MERS CoV

1. HOSPITAL OUTBREAK OF MIDDLE EAST
RESPIRATORY SYNDROME
CORONAVIRUS
JOSE SOCRATES “DEE” M. EVARDONE
YEAR LEVEL I
IM DEPARTMENT, CDUH

2. HOSPITAL OUTBREAK OF
MIDDLE EAST RESPIRATORY
SYNDROME
CORONAVIRUS
AUGUST 1, 2013 VOL. 369 NO. 5
PAGES 407-416
ABDULLAH ASSIRI, M.D., ALLISON MCGEER, M.D., TRISH M.
PERL, M.D., ET AL
JOSE SOCRATES “DEE” M. EVARDONE
YEAR LEVEL I
IM DEPARTMENT, CDUH

3. Study Overview
A novel coronavirus (MERS-CoV) is causing severe disease in
the Middle East.
In this report on a hospital outbreak of MERS-CoV infection, 23
confirmed cases and evidence of person-to-person
transmission were identified.
The median incubation period was 5.2 days.

4. Objectives:
To be able to review about Coronaviruses, Basic Epidemiology
To be able to understand about MERS Cov
 1) Virology
 2) Epidemiology
 3) Case definitions
 4) Clinical manifestations
 5) Diagnosis
 6) Treatment
 7) Prevention
 8) Outcomes
 9) Travel Recommendations

5. Methods

6. • Setting:
• The governorate of Al-Hasa, eastern Saudi Arabia
• Serves a mixed urban and rural population of 1.1 million persons.
• 1) Hospital A is a 150-bed general hospital in the largest urban area (Al-
Hufuf). The dialysis unit, which cares for 43 patients in two shifts per day,
is an open unit with 16 beds spaced 1.3 to 1.5 m apart. The intensive
care unit (ICU) contains two open 6-bed bays.
• 2)Hospitals B and C are also general hospitals in Al-Hufuf. Hospital D is a
regional referral hospital located 160 km from Al-Hufuf.
METHODS:
• The governorate of Al-Hasa, eastern Saudi Arabia
• Serves a mixed urban and rural population of 1.1 million persons.
• Hospital A is a 150-bed general hospital in the largest urban area (Al-
Hufuf).
• The dialysis unit: 43 patients, 2 shifts/day, open unit with 16 beds
spaced 1.3 to 1.5 m apart.
• The ICU contains two open 6-bed bays.
• Hospitals B and Hospital C are general hospitals in Al-Hufuf.
• Hospital D is a regional referral hospital located 160 km from Al-Hufuf.

7. METHODS:
Definitions:
Confirmed case of MERS-CoV infection:
1) laboratory evidence of MERS-CoV
2) either fever and at least one respiratory symptom or two respiratory symptoms
without another identifiable cause.
Probable case of MERS-CoV infection:
1) if he or she was a household, family, or health care contact of a person with a
confirmed case
2) if pneumonia developed without another confirmed cause
3) either laboratory testing for MERS-CoV was not performed or a single test was negative
and no other specimens were available for testing.

8. METHODS:
Definitions:
The date of onset:
• febrile patients: the first day of fever that persisted for more than 48 hours
• afebrile patients: the first day of new cough or shortness of breath.
Exposed patients:
had any face-to-face contact with a symptomatic patient who had a confirmed or
probable case,
1) Was in the same hospital room or ward as a symptomatic case patient >1hr
2) Moved into a bed vacated by a symptomatic case patient
3) Was being cared for by a health care worker who was also caring for a
symptomatic case patient, or
4) Was sharing hospital equipment with a symptomatic case patient.

9. METHODS:
• Laboratory Surveillance:
• September 2012, the Saudi Arabian Ministry of Health requested that all patients
with pneumonia requiring admission to the ICU be tested for MERS-CoV.
• Throat-swab (Eurotubo, Deltalab),
• sputum,
• tracheal-aspirate, or
• bronchoalveolar- lavage
placed in viral transport medium (Vircell), stored at 28°C, and transported within 72
hours to the Ministry of Health regional reference laboratory in Jeddah, Saudi
Arabia, where they were subjected to real-time reverse-transcriptase–polymerase-
chain-reaction (RT-PCR) assays totest for MERS-CoV.20
• For all patients, the results of RT-PCR tests were confirmed by measuring cycle-
threshold values for viral load.

10. METHODS:
Identification of Clusters, Collection of Case Data, and Assessment of
Exposure
• Hospital A initiated active surveillance for pneumonia on April 20, 2013, and conducted a
retrospective review of in-hospital deaths and cases of pneumonia from March 1 through
April 19.
• They also reviewed the medical charts of patients with confirmed MERS-CoV infection to
identify symptoms, laboratory findings, and clinical course. The Ministry of Health
interviewed household contacts of patients with confirmed MERS-CoV infection and
followed them for 14 days after exposure.

11. METHODS:
Identification of Clusters, Collection of Case Data, and Assessment of
Exposure
• Mapped confirmed and probable MERSCoV cases in time and in space within health care
facilities.
• For each case, we identified potential exposures, with the assumption that face-to-face
contact or time spent in the same area conferred a greater risk than shared caregivers,
which in turn conferred a greater risk than shared equipment.
• No assumptions were made about incubation periods.
• Three of the authors reviewed potential exposures independently; when more than one
potential exposure was possible,
• the most likely source of exposure was identified by consensus among those authors and
an additional author.
• The corresponding author vouches for the accuracy and completeness of the data.

12. METHODS:
Sequencing and Phylogenetic Analysis:
• Full-genome sequences were obtained from specimens from four patients
(Patients I, J, K, and V)

13. METHODS:
• Statistical Analysis:
• They calculated empirical cumulative density functions of the incubation period and serial
intervals by computing the cumulative fraction of all observations that fell below each observed
value in the respective data sets.
• They estimated the incubation period by identifying the earliest and latest time of possible
exposure and the time of symptom onset for each case.
• Treating these times as interval-censored estimates of the incubation period for each person, we
fit a log-normal distribution to these data using maximum-likelihood techniques.
• We then examined the robustness of our estimates with multiple definitions of onset and with
the exclusion of particular cases.

14. METHODS:
Statistical Analysis:
They estimated the serial interval by identifying the times of symptom onset in the
patient and in the person who transmitted the infection (infected–infector pairs) and
then fitting a lognormal distribution to these interval-censored
They estimated the medians and 5th and 95th percentiles of the incubation period
and the serial interval using the quantiles of the lognormal distribution fit to each
data

15. Results

16. RESULTS:
• Description of the Outbreak
April 1 and May 23, 2013,
a total of 23 confirmed cases of human infection with MERSCoV were
identified in the
eastern province of Saudi Arabia

17. RESULTS:
A: Illness in Patients at Hospital A
1) Community Introductions
2) Hemodialysis Unit
3) ICU
4) Medical Ward
B: Illness in Staff Members at Hospital A
C: Illness in Family Members
D: Illness with Onset in Other health care facilities

18. RESULTS:

20. RESULTS:
Demographic and Clinical Features

21. RESULTS:
Demographic and Clinical Features
• median time from the onset of symptoms to ICU admission = 5 days
(range, 1 to 10)
• median time to the need for mechanical ventilation = 7 days
(range, 3 to 11)
• median time to death = 11 days (range, 5 to 27)

22. RESULTS:
Transmission, Incubation Period, and Serial Interval
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); 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) (Fig. 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).

23. RESULTS:
Sequencing and Phylogenetic Analysis
Phylogenetic analysis of the four MERS-CoV genomes
showed that the viruses form a monophyletic clade with a
bootstrap support of 100%

24. Discussion

25. LABORATORY-CONFIRMED
MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS INFECTION, APRIL–
MAY 2013.Characteristics Patients with confirmed cases (n=23)
Male sex — no. (%) 17 (74)
Age — yr
Median 56
Range 24–94
Age ≥50 yr — no. (%) 17 (74)
Age ≥65 yr — no. (%) 6 (26)
Obesity — no./total no. (%)* 5/21 (24)
Underlying Illness — no. (%)
End-stage renal disease 12 (52)
Diabetes mellitus 17 (74)
Cardiac disease 9 (39)
Lung disease, including asthma 10 (43)
Immunosuppressive condition other than renal disease 0
Symptoms before presentation — no. (%)
Fever 20 (87)
Cough 20 (87)
Shortness of breath 11 (48)
Gastrointestinal symptoms
Any 8 (35)
Vomiting 4 (17)
Diarrhea 5 (22)

26. LABORATORY-CONFIRMED
MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS INFECTION, APRIL–
MAY 2013.
0
39%
43%
52%
74%
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8
Immunosuppressive condition other than renal disease
Cardiac disease
Lung disease, including asthma
End Stage Renal Disease
Diabetes mellitus
Underlying Illness
Underlying Illness

27. LABORATORY-CONFIRMED
MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS INFECTION, APRIL–
MAY 2013.Characteristics Patients with confirmed cases (n=23)
Male sex — no. (%) 17 (74)
Age — yr
Median 56
Range 24–94
Age ≥50 yr — no. (%) 17 (74)
Age ≥65 yr — no. (%) 6 (26)
Obesity — no./total no. (%)* 5/21 (24)
Underlying Illness — no. (%)
End-stage renal disease 12 (52)
Diabetes mellitus 17 (74)
Cardiac disease 9 (39)
Lung disease, including asthma 10 (43)
Immunosuppressive condition other than renal disease 0
Symptoms before presentation — no. (%)
Fever 20 (87)
Cough 20 (87)
Shortness of breath 11 (48)
Gastrointestinal symptoms
Any 8 (35)
Vomiting 4 (17)
Diarrhea 5 (22)

28. TABLE 1. CHARACTERISTICS AND SYMPTOMS OF PATIENTS WITH
LABORATORY-CONFIRMED
MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS INFECTION, APRIL–
MAY 2013.
17%
22%
35%
48%
87%
87%
0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%
GI {Vomiting} (4)
GI {Diarrhea} (5)
GI {Any} (8)
Shortness of breath (11)
Fever (20)
Cough (20)
Symptoms before presentation
GI {Vomiting} (4) GI {Diarrhea} (5) GI {Any} (8) Shortness of breath (11) Fever (20) Cough (20)

29. TABLE 1. CHARACTERISTICS AND SYMPTOMS OF PATIENTS WITH
LABORATORY-CONFIRMED
MIDDLE EAST RESPIRATORY SYNDROME CORONAVIRUS INFECTION, APRIL–
MAY 2013. (CONT..)Characteristics Patients with confirmed cases (n=23)
Laboratory testing at presentation — no./total no. (%)
Abnormal white-cell count† 5/23 (22)
Abnormal platelet count‡ 5/23 (22)
Elevated aspartate aminotransferase 3/13 (23)
Oxygen saturation <95% while breathing ambient air 7/23 (30)
Chest radiographic findings at presentation — no. (%)
Normal 3 (13)
Increased bronchovascular markings 4 (17)
Unilateral infiltrate 10 (43)
Bilateral infiltrates 5 (22)
Diffuse reticulonodular pattern 1 (4)
Clinical course — no. (%)
Admitted to hospital 22 (96)
Admitted to intensive care unit 18 (78)
Received mechanical ventilation 18 (78)
Outcome as of June 12, 2013 — no. (%)
Recovered 6 (26)
Remained in hospital§ 2 (9)
Died 15 (65)

30. DISCUSSION:
• Acute viral respiratory tract infections cause considerable morbidity and mortality and pose a risk of
outbreaks in health care settings.
• We describe a cluster of MERS-CoV infections and report health care–associated human-to-human
transmission of MERS-CoV. The 65% case fatality rate in this outbreak is of concern.

31. DISCUSSION:

32. DISCUSSION:

33. DISCUSSION:

34. Conclusions

35. 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.

36. EPIDEMIOLOGY
Occurrence of infectious diseases:
Sporadic - refers to a disease that occurs infrequently and
irregularly
Endemic - refers to the constant presence and/or usual prevalence
of a disease or infectious agent in a population within a geographic
area
Hyperendemic - refers to persistent, high levels of disease
occurrence.
Epidemic - refers to an increase, often sudden, in the number of
cases of a disease above what is normally expected in that population
in that area.
Principles of Epidemiology in Public Health Practice, 3rd Edition

37. EPIDEMIOLOGY
Occurrence of infectious diseases:
Outbreak- definition of epidemic, but is often used for a more
limited geographic area
Cluster - an aggregation of cases grouped in place and time that
are suspected to be greater than the number expected, even though
the expected number may not be known
Pandemic - an epidemic that has spread over several countries or
continents, usually affecting a large number of people.
Principles of Epidemiology in Public Health Practice, 3rd Edition

38. EPIDEMIOLOGY
Outbreaks
Definition
• Two or more people who experience a similar illness or
confirmed infection, and are linked by a common factor, or
• When the observed number of cases unaccountably
exceeds the expected number for a given place and time.
The terms epidemic and outbreak are used interchangeably.
Principles of Epidemiology in Public Health Practice, 3rd Edition

39. EPIDEMIOLOGY
Surveillance
the continuing scrutiny of all aspects of the occurrence and spread
of a disease that are pertinent to effective control.
It involves a systematic collection, collation and analysis of data
and the prompt dissemination of the resulting information to
those who need to know so that action can result
Principles of Epidemiology in Public Health Practice, 3rd Edition

40. CORONAVIRUS

41. CORONAVIRUS
VIROLOGY
Coronaviruses are members of the Nidovirus family, viruses that
replicate using a nested set of mRNAs (“nido-” for “nest”).
The human coronaviruses are classified in two genera:
1) alpha coronaviruses (HCoV-229E and HCoV-NL63) and
2) beta coronaviruses (HCoV-HKU1, HCoV-OC43),
a) Middle East respiratory syndrome coronavirus [MERS-CoV], and
b) Severe acute respiratory syndrome coronavirus [SARS-CoV]).

42. CORONAVIRUS
• Viral composition —
• medium-sized, enveloped, positive-stranded RNA viruses
• name derives from their characteristic crown-like appearance in electron
micrographs
• These viruses have the largest known viral RNA genomes, with a length of
27 to 32 kb.
• The host-derived membrane is studded with glycoprotein spikes and
surrounds the genome, which is encased in a nucleocapsid that is helical in
its relaxed form but assumes a roughly spherical shape in the virus particle

43. Phylogenetic relationships among members of the subfamily Coronavirinae and taxonomic position of
MERS-CoV.
de Groot R J et al. J. Virol. 2013;87:7790-7792

44. CORONAVIRUS VIRAL COMPOSITION
• —

45. CORONAVIRUSWhat is coronavirus?

46. NOVEL HUMAN CORONAVIRUSES
1) Human coronavirus 229E
2) Human coronavirus OC43
3) SARS-CoV (2003)
4) Human Coronavirus NL63 (HCoV-NL63, New Haven coronavirus) (2003)
5) Human coronavirus HKU1 (2005)
6) Middle East respiratory syndrome coronavirus (MERS-CoV), previously known as
Novel coronavirus 2012 and HCoV-EMC(2012)

47. CORONAVIRUS
What is MERS?
Middle East Respiratory Syndrome
(MERS)
-a viral respiratory illness
-caused by a coronavirus called “Middle East
Respiratory Syndrome Coronavirus” (MERS-
CoV).

48. MERS-COV
• Q: What are the symptoms of MERS?
• severe acute respiratory illness with symptoms of fever,
cough, and shortness of breath.
• About half of them died.
• Some people were reported as having a mild respiratory
illness.

49. MERS-COV
Genetic analysis—sufficient heterogeneity to support multiple separate
animal-to-human transfers
Cotten M, Watson SJ, Kellam P, et al. Transmission and
evolution of the Middle East respiratory syndrome coronavirus
in Saudi Arabia: a descriptive genomic study. Lancet 2013;
382:1993.

50. Saudi Arabia
United
Kingdom
France
Italy
Tunisia
Jordan
Qatar
United Arab
Emirates
Oman
Malaysia
United
States

51. MERS-COV
1) “Index
Patient”
June 2012
KSA
2) Sept 2012,
Qatar
3) Infected with no
Epidemiologic link
4) Oct & Nov 2012
4 Men in 1 Family, Riyadh
2 died
5) Jordan
2 confirmed cases
6) January 2013, U.K.
7) Feb 2013, Px’s son
8) Family member
9) March 2013, Abu
Dhabi, UAE
10) April 2013
23 confirmed cases
11 probable cases
11) May 2013, France
2 diagnosed
12) May 2013, Tunisia
3 cases
13) May 2013, Italy
3 cases

52. MERS-COV
Possible sources and modes of transmission:
1) Bats
2) Camels
3) Human-to-Human

53. MERS-COV
• Possible sources and modes of transmission:
BATS
• Bat Coronavirus RNA sequence closely related to MERS-CoV sequences
• Might be a reservoir of MERS-CoV
• unlikely that they are the immediate source

54. MERS-COV
• Possible sources and modes of transmission:
CAMELS

55. MERS-COV
Possible sources and modes of transmission:
CAMELS
• Intermediate Hosts
• viruses were quite similar and shared several unusual single nucleotide
polymorphism
• Attempts to isolate viruses were unsuccessful
• Serologic studies have also suggested that camels are an important source of
MERS-CoV
• Using stored serum samples from 1992 to 2010, antibodies to MERS-CoV were detected
as early as 1992
• 651 serum samples from dromedary camels (151 from 2003; 500 from 2013), 632
samples (97 percent) had antibodies against MERS-CoV, including all of the samples
collected in 2003, prior to the outbreak in humans

56. MERS-COV
What is the significance of the recent finding of MERS-CoV in a
camel?
The critical questions are :
• What is the route by which humans are infected?
• In what way are they exposed?
Most patients who have tested positive for MERS-CoV
• had neither a human source of infection
• nor direct exposure to animals, including camels
It is still unclear whether camels, even if infected with MERS-CoV, play a role
in transmission to humans.

57. MERS-COV
• Possible sources and modes of transmission:
• Human-to-human transmission

58. MERS-COV
• Possible sources and modes of transmission:
• Human-to-human transmission

59. REVISED INTERIM CASE DEFINITION FOR REPORTING TO WHO AS
OF 3 JULY 2013
CASE DEFINITIONS
Confirmed case: A person with laboratory confirmation of infection with MERS-CoV
Probable case:
 A person with an acute respiratory infection (with or without fever) with clinical, radiographic,
or histopathologic evidence of pulmonary parenchymal disease
 No possibility of laboratory confirmation for MERS-CoV because either the patient or samples are
not available for testing and
 Close contact with a laboratory-confirmed case.

60. REVISED INTERIM CASE DEFINITION FOR REPORTING TO WHO
(AS OF 3 JULY 2013)
PROBABLE CASE
CLINICAL LABORATORY EPIDEMIOLOGICAL
acute febrile respiratory
illness with clinical,
radiological, or
histopathological evidence of
pulmonary parenchymal
disease
MERS-CoV is unavailable or
negative on a single
inadequate specimen
direct epidemiologic-link with
a confirmed MERS-CoV case
acute febrile respiratory
illness with clinical,
radiological, or
histopathological evidence of
pulmonary parenchymal
disease
inconclusive MERS-CoV
laboratory test
direct epidemiologic-link with
a confirmed MERS-CoV case
acute febrile respiratory
illness of any severity
inconclusive MERS-CoV
laboratory test
resident of or traveler to
Middle Eastern countries
where MERS-CoV virus is
believed to be circulating in
the 14 days before onset of
illness

61. CLINICAL MANIFESTATIONS
• Incubation period - 5.2 days (1.9-14.7 days)
• Clinical features :
• 1) severely ill with pneumonia and acute respiratory distress syndrome
• 2) some have had acute kidney injury

62. CORONAVIRUS
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
100%
98%
87%
83%
72%
32%
26%
21% 21%
17%
17%
CLINICAL PICTURE

63. MERS-COV
LABORATORY ABNORMALITIES — AMONG 47 CASES OF MERS-COV INFECTION
IN SAUDI ARABIA
11%
11%
14%
15%
34%
36%
49%
0% 10% 20% 30% 40% 50% 60%
Elevated ALT
Lymphocytosis
Leukopenia
Elevated AST
Lymphopenia
Thrombocytopenia
Elevated LDH
.

64. MERS-COV
Diagnosis
1) Polymerase chain reaction and sequencing
-real-time reverse-transcriptase polymerase chain reaction (rRT-
PCR) testing
2) Serology

65. MERS-COV
DIAGNOSIS
rRT-PCR - real-time reverse-transcriptase polymerase
chain reaction
Lower respiratory tract specimens
Serum samples

66. MERS-COV
DIAGNOSIS
rRT-PCR
Recommendations by WHO and CDC:
1) Lower respiratory tract specimens
2) Combined nasopharyngeal and oropharyngeal swab
specimen
3) Acute and convalescent
4) blood, urine, and stool (uncertain)
5) Continued sampling and testing by rRT-PCR is encouraged
6) Nucleic acid sequencing in certain cases

67. MERS-COV
DIAGNOSIS
rRT-PCR
• false-negative results
• specimen was of poor quality,
• collected late or very early in the illness,
• not handled and shipped appropriately, and
• technical problems with the test.
• Three rRT-PCR assays for routine detection of MERS-CoV
have been developed

68. MERS-COV
DIAGNOSIS
SEROLOGY
• Detection of MERS-CoV Antibodies:
• immunofluorescence assays
• protein microarray assay
• 2-stage approach by CDC
• Screening: enzyme-linked immunosorbent assay (ELISA)
• Confirmation: indirect immunofluorescence test or
microneutralization test

69. MERS-COV
Treatment
NO antiviral agents are recommended for the treatment of MERS-CoV
infection.
1) combination therapy with
a)Interferon (IFN)-alpha-2b and
b) Ribavirin appears promising
None of the patients responded to therapy and all died of their illness.
2) Convalescent plasma,
3) Monoclonal antibodies, and
4) Inhibition of the main viral protease

70. MERS-COV
OUTCOMES
April 26, 2014
261
36%
(93)
Laboratory
Confirmed
Died
Overestimate
14
19
(74%)
Routine
Surveillance
5
24
(21%)
Secondary Cases
AGE(47 patients)
39% (<50 yo)
48% (<60 yo)
75% (>60 yo)

71. MERS-COV
TRAVEL RECOMMENDATIONS
The Ministry of Health of Saudi Arabia recommended that in 2013, the following individuals postpone
their plans to travel to Mecca, Saudi Arabia, for Hajj and/or Umrah due to the outbreak of MERS-CoV
●Elderly individuals (>65 years of age)
●Individuals with chronic diseases (eg, heart disease, kidney disease, respiratory
disease, diabetes)
●Individuals with immunodeficiency (congenital or acquired)
●Patients with malignancy
●Patients with a terminal illness
●Pregnant women
●Children (<12 years of age)

72. THANK
YOU