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AN EARLY CLINICAL SIGN OF INFECTIOUS MONONUCLEOSIS
1054 Four of the fourteen treated cases and four of the twelve control cases were failures. The mean time taken to complete recovery in the successful cases was 63 days in the- treated group and 69 days in the control group. It is concluded that 1 g. of cortisone acetate orally neither lessens the incidence of denervation in Bell’s palsy nor hastens recovery in patients without
denervation. I am grateful to various physicians and surgeons of the Leeds region, in particular Dr. H. G. Garland and Mr. M. Ellis, F.R.C.S., for referring patients who took part in this trial. The Medical Research Council supplied the cortisone acetate. REFERENCES
Blockey, N. J., Wright, J. K., Kellgren, J. H. (1954) Brit. med. J. i, 1455.
Bunnell, S. (1937) Arch. Otolaryng., Chicago, 25, 235. Hall, A. (1951) Ibid, 54, 475. James, J. A., Russell, W. R. (1951) Lancet, ii, 519. Morris. W. M. (1938) Ibid, i, 429. Robison, W. P., Moss, B. F. (1954) J. Amer. med. Ass. 154, 142. Rothendler, H. H. (1953) Amer. J. med. Sci, 225, 358. Truelove, S. C., Witts, L. J. (1951) Brit. med. J. ii, 375. Whitty, C. W. M. (1953) Lancet, ii, 86.
INFECTIOUS MONONUCLEOSIS A. HOLZEL M.D. Prague, D.C.H. HEALTH,
UNIVERSITY OF MANCHESTER
SIXTY-FIVE years ago, when at
a
meeting
describing glandular Cologne,
of the Naturforscher in
fever Emil
Pfeiffer said : "
of
(1) The first was an adult who developed a severe tonsillitis which was accompanied by the enlargement of cervical and tonsillar glands and by the presence of abnormal lymphocytes in the blood picture but showed no increase in heterophil
AN EARLY CLINICAL SIGN OF
LECTURER IN CHILD
glandular fever. Since then this eruption on the has been observed in 15 sporadic cases of confirmed palate mononucleosis and in 2 others where the clinical manifestations or the blood picture were strongly suggestive but the serological investigations negative. The ages of these patients ranged from 4 years to 33. Only 2 of the 10 children among them had rubelliform skin rashes ; the petechial enanthem preceded the skin eruption byby twenty-four and forty-eight hours. The three clinical types (Tidy 1934)-anginose, glandular, and febrilewere represented among the 15 cases, and none of them showed any other signs of purpura or hsemorrhagie manifestations except the petechiae on the soft palate. Platelet-counts were made in only 7 of the patients and fell within the normal range. Clinical picture and course did not differ in these patients from the now well-known patterns of the disease and do not warrant detailed discussion. Heterophil agglutinin titres varied from 1 : 61 to 1 : 2048. Two patients had petechiae on the palatal mucosa but no definite evidene of glandular fever : one
intention is only to sketch for you the clinical picture basis for further observations and studies. No doubt this clinical picture, like so many of our syndromes, includes different disease processes, and bacteriological and pathological research is necessary before we can separate the forms which differ in aetiology and morbid anatomy."
My
as a
This statement is still valid. Numerous contributions to the clinical picture have been made, and there is hardly an organ or a system that has not been implicated in this disease ; but in the multitude of clinical manifestations the original outline of the sketch has become blurred, and what has been gained in width and depth of the picture has been lost in definition. For a time, the diagnosis seemed to rest on a solid foundation of clinical signs, haematological changes, and serological tests. Now these foundations, at least for the initial phase of the disease, have been shaken. The characteristic cells, first described by Longcope in 1922 and more accurately by Downey and McKinlay in 1923, have been found in various virus diseases, such
agglutinins. (2) The second was a girl, aged 3 years, with generalised lymphadenopathy (including the occipital glands) and a rubelliform rash which faded very rapidly, but neither haematological nor serological changes characteristic of the disease. and the final diagnosis was rubella.
petechial eruption was in all cases localised along junction of soft and hard palate, where the mucosa normally appears rather pale, and so was easily discernible. The petechiae varied in number from ten to fifty and were usually of pinhead size but occasionally somewhat bigger. They appeared grouped in a crescent-like arrangement due to the shape of the soft palate. Their earliest appearance was noticed on the third day after the onset of symptoms, and their latest at the end of the first week. This coincides with the stage of eruption (fourth to seventh day) in the febrile type (Cantor 1930, Tidy 1934). The spots generally persisted for three or four days. The exception was the first case, in which they were still present at the end of the third week. After The
the
hepatitis, atypical pneumonia, measles, rubella, herpes Further, zoster, and influenza B (Rominger 1953).
as
outbreaks of infectious mononucleosis have been reported in which a proportion of cases did not show the increase in heterophil antibodies (Halerow et al. 1943) or all the cases were seronegative (Shubert et al. 1954). Niggemeyer (1953) reported 42 sporadic cases from Germany with the clinical and haematological characteristics of the condition but, in most cases, low heterophil
agglutinins. As in 1889, the question again arises : is glandular fever a disease or a syndromeSerology and haematology do not give unequivocal answers, particularly at the onset, when it would be desirable to have further supportive or indicative clinical features. The following clinical sign may therefore be of some interest. Twelve years ago a soldier who had been ill for three weeks was admitted to hospital with pyrexia, enlarged cervical glands, palpable spleen, cedema of the eyelids, and a petechial eruption on the soft palate. Serological and haematological investigation proved the case to be
Petechial eruption
on
border of soft and hard palate in first week of glandular fever.
1055
subsiding the
the
mucosa
petechiae
which faded
left a a few
yellowish discoloration of days later without trace.
THE DIAGNOSIS OF TOXOPLASMOSIS LACK OF SPECIFICITY OF SABIN-FELDMAN DYE TEST
Discussion
Although
the
purpuric spots
are
usually distinctly
of the soft palate at the junction with that of the hard is often dotted with small spider nsevi or haemangiomata which on superficial inspection may give the impression of petechiae. Thorough exami-nation will prevent such a mistake. Small traumatic haemorrhages have occasionally been seen in children who vigorously resisted any attempt to examine their mouths. These are as a rule few, asymmetrical in distribution, and localised on the mucosa of the hard palate. Purpuric lesions in the mouth of patients with glandular fever have previously been described but were not limited to the strip of mucosa adjoining the hard palate, and were associated with purpuric manifestations on other parts of the oral mucosa-e.g., the lateral margins of the tongue, the buccal mucosa, and the lips-and often accompanied by purpura of the skin. They were seen in
visible, the
mucosa
complicated by thrombocytopenia (Finlayson 1951, Goldbloom and Denton 1948, Kilham and Steigman 1942). Kilham and Steigman also described in 1 patient an eruption of red tender papules of irregular shape and about 0-5 cm. in diameter, discovered on the fourteenth day of his illness and persisting for three days. Read and Helwig (1945), in a review of 300 cases, found 4 in which petechiæ were noticed in the oral cavity, but they do not state their localisation. Muller (1950) mentions dark red spots on the soft palate in 2 cases. The frequency with which petechiæ appear on the soft palate in infectious mononucleosis cannot be assessed on the basis of these observations, because they were made on sporadic cases and not during an epidemic of the disease. Some patients with glandular fever did not show the petechial rash, but they all came under observacases
tion at the end of the second or third week of their illness and were therefore unlikely to bear any evidence of its presence. In the more recent of the cases reported here the petechial rash suggested the correct diagnosis before any other characteristic signs were found. A house-physician in a children’s hospital developed a feverish illness with severe pain in his limbs and back, rigor, and a sore throat. Examination on the first three days revealed nothing to suggest the diagnosis. On the fourth day the petechial eruption on the soft palate was noticed. A bloodcount at first was unhelpful but several days later was typical of glandular fever. Heterophil agglutinins increased to a titre of 1 : 1024. Platelets were present in large numbers.
Summary
petechial eruption on the soft palate is described as an early manifestation of infectious mononucleosis. The purpuric spots vary in number and slightly in size. They are localised at the junction of soft and hard palate in a crescent-like arrangement, appear between the third and the seventh days of the illness, and fade after three to four further days. A
My thanks
are
due to Prof. W. F. Gaisford for his kind and Davison I am indebted for the for the photograph.
helpful criticism ; to Miss D. drawing, and to Mr. G. Ward
REFERENCES
Cantor, M. W. (1930) Brit. med. J. i, 1197. Downey, H., McKinlay, C. A. (1923) Arch. intern.
Med. 32, 82.
Finlayson, R. (1951) Brit. med. J. ii, 1563. Goldbloom, A., Denton, R. (1948) Canad. med. Ass. J. 58, 189. Halcrow, J. P. A., Owen, L. M., Rodger, N. O. (1943) Brit. med. J. ii, 443.L., Steigman, A. J. (1942) Lancet, ii, 452. Kilham, Longcope, W. T. (1922) Amer. J. med. Sci. 164, 781. Müller, G. (1950) Z. klin. Med. 146, 1. Niggemeyer, H. (1953) Arch. Kinderheilk. 146, 118. Pfeiffer, E.(1889) Jb. Kinderheilk. 29, 257. Read, J. T., Helwig, F. C. (1945) Arch. intern. Med. 75, 376. Rominger, E. (1953) Arch. Kinderheilk. 146, 97. Shubert, S., Collee, J. G., Smith, B. J. (1954) Brit. med. J. i, 671. Tidy, H. L. (1934) Lancet, ii, 180.
Ph.D.
F. I. AWAD Lond., B.V.Sc. Cairo, M.R.C.V.S.
DEPARTMENT OF PARASITOLOGY, LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE
AN
antibody, called cytoplasm-modifying antibody, toxoplasma infections modifles the staining properties living toxoplasma (Sabin and Feldman 1948). Toxoplasma suspended in peritoneal exudate can be stained with methylene-blue, the organisms at the same time tending to lose their crescentic shape and to become spheroidal. If, however, they are incubated with immune serum before the methylene-blue is added, some of them, depending on the strength of the antibody, retain their crescentic shape and do not take up the stain. A labile in of
"
accessory factor,"
present in small
amounts in human
serum, is necessary for the action of the "
cytoplasmmodifying antibody." Cathie and Dudgeon (1949) modified the SabinFeldman technique by using normal human serum to dilute both the mouse peritoneal exudate 1 in 2 and for the serial dilution of the suspected serum so as to have sufficient " accessory factor." Muhlpfordt (1951) used the Sabin-Feldman dye test in an attempt to differentiate between infections of toxoplasma and sarcocystis. Sarcocysts recovered from the gullet muscles of sheep or of goats were inoculated either per os or intraperitoneally into guineapigs, rats, and hamsters, and the sera of these animals were tested by the dye test against toxoplasma. In every case preliminary tests made before the inoculation with sarcocysts produced negative results, but after the infection was allowed to establish itself the animals reacted positively, thus showing that the antibodies reacting with toxoplasma were produced by the sarcocystis infection. Tests were next made with the sera of 45 sheep, and the reaction was positive in 48-8% of the sheep. Muhlpfordt concludes that the Sabin-Feldman dye test can be used in the diagnosis of sarcocystis infection but cannot differentiate between sarcosporidiosis and toxoplasmosis. Michalzik (1953) applied the Sabin-Feldman dye test in 50 adult women infected with Trichomonas vaginalis and obtained a positive reaction in 64% of them with a titre of 1 : 25. Awad and Lainson (1954a) have confirmed Muhlpfordt’s findings- and conclude that infection with sarcocystis gives a cross-reaction in the dye test against toxoplasma. Awad (1954) described the use of Sarcocystis tenella spores in a new dye test for toxoplasma and sarcocystis infections. The new dye test gave positive reactions in both toxoplasma and sarcocystis infections, which fact proves that neither the Sabin-Feldman test nor the new test is specific for toxoplasmosis. The Sabin-Feldman dye test has been extensively used for the diagnosis of toxoplasmosis. Whenever doubts have been cast on the specificity of the dye test, it has been said that the animals in question might have reacted positively to the test because they had been previously infected with toxoplasma. The crossreaction of toxoplasma and sarcocystis has, however, now been proved. I report here an investigation of the cross-reactions in the dye test with two protozoa-Trichomonas vaginalis and Trypanosania cruzi-in laboratory animals known to have had no contact with toxoplasma. Materials and Methods
Collection of toxoplasma.-The peritoneal exudate was collected from mice three or four days after intraperitoneal inoculation with the RH strain of toxoplasma.
denervation. I am grateful to various physicians and surgeons of the Leeds region, in particular Dr. H. G. Garland and Mr. M. Ellis, F.R.C.S., for referring patients who took part in this trial. The Medical Research Council supplied the cortisone acetate. REFERENCES
Blockey, N. J., Wright, J. K., Kellgren, J. H. (1954) Brit. med. J. i, 1455.
Bunnell, S. (1937) Arch. Otolaryng., Chicago, 25, 235. Hall, A. (1951) Ibid, 54, 475. James, J. A., Russell, W. R. (1951) Lancet, ii, 519. Morris. W. M. (1938) Ibid, i, 429. Robison, W. P., Moss, B. F. (1954) J. Amer. med. Ass. 154, 142. Rothendler, H. H. (1953) Amer. J. med. Sci, 225, 358. Truelove, S. C., Witts, L. J. (1951) Brit. med. J. ii, 375. Whitty, C. W. M. (1953) Lancet, ii, 86.
INFECTIOUS MONONUCLEOSIS A. HOLZEL M.D. Prague, D.C.H. HEALTH,
UNIVERSITY OF MANCHESTER
SIXTY-FIVE years ago, when at
a
meeting
describing glandular Cologne,
of the Naturforscher in
fever Emil
Pfeiffer said : "
of
(1) The first was an adult who developed a severe tonsillitis which was accompanied by the enlargement of cervical and tonsillar glands and by the presence of abnormal lymphocytes in the blood picture but showed no increase in heterophil
AN EARLY CLINICAL SIGN OF
LECTURER IN CHILD
glandular fever. Since then this eruption on the has been observed in 15 sporadic cases of confirmed palate mononucleosis and in 2 others where the clinical manifestations or the blood picture were strongly suggestive but the serological investigations negative. The ages of these patients ranged from 4 years to 33. Only 2 of the 10 children among them had rubelliform skin rashes ; the petechial enanthem preceded the skin eruption byby twenty-four and forty-eight hours. The three clinical types (Tidy 1934)-anginose, glandular, and febrilewere represented among the 15 cases, and none of them showed any other signs of purpura or hsemorrhagie manifestations except the petechiae on the soft palate. Platelet-counts were made in only 7 of the patients and fell within the normal range. Clinical picture and course did not differ in these patients from the now well-known patterns of the disease and do not warrant detailed discussion. Heterophil agglutinin titres varied from 1 : 61 to 1 : 2048. Two patients had petechiae on the palatal mucosa but no definite evidene of glandular fever : one
intention is only to sketch for you the clinical picture basis for further observations and studies. No doubt this clinical picture, like so many of our syndromes, includes different disease processes, and bacteriological and pathological research is necessary before we can separate the forms which differ in aetiology and morbid anatomy."
My
as a
This statement is still valid. Numerous contributions to the clinical picture have been made, and there is hardly an organ or a system that has not been implicated in this disease ; but in the multitude of clinical manifestations the original outline of the sketch has become blurred, and what has been gained in width and depth of the picture has been lost in definition. For a time, the diagnosis seemed to rest on a solid foundation of clinical signs, haematological changes, and serological tests. Now these foundations, at least for the initial phase of the disease, have been shaken. The characteristic cells, first described by Longcope in 1922 and more accurately by Downey and McKinlay in 1923, have been found in various virus diseases, such
agglutinins. (2) The second was a girl, aged 3 years, with generalised lymphadenopathy (including the occipital glands) and a rubelliform rash which faded very rapidly, but neither haematological nor serological changes characteristic of the disease. and the final diagnosis was rubella.
petechial eruption was in all cases localised along junction of soft and hard palate, where the mucosa normally appears rather pale, and so was easily discernible. The petechiae varied in number from ten to fifty and were usually of pinhead size but occasionally somewhat bigger. They appeared grouped in a crescent-like arrangement due to the shape of the soft palate. Their earliest appearance was noticed on the third day after the onset of symptoms, and their latest at the end of the first week. This coincides with the stage of eruption (fourth to seventh day) in the febrile type (Cantor 1930, Tidy 1934). The spots generally persisted for three or four days. The exception was the first case, in which they were still present at the end of the third week. After The
the
hepatitis, atypical pneumonia, measles, rubella, herpes Further, zoster, and influenza B (Rominger 1953).
as
outbreaks of infectious mononucleosis have been reported in which a proportion of cases did not show the increase in heterophil antibodies (Halerow et al. 1943) or all the cases were seronegative (Shubert et al. 1954). Niggemeyer (1953) reported 42 sporadic cases from Germany with the clinical and haematological characteristics of the condition but, in most cases, low heterophil
agglutinins. As in 1889, the question again arises : is glandular fever a disease or a syndromeSerology and haematology do not give unequivocal answers, particularly at the onset, when it would be desirable to have further supportive or indicative clinical features. The following clinical sign may therefore be of some interest. Twelve years ago a soldier who had been ill for three weeks was admitted to hospital with pyrexia, enlarged cervical glands, palpable spleen, cedema of the eyelids, and a petechial eruption on the soft palate. Serological and haematological investigation proved the case to be
Petechial eruption
on
border of soft and hard palate in first week of glandular fever.
1055
subsiding the
the
mucosa
petechiae
which faded
left a a few
yellowish discoloration of days later without trace.
THE DIAGNOSIS OF TOXOPLASMOSIS LACK OF SPECIFICITY OF SABIN-FELDMAN DYE TEST
Discussion
Although
the
purpuric spots
are
usually distinctly
of the soft palate at the junction with that of the hard is often dotted with small spider nsevi or haemangiomata which on superficial inspection may give the impression of petechiae. Thorough exami-nation will prevent such a mistake. Small traumatic haemorrhages have occasionally been seen in children who vigorously resisted any attempt to examine their mouths. These are as a rule few, asymmetrical in distribution, and localised on the mucosa of the hard palate. Purpuric lesions in the mouth of patients with glandular fever have previously been described but were not limited to the strip of mucosa adjoining the hard palate, and were associated with purpuric manifestations on other parts of the oral mucosa-e.g., the lateral margins of the tongue, the buccal mucosa, and the lips-and often accompanied by purpura of the skin. They were seen in
visible, the
mucosa
complicated by thrombocytopenia (Finlayson 1951, Goldbloom and Denton 1948, Kilham and Steigman 1942). Kilham and Steigman also described in 1 patient an eruption of red tender papules of irregular shape and about 0-5 cm. in diameter, discovered on the fourteenth day of his illness and persisting for three days. Read and Helwig (1945), in a review of 300 cases, found 4 in which petechiæ were noticed in the oral cavity, but they do not state their localisation. Muller (1950) mentions dark red spots on the soft palate in 2 cases. The frequency with which petechiæ appear on the soft palate in infectious mononucleosis cannot be assessed on the basis of these observations, because they were made on sporadic cases and not during an epidemic of the disease. Some patients with glandular fever did not show the petechial rash, but they all came under observacases
tion at the end of the second or third week of their illness and were therefore unlikely to bear any evidence of its presence. In the more recent of the cases reported here the petechial rash suggested the correct diagnosis before any other characteristic signs were found. A house-physician in a children’s hospital developed a feverish illness with severe pain in his limbs and back, rigor, and a sore throat. Examination on the first three days revealed nothing to suggest the diagnosis. On the fourth day the petechial eruption on the soft palate was noticed. A bloodcount at first was unhelpful but several days later was typical of glandular fever. Heterophil agglutinins increased to a titre of 1 : 1024. Platelets were present in large numbers.
Summary
petechial eruption on the soft palate is described as an early manifestation of infectious mononucleosis. The purpuric spots vary in number and slightly in size. They are localised at the junction of soft and hard palate in a crescent-like arrangement, appear between the third and the seventh days of the illness, and fade after three to four further days. A
My thanks
are
due to Prof. W. F. Gaisford for his kind and Davison I am indebted for the for the photograph.
helpful criticism ; to Miss D. drawing, and to Mr. G. Ward
REFERENCES
Cantor, M. W. (1930) Brit. med. J. i, 1197. Downey, H., McKinlay, C. A. (1923) Arch. intern.
Med. 32, 82.
Finlayson, R. (1951) Brit. med. J. ii, 1563. Goldbloom, A., Denton, R. (1948) Canad. med. Ass. J. 58, 189. Halcrow, J. P. A., Owen, L. M., Rodger, N. O. (1943) Brit. med. J. ii, 443.L., Steigman, A. J. (1942) Lancet, ii, 452. Kilham, Longcope, W. T. (1922) Amer. J. med. Sci. 164, 781. Müller, G. (1950) Z. klin. Med. 146, 1. Niggemeyer, H. (1953) Arch. Kinderheilk. 146, 118. Pfeiffer, E.(1889) Jb. Kinderheilk. 29, 257. Read, J. T., Helwig, F. C. (1945) Arch. intern. Med. 75, 376. Rominger, E. (1953) Arch. Kinderheilk. 146, 97. Shubert, S., Collee, J. G., Smith, B. J. (1954) Brit. med. J. i, 671. Tidy, H. L. (1934) Lancet, ii, 180.
Ph.D.
F. I. AWAD Lond., B.V.Sc. Cairo, M.R.C.V.S.
DEPARTMENT OF PARASITOLOGY, LONDON SCHOOL OF HYGIENE AND TROPICAL MEDICINE
AN
antibody, called cytoplasm-modifying antibody, toxoplasma infections modifles the staining properties living toxoplasma (Sabin and Feldman 1948). Toxoplasma suspended in peritoneal exudate can be stained with methylene-blue, the organisms at the same time tending to lose their crescentic shape and to become spheroidal. If, however, they are incubated with immune serum before the methylene-blue is added, some of them, depending on the strength of the antibody, retain their crescentic shape and do not take up the stain. A labile in of
"
accessory factor,"
present in small
amounts in human
serum, is necessary for the action of the "
cytoplasmmodifying antibody." Cathie and Dudgeon (1949) modified the SabinFeldman technique by using normal human serum to dilute both the mouse peritoneal exudate 1 in 2 and for the serial dilution of the suspected serum so as to have sufficient " accessory factor." Muhlpfordt (1951) used the Sabin-Feldman dye test in an attempt to differentiate between infections of toxoplasma and sarcocystis. Sarcocysts recovered from the gullet muscles of sheep or of goats were inoculated either per os or intraperitoneally into guineapigs, rats, and hamsters, and the sera of these animals were tested by the dye test against toxoplasma. In every case preliminary tests made before the inoculation with sarcocysts produced negative results, but after the infection was allowed to establish itself the animals reacted positively, thus showing that the antibodies reacting with toxoplasma were produced by the sarcocystis infection. Tests were next made with the sera of 45 sheep, and the reaction was positive in 48-8% of the sheep. Muhlpfordt concludes that the Sabin-Feldman dye test can be used in the diagnosis of sarcocystis infection but cannot differentiate between sarcosporidiosis and toxoplasmosis. Michalzik (1953) applied the Sabin-Feldman dye test in 50 adult women infected with Trichomonas vaginalis and obtained a positive reaction in 64% of them with a titre of 1 : 25. Awad and Lainson (1954a) have confirmed Muhlpfordt’s findings- and conclude that infection with sarcocystis gives a cross-reaction in the dye test against toxoplasma. Awad (1954) described the use of Sarcocystis tenella spores in a new dye test for toxoplasma and sarcocystis infections. The new dye test gave positive reactions in both toxoplasma and sarcocystis infections, which fact proves that neither the Sabin-Feldman test nor the new test is specific for toxoplasmosis. The Sabin-Feldman dye test has been extensively used for the diagnosis of toxoplasmosis. Whenever doubts have been cast on the specificity of the dye test, it has been said that the animals in question might have reacted positively to the test because they had been previously infected with toxoplasma. The crossreaction of toxoplasma and sarcocystis has, however, now been proved. I report here an investigation of the cross-reactions in the dye test with two protozoa-Trichomonas vaginalis and Trypanosania cruzi-in laboratory animals known to have had no contact with toxoplasma. Materials and Methods
Collection of toxoplasma.-The peritoneal exudate was collected from mice three or four days after intraperitoneal inoculation with the RH strain of toxoplasma.