Download INFECTIOUS MONONUCLEOSIS* Infectious mononucleosis may be

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 Selander2 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 Bunnell3 described the
presence of heterophile antibodies in infectious mononucleosis.
At this time Hobson4 was attempting to differentiate excised
* Received for publication June 11th, 1938.
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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.
Wulff8 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 Lehndorff9 reported a small series of cases of "glandular
fever" using the Paul and Bunnell technique which consisted of
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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 Davidsohn10 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. Strauss11 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 Ravenswaay12 points out, there are two possible explanations for the presence of these antibodies: (1) That they are
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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 Foord13. Bailey
and Raffel14 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 Erf16 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 Dameshek16. 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
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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
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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, 994, 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.
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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)
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.
SPRUNT,
(5) ROSENTHAL, N., AND WBNKEBACH, G.: Significance of heterophile antibody
(6)
(7)
(8)
(9)
(10)
reaction for diagnosis of infectious mononucleosis. Klinische
Wochenschrift, Berlin, 12, 499 (Apr. 1) 1933.
DOWNEY, HAL, AND STASNEY, JOSEPH: Infectious mononucleosis. J. A.
M. A., 105, 764 (Sept. 7) 1935.
MCKINLEY, C. A.: Infectious mononucleosis. J. A. M. A., 106, 761
(Sept. 7) 1935.
WULPF, F.: Infectious mononucleosis with especial regard to differential
diagnosis with diphtheria. Ugeskrift for Laeger, Copenhagen,
95,131 (Feb.) 1933.
LEHNDOBFF, H.: Seroreaction valuable for diagnosis of glandular fever.
Munchener Medizinische Wochenschrift, Munich, 81, 447 (March
23) 1934.
DAVIDSOHN, I.: Infectious mononucleosis, I. Am. J. Dis. Child., Chicago,
49,1222 (May) 1935.
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(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 E R F , 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.