Synthesizing data and models for the spread of MERS-CoV, 2013: Key role of index cases and hospital transmission

Abstract The outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) has caused 209 deaths and 699 laboratory-confirmed cases in the Arabian Peninsula as of June 11, 2014. Preparedness efforts are hampered by considerable uncertainty about the nature and intensity of human-to-human transmission, with previous reproduction number estimates ranging from 0.4 to 1.5. Here we synthesize epidemiological data and transmission models for the MERS-CoV outbreak during April–October 2013 to resolve uncertainties in epidemic risk, while considering the impact of observation bias. We match the progression of MERS-CoV cases in 2013 to a dynamic transmission model that incorporates community and hospital compartments, and distinguishes transmission by zoonotic (index) cases and secondary cases. When observation bias is assumed to account for the fact that all reported zoonotic cases are severe, but only ∼57% of secondary cases are symptomatic, the average reproduction number of MERS-CoV is estimated to be 0.45 (95% CI:0.29–0.61). Alternatively, if these epidemiological observations are taken at face value, index cases are estimated to transmit substantially more effectively than secondary cases, (R i =0.84 (0.58-1.20) vs R s =0.36 (0.24–0.51)). In both scenarios the relative contribution of hospital-based transmission is over four times higher than that of community transmission, indicating that disease control should be focused on hospitalized patients. Adjusting previously published estimates for observation bias confirms a strong support for the average R <1 in the first stage of the outbreak in 2013 and thus, transmissibility of secondary cases of MERS-CoV remained well below the epidemic threshold. More information on the observation process is needed to clarify whether MERS-CoV is intrinsically weakly transmissible between people or whether existing control measures have contributed meaningfully to reducing the transmissibility of secondary cases. Our results could help evaluate the progression of MERS-CoV in recent months in response to changes in disease surveillance, control interventions, or viral adaptation.

[1]  R. Brookmeyer,et al.  Incubation periods of acute respiratory viral infections: a systematic review , 2009, The Lancet Infectious Diseases.

[2]  C. Fraser,et al.  Seroprevalence of IgG antibodies to SARS-coronavirus in asymptomatic or subclinical population groups , 2005, Epidemiology and Infection.

[3]  Marion P G Koopmans,et al.  Middle East respiratory syndrome coronavirus in dromedary camels: an outbreak investigation , 2013, The Lancet Infectious Diseases.

[4]  C P Farrington,et al.  Branching process models for surveillance of infectious diseases controlled by mass vaccination. , 2003, Biostatistics.

[5]  C. Fraser,et al.  Public Health Risk from the Avian H5N1 Influenza Epidemic , 2004, Science.

[6]  C. Fraser,et al.  Transmission Dynamics of the Etiological Agent of SARS in Hong Kong: Impact of Public Health Interventions , 2003, Science.

[7]  Heikki Haario,et al.  DRAM: Efficient adaptive MCMC , 2006, Stat. Comput..

[8]  A. Osterhaus,et al.  Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. , 2012, The New England journal of medicine.

[9]  Barney S. Graham,et al.  Major increase in human monkeypox incidence 30 years after smallpox vaccination campaigns cease in the Democratic Republic of Congo , 2010, Proceedings of the National Academy of Sciences.

[10]  Mark A. Miller,et al.  Transmission potential of influenza A/H7N9, February to May 2013, China , 2013, BMC Medicine.

[11]  J. Hyman,et al.  Estimation of the reproductive number of the Spanish flu epidemic in Geneva, Switzerland. , 2006, Vaccine.

[12]  James O. Lloyd-Smith,et al.  Inference of R 0 and Transmission Heterogeneity from the Size Distribution of Stuttering Chains , 2013, PLoS Comput. Biol..

[13]  Victor M Corman,et al.  Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study , 2013, The Lancet Infectious Diseases.

[14]  Stefanie Gierer,et al.  Lack of MERS Coronavirus Neutralizing Antibodies in Humans, Eastern Province, Saudi Arabia , 2013, Emerging infectious diseases.

[15]  Junya Fukuoka,et al.  Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore , 2003, Human Pathology.

[16]  C. Fraser,et al.  Epidemiological determinants of spread of causal agent of severe acute respiratory syndrome in Hong Kong , 2003, The Lancet.

[17]  Michael G. Katze,et al.  Middle East respiratory syndrome coronavirus (MERS-CoV) causes transient lower respiratory tract infection in rhesus macaques , 2013, Proceedings of the National Academy of Sciences.

[18]  Xilin Yang,et al.  SARS in Three Categories of Hospital Workers, Hong Kong , 2004, Emerging infectious diseases.

[19]  J. Lloyd-Smitha,et al.  Comparing methods for estimating R0 from the size distribution of subcritical transmission chains , 2013 .

[20]  A. J. Hall.  Infectious diseases of humans: R. M. Anderson & R. M. May. Oxford etc.: Oxford University Press, 1991. viii + 757 pp. Price £50. ISBN 0-19-854599-1 , 1992 .

[21]  U. Emirates.  b Middle East respiratory syndrome coronavirus (MERS-CoV): update , 2014 .

[22]  Frank Diederich,et al.  Mathematical Epidemiology Of Infectious Diseases Model Building Analysis And Interpretation , 2016 .

[23]  Leif Gustafsson,et al.  Bringing consistency to simulation of population models--Poisson simulation as a bridge between micro and macro simulation. , 2007, Mathematical biosciences.

[24]  Nathan D. Wolfe,et al.  Origins of major human infectious diseases , 2007, Nature.

[25]  D. Cummings,et al.  Hospital outbreak of Middle East respiratory syndrome coronavirus. , 2013, The New England journal of medicine.

[26]  A. Tavakoli,et al.  Middle East Respiratory Syndrome Coronavirus (MERS-CoV) , 2014, Krankenhaus-Hygiene + Infektionsverhütung.

[27]  Z. Memish,et al.  Taking stock of the first 133 MERS coronavirus cases globally--Is the epidemic changing? , 2013, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[28]  Z. Memish,et al.  Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study , 2013, The Lancet Infectious Diseases.

[29]  P. Tambyah,et al.  SARS: understanding the coronavirus , 2003, BMJ : British Medical Journal.

[30]  Peter Cameron,et al.  A major outbreak of severe acute respiratory syndrome in Hong Kong. , 2003, The New England journal of medicine.

[31]  Simon Cauchemez,et al.  Edinburgh Research Explorer Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility , 2022 .

[32]  M. E. Alexander,et al.  Modelling strategies for controlling SARS outbreaks , 2004, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[33]  Z. Memish,et al.  Investigation of Anti–Middle East Respiratory Syndrome Antibodies in Blood Donors and Slaughterhouse Workers in Jeddah and Makkah, Saudi Arabia, Fall 2012 , 2013, The Journal of infectious diseases.

[34]  S. Blumberg,et al.  Comparing methods for estimating R0 from the size distribution of subcritical transmission chains. , 2013, Epidemics.

[35]  Astrid Gall,et al.  Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study , 2013, The Lancet.

[36]  E. Galanis,et al.  Investigation of a nosocomial outbreak of severe acute respiratory syndrome (SARS) in Toronto, Canada. , 2003, CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne.

[37]  Julien Riou,et al.  Interhuman transmissibility of Middle East respiratory syndrome coronavirus: estimation of pandemic risk , 2013, The Lancet.

[38]  T. E. Harris,et al.  The Theory of Branching Processes. , 1963 .

[39]  P. Formenty,et al.  State of Knowledge and Data Gaps of Middle East Respiratory Syndrome Coronavirus (MERS-CoV) in Humans , 2013, PLoS currents.

[40]  S. Africa.,et al.  Close Relative of Human Middle East Respiratory Syndrome Coronavirus in Bat , 2013 .

[41]  J. Peiris,et al.  Effectiveness of precautions against droplets and contact in prevention of nosocomial transmission of severe acute respiratory syndrome (SARS) , 2003, The Lancet.

[42]  G. Chowell,et al.  SARS outbreaks in Ontario, Hong Kong and Singapore: the role of diagnosis and isolation as a control mechanism , 2003, Journal of Theoretical Biology.

[43]  J. A. Comer,et al.  A novel coronavirus associated with severe acute respiratory syndrome. , 2003, The New England journal of medicine.

[44]  James O. Lloyd-Smith,et al.  Epidemic Dynamics at the Human-Animal Interface , 2009, Science.

[45]  F. Fenner.  Smallpox and its eradication , 1988 .

[46]  Kenneth Lange,et al.  Applied Probability , 2003 .

[47]  Amit Kapoor,et al.  Middle East Respiratory Syndrome Coronavirus Infection in Dromedary Camels in Saudi Arabia , 2014, mBio.

[48]  Z. Memish,et al.  Screening for Middle East respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: a prospective descriptive study , 2014, Clinical Microbiology and Infection.

[49]  V. Corman,et al.  Close Relative of Human Middle East Respiratory Syndrome Coronavirus in Bat, South Africa , 2013, Emerging infectious diseases.

[50]  J. Hyman,et al.  Model Parameters and Outbreak Control for SARS , 2004, Emerging infectious diseases.

[51]  Y. Guan,et al.  MERS Coronaviruses in Dromedary Camels, Egypt , 2014, Emerging infectious diseases.

[52]  J. Robins,et al.  Transmission Dynamics and Control of Severe Acute Respiratory Syndrome , 2003, Science.