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Outbreak of Human Monkeypox, Democratic Republic of Congo, 1996 to 1997

Outbreak of Human Monkeypox, Democratic Republic of Congo, 1996 to 1997 Research Outbreak of Human Monkeypox, Democratic Republic of Congo, 1996–1997 Yvan J.F. Hutin,* R. Joel Williams,* Philippe Malfait,† Richard Pebody,† Vladamir N. Loparev,* Susan L. Ropp,* Mariangelli Rodriguez,* Janice C Knight,* Florimont K. Tshioko,‡ Ali S Khan,* Mark V. Szczeniowski,‡ and Joseph J. Esposito* *Centers for Disease Control and Prevention, Atlanta, Georgia, USA; †European Programme for Intervention Epidemiology Training, Brussels, Belgium; and ‡World Health Organization, Geneva, Switzerland Human monkeypox is a zoonotic smallpox-like disease caused by an orthopoxvirus of interhuman transmissibility too low to sustain spread in susceptible populations. In February 1997, 88 cases of febrile pustular rash were identified for the previous 12 months in 12 villages of the Katako-Kombe Health Zone, Democratic Republic of Congo (attack rate = 22 per 1,000; case- fatality rate = 3.7%). Seven were active cases confirmed by virus isolation. Orthopoxvirus-neutralizing antibodies were detected in 54% of 72 patients who provided serum and 25% of 59 wild-caught animals, mainly squirrels. Hemagglutination-inhibition assays and Western blotting detected antibodies in 68% and 73% of patients, respectively. Vaccinia vaccination, which protects against monkeypox, ceased by 1983 after global smallpox eradication, leading to an increase in the proportion of susceptible people. Human monkeypox, a sporadic smallpox-like zoonotic person-to-person transmission and prolonged chains of viral exanthema that occurs in the rain forests of Central and transmission. Two cases were confirmed by monkeypox virus isolation from lesion material (10). In February 1997, an West Africa, was discovered in 1970 (1-3). The illness is caused by an orthopoxvirus, monkeypox virus, which was first investigation was initiated (11). Our report describes isolated from primate tissues (4). Animal antibody surveys in epidemiologic observations and laboratory results supporting the conclusion that repeated animal reintroduction of the Democratic Republic of Congo (DRC; former Zaire) suggested that squirrels play a major role as a reservoir of the monkeypox virus is needed to sustain the disease in the local virus and that humans are sporadically infected (3,5,6). human population. Human-to-human transmission occurs with an incubation Methods period of 12 days (range 7-21 days) (3). After smallpox eradication, surveillance for human Epidemiologic and Clinical Studies monkeypox from 1981 to 1986 in the DRC identified 338 cases Before civil unrest in the area curtailed the study, a (67% confirmed by virus culture). The case-fatality rate was dwelling-to-dwelling search was conducted for cases that 9.8% for persons not vaccinated with vaccinia (smallpox) occurred from February 1996 and February 1997 in 12 vaccine, which was about 85% efficacious in preventing villages (total population 4,057) in the Katako-Kombe Health human monkeypox (3,7). The secondary attack rate in Zone, located around Akungula, a village reported to be the unvaccinated household members was 9.3%, and 28% of case- epicenter of the current outbreak. A clinical case of patients reported an exposure to another case-patient during monkeypox was defined as the occurrence of fever with a rash the incubation period. Transmission chains beyond secondary recognized as being similar to that in a reference photo were rare (8,9). A mathematical model to assess the potential provided by the World Health Organization. Monkeypox cases for monkeypox to spread in susceptible populations after were classified as active until desquamation of the rash. After cessation of vaccinia vaccination indicated that person-to- desquamation, cases were identified retrospectively by person transmission would not sustain monkeypox in interview and examination for residual scars. Onset dates humans without repeated reintroduction of the virus from the were estimated by using local event calendars. wild (7). Patients (or their adult respondent) who agreed to In 1996, 71 suspected human monkeypox cases were participate were queried by using a standardized data reported from the Katako-Kombe Health Zone, Kasai collection instrument to obtain information on demograph- Oriental, DRC. These initial reports suggested predominant ics, signs and symptoms of disease, exposures to wild animals, presence of a smallpox vaccination scar, and Address for correspondence: Joseph J. Esposito, Director, WHO exposure to another patient. Consenting participants Collaborating Center for Smallpox and Other Poxvirus Infections, underwent a physical examination, and a blood sample for Centers for Disease Control and Prevention, 1600 Clifton Road, MS G18, Atlanta, GA 30333, USA; fax: 404-639-3111; e-mail: [email protected] serum was obtained. Emerging Infectious Diseases 434 Vol. 7, No. 3, May–June 2001 Research Animal Studies Results Local trappers were asked to capture and bring to the study veterinarian wild animals, especially rodents, Epidemiologic and Clinical Studies squirrels, and nonhuman primates, for which the trappers Eighty-eight clinical cases (7 active and 81 retrospective- ly identified) were discovered in 9 of the 12 villages (attack were paid as an incentive. Animals were processed in a field laboratory (12), identified to genus and species, and bled for rate 22 per 1,000). Fifty (56.8%) of 88 case-patients were male; serum. Representative voucher specimens of each animal the median age at onset was 10 years (quartiles 5-19; range 1 were preserved in 10% formalin for definitive identification. month to 62 years). The number of clinical cases reported per month Laboratory Studies increased from February to August 1996, followed by a decline Human and animal sera were clarified by low-speed until January 1997 and a resurgence of cases in February centrifugation, immediately stored in liquid nitrogen, and 1997 (Figure 1). Attack rates in the villages ranged from zero shipped to the Centers for Disease Control and Prevention to 105 per 1,000 population in Akungula, where 42 cases were (CDC) in Atlanta. At CDC, an aliquot of each serum was identified in 14 of the 62 village households. heated at 56 C for 30 minutes, the following tests were performed: 1) vaccinia virus hemagglutination-inhibition (HAI) assay (13); 2) monkeypox 50% plaque-reduction neutralization assay (13); and 3) Western blot assays for immunoglobulin G (IgG) against monkeypox antigens essentially by using Towbin’s and colleagues’ methods adapted to mini-transblot and multiscreen apparatuses (Bio-Rad, Hercules, CA) (14). Western blotting used selected human sera and antigen preparations that consisted of a soluble antigen (20x culture medium concentrate) from monkeypox virus-infected Vero cells (15). Positive controls consisted of sera collected in the 1980s from convalescent-phase monkeypox cases from the prospective study in the DRC and from vaccinia-vaccinated persons; negative controls consisted of sera collected in the 1980s from DRC inhabitants with no history of vaccinia vaccination or monkeypox. Human sera were also tested for antibodies against varicella virus by using kits to detect human IgM or IgG by enzyme-linked immunosorbent assays (ELISA; Wampole Laboratories, Cranberry, NJ). Samples of crusted scab or pustule lesion were cultured for monkeypox Figure 1. Human monkeypox cases by month of onset in 12 villages, virus using the monkey cell lines Vero, LLCMK-2, or OMK according to results of neutralization assay, Katako-Kombe Health Zone, February 1996 to February 1997. (13,16), and assayed by polymerase chain reaction (PCR) amplification for monkeypox virus-specific DNA (16,17) and for varicella virus gene 1 (P. Pellett, pers. comm.). In addition, In Akungula, where the age and sex distributions of the the gene encoding the hemagglutinin (HA) protein of selected population were available, the attack rate was identical for monkeypox isolates was sequenced by fluorescence-based males and females, but was higher (30 of 206 = 146/1,000) in methods (Applied Biosystems, Inc., Foster City, CA). children <15 years of age than in persons 15 to 24 years old Available duplicate coded sera were tested anonymously in (4 of 85 = 47 /1,000) and >25 years of age (8 of 109 = 73/1,000). Kinshasa, DRC, for antibodies against HIV (Vironostika Of 78 retrospectively identified case-patients for whom Human Form II ELISA, Organon Teknika, Denmark). information was available, 40 (51.3%) reported swelling The relatedness of isolates was examined by comparing consistent with lymphadenopathy. All 75 examined patients DNA restriction endonuclease patterns with patterns of had scars from a rash (median 50; range 4 to 830; standard previously mapped monkeypox virus isolates (18) and by deviation 179). Thirteen (15.5%) of 84 patients for whom comparing the hemagglutinin gene sequences with cognate information was available had a vaccination scar on the upper sequences of other monkeypox isolates. left arm compatible with prior vaccinia vaccination; all >20 years of age. Alopecia was seen in three patients were Statistical Methods cases with acute rash illness. Three deaths occurred among 81 Attack rates were calculated by using a census conducted of the 88 cases for which follow-up information was available during the dwelling-to-dwelling case search; information on (3.7% case-fatality rate), all in children <3 years of age who the age and sex of each person living in Akungula was also died within 3 weeks of rash onset. No information was obtained. Secondary attack rates within households were available to attribute the deaths to monkeypox, superinfec- calculated by dividing the number of cases that occurred 7 to tion, or other cause. 21 days following one or more index cases in a household Seven case-patients (six in a single household) had active (first-generation secondary cases) by the total number of disease at the time of the investigation. Each had household members, excluding index cases. Confidence lymphadenopathy and more than 100 crusty skin lesions. intervals (CI) for proportions were calculated with exact Five had a rash on the soles and palms. Sixty-two (73%) of 85 methods and compared with Fisher’s exact tests as case-patients for whom information was available reported appropriate by using Epi-Info software (19). exposure to another patient 7 to 21 days before onset of their Vol. 7, No. 3, May–June 2001 435 Emerging Infectious Diseases Research illness. The remaining 23 (27%) patients reported either no Seventy-two of the 81 retrospectively identified cases exposure to other cases (n=13; 15%) or an exposure to another provided a serum sample, although 2 were low in volume. case from 0 to 6 days before onset of illness (n=10; 12%). Dates Orthopoxvirus antibodies were detected by neutralization of onset for patients who reported no exposure to other cases assay in 39 (54%, Figure 1) of the 72 sera; by HAI in 51 (73%) during the incubation period were distributed throughout the of 70 sera, and by a new, nonvalidated Western blot test in 49 study period (11). Exposures during the incubation period (68%) of 72 sera. Thirty-eight (54%) of 70 available sera were that were reported by all six patients who resided in a single positive by all three tests, 45 (64%) were positive by two tests, household and who had active disease at the time of this and 62 (89%) were positive by at least one test. Western investigation included exposure to a patient within the blotting and HAI test results were concordant for 79% of the household and eating monkey, gazelle, pig, and rat. sera; Western blotting and neutralization test results agreed The 88 clinical cases were identified for 39 households, in for 83% of the sera; and HAI and neutralization test results which 297 persons resided (overall attack rate in affected agreed for 79% of the sera. Fifty-five (76%) of the 72 patients households = 30%). For 240 household members for whom who provided serum had detectable varicella IgG antibodies, information was available, rash that met the clinical case 1 had varicella IgM, and none showed detectable HIV antibodies. >1 definition developed in 20 in 7 to 21 days after exposure to Based on DNA assays (16-18), monkeypox virus isolates index cases in a household (household secondary attack rate from the seven active cases appeared virtually identical to 8.3 per 100; 95% CI 5.2% to 12.6%). each other and very closely related to two isolates from Eating wild animals was common for all patients. humans in 1996 and an isolate from a squirrel trapped in the However, patients who had no exposure to other case-patients Equateur Province of the DRC in 1985. Analysis of sequences during the incubation period were more likely to eat coding for the viral HA protein (Figure 2) indicated that porcupine at least once a month (Table 1). All queried viruses isolated in the DRC since 1970 comprised a clade participants reported trapping animals less frequently. distinguishable from a clade comprising isolates from other African countries and from outbreaks in primate-holding Laboratory Studies facilities in Europe and the United States. The group of nine Human monkeypox was confirmed in all seven active isolates from the 1996-97 outbreak, which showed identical cases by virus isolation and monkeypox virus-specific DNA HA sequences, and from the squirrel from 1985 constituted a amplification from skin lesion samples; antibodies against subset of the clade of examined viruses previously isolated in orthopoxvirus were detected in two by neutralization assay, the DRC. in three by HAI assay, and in six by Western blotting. In addition, IgM antibodies against varicella virus were detected Animal Studies in five active cases in patients who lived in the same Fifty-nine captured animals representing 14 species were household. Varicella virus DNA was detected in lesion tested. Sera from 42% of the various squirrel species, from 16% material from two of these patients. of Gambian rats, and from an elephant shrew and a domestic pig showed orthopoxvirus neutralizing antibodies (Table 2). Table 1. Exposure to wild animals reported by monkeypox case-patients according to history of exposure to another case-patient, Katako-Kombe Health zone, February 1996 to February 1997 Cases without Cases with exposure to exposure to other case- other case- patients during patients during Exposures reported incubation incubation to occur usually (N=23) (N=62) on a monthly basis (#) (%) (#) (%) p value Exposure to squirrels Trapping 2 8.7 9 14.8 0.79 Exposure to raw meat 11 47.8 33 54.1 0.78 Eating 19 86.4 52 85.2 1.00 Exposure to monkeys Trapping 1 4.3 4 6.6 1.00 Exposure to raw meat 16 69.6 34 55.7 0.36 Eating 21 91.3 58 95.1 0.61 Exposure to rats Figure 2. Phylogenetic inference relationships of the open reading Trapping 5 21.7 18 29.5 0.66 frames encoding the viral hemagglutinin protein of various Exposure to raw meat 13 56.5 40 65.6 0.60 monkeypox virus isolates and selected strains of vaccinia, variola, Eating 22 95.7 55 90.2 0.66 and cowpox viruses. Nucleotide sequences of polymerase chain Exposure to porcupines reaction-generated amplicons were analyzed using PAUP parsimony Trapping 1 4.3 3 4.9 1.00 analysis software version 3.1.1, as described (10). Parsimony Exposure to raw meat 12 52.2 24 39.3 0.41 analysis used 5,000 bootstraps and weighted the sequences for a Eating 22 95.7 42 68.9 0.02 transition-transversion ratio of 2 (bootstrap confidence intervals Exposure to gazelles shown on branches). Trapping 1 4.3 2 3.3 1.00 Exposure to raw meat 14 56.5 28 45.9 0.53 Eating 21 91.3 47 77.0 0.21 Emerging Infectious Diseases 436 Vol. 7, No. 3, May–June 2001 Research Table 2. Species of animals caught in the wild and monkeypox virus the HAI test may be less specific, and antibody titers detected plaque reduction neutralization antibody assay results, Katako-Kombe by it decrease rapidly after infection and would be unlikely to Health Zone, February 23-27, 1997 be residual from prior vaccination in the small percentage of No. Proportion patients who had been vaccinated (3,21,23). Finally, 72% of Animal species Common name Tested Pos. pos. sera from retrospectively identified cases tested positive in a Cercopithecus Spot-nosed monkey 2 0 0.0% new, nonvalidated Western blot orthopoxvirus antibody test ascanius Cercopithecus Debrazza monkey 1 0 0.0% for which sensitivity and specificity have not been neglectus determined. Chickenpox, which can be mistaken for Perodicticus Bosman’s potto 1 0 0.0% monkeypox (24), was reported in the area during the study potto period. Some patients may have had dual infection by Galogoides Demidoff galago 2 0 0.0% monkeypox and varicella viruses. Within one household, five demidovi Genetta Genet 1 0 0.0% patients from whom monkeypox virus was isolated showed rubiginosa serologic evidence of recent varicella virus infection, and two Sus scrofa Domestic pig 1 1 100.0% of those had detectable varicella virus DNA in skin lesion Praomys Forest rat 1 0 0.0% samples. Thus, a substantial percentage of cases may have jacksoni Cricetomys Gambian rat 19 3 15.8% been chickenpox, thereby explaining why the case-fatality emini rate from this study (3.7%) was lower than the 9.6% Cavia sp. Guinea pig 3 0 0.0% previously reported (3,24). However, the presence of Petrodromus Elephant shrew 3 1 33.3% antibodies against orthopoxviruses by three different assays tetradactylus in 54% of patients suggests that varicella virus was not Dendrohyrax Tree hyrax 1 0 0.0% arboreus responsible for most cases during the study period. Funisciurus Thomas’s tree squirrel 4 2 50.0% The 1996-97 crude secondary attack rate of about 8% in anerythrus households cannot be compared with the 3.7% risk of attack Funisciurus Kuhl’s tree squirrel 18 7 38.9% for household contacts from the 1981-1986 study (3) because congicus Heliosciurus Sun squirrel 2 1 50.0% the proportion of susceptible (unvaccinated) persons in rufobrachium household members increased markedly from 1981-1986 to Total 59 15 25.4% 1996-97. However, the 1996-97 secondary attack rate within households was similar to the 1981-1986 rates (3) of 9.3% for unvaccinated household members. This similarity is Conclusion consistent with the high degree of similarity noted in The epidemiologic and laboratory evidence presented comparing current monkeypox virus isolate DNAs with DNAs here suggests that this monkeypox outbreak is the largest of isolates from the DRC in the 1970s, including the HA reported. Epidemiologic features of monkeypox that differed sequences (Figure 2). While the virus and its person-to-person from those described during an intensified prospective study transmission potential have not changed substantially, the in the DRC in the 1980s included an increase in the proportion proportion of susceptible persons among exposed household of patients reporting an exposure to another case during the members increased most likely because vaccinia vaccination incubation period (28% in the 1980s, 73% this study) and the ceased after smallpox eradication. The reduced herd clustering of successive cases within households, with as immunity probably also caused a higher proportion of cases to many as eight consecutive cases in one instance (3,10). be attributable to person-to-person transmission, as the Prospective surveillance in the 1980s in the DRC increase in the proportion of patients who reported exposure provided opportunities to observe most patients with active- to another patient during the incubation interval would stage monkeypox; thus, skin lesion samples were available for suggest. HIV was not a cofactor of this outbreak because no virus isolation to confirm clinical diagnosis. In contrast, the HIV antibodies were detected in patients’ sera. present study identified most patients retrospectively and Exposure to an animal reservoir might have been the relied on serologic testing for confirmation of the diagnosis; source of infection for at least 27% of patients who reported no only seven clinically active cases could be confirmed by virus exposure to other patients during the incubation period. Past isolation and PCR (17) for monkeypox virus. Because animal studies pointed to several species of squirrels as monkeypox is the only known indigenous orthopoxvirus of animal reservoirs (5,6). Although the possibility of infection of Africa that infects humans systemically, seropositive cases animals with another unknown indigenous orthopoxvirus showing genus-specific antibodies can be reasonably cannot be ruled out in animals with neutralizing antibodies, interpreted as cases that had a monkeypox virus infection the results of our investigation suggest that, in addition to (20). Of 72 retrospectively identified cases tested, 54% had squirrels, Gambian rats may play a role in monkeypox virus antibodies by plaque-reduction assay, a preferred test for circulation. Villagers ate a number of different animals, and it verifying orthopoxvirus infections during smallpox eradica- was impossible to draw any conclusions as to whether any one tion (20,21). However, this neutralization test was only 83% species was a greater risk factor than any other. However, sensitive for the detection of vaccinia vaccine-induced antibody surveys could be used to evaluate porcupines as a antibodies and may have been negative (3) in some patients possible reservoir (Table 1), which was not done during our with monkeypox virus infection during this study interval. A investigation because no porcupines were captured by trappers. higher proportion of sera from retrospectively identified cases Our study had several limitations, some of which related (73%) tested positive by the HAI test, which had a higher to the brevity imposed by the civil unrest. Most cases were sensitivity (96%) than the neutralization test for the identified retrospectively and without a case-control group; identification of vaccinia-induced antibodies (22). However, thus, they could not be confirmed by a serologic test for which Vol. 7, No. 3, May–June 2001 437 Emerging Infectious Diseases Research 2. Arita I, Jezek Z, Khodakevich L, Ruti K. Human monkeypox: a the sensitivity and the specificity had been measured using a newly emerged orthopoxvirus zoonosis in the tropical rain forests of standard technique and case-control sera. Because informa- Africa. Am J Trop Med Hyg 1985;34:781-9. tion was not available regarding the vaccination status of 3. Jezek Z, Fenner F. Human monkeypox. In: JL Melnick, editor. other members of the patients’ households, secondary attack Monographs in virology. Volume 17. Basel: Karger; 1988. rates within households could not be calculated according to 4. von Magnus P, Andersen EK, Petersen KB, Birch-Andersen A. A the vaccination status. We did not assess the environmental pox-like disease in cynomolgus monkeys. Acta Pathol Microbiol changes that could have facilitated this outbreak, including Scand 1959;46:156-76. increases in household sizes, rates of monkeypox virus 5. Khodakevich L, Jezek Z, Messinger D. Monkeypox virus: ecology and public health significance. Bull World Health Organ 1988;66:747-52. infection in the animal population, and a change in rate and 6. Khodakevich L, Szczeniowski M, Manbu-ma-Disu, Jezek Z, type of exposure to wild animals among residents. We were Marennikova S, Nakano J, et al. The role of squirrels in sustaining unable to attribute infections in patients who reported an monkeypox virus transmission. Trop Geogr Med 1987;39:115-22. exposure to another patient during the incubation period to 7. Fine PE, Jezek Z, Grab B, Dixon H. The transmission potential of person-to-person transmission because some of these patients monkeypox virus in human populations. Int J Epidemiol may also have been exposed to infected animals. Finally, 1988;17:643-50. 8. Jezek Z, Grab B, Szczeniowski MV, Paluku KM, Mutombo M. patients with a history of exposure to a patient during the Human monkeypox: secondary attack rates. Bull World Health incubation period were the only controls available to generate Organ 1988;66:465-70. hypotheses regarding the type of animal exposure possibly 9. Jezek Z, Arita I, Mutombo M, Dunn C, Nakano JH, Szezeniowski associated with infection in patients not reporting an M. Four generations of probable person-to-person transmission of exposure to other patients during the incubation period. This human monkeypox. Am J Epidemiol 1986;123:1004-12. aspect may have caused bias because cases clustered within 10. Mukinda VB, Mwema G, Kilundu M, Heymann DL, Khan AS, households where exposures to animals may have been Esposito JJ. Re-emergence of human monkeypox in Zaire in 1996. Lancet 1997;349:1449-50. identical and because cases may have been misclassified as to 11. Centers for Disease Control and Prevention. Human monkeypox- their purported source of infection. Zaire, 1996-1997. MMWR Morb Mortal Wkly Rep 1997;46:304-7. There is no evidence to date that person-to-person 12. Mills JN, Childs JE, Ksiazek TG, Peters CJ, Velleca WM. Methods transmission alone can sustain monkeypox in the local for trapping and sampling small mammals for virologic testing. population. However, our study suggests that in a population Atlanta: Centers for Disease Control and Prevention; 1995. with low herd immunity, person-to-person transmission and 13. Esposito JJ, Massung RF. Poxvirus infections in humans. In: repeated introduction of virus from the animal reservoir may Murray PR, Tenover F, Baron EJ, Pfaller MA, Yolken RH, editors. Manual of clinical microbiology. 6th ed. Washington: ASM lead to more and larger clusters of human monkeypox cases in Press;1995. p. 1131-8. African rain forest areas (25). Further studies are needed to 14. Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins measure the sensitivity and the specificity of the serologic from polyacrylamide gels to nitrocellulose sheets: procedure and some tests currently available so they can be used in the future to applications. Proc Natl Acad Sci U S A 1979;76:4350-4. better confirm retrospectively identified cases, identify the 15. Loparev VN, Parsons JM, Knight JC, Panus JF, Ray CA, Buller type of animal or patient exposures associated with RM, et al. A third distinct tumor necrosis factor receptor of acquisition of illness, and evaluate the respective roles of orthopoxviruses. Proc Natl Acad Sci U S A 1998;95:3786-91. 16. Ropp SL, Esposito JJ, Loparev VN, Palumbo G. Poxviruses person-to-person and animal-to-human transmission. How- infecting humans. In: Murray PR, Barron CJ, Pfaller MA, Tenover ever, access to the Kasai region has been limited since our FC, Yolken RH, editors. Manual of clinical microbiology. 7th ed. study, and little information has become available to better Washington: ASM Press; 1999. p. 1137-44. document the current dynamics of monkeypox occurrences or 17. Ropp SL, Jin Q, Knight JC, Massung RF, Esposito JJ. PCR improve World Health Organization recommendations to strategy for identification and differentiation of smallpox and other prevent human monkeypox more substantially. orthopoxviruses. J Clin Microbiol 1995;33:2069-76. 18. Esposito JJ, Knight JC. Orthopoxvirus DNA: A comparison of Acknowledgments restriction profiles and maps. Virology 1985;143:230-51. 19. Dean AG, Dean JA, Coulombier D, Burton AH, Brendel KA, Smith The authors thank T.P. Muamba, G. Mwema, D. Messinger, K. DC. Epi Info, version 6: A word-processing, database, and statistics Kilundu, V.B. Mukinda, L.V. Okito, and V.L. Mangindula for assistance in data collection; L. Otshudi for assistance in setup of the investigation; program for public health on IBM-compatible microcomputers. Atlanta: Centers for Disease Control and Prevention; 1994. J.J. Muyembe-Tamfum for HIV testing; A. Moudi; J.A. Stewart and J. Patton for varicella virus testing; A. Moren, W.C. Reeves, C.J. Peters, 20. Fenner F, Wittek R, Dumbell KR. The Orthopoxviruses. San Diego: Academic Press; 1989. p. 162-5, 312-15. and D.A. Henderson for critically reading the manuscript; and J. 21. Ziegler DW, Hutchinson HD, Koplan JP, Nakano JH. Detection by O’Connor for editorial assistance. radioimmunoassay of antibodies in human smallpox patients and vaccinees. J Clin Microbiol 1975;1:311-7. The investigation was partly funded by the U.S. Agency for International Development. 22. Cherry JD, McIntosh K, Connor JD, Benenson AS, Alling DW, Rolfe UT, et al. Primary percutaneous vaccination. J Infect Dis Dr. Yvan Hutin was an Epidemic Intelligence Service officer with 1977;135:145-54. the Centers for Disease Control and Prevention at the time of this in- 23. McIntosh K, Cherry JD, Benenson AS, Connor JD, Alling DW, vestigation. He is now at the World Health Organization. Rolfe UT, et al. Clinical and serologic study of four smallpox vaccines comparing variations of dose and route of administration. Standard percutaneous revaccination of children who receive References primary percutaneous vaccination. J Infect Dis 1977;135:155-66. 1. Marennikova SS, Seluhina EM, Mal’ceva NN, Cimiskjan KL, 24. Jezek Z, Szczeniowski M, Paluku KM, Mutombo M, Grab B. Human Macevic GR. Isolation and properties of the causal agent of a new monkeypox: confusion with chickenpox. Acta Trop 1988;45:297-307. variola-like disease (monkeypox) in man. Bull World Health Organ 25. Centers for Disease Control and Prevention. Human monkeypox — 1972;46:599-611. Kasai Oriental, Democratic Republic of Congo, February 1996- Emerging Infectious Diseases 438 Vol. 7, No. 3, May–June 2001 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Emerging Infectious Diseases Unpaywall

Outbreak of Human Monkeypox, Democratic Republic of Congo, 1996 to 1997

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Research Outbreak of Human Monkeypox, Democratic Republic of Congo, 1996–1997 Yvan J.F. Hutin,* R. Joel Williams,* Philippe Malfait,† Richard Pebody,† Vladamir N. Loparev,* Susan L. Ropp,* Mariangelli Rodriguez,* Janice C Knight,* Florimont K. Tshioko,‡ Ali S Khan,* Mark V. Szczeniowski,‡ and Joseph J. Esposito* *Centers for Disease Control and Prevention, Atlanta, Georgia, USA; †European Programme for Intervention Epidemiology Training, Brussels, Belgium; and ‡World Health Organization, Geneva, Switzerland Human monkeypox is a zoonotic smallpox-like disease caused by an orthopoxvirus of interhuman transmissibility too low to sustain spread in susceptible populations. In February 1997, 88 cases of febrile pustular rash were identified for the previous 12 months in 12 villages of the Katako-Kombe Health Zone, Democratic Republic of Congo (attack rate = 22 per 1,000; case- fatality rate = 3.7%). Seven were active cases confirmed by virus isolation. Orthopoxvirus-neutralizing antibodies were detected in 54% of 72 patients who provided serum and 25% of 59 wild-caught animals, mainly squirrels. Hemagglutination-inhibition assays and Western blotting detected antibodies in 68% and 73% of patients, respectively. Vaccinia vaccination, which protects against monkeypox, ceased by 1983 after global smallpox eradication, leading to an increase in the proportion of susceptible people. Human monkeypox, a sporadic smallpox-like zoonotic person-to-person transmission and prolonged chains of viral exanthema that occurs in the rain forests of Central and transmission. Two cases were confirmed by monkeypox virus isolation from lesion material (10). In February 1997, an West Africa, was discovered in 1970 (1-3). The illness is caused by an orthopoxvirus, monkeypox virus, which was first investigation was initiated (11). Our report describes isolated from primate tissues (4). Animal antibody surveys in epidemiologic observations and laboratory results supporting the conclusion that repeated animal reintroduction of the Democratic Republic of Congo (DRC; former Zaire) suggested that squirrels play a major role as a reservoir of the monkeypox virus is needed to sustain the disease in the local virus and that humans are sporadically infected (3,5,6). human population. Human-to-human transmission occurs with an incubation Methods period of 12 days (range 7-21 days) (3). After smallpox eradication, surveillance for human Epidemiologic and Clinical Studies monkeypox from 1981 to 1986 in the DRC identified 338 cases Before civil unrest in the area curtailed the study, a (67% confirmed by virus culture). The case-fatality rate was dwelling-to-dwelling search was conducted for cases that 9.8% for persons not vaccinated with vaccinia (smallpox) occurred from February 1996 and February 1997 in 12 vaccine, which was about 85% efficacious in preventing villages (total population 4,057) in the Katako-Kombe Health human monkeypox (3,7). The secondary attack rate in Zone, located around Akungula, a village reported to be the unvaccinated household members was 9.3%, and 28% of case- epicenter of the current outbreak. A clinical case of patients reported an exposure to another case-patient during monkeypox was defined as the occurrence of fever with a rash the incubation period. Transmission chains beyond secondary recognized as being similar to that in a reference photo were rare (8,9). A mathematical model to assess the potential provided by the World Health Organization. Monkeypox cases for monkeypox to spread in susceptible populations after were classified as active until desquamation of the rash. After cessation of vaccinia vaccination indicated that person-to- desquamation, cases were identified retrospectively by person transmission would not sustain monkeypox in interview and examination for residual scars. Onset dates humans without repeated reintroduction of the virus from the were estimated by using local event calendars. wild (7). Patients (or their adult respondent) who agreed to In 1996, 71 suspected human monkeypox cases were participate were queried by using a standardized data reported from the Katako-Kombe Health Zone, Kasai collection instrument to obtain information on demograph- Oriental, DRC. These initial reports suggested predominant ics, signs and symptoms of disease, exposures to wild animals, presence of a smallpox vaccination scar, and Address for correspondence: Joseph J. Esposito, Director, WHO exposure to another patient. Consenting participants Collaborating Center for Smallpox and Other Poxvirus Infections, underwent a physical examination, and a blood sample for Centers for Disease Control and Prevention, 1600 Clifton Road, MS G18, Atlanta, GA 30333, USA; fax: 404-639-3111; e-mail: [email protected] serum was obtained. Emerging Infectious Diseases 434 Vol. 7, No. 3, May–June 2001 Research Animal Studies Results Local trappers were asked to capture and bring to the study veterinarian wild animals, especially rodents, Epidemiologic and Clinical Studies squirrels, and nonhuman primates, for which the trappers Eighty-eight clinical cases (7 active and 81 retrospective- ly identified) were discovered in 9 of the 12 villages (attack were paid as an incentive. Animals were processed in a field laboratory (12), identified to genus and species, and bled for rate 22 per 1,000). Fifty (56.8%) of 88 case-patients were male; serum. Representative voucher specimens of each animal the median age at onset was 10 years (quartiles 5-19; range 1 were preserved in 10% formalin for definitive identification. month to 62 years). The number of clinical cases reported per month Laboratory Studies increased from February to August 1996, followed by a decline Human and animal sera were clarified by low-speed until January 1997 and a resurgence of cases in February centrifugation, immediately stored in liquid nitrogen, and 1997 (Figure 1). Attack rates in the villages ranged from zero shipped to the Centers for Disease Control and Prevention to 105 per 1,000 population in Akungula, where 42 cases were (CDC) in Atlanta. At CDC, an aliquot of each serum was identified in 14 of the 62 village households. heated at 56 C for 30 minutes, the following tests were performed: 1) vaccinia virus hemagglutination-inhibition (HAI) assay (13); 2) monkeypox 50% plaque-reduction neutralization assay (13); and 3) Western blot assays for immunoglobulin G (IgG) against monkeypox antigens essentially by using Towbin’s and colleagues’ methods adapted to mini-transblot and multiscreen apparatuses (Bio-Rad, Hercules, CA) (14). Western blotting used selected human sera and antigen preparations that consisted of a soluble antigen (20x culture medium concentrate) from monkeypox virus-infected Vero cells (15). Positive controls consisted of sera collected in the 1980s from convalescent-phase monkeypox cases from the prospective study in the DRC and from vaccinia-vaccinated persons; negative controls consisted of sera collected in the 1980s from DRC inhabitants with no history of vaccinia vaccination or monkeypox. Human sera were also tested for antibodies against varicella virus by using kits to detect human IgM or IgG by enzyme-linked immunosorbent assays (ELISA; Wampole Laboratories, Cranberry, NJ). Samples of crusted scab or pustule lesion were cultured for monkeypox Figure 1. Human monkeypox cases by month of onset in 12 villages, virus using the monkey cell lines Vero, LLCMK-2, or OMK according to results of neutralization assay, Katako-Kombe Health Zone, February 1996 to February 1997. (13,16), and assayed by polymerase chain reaction (PCR) amplification for monkeypox virus-specific DNA (16,17) and for varicella virus gene 1 (P. Pellett, pers. comm.). In addition, In Akungula, where the age and sex distributions of the the gene encoding the hemagglutinin (HA) protein of selected population were available, the attack rate was identical for monkeypox isolates was sequenced by fluorescence-based males and females, but was higher (30 of 206 = 146/1,000) in methods (Applied Biosystems, Inc., Foster City, CA). children <15 years of age than in persons 15 to 24 years old Available duplicate coded sera were tested anonymously in (4 of 85 = 47 /1,000) and >25 years of age (8 of 109 = 73/1,000). Kinshasa, DRC, for antibodies against HIV (Vironostika Of 78 retrospectively identified case-patients for whom Human Form II ELISA, Organon Teknika, Denmark). information was available, 40 (51.3%) reported swelling The relatedness of isolates was examined by comparing consistent with lymphadenopathy. All 75 examined patients DNA restriction endonuclease patterns with patterns of had scars from a rash (median 50; range 4 to 830; standard previously mapped monkeypox virus isolates (18) and by deviation 179). Thirteen (15.5%) of 84 patients for whom comparing the hemagglutinin gene sequences with cognate information was available had a vaccination scar on the upper sequences of other monkeypox isolates. left arm compatible with prior vaccinia vaccination; all >20 years of age. Alopecia was seen in three patients were Statistical Methods cases with acute rash illness. Three deaths occurred among 81 Attack rates were calculated by using a census conducted of the 88 cases for which follow-up information was available during the dwelling-to-dwelling case search; information on (3.7% case-fatality rate), all in children <3 years of age who the age and sex of each person living in Akungula was also died within 3 weeks of rash onset. No information was obtained. Secondary attack rates within households were available to attribute the deaths to monkeypox, superinfec- calculated by dividing the number of cases that occurred 7 to tion, or other cause. 21 days following one or more index cases in a household Seven case-patients (six in a single household) had active (first-generation secondary cases) by the total number of disease at the time of the investigation. Each had household members, excluding index cases. Confidence lymphadenopathy and more than 100 crusty skin lesions. intervals (CI) for proportions were calculated with exact Five had a rash on the soles and palms. Sixty-two (73%) of 85 methods and compared with Fisher’s exact tests as case-patients for whom information was available reported appropriate by using Epi-Info software (19). exposure to another patient 7 to 21 days before onset of their Vol. 7, No. 3, May–June 2001 435 Emerging Infectious Diseases Research illness. The remaining 23 (27%) patients reported either no Seventy-two of the 81 retrospectively identified cases exposure to other cases (n=13; 15%) or an exposure to another provided a serum sample, although 2 were low in volume. case from 0 to 6 days before onset of illness (n=10; 12%). Dates Orthopoxvirus antibodies were detected by neutralization of onset for patients who reported no exposure to other cases assay in 39 (54%, Figure 1) of the 72 sera; by HAI in 51 (73%) during the incubation period were distributed throughout the of 70 sera, and by a new, nonvalidated Western blot test in 49 study period (11). Exposures during the incubation period (68%) of 72 sera. Thirty-eight (54%) of 70 available sera were that were reported by all six patients who resided in a single positive by all three tests, 45 (64%) were positive by two tests, household and who had active disease at the time of this and 62 (89%) were positive by at least one test. Western investigation included exposure to a patient within the blotting and HAI test results were concordant for 79% of the household and eating monkey, gazelle, pig, and rat. sera; Western blotting and neutralization test results agreed The 88 clinical cases were identified for 39 households, in for 83% of the sera; and HAI and neutralization test results which 297 persons resided (overall attack rate in affected agreed for 79% of the sera. Fifty-five (76%) of the 72 patients households = 30%). For 240 household members for whom who provided serum had detectable varicella IgG antibodies, information was available, rash that met the clinical case 1 had varicella IgM, and none showed detectable HIV antibodies. >1 definition developed in 20 in 7 to 21 days after exposure to Based on DNA assays (16-18), monkeypox virus isolates index cases in a household (household secondary attack rate from the seven active cases appeared virtually identical to 8.3 per 100; 95% CI 5.2% to 12.6%). each other and very closely related to two isolates from Eating wild animals was common for all patients. humans in 1996 and an isolate from a squirrel trapped in the However, patients who had no exposure to other case-patients Equateur Province of the DRC in 1985. Analysis of sequences during the incubation period were more likely to eat coding for the viral HA protein (Figure 2) indicated that porcupine at least once a month (Table 1). All queried viruses isolated in the DRC since 1970 comprised a clade participants reported trapping animals less frequently. distinguishable from a clade comprising isolates from other African countries and from outbreaks in primate-holding Laboratory Studies facilities in Europe and the United States. The group of nine Human monkeypox was confirmed in all seven active isolates from the 1996-97 outbreak, which showed identical cases by virus isolation and monkeypox virus-specific DNA HA sequences, and from the squirrel from 1985 constituted a amplification from skin lesion samples; antibodies against subset of the clade of examined viruses previously isolated in orthopoxvirus were detected in two by neutralization assay, the DRC. in three by HAI assay, and in six by Western blotting. In addition, IgM antibodies against varicella virus were detected Animal Studies in five active cases in patients who lived in the same Fifty-nine captured animals representing 14 species were household. Varicella virus DNA was detected in lesion tested. Sera from 42% of the various squirrel species, from 16% material from two of these patients. of Gambian rats, and from an elephant shrew and a domestic pig showed orthopoxvirus neutralizing antibodies (Table 2). Table 1. Exposure to wild animals reported by monkeypox case-patients according to history of exposure to another case-patient, Katako-Kombe Health zone, February 1996 to February 1997 Cases without Cases with exposure to exposure to other case- other case- patients during patients during Exposures reported incubation incubation to occur usually (N=23) (N=62) on a monthly basis (#) (%) (#) (%) p value Exposure to squirrels Trapping 2 8.7 9 14.8 0.79 Exposure to raw meat 11 47.8 33 54.1 0.78 Eating 19 86.4 52 85.2 1.00 Exposure to monkeys Trapping 1 4.3 4 6.6 1.00 Exposure to raw meat 16 69.6 34 55.7 0.36 Eating 21 91.3 58 95.1 0.61 Exposure to rats Figure 2. Phylogenetic inference relationships of the open reading Trapping 5 21.7 18 29.5 0.66 frames encoding the viral hemagglutinin protein of various Exposure to raw meat 13 56.5 40 65.6 0.60 monkeypox virus isolates and selected strains of vaccinia, variola, Eating 22 95.7 55 90.2 0.66 and cowpox viruses. Nucleotide sequences of polymerase chain Exposure to porcupines reaction-generated amplicons were analyzed using PAUP parsimony Trapping 1 4.3 3 4.9 1.00 analysis software version 3.1.1, as described (10). Parsimony Exposure to raw meat 12 52.2 24 39.3 0.41 analysis used 5,000 bootstraps and weighted the sequences for a Eating 22 95.7 42 68.9 0.02 transition-transversion ratio of 2 (bootstrap confidence intervals Exposure to gazelles shown on branches). Trapping 1 4.3 2 3.3 1.00 Exposure to raw meat 14 56.5 28 45.9 0.53 Eating 21 91.3 47 77.0 0.21 Emerging Infectious Diseases 436 Vol. 7, No. 3, May–June 2001 Research Table 2. Species of animals caught in the wild and monkeypox virus the HAI test may be less specific, and antibody titers detected plaque reduction neutralization antibody assay results, Katako-Kombe by it decrease rapidly after infection and would be unlikely to Health Zone, February 23-27, 1997 be residual from prior vaccination in the small percentage of No. Proportion patients who had been vaccinated (3,21,23). Finally, 72% of Animal species Common name Tested Pos. pos. sera from retrospectively identified cases tested positive in a Cercopithecus Spot-nosed monkey 2 0 0.0% new, nonvalidated Western blot orthopoxvirus antibody test ascanius Cercopithecus Debrazza monkey 1 0 0.0% for which sensitivity and specificity have not been neglectus determined. Chickenpox, which can be mistaken for Perodicticus Bosman’s potto 1 0 0.0% monkeypox (24), was reported in the area during the study potto period. Some patients may have had dual infection by Galogoides Demidoff galago 2 0 0.0% monkeypox and varicella viruses. Within one household, five demidovi Genetta Genet 1 0 0.0% patients from whom monkeypox virus was isolated showed rubiginosa serologic evidence of recent varicella virus infection, and two Sus scrofa Domestic pig 1 1 100.0% of those had detectable varicella virus DNA in skin lesion Praomys Forest rat 1 0 0.0% samples. Thus, a substantial percentage of cases may have jacksoni Cricetomys Gambian rat 19 3 15.8% been chickenpox, thereby explaining why the case-fatality emini rate from this study (3.7%) was lower than the 9.6% Cavia sp. Guinea pig 3 0 0.0% previously reported (3,24). However, the presence of Petrodromus Elephant shrew 3 1 33.3% antibodies against orthopoxviruses by three different assays tetradactylus in 54% of patients suggests that varicella virus was not Dendrohyrax Tree hyrax 1 0 0.0% arboreus responsible for most cases during the study period. Funisciurus Thomas’s tree squirrel 4 2 50.0% The 1996-97 crude secondary attack rate of about 8% in anerythrus households cannot be compared with the 3.7% risk of attack Funisciurus Kuhl’s tree squirrel 18 7 38.9% for household contacts from the 1981-1986 study (3) because congicus Heliosciurus Sun squirrel 2 1 50.0% the proportion of susceptible (unvaccinated) persons in rufobrachium household members increased markedly from 1981-1986 to Total 59 15 25.4% 1996-97. However, the 1996-97 secondary attack rate within households was similar to the 1981-1986 rates (3) of 9.3% for unvaccinated household members. This similarity is Conclusion consistent with the high degree of similarity noted in The epidemiologic and laboratory evidence presented comparing current monkeypox virus isolate DNAs with DNAs here suggests that this monkeypox outbreak is the largest of isolates from the DRC in the 1970s, including the HA reported. Epidemiologic features of monkeypox that differed sequences (Figure 2). While the virus and its person-to-person from those described during an intensified prospective study transmission potential have not changed substantially, the in the DRC in the 1980s included an increase in the proportion proportion of susceptible persons among exposed household of patients reporting an exposure to another case during the members increased most likely because vaccinia vaccination incubation period (28% in the 1980s, 73% this study) and the ceased after smallpox eradication. The reduced herd clustering of successive cases within households, with as immunity probably also caused a higher proportion of cases to many as eight consecutive cases in one instance (3,10). be attributable to person-to-person transmission, as the Prospective surveillance in the 1980s in the DRC increase in the proportion of patients who reported exposure provided opportunities to observe most patients with active- to another patient during the incubation interval would stage monkeypox; thus, skin lesion samples were available for suggest. HIV was not a cofactor of this outbreak because no virus isolation to confirm clinical diagnosis. In contrast, the HIV antibodies were detected in patients’ sera. present study identified most patients retrospectively and Exposure to an animal reservoir might have been the relied on serologic testing for confirmation of the diagnosis; source of infection for at least 27% of patients who reported no only seven clinically active cases could be confirmed by virus exposure to other patients during the incubation period. Past isolation and PCR (17) for monkeypox virus. Because animal studies pointed to several species of squirrels as monkeypox is the only known indigenous orthopoxvirus of animal reservoirs (5,6). Although the possibility of infection of Africa that infects humans systemically, seropositive cases animals with another unknown indigenous orthopoxvirus showing genus-specific antibodies can be reasonably cannot be ruled out in animals with neutralizing antibodies, interpreted as cases that had a monkeypox virus infection the results of our investigation suggest that, in addition to (20). Of 72 retrospectively identified cases tested, 54% had squirrels, Gambian rats may play a role in monkeypox virus antibodies by plaque-reduction assay, a preferred test for circulation. Villagers ate a number of different animals, and it verifying orthopoxvirus infections during smallpox eradica- was impossible to draw any conclusions as to whether any one tion (20,21). However, this neutralization test was only 83% species was a greater risk factor than any other. However, sensitive for the detection of vaccinia vaccine-induced antibody surveys could be used to evaluate porcupines as a antibodies and may have been negative (3) in some patients possible reservoir (Table 1), which was not done during our with monkeypox virus infection during this study interval. A investigation because no porcupines were captured by trappers. higher proportion of sera from retrospectively identified cases Our study had several limitations, some of which related (73%) tested positive by the HAI test, which had a higher to the brevity imposed by the civil unrest. Most cases were sensitivity (96%) than the neutralization test for the identified retrospectively and without a case-control group; identification of vaccinia-induced antibodies (22). However, thus, they could not be confirmed by a serologic test for which Vol. 7, No. 3, May–June 2001 437 Emerging Infectious Diseases Research 2. Arita I, Jezek Z, Khodakevich L, Ruti K. Human monkeypox: a the sensitivity and the specificity had been measured using a newly emerged orthopoxvirus zoonosis in the tropical rain forests of standard technique and case-control sera. Because informa- Africa. Am J Trop Med Hyg 1985;34:781-9. tion was not available regarding the vaccination status of 3. Jezek Z, Fenner F. Human monkeypox. In: JL Melnick, editor. other members of the patients’ households, secondary attack Monographs in virology. Volume 17. Basel: Karger; 1988. rates within households could not be calculated according to 4. von Magnus P, Andersen EK, Petersen KB, Birch-Andersen A. A the vaccination status. We did not assess the environmental pox-like disease in cynomolgus monkeys. Acta Pathol Microbiol changes that could have facilitated this outbreak, including Scand 1959;46:156-76. increases in household sizes, rates of monkeypox virus 5. Khodakevich L, Jezek Z, Messinger D. Monkeypox virus: ecology and public health significance. Bull World Health Organ 1988;66:747-52. infection in the animal population, and a change in rate and 6. Khodakevich L, Szczeniowski M, Manbu-ma-Disu, Jezek Z, type of exposure to wild animals among residents. We were Marennikova S, Nakano J, et al. The role of squirrels in sustaining unable to attribute infections in patients who reported an monkeypox virus transmission. Trop Geogr Med 1987;39:115-22. exposure to another patient during the incubation period to 7. Fine PE, Jezek Z, Grab B, Dixon H. The transmission potential of person-to-person transmission because some of these patients monkeypox virus in human populations. Int J Epidemiol may also have been exposed to infected animals. Finally, 1988;17:643-50. 8. Jezek Z, Grab B, Szczeniowski MV, Paluku KM, Mutombo M. patients with a history of exposure to a patient during the Human monkeypox: secondary attack rates. Bull World Health incubation period were the only controls available to generate Organ 1988;66:465-70. hypotheses regarding the type of animal exposure possibly 9. Jezek Z, Arita I, Mutombo M, Dunn C, Nakano JH, Szezeniowski associated with infection in patients not reporting an M. Four generations of probable person-to-person transmission of exposure to other patients during the incubation period. This human monkeypox. Am J Epidemiol 1986;123:1004-12. aspect may have caused bias because cases clustered within 10. Mukinda VB, Mwema G, Kilundu M, Heymann DL, Khan AS, households where exposures to animals may have been Esposito JJ. Re-emergence of human monkeypox in Zaire in 1996. Lancet 1997;349:1449-50. identical and because cases may have been misclassified as to 11. Centers for Disease Control and Prevention. Human monkeypox- their purported source of infection. Zaire, 1996-1997. MMWR Morb Mortal Wkly Rep 1997;46:304-7. There is no evidence to date that person-to-person 12. Mills JN, Childs JE, Ksiazek TG, Peters CJ, Velleca WM. Methods transmission alone can sustain monkeypox in the local for trapping and sampling small mammals for virologic testing. population. However, our study suggests that in a population Atlanta: Centers for Disease Control and Prevention; 1995. with low herd immunity, person-to-person transmission and 13. Esposito JJ, Massung RF. Poxvirus infections in humans. In: repeated introduction of virus from the animal reservoir may Murray PR, Tenover F, Baron EJ, Pfaller MA, Yolken RH, editors. Manual of clinical microbiology. 6th ed. Washington: ASM lead to more and larger clusters of human monkeypox cases in Press;1995. p. 1131-8. African rain forest areas (25). Further studies are needed to 14. Towbin H, Staehelin T, Gordon J. Electrophoretic transfer of proteins measure the sensitivity and the specificity of the serologic from polyacrylamide gels to nitrocellulose sheets: procedure and some tests currently available so they can be used in the future to applications. Proc Natl Acad Sci U S A 1979;76:4350-4. better confirm retrospectively identified cases, identify the 15. Loparev VN, Parsons JM, Knight JC, Panus JF, Ray CA, Buller type of animal or patient exposures associated with RM, et al. A third distinct tumor necrosis factor receptor of acquisition of illness, and evaluate the respective roles of orthopoxviruses. Proc Natl Acad Sci U S A 1998;95:3786-91. 16. Ropp SL, Esposito JJ, Loparev VN, Palumbo G. Poxviruses person-to-person and animal-to-human transmission. How- infecting humans. In: Murray PR, Barron CJ, Pfaller MA, Tenover ever, access to the Kasai region has been limited since our FC, Yolken RH, editors. Manual of clinical microbiology. 7th ed. study, and little information has become available to better Washington: ASM Press; 1999. p. 1137-44. document the current dynamics of monkeypox occurrences or 17. Ropp SL, Jin Q, Knight JC, Massung RF, Esposito JJ. PCR improve World Health Organization recommendations to strategy for identification and differentiation of smallpox and other prevent human monkeypox more substantially. orthopoxviruses. J Clin Microbiol 1995;33:2069-76. 18. Esposito JJ, Knight JC. Orthopoxvirus DNA: A comparison of Acknowledgments restriction profiles and maps. Virology 1985;143:230-51. 19. Dean AG, Dean JA, Coulombier D, Burton AH, Brendel KA, Smith The authors thank T.P. Muamba, G. Mwema, D. Messinger, K. DC. Epi Info, version 6: A word-processing, database, and statistics Kilundu, V.B. Mukinda, L.V. Okito, and V.L. Mangindula for assistance in data collection; L. Otshudi for assistance in setup of the investigation; program for public health on IBM-compatible microcomputers. Atlanta: Centers for Disease Control and Prevention; 1994. J.J. Muyembe-Tamfum for HIV testing; A. Moudi; J.A. Stewart and J. Patton for varicella virus testing; A. Moren, W.C. Reeves, C.J. Peters, 20. Fenner F, Wittek R, Dumbell KR. The Orthopoxviruses. San Diego: Academic Press; 1989. p. 162-5, 312-15. and D.A. Henderson for critically reading the manuscript; and J. 21. Ziegler DW, Hutchinson HD, Koplan JP, Nakano JH. Detection by O’Connor for editorial assistance. radioimmunoassay of antibodies in human smallpox patients and vaccinees. J Clin Microbiol 1975;1:311-7. The investigation was partly funded by the U.S. Agency for International Development. 22. Cherry JD, McIntosh K, Connor JD, Benenson AS, Alling DW, Rolfe UT, et al. Primary percutaneous vaccination. J Infect Dis Dr. Yvan Hutin was an Epidemic Intelligence Service officer with 1977;135:145-54. the Centers for Disease Control and Prevention at the time of this in- 23. McIntosh K, Cherry JD, Benenson AS, Connor JD, Alling DW, vestigation. He is now at the World Health Organization. Rolfe UT, et al. Clinical and serologic study of four smallpox vaccines comparing variations of dose and route of administration. Standard percutaneous revaccination of children who receive References primary percutaneous vaccination. J Infect Dis 1977;135:155-66. 1. Marennikova SS, Seluhina EM, Mal’ceva NN, Cimiskjan KL, 24. Jezek Z, Szczeniowski M, Paluku KM, Mutombo M, Grab B. Human Macevic GR. Isolation and properties of the causal agent of a new monkeypox: confusion with chickenpox. Acta Trop 1988;45:297-307. variola-like disease (monkeypox) in man. Bull World Health Organ 25. Centers for Disease Control and Prevention. Human monkeypox — 1972;46:599-611. 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