pets. The disparity between the number of immunizations given and the number of exposures reported suggests that some of these pets were vaccinated, probably as a result of military pet control programs.
Some significant problems did arise. An 11-week-old female dog belonging to B Troop, 2d Squadron (Airmobile), 17th Cavalry, 101st Airborne Division, exhibited lethargy, staggering gait, and excessive salivation. Examination by a veterinary unit following her isolation and death revealed fluorescent antibody and histological evidence of rabies. During interviews 65 members of B Troop admitted to being licked, scratched, or bitten by the animal during her infectious period. Sixty-three individuals were treated with a 14-day series of duck embryo vaccine, and two were also given hyperimmune serum. One individual developed an allergic reaction to the duck embryo vaccine and was hospitalized and treated with Benadryl, and the immunization was continued. Later, a littermate of the rabid dog, which belonged to another unit, exhibited lethargy, staggering gait, and excessive salivation. Since the unit was now alert to the rabies threat, the dog was destroyed by repeated blows upon the head with a rifle butt, rendering examination of the brain inconclusive. It was necessary, therefore, to immunize an additional 27 individuals (USARV-CHR Feb. 1970, Tab I). While immunizing 90 individuals may not seem to be a great task, it involved 1,260 injections, requiring considerable expenditure of time and effort by medical personnel. Fur
____________
*Headquarters, 5th U.S. Army Surgeon`s Office, Preventive Medicine Division. Inquiry, 2 Mar. 1973.
126
thermore, those 90 individuals could perform no activity in the field for 2 weeks while they received their immunizations.
Knowledge of which species carry rabies is of paramount importance in treating animal bite cases. A status report on rabies between January and June 1969, published in the USARV Medical Bulletin (Shroyer 1969), indicates that of 146 dogs whose heads were submitted for examination at the 9th Medical Laboratory, 26 were rabid; of 25 cats and 22 rats, none was (fig. 39). Monkey, mouse, bat, and chipmunk specimens were negative for rabies. One human specimen was positive.
In 1968, 300 rats examined at the laboratory were negative for rabies, as were 224 rats examined at the Navy Support Command Laboratory. The USARV medical consultant commented: "This report again reinforces the present policy of not administering rabies vaccine in cases of rat bite in Vietnam."
127
The question of whether or not to administer rabies prophylaxis following rodent bites is a thorny one, as rodents can carry rabies. The decision may depend on the circumstances of the bite. The USARV preventive medicine consul tant in 1969 noted (USARV-CHR Dec. 1970, p.13): "Although the 9th Medical Laboratory has not reported any positive specimens for rabies in rats, it is recommended that rabies advisory boards strongly consider initiation of rabies treatment following all unprovoked rat bites." Art must sometimes transcend science when making a decision regarding a disease which with rare exception has been 100 percent fatal (Rose, Schnurrenberger, and Martin 1971).
Rabies prevention programs during the Vietnam conflict were very effective; only one death occurred among Army troops, in Saigon in January 1973, just at the close of hostilities.``
Lt. Louis P. Definer, MC, USN (1970), reported on the death of a young marine. The description of the case follows:
A 20-year-old white man was bitten on the right middle finger by a stray dog on the evening of September 4, 1967. The dog was killed immediately, but study of the brain was not possible because of improper handling. The wound was vigorously cleaned and the patient arrived at the U.S. Naval Support Activity Station Hospital, Da Nang, Vietnam, on September 6, 1967. The only pertinent physical finding was a painfully swollen and lacerated right middle finger. Results of the hemogram and urinalysis were normal. The wound was recleaned, and a dose of 1,000 IU of rabies antiserum (equine) was given locally about the wound. An additional 4,000 IU were given intramuscularly. Duck embryo vaccine was started immediately and administered daily for 21 consecutive days. Booster doses were given 10 and 20 days after the completed series.
The patient returned to his unit and did well until December 17, 1967, when he noted tingling and some pain in his right hand, which subsided. Two days later, the tingling sensation recurred and involved his entire right arm, chest, and face. He noted that the right side of his body perspired more than the left. Physical examination on December 19, 1967, showed an alert, cooperative young man with a temperature of 102° F. Hyperesthesia of the right scalp, right side of the face, and right upper extremity were prominent. The remainder of the findings from examination were unremarkable. The following day, the patient became extremely hyperactive and disoriented. A lumbar puncture disclosed an opening pressure of 140 mm of water, and the fluid was clear. The cerebral spinal fluid protein was 45 mg/100 ml, and the sugar was 91 mg/100 ml. No cells were noted. His condition remained stable for the next 24 hours.
His final 24 hours were characterized by marked clinical deterioration. Physical examination showed extreme restlessness, disorientation, increased motor activity, and hyperventilation. He was gasping and unable to swallow. He responded only to simple commands. The abdominal re flexes were absent; findings from neurologic examination were otherwise negative. The white cell count was 26,600/mm3 with 90% neutrophils. The hemoglobin was 17.4 g/100 ml. The cerebrospinal fluid protein on a repeat lumbar puncture was 200 mg/100 ml, and the sugar was 157 mg/100 ml. No cells were noted. The patient died during an episode of vomiting 108 days after the dog bite.
The autopsy was performed 7 hours after death. The pertinent findings at autopsy were acute congestion and edema of the lungs and slight congestion of the liver.
The brain weighed 1,300 g. The leptomeninges were clear, and the cortical convolutions were unremarkable. There were no signs of increased intracranial pressure. The vasculature at the base of the brain was normal. The consistency of the brain on palpation was unremarkable. The brain was sectioned in the fresh state, and blocks were taken from the frontal lobes, hippocampal gyri, midbrain, medulla, and spinal cord for imprints and mouse inoculation. Tissue from these areas was fixed in Zenker`s formalin for histologic examination.
____________
* Infectious Disease Branch, PreventiveMedicine Division, Directorate of Health and Environment, Office of the Surgeon General. Inquiry, Jan. 1973.
128
Occasional eosinophilic intracytoplasmic inclusions consistent with Negri bodies were identified in Purkinje cells of the cerebellum. A moderate to marked perivascular inflammatory reaction composed predominantly of lymphocytes was present in the pons and medulla.
Homogenates from portions of the patient`s brain were injected intracerebrally into suckling white mice. All animals became ill with central nervous system signs on the twelfth and fourteenth days after inoculation. Microscopic examination showed eosinophilic cytoplasmic structures in the neurons of the hippocampal gyri.
Although fluorescent antibody preparations showed equivocal results on portions of the patient`s brain, they were positive on tissue from the infected mouse brains.
The key to a good control program is an appointed rabies advisory board or control committee within each hospital-size facility (USARV-Reg). The committee should consist of at least three physicians who can be called together in person or on the telephone to discuss the advisability of prophylaxis in each individual animal bite case; thus, more than one person makes the decision, and the individual physician is assisted and directed by a knowledgeable group. The loss of more than one well-informed individual through simultaneous transfer is unlikely. Guidance and current information should be given the widest dissemination. Local commanders must be stimulated to publish regulations on the control of animals. Pets should be limited to one per company-size unit and must be immunized since this procedure is approximately 95 percent effective in preventing rabies (Rose, Schnurrenberger, and Martin 1971). All animals must be penned or kept on a leash. Finally, stray or unwanted animals should be presented to the nearest veterinarian or veterinary unit for euthanasia.
In Vietnam, as noted earlier, post exposure prophylaxis was a large part of the rabies program, as was pre exposure prophylaxis among veterinary personnel and others exposed to animals. The World Health Organization`s recommendations were followed. Reporting of animal bites and numbers of prophylactic immunizations was mandatory. In addition to giving command surgeons information necessary to obtain adequate supplies of vaccines, bite incidence statistics provide a system of monitoring the animal control programs so that, if these measures are ineffective, command pressure can be applied to rectify the situation.
REFERENCES
AB173-HR-Brigade surgeons, 173d Airborne Brigade (Separate). Monthly health reports to USARV surgeon, 1965-70.
Banatvala, J. E.; Best, J. M.; and Waller, D.K. 1972. Epstein-Barr virus-specific IgM in infectious mononucleosis, Burkitt lymphoma, and nasopharyngeal carcinoma. Lancet 1:1205-8.
Bell, S. D., Jr.; McComb, D. E.; Murray, E.S.; Chang, R. S.; and Snyder, J. C. 1959. Adenoviruses isolated from Saudi Arabia. I. Epidemiologic features. Am. J. Trop. Med. 8: 492-500.
Bender, C. E.1959. Clinical epidemiology of mononucleosis at a state university. Northwest Med. 58: 697-700.
Beverley, J. K. A., and Beattie, C. P. 1958.Glandular toxoplasmosis: A survey of 30 cases. Lancet 2: 379-84.
Blacklow, N. R.; Watson, B. K.; Miller, G.; and Jacobson, B. M. 1971. Mononucleosis with heterophil antibodies and EB virus infection. Acquisition by an elderly patient in hospital. Am. J. Med. 51: 549-52.
Buescher, E. L. 1965. Behavior of rubella virus in adult populations. Arch. ges. Virus for sch. 16: 470-76.
CD1-HR-Division surgeons, 1st Cavalry Division (Airmobile). Monthly health reports to USARV surgeon, 1965-70.
Chanock, R.; Chambon, L.; Chang, W.; Goncalves Ferreira, F.; Gharpure, P.; Grant, L.; Hatem, J.; Imam, L;Kalra,S.; Lim, K.; Madalengoitia, J.; Spence, L.; Teng, P.; and Ferreira, W.1967. WHO respiratory disease survey inchildren. A serological study. Bull. World Health Organ. 37:363-69.
Chanock, R. M.; Fox, H. H.; James, W. D.;Gutekunst, R. R.; White, R. J.; and Senterfit, L. B. 1967. Epidemiology of M. pneumoniae infection in military recruits. Ann. New YorkAcad. Sc. 143: 484-96.
Delmer, L. P. 1970. Human rabies encephalitis in Vietnam. Ann. Int. Med. 72: 375-78.
Diehl, V.; Henle, G.; Henle, W.; and Kohn,G.1968. Demonstration of herpes group virus in cultures of peripheral leukocytes from patients with infectious mononucleosis. J. Virol.2: 663-69.
Dingle, J. H., and Langmuir, A. D. 1968.Epidemiology of acute respiratory disease in military recruits. Studies at Fort Bragg, North Carolina, during World War II. Am. Rev. Resp. Dis.97: 1-65.
Evans, A. S.; Niederman, J. C.; and McCollum, R. W. 1968. Sero epidemiologic studies of infectious mononucleosis with EB virus. New England J. Med. 279: 1121-27.
1st Cavalry Division (Airmobile), monthly health reports. See CD1-HR.
Fransen, H.; Sterner, G.; Forsgren, M.; Heigl, Z.; Wolontis, S.; Svedmyr, A.; and Tunevall, G. 1967. Acute lower respiratory illness in elderly patients with respiratory syncytial virus infection. Acta med. scandinav. 182: 323-30.
Gerber, P.; Nonoyama, M.; Lucas, S.; Perlin, E.; and Goldstein, L. I. 1972. Oral excretion of Epstein Barr virus by healthy subjects and patients with infectious mononucleosis. Lancet2: 988-89.
Gerber, P.; Walsh, J. H.; Rosenblum, E. N.; and Purcell, R. H. 1969. Association of EB-virus infection with post-perfusion syndrome. Lancet 1: 593-95.
Golden, H. D.; Chang, R. S.; Lou, J. J.; and Cooper, T. Y.1971. A filterable agent in throat washings of patients with infectious mononucleosis. J. Infect. Dis. 124: 422-24.
Golden, H. D.; Chang, R. S.; Prescott, W.; Simpson, E.; and Cooper, T. Y. 1973. Leukocyte-transforming agent: Prolonged excretion by patients with mononucleosis and excretion by normal individuals. J. Infect. Dis. 127: 471-73.
Griffin, J. P., and Crawford, Y. E. 1969.Association of Mycoplasma pneumoniae infection with primary atypical pneumonia. Am. Rev. Resp. Dis. 100: 206-12.
Hampar, B.; Hsu, K. C.; and Martos, L. M.1971. Serologic evidence that a herpes-type virus is the etiologic agent of heterophile-positive infectious mononucleosis. Proc. Nat. Acad Sc. USA68: 1407-11.
Henle, G.; Henle, W.; and Diehl, V. 1968.Relation of Burkitt`s tumor-associated herpes-type virus to infectious mononucleosis. Proc. Nat. Acad. Sc. USA 59: 94-101.
Henle, W., and Henle, G. 1973. Epstein-Barr virus and infectious mononucleosis. New England J. Med. 288:263-64.
Hoagland, R. J. 1967. Infectious mononucleosis, pp. 1-132. New York: Grune & Stratton.
Hoff, G., and Bauer, S. 1965. A new rapid slide test for infectious mononucleosis. J.A.M.A. 194: 351-53.
Horstmann, D. M.; Pajot, T. G.; and Liebhaber, H.1969. Epidemiology of rubella. Subclinical infection and occurrence of reinfection. Am. J. Dis. Child 118: 133-36.
ID9-HR-Division surgeons, 9th Infantry Division. Monthly health reports to USARV surgeon, 1965-70.
Klemola, E.; von Essen, R.; Henle, G.; andHenle, W. 1970. Infectious-mononucleosis-like disease with negative heterophile agglutination test. Clinical features in relation to Epstein-Barr virus and cytomegalovirus antibodies. J.Infect. Dis. 121: 608-14.
Klemola, E.; von Essen, R.; Wager, 0.;Haltia, K.; Koivuniemi, A.; and Salmi, I. 1969. Cytomegalo virus mononucleosis in previously healthy individuals: Five new cases and follow-up of 13 previously published cases. Ann.Int. Med. 71: 11-19.
Kravetz, H. M.; Knight, V.; Chanock, R. M.; Morris, J. A.; Johnson, K. M.; Rifkind, D.; and Utz, J. P. 1961.Respiratory syncytial virus. III. Production of illness and clinical observations in adult volunteers. JA.M.A. 176: 657-63.
Lehane, D. E. 1970. A sero epidemiologic study of infectious mononucleosis. The development of EB virus antibody in a military population. J.A.M.A. 212: 2240-42.
Miller, G.; Niederman, J. G.; and Andrews, L.L.1973. Prolonged oropharyngeal excretion of Epstein Barr virus after infectious mononucleosis. New England J. Med. 288: 229-32.
ML9-AR-9th Medical Laboratory. Activities Reports, 1966-69. On file at U.S. Army Center of Military History.
Mogabgab, W. J. 1968. Mycoplasma pneumoniae and adenovirus respiratory illnesses in military and university personnel, 1959-1966. Am. Rev. Resp. Dis. 97: 345-58.
Monto, A. S., and Johnson, K. M. 1967. A community study of respiratory infections in the tropics. I. Description of the community and observations on the activity of certain respiratory agents. Am. J. Epidemiol. 86:78-92.
Niederman, J. C.; Evans, A. S.; Subrahmanyan, L.; and McCollum, R. W. 1970. Prevalence, incidence and persistence of EB virus antibody in young adults. New England J. Med. 282:361-65.
Niederman, J. C.; McCollum, R. W.; Henle, G.; and Henle, W.1968. Infectious mononucleosis. Clinical manifestations in relation to EB virus antibodies. J.A.M.A. 203: 205-9.
9th Infantry Division, monthly health reports. See ID9-HR.
9th Medical Laboratory, activities reports. SeeML9-AR.
Office of the Surgeon General, Department of the Army. Health of the Army, May 1967 and May 1968. Copies at Uniformed Services University of the Health Sciences.
Olson, L. C.; Lexomboon, U.; Sithisarn, P.; and Noyes, H. E. 1973. The etiology of respiratory infections in a tropical country. Am. J. Epidemiol 97: 34-43.
173d Airborne Brigade (Separate), monthly health reports. See AB173-HR.
Plotkin, S. A., and Clark, H. F. 1971.Prevention of rabies in man. J. Infect. Dis. 123: 227-40.
Post exposure anti-rabies treatment, USARV Regulation. See USARV-Reg.
Reilly, C. M.; Stokes, J., Jr.; McClelland, L.; Cornfield, D.; Hamparin, V. V.; Ketler, A.; and Hilleman, M. R.1961.Studies on acute respiratory illness caused by respiratory syncytial virus. 3. Clinical and laboratory findings. New England J. Med. 264: 1176-82.
Remington, J. S.; Barnett, C. G.; Meikel, M.; and Lunde, L. N. 1962. Toxoplasmosis and infectious mononucleosis. Arch. Int. Med. 110: 774-53.
Rose, N. J.; Schnurrenberger, P. R.; and Martin, R. J. 1971. Rabies prophylaxis. Arch. Environ. Health23: 57-59.
Rosenbaum, M. J.; DeBerry, P.; Sullivan, E.J.; Pierce, W. E.; Mueller, R. E.; and Peckinpaugh, R. 0. 1971.Epidemiology of the common cold in military recruits with emphasis on infections by rhinovirus types 1A, 2, and two unclassified rhinoviruses. Am. J. Epidemiol. 93: 183-93.
Sanford, J. P. 1969. Influenza: Consideration of pandemics. Advances Int. Med. 15: 419-53. Sawyer, R. N.; Evans, A. S.; Niederman, J. C.; and McCollum, R. W. 1971. Prospective studies of a group of Yale University freshmen. I. Occurrence of infectious mononucleosis. J. Infect. Dis. 123:263-70.
Schmitz, H., and Scherer, M. 1972. Ig M antibodies to Epstein-Barr virus in infectious mononucleosis. Arch. ges. Virusforsch. 37: 332-39.
Shope, T., and Miller, G. 1973. Epstein-Barr virus. Heterophile responses in squirrel monkeys inoculated with virus-transformed autologous leukocytes. J. Exper. Med. 137:140-47.
Shroyer, E. L. 1969. Status report on rabies. USARV M. Bull. (USARV Pam 40-17), Sept.-Oct., pp. 39-41. Copy in Joint Medical Library, Office of the Surgeons General.
Smith, R. T., and Bausher, J. C. 1972.Epstein-Barr virus infection in relation to infectious mononucleosis and Burkitt`s lymphoma. Ann. Rev. Med. 23: 39-56.
Smith, T. J.; Olson, L. C.; Kandel, G. E.; and Snitbahn, R. 1970. Hong Kong influenza in U.S. military airmen in Thailand. Am. J. Trop. Med. 19: 866-71.
Turner, A. R.; MacDonald, R. N.; and Cooper, B. A. 1972. Transmission of infectious mononucleosis by transfusion of pre-illness plasma. Ann. Int. Med. 77: 751-53.
USARV-CHR-USARV surgeons. Monthly Command Health Reports to USARV commander, 1965-Feb. 1971. On file at U.S. Army Center of Military History.
USARV-Reg-Headquarters, USARV. 1967. Guide for post exposure anti-rabies treatment. USARV Regulation No. 40-15, 1Sept. 67, Annex A.
USARV monthly Command Health Reports. See USARV-CHR.
Ward, T. G. 1973. Viruses of the respiratory tract. Progr. med. Virol 15: 126-58.
Wenzel, R. P.; McCormick, D. P.; Smith, E.P.; and Beam, W. E., Jr. 1971. Acute respiratory disease: Clinical and epidemiologic observations of military trainees. Mil. Med. 136:873-80.
