Unraveling the drivers of MERS-CoV transmission.

With more than 1,700 laboratory-confirmed infections, Middle East respiratory syndrome coronavirus (MERS-CoV) remains a significant threat for public health. However, the lack of detailed data on modes of transmission from the animal reservoir and between humans means that the drivers of MERS-CoV epidemics remain poorly characterized. Here, we develop a statistical framework to provide a comprehensive analysis of the transmission patterns underlying the 681 MERS-CoV cases detected in the Kingdom of Saudi Arabia (KSA) between January 2013 and July 2014. We assess how infections from the animal reservoir, the different levels of mixing, and heterogeneities in transmission have contributed to the buildup of MERS-CoV epidemics in KSA. We estimate that 12% [95% credible interval (CI): 9%, 15%] of cases were infected from the reservoir, the rest via human-to-human transmission in clusters (60%; CI: 57%, 63%), within (23%; CI: 20%, 27%), or between (5%; CI: 2%, 8%) regions. The reproduction number at the start of a cluster was 0.45 (CI: 0.33, 0.58) on average, but with large SD (0.53; CI: 0.35, 0.78). It was >1 in 12% (CI: 6%, 18%) of clusters but fell by approximately one-half (47% CI: 34%, 63%) its original value after 10 cases on average. The ongoing exposure of humans to MERS-CoV from the reservoir is of major concern, given the continued risk of substantial outbreaks in health care systems. The approach we present allows the study of infectious disease transmission when data linking cases to each other remain limited and uncertain.

Hospital outbreak of Middle East respiratory syndrome coronavirus.

BACKGROUND: In September 2012, the World Health Organization reported the first cases of pneumonia caused by the novel Middle East respiratory syndrome coronavirus (MERS-CoV). We describe a cluster of health care-acquired MERS-CoV infections. METHODS: Medical records were reviewed for clinical and demographic information and determination of potential contacts and exposures. Case patients and contacts were interviewed. The incubation period and serial interval (the time between the successive onset of symptoms in a chain of transmission) were estimated. Viral RNA was sequenced. RESULTS: Between April 1 and May 23, 2013, a total of 23 cases of MERS-CoV infection were reported in the eastern province of Saudi Arabia. Symptoms included fever in 20 patients (87%), cough in 20 (87%), shortness of breath in 11 (48%), and gastrointestinal symptoms in 8 (35%); 20 patients (87%) presented with abnormal chest radiographs. As of June 12, a total of 15 patients (65%) had died, 6 (26%) had recovered, and 2 (9%) remained hospitalized. The median incubation period was 5.2 days (95% confidence interval [CI], 1.9 to 14.7), and the serial interval was 7.6 days (95% CI, 2.5 to 23.1). A total of 21 of the 23 cases were acquired by person-to-person transmission in hemodialysis units, intensive care units, or in-patient units in three different health care facilities. Sequencing data from four isolates revealed a single monophyletic clade. Among 217 household contacts and more than 200 health care worker contacts whom we identified, MERS-CoV infection developed in 5 family members (3 with laboratory-confirmed cases) and in 2 health care workers (both with laboratory-confirmed cases). CONCLUSIONS: Person-to-person transmission of MERS-CoV can occur in health care settings and may be associated with considerable morbidity. Surveillance and infection-control measures are critical to a global public health response.

Hajj: infectious disease surveillance and control.

Religious festivals attract a large number of pilgrims from worldwide and are a potential risk for the transmission of infectious diseases between pilgrims, and to the indigenous population. The gathering of a large number of pilgrims could compromise the health system of the host country. The threat to global health security posed by infectious diseases with epidemic potential shows the importance of advanced planning of public health surveillance and response at these religious events. Saudi Arabia has extensive experience of providing health care at mass gatherings acquired through decades of managing millions of pilgrims at the Hajj. In this report, we describe the extensive public health planning, surveillance systems used to monitor public health risks, and health services provided and accessed during Hajj 2012 and Hajj 2013 that together attracted more than 5 million pilgrims from 184 countries. We also describe the recent establishment of the Global Center for Mass Gathering Medicine, a Saudi Government partnership with the WHO Collaborating Centre for Mass Gatherings Medicine, Gulf Co-operation Council states, UK universities, and public health institutions globally.

Prevalence of MERS-CoV nasal carriage and compliance with the Saudi health recommendations among pilgrims attending the 2013 Hajj.

BACKGROUND: Annually, Saudi Arabia is the host of the Hajj mass gathering. We aimed to determine the Middle East respiratory syndrome coronavirus (MERS-CoV) nasal carriage rate among pilgrims performing the 2013 Hajj and to describe the compliance with the Saudi Ministry of Health vaccine recommendations. METHOD: Nasopharyngeal samples were collected from 5235 adult pilgrims from 22 countries and screened for MERS-CoV using reverse transcriptase-polymerase chain reaction. Information regarding the participants' age, gender, country of origin, medical conditions, and vaccination history were obtained. RESULTS: The mean age of the screened population was 51.8 years (range, 18-93 years) with a male/female ratio of 1.17:1. MERS-CoV was not detected in any of the samples tested (3210 pre-Hajj and 2025 post-Hajj screening). According to the vaccination documents, all participants had received meningococcal vaccination and the majority of those from at-risk countries were vaccinated against yellow fever and polio. Only 22% of the pilgrims (17.5% of those ≥65 years and 36.3% of diabetics) had flu vaccination, and 4.4% had pneumococcal vaccination. CONCLUSION: There was no evidence of MERS-CoV nasal carriage among Hajj pilgrims. While rates of compulsory vaccinations uptake were high, uptake of pneumococcal and flu seasonal vaccinations were low, including among the high-risk population.

Transmission and evolution of the Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive genomic study.

BACKGROUND: Since June, 2012, Middle East respiratory syndrome coronavirus (MERS-CoV) has, worldwide, caused 104 infections in people including 49 deaths, with 82 cases and 41 deaths reported from Saudi Arabia. In addition to confirming diagnosis, we generated the MERS-CoV genomic sequences obtained directly from patient samples to provide important information on MERS-CoV transmission, evolution, and origin. METHODS: Full genome deep sequencing was done on nucleic acid extracted directly from PCR-confirmed clinical samples. Viral genomes were obtained from 21 MERS cases of which 13 had 100%, four 85-95%, and four 30-50% genome coverage. Phylogenetic analysis of the 21 sequences, combined with nine published MERS-CoV genomes, was done. FINDINGS: Three distinct MERS-CoV genotypes were identified in Riyadh. Phylogeographic analyses suggest the MERS-CoV zoonotic reservoir is geographically disperse. Selection analysis of the MERS-CoV genomes reveals the expected accumulation of genetic diversity including changes in the S protein. The genetic diversity in the Al-Hasa cluster suggests that the hospital outbreak might have had more than one virus introduction. INTERPRETATION: We present the largest number of MERS-CoV genomes (21) described so far. MERS-CoV full genome sequences provide greater detail in tracking transmission. Multiple introductions of MERS-CoV are identified and suggest lower R0 values. Transmission within Saudi Arabia is consistent with either movement of an animal reservoir, animal products, or movement of infected people. Further definition of the exposures responsible for the sporadic introductions of MERS-CoV into human populations is urgently needed. FUNDING: Saudi Arabian Ministry of Health, Wellcome Trust, European Community, and National Institute of Health Research University College London Hospitals Biomedical Research Centre.

Middle East respiratory syndrome coronavirus in bats, Saudi Arabia.

The source of human infection with Middle East respiratory syndrome coronavirus remains unknown. Molecular investigation indicated that bats in Saudi Arabia are infected with several alphacoronaviruses and betacoronaviruses. Virus from 1 bat showed 100% nucleotide identity to virus from the human index case-patient. Bats might play a role in human infection.

Seroprevalence of Alkhurma and other hemorrhagic fever viruses, Saudi Arabia.

A 2009 deployment of military units from several Saudi Arabian provinces to Jazan Province, Saudi Arabia, enabled us to evaluate exposure to Alkhurma, Crimean-Congo, dengue, and Rift Valley hemorrhagic fever viruses. Seroprevalence to all viruses was low; however, Alkhurma virus seroprevalence was higher (1.3%) and less geographically restricted than previously thought.

Meningococcal disease during the Hajj and Umrah mass gatherings.

The Hajj and Umrah religious mass gatherings hosted by the Kingdom of Saudi Arabia can facilitate the transmission of infectious diseases. The pilgrimages have been associated with a number of local and international outbreaks of meningococcal disease. These include serogroup A disease outbreaks in 1987 and throughout the 1990s and two international serogroup W135 outbreaks in 2000 and 2001. The implementation of strict preventative measures including mandatory quadrivalent meningococcal vaccination and antibiotic chemoprophylaxis for pilgrims from the African meningitis belt has prevented pilgrimage-associated meningococcal outbreaks since 2001. However, the fluid epidemiology of the disease and the possibility of outbreaks caused by serogroups not covered by the vaccine or emerging hyper-virulent strains, mean that the disease remains a serious public health threat during these events. Continuous surveillance of carriage state and the epidemiology of the disease in the Kingdom and globally and the introduction of preventative measures that provide broad and long-lasting immunity and impact carriage are warranted.

Prevention of meningococcal disease during the Hajj and Umrah mass gatherings: past and current measures and future prospects.

The Kingdom of Saudi Arabia (KSA) has a long history of instituting preventative measures against meningococcal disease (MD). KSA is at risk of outbreaks of MD due to its geographic location, demography, and especially because it hosts the annual Hajj and Umrah mass gatherings. Preventative measures for Hajj and Umrah include vaccination, targeted chemoprophylaxis, health awareness and educational campaigns, as well as an active disease surveillance and response system. Preventative measures have been introduced and updated in accordance with changes in the epidemiology of MD and available preventative tools. The mandatory meningococcal vaccination policy for pilgrims has possibly been the major factor in preventing outbreaks during the pilgrimages. The policy of chemoprophylaxis for all pilgrims arriving from the African meningitis belt has also probably been important in reducing the carriage and transmission of Neisseria meningitidis in KSA and beyond. The preventative measures for Hajj and Umrah are likely to continue to focus on vaccination, but to favour the conjugate vaccine for its extra benefits over the polysaccharide vaccines. Additionally, the surveillance system will continue to be strengthened to ensure early detection and response to cases and outbreaks; ongoing disease awareness campaigns for pilgrims will continue, as will chemoprophylaxis for target groups. Local and worldwide surveillance of the disease and drug-resistant N. meningitidis are crucial in informing future recommendations for vaccination, chemoprophylaxis, and treatment. Preventative measures should be reviewed regularly and updated accordingly, and compliance with these measures should be monitored and enhanced to prevent MD during Hajj and Umrah, as well as local and international outbreaks.

Secular trend and epidemiology of measles in the Kingdom of Saudi Arabia: 2009-2012.

PURPOSE: To determine incidence of measles and progress towards its elimination in Saudi Arabia. METHODS: A retrospective analysis of routinely collected active and passive surveillance data on measles at the Ministry of Health, Saudi Arabia. All laboratory confirmed measles from (2009-2012) were analyzed to determine measles annual incidences and distribution by age, gender, nationality, seasonality, vaccination status and spatial distribution by region. RESULTS: Measles incidence per 1,000,000 populations increased from 3.2 in 2009 to a peak of 12.8in 2011 and a slight fall to 9.9 in 2012. About 50% of cases were in children under-five years, 12% were infants and 33% were 15 years and above. Of the total, 39%were unvaccinated and16% had unknown vaccination status. Fifty-five percent of infants were not due for vaccination. Of children <5 years, 42% received vaccination. Spatial distribution is not countrywide in each of the four years but seemed to concentrate in the central and South West regions with40% in Jizan and Jeddah. CONCLUSION: High incidence of confirmed measles among unvaccinated infants requires strengthening of the immunization services. Improvement in measles case surveillance for completeness of vaccination status, vaccination of unvaccinated youths and comprehensive immunization are needed for measles elimination.

Middle East respiratory syndrome coronavirus (MERS-CoV): A cluster analysis with implications for global management of suspected cases.

Since the initial description of the Middle East respiratory syndrome (MERS) in September 2012, a total of 1038 cases of MERS-CoV including 460 deaths have been reported from Saudi Arabia. From August 24, 2013 to September 3, 2013, a total of 397 patients and contacts were tested for MERS-CoV. Of those tested, there were 18 (4.5%) MERS-CoV cases reported in Al-Madinah al-Munawwarah with one large cluster. In this report, we describe the outcome, epidemiology and clinical characteristics of this cluster of which 4 cases involved healthcare workers. Fourteen cases appeared to be linked to one cluster involving healthcare workers (HCWs), family and patient contacts. Of the 18 cases, five (including 2 HCWs) were community acquired, two were household contacts, and 11 were healthcare associated (including 4 HCWs). All except 4 cases were symptomatic and the case fatality rate was 39% (7 of 18). The outbreak resulted in human to human transmission of an estimated 6 cases. Contact screening showed positive test in 1 of 56 (1.8%) household contacts, and 3 of 250 (1.2%) HCWs.

Toward malaria eradication in Saudi Arabia: evidence from 4-year surveillance in Makkah.

BACKGROUND AND OBJECTIVES: Saudi Arabia has implemented strategies for the eradication of malaria. However, influx of people from countries endemic for malaria for either employment or Hajj makes the country highly susceptible to malaria importation. The Makkah region is known to host millions of immigrants yearly and has a surveillance system to monitor the incidence of malaria. The objective of this study was to examine malaria patients, nationality, and parasite type in Makkah region between 2008 and 2011. DESIGN AND SETTINGS: A retrospective analysis of all reported malaria cases from 19 sentinel sites in Makkah region, Saudi Arabia, for the period between 2008 and 2011. METHODS: Analysis of surveillance data were analyzed using SPSS software, version 15.0 (SPSS Inc, Chicago). RESULTS: A total of 318 malaria cases were reported in these 4 years, of which only 3.6% of cases were less than 10 years of age, including 2 cases below 5 years. Non-Saudis were 95% and Pakistanis, Nigerians, and Indians accounted for 62.0%. Plasmodium falciparum (67%). Plasmodium vivax (32%) and Plasmodium ovale (1.6%) were the notable parasites. CONCLUSION: The low frequency of malaria in Makkah suggests that Saudi Arabia is in the consolidation phase of malaria eradication. The absence of local transmission of malaria is indicated by low frequency of malaria in children less than 5 years of age, and high frequency of malaria in non-Saudis is evidence of malaria importation. Health workers attending to foreigners with febrile illness from Pakistan, Nigeria, and India should consider malaria as their first line of suspicion.

Is the epidemiology of alkhurma hemorrhagic fever changing?: A three-year overview in Saudi Arabia.

BACKGROUND: The epidemiology of Alkhurma hemorrhagic fever disease is yet to be fully understood since the virus was isolated in 1994 in the Kingdom of Saudi Arabia. SETTING: Preventive Medicine department, Ministry of Health, Kingdom of Saudi Arabia. DESIGN: Retrospective analysis of all laboratory confirmed cases of Alkhurma hemorrhagic fever disease collected through active and passive surveillance from 1(st)-January 2009 to December, 31, 2011. RESULTS: Alkhurma hemorrhagic fever (AHFV) disease increased from 59 cases in 2009 to 93 cases in 2011. Cases are being discovered outside of the region where it was initially diagnosed in Saudi Arabia. About a third of cases had no direct contact with animals or its products. Almost all cases had gastro-intestinal symptoms. Case fatality rate was less than 1%. CONCLUSIONS: Findings in this study showed the mode of transmission of AHFV virus may not be limited to direct contact with animals or its products. Gastro-intestinal symptoms were not previously documented. Observed low case fatality rate contradicted earlier reports. Close monitoring of the epidemiology of AHFV is recommended to aid appropriate diagnosis. Housewives are advised to wear gloves when handling animals and animal products as a preventive measure.

Community case clusters of Middle East respiratory syndrome coronavirus in Hafr Al-Batin, Kingdom of Saudi Arabia: a descriptive genomic study.

The Middle East respiratory syndrome coronavirus (MERS-CoV) was first described in September 2012 and to date 86 deaths from a total of 206 cases of MERS-CoV infection have been reported to the WHO. Camels have been implicated as the reservoir of MERS-CoV, but the exact source and mode of transmission for most patients remain unknown. During a 3 month period, June to August 2013, there were 12 positive MERS-CoV cases reported from the Hafr Al-Batin region district in the north east region of the Kingdom of Saudi Arabia. In addition to the different regional camel festivals in neighboring countries, Hafr Al-Batin has the biggest camel market in the entire Kingdom and hosts an annual camel festival. Thus, we conducted a detailed epidemiological, clinical and genomic study to ascertain common exposure and transmission patterns of all cases of MERS-CoV reported from Hafr Al-Batin. Analysis of previously reported genetic data indicated that at least two of the infected contacts could not have been directly infected from the index patient and alternate source should be considered. While camels appear as the likely source, other sources have not been ruled out. More detailed case control studies with detailed case histories, epidemiological information and genomic analysis are being conducted to delineate the missing pieces in the transmission dynamics of MERS-CoV outbreak.

Middle East respiratory syndrome coronavirus disease in children.

BACKGROUND: In the initial description of Middle East respiratory syndrome coronavirus (MERS-CoV) infection, many affected patients were adults with underlying medical comorbidities. Data on the clinical presentation and outcome of pediatric cases are lacking. We report the clinical presentation and outcome of MERS-CoV infection in 11 pediatric patients. METHODS: The clinical presentation, demographic and laboratory data of pediatric patients with MERS-CoV were analyzed. RESULTS: A total of 11 pediatric cases that tested positive by screening and confirmatory polymerase chain reaction for MERS-CoV were reported from Saudi Arabia. Two patients were symptomatic and the other 9 cases were asymptomatic. The median age of patients was 13 (range 2-16) years. There were 8 females and 3 males (2.7:1 ratio). One symptomatic patient died and the other symptomatic patient recovered. The diagnosis of patients was based on positive nasopharyngeal swabs on 10 patients. CONCLUSIONS: MERS-CoV disease is not limited to adults. Most cases of childhood MERS-CoV infection were asymptomatic and tested positive during contact investigation of older patients. Severe disease can occur in children with underlying conditions.

Spread, circulation, and evolution of the Middle East respiratory syndrome coronavirus.

UNLABELLED: The Middle East respiratory syndrome coronavirus (MERS-CoV) was first documented in the Kingdom of Saudi Arabia (KSA) in 2012 and, to date, has been identified in 180 cases with 43% mortality. In this study, we have determined the MERS-CoV evolutionary rate, documented genetic variants of the virus and their distribution throughout the Arabian peninsula, and identified the genome positions under positive selection, important features for monitoring adaptation of MERS-CoV to human transmission and for identifying the source of infections. Respiratory samples from confirmed KSA MERS cases from May to September 2013 were subjected to whole-genome deep sequencing, and 32 complete or partial sequences (20 were ≥ 99% complete, 7 were 50 to 94% complete, and 5 were 27 to 50% complete) were obtained, bringing the total available MERS-CoV genomic sequences to 65. An evolutionary rate of 1.12 × 10(-3) substitutions per site per year (95% credible interval [95% CI], 8.76 × 10(-4); 1.37 × 10(-3)) was estimated, bringing the time to most recent common ancestor to March 2012 (95% CI, December 2011; June 2012). Only one MERS-CoV codon, spike 1020, located in a domain required for cell entry, is under strong positive selection. Four KSA MERS-CoV phylogenetic clades were found, with 3 clades apparently no longer contributing to current cases. The size of the population infected with MERS-CoV showed a gradual increase to June 2013, followed by a decline, possibly due to increased surveillance and infection control measures combined with a basic reproduction number (R0) for the virus that is less than 1. IMPORTANCE: MERS-CoV adaptation toward higher rates of sustained human-to-human transmission appears not to have occurred yet. While MERS-CoV transmission currently appears weak, careful monitoring of changes in MERS-CoV genomes and of the MERS epidemic should be maintained. The observation of phylogenetically related MERS-CoV in geographically diverse locations must be taken into account in efforts to identify the animal source and transmission of the virus.