Human monkeypox, 1970-79*

rtile in the Updat*seris Les article de la~rbiu / / / ~~~~~~~andup-to-date survey of the /bilan concis et fiiable de la ITrns tN / / ~~present position in the se- /situation actuelle dans le L_JjJcI iate lected fields, and, over a domaine considere. Des ex-/ /period of years, will cover /perts couvriront ainsi suc- / / / ~~~~~~~manydiffierent aspects of /cessivement de nombreux I Xr * + , , ~~~~the biomedical sciences /aspects des sciences bio- e o I ln t and public health. Most of meidicales et de la santethe articles will be writ- publique. La plupart de ces ten, by invitation, by ack- articles auront donc ete nowledged experts on the reFdiges sur demande par les ILsubject. I specialistes lesplus autorises / Bulletin of the World Health Organization, 58 (2): 165-182 (1980) Human monkeypox, 1970-79* J. G. BREMAN,1 KALISA-RUTI,2 M. V. STENIOWSKI,3 E. ZANOTTO,3 A. I. GROMYKO,1 & I. ARITA1 Increasing attention has been given to human monkeypox since the achievement of global smallpox eradication. Monkeypox, which was first described in Central Africa in 1970, resembles smallpox clinically but differs from it epidemiologically. Forty-seven cases of human monkeypox have occurred since 1970 in 5 Central and West African countries; 38 of these cases have been reported from Zaire. The evolution of the illness and the sequelae of monkeypox and smallpox are the same; monkeypox has a case-fatality rate of about 17%. Children below 10 years of age comprise 83% of the cases. All cases have occurred in tropical rainforest areas and clustering of cases has been observed in certain zones within countries and within families. Person-to-person spread may have occurred in 4 cases; the secondary attack rate among susceptible, very closefamily members was 7.5% (3 cases/40 contacts) and among allsusceptible contacts was3.3% (4 cases/123 contacts)-much lower than the 25-40% secondary attack rate that occurs with smallpox. Although the low transmis- sion rate and the low frequency of disease indicate that monkeypox is not a public health problem, more data are needed. Whilst many animals near human monkeypox cases have been demonstrated to have orthopoxvirus antibodies, the natural reservoir(s) and the vector(s) ofmonkey- pox virus are unknown. Studies are in progress to identify the natural cycle of monkeypox virus and to defi-ne better the clinical and epidemiologicalfeatures ofthis disease. Monkeypox was first discovered in man in Basankusu district, Equateur Region, Zaire, in 1970, 2 years after the last case of smallpox had occurred in the area. It is a disease that resembles smallpox clinically, but which differs from it in important epidemiological aspects. Some features of the first 21 human monkeypox cases have been reviewed earlier.a This report describes the clinical and epidemiological characteristics of all the 47 cases of human monkeypox reported from 1970 up to the end of 1979. * A French translation of this article will appear in a later issue of the Bulletin. ' Smallpox Eradication, World Health Organization, 1211 Geneva 27, Switzerland. 2 Expanded Programme on Immunization, Ministry of Public Health, Republic of Zaire. 3Epi iological Surveillance, Expanded Programme on Immunization, World Health Organization, Republic of Zaire. a LADN\, I. D. ET AL. Bulletin ofthe World Health Organization, 46:593-597(1972); MARENNIKOVA, S. 5. ET AL. Bulletin of the Worldfealth Organization, 46: 599-611 (1972); FOSTER, S. 0. ET AL. Bulletin of the World Health Organization, 46: 569-576(1972)\ ARITA, I. & HENDERSON, D. A. Bulletin ofthe WorldHealth Organization, 53: 347-353 (1976); BREMAN, J. G. ET AL. Americ&n journal of tropical medicine and hygiene, 26: 273-281 (1977). 3936 -165- J. G. BREMAN ET AL. As global eradication of smallpox has now been achieved, and most countries have stopped vaccination, immunity levels in the population will soon decline rapidly; it thus is extremely important that diseases resembling smallpox be carefully evaluated. Such investi- gations are essential to provide continuing assurance to health officials and the public alike that smallpox has indeed been eradicated and that vaccination is no longer necessary. CLINICAL FEATURES The major clinical features of human monkeypox are similar to those of smallpox. There is a 2-4-day prodromal illness with fever and prostration before the eruption begins. As with smallpox, the lesions develop more or less simultaneously and evolve together at the same rate through papules, vesicles, and pustules before umbilicating, drying, and desqua- mating. This process usually takes about 2-4 weeks, depending on the severity of the disease. The distribution of the rash is mainly peripheral. Severe eruptions may cover the entire body (Fig. 1-6), including the palms and soles. Six (13%) of the 47 known cases had a mild illness (less than 25 lesions, with no incapacity, not usually requiring medical care), 18 (38Gb) had moderate disease (more than 25 lesions, with moderate incapacity, usually requiring medical care), and 23 (49%) had severe disease (more than 100 lesions, severe incapacity, requiring medical care) (Table 1). Most skin lesions are about 0.5 cm in diameter but some up to 1 cm have been seen. Lesions have been noted on the mucous membranes, the tongue, and the genitalia (Fig. 4 and 6). Lymphadenopathy, especially in the neck (submandibular and cervical) and the inguinal areas, was particularly prominent in 18 cases (Fig. 4 and 5). Pitting scars develop most frequently on the face, and diminish with time. Secondary infection of the lesions is common and may play a role in scarring. About half of the scars from lesions seen initially on the face and body were detectable 1-4 years after the acute illness. Desquamation of crusts leaves areas of hypopigmentation. Hyperpigmentation follows after a few months and diminishes with time (Fig. 7). In some cases, large shallow residual scars are seen. In one case a primary corneal lesion caused unilateral blindness (Fig. 8). Another patient who was vaccinated several years previously developed only 1 lesion (Fig. 9) further emphasizing that some cases can be exceedingly mild and may go unreported. Only 4 of the 47 patients (9%) had a vaccination scar. These were persons, aged 35, 30, 24, and 8 years, who had been vaccinated more than 5 years previously. Eight (17Vo) of the patients died from monkeypox during the acute illness. They were between 7 months and 7 years of age. None had been vaccinated. Three other patients died of other causes 2 months, 4 months, and 14 months, respectively, after their illness. Comparatively few laboratory tests have been done on these patients, mainly because of delays in reaching the patient after notification, difficulties in collecting scrapings from lesions or obtaining serum, and problems in procuring follow-up samples. Table 2 gives virological and serological test results. For the 47 patients, monkeypox virus isolation confirmed the diagnosis in 30 out of 39 patients from whom skin scrapings were taken. Poxvirus particles were seen on electron microscopic (EM) examination of skin samples from 7 others, but virus was not isolated. Ten others had serological as well as clinical and epidemiological evidence of monkeypox infection; skin specimens were not collected from seven of these patients, and another specimen was not suitable for testing. The virus could be isolated from specimens taken up to 18 days after onset of the rash. A specimen from1 patient (case 19) which was EM-negative, was positive for monkeypox virus upon culture. The precipitation-in-gel test was less helpful than other virological methods; in no instance was the test positive when EM and/or culture were negative. 166 167HUMAN MONKEYPOX U)C LD cnco -N w CI I 03 E 0 CL 0 Z r- CL 15e C4 cn 0 cn 0 - 0 EC4 0 U) E t ?r co CLE CL m CL 0 0 E -if ? O.- u C4 0 C4 c E 0M0 0 CLCL CL E c6 06 6 E lu 0 'v Eco cl. E co CL E wE 0 0 rco0 t!'o c Ec r- 40 to co 0a co E co M r 0 t CLO Z 0 0 0 , c #,= 0 -CL 0 0 c 0 CL9 0 0 15 - 9 0 9 9 co 2 zm co cn co cc Z cn + + + + + + + CL 0 M N N N N M N N M M M N N M N M N M M M N N N M M M cn C,4 cn cn M C,4 cn C,4 cn M M C,4 cn C-4 cn (n cn 0 0 N N N N N m m m v Ln w w w w r- r, r, r, r- r- co co co CD co co co co W co co W 0) M cn CD (n 0) C rIt P.: r. P. r- r- rl- r- r, r- r- r- r- r- r- r- p- r, PI PI p- P. P. PI r- r- r- r, r- r, r- r- r, r- r- PI r- r- r- r, r- r- r- r- r- r- r- 0) M cn ci c4 4 4 ci ei P. r-.Z ai 6 ui ad c-4 c-i c-i C6 ad cj c-4 6 c-i c-i vi _: cq C4 cq L6 ai oi cj C4 C. cn O.0 4 C4 C6 vi 7 -: ai 06 -: C'i r.: rz (6 -:,6 's 6 'i 0; 'i Z .: cq C4 'i r.: -i 'i ui C6 06 (6 _: Cd 7 7 -:17 6 9 ui C; ciN - - - N- -CO c4c4-8- C4 -c4c"CoWn- C4 O C-4 .0 S10 0 -0 0 0 0 0 > x cn 'M C-4 C4 2. 7. "'t V v 0 - M C4 Cn La LnCV) r, v -- u" v V r,,t w Ln e4 CO CV) r- cn CV) C14 cnCIS! C4 C14 -M M M (D 0 L) A 40co -,r- 4-- 0 M, O9:3:3:35cozz C 0 .a C .c 0 .20 I - "a 03'o Z Z r- r- zoo 00co e 1 g e=4-- *.-.- 41 0 Z = S. 0 0 0 Ln co a aco 0 qcl .2 c"10 0c C Z cr cr cr cr a Cr C7 C7 C7 co icram a 2 O' a 0 8CD < LU' le 12. C'o N'e N'e LZ Lu7 Lff .m. LU M LU Ui Nex CD LU LU uj co Ui LU Ui Ui Co .e Lu Lu Co Lu le Uj Lu Co v M0 2 a04 Ne(D _le 0 0 E E 0 0 CD CD r--2 2 ie co 6 co c c = COco 0 co a 0 *. .; 2 co a a 08.5, r r.2.2 Z E cc cmW 60 cm CD E 0 c -W XA. i -r- - c-4 cnE E E co co ig - -90 Og:3 -az cm E CL co o a Ozlnco 0 Z j5 Lu >. 2 >m co lo 0 Om wx. E =0co co co co co co co EOLU 2 0 >- < >T 3 to co M O (D :5 1 6 - c4 mw Ln w r, w cn c c4 cnw La co r- co a) o cn -w u) r... m m L) NN NNN NNN?)-mmm MMM M vvv vvqr J. G. BREMAN ET AL. Table 2. Virological and serological examinations done on monkeypox cases Virological tests Serological tests Days Days Orthopox virus antibodies Monkeypox after after (reciprocal of titre) virus Case onset Virus Precipitation onset specific no. of rash EM isolation in gel of rash HI CF Neut. RIA antibody 1 8 NT + NT ... 2 13 64 < 8 500 3 5 + + + 90 64 8 4 12 16 < 8 128 5 8 + + - 8 128 16 1024 6 10 + + + 14 160 16 450 7 6 + + + 1518 70 FA + 8 ?2 - - NT 1509 178 FA + 9 44 80 32 16 57 40 128 45 333 40 8 12 1310 29 FA + 10 18 + + NT 1383 < 5 32 11 9 + + + ... 12 ... 105 40 16 64 1663 80 20 450 13 12 + - + ... 14 10 + + + ... 15 11 + + + 30 514 1280 1491 80 20 1200 230 RIA + 16 16 + - - 18 640 1280 1482 80 20 640 400 RIA+ 17 8 + + + ... 18 3 + + + 19 16 - + - 81 40 60 20 15 + + - 100 20 80 774 < 5 < 10 365 RIA+ 21 6 + - - 350 320 20 1200 4700 RIA + 22 16 + + + 237 80 10 256 23 7 + + + 63 20 40 90 8200 RIA+ 24 7 + + + 7 1280 80 < 4 13 + + + 73 10 570 5900 RIA+ 25 9 + + - 70 < 5 < 10 740 26 9 + + + 53 3900 RIA+ 27 6 + + - 50 225 50 2300 RIA + 28 15 + + + 49 20 40 29 11 + - + 213 160 20 3300 RIA + 30 6 + + - 64 40 10 < 10 3000 RIA+ 31 15 + + + ... 32 11 + - + 48 40 40 120 33 9 + + - 46 80 80 36 34 5 + + + ... 35 12 + + + ... 36 ... 58 20 10 5900 RIA + 168 10 10 2600 RIA + 37 21 - - NT 21 40 20 < 4 38 5 + + NT 15 80 20 483 RIA+ 15 + + NT 15 5 10 418 10 39 15 + + - 15 160 NT 220 30 160 20 32 6300 RIA+ 40 ... 14 80 40 < 4 7200 RIA+ 302 10 168 Fig. 1. 7-year-old girl with monkeypox from Equateur Region, Zaire. Front view, during day 8 of rash. Fig. 2. Same patient as Fig. 1, rear view. Fig. 3. Same patient as Fig. 1. The old scar on the arm is not due to vaccination. Fig. 4. Heavy concentration of lesions on the hands, inguinal lymphadenopathy, and pustules on genitalia. Fig. 5. Swollen lower face and neck due to cervical and submandibular lymphadenopathy. 0 C-0 0 0a .2 -ELu 0. ._CV CO Q~ C 0E. COn oE D~ C = > .' _ @ co 00X C(0 0. mC C r..C 4-6v .o in X C 0' *0 0. 0C 0 . 0 U ._ Fig. 8. 8-year-old boy with unilateral blindness following primary lesion on cornea; monkeypox occurred 1 year previously. Fig. 9. 0.5-mm pockmark in centre of upper lip in 35-year-old woman who had disease 3 months previously; this was the only lesion on this patient, who had been vaccinated more than 10 years before. Monkeypox viruswas grown from the scab taken during the acute illness. HUMAN MONKEYPOX 173 Table 2. Virological and serological examinations done on monkeypox cases (continued) Virological tests Serological tests Days Days Orthopox virus antibodies Monkeypox after after (reciprocal of titre) virus Case onset Virus Precipitation onset specific no. of rash EM isolation in gel of rash HI CF Neut. RIA antibody 41 4 + + NT 91 < 5 < 10 50 42 6 + - - 93 10 10 460 6800 RIA + 12 + - NT 251 20 43 6a 193 40 458 RIA + 44 5 + NT NT ... 45 ... 70b 31 46 11 + + NT 132 80 10 47 4 + + NT ... = no specimen; EM = electron microscope; HI = haemagglutination-inhibition; CF = complement-fixation; RIA = radioimmunoassay; FA = fluorescent antibody; NT (virological) or blank space (serological) = not tested. " Specimen in formol. b ELISA titre 256. Serological tests confirmed a previous orthopoxvirus infection in 35 out of 36 patients tested (Table 2). The fluorescent antibody testb and radioimmunoassayc identified monkeypox antibodies in sera from 19 of the patients. One of these was negative by virological tests, and skin samples could not be collected from 4 others. In an attempt to detect specific immunological defects, IgG and IgM were determined for 6 patients, using a radioimmunoassay technique. All monkeypox cases had elevated IgG and some were markedly increased; 3 cases had increased IgM. This may reflect only the consequences of the parasitic, bacterial, and viral infections to which these patients had been exposed. EPIDEMIOLOGY Geographical and temporal distribution Cases have been detected in five countries: Zaire (38), Liberia (4), Nigeria (3), Ivory Coast (1), and Sierra Leone (1). One recent case, number 39, originated in Nigeria, but was detected in Benin. All 47 cases have occurred in the tropical rain forest areas of Central and West Africa, between latitudes 8°N and 8°S, where hunting of wild animals for food is common (Fig. 10 and 11). All but 1 of the cases had lived in villages of about 200-1000 persons. The exception (case 18) ate meat originating from the tropical rainforest before disease onset. Clustering of patients has been observed in countries, in localities within countries, and within families (Fig. 10 and 11). Three of the 4 cases in Liberia (cases 2, 3 and 4) lived in one village, as did 2 of the 3 patients in Nigeria. In Zaire, 21 (55%/) of the 38 cases occurred in the northwestern Equateur region. Within this region, 13 (620o) of the 21 cases have been reported from the Bumba zone, 1 of 21 zones in the Equateur region. Nine cases occurred in the Kasai Oriental region; 8 of these came from the Kole zone, 1 of 12 zones in this region. Seven cases were detected in Bandudu region and 4 of these were in the Popokabaka zone. b GISPEN, R. ET AL. Bulletin of the World Health Organization, 53: 355-360 (1976). C WALLS, H. H. ET AL. Bulletin of the World Health Organization, 58: 131-138 (1980). J. G. BREMAN ET AL. In 5 instances, presumed co-primary cases occurred in the same family (cases 2 and 3, 11 and 12, 26 and 27, 32 and 33, 37 and 38). Case 4 lived next door to one of these families (cases 2 and 3). The interval between onset of illness was less than 24 hours for 1 case, 1 day for 2 cases, 2 days for 1 case, 3 days for 1 case, and 5 days for 1 case; the latter patient (case 38) developed a rash 7 days after the co-primary case (case 37). The cases have occurred sporadically since August 1970. Six cases were reported in 1970, 3 in 1971, 5 in 1972, 3 in 1973, 1 in 1974, 2 in 1975,3 in 1976, 6 in 1977, 12 in 1978, and 6 in 1979. Cases occurred most often in the dry season, although they have been reported throughout the year (Fig. 12). Twenty of the 38 cases in Zaire had onset of rash between January and March. Age and sex distribution Children were affected more frequently than adults. The mean age of the patients was 8 years (range 7 months-35 years); the median was 4 years. Thirty-nine of the 47 cases (83%o) were below 10 years of age; 25 (5507o) were below 5 years, and 5 (11 No) were below 1 year. Twenty-six patients were male and 21 were female. However, among patients older than 15 years, 5 of 7 were women. Person-to-person spread In 4 families, the onset of rash in secondary cases occurred 9, 12, 15, and 17 days, respectively, after the first case (Table 3). These cases may have been infected from a common source or secondary transmission may have occurred. Three of the 4 index patients had severe disease and the fourth had moderate disease. The disease in secondary cases was milder than in the primary case in two instances and in the other two the secondary cases were of comparable severity. All of the index and secondary cases were unvaccinated. No cases of possible tertiary spread were found. If it is assumed that all 4 cases represented person-to-person spread of monkeypox, the potential for transmission may be assessed by relating the number of cases to the total Fig. 10. Distribution of tropical rainforest and 47 human monkeypox cases, 1970-79. 174 HUMAN MONKEYPOX 220E -- - International boundary --- iRegional boundary ...--..- ---- Zonal boundary 0 250 km * One monkeypox case Two monkeypox cases same village @4 Two monkeypox cases - same village - evidence of secondary transmission 0 Major city or town Fig. 11. Distribution of 31 human monkeypox cases in northwestern and central Zaire, 1970-79. 0 Inongo * BANDUNDU REGION O Bandundu 175 J. G. BREMAN ET AL. miny season* £ 4 (a c 3 J F M A M J J A S 0 N D *Based on average monthly rainfall, Yaligimba, Bumba zone WEST AFRICA (9 cases) Rainy sao (0at J F M A M J J A S 0 N D N - Nigeria, L - Liberia, IC - Ivory Coast, SL - Sierra Leone WHO 80078 Fig. 12. Seasonal distribution of human monkeypox cases, 1970-79. 176 HUMAN MONKEYPOX 177 Table 3. Pairs of cases of human monkeypox representing possible secondary spread Laboratory resultsb Virological Serological Days Orthopoxvirus antibodies Date of Vacci- Virus Precipi- after (reciprocal of titre) Monkeypox Case onset nation Sever- iso- tation onset specific no. Age Sex Relation of rash scar itya EM lation in gel of rash HI CF Neut. RIA antibody 7 4 F - 9.4.71 - 3 + + + 1518 ... ... 70 ... FA + 8 24 F Mother of 18.4.71 - 1 - - ... 1509 ... ... 178 ... FA+ case 7 15 3 F - 10.1.73 - 2 + + + 30 514 1280 1491 80 20 1200 230 RIA + 16 5 F Sister of 22.1.73 Doubt- 2 + 18 640 1280 case 15 ful 1482 80 20 640 400 RIA + 35 2 M - 11.9.78 - 3 + + + ... ... ... ... ... 36 6 M Cousin of 28.9.78 - 3 ... ... ... 58 20 10 ... 5900 RIA + case 35 44 3 M - 5.2.79 - 3 + necropsy ... ... ... ... ... 45 9/12 M Brother of 20.2.79 - 2 .. ... ... 70c 32 ... .. ... ... case 43 a 1 = mild (less than 25 lesions with no incapacity, not usually requiring medical care) 2 = moderate (more than 25 lesions, moderate incapacity; usually requiring medical care but not always hospitalized) 3 = severe (more than 100 lesions, severely incapacitated, requiring medical care). b EM = electron microscope; HI = haemagglutination-inhibition; CF = complement-fixation; RIA = radioimmunoassay; FA = fluorescent antibody. c ELISA titre 256. number of susceptibles (those without a vac- cination scar) among family and other close contacts. In this setting the vaccination scar rate among contacts was 700o or more. Among immediate family members (parents, siblings, children, or spouse), the secondary attack rate among susceptibles was 7.5'0o (3/40) (Table 4); susceptible siblings of monkeypox cases had a 10%o attack rate (2/20). Among all other persons having known face-to-face contacts with patients, including more distant relatives, the secondary attack rate among suscep- tibles was 1.2%7o (1/83). The total secondary attack rate among all known susceptible contacts was 3.3%7o (4/123); this is low compared with smallpox where the second- ary attack rate is about 25-4007o. Table 4. Vaccination scar rates of contacts of human monkeypox cases, and secondary transmission rates Without Secondary vaccination monkeypox scar cases Total Attack rate no. among Contact of con- suscep- type tacts No. % No. tibles(%) Immediate familya 171 40 23 3 7.5 Otherb 276 83 30 1 1.2 Total 447 123 28 4 3.3 a Parents, siblings, children, or spouse, living in same house during illness. b All other persons, including more distant relatives, having contact with patient during illness, but not neces- sarily living in same house. 178 J. G. BREMAN ET AL. SURVEILLANCE FOR MONKEYPOX Human In 1975, special vaccination-scar and facial-pockmark surveys were conducted among populations living near where human monkeypox cases had occurred during the previous 4-5 years in the Ivory Coast, Nigeria, and Sierra Leone. Immunity levels were compara- tively low in the younger age groups in these countries and 57% of 2125 children 0-4 years of age, and 29%o of 8047 school-age children had no vaccination scars, indicating their probable susceptibility to monkeypox infection. In those areas, there was no evidence of other cases of monkeypox (or smallpox) as determined by surveys of facial pockmarks or by examination of the health units in the area. From 1975 to 1977, widespread facial pockmark surveys were conducted in Central and West Africa to detect possible cases of smallpox. Over 6 500 000 children of school age and younger were seen; 1 825 380 were of preschool age. None had facial pockmarks suggestive dof smallpox or monkeypox, other than the cases known previously. Data in Table 5 show the results of smallpox vaccination scar surveys done in 1978 and 1979 in villages where cases occurred and in surrounding villages. Less than one-half of the children aged 0-4 years had been vaccinated in villages where cases occurred and about 600o of this age group had been vaccinated in nearby villages. The vaccination coverage in Table 5. Vaccination scar surveys by age group done near human monkeypox cases, 1978-79 Village where case occurred Surrounding villages 0-4 years 5-14 years > 15 years 0-4 years 5-14 years > 15 years Case no. No. % vacc. No. % vacc. No. % vacc. No. % vacc. No. % vacc. No. % vacc. 30 25 88 28 93 64 100 a _ a a 31 b b b 627 81 1 126 94 1 500 95 32, 33 b b b 1212 58 1363 93 2255 97 34 42 50 21 100 47 98 278 69 2296 95 396 93 35, 36c 57 7 71 83 119 94 256 34 385 83 513 97 37, 38 112 56 332 95 246 83 d d d 39e 205 36 485 53 1897 63 144 45 231 55 569 65 40 118 51 148 78 219 89 2602 66 3883 92 5291 90 41 3 67 20 84 43 99 197 50 362 84 581 99 42 70 37 107 91 131 96 997 52 1537 95 1987 92 43 25 68 6 100 24 100 106 58 155 95 87 99 44,45c 207 46 226 86 421 97 1796 55 2420 89 2288 96 46 161 46 196 83 340 100 - - - Total 1025 44 1640 77 3551 77 8215 60 13758 91 15467 92 a Age breakdown not available; 2558 persons seen, 93% vaccinated. b Combined with data from surrounding villages. c Secondary case. d Included in data for case 40, which was discovered while investigating cases 37 and 38. e Survey done in Omifounfoun, Oyo State, Nigeria; all others done in Zaire. d BREMAN, J. C. (sic) Medecine et maladies infectieuses, 11: 550-558 (1978). HUMAN MONKEYPOX the area in Nigeria where case 39 occurred was substantially less than in Zaire. In some areas of the Bumba Zone, over 90'70 of children less than 15 years old had smallpox vaccination scars as did virtually all adults, as a result of repeated vaccination associated with investi- gations of monkeypox cases. During the past 10 years, 1660 specimens have been collected from patients with febrile eruptive disease in Central and West Africa to confirm or rule out smallpox or monkeypox infection (Table 6). Some specimens were collected in preparation for visits of Inter- national Commissions to certify freedom from smallpox. Seventy-four per cent of these specimens came from Zaire-the country in which 81% of the cases have been detected- probably because, since 1971, 14 surveillance teams have been in the field in Zaire and a widely publicized reward of about US$ 40 has been given to anybody reporting a confirmed monkeypox case. However, all but 2 of the monkeypox cases were detected and reported by the fixed health units. Two cases were found in Bumba zone by active surveillance in villages near known foci of monkeypox. Within Zaire there have been differences among regions in specimen collection activities (Table 7). Over 52% of the specimens came from the Equateur and Haut-Zaire regions, but 21 of the 38 cases occurred in Equateur and none in Haut-Zaire. The ratio of monkeypox cases to specimens collected was highest in Kasai Oriental (1 in 8). Roughly 40% of the African tropical rainforest is in Zaire. No cases have been found outside of rainforest areas in Zaire or elsewhere. Animal Although cases and outbreaks of monkeypox infection have occurred among nonhuman primates and other animals in laboratories and zoos in Europe and North America, animal Table 6. Number of specimens received by WHO from selected countries in sub-Saharan Africa, 1970-791 Country 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 Angola b - - - - - - - 1 99 23 Benin b _ - - - - - 1 - 1(1) 6 Burundi 3 _ 5 4 3 1 - - - Central African Republicb - - - - - - - - - 3 Congob - - 3 - _ _ - 2 1 - Gambiab - - - 1 - - - Ghanab - - 1 - - - - Ivory Coastb - 1 (1) - 9 1 - - - Liberiab 4 (4) - -- 9 - - - Nigeriab - 2 (2) - - - 4 3 - 1 - Rwandab 10 - - 2 - - - 3 - - Senegalb - - - - - - 1 - Sierra Leoneb 1 (1) - - - - 5 3 1 - 1 Uganda - - - - - 1 1 - 119 - Zaireb 23 (1) 67 140 (5) 79 (3) 63 (1) 207 (2) 125 (3) 181 (6) 120 (11) 213 (6) Zambia - - - - - 2 - 50 50 - Total 41 (6) 70 (3) 148 (5) 85 (3) 66 (1) 239 (2) 136 (3) 238 (6) 391 (12) 246 (6) a The numbers of cases of monkeypox are shown in round brackets. b Has tropical rainforest. 179 180 J. G. BREMAN ET AL. Table 7. Specimens received by Ministry of Public Health, Zaire, 1971-79a Esti- Ratio of mated monkey- popu- % No. No. % of pox lation of of of % of speci- cases/ 1974 total medical sur- Total monkey- mens speci- (mil- popu- units veillance (1971- pox col- mens Region lions) lation (1974) units 1971 1972 1973 1974 1975 1976 1977 1978 1979 79) cases lected collected Bandundu 3.0 11.8 976 2 11 21 7 7 14 4 15 38 6 123 18 10.1 1/18 (1) (1) (1) (1) (2) (7) Bas Zaire 1.7 6.7 236 1 14 4 3 3 2 3 18 2- 50 - 4.1 - Equateur 2.7 10.6 402 2 8 47 49 9 33 44 58 66 144 458[11 55 36.6 1/22 [11 (3) (3) (1) (2) (3) (4) (4) (21) b Haut-Zaire 3.6 14.1 618 2 7 16 8 7 104 21 24 7 8 202 - 16.6 - Kasai 2.8 11.0 268 1 49 15 9 2 8 2 2 3 4 94[2] - 7.4 - Occidental [2) Kasai 2.1 8.3 386 1 11 6 2 2 6 2 16 18 13 76 24 6.2 1/8 Oriental (1) (1) (1) (5) (1) (9) Kinshasa 2.4 9.4 120 1 21 7 5 7 11 27 13 5 1 97 - 7.9 - Kivu 3.9 15.4 645 2 20 9 3 8 6 5 14 4 4 73 3 6.0 1/73 (1) (1) Shaba 3.2 12.6 497 2 27 12 3 8 5 - 4 1 4 64 - 5.2 - 25.4 100.0 4148 14 168 138 89 53 189 108 164 144 184 1237C[3J 100 100.1 1/34Total [31 (5) (3) (1) (2) (3) (6) ( 11) (5) (38)b a Some discrepancies with WHO records were noted owing to administrative factors such as the date when the specimens were received, receipt of multiple specimens from some patients, etc. The figures in square brackets give the number of cases of variola, and those in round brackets the number of monkeypox cases. b Includes one monkeypox case detected in 1970; this case is not included in the ratio of monkeypox cases to specimens collected. c Twenty-three specimens taken in 1970 are not included because the breakdown by region is not available. cases have not been detected in nature; thus the source of human monkeypox infection is still unknown. Epidemiological studies have suggested monkeys and/or rodents as possible sources but, until recently, only a small number of specimens for viral culture had been obtained. Earlier serological studies showed a low prevalence of orthopoxvirus neutralizing antibodies in mammals captured in western and central Africa. In one survey, 10 of 372 sera were positive;e 7 were from nonhuman primates (4 chimpanzees from Sierra Leone, 2 monkeys from the Ivory Coast, and 1 monkey from Liberia). Another serological survey failed to detect significant antibodies in over 2000 sera taken from Asian and African nonhuman primates, although none of these animals were known to have come from areas near human monkeypox cases! However, more recent surveys conducted in areas where human monkeypox cases have occurred have shown a 20%o (11/55) to 23%/o (50/215) pre- valence of poxvirus neutralizing antibodies in nonhuman primates.8 In one of these studies antibodies were also found in rodents, other larger mammals, and birds in forest areas of the Ivory Coast and antibodies have also been found in rodents in Zaire. However, only e FOSTER, S. 0. Bulletin of the World Health Organization, 46: 569-576 (1972). f ARITA, 1. ET AL. Bulletin of the World Health Organization, 46: 625-631 (1972). 8 MARENNIKOVA, S. S. ET AL. Voprosyvirusologii, No.3, pp. 321-326(1975) (in Russian); BREMAN, J. G. ETAL.Americanjournal of tropical medicine and hygiene, 26: 273-281 (1977); BREMAN, J G. ET AL. Bulletin of the World Health Organization, 55: 605-612 (1977). HUMAN MONKEYPOX 181 recently has it been possible to determine that these antibodies had developed specifically in response to monkeypox virus infection and not to infection caused by any other ortho- poxvirus species that might have infected mammals and birds. These, and further refined tests,' will serve as valuable tools for epidemiological studies under way in Zaire and others that are still being planned. Special ecological studies began in the Equateur region of Zaire in June 1979 and the results will be reported separately. Although attempts to isolate monkeypox virus from animals captured near human monkeypox cases have failed, four whitepox virus strains have been identified in organs of animals captured in the wild near such cases. These "wild whitepox" strains came from kidney tissue of one chimpanzee (Pan troglodytes), one forest dwelling monkey (Cerco- pithecus ascanius), and two rodents (the sun squirrel, Heliosciurius rufobrachium, and the multimammate rat, Mastomys natalensis) captured in Zaire. Prior to these isolations two strains of whitepox virus had been previously isolated from routine Cynomolgus kidney cell cultures.k Whitepox virus cannot be distinguished from variola virus by current biological and chemical methods and, thus, these isolations are of special interest. These findings, however, must be interpreted with caution since the possibility exists that these isolates might represent laboratory cross-contamination rather than primary isolations. Also, it is important to note that existing epidemiological evidence indicates that the virus causing smallpox is not present in Zaire because no human infections with a variola-like virus have occurred there in the period of more than 8 years since the last smallpox case occurred. It can be presumed that the surveillance system is sensitive enough to have detected such cases, since many monkeypox cases have been found. DISCUSSION Most cases of human monkeypox have a characteristic clinical appearance, with a 2-day prodrome and typical smallpox-like rash evolving over 2-4 weeks. Severe lymphadeno- pathy is more prominent among patients with monkeypox than those with smallpox. Six (13 o) of 47 cases have been mild or very atypical, suggesting the possibility that unidenti- fied cases may have occurred, especially in areas where surveillance is poor. While clinical features cannot readily distinguish between smallpox and monkeypox, the epidemiological features are quite distinct. Human monkeypox is a sporadic, infrequent disease detected in small villages in the tropical rainforest of central and western Africa. Only four episodes of possible secondary spread of human monkeypox have been recorded. The 7.5% interhuman transmission rate of monkeypox to susceptible, close family members is much less than that for smallpox. These characteristics, plus the results of sero- logical surveys in animals, indicate that the disease is probably a zoonosis. In addition to these important epidemiological differences, monkeypox and variola virus, both orthopox- viruses, have distinct biological and genetic differences.' The distribution of human monkeypox cases gives only general clues as to the source of this infection. The disease appears to be more frequent in the dry season, as is the case with smallpox. Whether this relates to a possible respiratory mode of transmission, as occurs h GISPEN, R. ET AL. Bulletin of the World Health Organization, 53: 355-360 (1976); BREMAN, J. G. ET AL. Bulletin of the World Health Organization, 55: 605-612 (1977). WALLS, H. H. ET AL. Bulletin of the World Health Organization, 58: 131-138 (1980). i MARENNIKOVA, S. S. ET AL. Bulletin ofthe World Health Organization, 46: 613-620(1972); MARENNIKOVA, S. S. ET AL. Acta virologica, 20: 80-82 (1976). k MARENNIKOVA, S. S. ET AL. Voprosy virusologii, No. 4, pp. 470-473 (1971) (in Russian); GISPEN, R. & BRAND- SAATHOF, B. Bulletin of the World Health Organization, 46: 585-592 (1972). FENNER, F. Progress in medical virology, 23:1-21(1977); ESPOSITO, J. J. ETAL. Virology, 89:53-66(1978); MACKETT, M. & ARCHARD, L. C. Journal ofgeneral virology, 45: 683-701 (1979). 182 J. G. BREMAN ET AL. with smallpox, is unknown. The geographical distribution may represent, in part, an artefact and may be a function of the sensitivity of surveillance and the number of specimens sent for analysis. Most people in these areas have multiple contacts with a variety of wild animals. All cases have had contact with primates and almost all have had contacts with 2 or more other animals. Young, unvaccinated children and adult females seem to be at special risk; the former, perhaps, because they play with the carcasses of animals after the hunters return to the village and the latter because they are responsible for dressing and cooking the animals and may inoculate themselves during this procedure. The incubation period of naturally transmitted human monkeypox is unknown, although experiments with monkeys infected by the parenteral route have shown an incu- bation period of 7-14 days, resembling that of smallpox.'m Based on evidence from the few cases who had only 1 or 2 animal contacts in the month preceding infection, the incubation time in humans may be about 12 days, similar to that observed in smallpox. Possible "secondary" cases were generally milder and atypical, if indeed they represented inter- human spread rather than primary infection from a common source. When the level of vaccination immunity decreases in Zaire, and elsewhere in West and Central Africa, an increase in cases of human monkeypox may occur, thus providing further information. Although the natural source of human cases is still obscure, epidemiological and sero- logical surveys suggest that certain animals (forest dwelling monkeys, squirrels, porcu- pines, or pangolins) may be involved in the natural cycle of transmission. Field studies should focus initially on these animals. Concurrently, serological techniques are being developed which will permit precise measurement of past infection with monkeypox and other orthopoxviruses. This will greatly aid epidemiological investigations of human and animal populations. The finding of whitepox virus requires that, as for monkeypox, surveillance be main- tained and specimens promptly collected and tested if monkeypox/smallpox-like disease occurs in tropical rainforest areas. Laboratory analysis of these and similar strains is necessary for continued confirmation that there is no animal reservoir of variola virus and to monitor orthopoxviruses that might menace man in the future. ADDENDUM Monkeypox case 48. A 3-year-old unvaccinated girl from the forest area in the south of the United Republic of Cameroon developed a severe rash on 14 September 1979. Specimens were collected on 30 September. Owing to special problems, monkeypox virus was not isolated from these specimens until January 1980. In February 1980, a complete field investigation was done by a joint team from the Cameroon Ministry of Health, the Organisation de Coordination pour la lutte Contre les Endemies en Afrique Centrale (OCEAC), and WHO. The team confirmed the diagnosis. No other human cases were detected. The child had been in contact with a dead squirrel about two weeks before the illness began. This is the first case of monkeypox reported from this country. ACKNOWLEDGEMENTS We are grateful to the many health workers and administrative authorities in Zaire and elsewhere in West and Central Africa for their participation in monkeypox surveillance activities; to Dr J. H. Nakano and Dr S. S. Marennikova and their staffs at, respectively, the Center for Disease Control, Atlanta, GA, USA, and the Research Institute of Virus Preparations, Moscow, USSR, for laboratory support; Dr A. H. Abou-Gareeb, Dr C. Algan, Dr J. Mahoney, Dr H. Ramamonjy-Ratrimo, and staff at the WHO Regional Office for Africa for technical and administrative support; to Dr F. Fenner (John Curtin School of Medical Research, The Australian National University), Dr D. A. Henderson (John Hopkins University, School of Hygiene and Public Health), and Dr J. Tulloch (WHO) for manuscript review; and to Miss C. Sands for help in preparation of the manuscript. The photographs were taken by Dr J. G. Breman (Fig. 8) and Mr M. V. Steniowski (Fig. 1-7 and 9). mCHo, C. T. & WENNER, H. A. Bacteriological reviews, 37: 1-18 (1973).