9

GLANDULAR FEVER:INFECTIOUS MONONUCLEOSIS

By SIR HENRY TIDY

E. Pfeiffer, a paediatrician of Vienna, gave, in1889, the first clear description of this diseaseunder the title Drusenfieber or glandular fever.He recognized that it was infectious and occurredin epidemics, described accurately the course ofthe enlargement of the cervical glands in youngchildren, though he denied that other glands wereinvolved, and stated that the glands never sup-purated and that the prognosis was uniformlyfavourable. The blood was not mentioned.

Other observers in Germany soon reportedepidemics. Spread of its knowledge was some-what slow but Park West (i896) reported anepidemic in America and Dawson Williams (1897)one in England. The disease appeared to besuccessfully launched, but the diagnosis in sporadiccases rested on rather indefinite clinical features.It became confused with septic infections andrapidly fell into disfavour. By i900 it was nearlydead. No mention of it appears in the ' MedicalHistory of World War I,' although subsequent in-formation proves that it was not uncommon.Burnford (i9i8) is the single observer to whom thepossibility occurred; he suggested that a group ofcases with pyrexia and enlarged glands belongedto Pfeiffer's Drilsenfieber. Its memory was justkept alive by brief descriptions in general text-books copied verbatim from book to book. It re-mained in suspended animation until I920.

It is remarkable that during a period of 30 years,covering rapid developments in the knowledge ofhaematology, there should have been no systematicexamination of the blood in a condition character-ized by enlargement of lymphatic glands and oftenby enlargement of the'spleen. To this lack ofobservation there is one exception. J. E. Burns(1908) fully described the lymphocytosis in twoepidemics which he diagnosed as glandular fever,and published a well-documented report. Thecommunication was overlooked until it was quotedby Bernstein (1940) in his monograph. Priorityfor the recognition of infectious mononucleosisclearly belongs to Burns.

Nevertheless the establishment of the haemato-logical features of the disease did not come, forpractical purposes, until I920. Sprunt and Evansin November, I920, published their observationson transient mononucleosis recorded in a series ofsix college students during the previous six years.They recognized that the condition was infectious,observed the general glandular enlargement and

gave an accurate though brief description of thevarious types of cells in the blood. They were un-aware of the existence of Pfeiffer's glandular feverand thought they had discovered a new disease-a very venial mistake-and named it ' infectiousmononucleosis.' Downey and McKinley (1923)gave a complete description of the cells, beautifullyillustrated, to which nothing effective has beensubsequently added.Meanwhile Morley and I, in June, 1920, had

found a transient lymphocytosis in the case of aboy whom we diagnosed as suffering fromglandular fever, and we reported it with othercases at a meeting of the Royal Society of Medicinein December, 1920.The recognition of the identity of infectious

mononucleosis and glandular fever was not im-mediate in America, though Longcope used bothterms Mi 1922, but it was probably general by1925. The material on which the observationswere based in America was, and still is, pre-dominantly from college students about the agesof i8 to 24 years, while in England it was mainlysupplied by resident preparatory schlool boys of8 to I4 years. Although any type of the diseasemay occur at any age, there are considerabledifferences, when numbers of individuals are in-volved, between the clinical manifestations in thetwo age-groups, the glandular enlargement beingmore marked at the younger ages. These factorsno doubt account for the differences in nomen-clature, for the disease is invariably known as in-fectious mononucleosis in America while in Britainit is generally named glandular fever.

Paul and Bunnell (1932) made the curious dis-covery that heterophil agglutinins to sheep's redcells are present in high titre in the blood inglandular fever and in no other known disease, adiscovery which increased the interest in thecondition.

Glandular fever commenced its clinical life as asimple, harmless adenitis. In I922 the additionof the anginose type or monocytic angina widenedthe field. The epidemic of 1930 added prolongedfebrile forms. About 1935 the onset with jaundicewas found to be not uncommon. The latestaddition is the recognition of its association withneurological disturbances of a varied and oftenbizarre character but without permanent ill-effects. One may wonder in what guise glandularfever will next make its appearance.

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Clinical Manifestations in Glandular Fever'Juvenile ' and ' Adolescent' TypesThe onset in young children is usually acute.

There may be a short prodromal period of malaisebut this is commonly overlooked and the glandularenlargement often first attracts attention.The cervical glands are most frequently in-

volved. They tend to enlarge rapidly and mayform a visible tumour within 24 hours. The massis normally painless and only slightly tender,though young children may object to palpation.The gland which is most characteristically en-larged is deep to the sterno mastoid muscle, aboutthe middle of its length, and somewhat below theangle of the jaw; it lies transversely and can befelt on both sides of the muscle. There is usuallysome enlargement of axitlary glands. Either hereor at other sites this may be sufficient to constitutedefinite masses. Such a mass may be presentwithout any involvement of the cervical groups.

In the fauces there is little change though somecomplaint of sore-throat is common. Eruptionsare unusual. Torticollis is an occasional com-plication.The temperature is raised to about IoiO to

103°. Constitutional symptoms are slight andthe patient does not appear ill. The spleen be-comes palpable in about half the cases, but onlyone or two finger-breadths. The main mass ofthe glands and the constitutional disturbancesgenerally subside in the course of a few days, andthe patient has recovered in one to two weeks.

Suppuration of the glands is no part of theordinary course of glandular fever but in veryrare cases has followed a pre-existing tonsillitis.The glands, although much smaller, may remain

palpable for many weeks or even several months.Mononucleosis is often, but not invariably,

present when the glands appear, otherwise itdevelops within a few days; not infrequently thisis the date of the first examination. The totalleucocytes in most cases lies between io,ooo and20,ooo per cm. with 6o to 8o per cent. of mono-nuclear cells. Both monocytes and lymphocytescontribute to the excess, but the monocytes sub-side rapidly and leave the lymphocytes to pre-dominate. Some degree of lymphocytosis maylinger for several months.

Recrudescences or relapses are far more fre-quent than is usually believed. The course maybe similar to the original attack but tends to bemilder. Recurrences may take place after con-siderable periods of freedom; there may beseveral over a period of some months, graduallydecreasing in severity. I have been told of casesin which they extended over one or more yearsbut I have not seen them, and the diagnosis shouldI e carefully reviewed.

The incubation period is between five and Idays in the great majority of cases, but in spite ofmany studies it is impossible to fix an upper limit.The description given above applies especially

to the type which is seen in children between theages of 5 and 15 or i6 years, sometimes referredto as the 'juvenile form.' Under the age of 5years the picture is less characteristic; the con-stitutional symptoms are often more severe andthe glandular enlargement slighter, and thediagnosis may be difficult.Among adolescents and young adults the course

tends to be longer and more insidious and theglandular enlargement less marked than in thejuvenile form. The onset is slow with fatigue anddepressed health, gradually becoming sufficient tocause the subject to report to a medical officer.The glands may be found then or subsequently,often on routine examination. This is the formin which glandular fever is commonly seen inAmerica among college students, and Americandescriptions of the disease are essentially based onthis age-group. They have few resident ' pre-paratory schools' as we know them and con-sequently their clinicians have only a limited ex-perience of the juvenile type.Ap mentioned above, any superficial glands

may enlarge; this includes the pre-auricular, sub-maxillary, submental, supra-trochclear and oc-cipital glands. There is also evidence that thedeep glands may be involved. I have seen cases inwhich pressure on the bronchi has producedtransient obstruction with very confusing physicalsigns. This complication has been confirmedradiologically by Nelken (1926). Abdominal painmay be severe and due to enlargement of deepglanjis.

Anginose Type, Monocytic AnginaNeither resident college life nor resident pre-

paratory schools are a part of the educationalsystem in Europe outside Britain, and the recog-nition on the Continent of a recoverable mono-nucleosis (other than that of whooping cough) wasinitially based on a different type of materialappearing in entirely other guise from theglandular forms presenting in America andEngland.

Deussing, in f9i8, reported a series of caseswith transient absolute lymphocytosis under thetitle ' Ueber diphtherieihnlicher Anginen mitlymphatischer Reaction ' (angina resembling diph-theria with a lymphatic reaction). But it was acommunication by Schultz in 1922, to the Congressfor Internal Medicine, on ' Monozytenangina 'which first attracted attention to the subject.Both communications were based on patientsadmitted to a hospital for communicable diseases

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TIDY: Glandular Fever:

with membranous tonsillitis in which no diphtheriabacilli were found and in whom recovery followedwithout the injection of antitoxin.The Continental authorities went astray from

the start. They were obsessed with the idea thatthe development of the lymphocytosis was due toa constitutional peculiarity of the patient resultingin a ' lymphatic reaction' and that the sameangina in other individuals would result in apolynucleosis. The possibility of infection wasscarcely considered. Secondly, they embarked ona tedious and sterile dispute amongst themselvescovering many years as to whether the cells weremonocytes or lymphocytes. They failed torecognize that both types of cells were oftenpresent at the same time and that either typemight predominate at different periods in the samepatient. Not until Glanzmann's monograph in1930 did they admit that monocytic angina was amanifestation of infectious mononucleosis andrecognize the influence of an infective factor asopposed to a constitutional diathesis.The definite differentiation of monocytic angina

from diphtheria was a clinical advance of im-portance, and it is surprising that so little noticehas been taken of it in American and Britishliterature. It is rarely~properly described in text-books under the headings of either tonsillitis ordiphtheria or glandular fever, and its existence isnot yet generally recognized by the profession.Even nowadays it is frequently diagnosed as acutetonsillitis, treated with sulphonamides or penicillinand the favourable course ascribed to the therapy.Yet it is a condition of considerable severity and isproof of the presence of glandular fever.

Monocytic angina or the anginose type ofglandular fever is characterized by the develop-ment of a tonsilbr membrane or of ulceration.The membrane in typical cases is indistinguishablein appearance from that of diphtheria, although itis a true membrane, and it often forms very rapidly.It never involves the larynx. Oedema of the neckand tenderness of the enlarged cervical glands iscommon, but not to the extreme degree of diph-theritic bullneck, and suppuration is very rare.Oedema of the fauces causes great discomfortand anxiety, but in spite of this and the hightemperature, often about 1040, the patient does notappear to be toxic nor does he become so, althoughthe membrane may persist for severa~l days ormore than a week before separating, after whichthe symptoms improve with surprising rapidity.There has sometimes been a previous period ofslight malaise for two or three weeks with in-creasing sore throat, and some glandular enlarge-ment may or may not have been observed.

Mononucleosis is generally present at the timeof appearance of the membrane and is always

January I950 Infectious Mononucleosis I I

present and absolute within a day or two, but atthe onset it is often only relative and an initialleucopenia is common. It is possible that theangina is a complication following a mild attack ofglandular fever two or three years previously. Thedevelopment may be the result of the leucopeniawhich is often present initially or of the mono-nucleosis. There is no proof that the disease isinfectious at this stage or that it spreads in thisform.

Prolonged Febrile TypesAn extensive epidemic in England in 1930 was

characterized by the severity and long duration ofthe attacks and by the high proportion occurringin adults. It apparently represents the full de-velopment of glandular fever. Sporadic cases andmilder grades are fairly common but this is theonly recorded occurrence of the type in epidemicform (Tidy, 1931).At the beginning the diagnosis of typhoid was

often made in spite of the uniformly negativeagglutinations and it was some time before theepidemic was recognized as glandular fever. In-deed the identity could scarcely have been sus-pected before the discovery of the changes in theblood.The epidemic exhibited clearly that in severe

forms the characteristic features of glandular en-largement and mononucleosis develop late and theglands rarely attain any great size. In many casesthe severe constitutional disturbances are alreadysubsiding before the glands become palpable.The initial febrile period is of variable duration,

and recrudescences may lengthen it to many weeks.During this stage there may be no diagnosticfeatures either on physical or laboratory investiga-tion. Headache is often severe. There may be afew rigors. Sweats are nearly always profuse;they are greatly increased by the administration ofantipyretics and then become associated with ex-treme exhaustion. Wassermann reaction- andKahn's test may become temporarily positive.An eruption is common. The type varies but it

may be noted here that it is sometimes in-distinguishable from typhoid.The temperature has no regular course but it

has generally fallen to normal or nearly normalbefore the glands enlarge, when it rises again.The glands are often discovered by chance or bya routine examination when the temperature rises.The spleen may become palpable at this stage.Rapid improvement often follows and con-valescence sets in, but recurrences are not un-common.The course of the blood changes is important.

At the onset there may be a definite polynucleosis;this often misleads observers who are unaware -of

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the possibility. The polynuclear cells always falland for a period the blood count may be strictlywithin normal limits. Leucopenia is often presentabout the time the glands commence to enlarge.In some cases there is a leucopenia at the onset,but the febrile period in these is rarely prolonged;the earlier stage seems to have been cut off so tospeak. The glandular enlargement is alwaysassociated with mononucleosis.Four groups of clinical manifestations have so

far here been indicated: (i) Pfeiffer's glandularfever, in the 'juvenile' form usually seen inchildren, characterized by rapid and visibleswelling of the cervical glands and a short dura-tion, (2) infectious mononucleosis in young maleswith a longer but milder febrile stage and com-paratively slight glandular swelling, (3) theanginose type or ' monocytic angina,' and (4)fqbrile types with late and slight enlargement ofglands.

This grouping was useful while the clinicalfeatures of the disease were being carefully studied,but the disease is a single entity and every per-mutation and combination of the four groupsoccur.

EruptionsThe rash in glandular fever may cause con-

siderable difficulty owing to its close simulation ofmany of the exanthemata.

During the course of glandular and ;inginosetypes well-defined eruptions are rare and tend tobe transient. In the febrile forms eruptions arecommoner, though the incidence has varied greatlyin different epidemics; the rash usually appearswithin a few days of the onset but may develop atany point in the course.There are two common types: (a) macular or

maculo-papular; this is the eruption most fre-quently seen in the febrile forms and may closelyresemble the rash of typhoid, and (b) rubelliform;this is the commoner type in the glandular formsand may be indistinguishable from rubella. It isof interest that I have on several occasions knowna rubelliform eruption appear and subside a weekor two before the development of an attack ofglandular fever, an initial diagnosis of rubellahaving been made without hesitation. I havealso been told on good evidence of transienteruptions a week or two before the developmentof the membrane in the angiose form.

Cases of glandular fever have been admitted toinfectious disease hospitals with rashes resemblingtyphus, measles,' scarlet fever, chicken-pox, ery-thema nodosum and urticaria. I have neverpersonally seen an eruption resembling fully-developed chicken-pox.

The Blood PictureIt is probable that mononucleosis develops in

every case of glandular fever.All the blood-forming tissues are affected,

myeloid, monocytic (or reticulo-endothelial) andlymphoid, but at different times and to differentdegrees and varying in different cases and,indeed, in the same case at different stages. Theeffect on one system may be decreasing while onanother it is increasing thus producing the rapidchanges in the blood picture which are so charac-teristic of the disease. The full sequence of thechanges is best observed in the long severe febrilecases but unfortunately the diagnosis is rarelymade in their early stages.The myeloid system is earliest involved but less

constantly or severely and for a shorter time thanthe other systems. In mild cases there may be nochange in the circulating myeloid cells, but inseverer forms an initial polynucleosis, such as15,ooo to 20,ooo leucocytes per cm. with 75 percent. polynuclears is not infrequent. The pos-sibility of such polynucleosis is not generallyrealized and frequently causes an error indiagnosis. Polynucleosis is always transient andinitial and never develops during the course of theattack. The rise of the mononuclear reaction mayoverlap the fall of the polynuclear cells, but in themore severe forms this reaction is delayed and theblood count becomes within normal limits andmay remain so' for two to three weeks or more, ormay fall further to a leucopenia before the mono-nucleosis appears. Leucopenia also is fairlycommon at the onset; it is mainly due to granu-lopenia but even the lymphocytes may fall. Inmilder clinical types, such as the ordinaryglandular forms, a mononuclear reaction may bepresent at the first examination" or within a fewdays of onset.The monocytic and lymphocytic reactions over-

lap but the monocytic system is the first to sub-side and a pure lymphocytosis is finally left. Sorapidly may alterations take place in the types ofwhite cells and their number and so great are thedifferences in different cases that no single bloodpicture is exclusively typical of the disease. Butmost characteristic during the active stages is thepresence simultaneously of various types of mono-nuclear cells, particularly with a high incidence ofmonocytes, and the rapidity with which the relativeproportions change.The total number of leucocytes does not rise to

very high figures. About i0,000 to 15,000 percm. is common, over 20,ooo is unusual and over30,000 is rare. The limit is about 5o,ooo butsomewhat higher numbers have been recorded ininfants.The percentage of mononuclear cells is gener-

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TIDY: Ginadular Fever: Infectious Mononucleosis

ally between 6o and 70 when the disease is fullydeveloped,' over 8o per cent. is rare and over goper cent. very rare, but there are authenticinstances and I have seen it several times.The existence of a specific ' infectious mono-

nucleosis cell '. is in dispute. American authoritiesof standing have described them minutely.British authorities, such as Whitby and Britton,believe that they are primitive monocytes, anopinion with which I agree.' It would be unsafe tobase a diagnosis on the presence of such cells andcertainly unsafe to exclude glandular fever on theirabsence, since as the attack subsides the survivingcell is undoubtedly a lymphocyte, large or small.

Heterophil Antibodies, Paul-Buimnell ReactionThe term heterophil antibodies is applied to

antibodies which can react with certain antigenswhich are unrelated to the cause of their develop-ment. Here it is a question of the development inhuman serum of antibodies which agglutinatesheep's red cells. Such antibodies are present inlow titre in normal serum and similar antibodiesmay be present to a higher titre in serum sicknessor after injections of horse serum. Paul andBunnell in 1932 discovered the curious fact thatsuch antibodies develop in high titre in humanserum in glandular fever, and in no other disease,with some academic exceptions. Though similar,the three types of agglutinins are not identical andthey can be separated by appropriate absorptiontests.The technique of the reaction unfortunately has

not been standardized. Confusion has arisen inAmerica over the method of recording the dilutionof serum, but this does not appear to havehappened in Britain. With a simple techniquesuch as that described by Smeall (I942) a titre ofI/64 is almost proof of glandular fever and a titreof I/I28 is absolute proof. If there is any doubtwhen the *,itre is I/64, the test can be repeated orabsorption tests performed.

Important questions which arise are at whatstage the reaction becomes positive, in what pro-portion of cases it is positive, and whether or nota negative reaction excludes glandular fever.

In the ordinary mild types the reaction is fre-quently positive at the first examination, whichmay be four or five days after the onset. If theexamination is earlier the test may be negative or-indefinite, the titre rising in the next few days.Owing to the certainty with which the diagnosiscan often be made on clinical and haematologicalgrounds, the test is not always repeated. Neverthe-less in these circumstances the reaction is positivein nearly go per cent.

But in the severer febrile forms the reaction mayand generally does remain negative during the

weeks of pyrexia and constitutional disturbances,and becomes positive about the same time as themononucleosis and glandular swelling develop.It is striking how often the' constitutional symp-toms rapidly abate within a few days of the rise intitre. Thus a positive reaction is related to theend of an attack rather than to the beginning, andit may well be connected with the development ofimmunity as Himsworth (i940) suggested. Onmore than one occasion I have known the reactionbecome positive for the first time during a relapse,but I have also known relapses take place whilethe titre is still high.

It is very important that this time-relationshipshould be borne in mind. The development ofagglutinins appears to be associated with or rte-lated to the stage of glandular enlargement andmononucleosis. A negative reaction during thestage of constitutional symptoms is therefore notsurprising and must not be interpreted as ex-cluding the possibility of glandular fever. Theagglutination reaction is of most value, in con-firming that enlarged glands and mononucleosisare due to glandular fever.The titre has no constant relationship to the'

severity of the disease, the extent of the glandularswelling or to the degree of mononucleosis. Thetime during which a reaction remains positive isvery variable, but little more is known. The"titre may rise to a very high dilution and fall againmto negative in the course of a fpw days.' Inordinary mild -cases it usually becomes negativewithin two weeks of recognition, but it may per-sist for several weeks and has been found stillpositive after several months.'The significance of a negative test specially

arises in epidemics in which all cases are reportedas negative, and in sporadic cases in which thetest is repeatedly negative. The question 'ariseswhether or not there are two types of glandularfever giving respectively positive and negative re-actions. There is nothing inherently improbablein the existence of two viruses, but until we knowmore about heterophil agglutination the evidencemust be regarded as inconclusive.

I agree with the opinion of Paul and others that*a positive reaction is proof of glandular fever anda negative reaction does not exclude it.

Neurological ManifestationsThe neurological manifestations of glandular

fever have attracted attention recently and a num-ber of cases have been recorded in the last fewyears(Geliebter, I946; Schneider, 1947). The presenceof glandular fever in similar cases must previouslyhave been overlooked. The existence of en-cephalitis was suspected by Longcope (1922) andby Glanzmann (1930), but the first clear descrip-

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tions of neurological features 'were given byEpstein and Damneshek (I93i) and by Johannsen(1930I). The clinical pictures are extraordinarilyvaried and bizarre, and no two cases appear to bequite similar. The brain (encephalitis), meninges,cord, cranial nerves and peripheral nerves may beaffected either separately or in combinations orsequences. There is no constant order in whichthe ordinary manifestations of glandular feverand the neurological symptoms respectively de-velop, or in their comparative severity. Thus theglandular enlargement, lymphocytosis in the bloodand in the cerebrospinal fluid, and meniingeal orother neurological symptoms may develop andsubside simultaneously as in Epstein and Dame-shek's case. In other cases the glandular fevermay run its course and subside to be followed bynervous symptoms, and lymphocytosis in thecerebrospinal fluid, but with a normal bloodpicture and agglutination titre. Or again thesymptoms of a benign lymphocytic meningitismay be subsiding before the features of glandularfever appear. In this last group the blood countmay show an initial polynucleosis even with ahigh mononucleosis in the cerebrospinal fluid. Itis noteworthy that in the more severe neurologicalforms the glandular swelling tends to be slight aswith other severe types of glandular fever andmay be overlooked during convalescence fromthe nervous features unless specifically sought.The interpretation of the Paul-Bunnell reaction

in neurological cases needs careful consideration.The heterophil agglutinins have been estimated inall recorded cases since 1938, and the test alwayshas been positive in the blood at some stage withthe exception of two doubtful cases in sisters(Thelander and Shaw, I941), but not in thecerebrospinal fluid. This may only mean thatthe diagnosis of glandular fever is not made unlessthe reaction is positive.

In assessing the value of a negative reaction thetime-relations described above must be taken intoconsideration. Cases of benign lymphocyticmeningitis have been recorded in the neurologicalliterature in which glandular fever is held to befinally excluded by a negative agglutination,although the reaction has been performed at apoint during the course when it would not beexpected to be positive. Neurologists have notentirely familiarized themselves with the proteanmanifestations of glandular fever and the time-relations of the development of agglutinins.The symptoms of benign lymphocytic meningitis

are exactly'reproduced in certain of the cases.There are, of course, a number of infections andviruses which are known to produce this syndrome,and it is not suggested that more than a proportionis due to glandular fever. But some undoubtedly

are, and the association with glandular fever iseasily overlooked. The identification of a virus ina case of benign lymphocytic meningitis does notexclude the possibility.

Recovery from neurological manifestations cantake place with extraordinary rapidity. A coma-tose and paralysed patient with an extensorplantar response may be apparently normalmentally and physically in three days. Thequestion of encephalitis requires further observa-tion. Severe headache is the commonest symp-tom in neurological castes and is also an occasionalcomplaint in ordinary types. It is often observedthat children and adolescents may take a sur-prisingly long time, six to i2 months, to re-cover their previous powers of concentration andapplication after a simple attack, and it is possiblethat this is a sequel of encephalitis.

Association with JaundiceJaundice is now not uncommon at the onset or

during the course of the severer forms but theassociation has become frequent only in the last15 years. It was not recorded in the epidemic inEngland in 1930, but in 1935 and 1936 manycases were observed in St. Thomas's Hospital andit is now a recognized complication. Whenoccurring at the onset the jaundice is often ofconsiderable severity and there is nothing to dis-tinguish the clinical condition from an ordinaryinfective hepatitis. As the jaundice subsides thepyrexia persists and the diagnosis of glandularfever often follows the discovery of lymphocytosisin a routine blood count or the observation of someglandular swelling.

Jaundice adds the symptoms of infectivehepatitis to the symptoms of glandular fever butdoes not appear otherwise to affect the course.Jaundice is rarely severe when developing later inthe illness. Whether or not the jaundice is due toa separate virus cannot at present be determined.

PrognosisI have personally never seen a case of glandular

fever in which recovery was not complete. Never-theless there are exceptions. Several of the smallnumber of recorded deaths are open to doubt, buta few are authentic. In some of these there hasbeen an extraneous factor such as pre-existingsepsis or debility in children. A patient has diedin the comatous stage of a neurological complica-tion. But it can be accepted that the ordinaryforms are devoid of danger. The long period ofpartial debility and lack of concentration whichmay follow even mild attacks especially in childrenhas been referred to above. This was formerlyascribed to an effect on the blood but there is no

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January I950 TIDY: Glandular Fever: Infectious Mononucleosis 15

evidence of resulting anaemia and it may be dueto encephalitis. a

ProphylaxisThe degree of infectivity is not great and second

cases in a family are unusual. On the other hand,susceptibility appears to be almost universal.Consequently, if two or three cases develop in aschool and there is an opportunity for mass in-fection all the other children may become infected.

It is extremely difficult to be dogmatic about theduration of infectivity. It is probable that thedisease is infectious only in its early stages but thepossibility of infectivity during relapses cannot beexcluded. It is reasonably certain that theanginose type is non-contagious.

Isolation should be carried out in accordancewith the dictates of common sense for a diseasewhich is undoubtedly infectious but only of amoderate degree of infectivity and with a favour-able prognosis. A reasonable course is to isolate acase for one week after the mass of the glands hassubsided and the temperature has become normal.

DiagnosisPossible errors in diagnosis are numerous and

mistakes in practice are not uncommon, but inordinary attacks they usually settle themsdlveswithout important consequences. They will notbe considered seriatim or fully but the followingbrief points may be noted.The distinction from mumps is decided by the

fact that the parotid gland is never affected. Thedifferential diagnosis from sepsis may be difficult;the cases in which I have been in serious doubthave nearly always proved to be sepsis, and it isadvisable to treat them as such. Vincent's anginanever causes lymphocytosis. From rubella therash may be indistinguishable.

In the severer febrile forms there may be nomeans, either clinical or pathological, of estab-lishing the diagnosis for several weeks. This mayalso apply to onset with jaundice or with neuro-logical symptoms. The correct interpretation of anegative agglutination reaction is important. Inthe blood the most characteristic features are thesimultaneous presence' of numerous types ofmononuclear cells, and increased number ofnmonocytes normal or slightly abnormal, and therapidity with which the differential count changes.Difficulties may arise from the initial polynucleosisor initial leucopenia or from the almost normalblood count which may be temporarily present inthe course of the long febrile forms. The bloodchanges should not cause difficulty in differ-entiation from chronic leukaemia. In acuteleukaemia the toxic symptoms are always severe.An occasional but extremely difficult diagnosis

may be caused by the rare, slowly-progressivechronic lymphoid leukaemia. In the earlierstages there are periods of exacerbation withpyrexia and moderate glandular swelling. Thelymphocytes for several years may be only at theupper limits of normal. They gradually creep upand the diagnosis long suspected slowly becomesconfirmed. Diagnosis is specially difficult when itis asked for on a patient some months after apyrexial attack with lymphocytosis considered atthe time to be glandular fever. Either lympho-cytosis or glandular swelling may persist forseveral months after glandular fever, but if bothfeatures are present for six montjhs the diagnosismust be considered to be in doubt, unless it hasbeen fully established. I have watched three suchcases, originally diagnosed doubtfully as glandularfever, which gradually developed into fatallymphoid leukaemia or lymphosarcoma overperiods of three to ten years.

Treatment.Many drugs have been claimed to abort attacks

and one by one have been discarded. I havefound no difference between those so treated andthose untreated. Sulphonamides are valueless,and their use should be deprecated in a conditionin which the blood-forming tissues are in asensitive state. Antipyretics are contraindicatedin severe febrile cases as they aggravate thesweating and increase prostration. Penicillin isindicated in the anginose type and there is evidenceof its value; it has no influence on the course ofother types. I have no experience of chloro-mycetin or aureomycin.

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32, 82.EPSTEIN, S. H., and DAMESHEK, W. (I93I), New England J7.

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