Description of the Outbreak

Figure 1. Figure 1. Epidemiologic Plot of Confirmed and Probable Cases of MERS-CoV Infection in Saudi Arabia, April 1–May 23, 2013. All confirmed and probable cases are shown, according to the location of the most probable transmission. One of the five family contacts (Patient M) who is included as having been exposed in Hospital A was also exposed through caring for the patient at home and may have acquired the infection either in the hospital or in the community.

Between April 1 and May 23, 2013, a total of 23 confirmed cases of human infection with MERS-CoV were identified in the eastern province of Saudi Arabia (Fig. S1 in the Supplementary Appendix). All confirmed cases and 11 probable cases were part of a single outbreak involving four health care facilities (Figure 1).

Illness in Patients at Hospital A

Community Introductions

On April 5, 2013, Patient A was admitted to the medical ward with dizziness and diaphoresis. On hospital day 4, fever and progressive pulmonary infiltrates developed. The patient was not tested for MERS-CoV, but his son (Patient O) subsequently had a confirmed case of MERS-CoV infection (Fig. S2 and Table S1 in the Supplementary Appendix).

On April 4, Patient B was admitted to the ICU with a diagnosis of stroke. On hospital day 6, fever developed, and a throat-swab specimen was obtained, which was negative for MERS-CoV. When pneumonia developed in the patient, MERS-CoV was identified on repeat testing. No epidemiologic link between Patients A and B could be established.

Patient C, who had been undergoing long-term hemodialysis, was admitted to Hospital A on April 6 to the room adjacent to Patient A. He was still in that room on April 8, which was the day on which fever developed in Patient A. Fever developed in Patient C 3 days later. He underwent dialysis in the hospital's outpatient hemodialysis unit twice after the onset of symptoms — on April 11 and April 13.

Hemodialysis Unit

Between April 14 and April 30, MERS-CoV infection was confirmed in nine additional patients, who were undergoing hemodialysis in Hospital A (Fig. S2 in the Supplementary Appendix). Six of these patients (Patients D, E, F, G, H, and I) underwent hemodialysis at times that overlapped with the times Patient C was undergoing hemodialysis on either April 11 or April 13; three of them underwent the procedure in beds adjacent to Patient C's bed. Two patients (Patients K and P) underwent hemodialysis at times that overlapped with the times Patient F was undergoing hemodialysis after the onset of his symptoms, and one patient (Patient L) underwent hemodialysis in a bed adjacent to symptomatic Patient E. Eight additional probable cases occurred among patients undergoing hemodialysis between April 15 and April 30. There were no links between individual dialysis nurses or machines and case patients.

Among the nine patients undergoing hemodialysis at Hospital A who had confirmed MERS-CoV infection, eight had an onset of disease before or within 24 hours after infection-control interventions were implemented on April 21. These interventions included monitoring hand hygiene, implementing droplet and contact precautions for febrile patients, testing patients with fever for MERS-CoV, putting masks on all patients undergoing hemodialysis, not allowing patients with suspected MERS-CoV infection into the dialysis unit, enhancing environmental cleaning, and excluding visitors and nonessential staff. In the 8 days after implementation of precautions, illness developed in six patients: MERS-CoV infection was confirmed in one patient (Patient P) and was classified as probable in five patients; no additional confirmed cases occurred from May 1 to May 23.

ICU

Between April 9 and April 26, Patients A, C, D, and E were treated with continuous positive airway pressure and received nebulized medications; six cardiac arrests occurred among these four patients. MERS-CoV infection developed in two additional patients (Patients J and Q, both with confirmed cases) who were present in the same ICU during this time. Infection-control measures similar to those in the hemodialysis unit were implemented throughout the hospital on April 26. No further confirmed cases occurred in the ICU.

Medical Ward

Figure 2. Figure 2. Transmission Map of Outbreak of MERS-CoV Infection. All confirmed cases and the two probable cases linked to transmission events are shown. Putative transmissions are indicated, as well as the date of onset of illness and the settings. The letters within the symbols are the patient identifiers (see Fig. S2 in the Supplementary Appendix).

One patient undergoing hemodialysis (Patient H) who had confirmed infection was admitted to a medical ward (Figure 2) on April 21. Patient N, who was separated from Patient H by two rooms, became ill on April 25, and Patient U, who was separated from Patient H by three rooms, became ill on April 28.

Illness in Staff Members at Hospital A

One of the 124 health care worker contacts of patients with confirmed MERS-CoV infection reported a 48-hour history of febrile illness without respiratory symptoms beginning on May 5; testing for MERS-CoV was not performed. On May 8, MERS-CoV infection developed in a nurse administrator (Patient R), who was not known to have been exposed to any patients identified as having MERS-CoV infection. She was in the ICU during two simultaneous cardiac resuscitations on April 15 and had face-to-face contact on May 5 with the febrile health care worker described above. No other potential exposures were identified.

Illness in Family Members

A total of 217 household contacts of patients with confirmed cases were followed up, including 120 adults (median age, 26 years; range, 18 to 100) and 97 children. MERS-CoV infection developed in 5 adult family members who were hospital visitors of Patients A, G, and N; 3 were confirmed cases (in patients M, O, and S) and 2 were probable (Figure 2, and Fig. S2 and Table S1 in the Supplementary Appendix).

Illness with Onset in Other Health Care Facilities

Patient Q, who became infected with MERS-CoV in the ICU of Hospital A, had been undergoing long-term hemodialysis at an outpatient clinic in Hospital C and underwent hemodialysis in that unit while he was symptomatic. MERS-CoV infection developed in two additional patients (Patients T and W) at Hospital C. Patient T regularly traveled from home to the dialysis unit with Patient Q. Patient W underwent hemodialysis in the same 13-bed room and during the same shift as Patient Q.

Eight patients (Patients B, E, F, G, H, I, K, and L) with confirmed MERS-CoV infection were transferred to Hospital D between April 18 and April 27. MERS-CoV infection developed in two patients (Patients X and Y) who were hospitalized on the same ward as Patient G and in a physician (Patient V) who cared for Patient K. Overall, two laboratory-confirmed cases occurred among more than 200 health care worker contacts who were followed after exposure.

Demographic and Clinical Features

Table 1. Table 1. Characteristics and Symptoms of Patients with Laboratory-Confirmed Middle East Respiratory Syndrome Coronavirus Infection, April–May 2013.

Most of the case patients were men, and the median age was 56 years (Table 1). The most common signs and symptoms were fever (in 87% of the patients) and cough (in 87%), and 35% presented with vomiting or diarrhea. Among patients in whom the illness progressed, the median time from the onset of symptoms to ICU admission was 5 days (range, 1 to 10), the median time to the need for mechanical ventilation was 7 days (range, 3 to 11), and the median time to death was 11 days (range, 5 to 27). Three of four patients (75%) whose cases were detected by active surveillance during the outbreak, as compared with 3 of 19 (16%) whose cases were identified clinically, have recovered (P=0.04).

Transmission, Incubation Period, and Serial Interval

Figure 3. Figure 3. Estimates of the Incubation Period and Serial Interval of MERS-CoV Infection. The empirical cumulative density function of the observed cases (the fraction of all observations that fell below each observed value) (black lines) with respect to the incubation period (Panel A) and serial interval (the time between the onset of illness in a case patient and the onset of illness in a contact) (Panel B) is shown, with a plot of the cumulative distribution of log-normal distributions fit to the data indicated by thick yellow and blue lines, respectively. The 95% confidence intervals for the 5th, 50th, and 95th percentiles of these fitted distributions are indicated by the yellow and blue horizontal lines. Yellow and blue shading indicates cumulative distributions of log-normal distributions fit to bootstrapped samples of our observed data.

One patient transmitted the infection to seven persons, one patient transmitted the infection to three persons, and four patients transmitted the infection to two persons each. The incubation period of confirmed cases was 5.2 days (95% confidence interval [CI], 1.9 to 14.7) (Figure 3); distributions that were fit to our observed data indicated that 95% of infected patients would have an onset of symptoms by day 12.4 (95% CI of 95th percentile, 7.3 to 17.5), whereas 5% would have an onset of symptoms by day 2.2 (95% CI of 5th percentile, 1.2 to 3.1).

We estimated that the serial interval was 7.6 days (95% CI, 2.5 to 23.1) (Figure 3). The distributions that were fit to our observed data indicate that the serial interval was less than 19.4 days in 95% of cases (95% CI of 95th percentile, 11.7 to 27.0) and less than 3.0 days in 5% of cases (95% CI of 5th percentile, 1.8 to 4.2).

Sequencing and Phylogenetic Analysis

Figure 4. Figure 4. Phylogenetic Analysis of the Sequences of All Genes Identified in Four Patients Infected with MERS-CoV. Panel A shows single-nucleotide differences (vertical colored bars) between the England2 genome and the four Al-Hasa genomes as well as the four additional full genomes available; gray indicates a gap in the query sequence, orange a change to A, crimson a change to T, blue a change to G, and purple a change to C. The reference genomes we used were from a Jordanian patient in April 2012 (GenBank accession number, KC776174), EMC/2012 from a Saudi Arabian patient in July 2012 (JX869059),19 England/Qatar/2012 from a London Qatari patient in September 2012 (KC667074),22 England2 from a patient who had traveled to Pakistan and Saudi Arabia in February 2013,13 and the Munich/AbuDhabi sequence from a patient from the United Arab Emirates in March 2013.23 Panel B shows an unrooted maximum-likelihood phylogeny inferred under a generalized-time-reversal (GTR)+Gamma substitution model that compares the five previously identified Middle East respiratory syndrome (MERS) genomes with the four Al-Hasa genomes. Bootstrap values are shown for the highly supported nodes. Panel C shows a time-resolved maximum clade credibility tree for the five previously identified genomes and the four Al-Hasa MERS coronavirus genomes. Posterior probability values are shown for nodes with posterior support greater than 0.5. Findings are consistent with previously published estimates.24

Among the four MERS-CoV isolates, Al-Hasa_1_2013 (GenBank accession number, KF186567) from Patient V and Al-Hasa_4_2013 (KF186564) from Patient K have identical genomes, whereas Al-Hasa_2_2013 (KF186566) from Patient J and Al-Hasa_3_2013 (KF186565) from Patient I have two or three nucleotide differences from Al-Hasa_1_2013 (Figure 4A).

Phylogenetic analysis of the four MERS-CoV genomes showed that the viruses form a monophyletic clade with a bootstrap support of 100% (Figure 4B). The most closely related sequence to this clade is England2, with a genetic distance of 0.0008 substitutions per site. The Al-Hasa lineage has 15 defining mutations (4 nonsynonymous: A1643S and V2550I in ORF1ab, Q1208H in S protein, and F58S in ORF3).

We estimated that the date of the most recent common ancestor of MERS-CoV was August 18, 2011 (95% highest posterior density [HPD, intervals for nucleotide sequences], November 1, 2009, to April 14, 2012). The date of the divergence of the Al-Hasa lineage was December 6, 2012 (95% HPD, July 18, 2012, to February 3, 2013), and the date of the most recent common ancestor of the Al-Hasa lineage was April 2, 2013 (95% HPD, February 7, 2013, to April 21, 2013) (Figure 4C).