Review

Infectious Mononucleosis A Study of 210 Sporadic Cases

JOHN E. STEVENS, M.D., * EDWIN D. BAYRD, M.D. and FRANK J. HECK, M.D.

Fellow in Medicine, Mayo Foundation Division of Medicine, Mayo Clinic

Rochester, Minnesota

I NFECTIOUS mononucleosis, a disease of

varied guise, frequently escapes detection. With an expanding armamentarium for

the treatment of infectious diseases, both bac- terial and viral, early accurate diagnosis once again becomes important in the selection of the

Ade incidence

0 10 20 30 40 50 60 70 A@ in years

FIG. 1. Age incidence.

proper therapeutic agent. It was with this in mind that the following study of 210 sporadic cases observed at the Mayo Clinic over a period of ten years, 1937 through 1946, was undertaken.

For convenience the history of infectious mononucleosis may be considered in four parts. The first phase was largely descriptive. Filatow in 1885 described an idiopathic adenitis oc- curring in children which was probably in- fectious mononucleosis. Pfeiffer16v23 in 1889 described Drtisenfieber (“glandular fever”) as a clinical entity which he considered a specific disease of the lymph glands in infants and children. Other names applied were acute idiopathic lymphadenitis,21 monocytic an- gina, l acute benign lymphoblastosis2 and acute lymphadenosis. g

Sprunt and Evans in 1920 drew attention to the characteristic changes in the peripheral blood and proposed the name infectious mono-

nucleosis, initiating the second period. Earlier observers had previously noted leukocytosis,i3 large lymphocytes26 and an increase of mono- nuclear elements in the blood.3*4v’8 Long-cope described the morphologic abnormalities in the blood and the histology of excised lymph nodes. The studies of Downey and McKinlay in 1923 on the morphology of the lymphocytes found in this disease concIuded this phase of investiga- tion and left little of importance to be added from a hematologic point of view.

The third phase of interest in infectious mononucleosis was introduced in 1932 when Paul and Bunnell first described their now well known sheep cell heterophil agglutination test.

The present phase may be considered to date from 1944 when Ziegler published the first report of necropsy in a case of infectious mononucleosis in which death was due to rupture of the spleen. Other reports followed7.16*1g~24~27 and showed that the disease process was generalized and affected many organs. The general pathologic aspects have been well summarized by Custer and Smith. Hovde and Sundberg have recently described focal granulomas in the bone marrow.

STUDY OF 210 SPORADIC CASES ENCOUNTERED

AT THE MAYO CLINIC

Cases in which either the blood smear or the heterophil agglutination test was positive for infectious mononucleosis and the clinical find- ings were compatible with this diagnosis were accepted for this study. A blood smear was considered to be positive when at least 50 per cent of the leukocytes were lymphocytes and a significant number of the lymphocytes were of the abnormal infectious mononucleosis type described by Downey. Heterophil agglutination was considered to be positive when the patient’s

* Present address Richmond, Va.

202 AMERICAN JOURNAL OF MEDICINE

Infectious Mononucleosis-Stevens et al. 203

serum contained agglutinins for sheep red blood cells in a titer of 1: 224.

Age, Sex, and Seasonal and Occupational Variation. The age of the patients ranged from nine months to sixty-eight years (Fig. 1) with 59 per cent occurring between the ages of sixteen and

SGX Fema.1 es Ma1 es

apical abscesses. One of these was seen at the clinic because of the third relapse of infectious mononucleosis and stated that for the preceding five months one of his principal complaints had been toothache. Examination revealed a peri- apical abscess that had ruptured. Subsequent

Season Spying 24 %

Sum&r Fall Winter

og;U&L;;o”

NtiESe Cleuk Farmer Physician House wife Secretary Waitress Merchant Lab. technician Miscellaneous

I I I I I I 0 10 2.0 30 40 50 60

Peu cent FIG. 2. Incidence by sex, season and occupation.

twenty-six years. Ninety-three per cent of the patients were less than thirty-five years of age. Fifty-seven per cent were females. (Fig. 2.) No racial predilection was noted. The highest incidence (31 per cent) was in the summer months. (Fig. 2.) This is contrary to the experi- ence of others and may be related to the increased patient load at the clinic in those months. Pa- tients of no one particular occupation (Fig. 2) were especially affected.

Epidemiology. Information relative to epi- demiology was limited, the incubation period could not be estimated. Eight patients (4 per cent) of the total group were found to have had dental sepsis or recent dental extraction. Five of these patients volunteered the information that the symptoms of which they complained on admission had their onset from three to twenty- one days following the extraction of an infected tooth. Three other patients when seen on ad- mission were found to have one or more peri-

AUGUST, 1951

to or coincidental with extraction of the offend- ing tooth an uneventful recovery without further relapse occurred.

Infectious mononucleosis developed during convalescence from a surgical procedure in eight cases.

Clinical Manifestations and Complications. The protean nature of infectious mononucleosis may be appreciated by noting the most frequent chief complaints (Fig. 3) and the more common clinical findings. (Fig. 4.) The significance of this is even more apparent when a review is made of the numerous diagnoses on admission. (Fig. 5.)

The onset was insidious in 58.5 per cent while in the remainder it was acute. (Fig. 3.) Rarely symptoms were absent and the disease was dis- covered in the course of a routine physical examination. In contrast, others were prostrate with high fever and their disease ran a pro- tracted course.

204 Infectious Mononucleosis-Stevens et al.

OfIS& Gmdual Sudden

Headache. FQveu Painful cervical adenopathy Malaise Chills Abdominal pain Anorexia Nausea and vomiting Nontendev cervical adenopathy Night sweats Fatigue Dysphagia Generalized aching Earache Peuioubital edema Cervical rigidity

26%

25%

Incidence of most Puequent

initial complaints

1 I I I I I I 0 10 20 30 40 50 60

Peu cent FIG. 3. Type of, onset and most frequent chief complaints in this series.

Clinical findings Adenopathy

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‘Tonsillitis Exudative Nonexudative

I-f S lenomegaly epatomegaly

Dermatitis-all types Jaundice Stomatitis Epistaxis

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Positive Yoenttgeno@am C.N. S. manii’estations

Cevvicat rigidity

%%i$t Somniilence Visual disturbances Incoovdination

I I I I I I 0 10 20 30 40 50 60

PQY cent FIG. 4. Incidence of more common findings in 210 patients.

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Infectious Mononucleosis-Stevens et al. 205 Respiratory manifestations: Sore throat was case it was still palpable eight months after the

the outstanding complaint of the patients (52 acute stage had subsided. per cent) in this series. (Fig. 3.) Exudative or Hepatomegaly was found in 15 per cent of membranous lesions on the tonsils or pharynx the cases and was discovered by the fourteenth were noted in 40 per cent. (Fig. 4.) Lymphoid day of the disease in about half of these cases. hyperplasia and marked edema caused dys- As with splenic enlargement hepatomegaly

Diaeosis on admission Acute Polliculav tonsillitis

Acute phayyngitis

InPl uenza

Leukemia

Infectious mononucleosis

Cewical adenopathy - cause uihdetevmined

Bw_icellosis

Inf’ectious hepatitis

Diphtheria

Pyelonephvitis

Hodgkin’s disease

Rheumatic fever

Incidcznce of most common diagnoses on admission

Chronic newous exhaustion 1.4 %

I I I I 5 10 15 2.0

Peu cent FIG. 5. Diagnosis on admission in 210 cases in which the diagnosis of infectious mononucleosis was made later.

phagia in 12 per cent. Stomatitis was observed in 3.8 per cent of the cases. In twenty-three cases beta hemolytic streptococci were cultured from the pharynx. In one instance peritonsillar ab- scess had developed as a sequel to severe tonsil- litis. Another patient had an abscess in the posterior nasopharyngeal vestibule.

Roentgenographic evidence of pulmonary involvement was found in only 2 per cent of the patients in this series although cough, pleuritic pain and rales found on auscultation were noted in varying degree. (Fig. 4.)

Chills ushered in the disease in 17 per cent of the cases, rhinitis in 5 per cent and marked dyspnea in another 5 per cent.

Abdominal manifestations: Splenomegaly was detected in 43 per cent of the series (Fig. 4) and was encountered between the tenth and twenty- first days in 62 per cent of those in which it was present. Enlargement of the spleen was still present four months after the acute stage of the disease had subsided in two cases and in one

AUGUST, 1951

might persist for weeks or months. Jaundice appeared in only fourteen of our patients, 6.6 per cent.

Abdominal pain was the presenting complaint in 14.8 per cent. (Fig. 3.) In two cases it was of such severity that surgical exploration was per- formed as an emergency measure. In both cases the only significant finding was mesenteric adenitis. Anorexia, nausea and vomiting oc- curred with approximately equal frequency. Diarrhea was noted in seven cases. In two of these cases stools contained blood.

Neuromuscular manifestations: Myalgia, bachache and generalized aching was a common distressing, early complaint. About 35 per cent complained of headache, especially at the onset. Cervical rigidity was found in 5 per cent while somnolence, often prodromal, vertigo and visual disturbances, such as blurring, diplopia and scotomas each were noted in approximately 3 per cent. (Fig. 4.)

Mania was observed in one case in which the

206 Infectious Mononucleosis-Stevens et al.

clinical appearance was that of meningo-en- cephalitis while in another delirium was marked.

Vascular and lymphatic manifestations: Epi- staxis occurred in 2 per cent of our patients. The bleeding varied from mild to severe and was recurrent over a period of a month in one case. Hematuria either gross or microscopic was observed in 13 per cent.

ous mononucleosis. In 55 per cent such a picture had appeared by the eighth day of the disease; the average day of appearance for all cases was the fourteenth day, with the time of their occur- rence ranging from the first day to the eighth month of the disease. Serial smears were not made in each case but it is possible that, had this been done, the characteristic changes in the lymphocytes would have been exhibited in all.

Demonstrable lymphadenopathy is not a sine Shift of the neutrophils to the left and granu- qua non of this disease; however, cervical aden- locytic immaturity to the early myelocyte were opathy was observed in 76.2 per cent and was encountered occasionally but toxic changes in the most consistent physical finding. (Fig. 4.) the neutrophils were uncommon. The lowest Generalized enlargement of the lymph nodes total leukocyte count was 600 per cu. mm. of occurred in only 19.5 per cent of cases. Lym- blood; the highest was 42,000. In general, the phadcnopathy in order of frequency was noted higher counts were noted among the more as follows: cervical, axillary and inguinal. severely ill patients.

Cutaneous manifestations: In sixteen cases (7.6 per cent) skin lesions developed. They were described as maculopapular in three cases, polymorphous (appearance of erythema multi- forme) in three, urticarial in three, macular in two, morbilliform in two, hemorrhagic in two and nodular in one case. There seemed to be no correlation between the appearance of a rash and the clinical course.

In Figure 6 the total number of leukocytes and the percentage of lymphocytes are noted in relation to the duration of the disease. No consistent pattern of rise and fall was detected.

Ocular manifestations: Edema of the eyelids and periorbital tissues was noted in 6.6 per cent. (Fig. 3.) Photophobia occurred in 4 per cent and, like burning and lacrimation seen in 2 per cent, it was an early manifestation. Conjunc- tivitis was observed in only two cases and uveitis in one.

Agranulocytosis occurred in one case. This patient, a physician sixty-five years old, was observed to have 7,600 leukocytes with 96.5 per cent lymphocytes and 3.5 per cent monocytes on the twenty-third day after admission. Four days later neutrophils reappeared in the periph- eral blood and the subsequent course was un- eventful.

Relapses and recurrences: In ten cases a re- lapse occurred within a period of four months. A relapse was considered to be reactivation of the disease before all manifestations of the preceding attack had disappeared. An increase in jaundice was the principal indication of relapse in three cases. Tonsillitis was the chief manifestation of relapse in four. Four months was the longest interval between attacks; the average interval was twenty-one to twenty-five days.

While one expects to see lymphocytosis at some stage in the disease, it may not occur early. (Fig. 6.) Three patients, for example, had less than 20 per cent. lymphocytes in the pe- ripheral blood at the first determination. The average was between 65 and 70 per cent; two had more than 95 per cent lymphocytes. Usually a reversion to more nearly normal values began after the peak was reached, gen- erally by the fifteenth day, and was completed by the twenty-fifth to the thirtieth day. Lympho- cytosis persisting for months was not uncommon, however.

Recurrence was used to denote a second attack of infectious mononucleosis following an interval during which the patient was sub- jectively and objectively free of manifestations of the disease. Only two patients in this study could be classified as having had a recurrence. In both instances eight months elapsed between attacks.

Of eight cases in which tests for liver function were performed all showed impaired function. This has been noted by others.6~8~10~12~20

Bile was found in the urine of seven patients; glycosuria was found in thirteen. Hematuria was seen in 13 per cent.

Laboratory findings: In 97 per cent of cases smears of the peripheral blood showed a signifi- cant increase in atypical lymphocytes of infecti-

Agglutination of sheep’s erythrocytes (hetero- phi1 agglutination) was noted in significant titer (1: 224) in 91 per cent of 142 cases in which this test was performed. The highest titer encountered was 1 :7,168. Most of the elevated heterophil agglutination titers were obtained after the

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AUGUST, 1951

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208 Infectious Mononucleosis-Stevens et al.

seventh day of the disease (Fig. 7) and in 51.4 per cent of cases a significant elevation was demonstrated by the fifteenth day. Blood with- drawn early in the disease was frequently nega- tive. The titer remained elevated (Fig. 7) in some instances for more than three months. At other times elevations in titer were temporary and without frequent determinations might escape detection.

Four patients temporarily had positive sero- logic reactions for syphilis.

SUMMARY AND CONCLUSIONS

A study was made of 210 sporadic cases of infectious mononucleosis seen at the Mayo Clinic from 1937 through 1946. The clinical findings suggesting infectious mononucleosis are too indefinite and diverse to serve as final criteria on which to base a diagnosis. Reliance, therefore, must be placed on the observation of increased number of lymphocytes, with an appreciable number of leukocytoid forms and a significant titer of heterophil antibody. How- ever, familiarity with the disease’s varied cloak should guide the thoughtful clinician past the obstacles which beset the unwary.

REFERENCES

1. BAADER, E. Die Monocytenangina. Deutsches Arch. f. klin. Med., 140: 227, 1922.

2. BLOEDORN, W. A. and HOUGHTON, J. E. The occur- rence of abnormal leukocytes in the blood in acute infections; acute benign lymphoblastosis. Arch. Int. Med., 27: 315, 1921.

3. BURNS, J. E. Glandular fever; report of an epidemic in the children’s ward of the Union Protestant Infirmary. Arch. Znt. Med., 4: 118, 1909.

4. CABOT, R. C. The lymphocytosis of infection. .4m. 3. M. SC., 145: 335, 1913.

5. COHN, C. and LIDMAN, B. I. Hepatitis without jaundice in infectious mononucleosis. 3. Clin. Investigation, 25: 145, 1946.

6. CUSTER, R. P. and SMITH, E. B. The pathology of infectious mononucleosis. Blood, 3: 830, 1948.

7. DARLEY, W., BLACK, W. C., SDI~TH, C. and GOOD, F. A. Spontaneous splenic rupture in infectious mononucleosis; a case and pathologic report. Am. 3. M. SC., 208: 381, 1944.

8. DEMARSH, Q. B. and ALT, H. L. Hepatitis without jaundice in infectious mononucleosis. Arch. ht. Med., 80: 257, 1947.

9. DOWNEY, H. and MCKINLAY, C. A. Acute lymph- adenosis compared with acute lymphatic leukemia. Arch. Int. Med., 32: 82, 1923.

10. EVANS. A. S. Liver involvement in infectious mono-

11.

12.

13.

14.

15.

16.

17.

18.

19.

20.

21. 22.

23.

24.

25.

26.

27.

28.

nucieosis. 3. Clin. Znoestigation, 27: 106, 1948. FILATOW, N. Quoted by BERNSTEIN, A. Infectious

mononucleosis. Medicine, 19: 85, 1940. GALL, E. A. Serum phosphatase and other tests of

liver function in infectious mononucleosis. .4m. 3. Clin. Path., 17: 529, 1947.

GOURICHON, H. Quoted by BERNSTEIN, A. Infectious mononucleosis. Medicine, 19: 85, 1940.

HOVDE, R. F. and SIJNDBERG, R. D. Granulomatous lesions in the bone marrow in infectious mono- nucleosis; a comparison of the changes in the bone marrow in infectious mononucleosis with those in brucellosis, tuberculosis, sarcoidosis and lymphatic leukemia. Blood, 5: 209, 1950.

KING, R. B. Spontaneous rupture of the spleen in infectious mononucleosis; report of a case. New England 3. Med., 224: 1058, 1941.

LEHNDORFF, H. Emil Pfeiffer; 100th anniversary of his birth; some historical remarks on glandular fever and infectious mononucleosis. Arch. Pediat., 63: 218, 1946.

LONGCOPE, W. T. Infectious mononucleosis (glandu- lar fever), with a report of ten cases. Am. 3. M. SC., 164: 781, 1922.

MARCHAND, F. Ueber ungewijhnlich starke Lympho- cytose im Anschluss an Infektionen. Deutsches Arch.f. klin. Med., 110: 359, 1913.

MILNE, J. Infectious mononucleosis. Jvew England 3. Med., 233: 727, 1945.

MORRIS, M. H., ROBBINS, A. and RICHTER, E. Acute infectious mononucleosis with hepatitis; presenta- tion of two cases. NeNew York State 3. Med., 44: 1579, 1944.

NEUMANN. Quoted by LEHNDORFF, H.‘s PAUL, J. R. and BUNNELL, W. W. Presence of hetero-

phile antibodies in infectious mononucleosis. Am. 3. M. SC., 183: 90, 1932.

PFEIFFER, E. Driisenfieber. Johrb. f. Kinderh., 29: 257, 1889.

SMITH, E. B. and CUSTER, R. P. Rupture of spleen in infectious mononucleosis; clinicopathologic report of seven cases. Blood, 1: 317, 1946.

SPRUNT, T. P. and EVANS, F. A. Mononuclear leuco- cytosis in reaction to acute infections. Bull. Johns Hopkins Hosp., 31: 410, 1920.

T~~RK, W. Quoted by BERNSTEIN, A. Infectious mononucleosis. Medicine, 19: 85, 1940.

VAUGHN, S. L., REGAN, J. S. and TERPLAN, K. In- fectious mononucleosis complicated by spontane- ous rupture of spleen and central nervous system involvement. Blood, 1: 334, 1946.

ZIEGLER, E. E. Infectious mononucleosis; report of a fatal case with autopsy. Arch. Path., 37: 196, 1944.

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