CHAPTER 1

THE CLINICAL FEATURESOF SMALLPOX

Contents

1

Page

Introduction 2

Varieties of smallpox 3

The classification of clinical types of variola major 4

Ordinary-type smallpox 5The incubation period 5Symptoms of the pre-eruptive stage 5The eruptive stage 19Clinical course 22Grades of severity 22

Modified-type smallpox 22

Variola sine eruptione 27

Subclinical infection with variola major virus 30Evidence from viral isolations 30Evidence from serological studies 30

Flat-type smallpox 31The rash 31Clinical course 32

Haemorrhagic-type smallpox 32General features 32Early haemorrhagic-type smallpox 37Late haemorrhagic-type smallpox 38

Variola minor 38Clinical course 38Variola sine eruptione and subclinical infection 40

Smallpox acquired by unusual routes of infection 40Inoculation variola and variolation 40Congenital smallpox 42

Effects of vaccination on the clinical course of smallpox 42Effects of vaccination on toxaemia 43Effects of vaccination on the number of lesions 43Effects of vaccination on the character and evolution of

the rash 43Effects of vaccination in variola minor 44

Laboratory findings 44Virological observations 44Serological observations 45Haematological observations 46

INTRODUCTIONAs this book went to press, endemic

smallpox had been eradicated from Europeand North America for almost half a centuryand from the populous countries of China andIndia for some 25 and 10 years respectively .The majority of people-including themajority of physicians now living havenever seen a case of this once-dreaded disease .What was it like? For the physician, whatwere its clinical features and its complica-tions? What factors influenced the prog-nosis? What diseases entered into its differen-tial diagnosis? Nowhere is there a betteranswer to these questions than in the bookwritten by Ricketts and illustrated by Bylesover three-quarters of a century ago (Ricketts,1908) .

Since then, however, long series of careful-ly studied cases of both variola major (Rao,1972) and variola minor (Marsden, 1936)have been documented, and laboratory inves-tigation has become a powerful tool for

confirmation of the diagnosis in puzzlingcases. Further, during the global smallpoxeradication programme a large number ofWHO epidemiologists and their nationalcounterparts had extensive experience ofsmallpox as it occurred in the field in urbanand rural areas and among nomads, as distinctfrom the hospitals from which Ricketts's,Rao's and Marsden's material was drawn.However, only limited clinical studies werepossible in rural situations, outside of hospi-tals. The most comprehensive clinical study ofvariola major in a non-hospital setting is aseries of 539 cases seen in their houses inPakistani Punjab in 1966-1967 (Mack et al.,1970). Where relevant, data from this studywill be used to supplement the description ofhospital-based cases described by Rao (1972) .An attempt has been made to interpret thesymptoms in the light of current understand-ing of the pathogenesis and immunology oforthopoxvirus infections, as outlined inChapter 3 .

2 SMALLPOX AND ITS ERADICATION

PageComplications 47

The skin 47Ocular system 47Joints and bones 47Respiratory system 48Gastrointestinal system 48Genitourinary system 49Central nervous system 49

Sequelae 49Pockmarks 49Blindness 50Limb deformities 50

Prognosis of variola major 50Calculation of case-fatality rates 50Effects of immunity 51Effects of age 54Effects of pregnancy 54Clinical type of disease 55

Differential diagnosis 55Ordinary- and flat-type smallpox 56Haemorrhagic-type smallpox 62Effects of prior vaccination on symptomatology 63Alternative diagnoses 64

Laboratory confirmation of smallpox diagnosis 64Treatment : prophylactic and curative 64

Vaccination during the incubation period 64Immunoprophylaxis and immunotherapy 65Chemoprophylaxis and chemotherapy 66Symptomatic treatment 68

The plan of the present chapter followsRicketts in that the account of the clinicalfeatures of smallpox consists mainly of adescription of the rash, based on photographsof patients, most of which were preparedduring the global smallpox eradication pro-gramme. Because smallpox is now extinct, wehave to take the unusual step, in the clinicaldescription of a human disease, of referring toit in the past tense ; this was previously thecase only with diseases that apparently disap-peared and could be identified only by con-temporary descriptions, such as the "Englishsweat", or the "sweating sickness" .

Plate I .I . Thomas Frank Ricketts (1865-1918).Medical Superintendent of the Smallpox Hospitalsand of the River Ambulance Service of the Metro-politan Asylums Board, London . His book on theclinical features of smallpox was based on the personalexamination of many thousands of cases of variolamajor.

VARIETIES OF SMALLPOX

From the time it was first recognized as adistinct disease until about the end of the 19thcentury, smallpox was regarded as a uniformlysevere disease, associated with a high case-fatality rate, in every part of the world . Mildcases and even mild outbreaks of smallpox

1 . CLINICAL FEATURES 3

were occasionally mentioned in the old litera-ture, but they were the exception ; nowheredid endemic mild smallpox occur . Smallpoxwas designated by many names in variouslanguages, but no one saw a need to distin-guish different varieties of smallpox, al-though the existence of different clinicaltypes (see below) was recognized from thetime of Thomas Sydenham (1624-1689) inEurope and much earlier in India and China .

The situation changed when Korte (1904)described a very mild smallpox-like disease,with a case-fatality rate of 1 % or less inunvaccinated persons, that had occurred inSouth Africa for several years and was knownlocally as kaffir-pox, or "amaas", a word ofuncertain origin, possibly a corruption of theDutch word masels or mazelen (measles) (Dix-on, 1962). Subsequently, Chapin (1913, 1926)recognized that a similar mild disease hadbeen occurring in North America since about1896, and had subsequently been exportedfrom there to South America, Europe andAustralia. There was controversy about therelationship of this disease to smallpox untilthe mid-1950s (Jong, 1956), but virologicalstudies (see Chapter 2) showed that there wasno doubt that "amaas" and "alastrim" (fromthe Portuguese alastra, something which"burns like tinder, scatters, spreads from placeto place"), as it was called in South America,were indeed mild varieties of smallpox . Al-though many other names were used, thisclinico-epidemiological variety of smallpoxhas come to be called "variola minor", adesignation that led to the use of the term"variola major" for "classical" smallpox .

Recent studies of viral strains recoveredfrom outbreaks of variola minor in variouscountries have shown that they fall into twogroups distinguishable by biological proper-ties, one consisting of strains derived fromoutbreaks in South America or traceable to anAmerican source (which we shall call "alas-trim" virus) and the other comprising moststrains from Africa (see Chapter 2) .

During the first half of the 20th century alloutbreaks of smallpox in Asia and most ofthose in Africa were due to variola major(with case-fatality rates of 20 % or more in theunvaccinated). Variola minor (with case-fatality rates of 101 or less) was endemic insome countries of Europe and of North andSouth America and, together with variolamajor, in many parts of Africa. With the morecareful study that began after global eradica-tion had been proclaimed as a goal of WHO in

4

SMALLPOX AND ITS ERADICATION

1959, it was recognized that some outbreaksof smallpox in western, central and easternAfrica and in Indonesia were associated with alower case-fatality rate than classical variolamajor, in the range of 5-15% instead of over20%. Some of these lower figures resultedfrom aggregating all reported cases in placeswhere both varieties of smallpox were ende-mic (see Chapter 8), but there were otherplaces where this was not the explanation .The clinical picture of smallpox with a case-fatality rate of 5-15"o was indistinguishablefrom that of variola major, both haemorrha-gic and flat types of the disease occurring withabout the same frequency as in classicalsmallpox. Preliminary tests suggested thatcertain laboratory characteristics of some ofthe strains recovered from these outbreakswere intermediate between those of variolamajor and variola minor (see Chapter 4), butlater studies failed to support the differenti-ation of a separate "intermedius" virus . In thisbook all outbreaks of smallpox will be catego-rized as either variola major, with case-fatalityrates of 5-25°,o and occasionally more, orvariola minor, with case-fatality rates of about10 . or less.

THE CLASSIFICATION OF CLINICALTYPES OF VARIOLA MAJOR

It has long been recognized that severalclinical types of variola major could bedistinguished which differed in prognosis,differential diagnosis and transmissibility.The old subdivision according to the densityof the focal eruption was shown by Dixon(1962) and Rao (1967) to have less prognosticvalue than a classification based on the natureand evolution of the rash . For this reason aWHO Scientific Group on Smallpox Eradica-tion (1968) adopted the classification pro-posed by Rao and fully described in his bookon smallpox (Rao, 1972). A WHO ExpertCommittee on Smallpox Eradication (1972)reaffirmed its acceptance of this classification(Table 1 .1), according to which the common-est clinical type (ordinary-type smallpox) issubdivided in relation to the density of therash, since this had prognostic significance .The great majority of cases of variola majorseen in hospitals among both unvaccinatedand vaccinated persons -88.8% and 70%respectively in Rao's series of 6942 cases

Plate 1 .2 . A . Ramachandra Rao (b . 1917) . FormerlySuperintendent of the Infectious Diseases Hospital,Madras, India . His book on smallpox was based onthe personal study of nearly 7000 hospitalized casesof variola major. He also made important contribu-tions to the understanding of the epidemiology ofsmallpox in India (see Chapter I5) .

Table 1 .1 . A classification of clinical types of variolamajora

Ordinary type

Modified type

Variola sineeruptione

Flat type

a Based on Rao (1972) .

Raised pustular skin lesions . Threesubtypes:confluent-confluent rash on faceand forearms;semiconfluent-confluent rash onface, discrete elsewhere;discrete-areas of normal skinbetween pustules, even on face .

Like ordinary type but with anaccelerated course .

Fever without rash caused by variolavirus ; serological confirmationrequired .

Pustules remained flat ; usuallyconfluent or semiconfluent .Usually fatal.

Haemorrhagic type

Widespread haemorrhages in skin andmucous membranes . Two subtypes :early, with purpuric rash ; alwaysfatal ;late, with haemorrhages into baseof pustules ; usually fatal .

Table 1 .2 . The frequency and case-fatality rates of different clinical types of variola major, according tovaccination status (presence of a scar) in hospitalized patients in Madrasa

a Based on Rao (1972) .

(Table 1 .2)-were ordinary-type smallpox(and other reported series confirm this) ; thecase-fatality rates in unvaccinated cases withconfluent, semiconfluent and discrete rasheswere 62%, 37% and 9.3% respectively.Although its use was suggested by Rao, such asubclassification is hardly justified for modi-fied-type or flat-type cases, but it is useful toconsider early and late haemorrhagic-typecases separately, since they were probably theresults of different pathophysiologicalprocesses .

A special comment is required on thedesignation of cases as vaccinated by both Rao(1972) and other investigators. Until freeze-dried vaccine became available and regularassessment was made of the results of vaccina-tion, many vaccinations, especially in tropicalcountries, were performed with vaccine ofless than the required potency (see Chapter11). The categorization of a subject as "vaccin-ated" was made on the basis of the presence ofwhat was regarded as a vaccination scar . Thepresence of such a scar was, however, notcertain evidence of successful vaccination .The rotary lancet, used for vaccination on theIndian subcontinent, was attended by consid-erable trauma, and sometimes bacterial infec-tion alone could produce scarring . On theother hand, vaccination by the jet injectorsometimes resulted in a very small scar whichmight be overlooked on the skin of subjectsbearing many scars of traumatic origin . Inspite of these shortcomings, the vaccinationscar provided a more easily determined andreliable index of an individual's immunestatus vis-a-vis smallpox than was possiblewith other infectious diseases .

1 . CLINICAL FEATURES

ORDINARY-TYPE SMALLPOX

The Incubation Period

The incubation period is the intervalbetween the implantation of infectious virusand the onset of the first symptoms, which insmallpox were fever and constitutional dis-turbances. Determination of the length of theincubation period is discussed in detail inChapter 4 ; in exceptional instances the dura-tion, from the time of infection until theonset of fever, was as short as 7 days or as longas 19 days, but in the great majority of casesthe period extended over 10-14 days, usually12 days.

Symptoms of the Pre-eruptive Stage

The incubation period in smallpox was aperiod of intense activity in terms of viralreplication and spread within the body andthe development of the immune response(see Chapter 3), of which there was at thattime no clinical evidence . It ended when thepatient became feverish and ill (Fig . 1 .1) . Theonset of fever and malaise was sudden, thetemperature usually rising to between 38 .5 °Cand 40.5 °C. Other symptoms varied in fre-quency (Table 1 .3) . Patients suffering fromvariola major usually complained of a split-ting headache, sometimes frontal but usuallygeneralized, and many complained of severebackache (Rao, 1972). A small proportion ofchildren had convulsions and some adultswere delirious at this stage. Vomiting oc-curred in about half of all patients, and

5

Unvaccinated subjects Vaccinated subjects

Clinical typeNumber of

casesPercentage of

totalCase-fatality

rate (%)Number of

casesPercentage of

totalCase-fatality

rate (%)

Ordinary type : 3 147 88.8 30 .2 2 377 70 .0 3 .2Confluent 808 22.8 62 .0 156 4 .6 26 .3Semiconfluent 847 23 .9 37 .0 237 7 .0 8 .4Discrete 1 492 42.1 9 .3 1984 58 .4 0.7

Modified type 76 2.1 0 861 25 .3 0

Flat type 236 6.7 96 .5 45 1 .3 66 .7

Haemorrhagic type : 85 2 .4 96 .4 1 15 3 .4 93 .9Early 25 0 .7 100 .0 47 1 .4 100 .0Late 60 1 .7 96 .8 68 2 .0 89 .8

Total 3 544 35 .5 3 398 6 .3

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9

SMALLPOX AND ITS ERADICATION

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1 1 1

Fig . 1 .1 . The clinical course of moderately severe ordinary-type smallpox in an unvaccinated subject : thetemperature chart, the development of rash, the presence of virus in the blood and oropharyngeal secretionsand the time of appearance of neutralizing antibody in the serum . (Data from various sources .)

diarrhoea in about 10% . Some suffered ab-dominal colic, which could lead to a diagnosisof appendicitis . The patient was usually ill,with an appearance of general toxaemia . Bythe 2nd or 3rd day (rarely the 4th) thetemperature had fallen and the patient feltsomewhat better ; at this time the macularrash appeared.

In older writings (e.g., Ricketts, 1908) therewas often reference to the occurrence of anerythematous rash during the pre-eruptivephase (prodromal rash), best seen in fair-

Table 1 .3. Frequency of symptoms (percentages of cases) in the pre-eruptive stage in variola major andvariola minor

skinned subjects (Plate 1 .3A and B). Someauthors (Dixon, 1962 ; Rao, 1972) have castdoubt on its occurrence in unvaccinatedsubjects, but all agree that a fleeting "allergic"rash sometimes occurred in vaccinated indi-viduals, most readily visible around the vacci-nation scar (see Plate 1 .3), in the axillae,behind the knees and in the inguinal region .The erythematous rash common in the earlystages of haemorrhagic-type smallpox had tobe distinguished from the prodromal rash ofordinary-type or modified-type smallpox .

00

VN

Varlola malora Variola minors

Symptom 6942 cases(Rao, 1972)

12 847 cases(Marsden, 1936)

859 cases(Noble et al., 1970)

Fever 100 .0 98 .2Headache 90 .0 75 .0 79 .4Malaise 66 .7Chills 60 .0 34 .0 62 .4Anorexia 60 .6Backache 90 .0 38 .8 44.2Pharyngitis 15 .0 20.6 38 .2Nausea 11 .0 37 .0Vomiting 50 .0 34 .2 30.3Diarrhoea 10 .0 3 .6Delirium 15 .0Abdominal colic 13 .0Convulsions 7 .0

A

Plate 1 .3 . A and B: Prodromal rashes. Thesewere best seen in fair-skinned persons (for exam-ple, Caucasians and Japanese) and were morecommon in those previously vaccinated. A :Erythematous prodromal rash on the upper arm,near the sites of vaccination performed 8 daysearlier but sparing the skin immediately adjacentto the vaccination lesions . B : Measles-likeprodromal rash on the lateral side of the trunk onthe 4th day of illness . C: The enanthem . Lesionsoccurred throughout the oropharynx and in thenasal cavity, as well as on the tongue. The lesionson the palate were usually smaller than those onthe posterior pharyngeal wall and tonsil . (FromUchida, 1955 .)

1 . CLINICAL FEATURES 7

C