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One hundred fifty five patients out of the total 1797 confirmed cases (8.6%), reported their exposure to animals, of which, 130 out of 155 cases (83.9%) were exposed to camels, while 25 out of 155 (16.1%) stated exposure to other animals including sheep, cows and poultry (Table 2). Despite the fact that 674 out of 1797 MERS-CoV cases (37.5%) were health care-associated infections and 284 out of 1797 cases (15.8%) involved contact with an infected family member, 147 cases (8.2%) were still reported with no exposure to any of the above. The exposure data were found missing for the remaining 537 (29.9%) patients.
The most frequent comorbidities among the patients were diabetes (58.33%), hypertension (37.50%), and chronic kidney disease (16.66%) (Table 2). A few number of patients suffered from coronary artery disease, liver disease, asthma, peripheral vascular disease, and cancer. Fever (50.00%), sore throat (41.67%), chills (41.67%), cough (37.50%), and runny nose (25.00%) were the most frequent presenting symptoms. Within the 2 weeks prior to hospital admission, one patient had contact with camels or their products, while 11 (45.83%) were exposed to a MERS case (Table 2). Three patients (12.5%) were hospitalized within the previous 2 weeks, two (8.33%) had acute respiratory distress syndrome, and four had H1N1 influenza. The length of hospital stay varied significantly, ranging from 1 to 31 days, with a mean of 4.96 ± 7.29 days. Two of the 24 patients died, and 22 were discharged (Table 2).
All but six patients were admitted to the hospital due to flu-like symptoms (Table 3). The remaining six patients were admitted for septic arthritis, abdominal pain and dysuria, black discoloration of toes, bleeding during pregnancy, and hyponatremia, which are not typically associated with the MERS-CoV infection. Patients presenting with flu-like symptoms were diagnosed with MERS on the day of admission, while in the other instances the time from admission to the diagnosis of MERS varied from 1 day (abdominal pain and dysuria, bleeding during pregnancy) to 6 days (black discoloration of toes) as shown in Table 3. Notably, 14 patients (58.3%) were discharged home within 24 hrs of their diagnosis.
The distributions of MERS-CoV infections among 6 Gulf countries are illustrated in Table 3 and Fig 1B. The majority of MERS-CoV infections (93%) reported between the time period from June 2012 to July 2016, were from Saudi Arabia. While, the remaining 5 GCC countries contributed only 7% of the cases with the distributions as follows: United Arab Emirates (5.0%), Qatar (1.0%), Oman (0.5%), Kuwait (0.2%) and Bahrain (0.06%). Gender analysis shown in Table 3 reveals that 60% of the patients were male and 31% were female. Moreover, age-specific risk distributions of MERS-CoV showed a positive correlation between the incidence and the age. Regarding cases reported from Saudi Arabia, 2% occurred in age group ≤20 yrs while 25% cases were observed in patients aged 20–39 yrs. The highest risk age group was 40 yrs and above. Together, they represent 65% of all cases reported from Saudi Arabia.
We first analyzed the correlation between ILIs infections and age. The frequency of infections varied markedly between different age groups. The highest rate of influenza A viruses was observed among patients aged between 31 and 40 years, with a frequency of 19.9%. Influenza B virus was more detected among 15–30 years age group, reaching to 6.1% positive cases. To the contrary, individuals aged above 50 years had significantly lower infection rates with both influenza A (13.9%) and B (4.2%) types. Nonetheless, this age group demonstrated significantly elevated infections with RSV, HMPV, HboV, and HPIV-3 (3.4%, 3.3%, 0.8%, and 1.7% respectively), compared to younger age groups. HCoVs rates correlated variably with the age. Both 229E and HKU1 CoVs were more detected among 31 to 40 years age group, with a frequency of 1.7% and 1.2% respectively. Conversely, NL63 CoV was more commonly detected in younger individuals (15–30 age group), accounting for 0.9% infection rate. MERS CoV showed similar prevalence in both, individuals aged between 15 to 40 years and those above 50 years old (0.1%). On the other hand, OC43 CoV infection was comparable among different age groups with no significant differences (1.7–2%). Infection with HRVs, M. pneumoniae and adenoviruses inversely correlated with age, with the highest rate detected among 15–30 years age group (10.9%, 4.7%, 3.2% and 1.1%, respectively). A significant difference was also observed in the rates if infection with enteroviruses. The highest infection rate was detected in age groups below the age of 40 years (1.1% each), whereas older age groups (>40 years) recorded lower rates reaching to 0.6%. Low number of positive cases for parechovirus prohibits any correlation analysis with age (Table 4).
The association between gender and different infections was then explored for the available data. Males had a strong statistical correlation with elevated HRVs (11.9%) and enteroviruses (1.1%), compared to females (9.5 and 0.7%). On the other hand, females had significantly higher rates of influenza A, influenza B, RSV, HPIVs and HMPV infections (20.6%, 6%, 3.6%, 3.2% and 2.7% respectively) in comparison to males (16.6%, 4.9%, 2.6%, 2.6%, and 2% respectively). On the contrary, rates of non-MERS HCoV, M. pneumonia, adenoviruses, HboV, and parechovirus infections were comparable between the two groups with no significant correlation (Fig 5). Yet, MERS CoV was significantly higher among males (0.2%), compared to females (0.01%). In other words, out of 24 reported MERS-CoV, 23 (95.8%) were males, only one case (4.2%) was a female.
Qatar is characterized by subtropical dry, hot desert climate with low annual rainfall, very high temperatures in summer and a big difference between maximum and minimum temperatures. On the other hand, winter is cooler with occasional rainfalls. The weather during spring and autumn is usually warm during the days and cooler at nights. Importantly, there are occasional drops in the temperature during cool months with heavy fog conditions. This could affect the respiratory mucosa and increase individuals’ susceptibility to infections. Also, it is known that cold temperatures facilitate the survival and spread of viruses more easily. Another feature of cold months is that schools are open at that time, which also contribute to infections spread. Accordingly, we investigated the patterns of seasonality of all the tested viruses to understand the temporal circulation of respiratory pathogens.
In general, our data indicated that influenza and other respiratory pathogens exhibit strong seasonal peaks. Both, the number of reported ILI cases and the rate of positive results increased significantly during cooler months (Fig 2). Over the six-year study period, the highest number of received samples was recorded during the winter between December and February (31.3%), followed by fall months between September and November (29%). Samples received in spring and summer months represented 25.1% and 14.6%, respectively. Similarly, the overall rate of positive cases for at least one pathogen was significantly greater in winter (7205 cases; 16.5%), followed by fall (5920 cases; 13.6%), spring (4888 cases; 11.2%), then summer (2295 cases; 5%) positive cases (p <0.000).
Consistently, influenza viruses were circulating throughout the year; however, data from the entire six years period clearly identified major peaks during cold months. The highest rates of influenza infections were seen between November and February during 2013 to 2017, with a detection rate up to 38.5% of all tested specimens. Interestingly, a unique pattern was observed in 2012, where the highest peaks of influenza infections was recorded during March and April (40% and 30% respectively), which declined afterwards to less than 5% starting from June to September. Subsequently, dramatic increase of influenza cases was then recorded in October and November, reaching 26.7% of tested samples. Fig 3 illustrates the seasonality of influenza viruses during all the surveillance years.
Although the overall rate of respiratory illnesses was considerably higher in the winter, the seasonality of different respiratory pathogens was variable as illustrated in Fig 4. HRVs ranked as second leading cause of ILIs in adults. This virus tends to circulate during fall months, specifically between September and November, with a detection rate reaching 17%. Still, a high frequency of this virus was also observed in warmer months between March and May, representing 10%- 20% of tested samples. This coincided with low influenza rates around the same time of the year. Conversely, other viral agents, particularly RSV and HMPV, were predominating along with influenza viruses during the winter season and demonstrated a consistent seasonality. RSV had a unimodal peak during November or December each year, with a maximum detection rate of 9.7% recorded in 2017. On the other hand, HMPV was circulating more during January and March with a detection frequency reaching to 7.9%. M. pneumonia infection accounted for 3% of ILIs infections, in which most of the cases were detected in the period between January and April.
Virus seasonality was less interpretable for adenoviruses, coronaviruses, parainfluenza viruses (1–4), since they were distributed all over the years, with no clear temporal patterns of infection fluctuations. As for enteroviruses, HboV, and parechovirus, low rate of less than 1% positive cases were reported, with no unique cyclic occurrence.
One hundred and forty-six patients reported to the hospital with symptoms consistent with MERS within the study period. In 44 of them, MERS-CoV was confirmed. However, a complete set of relevant information was available only for 24 patients (Figure 1). Sociodemographic characteristics of the patients are listed in Table 1. The majority of patients were female (62.5%), and the mean age was 52.54 ±11.27 years. More than half of the patients were married (54.17%), and more than one-third of them were divorced (37.50%). Saudi nationals constituted 62.50% of the study sample, and one-third of the patients were health care workers. Of the 24 MERS patients, 20 were from Riyadh, and one each from Al-Madinah, Al-Qaseem, Aseer, and Tabouk.
Patients with MERS have a wide range of symptoms from being completely asymptomatic to suffering from severe respiratory illnesses. Fever cough, chills and myalgia are some of the most commonly reported symptoms in mild cases, but respiratory distress, kidney failure and septic shock have been reported in acute cases [17, 18]. There are neither vaccines nor specific medications against MERS-CoV, so treatments are usually palliative in nature [17, 19]. More than a third of those infected with MERS-CoV die. For comparative perspective, case fatality was one in ten for the SARS pandemic of 2003.
Research is yet to be done on the relationship between symptoms and transmissibility. Given that clinical procedures for acute patients can generate aerosolized viral particles, patients with severe respiratory distress would be more likely to transmit the virus compared to asymptomatic patients, but transmissibility of airborne MERS-CoV is unknown. In addition, research in transmission is essential with regards to ‘superspreaders’ who are sources for large number of cases for healthcare associated outbreaks.
On an annual basis, most of the MERS-CoV cases in Saudi Arabia between 2012 and 2019 occurred in 2014 (n = 662, 32.97%), followed by 2015 (n = 454, 22.61%). Afterwards, the MERS-CoV incidence decreased between 2016 and 2019 (n = 105 to 248, 5.23% to 12.35%). In terms of the seasonality of MERS-CoV infections, our results showed that the largest proportion of total MERS-CoV infections occurred during spring (n = 841, 41.88%). This was followed by summer (n = 460, 22.91%), winter (n = 375, 18.68%) and fall (n = 332, 16.53%). On a monthly basis, approximately one-third (31.33%) of the total MERS-CoV cases occurred during April (n = 316) and May (n = 313), followed by March, February and June (n = 201 to 212; 10.01% to 10.56%). The epidemic curve of MERS-CoV infection in Saudi Arabia during the seven-year study period showed significant variations over time (Figure 1). Two prominent outbreaks of MERS-CoV infection were observed in 2014, one in April (n = 253, 12.59%) and another in May (n = 213, 10.60%). This was followed by an outbreak in August 2015 (n = 115, 5.72%). Two minor outbreaks with fairly comparable numbers of MERS-CoV cases (n = 69 and n = 66) occurred in September 2015 and February 2019. In addition to the observed epidemics, sporadic MERS-CoV cases were also reported throughout the study period.
Overall mean seroprevalence of MERS-CoV antibodies in the sampled population is 46.9% (95% CI 41.4–52.5) with a prevalence of 60.8% (53.6–67.7) in the adult, 21.3% (12.9–31.8) in the juvenile, and 39.3% (27.1–52.7) in the young cohorts (S2 Fig; S1 Table). All nine herds had at least one positive camel, with the lowest mean herd prevalence of 14.3% (95% CI 4.8–30.3%) and the highest of 82.9% (95% CI 66.4–93.4) (S1 Table).
In addition to MERS-CoV antibodies, there was a high level of circulation of BCoV (based on HCoV-OC43 S1 as a proxy) in the camels as has been previously documented in other dromedary camel populations (S2 Fig),. All samples tested negative for severe acute respiratory syndrome SARS-CoV (S1 Fig). Analyses of exposure by age provides evidence of higher levels in older individuals (F2,23 = 2.661 p = 0.09); young animals had a significantly lower prevalence compared to adults (Duncan's test, P<0.05), as well as a trend towards higher prevalence rates in smaller herds (F1,6 = 4.23; p = 0.085). There was no statistical effect based on herd management type, with prevalence in commercial herds (43.6%; 35.8–49.6), commercial/pastoralist herds (51.9%; 37.6–66.0) and nomadic herds (56.8%; 44.7–68.2) (X
2; P = 0.1). Additionally, there was no statistical difference in prevalence based on herd isolation with high (40%; 28.2–54.6), intermediate (52%; 41.2–60.5), and low (54%; 44.7–68.2) isolation (X
2; P = 0.6).
All laboratory-confirmed MERS-CoV cases reported between June 13, 2012 and March 31, 2019 were compiled from the official websites of the Saudi Ministry of Health (SMOH) and the WHO. We undertook a detailed review of the MERS-CoV data and performed a range of checks for data consistency, completeness and fitness for the study purpose. We then developed a dataset with variables of interest for each individual with MERS-CoV. The dataset included the following: diagnosis date, gender, age, nationality, healthcare, employment status and source of infection, as well as the city, governorate and province of residence.
A confirmed case is defined as a suspected case that has a laboratory confirmation of MERS-CoV infection. A suspected case is defined as either (i) an adult patient presenting with severe pneumonia or acute respiratory distress syndrome, based on clinical or radiological evidence, or (ii) an adult patient presenting with an unexplained deterioration of a chronic condition, such as congestive heart failure or chronic kidney disease being treated with hemodialysis, or (iii) a child or an adult patient exposed to a confirmed case of MERS-CoV or who has visited a healthcare facility where a MERS-CoV patient was recently identified, or has had a history of contact with dromedary camels or consumption of camel products within 14 days before symptoms and who presents with either (a) acute febrile illness (temperature ≥ 38 °C) with or without respiratory symptoms, or (b) gastrointestinal symptoms and leukopenia or thrombocytopenia. Laboratory testing for MERS-CoV is performed at approved regional SMOH and selected non-SMOH governmental laboratories to confirm a clinically suspected case and to screen contacts by using validated, commercial, real-time, reverse-transcription polymerase chain reaction (rRT-PCR) assays. The laboratory confirmation of MERS-CoV infection requires either a positive rRT-PCR result for at least two specific genomic targets, or a region upstream and open reading frame1a (upE and ORF1a).
A primary case is defined as a person with a laboratory-confirmed MERS-CoV infection with no evidence of contact with infected individuals but is known or believed to have had direct or indirect exposure to camels or camel habitats. Exposure to camels includes direct physical contact with camels or their surroundings (milking and handling excreta), drinking raw camel milk or other unpasteurized products derived from camel milk and handling raw camel meat. Indirect contact includes casual contact with sites where camels have been (e.g., camel markets or farms) but without direct physical contact with camels, or living with a household member who has had direct contact with camels. By contrast, a secondary case is defined as a person who has shared the same enclosed space (e.g., a room or office) for frequent or extended periods with an individual with a symptomatic MERS-CoV infection. MERS-CoV is believed to spread between humans mainly through contact and respiratory droplets. However, transmission through small particle droplet nuclei (aerosols) may occur. Environmental contamination during outbreaks in healthcare facilities can be extensive and might contribute to outbreak amplification, if adequate disinfection procedures are not followed.
MERS-CoV is the second coronavirus after Severe Acute Respiratory Syndrome (SARS)-CoV with the potential to cause a pandemic. Characterized by its ‘corona’ or crown shape, it is a single-stranded RNA virus with approximately 30,000 nucleotides in its genome.
While current literature mostly concur that camels are important zoonotic reservoirs for MERS-CoV, there has been some evidence that bats might be primary viral reservoirs and that MERS-CoV will jump to a different host such as dromedary camels, and subsequently humans, when opportunities arise; similar transmission dynamic has been observed with SARS-CoV where palm civets acted as intermediary host between bats and humans [4, 5]. However coronaviruses isolated from bats are more genetically distant from human MERS-CoV than those isolated from camels, which have shown very high similarities to humans’.
Virus transmission from camels is thought to be connected to consuming camel milk or urine, working with camels and/or handling camel products. Secondary transmissions are largely associated with hospitals or close contacts of MERS cases. As shown with the family cluster in the United Kingdom (UK), relatives or people living in close contact with an infected patient are susceptible to the pathogen even outside of hospital settings.
While the exact methods of MERS-CoV transmissions are unknown respiratory droplet and aerosol transmissions are cited as most probable, but there is no conclusive evidence on how close a person has to be for exposure and what protection is most suitable [3, 9]. For example, the Korean Ministry of Health and Welfare (KMoH) classified close contacts as those who were within 2 meters of MERS-CoV infected patient or in contact with respiratory droplets without personal protective equipment, yet the extent to which of those close contacts were infected is unknown. It has been hypothesized that camels can transmit a higher dose of viruses to humans while the quantity is lower between humans, and that MERS-CoV has not fully adapted for human-to-human transmission [11, 12]. Food, oral-fecal, and fomite transmissions are also possible transmission routes since the virus has been detected in camel milk, patient fecal sample and hospital surfaces [13–16].
The contact investigation was carried out for both family contacts and healthcare worker contacts. Among the family contacts, 7 out of 36 (19.4%) tested positive and 1 of 51 (2%) healthcare worker contacts tested positive for MERS-CoV (p = 0.0078).
Of the general population group (n = 186), 5% had dromedaries around the home, 3% had direct, recurrent contact with dromedaries, 18% frequently consumed raw camel meat and 22% consumed unpasteurised camel milk more than once per week .
MERS-CoV may infect a wide group of people ranging from very young ages, even infants less than one year of age, to 109 years of age (CDC, 2016). However, children are less likely to be infected with MERS-CoV when compared to adults and, if infected, they tend to have asymptomatic or mild disease (Arwady et al., 2016). The reason for this is still not entirely clear and requires further study.
The case fatality rate is always very high in case of the immunocompromised infected patients especially those who are suffering from chronic diseases such as cancer, diabetes, blood pressure, kidney problems, etc. (Arwady et al., 2016).
Human-to-human transmission is reported in many cases. MERS-CoV replicates efficiently in various in vitro and ex vivo models (Chan et al., 2014). Moreover, many family clusters and hospital outbreaks were reported in the past 5 years (Arwady et al., 2016; Drosten et al., 2014; Memish et al., 2013). This confirms the potential spread of MERS-CoV among those who are in close contact in the population (Mollers et al., 2015). The most at-risk groups are healthcare workers including nurses, medical doctors and other hospital staff and the elderly with underlying chronic diseases (Arabi et al., 2014).
The prevalence rate of MERS-CoV in primary cases among males is relatively higher than that of females (Darling et al., 2017), which may be because exposure to infected dromedary camels is much higher in males than in females.
MERS-CoV infection triggers some unique interferons and cytokine gene expression profiles. The virus seems to be a poor interferon inducer (Chan et al., 2014). This suggests the potential immune evasion strategies triggered by the virus to hijack the host immune system and may be responsible for the high fatality rate, at least in part. Viral spreading among people seems to not yet be very efficient. Those in close contact are among the at-risk groups for infection (Drosten et al., 2014), as observed in many hospital outbreaks as well as family clusters (Alfaraj et al., 2018; Choi et al., 2017; Xiao et al., 2018). This suggests that transmission of the virus among people requires exposure to a high viral load, which will sometimes produce active infection in people who are in close contact. Several MERS-CoV family clusters have been reported (Drosten et al., 2014). Interestingly, MERS-CoV is reported in the dromedary camels in many African countries (Egypt, Nigeria, Tunisia, and Ethiopia), but no primary human cases have been reported in these countries to date (Ali et al., 2017; Roess et al., 2016; Van Doremalen et al., 2017), which may be related to some variation in the circulating Asian and African strains of MERS-CoV.
Some important deletions in the MERS-CoV currently circulating in dromedary camels from Africa were recently reported (Chu et al., 2018). These deletions may explain at least in part the reason behind the variations in the pathogenesis among the Asian and African strains of MERS-CoV. Another potential reason behind the absence of human cases in the African countries is the diverse cultural habits among people in Africa and the Arabian Peninsula (FAO, 2016). People in Arabian Peninsula get in more close touch with camels during the camel show, sports, trade than in Africa. This make the human risk of exposure much higher in the AP than Africa. MERS-CoV infection varies from severe respiratory illness accompanied by a high fever and respiratory distress to mild asymptomatic cases. Patients are usually admitted to the intensive care unit (ICU) and provided with a source of oxygen. Most cases result in pneumonia, which is fatal in almost 40% of the affected patients (Hong et al., 2017; Rubio et al., 2018). Some patients may develop renal failure. Several MERS-CoV travel-associated infections were in many cases associated with the Middle East (Bayrakdar et al., 2015; Rubio et al., 2018). Among these reported was the Korean outbreak in early 2015 (Choi et al., 2017; Kim, Andrew & Jung, 2017; Xiao et al., 2018). One Korean citizen visited some countries in the Middle East and then returned home ill. This person visited several healthcare facilities in Korea. This resulted in the largest MERS-CoV human outbreak outside the Arabian Peninsula (AP) (Xiao et al., 2018). This outbreak confirmed the human-to-human transmission. During this outbreak, MERS-CoV was isolated from air samples from the hallways of the healthcare facilities close to the hospitalized patients (Xiao et al., 2018). This at least explains in part the rapid development of MERS-CoV hospital outbreaks.
In September 2012, a novel coronavirus, Middle East respiratory syndrome coronavirus (MERS-CoV), was identified from a patient with a fatal viral pneumonia in Saudi Arabia. This coronavirus is genetically related, but not identical, to the severe acute respiratory syndrome (SARS) coronavirus which emerged in southern China in 2002. As of 21 March 2017, 1,917 human cases have been reported to the World Health Organization (WHO) with at least 684 deaths. Most zoonotic infections have occurred in the Arabian Peninsula, particularly in Saudi Arabia, although nosocomial outbreaks arising from travellers coming from the Arabian Peninsula have been reported in Africa, Asia, Europe and North America. For example, between May and June 2015, 186 human infections in South Korea arose from one returning traveller, highlighting the cause for global public health concern.
Human disease ranges from mild or asymptomatic infection to a fulminant viral pneumonia progressing to severe respiratory failure and death. Dromedary camels are strongly suspected to be the source of human infections. It is believed that humans can get infected via direct contact with mucous membranes of infected camels or by consuming unpasteurised camel milk. However, the virus has not been detected in camel urine or in raw camel meat. Secondary infections in humans are reported, especially within nosocomial settings or to a smaller extent, within households, suggesting that human-to-human transmission may become efficient enough to trigger outbreaks beyond the current epicentre in the Middle East. The WHO has identified MERS-CoV as one of the pathogens of greatest concern for global public health for which few or no medical countermeasures exist. To date there are no vaccines or antivirals available for MERS-CoV in humans. Camel vaccines have given promising results with the use of a vaccinia Ankara (MVA) vectored vaccine.
MERS-CoV only causes mild respiratory symptoms in camels and it is consequently not easily recognised and difficult to diagnose clinically. High levels of seropositivity and virus detection rates have been observed in dromedary camels in the Arabian Peninsula. MERS coronaviruses detected in camels are genetically very similar or identical to those infecting humans. MERS-CoV antibodies have also been detected in dromedary camel populations of many countries outside the Arabian Peninsula. Serological studies in Africa indicate high seropositivity rates and the testing of retrospectively collected serum samples provide evidence that this virus has been infecting camels in East Africa since as early as 1983. More recent specimens collected between 2009 and 2013 show high rates of detection of MERS-CoV antibodies in camels in Egypt, Ethiopia, Kenya, Nigeria, Sudan and Tunisia and also in the Canary Islands.
Surprisingly, the only indication of locally acquired primary zoonotic human infections outside the Arabian Peninsula is the recent detection of antibodies against MERS-CoV in autochthonous livestock handlers in Kenya between 2013 and 2014. Possible reasons for the absence of reports of MERS-CoV infections in humans in Africa may include (i) underdiagnosis in humans due to a possible lack of awareness, lack of viral diagnostic capacity and weak healthcare systems, (ii) differences in virus strains or in camel breeds resulting in low infectiousness towards humans, (iii) differences in cultural practices in interaction between humans and dromedary camels, or any combination of these. Research recommendations from workshops on MERS-CoV in Doha April and Cairo May 2015, organised by the Food and Agriculture Organisation (FAO), the Organisation of the United Nations for Animal Health (OIE) and the WHO identified the apparent absence of human MERS-CoV infections in Africa despite intense virus circulation among dromedaries as a key research question. In order to address this question, it is important to understand the ecological and farming husbandry factors that may promote the likelihood of MERS-CoV infection in camels in Africa.
We report a descriptive serological and virological survey of MERS-CoV from west to east across the African continent, which was conducted by sampling camels in Burkina Faso, Ethiopia and Moroco. Sampling was designed so as to also assess the influence of the herd size, camel function (raised for milk, meat or transport) and lifestyle (either nomadic, sedentary or a mix of the two lifestyles) on likelihood of MERS-CoV infection.
From January 2013 to December 2016, 93 adult patients, classified as possible MERS-CoV cases, were hospitalized in the two participating isolation wards. The male: female ratio was 1.1 and the median age was 63.4 years (interquartile range; IQR, 56–71.5). Of 82 (88.2%) patients who were returning from the KSA, 74 (90.2%) had travelled for the pilgrimage, two (2.1%) for professional reasons, and four (4.9%) for tourism; two (2.4%) were KSA residents (Fig. 1). There was an obvious seasonal trend with a major annual increase in the number of admitted patients during the annual Hajj period (Fig. 2). The median travel duration was 23 days (IQR = 17–27). The median lag time between the first symptoms and admission to the isolation ward was 8.2 days (IQR, 0–28). The median lag time between arrival in France and admission to the isolation ward was 2 days (IQR, 1–5 days), and only 19 (20.4%) patients had the first symptoms after their arrival in France.
The first symptoms described by the patients were cough (n = 62, 67%), influenza-like symptoms (n = 18, 19%), and dyspnea (n = 6, 6%). Other symptoms were diarrhea (n = 2, 2%), fever (n = 2, 2%), vomiting (n = 1, 1%), general illness (n = 1, 1%) and headache 1(1%). Thirty-four (36.5%) patients had consulted a physician in the at-risk countries and nine (9.7%) had prior hospitalization in these countries.
Close contact with ill travelers with respiratory symptoms during travel was found in 43 (46.7%) patients. Exposure to dromedary camels or contaminated camel milk or meat was found in five (5.4%) patients.
Initial clinical findings of patients admitted to isolation wards are reported in Tables 1 and 2. The most common signs were cough (95.7%), with 63 (70.7%) patients having sputum production, and 26 (29.3%) dry cough. Pulmonary auscultation revealed crackles in 61 (65.5%) patients, bilateral in 25 (26.9%). Ten (11%) patients required oxygen therapy at initial evaluation. Other clinical symptoms are listed in Table 2. Ten patients (11%) were admitted to intensive care directly (n = 6) or after evaluation in isolation wards (n = 5).
Seventy-five (80.6%) patients had underlying medical conditions with a median of 2 (1–3) different comorbidities such as hypertension (n = 57, 61.3%), chronic respiratory diseases (n = 22, 23.6%), chronic cardiac disease (n = 21, 22.6%), or obesity (n = 19, 20.4%). Nine patients (9.7%) had a history of neoplastic or hematological disease, six (6.4%) were receiving corticosteroids, and six (6.4%) immunosuppressive drugs.
According to the KSA Ministry of Health, nearly half of all MERS cases are classified as primary cases: zoonoses originating from direct or indirect contact with infected dromedary camels, or from an unidentified source which had no link to any other (known) human case. The precise mechanism by which MERS-CoV spreads from camels to humans is unknown but is not essential for enacting precautions to reduce exposure to infected animals. Secondary cases make up slightly more than half of all MERS cases, mostly resulting from exposure associated with a healthcare facility.
Infectious MERS-CoV is presumed to be found in droplets but modelling has also suggested the possibility of airborne spread. Virus remains viable for at least 48 h on plastic and steel surfaces, presumably underpinning the extensive contamination of air and surfaces in hospitals housing patients with MERS. The virus appears sensitive to standard heat and chemical inactivation measures.
Antibodies to MERS-CoV have been found in camel sera as far back as 1983. In each animal, antibodies to MERS-CoV are short-lived and do not prevent reinfection.
Human contact with camels is often associated with the collection, preparation, and ingestion of camel milk or meat. Female camels, especially those bred for milking, have the highest rates of MERS-CoV seropositivity; MERS-CoV RNA has been detected in milk from one study and virus was found to be stable after being spiked into milk samples from another study. Camels in larger herds have higher rates of seropositivity compared with smaller herds. Female and young camels also have higher rates of MERS-CoV RNA than older and male camels. While no evidence for human infection resulting from ingestion has been presented, it has been found that experimentally inoculated human intestinal cells and organoids can host productive MERS-CoV infection and that MERS-CoV can remain infectious after transit through gastric acids. Further, intestinal, respiratory, and neurological infection follows intragastric inoculation of DPP-4 transgenic mice. Whether camel milk and meat actually contain a suitable infectious dose to cause intestinal infection of humans is yet to be determined. It seems likely that the processes of milking and butchery may contaminate surfaces and generate infectious droplets that include sufficient inoculum from which a human infection could result via inhalation or self-inoculation. It is not known whether the eyes act as a portal for MERS-CoV entry.
Since the majority of human-to-human MERS-CoV infections are associated with healthcare, improved infection control and prevention is considered key for preventing outbreaks among humans not at occupational risk of exposure to infected animals. In the outbreak in the Republic of Korea, 5 of 186 cases were responsible for 83% of transmission events; most new cases did not result in any identified onward transmission; the reproduction (R0) number was calculated as 3.9 and 1.9–6.9 from selected KSA outbreaks. Three of these five cases were coughing; prolonged exposures, crowding, and large numbers of contacts were important factors for disproportionate virus transmission.
The role, if any, for mild or subclinical MERS-CoV infections in maintaining the virus in the human population has not been convincingly addressed. A healthcare worker found to shed viral RNA for more than five weeks in the absence of disease adds urgency to the need for such studies. None among 82 contacts of a mildly symptomatic MERS-CoV-infected healthcare worker seroconverted, but there was no mention of whether the index case seroconverted. In a KSA hospital outbreak investigation, contacts of subclinical MERS-CoV-infected healthcare workers became RT-PCR positive, suggesting transmission was a possibility. Some studies report very rare camel contact among human cases and no history of contact with other MERS-CoV-infected humans, and this raises the question of how these primary cases acquire infection. Community spread and subclinical transmission need more attention.
The Hajj pilgrimage, an annual mass gathering in the KSA, provides many opportunities for MERS-CoV to transmit and then spread globally. However, it is rhinoviruses, influenza viruses, and other seasonal respiratory viruses that have, to date, driven the bulk of respiratory disease associated with the Hajj. This indirectly reinforces that MERS-CoV does not transmit efficiently among humans outdoors. In hospital environments, healthcare workers and other patients and carers who experience prolonged exposure to infectious cases, in the absence of suitable personal protective equipment (PPE), are those who usually become infected. There have been examples of the 20/80 rule, whereby relatively few infected individuals are responsible for a disproportionate number of new cases. Insufficient cleaning of room surfaces, inadequate room ventilation, and overcrowding have also been suggested to drive indoor MERS-CoV transmission.
The case-patient data reported to WHO by member states is anonymized, thus, neither informed consent, nor approval from an institutional review board were required.
The seroprevalence of MERS-CoV antibodies increases with age in camels, while the fraction of camels that test positive for MERS-CoV RNA in their nasal swabs decreases with age [17, 31, 36, 38, 39]. When all serological results of papers that included sufficient age information is combined, the median seroprevalence of camels aged under 2 years is 52% (992/1972; range 0–100%), while the age groups 2–5 years (702/924; range 30–100%) and over 5 years old (1226/1370; range 0–100%) had a combined median seroprevalence of 97%. In the virological studies reporting age breakdown, the median rate of nasal shedding in 0–2 years old camels was 34% (718/2612; range 0–100%) of cases, compared with 2% (91/1142; range 0–100%) in camels older than 2 years.
The administrative regions of Guelmim-Oued Noun, Laâyoune-Sakia El Hamra and Dakhla-Oued Ed-Dahab were selected for study because 83.2% of all dromedary camels in Morocco are in these three regions. The population of these regions was considered at high-risk of MERS-CoV infection because of direct or indirect contact with dromedaries, and for the study purposes, further divided into in three categories; camel herders and slaughterhouse workers, both with occupational exposure, and the general population, i.e. individuals living in high-risk areas who did not have direct occupational contact with dromedaries.
Though much is already known, it remains important to clarify the routes of human infection, including the role of the eyes in contracting infection, among primary human cases. The development of rapid molecular POCT tests and alternatives to serology, such as CD8+ detection can help us understand MERS-CoV transmission, which can lead to reductions in outbreaks. The scale of mild and subclinical cases among non-hospitalised Arabian Peninsula communities is unknown, as is their role in transmission. Most knowledge of MERS comes from studies of hospital-based populations or linked community contacts. Future prospective long-term cohort studies of mild community respiratory illnesses using molecular methods would be useful. Children have so far been largely absent from the MERS case tally, but they may represent an important population for prospective study. Recent lessons from the Zika and Ebola viruses should also inform new studies seeking possible long-term sequelae and viral persistence and highlight the need to follow-up severe MERS patients.
High rates of co-infection with other respiratory viruses are commonly reported. Viruses frequently associated with co-infection include enterovirus, rhinovirus and PIV however reports of co-infection with two human coronaviruses are limited. Dijkman et al. recently demonstrated that HCoV-OC43 and HCoV-NL63 may elicit immunity that protects against HCoV-HKU1 and HCoV-229E, respectively. Clinical progression and outcomes of disease in patients presenting with co-infection are however similar to patients presenting with mono-infection. There is also no substantial difference in coronaviral load between co-infected and mono-infected patients. No substantial difference in disease progression in co-infected versus mono-infected patients has been reported and therefore understood to have little impact; however, the role in facilitation of infection of one respiratory virus by another is still speculative.
Around 70 camels are slaughtered daily at the abattoir in Kano, Nigeria. We collected around 20 nasal swabs daily from 12 October to 2 December 2015 and from 11 January to 29 February 2016. Swab samples were placed in viral transport medium and stored at -80°C.
Abattoir workers with and without occupational exposure to camels were recruited for a serological study after obtaining informed consent, during April–November 2016. A questionnaire was administered to each participant to ascertain demographic information, type and duration of occupational exposure to camels or other livestock, practices such as consuming camel milk or use of camel urine for food or health purposes. Camel exposures in the abattoir were classified as ‘direct’ (exposure to live or freshly slaughtered camels or camel meat) or ‘indirect’ (no exposure to live camels or freshly slaughtered camels or meat; exposure only being to cooked meat or dried bones etc. as further described in the Table). Duration of exposure to camels in the abattoir was categorised as < 1 year, 1–5 years or > 5 years. These workers used no personal protective equipment.
MERS-CoV cases reported from the Hafr Al-Batin region were selected for study. Epidemiological, clinical and laboratory details were collected. Clinical information included demographic data, clinical symptoms and signs, co-morbidities, contact with animals and travel history
In the modelling of variations of seropositivity rates (Figure 2A and Table 3), the retained explanatory variables were herd size category (p-value = 0.061), camel’s function (p-value = 0.01) and lifestyle (p-value < 0.005).
Higher seropositivity rates were observed (i) in large/medium herds as compared with small herds; (ii) in camels bred for meat or milk as compared with camels bred for transport, and (iii) in nomadic or sedentary herds than in herds with a mix of these lifestyles. Seropositivity rates also increased with age (p-value = 0.032; Figure 3) and were higher in females than in males.
In the modelling of virus RNA detection rate (Figure 2B and Table 3), camel’s function had a significant effect (p-value = 0.01) with higher viral RNA detection rates observed in camels bred for milk or for meat as compared with transport. Probability of detecting virus RNA also decreased with increasing age (p-value = 0.06; Figure 3) and was higher in females than in males (according to collinearity index as the variables function and sex strongly associated).