If You Get Monkeypox Can You Get It Again

• Journal Listing
• Emerg Infect Dis
• v.22(6); 2016 Jun
• PMC4880088

Emerg Infect Dis. 2016 Jun; 22(6): 1014–1021.

Extended Man-to-Human Manual during a Monkeypox Outbreak in the Democratic Republic of the congo

Leisha Diane Nolen, Lynda Osadebe, Jacques Katomba, Jacques Likofata, Daniel Mukadi, Benjamin Monroe, Jeffrey Doty, Christine Marie Hughes, Joelle Kabamba, Jean Malekani, Pierre Lokwa Bomponda, Jules Inonga Lokota, Marcel Pie Balilo, Toutou Likafi, Robert Shongo Lushima, Benoit Kebela Ilunga, Frida Nkawa, Elisabeth Pukuta, Stomy Karhemere, Jean-Jacques Muyembe Tamfum, Beatrice Nguete, Emile Okitolonda Wemakoy, Andrea Yard. McCollum, and Mary G. Reynolds

Abstract

A 600-fold increase in monkeypox cases occurred in the Bokungu Health Zone of the Democratic Republic of the Congo during the second one-half of 2013; this increase prompted an outbreak investigation. A total of 104 possible cases were reported from this health zone; among 60 suspected cases that were tested, 50 (48.1%) cases were confirmed by laboratory testing, and 10 (9.6%) tested negative for monkeypox virus (MPXV) infection. The household assault rate (i.eastward., rate of persons living with an infected person that develop symptoms of MPXV infection) was 50%. Nine families showed >ane transmission effect, and >half-dozen transmission events occurred within this health zone. Mean incubation period was 8 days (range 4–14 days). The high assail charge per unit and manual observed in this study reinforce the importance of surveillance and rapid identification of monkeypox cases. Community instruction and preparation are needed to prevent transmission of MPXV infection during outbreaks.

Keywords: monkeypox, monkeypox virus, viruses, transmission, incubation, animal diseases, Africa, orthopoxvirus, zoonosis, Democratic republic of the congo

Monkeypox virus (MPXV), which belongs to the genus Orthopoxvirus, is zoonotic and endemic to western and central Africa. MPXV is a close relative of the variola virus, and monkeypox illness resembles a smallpox-like infection but is less severe than smallpox. Well-nigh patients initially develop a fever, followed past rash a few days after. Lymphadenopathy is a common sign and occurs just before or concomitant with the rash (i , 2). Up to 11% of unvaccinated affected persons die (iii). No targeted medications are licensed to treat this infection. Although smallpox vaccination can provide some protection confronting infection, this vaccination is not used in MPXV-endemic areas because of cost considerations and safety concerns well-nigh using a vaccine that contains live vaccinia virus.

MPXV transmission among close contacts within households is well documented; previous reports have shown up to vi intrafamily transmission events (4). Transmission is idea to occur by means of salivary or respiratory droplets or contact with lesion exudate (v , six); however, evidence suggests that infection tin can occur by direct inoculation (7). Previous household attack rates (i.east., rates of persons living with an infected person and developing symptoms of MPXV infection) of 3%–xi% have been reported (vi , 8). Although some reports show a high incidence of households with single isolated cases (eight), other reports have documented frequent manual events inside households (6 , 9). Attack rates have been plant to be much college among persons living in households with an MPXV patient and among persons with no evidence of prior smallpox vaccination (6 , viii).

Monkeypox is a reportable disease in the Democratic republic of the congo (DRC), and cases are reported from 26 wellness districts (containing 512 health zones). During 2013, a substantial increase in the number of suspected homo monkeypox cases was noted in the Bokungu Health Zone inside Tshuapa District of DRC's Equateur province (Effigy 1). In Dec 2013, we conducted an investigation of monkeypox for this wellness zone and focused on cases reported during July i–Dec viii, 2013.

Region affected by monkeypox illness. A) The Democratic Republic of the congo is outlined; Tshuapa District is highlighted in yellow and Bokungu Health Zone in red. B) Wellness zones within Tshuapa Commune; Bokungu Health Zone is highlighted in red. The village with the largest cluster of cases is indicated by a yellow square. C) Distribution of cases (shown past red triangles) in the village with the almost cases during this outbreak.

Methods

DRC has a regional surveillance system that collects reports of all suspected monkeypox cases. When possible, cases are investigated, a monkeypox-specific case report form is completed, and replicate diagnostic specimens (derived from lesions) are collected. During this investigation, additional retrospective cases within affected villages and households were identified on the ground of physical symptoms that were reported by patients and family members but that had not previously reported to the surveillance system.

Instance Definitions

Cases in our investigation must have occurred during July 1–December 8, 2013. Nosotros used the following case definitions as part of the enhanced surveillance system in Tshuapa District. A confirmed case occurred in a person with a history of loftier fever, a vesicular-pustular rash, and >1 of the following 3 characteristics: i) rash on the palms and soles, 2) lymphadenopathy, three) fever preceding rash. In addition, this person has a PCR-tested diagnostic specimen that yielded a positive result for Orthopoxvirus or had MPXV Dna signatures. A probable example occurred in a person with a history of high fever, a vesicular-pustular rash, and >1 of the post-obit 3 characteristics: 1) rash on the palms and soles, 2) lymphadenopathy, three) fever preceding rash. In addition, this person has a history of contact with a person or animal with confirmed monkeypox during the 14 days before illness onset. A suspected example occurred in a person with a history of high fever, a vesicular-pustular rash, and >i of the post-obit three characteristics: ane) rash on the palms and soles, ii) lymphadenopathy, 3) fever preceding rash.

Clinical symptoms were documented by a trained healthcare provider or investigator who used a standardized case-reporting form. Smallpox vaccination status was documented on the ground of patient think and presence of a vaccination scar on the left upper arm. Analysis of vaccination status was performed with χ^two examination by using STATA 14.0 (https://www.stata.com/). Age was considered dichotomous because vaccination was bachelor just to those >33 years of age, equally a outcome of the discontinuation of smallpox vaccination in DRC (and other countries) 33 years before (1980) after the announcement of smallpox eradication.

Diagnostic specimens (crusts, vesicular fluid, or ocular fluid) were nerveless and shipped to the Institut National de Recherche Biomedicale in Kinshasa, DRC, for analysis. Deoxyribonucleic acid was extracted from each specimen, and an Orthopoxvirus-specific real-time PCR assay (x) was performed for diagnostic confirmation. If no Orthopoxvirus Deoxyribonucleic acid was amplified, then a 2nd real-time PCR analysis was performed for varicella zoster virus (VZV)–specific Deoxyribonucleic acid (US Army Medical Research Establish of Infectious Diseases, unpub. data).

Symptom Intervals

Incubation menstruation was defined equally the number of days between contact with a symptomatic monkeypox patient and development of rash. Rash was called as the criterion of infection for estimating incubation periods because families were better able to recall the mean solar day of rash onset than to recall the 24-hour interval of fever onset. To obtain the best approximate of the MPXV incubation menstruation, we identified patients who reported clear dates of exposure and rash onset in our investigation and in the published literature (4 , 9 , 11). We determined a mathematical distribution of incubation times and calculated the mean, median, and range for the cardinal 75% of the cases (that is, we excluded information for patients at either finish of the distribution).

We conducted a larger analysis that combined the information from those persons with conspicuously identified dates of exposure with data containing household transmission intervals. The household data was calculated by determining the fourth dimension between onset of rash for the showtime and second cases in a household. Cases were eliminated from this analysis if the beginning 2 cases in a household were separated by <3 days because we causeless that these case-patients were infected by the same source. Nosotros determined a mathematical distribution for the incubation times of this larger grouping. A secondary assay of the dataset containing only persons with conspicuously defined dates of exposure and the dataset which included household transmission was performed by using an culling formula that was adult to model series example intervals for respiratory infections (xi).

Manual Chains

We estimated transmission bondage (i.due east., a serial of persons who sequentially pass the infection to the next person) within families and villages on the footing of the calculated incubation periods for household manual. Cases were considered independent when the interval betwixt the onset of rash for a case-patient in the household or village was >8 days from the onset of symptoms for the previous example-patient. This value was chosen because we assumed that the start case occurred later on the shortest possible incubation catamenia (5 days) and that the last possible case occurred afterwards the longest possible incubation flow (xiii days). Any cases occurring after this window of v–13 days are considered to event from an independent infection either inside or outside the household. Coordinates for case households were recorded with handheld global positioning organisation units (eTrex 10; Garmin, Olathe, KS, USA) and compiled with the locations of residential structures digitized from satellite images (DigitalGlobe, Westminster, CO, Us). Household counts were aggregated into a fifty-square-meter filigree covering the entire populated area. Tests for spatial autocorrelation were performed by using the Global Moran's I tool in ArcGIS ten.two (ESRI, Redlands, CA, U.s.a.) at distances of fifty–one,000 meters in 50-meter increments.

Results

Monkeypox in Bokungu Wellness Zone

During 2013, a total of 104 suspected example-patients with man MPXV infection and 10 deaths (9.6%) were reported from the Bokungu Health Zone to the national surveillance organization, with October showing a dramatic increase in number of cases (Table 1). Of the 104 suspected case-patients, sixty (57.seven%) had active lesions, and specimens were collected from these persons for testing. Of tested specimens, l (83.3%) were confirmed MPXV infections. Because MPXV infection and VZV infection have clinical similarities, testing for VZV was also performed. Five (8.3%) of the 60 patients had specimens that tested positive for VZV, and specimens for 5 (8.iii%) failed to yield a positive result for either virus.

Table 1

Reported monkeypox cases and deaths by month, Bokungu Health Zone, 2013*

Cases and deaths	Jan	Feb	Mar	April	May	Jun	Jul	Aug	Sep	Oct	Nov	December	Total
Cases, no.	3	0	2	iii	0	10	vi	0	1	61	two	sixteen	104
Deaths, no.	0	0	0	0	0	1	0	0	0	8	0	1	10
*All cases, not notwithstanding characterized as confirmed, probable, or suspected.

During the focused investigation flow (July–December 2013), nosotros identified and interviewed 63 example-patients in 16 households (Tabular array two). Of these example-patients, 26 had previously been identified, investigated, and reported past local health authorities; our investigation identified an boosted 37 case-patients, including four with acute disease. Of the total 63 case-patients, 20 were confirmed, 19 were probable, and 24 were suspected cases. Median age of case-patients was 10 years (range four months–68 years); 17.7% were <v years of age (Table 2). Of the 63 case-patients, 36 (57.1%) were male. Most cases occurred within a 74-twenty-four hour period period betwixt the showtime week of September and the last week of October (Effigy 2). All 63 cases included in the six-month investigation occurred inside a 144-day window.

Table 2

Characteristics of patients with monkeypox infections, Bokungu Health Zone, July–December 2013

Characteristic	Full cases, N = 63	Confirmed cases, due north = 20	Likely cases, n = xix	Suspected cases, n = 24	Unaffected household members,* due north = 53
Median historic period, y (hateful)	10 (15.five)	14 (20.four)	7 (6.7)	ten (16.4)	20 (23)
Age range	4 mo–68 y	8 mo–68 y	four mo–21 y	6 mo–65 y	2 mo–72 y
Male sex, no. (%)†	36 (57)	12 (threescore)	9/xviii (fifty)	xv/22 (68)	19/fifty (38)
Vaccinated, no. (%)†	ix/59 (15)	five/18 (28)	0/18 (0)	4/23 (17)	14/53 (26)
*Persons in households without symptoms and not tested. †Denominators signal no. patients with data available in that category.

Epicurve of cases included in investigation and monkeypox cases during investigation menstruum (July i–December 8, 2013). Black represents suspected cases, white represents probable cases, and greyness represents confirmed cases.

In the 16 investigated households, 9 (15%) of affected household members had bear witness of a prior smallpox vaccination, compared with 30% of unaffected household members; χ^two assay showed that that this difference was non meaning (p>0.05). Even so, vaccination status and age >33 years were most perfectly correlated (p< 0.001).

The median number of persons affected within each household was 3 (hateful 3.ix; range i–8). The median attack charge per unit within households was 50%; mean was 52.one% (range 50%–100%). For one of the 16 families investigated, all vi household members were affected. For all households, the median interval betwixt the time that rash developed in the first person in the household to time that rash developed in the last person was ten days (range 2–41 days).

Incubation Period

Iv case-patients were able to identify a specific date of monkeypox exposure and rash onset. These persons reported that rash developed five–8 days after contact with an earlier case-patient. A PubMed (http://www.ncbi.nlm.nih.gov/pubmed) search identified 12 additional persons who had confirmed or probable infection and well-divers incubations periods; these case-patients had an incubation period of nine–14 days (iv , nine , eleven). When the iv case-patients in our investigation and the 12 historical instance-patients were considered together, mean incubation menses for all was 9.6 days and median was 9 days. The primal 75% of these case-patients had an incubation menstruation of vi–13 days (Effigy 3).

Distribution of incubation periods from 2 split up analyses. Dark greyness shows the distribution of incubation periods on the basis of case-patients with well-divers dates of exposure identified in our investigation and in the published literature (n = xvi). Light gray shows the distribution of incubation periods from the literature and incubation periods calculated by using the outset ii case-patients in each family unit (n = 28).

A 2d analysis was conducted with boosted incubation periods that were calculated by using the difference in fourth dimension of onset between the kickoff and second cases within 12 households. These boosted data were added to the sixteen information points from the first analysis. For the total 28 data points available for this second assay, the mean incubation period was eight.3 days and median was 8 days. From the second analysis, the fundamental 75% of instance-patients had an incubation menstruum of 5–12 days (Figure 3). For subsequent calculations in this investigation, we used the extremes in the 2 analyses as the incubation range (5–thirteen days, a range indicating the least and most number of days between exposure and onset of rash).

A 3rd analysis of this information was performed by using the model described by Jezek et al. (11). In this analysis, which generates a model of serial intervals from the observed information, the transmission interval of the sixteen well-described cases was 9.7 (95% CI eight.35–10.95) days; the interval for all 28 cases was 7.four (95% CI 6.76–7.99) days.

Transmission Chains

Using the range of 5–13 days as the incubation period, we reconstructed transmission events inside families and villages. When the longest incubation period (xiii days) was used, 9 of xvi households showed >1 transmission event. When the shortest time of incubation was used (five days), an additional 4 households showed patterns consistent with transmission inside the household (Figure 4, console A). Two households had cases separated by a considerable period, suggesting the occurrence of either an unknown transmission event inside the household or an exposure outside of the household (Figure four, console B). When customs-broad transmission was considered within the health zone, longer manual chains were observed, with the longest being in the village of Bokungu, where >7 suspected manual events resulted in 42 apparent cases (Figure 4, panel C). Tests for spatial autocorrelation showed that case households for were more spatially clustered (z-scores >2.0) than would be expected randomly at all distances of 50–1,000 meters.

Reconstruction of monkeypox virus transmission events in the Democratic Republic of the Congo past using an estimated incubation period. Each column represents a calendar twenty-four hours. Red boxes correspond a single case of monkeypox infection. A cluster is defined as a set of example-patients that could have resulted from a single exposure and are delimitated with dark vertical lines. Nighttime arrows point the first instance inside a cluster, and the dotted arrow indicates the time during which a potential single exposure could accept produced symptoms in the first person in that group to the last (i.eastward., 5–13 days). A) Manual events in the village of Bokungu in the Autonomous Republic of the congo. B) A household with testify of 3 known transmission events. C) A household with evidence of 1 known and 1 unknown transmission event. The orangish bar represents the days when the case-patient, represented by an asterisk (*), would be expected to have been exposed.

Discussion

Homo MPXV infection is endemic to DRC, with cases occurring throughout the Congo Bowl. Many of these cases occur in isolation or in minor clusters, but large outbreaks occasionally occur that involve many persons over a large geographic area. During 2013, a total of 104 cases of human monkeypox illness were reported in the Bokungu Health Zone. In contrast, but 17 cases were reported in 2011 and 13 in 2012. The surveillance system did not alter substantively during this menses; consequently, the rate in 2013 represents an increment of >600%, compared with rates for previous years. Our investigation focused on cases that occurred during the height of the 2013 outbreak.

Inside the investigation period, 57% of affected persons were male, and median historic period was x years; xviii% were <5 years of age. Co-ordinate to the United Nations World Population Prospects (http://esa.un.org/unpd/wpp/), 17.8% of the population in DRC is <v years of age. Consequently, the historic period demographics of patients during the monkeypox outbreak correspond to those of the full general population, suggesting that immature children are not more prone to MPXV infection than others. A parallel study performed during this outbreak found no association between monkeypox disease and hunting or consumption of specific animals (12).

Previous publications have reported attack rates of 3%–11% (6,8); our investigation found a median attack rate of 50%, and 1 family had 100% of persons affected. The previously published attack rates are considerably lower than those for other viruses with similar routes of manual; for example, smallpox has assail rates of 35%–88% (13 – 15), and variola virus had an assault rate of 90% (xvi). The departure between the findings reported hither and those reported previously may effect from several different causes. Commencement, the high attack charge per unit reported here perchance results from changing private- and population-level immunity caused by elimination of routine babyhood smallpox vaccination (17). Earlier investigations may accept found lower attack rates because more persons had vaccine-derived amnesty; all the same, some persons in the outbreak that nosotros investigated had MPXV infection and prior smallpox vaccination, which suggest possible waning immunity over fourth dimension, a cistron that should be considered in futurity investigations. Second, a viral strain unlike from that plant in previous investigations could have circulated in this outbreak and resulted in the loftier set on charge per unit. However, we accept no evidence for accepting or rejecting this possibility. Third, the high assail rate mayhap reflects a high charge per unit of instance-patient identification in this investigation. We found that many persons are oft affected in a household but that only one household member normally seeks medical attention, causing only one case to exist recorded or investigated for surveillance. Case reporting on the basis of persons seeking healthcare may have caused the surveillance organisation to underestimate of the number of man monkeypox cases. Because we used in-abode interviews, many previously unidentified cases were uncovered, enabling the calculation of a more authentic attack rate.

Previous investigations have shown a limited transmission capacity of MPXV within the human population. The highest number of suspected serial manual events previously recorded is 6 (4 , 9). The ability to identify manual events is express by our lack of knowledge of the dynamics of infection. Oft, whether 2 persons were co-infected by the same person and have different incubation periods or whether the persons were sequentially infected is difficult to decide. Understanding the incubation period of MPXV is vital for creating accurate transmission chains and determining if multiple introductions (human being or zoonotic) occurred.

Sixteen patients with well-defined incubation periods were identified in our investigation and in the literature. Although these defined incubation periods are the all-time information bachelor, they are as well limited in number. Consequently, we also included apparent incubation periods within households. The time between onset of rash in 1 case and onset of rash in a subsequent case within a household provide an judge incubation period. The longer that MPXV is present in a household, the more difficult identifying a clear infection chain is; therefore, but the manual between the starting time and second case was used for the assay. However, these 2 persons could have been infected by an outside source instead of by man-to-homo transmission. The 3 analyses that we developed and presented here yielded like results; 75% of the incubation periods were 5–13 days. Analysis of the aforementioned data by using the model proposed past Jezek et al. (11) yielded transmission intervals that matched data from our mathematical distribution model when we analyzed the 16 well-described cases. When all 28 cases were analyzed, the Jezek model produced an interval ane twenty-four hours shorter than that for the mathematical distribution. The difference between these numbers likely results from the weighting that is included in the Jezek model. Farther piece of work is needed to evaluate which model all-time fits the biology of MPXV.

Our investigation suggests a shorter incubation period for MPXV than that observed in many animate being models (7 , xviii , nineteen). Differences in organism and exposure may business relationship for this departure. Experimental animals are often exposed to a virus for a brief time, and the interval between that exposure and development of symptoms is recorded as the incubation period. In contrast, the incubation menstruation in this study was defined as the time between onset of rash for the showtime person infected and onset of rash in the second. Although high levels of viral shedding brainstorm with the onset of rash, virus may be transmitted before the onset of rash. Research in prairie dogs has shown that oral shedding of virus begins before the evolution of dermal rash (five); this finding indicates that spread of MPXV is possible before the appearance of external peel lesions. Therefore, the time from beginning exposure to development of symptoms calculated in laboratory settings may be longer than the time calculated in this analysis.

Picayune information is available regarding the incubation period of MPXV in humans. A monkeypox outbreak in the United States revealed that the incubation period varied (range 12–14 days), and this period was dependent on the route and nature of exposure (7). All US cases resulted from exposure to infected pets. In dissimilarity, the infections described in this commodity are likely caused by exposure to wildlife or an infected homo. The type of exposure and route of virus transmission may result in incubation periods during the Usa outbreak that differ substantially from those observed in the outbreak that was the focus of our investigation. In add-on, previous outbreaks were caused by viruses from a different genetic clade than that which caused the outbreak reported here. Transmission times may differ considering of the specific virus involved.

Altogether, the Bokungu Health Zone had 42 cases in >seven infection clusters (i.e., a group of cases that could accept resulted from a single infectious exposure). These clusters could have been created in 3 different ways. First, the clusters could be linked sequentially, whereby the infection could be externally introduced into a cluster so passed by 1 person from that group to cluster 2 and so on. Second, transmission may non have occurred in a clear linear fashion, just persons may have had multiple human exposures. Third, MPXV could take been reintroduced into the community from an external source (zoonotic or man) during the course of the outbreak. Although nosotros cannot determine which of these possibilities is most probable, we favor the second model because community interactions would brand a strictly linear pattern of spread unlikely to occur. Farther, the limited number of cases in the population every bit a whole makes it less probable that an external source was causing frequent reintroductions. We tin can conclude that >6 transmissions or introductions occurred in this health zone after the initial infection.

This report has limitations that should be considered. First, MPXV infection was laboratory confirmed in 48% of the cases by using PCR; the remaining cases were identified past patients' symptoms. Laboratory confirmation was not possible for many cases because patients were interviewed afterwards symptoms had resolved. Local resources for performing specimen collection were unavailable during all phases of the outbreak, so confirmation of MPXV infection for many cases was not possible. The lack of specimen collection has been noted as a limitation of the electric current surveillance program, and nosotros are actively addressing this outcome. Second, modeling of the incubation period was express by the disability of most patients to identify a specific source of infection or a date of exposure. We causeless a minimum incubation period of 3 days when we created the incubation period model. This assumption was necessary to forestall bias toward very short incubation periods and is advisable because of the longer incubation periods observed in fauna models (18 , 20). 3rd, calculations were performed in our investigation with the assumption that manual occurs one time a person is symptomatic. Because information regarding transmission of MPXV are limited, this assumption was necessary; however, this assumption should be considered for evaluating incubation times and transmission.

This assay provides insight into the dynamics of MPXV infection. We observed an average household attack rate of 50%, a much higher charge per unit than reported in previous studies. Measures to decrease this attack rate should be implemented, including family-based educational activity related to hygiene and isolation of patients. The transmission patterns observed in this outbreak besides suggest transmission at the community level; therefore, customs-broad education should begin as soon as the first monkeypox case is identified in an area. The calculated incubation flow of 5–xiii days farther refines our understanding of the longest menstruum of MPXV transmission risk after exposure in a natural setting. Knowledge of transmission adventure is helpful for considering the appropriate monitoring period for exposed persons. This investigation and future work will meliorate our understanding of MPXV infection and our ability to limit its spread.

Acknowledgments

Nosotros give thanks all patients and the communities we worked with during this investigation.

Biography

•

Dr. Nolen served as an Epidemic Intelligence Service officer during this investigation, working in the Bacterial Special Pathogens Co-operative, Partition of Loftier-Effect Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases at CDC. She currently works in the Field Epidemiology Training Program. Her research interests include the public wellness effects of infectious diseases.

Footnotes

Suggested citation for this commodity: Nolen LD, Osadebe L, Katomba J, Likofata J, Mukadi D, Monroe B, et al. Extended man-to-human transmission during a monkeypox outbreak in the Democratic Republic of the congo. Emerg Infect Dis. 2016 Jun (date cited). http://dx.doi.org/x.3201/eid2206.150579

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