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The epidemiology of Middle East respiratory syndrome coronavirus in the Kingdom of Saudi Arabia, 2012–2015

Open AccessPublished:February 10, 2016DOI:https://doi.org/10.1016/j.ijid.2016.02.004

      Highlights

      • Patients with a primary infection, those of older age, and cases with comorbidities were more severely unwell.
      • Early admission of Middle East respiratory syndrome coronavirus (MERS-CoV) cases did not improve the disease outcome.
      • Healthcare workers and household contacts had a lower mortality.
      • The high prevalence of renal disease in inpatients reflects the nosocomial outbreaks.
      • The clinical significance of asymptomatic infection is not yet known.

      Summary

      Objectives

      The aim of this study was to review the epidemiology of cases of Middle East respiratory syndrome coronavirus (MERS-CoV) reported in the Kingdom of Saudi Arabia from 2012 when the first MERS-CoV was confirmed up to July 2015.

      Methods

      MERS-CoV data were obtained from the Saudi Ministry of Health for the period 2012 to July 2015. Descriptive statistics were used to summarize the results regarding the risk factors and mortality of MERS-CoV infection.

      Results

      In this series, the risk factors and outcomes of 939 cases of MERS-CoV occurring in the last 3 years are described. The majority of the affected patients were aged ≥40 years (n = 657; 70%). Of the 657 patients aged ≥40 years, 377 (57.3%) died.

      Conclusions

      The case-fatality ratio was found to increase significantly with age. It ranged from 12.5% in those aged ≤19 years to 86.2% in those aged ≥80 years. The results confirmed the association between severe MERS-CoV illness and patients with a pre-existing health morbidity. The duration from symptom onset to admission was not statistically associated with the disease outcome.

      Keywords

      1. Introduction

      Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in the Kingdom of Saudi Arabia in 2012.
      • Zaki A.M.
      • van Boheemen S.
      • Bestebroer T.M.
      • Osterhaus A.D.
      • Fouchier R.A.
      Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia.
      • Leshem E.
      Severe respiratory illness associated with a novel coronavirus — Saudi Arabia and Qatar, 2012.
      Although MERS-CoV is thought to be a zoonosis, probably involving dromedary camels,
      • Memish Z.A.
      • Cotten M.
      • Meyer B.
      • Watson S.
      • Asahafi A.J.
      • Al Rabeeah A.A.
      • et al.
      Human infection with mers coronavirus after exposure to infected camels, Saudi Arabia, 2013.
      clusters due to human-to-human transmission are well recognized.
      • Al-Tawfiq J.A.
      • Assiri A.
      • Memish Z.A.
      Middle East respiratory syndrome novel corona (MERS-CoV) infection: epidemiology and outcome update.
      • Drosten C.
      • Muth D.
      • Corman V.M.
      • Hussain R.
      • Al Masri M.
      • Haj Omar W.
      • et al.
      An observational, laboratory-based study of outbreaks of Middle East respiratory syndrome coronavirus in Jeddah and Riyadh, Kingdom of Saudi Arabia, 2014.
      • Assiri A.
      • McGeer A.
      • Perl T.M.
      • Price C.S.
      • Al Rabeeah A.A.
      • Cummings D.A.
      • et al.
      Hospital outbreak of Middle East respiratory syndrome coronavirus.
      Locally acquired cases have been reported primarily in countries of the Middle East including Iran, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, United Arab Emirates, and Yemen; imported cases (or import-related cases) have also occurred in Algeria, Austria, China, Egypt, France, Germany, Greece, Italy, Malaysia, Netherlands, Philippines, South Korea, Thailand, Tunisia, Turkey, UK, and the USA.

      World Health Organization. Global Alert and Response. Coronavirus infections, 2015. WHO; 2015. Available at: http://www.who.int/csr/don/archive/disease/coronavirus_infections/en/ (accessed October 27, 2015).

      The aim of this study was to review the epidemiology of cases of MERS-CoV in the Kingdom of Saudi Arabia prior to July 2015.

      2. Methods

      Data were obtained from the Saudi Ministry of Health for the period 2012 to July 2015. Cases were defined as patients with a positive nucleic acid test for MERS-CoV, whether diagnosed due to clinical presentation because of illness, or active surveillance in known contacts. Primary cases were defined as patients who were diagnosed with MERS-CoV following presentation for medical care, and secondary cases were patients who were tested as a contact of a known case, whether in a household, as an inpatient in hospital, or as a healthcare worker caring for a case.
      Descriptive statistics were used to summarize the results. Proportions were compared between groups using the Chi-square test, and continuous variables were compared using the Mann–Whitney test or Kruskal–Wallis test, as appropriate. Univariate and a multivariate logistic regression models were used to determine risk factors for mortality, excluding asymptomatic patients and those for whom medical morbidities or the outcome were not ascertained. Statistical tests were performed using Stata 14 for Windows (StataCorp, College Station, TX, USA).
      This study was approved by the Ministry of Health of the Kingdom of Saudi Arabia.

      3. Results

      During the period 2012 to July 2015, 939 cases of MERS-CoV were reported to the Saudi Ministry of Health. Of these, 624 patients (66%) were male, 33% were elderly (>60 years), and 3.2% were children (<20 years) (Table 1). Compared to the other groups, a higher proportion were female in the group of healthcare workers. The largest proportion of cases were from the Riyadh region (n = 369; 39.3%), followed by Jeddah (n = 195; 20.8%) and the Eastern region (n = 125; 13.3%). The majority of cases in Riyadh (n = 197; 53.4%) and Jeddah (n = 197; 91.8%) occurred in 2014, while most cases in the Eastern region (n = 67; 53.6%) were reported in 2015.
      Table 1Characteristics of MERS-CoV cases in the Kingdom of Saudi Arabia prior to July 2015, by location of acquisition
      PrimarySecondaryUnknownTotalp-Value
      p-Values represent results of the Chi-square test for the null hypothesis of no difference in proportions across groups, excluding patients with an unknown source of acquisition.
      HouseholdInpatientHCW
      Number
      Denominator unless reported otherwise.
      329114174171151939
      Year<0.001
       20123 (0.9%)2 (1.8%)0 (0.0%)0 (0.0%)0 (0.0%)5 (0.5%)
       201338 (11.6%)26 (22.8%)40 (23.0%)26 (15.2%)6 (4.0%)136 (14.5%)
       2014168 (51.1%)55 (48.2%)73 (42.0%)127 (74.3%)134 (88.7%)557 (59.3%)
       2015120 (36.5%)31 (27.2%)61 (35.1%)18 (10.5%)11 (7.3%)241 (25.7%)
      Age group, years<0.001
       ≤197 (2.1%)16 (14.0%)4 (2.3%)0 (0.0%)5 (3.3%)32 (3.4%)
       20–3952 (15.8%)40 (35.1%)25 (14.4%)104 (60.8%)29 (19.2%)250 (26.6%)
       40–59135 (41.0%)41 (36.0%)53 (30.5%)62 (36.3%)54 (35.8%)345 (36.7%)
       60–79112 (34.0%)15 (13.2%)71 (40.8%)5 (2.9%)50 (33.1%)253 (26.9%)
       ≥8023 (7.0%)2 (1.8%)21 (12.1%)0 (0.0%)13 (8.6%)59 (6.3%)
      Male250 (76.0%)80 (70.2%)124 (71.3%)71 (41.5%)99 (65.6%)624 (66.5%)<0.001
      Resident of KSA236 (71.7%)92 (80.7%)144 (82.8%)29 (17.0%)112 (74.2%)613 (65.3%)<0.001
      Comorbidities
       Diabetes116/198 (58.6%)19/38 (50.0%)49/99 (49.5%)10/34 (29.4%)30/52 (57.7%)224/421 (53.2%)0.014
       Hypertension96/198 (48.5%)13/38 (34.2%)58/99 (58.6%)6/34 (17.6%)27/52 (51.9%)200/421 (47.5%)0.001
       Renal disease22/198 (11.1%)2/38 (5.3%)31/99 (31.3%)1/34 (2.9%)12/52 (23.1%)68/421 (16.2%)0.001
       Pulmonary disease19/198 (9.6%)0/38 (0.0%)11/99 (11.1%)2/34 (5.9%)5/52 (9.6%)37/421 (8.8%)0.18
       Cardiac disease37/198 (18.7%)8/38 (21.1%)34/99 (34.3%)3/34 (8.8%)15/52 (28.8%)97/421 (23.0%)0.004
       Cancer9/198 (4.5%)1/38 (2.6%)9/99 (9.1%)0/34 (0.0%)4/52 (7.7%)23/421 (5.5%)0.13
       Other chronic disease46/198 (23.2%)2/38 (5.3%)32/99 (32.3%)4/34 (11.8%)14/52 (26.9%)98/421 (23.3%)0.003
      Presentation: asymptomatic0/325 (0.0%)25/110 (22.7%)4/172 (2.3%)56/170 (32.9%)8/147 (5.4%)93/924 (10.1%)0.001
      Notification from symptom onset >7 days146/317 (46.1%)28/99 (28.3%)38/167 (22.8%)27/146 (18.5%)62/137 (45.3%)301/866 (34.8%)0.001
      Died184/325 (56.6%)18/110 (16.4%)132/172 (76.7%)15/170 (8.8%)76/147 (51.7%)425/924 (46.0%)0.001
      MERS-CoV, Middle East respiratory syndrome coronavirus; HCW, healthcare worker; KSA, Kingdom of Saudi Arabia.
      a p-Values represent results of the Chi-square test for the null hypothesis of no difference in proportions across groups, excluding patients with an unknown source of acquisition.
      b Denominator unless reported otherwise.
      Primary cases and secondary case hospital inpatients were older than household contacts and secondary case healthcare workers (Figure 1).
      Figure thumbnail gr1
      Figure 1Age distribution of MERS-CoV cases reported in the Kingdom of Saudi Arabia during the period 2012 to July 2015, by location of acquisition.
      The distribution of MERS-CoV cases in the Kingdom of Saudi Arabia from September 2012 to July 2015 by month of symptom onset showed no specific constant seasonal pattern. Most of the cases occurred during the first 6 months of the year (Figure 2).
      Figure thumbnail gr2
      Figure 2Distribution of MERS-CoV cases in the Kingdom of Saudi Arabia during the period 2012 to July 2015, by month of onset of symptoms.

      3.1 Clinical presentation

      The location of diagnosis was reported for 788 patients. Of these, 329 patients were diagnosed following presentation with illness. Of the remaining 459 patients who were diagnosed as contacts, 114 were contacts of known cases in the community, 174 were inpatient contacts of known cases, and 171 were healthcare worker contacts (Table 1). Of the secondary cases, 93 were asymptomatic; this proportion was highest in healthcare workers (32%), followed by household cases (23%).

      3.2 Risk factors

      Medical comorbidities were reported in 421 patients (Table 1). Overall, 351 patients (44%) had one or more comorbidity; the proportion with comorbidities was higher in patients who were >60 years of age and those who were secondary cases in hospital inpatients. Diabetes was common in all groups (53% overall).

      3.3 Mortality

      The case-fatality ratio increased with age, with a mortality of 12.5% in children aged <20 years rising to 86% in elderly patients aged >80 years. In the univariate analysis of patients for whom complete data were available and excluding asymptomatic cases, acquisition as a hospital inpatient, hypertension, renal disease, cardiac disease, and cancer were positively associated with mortality (Table 2). On multivariate analysis, age >80 years, cardiac disease, and cancer were independently associated with mortality. Compared to primary cases, mortality was lower in household cases and healthcare workers. The duration from symptom onset to admission was not statistically associated with the disease outcome.
      Table 2Factors associated with mortality in 403 symptomatic MERS-CoV cases in the Kingdom of Saudi Arabia for the period 2012 to July 2015, for whom comorbidities and the outcome were ascertained
      Unadjusted OR (95% CI)Adjusted OR (95% CI)
      Age group, years
       ≤190.40 (0.04, 3.95)0.37 (0.03, 3.95)
       20–390.54 (0.30, 0.96)0.64 (0.32, 1.27)
       40–5911
       60–792.44 (1.51, 3.93)1.49 (0.87, 2.56)
       ≥806.51 (2.38, 17.82)4.07 (1.41, 11.78)
      Male0.93 (0.60, 1.45)0.78 (0.45, 1.34)
      Comorbidities
       Diabetes1.43 (0.96, 2.11)0.86 (0.49, 1.52)
       Hypertension2.34 (1.56, 3.49)1.41 (0.80, 2.48)
       Renal disease1.84 (1.06, 3.18)1.06 (0.56, 2.03)
       Pulmonary disease1.38 (0.68, 2.79)1.10 (0.48, 2.54)
       Cardiac disease3.86 (2.25, 6.60)2.80 (1.52, 5.16)
       Cancer6.46 (1.89, 22.10)5.98 (1.64, 21.79)
      Location of acquisition
       Primary11
       Secondary/household0.24 (0.10, 0.58)0.25 (0.09, 0.68)
       Secondary/inpatient3.32 (1.90, 5.82)2.61 (1.41, 4.82)
       Secondary/HCW0.10 (0.03, 0.35)0.17 (0.05, 0.59)
       Unknown1.20 (0.63, 2.26)1.02 (0.50, 2.06)
      MERS-CoV, Middle East respiratory syndrome coronavirus; OR, odds ratio; CI, confidence interval; HCW, healthcare worker.
      MERS cases were notified to the Saudi Ministry of Health (MOH) from different regions of the Kingdom. The present data showed that 564 (65.1%) patient cases were notified within 7 days after the onset of symptoms, while 301 (34.8%) patient cases were notified at >7 days after symptom onset (Table 1).

      4. Discussion

      In this series, the risk factors and outcomes of more than 900 cases of MERS-CoV occurring over 3 years are described. These represent 60% of the 1570 cases reported worldwide.
      A distinct clinical profile was found in the different populations based on their likely location of acquisition, which reinforces the association of chronic comorbidity and severe infection. While previous studies have noted a lower mortality in secondary cases consistent with a detection bias in primary cases,
      • Assiri A.
      • Al-Tawfiq J.A.
      • Al-Rabeeah A.A.
      • Al-Rabiah F.A.
      • Al-Hajjar S.
      • Al-Barrak A.
      • et al.
      Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study.
      it was found that the case fatality varied in the different groups with secondary infection. Patients who presented with primary infection were more severely unwell but had a similar mortality as hospital inpatients who acquired the infection in hospital. Healthcare workers and household contacts had a lower mortality, reflecting a lower severity of illness in these populations who were previously well.
      The present findings confirm the association between comorbidities in patients and severe illness.
      • Alghamdi I.G.
      • Hussain I.I.
      • Almalki S.S.
      • Alghamdi M.S.
      • Alghamdi M.M.
      • El-Sheemy M.A.
      The pattern of Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive epidemiological analysis of data from the Saudi Ministry of Health.
      • Memish Z.A.
      • Zumla A.I.
      • Al-Hakeem R.F.
      • Al-Rabeeah A.A.
      • Stephens G.M.
      Family cluster of Middle East respiratory syndrome coronavirus infections.
      • Majumder M.S.
      • Kluberg S.A.
      • Mekaru S.R.
      • Brownstein J.S.
      Mortality risk factors for middle east respiratory syndrome outbreak, South Korea, 2015.
      Previous studies have defined obesity, diabetes, and renal disease as risk factors when comparing cases to test-negative hospital-based controls with respiratory illnesses.
      • Assiri A.
      • Al-Tawfiq J.A.
      • Al-Rabeeah A.A.
      • Al-Rabiah F.A.
      • Al-Hajjar S.
      • Al-Barrak A.
      • et al.
      Epidemiological, demographic, and clinical characteristics of 47 cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia: a descriptive study.
      • Alghamdi I.G.
      • Hussain I.I.
      • Almalki S.S.
      • Alghamdi M.S.
      • Alghamdi M.M.
      • El-Sheemy M.A.
      The pattern of Middle East respiratory syndrome coronavirus in Saudi Arabia: a descriptive epidemiological analysis of data from the Saudi Ministry of Health.
      • Memish Z.A.
      • Zumla A.I.
      • Al-Hakeem R.F.
      • Al-Rabeeah A.A.
      • Stephens G.M.
      Family cluster of Middle East respiratory syndrome coronavirus infections.
      Diabetes was very common across all groups, including healthcare workers. The high prevalence of renal disease in hospital inpatients reflects the wards in which nosocomial outbreaks occurred.
      Patients with secondary infections were detected by active surveillance and therefore are more likely to reflect the full spectrum of illness. Of note, a significant proportion of household infections and healthcare worker infections were reported to be asymptomatic, and previous cases have been noted to have prolonged viral shedding.
      • Drosten C.
      • Muth D.
      • Corman V.M.
      • Hussain R.
      • Al Masri M.
      • Haj Omar W.
      • et al.
      An observational, laboratory-based study of outbreaks of Middle East respiratory syndrome coronavirus in Jeddah and Riyadh, Kingdom of Saudi Arabia, 2014.
      • Spanakis N.
      • Tsiodras S.
      • Haagmans B.L.
      • Raj V.S.
      • Pontikis K.
      • Koutsoukou A.
      • et al.
      Virological and serological analysis of a recent Middle East respiratory syndrome coronavirus infection case on a triple combination antiviral regimen.
      • Drosten C.
      • Seilmaier M.
      • Corman V.M.
      • Hartmann W.
      • Scheible G.
      • Sack S.
      • et al.
      Clinical features and virological analysis of a case of Middle East respiratory syndrome coronavirus infection.
      • Poissy J.
      • Goffard A.
      • Parmentier-Decrucq E.
      • Favory R.
      • Kauv M.
      • Kipnis E.
      • et al.
      Kinetics and pattern of viral excretion in biological specimens of two MERS-CoV cases.
      Similar to a previous study, it was found that acute disease (with a short duration of symptoms at the time of hospital admission) was not associated with increased mortality.
      • Majumder M.S.
      • Kluberg S.A.
      • Mekaru S.R.
      • Brownstein J.S.
      Mortality risk factors for middle east respiratory syndrome outbreak, South Korea, 2015.
      It was reassuring to find that the majority of cases were admitted within a week, as early diagnosis is required to ensure that control measures are effective.
      • Su S.
      • Wong G.
      • Liu Y.
      • Gao G.F.
      • Li S.
      • Bi Y.
      MERS in South Korea and China: a potential outbreak threat?.
      A small proportion who were asymptomatic was noted; the clinical significance of asymptomatic infection, and particularly the potential for transmission, is not yet known.
      There were several limitations in reviewing this public health database. The data reported here represent almost 90% of the 1045 laboratory-confirmed cases of MERS-CoV reported in the Kingdom of Saudi Arabia, but the reasons for the missing data are not apparent. Available clinical data on diagnosis and treatment were scarce, and a significant proportion had missing data on comorbidities. As primary cases were detected following presentation with illness, unknown selection biases may be present. It is not possible to comment on risk factors for the acquisition of MERS-CoV without a control group without infection.

      Acknowledgements

      We thank the Research and Studies General Department and King Fahad Medical City, Ministry of Health, Riyadh, Saudi Arabia for the ethical approval of this study and the Ministry of Health, Riyadh, Saudi Arabia for providing us with the MERS- CoV data.
      Conflict of interest: All authors declare that they have no competing interests.

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