INFECTIOUS MONONUCLEOSIS* EDWARD A. MARSHALL Cleveland, Ohio * Infectious mononucleosis may be described as a disease characterized by fever (although this is not always present) lasting ten days to several weeks, lymph node enlargement, throat infection, headache, weakness and general malaise. The spleen is probably enlarged in half the cases and in those cases not characterized by throat infection there may be a predominance of abdominal symptoms. It is also possible to have the combination of a throat infection and predominant cerebral symptoms and as intimated above, there may be an afebrile type. Although "infectious mononucleosis" was the term applied to this disease by Sprunt and Evans 1 in 1920, there is still considerable argument as to its cause and amenability to tissue diagnosis. The question of differentiation from other diseases has been pretty well settled through the use of various methods which demonstrate the presence of heterophile antibodies in the blood and the question of treatment can be summed up in one sentence: Do nothing and they will all get well. Forssman began the work in 1911 which culminated in a diagnostic test. At that time infectious mononucleosis, lymphatic angina, monocytic angina, and most of the other related diseases were grouped under the broad term "glandular fever." As late as 1932 Selander 2 made the statement that the differential diagnosis between lymphatic leukemia and infectious mononucleosis rested on the favorable outcome of the latter, although in that same year Paul and Bunnell 3 described the presence of heterophile antibodies in infectious mononucleosis. At this time Hobson 4 was attempting to differentiate excised * Received for publication June 11th, 1938. 298
INFECTIOUS MONONUCLEOSIS 299 lymph glands in this disease from other lympho-glandular pathology but found nothing in his tissue studies which would help in this differentiation, though he noted the increase in the neutrophiles in the blood stream at the onset. He also mentioned the presence of an enlarged lymph node in the posterior neck near the base of the skull. In 1933 Rosenthal and Wenkebach 6 reported twenty-eight cases, using the heterophile reaction to differentiate monocytic angina and glandular fever from infectious mononucleosis. This they were unable to do, probably because these diseases are very closely related, if not all varying types of the same disease. Since that time the technique of the test has been refined to such an extent that it seems unnecessary to resort to biopsy for diagnosis although Downey and Stasney 6 claim that such a procedure is not difficult because of the relatively slight immaturity of the lymphocytes and the proliferation of the reticular cells in infectious mononucleosis. In 1936 McKinley 7, who reported fifty cases, quoted Kracke and Garver as stating that morphologically acute lymphatic leukemia and infectious mononucleosis cannot be differentiated with certainty and stressed the occasional presence of abdominal symptoms and the necessity for frequent blood counts to differentiate abdominal disease. He found throat involvement in 78 per cent of his cases. Certainly every laboratory should be able to perform one of the tests for the presence of heterophile antibodies in the blood stream because this disease can so easily be confused with: influenza, cervical adenitis, tonsilitis, lymphatic leukemia, Hodgkin's disease, syphilis, meningitis, tuberculous adenitis and meningitis, undulant fever, encephalitis. Wulff 8 points to the necessity for ruling out diphtheria and stresses the differential count as being important in differentiating these two diseases. This is probably impractical because several days may elapse after the onset before the lymphocytes predominate. In 1934 Lehndorff 9 reported a small series of cases of "glandular fever" using the Paul and Bunnell technique which consisted of
300 EDWARD A. MARSHALL making dilutions of 1:2 to 1:1024 of inactivated serum, mixing equal parts of these dilutions with 2 per cent washed sheep cells in saline, incubating in a water bath for one hour at 38 C. and refrigerating overnight before examining for agglutination. In 1935 Davidsohn 10 described a modified procedure in which the mixture was placed in 75 x 12 mm. test tubes and only refrigerated for 1 hour, thus'permitted the reading of the test in two hours. It was from Davidsohn that Paul and Bunnell got the idea which led to their original thirteen hour technique. He had previously been using the test in serum sickness and had found it positive in a high percentage of patients who had been given horse serum at any time. He has since been able to differentiate the antibodies developed from horse serum, which are true Forssman antibodies, from those of infectious mononucleosis by treating the serum with suspensions of guinea pig kidney. This treatment will remove Forssman antibodies but not affect the agglutination power of the serum of a patient suffering infectious mononucleosis. This finding may prove to be very valuable in cases of infectious mononucleosis which have received horse serum. In our cases the technique described by R. Strauss 11 was used. This technique, although a modification of that of Paul and Bunnell, is considerably faster than even the two hour modification of Davidsohn. It follows: 1. Heat sera for one-half hour in water bath at 56 C. 2. Make dilutions from 1:2 and 1:1024 or more. 3. Place 1 cc. of diluted serum in test tube. 4. Add 1 cc. of 2 per cent suspension of washed sheep cells. 5. Centrifuge for five minutes at about two thousand revolutions per minute. 6. Shake and read. The tubes are shaken by starting with the control tube, noting the vigor necessary to shake up the cells, then going to the tube with the highest dilution and working down. The lower dilutions show a single large red clump which is designated as four plus agglutination. Smaller clumps are designated three plus, two plus and one plus. As Van Ravenswaay 12 points out, there are two possible explanations for the presence of these antibodies: (1) That they are
INFECTIOUS MONONUCLEOSIS 301 built by virus antigen action. (2) That they represent increased normally present agglutinins. Regardless of the reason for their presence in the blood stream in this disease, sufficient work has now been done to prove practically every case of infectious mononucleosis. The height of the agglutination titer seems to depend on the stage of the disease, but for the first two or three weeks it is constantly increasing according to Butt and Foord 13. Bailey and Raffel 14 claim that ox cells can be used as well as sheep cells and agree with Davidsohn that the antibodies are not Forssman in type. Wiseman, Doan and Erf 16 call attention to the additional information to be gleaned from the red, white and differential blood count, and state that after the initial rise in leukocytes there is a steady decrease in the circulating granulocytes accompanying the rise in lymphocytes and that, as the lymphocytes increase, the red cells fall. We have recently seen four cases at Huron Road Hospital and one in the office which, because of the possibility of mistake in diagnosis from the symptoms presented, caused us to make the above review of the literature. The first case, A. P., presented the most difficult problem because his symptoms were predominantly cerebral. We have found only one other case of this type in the literature, that reported by Epstein and Dameshek 16. We report this case in detail and give a short summary of the other two. Case 1. A. P., a male, aged 29, was admitted to the hospital August 22, 1937 with chief complaints of headache, stiff neck, sore throat, weakness and general aching. Ten days previously he had noticed weakness and sore throat, which complaints had increased during the three days following onset when the patient was put to bed where he remained until the time of admission. His symptoms increased in severity and he became drowsy and presented the appearance of having bilateral ptosis, but could open his eyes wide if requested. On admission to the hospital photophobia was marked and the neck was moderately rigid. He complained of constant headache and the temperature for the previous seven days had ranged from 100 to 103 F. There was no history of cough or respiratory distress but there was marked swelling of the
302 EDWARD A. MARSHALL lymph glands of the neck, especially the posterior cervical chains, and one nodule in the posterior neck near the occiput was especially large. He answered all questions with effort and he did not articulate well. Ears and nose were normal. The eyes showed a horizontal nystagmus but the reflexes were normal. The mucous membrane of the throat was slightly injected and a provisional diagnosis of lethargic encephalitis was made. The blood count at this time was red cells 4,000,000, white count 5,500, leukocytes 68 per cent, with 26 per cent juveniles, lymphocytes 30 per cent and large mononuclears 1 per cent. Spinal fluid at this time showed sugar 62 mgm. per 100 cc, cell count 0, colloidal gold 0000000000. The Kline test, diagnostic and exclusion, was negative. The urine showed a faint trace of albumin with rare pus cells. Two days later the consultant neurologic diagnosis was "meningismus, as a result of toxic absorption produced by fever which is as yet of unknown origin but we suspect lymph glands." It might be added that by this time the inguinal and axillary nodes were prominent and sore. The blood culture after 36 hours incubation was negative and two days after admission, August 24, 1937, the blood count showed: white cells 7,300, leukocytes 61 per cent and lymphocytes 37 per cent. On August 25,1937, he was obviously improved and because of this a second spinal tap was not done. The urine showed the same findings as the previous examination and the temperature began to go down. On August 28, 1937, six days after admission to the hospital, the white count was 13,100, leukocytes 34 per cent, lymphocytes 62 per cent and large mononuclears 4 per cent. Up to this time the temperature had ranged between 103.6 and 99.4, the peak being reached each day at 8:00 p.m. The tests for undulent fever, etc. were all negative. Because of the lymphocytosis, weakness and generalized adenopathy, an agglutination test for heterophile antibodies by the Strauss method was done and proved to be positive in a dilution of 1:512. He was discharged from the hospital on August 29, 1937, was confined to his bed at home until September 10, 1937, and was able to come to the office on September 16, 1937, at which time he complained only of weakness. The glandular enlargement had subsided and his blood count was normal. The treatment was purely symptomatic, consisting of hot packs to the neck, 50 per cent glucose intravenously, analgesics and sedatives. Case 2. K. S., a male, aged 25, was admitted to the hospital on May 25, 1937, with a provisional diagnosis of acute lymphatic leukemia. He had never been sick, except for childhood diseases, until one week before when he noticed headache, afternoon rise in temperature, backache and sore eye balls. He developed some coughing, epigastric distress. At the time of admission glands could be palpated in both the cervical and inguinal regions. The patient was anemic in appearance, thin, white and a
INFECTIOUS MONONUCLEOSIS 303 mouth-breather. The heart and lungs and abdomen were negative. Urinalysis was negative as was the chest x-ray. He complained of considerable weakness and the temperature was 104. The blood count at this time showed the hemoglobin to be 83 per cent, red count 4,500,000, white count 5,900, leukocytes 32 per cent, lymphocytes 62 per cent and large mononuclears 6 per cent. During his stay in the hospital the temperature ranged between 104 and normal with no regular daily remissions, and fell to normal on the eighteenth day by lysis. Pulse was low in proportion to the temperature at all times. Blood culture was negative but the white count increased in four days to 20,000 with 86 per cent lymphocytes and by June 8, 1937, the white count was 10,950 with 76 per cent lymphocytes. The agglutination test for heterophile antibodies was positive in a dilution of 1:1024 by the Strauss method. He was discharged June 14,1937 with weakness his only important complaint. Case 3. B. B., a female, aged 21, was seen October 19, 1937, with a chief complaint of sore throat of two weeks' duration. One day later the mucous membrane was so swollen as to permit some difficulty in respiration and there were large follicles on the tonsils. The neck showed anterior and posterior cervical adenopathy. A smear and culture were negative for diphtheria. Four days after the onset a blood count showed the white cell count to be 16,000, leukocytes 10 per cent, lymphocytes 80 per cent and mononuclears 10 per cent. Five days after the onset an agglutination test for heterophile antibodies by the Strauss method was positive in a dilution of 1:256 and partially positive in a dilution of 1:512. Uninalysis was negative. The temperature was never higher than 99.4 and the pulse stayed below 100. Eight days after the onset the patient was able to leave her home and shortly after that returned to school. She had no sequelae in the form of weakness or gland enlargement beyond two weeks from the onset. Case 4- B. B., a male, aged 28, came to the office on October 18, 1937, with a history of feeling of warmth, lack of appetite, lassitude over a period of two weeks. He also complained of a mildly sore throat and post-nasal drip. His past history was non-contributory. Physical examination showed a slight fever, 99 4, and enlargement of the posterior and anterior cervical lymph glands, mildly injected throat and a post-nasal drip was evident. Because of previous interest in infectious mononucleosis and a negative throat smear, a blood count was immediately taken which showed 70 per cent lymphocytes. On the strength of this a heterophile antibody test was made and was found to be positive in a dilution of 1:512. The differential count showed neutrophiles 27 per cent and mononuclears 3 per cent.
304 EDWARD A. MARSHALL On October 25, 1937, one week after diagnosis was made, the temperature became normal and on October 29, 1937, all symptoms had ameliorated except the weakness and anorexia. At this time the hemoglobin was 80 per cent, the temperature was normal, throat was normal but there was still some glandular enlargement. By November 15, 1937, all symptoms had completely disappeared. SUMMARY Four cases of infectious mononucleosis are reported. Each case simulated a different disease, one predominating in cerebral symptoms, one simulating acute lymphatic leukemia, one with all appearances of follicular tonsilitis and one with weakness the outstanding symptom. All cases gave us positive agglutinations to sheep cells, the socalled heterophile antibodies by the Strauss method, completed within a few minutes after the blood was taken. REFERENCES (1) SPRUNT, R. P., AND EVANS, F. A.: Mononuclear leukocytosis in infections (infectious mononucleosis). Bull. John Hopkins Hosp., 31, 410 (Nov.) 1920. (2) SELANDEB, P.: Glandular fever. Hygeia. Stockholm, 94, 257 (April 15) 1932. (3) PAUL, J. R., AND BUNNELL, W. W.: Presence of heterophile antibodies in infectious mononucleosis. Am. J. M. Sc, 183, 90-104 (Jan.) 1932. (4) HOBSON, S.: Infectious mononucleosis. New Orleans Med. and Surg. J., 84, 841 (May) 1932. (5) ROSENTHAL, N., AND WBNKEBACH, G.: Significance of heterophile antibody reaction for diagnosis of infectious mononucleosis. Klinische Wochenschrift, Berlin, 12, 499 (Apr. 1) 1933. (6) DOWNEY, HAL, AND STASNEY, JOSEPH: Infectious mononucleosis. J. A. M. A., 105, 764 (Sept. 7) 1935. (7) MCKINLEY, C. A.: Infectious mononucleosis. J. A. M. A., 106, 761 (Sept. 7) 1935. (8) WULPF, F.: Infectious mononucleosis with especial regard to differential diagnosis with diphtheria. Ugeskrift for Laeger, Copenhagen, 95,131 (Feb.) 1933. (9) LEHNDOBFF, H.: Seroreaction valuable for diagnosis of glandular fever. Munchener Medizinische Wochenschrift, Munich, 81, 447 (March 23) 1934. (10) DAVIDSOHN, I.: Infectious mononucleosis, I. Am. J. Dis. Child., Chicago, 49,1222 (May) 1935.
INFECTIOUS MONONUCLEOSIS 305 (11) STKAUSS, R.: Simple slide and tube tests for infectious mononucleosis. Am. J. Clin. Path., 6, no. 6 (Nov.) 1936. (12) VAN RAVENSWAAY, E. M.: The heterophile agglutination test in diagnosis of infectious mononucleosis. New Eng. J. Med., 211, 1001, 1934 (Nov. 29). (13) BUTT, E. M., AND FOOED, A. G.: Heterophile antibody reaction in diagnosis of infectious mononucleosis. J. Lab. and Clin. Investigation, N. Y., 14, 228 (March) 1935. (14) BAILEY, G. H., AND RAFFEL, S.: Hemolytic antibodies for sheep and ox erythrocytes in infectious mononucleosis. J. Clin. Investigation, N. Y., 14, 228 (March) 1935. (15) WISEMAN, B. K., DOAN, C. A., AND ERF, L. A.: Infectious mononucleosis. J. A. M. A., 106, 611 (Feb. 22) 1936. (16) EPSTEIN, S. H., AND DAMESHEK, W.: Involvement of central nervous system in case of glandular fever. New Eng. Med. J., 205, 1238 (Dec. 24) 1931.