Research

Likely effectiveness of pharmaceutical and non-pharmaceutical interventions for mitigating influenza virus transmission in KJ Bolton,a JM McCaw,a R Moss,a RS Morris,b S Wang,b A Burma,c B Darma,c D Narangerel,d P Nymadawac & J McVernona

Objective To assess the likely benefit of the interventions under consideration for use in Mongolia during future influenza pandemics. Methods A stochastic, compartmental patch model of susceptibility, exposure, infection and recovery was constructed to capture the key effects of several interventions – travel restrictions, school closure, generalized social distancing, quarantining of close contacts, treatment of cases with antivirals and prophylaxis of contacts – on the dynamics of influenza epidemics. The likely benefit and optimal timing and duration of each of these interventions were assessed using Latin-hypercube sampling techniques, averaging across many possible transmission and social mixing parameters. Findings Timely interventions could substantially alter the time-course and reduce the severity of pandemic influenza in Mongolia. In a moderate pandemic scenario, early social distancing measures decreased the mean attack rate from around 10% to 7–8%. Similarly, in a severe pandemic scenario such measures cut the mean attack rate from approximately 23% to 21%. In both moderate and severe pandemic scenarios, a suite of non-pharmaceutical interventions proved as effective as the targeted use of antivirals. Targeted antiviral campaigns generally appeared more effective in severe pandemic scenarios than in moderate pandemic scenarios. Conclusion A mathematical model of pandemic influenza transmission in Mongolia indicated that, to be successful, interventions to prevent transmission must be triggered when the first cases are detected in border regions. If social distancing measures are introduced at this stage and implemented over several weeks, they may have a notable mitigating impact. In low-income regions such as Mongolia, social distancing may be more effective than the large-scale use of antivirals.

Introduction designated across the country. At the Category-I surveillance sites, cases of influenza-like-illness (ILI) are reported daily and The efficient use of resources to mitigate the spread of an samples for virological analysis are collected routinely from emerging infectious disease is of global interest. However, each such case. At the other (Category-II and Category-III) the most appropriate control strategies in any given area sentinel surveillance sites, ILI cases are reported weekly and probably depend on the nature of the local population and samples for virological analysis are only collected occasion- environment. Implementing interventions against emerging ally. This approach to influenza surveillance allowed a large infectious diseases is particularly important in developing amount of epidemiological and virological information to be countries, such as Mongolia, where the capacity to provide collected during the 2009–2010 influenza season. health care and undertake detailed surveillance is limited. In week 40 of 2009 (i.e. at a time of year when seasonal Since the identification of highly pathogenic avian influenza influenza epidemics had previously occurred in Mongolia)2 in Mongolia in 2005,1 the Mongolian government has been sentinel surveillance sites first reported elevated levels of particularly aware of the threat posed by influenza to public ILI activity: between 20 and 50 cases per 10 000. The sites health. Mongolia’s vulnerability to influenza was reinforced by reporting such activity were all Category I and in the border the impact on the country of A(H1N1)pdm09, which was no aimags of Dornod, Dornogovi and . A(H1N1)pdm09 less severe than in countries affected earlier (even though the was virologically confirmed among the cases from these sites. virus was not recorded in Mongolia until 4 to 5 months after By week 42 the incidence of reported ILI exceeded 50 cases the first cases of human infection were detected in China and per 10 000 in and 20 cases per 10 000 in all the the Russian Federation).1 eastern aimags and, nationally, most subtyped viruses were Mongolia’s vast landscape of over 150 million hectares is identified as A(H1N1)pdm09. The establishment of A(H1N1) divided into 21 provinces called aimags. Although the mean pdm09 transmission in the dense population of Ulaanbaatar population density is only 1.5 people per square kilometre, probably led to the rapid spread of cases in the capital and the some regions of the country are now highly urbanized and rapid dissemination of the virus to the rest of Mongolia. The more than 30% of the country’s inhabitants reside in the epidemic reached a distinct peak in weeks 44–45, when the capital city, Ulaanbaatar. Recognition of the threat of highly reports of ILI were dominated by the cases in Ulaanbaatar, al- pathogenic avian influenza has been influential in overcoming though, by then, every aimag except Bayan-Ölgii in the far west the challenges of developing nationwide surveillance capabili- was reporting more than 50 ILI cases per 10 000 (Appendix A, ties. Over 100 influenza sentinel surveillance sites have been available at: http://mathmodelling.sph.unimelb.edu.au/publi-

a Melbourne School of Population Health, University of Melbourne, Carlton, Victoria 3010, Australia. b The World Bank Office, Beijing, China. c National Influenza Centre, National Centre for Communicable Diseases, Ministry of Health, Ulaanbaatar, Mongolia. d Public Policy Implementation and Coordination Department, Ministry of Health, Ulaanbaatar, Mongolia. Correspondence to KJ Bolton (e-mail: [email protected]). (Submitted: 28 September 2011 – Revised version received: 12 January 2012 – Accepted: 18 January 2012 )

264 Bull World Health Organ 2012;90:264–271 | doi:10.2471/BLT.11.093419 Research KJ Bolton et al. Mitigating influenza transmission in Mongolia cations/Bolton-BullWorldHealthOrgan- banning public gatherings and closing the likely impact of interventions on 2011-AppendixA.pdf). The period of markets. Provincial rail and road travel influenza have focused on the contain- prolonged, lower-level activity that was interrupted for a period of several ment of highly pathogenic avian influ- followed the epidemic peak probably weeks. In addition to these mandatory enza outbreaks in south-eastern Asia9,10 reflected the dissipation of the virus into social distancing measures, all citizens and the United States of America.11 remote areas, perhaps facilitated by the were advised to minimize activity out- There have been few recent, country- virus being brought into Mongolia again side of their homes and to wear facial specific evaluations of strategies for the via border crossings. The A(H1N1) 2009 masks, and symptomatic individuals mitigation of influenza, particularly pandemic activity had not long subsided were encouraged to stay in self-imposed in resource-poor settings. Our results when influenza B cases were reported, in quarantine at home.2 Institutions and provide novel insights into the probable week 6 of 2010. New cases of infection businesses were recommended to sup- benefits of anti-influenza interventions with A(H1N1)pdm09 subsequently be- ply staff with vitamin supplements to in Mongolia, some of which are poten- came rare as the population experienced “build health”.8 Although no formal tially relevant in pandemic planning in a severe epidemic of influenza B.3 evaluation of public compliance is other low-income regions. Sentinel surveillance reports, based available, anecdotal evidence indicates on medically reported cases of ILI in that the intervention measures were Methods 2009, reveal that the total ILI attack rate generally well accepted. Initiatives such Modelling transmission during (i.e. the percentage of the population as the broadcasting of school lessons interventions that became infected over the course on national television probably facili- of the pandemic) was about 10%. The tated compliance. While the resources Influenza transmission was explored results of the serological survey that and infrastructure deemed necessary using a stochastic, computational model enabled the A(H1N1)pdm09-specific for effective epidemic containment by of susceptibility, exposure, infection and attack rate to be determined have yet to non-pharmaceutical means are prob- recovery.12,13 Large-scale spatial trans- be reported (A Burma, personal com- ably found in very few settings,4 less mission was captured by geographically munication, 2011). ILI reporting rates stringent measures may still usefully dividing the population into 14 patches were highest among children aged less reduce the burden on acute health- chosen to isolate border crossings, senti- than 5 years and young adults,2 reflect- care services. International borders nel surveillance sites, urbanized regions ing the global experience.4 There were remained open during the 2009 pan- and other regions of national interest. also high rates of ILI among teenag- demic in Mongolia. Although border The 14 patches, which were allowed ers, probably, at least in part, because screening was in place in Ulaanbaatar, to interact via a travel matrix, 14 were people aged 10–20 years comprise 30% the first case of A(H1N1)pdm09 infec- individual aimags (Bayan-Ölgii, Bulgan, of the population.5Hospitalization rates tion was detected through the national -Uul, Dornod, Khovd, Orkhon, in the hospital-based sentinel surveil- surveillance network.2 Övörkhangai, Selenge, Uvs), combina- lance sites increased three- to fourfold The Mongolian government’s stock- tions of two (Dornogovi + Ömnögovi, during the pandemic, largely because pile of around 80 000 doses of the an- Govi-Altai + Zavkhan), three (Arkhan- of an increase in the number of hos- tiviral drug oseltamivir was exhausted gai + + Khövsgöl) or pitalized pneumonia cases.6 There was during the 2009 pandemic. Although five aimags (Dundgovi + Govisümber also a stark increase in the pneumonia oseltamivir was taken as prophylaxis + Khentii + Sükhbaatar + Töv), and the mortality rate among adults aged 20–59 by some health-care workers, the drug municipality of Ulaanbaatar (Appendix years.6 Disease severity during the was predominantly used to treat severe A). Inter-patch mixing was generally Mongolian influenza pandemic appears hospitalized cases.7 The Mongolian only significant between neighbouring to have exceeded that of similar epi- government purchased vaccine against patches and between each of the other demics in many developed countries, A(H1N1)pdm09, which was supple- patches and Ulaanbaatar. The importa- possibly because chronic conditions mented by donations from the World tion of A(H1N1)pdm09-infected cases such as renal and cardiovascular dis- Health Organization (WHO). However, into border patches was modelled using ease, which have been identified as vaccine roll-out only commenced in the time-courses of the 2009 pandemic potential risk factors for severe respira- January 2010 after the epidemic peaked.4 in neighbouring countries and the tory disease, are relatively common in Here we use the epidemiological relative frequency of border crossings. 7 Mongolia. data collected during the 2009 influenza The basic reproduction rate (R0) used The interventions implemented pandemic in Mongolia to calibrate a as the baseline in the model was based against influenza virus transmission computational model of influenza virus on epidemiological observations in during the 2009 pandemic were trig- dissemination in a Mongolian pan- other countries,15–19 but a wide range of gered by the detection of elevated ILI demic, with tailoring to the country’s values, including more severe scenarios activity in Ulaanbaatar in week 42. infrastructural and sociobehavioural with R0 varying around 2, was explored. The first intervention was the closure characteristics. We explore the likely The data were modelled and graphically of primary schools. High schools and impact of various nationwide social displayed using Matlab (MathWorks kindergartens were also soon closed distancing and pharmaceutical inter- Inc., Natick, USA). for a period of several weeks. In week ventions on mitigating the spread of a The model was configured to allow 45, further social distancing measures pathogen, with particular emphasis on evaluation of the likely effects of travel were imposed in Ulaanbaatar. Restric- a novel influenza strain with established restrictions, school closure, generalized tions included limiting the opening transmission in the human population. social distancing, quarantining of close hours of shops, cafes and restaurants, Earlier country-specific evaluations of contacts of presenting cases and distri-

Bull World Health Organ 2012;90:264–271 | doi:10.2471/BLT.11.093419 265 Research Mitigating influenza transmission in Mongolia KJ Bolton et al. bution of an antiviral drug to the ill and Fig. 1. Statistics used to characterize epidemic timing and severity and to assess their close contacts. intervention impact (upper panel), and observed and modelled incidences of Assessment of intervention influenza-like illness (ILI; lower panel), Mongolia, 2009–2010 strategies 300 Pandemic scenarios beginning at week 35 were simulated. The impact of travel Peak ILI incidence 250 restrictions, school closure and general- ized social distancing was assessed, with 200 each intervention beginning at various time points ranging from week 35 to 150 week 49 and varying in duration from 2 to 12 weeks. The effects of the ongoing 100 quarantining of the contacts of present- ing cases during the epidemic and of the 50 continuous distribution of an antiviral Duration of ILI reporting above 50 cases per 10 000 drug to contacts until the national stock- 0 pile of the drug was exhausted were also Time of reporting first Time of peak Time of reporting first falling below investigated, with the presumption that exceeding 50 cases per 10 000 ILI reporting 50 cases per 10 000 each of these interventions would be Time implemented from the first case. It was 300 conservatively assumed that the cases Model Observed themselves could not be quarantined 250 early enough to reduce their overall Incidence of ILI (cases per 10 000) infectiousness. 200 Latin-hypercube sampling (LHS)20 was used for a sensitivity analysis of 150 the various parameters describing the effects of intervention timing and effi- 100 ciency on intervention impact. The LHS technique allowed the average impact of 50 an intervention to be estimated despite uncertainties in the characteristics of 0 the pathogens involved and the nature 35 37 39 41 43 45 47 49 51 53 55 57 59 61 and intensity of the population mixing. Week Sampling was conducted over many dif- Note: The final attack rate, representing the percentage of the total population infected during the ferent parameters related to travel and epidemic, is given by the shaded area in the upper panel. The data shown in the lower panel cover the importation rates, the virus-dependent period in which A(H1N1)pdm09 was the dominant subtyped virus, with baseline parameters used in the factors of transmission and the details model. of each intervention (sampling ranges in Appendix A). The LHS approach al- pendix A). Patches encompassing ur- model, the mean attack rate was 9.7% lowed us to detect possible associations banized regions (such as Ulaanbaatar) and the mean peak ILI rate, which was between model parameters (including tended to exhibit early, rapidly-peaking seen at week 44.5, was about 240 cases those characterizing an intervention outbreaks, whereas patches containing per 10 000. In the severe epidemic sce- measure) and various statistics captur- rural regions (e.g. Selenge) exhibited nario, the mean attack rate was about ing the severity of the pandemic, as well more prolonged epidemics. Patches 23%, and the mean peak ILI rate, of 800 as to estimate the uncertainty around encompassing western aimags (such cases per 10 000, occurred, on average, these associations. By using LHS we as Uvs) tended to experience relatively during week 42. hoped to identify the intervention late-peaking epidemics. Several of the Non-pharmaceutical strategies that would be optimal across patches containing border regions (such interventions a range of potential pandemic scenarios as Bulgan and Ömnögovi) displayed in Mongolia. double-peaked epidemics. In the model, the apparent efficacy of Three key measures of intervention social distancing interventions rapidly Results success were evaluated in the model: the fell once the frequency of reported ILI total (presenting) ILI attack rate, the cases exceeded approximately 20 cases Epidemic curves for the baseline model peak ILI reporting rate and the time of per 10 000. At lower ILI reporting rates, are shown for Mongolia as a whole peak ILI reporting (Fig. 1). The mean representing the early phases of the (Fig. 1), along with the correspond- attack rates seen in the model when a modelled pandemic, school closures, ing observed data for the 2009–2010 single non-pharmaceutical or pharma- generalized social distancing or sus- pandemic. Our model was also able ceutical intervention was included are tained travel restrictions had a sub- to capture the diversity in observed shown in Fig. 2. When no intervention stantial mitigating effect. In the actual epidemic curves between patches (Ap- was included in the moderate-epidemic epidemic of 2009, an ILI reporting rate

266 Bull World Health Organ 2012;90:264–271 | doi:10.2471/BLT.11.093419 Research KJ Bolton et al. Mitigating influenza transmission in Mongolia

Fig. 2. Modelled mean attack rates (AR) for influenza-like illness (ILI) when any one of five interventions is introduced in a moderate pandemic, Mongolia, 2009

Travel restrictions School closureSocial distancing

9.65 9.4 9.6 9.8 9.5 9.8 9.6 9.4 9.3 9.5 9.7 9.6 9.4 9.6 9.55 9.3 9.5 9.2 9.2 9.4 9.3 9.5 9.1 9.4 9.45 9.0 9.1 9.2 9.2 9.3 9.4 8.9 9.0 9.1 8.8 9.0 9.2 9.35 8.7 8.8 9.0 9.1 9.3 8.6 8.9 8.6 8.9

Mean AR (ILI) in Mongolia (%) 119.25 Mean AR (ILI) in Mongolia (%) Mean AR (ILI) in Mongolia (%) 1 8.8 0.8 0.8 8.8 0.9 0.6 47 49 9.2 AR(adults)/AR(children)0.6 47 49 0.8 47 49 8.7 Relative transmission0.4 43 45 43 45 Relative transmission0.7 43 45 0.2 39 41 0.4 39 41 8.7 0.6 39 41 in population 0 35 37 0.2 35 37 in population 0.5 35 37 Start date of Start date of Start date of intervention (weeks) intervention (weeks) intervention (weeks) Quarantining Antiviral distribution 9.5 9.6 10 9.0 9.8 9.4 9.5 9.6 9.0 8.5 9.4 9.2 8.5 9.2 8.0 8.0 9.0 9.0 7.5 8.8 7.0 7.5 8.6 8.8 6.5 8.4 6.0 7.0 8.2 8.6 5.5 8.0

Mean AR (ILI) in Mongolia (%) 0 1 Mean AR (ILI) in Mongolia (%) 0 0 8.4 0.2 0.9 6.5 0.1 0.1 0.4 0.8 0.2 0.2 Proportion of contacts0.6 0.7 0.3 0.3 8.2 0.8 0.6 6.0 Proportion of cases0.4 0.4 1 0.5 0.5 0.5 quarantined treated Relative infectiousness Proportion of contacts of those quarantined given prophylaxis

Note: The attack rates shown are mean national values (over 500 simulated outbreaks) when the intervention was implemented for 4 weeks. For example, the upper left panel illustrates that the impact of 4 weeks of travel restrictions is greatest, reducing the attack rate to approximately 9.1%, when the propensity to travel is zero and the restrictions are implemented from week 42. of 20 cases per 10 000 was recorded by approximately 1.5 weeks if main- the pandemic peak by as long as 2 weeks. during week 40 in the border aimags of tained for 4 weeks and by about 1 week In general, school closure had only a Khovd, Dornod and Dornogovi. In the if maintained for 2 weeks. Travel re- modest impact on the modelled mean model, school closures or generalized strictions increased the time-scale over peak ILI rate. social distancing implemented before which the modelled pandemic occurred On average, the inclusion in the the ILI reporting rate reached 20 cases by slowing the spatial spread. They also model of social distancing measures per 10 000, resulted in better mitiga- resulted in a reduction in the peak ILI that reduced transmission probability tion than the very early implementa- rate, by about 12%, if enforced for 4 by 50% from week 40 reduced the attack tion of travel restrictions of limited weeks. They only reduced the modelled rate from 9.7% to 8.6% (Fig. 2), delayed duration (which left large numbers of attack rates by less than 0.1%, however, the time to the peak ILI reporting rate susceptible and infected hosts when the even when travel frequency was reduced by almost 2 weeks and reduced the peak restrictions were relaxed). Although by 95% (Fig. 2). case-load by about 8%. more prolonged interventions ap- Substantial reductions in the mean The model indicated that the impact peared relatively more effective in the attack rate could be seen, nonetheless, of the continuous quarantining of a pro- model, the long-term implementation when prolonged school closure or gen- portion of the individuals identified as of any intervention in the field may be eralized social distancing was added contacts of those who present with an ILI hampered by falling compliance and/or to the model. For school closure to be could be very substantial. In a scenario logistical challenges. Below we focus on effective, the attack rate in children had in which 50% of known contacts were the impact of 4-week interventions in to be over double that in adults. If, for traced and quarantined, for example, the the moderate-epidemic scenario, since example, schools were closed for 4 weeks peak case-load decreased by 25%, the at- the interventions used against the 2009 from week 40, when the attack rate in tack rate was reduced by more than 1.5% pandemic in Mongolia appear to have children was threefold higher than in (Fig. 2) and the time of peak incidence been successfully implemented for adults,21 the model indicates that the was delayed by around 1 week. about 4 weeks. overall attack rate would decrease from Targeted antiviral interventions In the model, a 50% reduction in 9.7% to approximately 8.6% (Fig. 2) mean travel frequency, if applied early and, perhaps more importantly, that the Using the model, we considered the in the epidemic (i.e. from week 40, as epidemic peak would be delayed by over treatment, from the first detected the ILI reporting rates reached 20 cases a week. School closure implemented case, of a percentage of infected hosts per 10 000), delayed the pandemic peak before week 40 could delay the time to and the timely prophylaxis of a pro-

Bull World Health Organ 2012;90:264–271 | doi:10.2471/BLT.11.093419 267 Research Mitigating influenza transmission in Mongolia KJ Bolton et al.

Fig. 3. Distributions of three different statistics capturing epidemic severity in models a week were observed. The modelled of influenza epidemics in Mongolia impact of each mitigation measure that was considered varied significantly 40 with the nature, timing and efficacy of 60 35 2000 the intervention. Although our results indicate that Mongolia’s capacity to 30 curtail a nationwide epidemic similar to 1500 55 25 the one in 2009 is limited, even modest reductions in epidemic severity may 20 1000 50 substantially ease the burden on health- 15 45 care systems in resource-poor settings 10 500 such as Mongolia. ILI final attack rate (%) 5 The benefits of travel restrictions in 40

0 of peak ILI incidence Time (weeks)

Peak ILI incidence (cases per 10 000) Peak curtailing a nationwide epidemic may be 0 limited once the pathogen involved has reached a congested city from which, and to which, there is widespread travel. ention (severe) ention (severe) ention (severe) ention (severe) ention (severe) ention (severe) ention (severe) ention (severe) ention (severe) In Mongolia, for example, travel restric- rv rv rv rv rv rv rv rv rv ention (moderate) ention (moderate) ention (moderate) ention (moderate) ention (moderate) ention (moderate) ention (moderate) ention (moderate) ention (moderate) TR, AD (moderate) TR, AD (moderate) ,TR,AD (moderate) rv rv rv tions would probably have little impact rv rv rv rv rv rv SC,SD,TR,AD (severe) SC,SD,TR,AD SC, SD, TR, AD (severe) SC, SD, SC, SD, TR, AD (severe) SC, SD, No inte NP inte No inte No inte NP inte NP inte SC,SD if implemented only after an epidemic . inte SC, SD, SC, SD, SC, SD, SC, SD, No inte NP inte No inte NP inte NP inte No AD only inte AD only inte AD only inte had been established in Ulaanbaatar, AD only inte AD only inte AD only inte the country’s pre-eminent cultural and AD, antiretroviral distribution; ILI, influenza-like illness; NP, non-pharmaceutical; SC, school closure; economic centre. The distinct temporal SD, social distancing; TR, travel restrictions. offsets seen between the epidemics in Note: The data on ILI are based on scenarios in which Mongolia is struck by a moderate or severe pandemic different states or territories during of influenza and there are no interventions or non-pharmaceutical interventions – school closure, social Australia’s A(H1N1) 2009 epidemic are distancing and travel restrictions – and/or targeted antiviral drug distribution. The bottom and top of each box indicate the 25th and 75th percentiles, with the height of the box therefore indicating the thought largely to reflect the role of sev- interquartile range. The line dissecting the box is the median value. Dashed lines (whiskers) extend 1.5 eral large or capital cities in disseminat- times the interquartile range, with any data points beyond the whisker length marked as crosses. ing the virus to the surrounding sparsely populated regions in this country.22 portion of their contacts, assuming a Discussion Although reduced community finite national stockpile of the antiviral mixing through school closures and drug used (10 000–500 000 doses). In Our model was able to capture the gross restricted social interaction on a a scenario in which half of the known characteristics of the actual 2009 influ- wider scale appears potentially useful, contacts were traced and given the an- enza pandemic in Mongolia, including it is difficult to establish the required tiviral drug, such a targeted interven- the variations between aimags. Although nature of effective, generalized, social tion reduced the mean attack rate by elevated ILI activity was first registered distancing measures. If we assume about 2%, delayed the peak case-load in several border aimags (including Dor- that the attack rate in children is over by a mean of 2–3 weeks and reduced nogovi) at about the same time in 2009, twice that in adults, as expected in a the peak case-load by approximately A(H1N1)pdm09 was probably spread pandemic scenario since children mix 30% (Fig. 2 and Fig. 3). Although the into Dornogovi from northern China intensely and lack protection, school attack rate decreased by a mean of and Ulaanbaatar (the site of Mongolia’s closure may delay the time to peak about 1% when the modelled stock- sole international airport) via high rates case-load by several weeks, as well as pile was increased from 50 000 doses of simultaneous importation of the modestly reduce the attack rate. As to 500 000, the corresponding range virus. The particularly severe winter of sociological studies indicate that up in the expected attack rates was much 2009–2010 is suspected to have affected to half of a person’s daily contacts can greater than this mean reduction, the pandemic in Mongolia. Our neglect typically be named by that person,23 it which suggests that the specific nature of seasonal and other secondary effects, may also often be possible to trace and of the epidemic has a larger impact on such as age-dependency in immune quarantine sufficient case contacts to the outcome of antiviral usage than response and population mixing, and substantially reduce epidemic severity. the stockpile size (Appendix A). Anti- perhaps our failure to consider all the The tracing of contacts of the very early viral drug use, as an isolated measure, interventions used, limited our ability cases, which usually occur before the appeared relatively more effective in to fit the modelled data to the detailed threat of a pandemic has been realized, the severe pandemic scenario, where shape of the actual epidemic curve seen is, however, often difficult. One limita- the presenting proportion is generally in the 2009 pandemic (Fig. 1). tion of this study is that no allowance higher than in the moderate pandemic In models involving a range of was made for virus transmission at the scenario. In both of these scenarios, possible nationwide mitigation strate- household level, which may be boosted however, a suite of non-pharmaceutical gies in moderate- and severe-pandemic when social distancing measures and interventions had a slightly greater scenarios, mean reductions in the at- quarantining are implemented. The average impact on the attack rate and tack rate of up to 2%, reductions in the apparent benefits of such measures peak ILI incidence than antiviral drug peak ILI reporting rate of up to 25%, may therefore have been somewhat use as a single intervention (Fig. 3). and delays to epidemic peak of over overestimated.

268 Bull World Health Organ 2012;90:264–271 | doi:10.2471/BLT.11.093419 Research KJ Bolton et al. Mitigating influenza transmission in Mongolia

The widespread prophylactic use border crossings, such as Dornogovi, Acknowledgements of antiviral drugs has more mitigation or international travel hubs, such as The authors thank medical personnel potential than case treatment alone.12,24 Ulaanbaatar, is crucial. Containment in the Mongolian influenza sentinel Diagnostic and delivery capabilities are, in regions contributing significantly to surveillance sites for collecting mor- however, crucial in determining the border crossings, together with the rou- bidity and mortality data and samples effectiveness of an antiviral campaign. tine international sharing of surveillance for virological examination, and the The effectiveness of prophylaxis early in data as recommended by WHO,1 should Centers for Disease Control and Preven- an epidemic is limited by the capacity to also enhance within-country mitigation tion (Atlanta, USA) for the technical distinguish seasonal and epidemic/pan- capabilities. and financial support of the National demic ILI cases, which typically requires The model used in this study was Influenza Centre in Mongolia, through expensive high-specificity diagnostic tailored to the ecology of Mongolia the US/Mongolia Cooperative Agree- testing based on polymerase chain during the 2009 pandemic. Climatic, ment (projects U50/CCU024411 and reactions. Even without considering demographic and infrastructural con- IU51IP000331). The staff of the National this limitation, the present modelling ditions will influence population dis- Emergency Management Agency kindly indicates that the timely implementation tribution, mixing characteristics and provided support during fieldwork in of a combination of non-pharmaceutical inter-provincial travel. For example, the Mongolia in July 2010. interventions would be at least as effec- higher propensity to travel in summer tive as the distribution of an antiviral owing to the traditional nomadic life- Funding: This paper reports on work drug. Given that even developed coun- style of many Mongolians may result in commissioned by the Avian and Hu- tries struggled to use antiviral drugs to more rapid spatial spread for an out-of- man Influenza Control, Preparedness achieve a significant mitigating impact season influenza epidemic than for the and Response Project, National Emer- on pandemic influenza in 2009,25 the use pandemic in the winter of 2009–2010. gency Management Agency, Mongolia, of non-pharmaceutical interventions – Infrastructural evolution driven by the sponsored by The World Bank. Authors instead of, or in combination with, anti- mining boom – such as the new rail received support from a University of viral distribution – is to be encouraged, and road networks linking Mongolia Melbourne McKenzie Fellowship (KJB) especially in resource-poor settings. with the Russian Federation and bor- and a National Health and Medical Timeliness is key to the success of der areas of China – may also alter the Research Council Career Development any within-country intervention strate- characteristic mixing between provinces Award (JM). gy. Effective intervention measures need and population clustering. Pandemic to be triggered by early case detection planning policy, even in a given coun- Competing interests: None declared. provided by nationwide surveillance try, needs to be regularly reassessed to systems with regular case reporting. ensure that it is relevant to the current Monitoring cases in areas containing sociobehavioural conditions. ■

ملخص الفعالية املحتملة للتدخالت الدوائية وغري الدوائية لتخفيف انتقال فريوس األنفلونزا يف منغوليا الغرضتقييم الفائدة املحتملة للتدخالت التي يتم دراسة متوسط معدل اهلجوم من حوايل 10 % إىل 7-8 %. وعىل نحو استخدامها يف منغوليا أثناء جائحات األنفلونزا يف املستقبل. مشابه، يف سيناريو جائحة حادة، خفضت هذه اإلجراءات متوسط الطريقة تم بناء نموذج رقعة مقسمة ذي تسلسل عشوائي معدل اهلجوم من 23 % إىل 21 % ًتقريبا. ويف كل من سيناريو للحساسية والتعرض والعدوى والشفاء اللتقاط التأثريات اجلائحة املعتدلة واحلادة، أثبتت جمموعة التدخالت غري الدوائية الرئيسية للتدخالت املتعددة عىل ديناميكيات وباء األنفلونزا، مثل فعالية متاثل فعالية االستخدام املستهدف للمضادات الفريوسية. فرض قيود عىل السفر، وإغالق املدارس، واملباعدة املعممة بني وبشكل عام، اتضح أن محالت مضادات الفريوسات املستهدفة الناس، فرض احلجر الصحي عىل األشخاص الذين يتم االتصال أكثر فعالية يف سيناريوهات اجلائحة احلادة عنها يف سيناريوهات هبم عن كثب، وعالج احلاالت باستخدام املضادات الفريوسية، اجلائحة املعتدلة. ووقاية األشخاص الذين يتم االتصال هبم عن كثب. وتم تقييم أشار االستنتاجنموذج حسايب النتقال األنفلونزا اجلائحة يف الفائدة املحتملة والتوقيت األمثل لكل من هذه التدخالت ومدته منغوليا إىل أن حتقيق النجاح يستلزم إحداث تدخالت ملنع االنتقال باستخدام تقنيات عينات املكعبات الالتينية الزائدة وحساب عند اكتشاف احلاالت األوىل يف املناطق احلدودية. ويف حالة اللجوء متوسط العديد من متثابتات االنتقال واالختالط االجتامعي إىل إجراءات املباعدة بني الناس يف هذه املرحلة وتنفيذها عىل املحتملة. مدار عدة أسابيع، ربام حتقق ًتأثريا ًختفيفيا ً ا.ملحوظ ويف األقاليم النتائجأدت التدخالت يف الوقت املناسب إىل ختفيض الفرتة منخفضة الدخل مثل منغوليا، قد تكون املباعدة بني الناس أكثر الزمنية لألنفلونزا اجلائحة وحدهتا يف منغوليا. ويف سيناريو جائحة فعالية من االستخدام واسع النطاق ملضادات الفريوسات. معتدلة، أدت اإلجراءات املبكرة للمباعدة بني الناس إىل خفض

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摘要 药物和非药物干预缓解蒙古流感病毒传播的可能效果 目的 评估考虑在未来流感大流行期间在蒙古实施的干预 行情况下,这种方法可以将平均发病率从大约 23% 降低至 的可能益处。 21%。在中度和严重流行情况下,一系列非药物干预已证 方法 构建敏感性、暴露、感染和复原的随机、区划补丁模 明具有和使用针对性抗病毒药一样的效果。针对性抗病 型捕捉多个干预(旅行限制、学校关闭、广义的社会疏远、 毒药活动在严重流行情况下的效果一般会比中度流行情 密切接触者隔离、抗病毒药病例治疗和预防接触)对流行感 况下的效果好。 冒力度的关键作用。使用拉丁超立方体采样技术,求出多个 结论 蒙古大流行性流感传播的数学模型表明,要想成功,需 可能的传播和社会混合参数平均值,评估每个干预的可能益 要在边境地区检测到首个病例时触发防止传播的干预措 处、最佳时间和持续时间。 施。如果在此阶段采用社会疏远方法并且持续多个星期, 结果 及时干预可能显著降低蒙古大流行性流感的时间进 则具有显著的缓解作用。在低收入地区,如蒙古,社会疏远 程和严重性。在中度流行情况下,早期社会疏远方法可以 方法比大规模使用抗病毒药物更有效。 将平均发病率从约 10% 降低至 7–8%。同样,在严重流

Résumé Efficacité probable des interventions pharmaceutiques et non pharmaceutiques pour la réduction de la transmission du virus de la grippe en Mongolie Objectif Évaluer le bénéfice probable des interventions à l’étude pour d’environ 10% à 7-8%. De même, en cas de scénario pandémique une utilisation en Mongolie lors des pandémies de grippes à venir. grave, de telles mesures diminuent le taux d’attaque moyen d’environ Méthodes Un modèle patch stochastique et compartimenté de la 23% à 21%. En cas de scénario pandémique tant grave que modéré, susceptibilité, de l’exposition, de l’infection et du rétablissement a été une série d’interventions non pharmaceutiques se sont révélées aussi établi afin d’appréhender les effets clés de plusieurs interventions – efficaces qu’une utilisation ciblée d’antiviraux. Les campagnes ciblées restrictions de déplacement, fermeture d’école, éloignement social sur les antiviraux se révèlent généralement plus efficaces en cas de généralisé, mise en quarantaine des proches contacts, traitement scénario pandémique grave qu’en cas de scénario pandémique modéré. des contacts par antiviraux et prophylaxies – sur les dynamiques des Conclusion Un modèle mathématique de la transmission de la épidémies de grippe. Le bénéfice probable ainsi que le moment et la grippe pandémique en Mongolie indique que, pour être efficaces, les durée optimaux de chacune de ces interventions ont été évalués au interventions visant à prévenir la transmission doivent être déclenchées moyen de techniques d’échantillonnage latin hypercube, en calculant dès la détection des premiers cas dans les régions frontalières. Si la moyenne de nombreux paramètres de transmission possible et de des mesures d’éloignement social sont introduites à ce stade-là et mixité sociale. appliquées durant plusieurs semaines, leur impact réductionnel pourra Résultats Les interventions effectuées à temps ont permis de réduire être significatif. Dans des régions à faible revenu telles que la Mongolie, significativement la progression et la gravité de la grippe pandémique l’éloignement social peut être plus efficace qu’une consommation en Mongolie. En cas de scénario pandémique modéré, des mesures d’antiviraux à grande échelle. précoces d’éloignement social ont diminué le taux d’attaque moyen

Резюме Предполагаемая эффективность фармацевтических и нефармацевтических мер по уменьшению распространения вируса гриппа в Монголии Цель Оценить предполагаемую эффективность и пользу гриппа в Монголии. В сценарии умеренной пандемии ранние рассматриваемых в Монголии мер, направленных на борьбу с меры по увеличению социальных расстояний снизили будущими пандемиями гриппа. среднюю интенсивность распространения с 10% до 7–8%. Методы Для получения основных результатов, демонстрирующих Подобным образом в сценарии сильной пандемии аналогичные влияние на динамику распространения пандемии гриппа меры снизили среднюю интенсивность распространения определенных мер, таких как ограничение поездок, закрытие приблизительно с 23% до 21%. В обоих сценариях – с умеренной школ, общее социальное дистанцирование, введение и сильной пандемией – комплекс нефармацевтических мер карантина для тесно контактирующих людей, лечение больных позволил достичь такой же эффективности, как и направленное противовирусными препаратам и профилактика контактов, была использование противовирусных средств. В сценариях с создана стохастическая блоковая модель восприимчивости, сильной пандемией направленные противовирусные кампании контактов с источником заражения, инфицирования и продемонстрировали более высокую эффективность по восстановления. Предполагаемые выгоды, а также оптимальные сравнению со сценариями с умеренной пандемией. сроки и продолжительность каждой из этих мер были оценены Вывод Математическая модель передачи вируса гриппа с использованием метода выборочного контроля «латинский в Монголии продемонстрировала, что для достижения гиперкуб», который позволяет вывести средние значения, успешных результатов применения мер по предотвращению основываясь на многих возможных путях передачи вируса и распространения вируса, необходимо задействовать эти параметрах взаимодействий в обществе. меры при обнаружении первых случаев обнаружения Результаты Своевременное принятие мер может существенно вируса в пограничных регионах. Если меры по социальному сократить продолжительность и интенсивность пандемии дистанцированию будут применены на этом этапе на протяжении

270 Bull World Health Organ 2012;90:264–271 | doi:10.2471/BLT.11.093419 Research KJ Bolton et al. Mitigating influenza transmission in Mongolia

нескольких недель, они могут в значительной степени уменьшить более эффективным, чем полномасштабное использование распространение вируса. В регионах с низким уровнем доходов, противовирусных препаратов. таких как Монголия, социальное дистанцирование может быть

Resumen Eficacia posible de las intervenciones farmacéuticas y no farmacéuticas con objeto de mitigar la transmisión del virus de la gripe en Mongolia Objetivo Evaluar la eficacia posible de las intervenciones que están tempranas de distanciamiento social disminuyeron la tasa de ataque siendo estudiadas para ser aplicadas en Mongolia durante pandemias de aproximadamente el 10% al 7-8%. De igual modo, en una hipótesis de gripe futuras. de pandemia grave, dichas medidas reducen la tasa media de ataque Métodos Se construyó un modelo de parche estocástico y de aproximadamente el 23% al 21%. En ambas hipótesis de pandemia, compartimental de susceptibilidad, exposición, infección y recuperación tanto moderada como grave, las intervenciones no farmacéuticas para detectar los efectos clave de varias intervenciones (restricciones de demostraron ser tan efectivas como el uso focalizado de antivirales. Las viaje, cierre de colegios, distanciamiento social generalizado, cuarentena campañas antivirales focalizadas parecieron por lo general más efectivas de contactos cercanos, tratamiento de casos con antivirales y profilaxis para las hipótesis de pandemia graves que para las hipótesis moderadas. de los contactos) sobre la dinámica de las epidemias de gripe. Se evaluó Conclusión Un modelo matemático de transmisión de gripe pandémica el beneficio posible, así como la coordinación óptima y la duración de en Mongolia indicó que, para que tengan éxito, las intervenciones cada una de dichas intervenciones por medio de métodos de muestreo para prevenir la transmisión deben ponerse en marcha en cuanto se por hipercubo latino realizando un cálculo a través de numerosos detecten los primeros casos en regiones fronterizas. Las medidas de parámetros posibles de transmisión y mezcla social. distanciamiento social podrían tener un impacto de mitigación notable Resultados Las intervenciones oportunas pudieron reducir de si se introducen en esta fase y se aplican durante varias semanas En las manera considerable la evolución y gravedad de la gripe pandémica regiones de ingresos bajos como Mongolia, el distanciamiento social en Mongolia. En una hipótesis de pandemia moderada, las medidas podría ser más eficaz que el uso de antivirales a gran escala.

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