case study 1: mers-cov - society for healthcare...

© SHEA 2017

SHEA/CDC OUTBREAK RESPONSE TRAINING PROGRAM

Case Study 1: MERS-CoV

Trish M. Perl, MD, MSc

Chief, Infectious Diseases

Jay P. Sanford Professor of Medicine

UT Southwestern Medical Center

© SHEA 2017


Financial Disclosures

Trish M. Perl, MD, MSc

Research support: VA and CDC (mask study), Medimmune

(not vaccine related)

Advisory Boards: Pfizer, Inc., Merck & Co, Inc., DebMed

Worked for Ministry of Health and National Guard Hospital on

MERS-CoV mitigation and control

© SHEA 2017


Learning Objectives

Upon completion, participants should be able to:

Recognize when to be concerned about potential emerging infections

Understand universal actions that can and should be taken to care for

patients, staff, and public

© SHEA 2017


Outline

Part I: Background on emerging respiratory infections

Part II: Case study: MERS-CoV

Part III: Reflections and recommendations

© SHEA 2017


Part I: Background on Emerging Respiratory Infections

© SHEA 2017


When Should You Be Concerned About an Emerging Infection? An unusual case or cluster of cases

A previously undetected or unknown infectious agent

A known agent that has:

Spread to new geographic locations or new populations

Re-emerged following a declining incidence of disease

A genetic adaptation changing illness severity

Examples: SARS, MERS-CoV, measles, Zika, human adenovirus 14p1,

influenza (variants H3N2, H7N9)

© SHEA 2017


Geographic Distribution of Recent Outbreaks*

*As of 2/28/2017. Publichealthwatch.

www.publichealthwatch.wordpress.com; Smith KF, et al. J R Soc Interface. 2014;11:20140950.

HCV

Cryptosporidiosis

Cyclosporiasis

E coli 0157:H7

Vancomycin-resistant

S aureus

Human

monkeypox

Anthrax

bioterrorism

Whitewater

arroyo virus

Hantavirus

pulmonary

syndrome

Dengue

Yellow fever Cholera

Human monkeypox

Diphtheria

Drug-resistant malaria

Multidrug-resistant tuberculosis

Typhoid

fever

Rift Valley

fever

Plague

HIV

Enterovirus 71

Hendra virus

Nipah virus

SARS

H5N1

influenza

Lassa fever

Marburg

haemorrhagic fever

vCJD

West Nile virus

Lyme disease

Ebola

haemorrhagic fever

Vancomycin-resistant

S aureus

E coli 0157:H7

© SHEA 2017


Transmission of Respiratory Viruses

Remains a source of controversy

Observational studies in healthcare settings indicate that contact

(direct and indirect) and droplet transmission are the primary means

of spread

Relative contributions of each type of transmission is unknown

Anecdotal experience with airborne transmission can be helpful in

understanding the factors that contribute to transmission

Drinka PJ, et al. J Am Geriatr Soc. 2004;52:847-8; Brankston G, et al. Lancet Infect Dis. 2007;7:257-65;

Cunney RJ, et al. Infect Control Hosp Epidemiol. 2000;21:449-54; Morens DM, et al. Infect Control Hosp Epidemiol. 1995;16:275-80.

© SHEA 2017


Which Interventions Are Best at Preventing Respiratory Infections?

Jefferson T, et al. Cochrane Database Syst Rev. 2011;7:CD006207.

Outcome or Subgroup Title

No. of

Studies

No. of

Participants Statistical Method Effect Size

Thorough disinfection

of living quarters

1 990 OR (M-H, Fixed, 95% CI) 0.30 [0.23, 0.39]

Frequent handwashing 6 2,077 OR (M-H, Fixed, 95% CI) 0.45 [0.36, 0.57]

Wearing mask 5 1,991 OR (M-H, Fixed, 95% CI) 0.32 [0.25, 0.40]

Wearing N95 mask 2 340 OR (M-H, Fixed, 95% CI) 0.09 [0.03, 0.30]

Wearing gloves 4 712 OR (M-H, Fixed, 95% CI) 0.43 [0.29, 0.65]

Wearing gowns 4 712 OR (M-H, Fixed, 95% CI) 0.23 [0.14, 0.37]

All interventions 2 369 OR (M-H, Fixed, 95% CI) 0.09 [0.02, 0.35]

Comparison 1. Case Control Studies

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Effectiveness of Precautions: Lessons From SARS

Case-control study in 5 Hong Kong hospitals with 241 noninfected

and 13 infected staff

Retrospective cohort study in 2 Toronto critical care units with

35 noninfected and 8 infected nurses

Seto WH, et al. Lancet. 2003;36:1519-20; Loeb M, et al. Emerg Infect Dis. 2004;10:251-5.

RR (95% CI)

Precaution Hong Kong Toronto

Handwashing 0.2 (0.07-1) N/A

Gloves 0.5 (0.14-1.6) 0.45 (0.14-1.46)

Gown Undef (P = .066) 0.36 (0.10-1.24)

Mask 0.08 (0.02-0.33) 0.23 (0.07-0.78)

© SHEA 2017


Source Control: Efficacy of Surgical and N95 Masks to Filter Influenza in Positive Patients

Johnson DF, et al. Clin Infect Dis. 2009;49:275-7.

Cycle Number

Patient or Variable Influenza

Type Nasal Swab

No Mask, Before Control (Step 1)

N95 Mask (Step 2)

Surgical Mask

(Step 3)

No Mask, After

Control (Step 4)

Duration of Illness, Days Per

Week

Patient

1 A 31 38 Negative Negative 39 3

2 A 26 40 Negative Negative Negative 1

3 A 22 Negative Negative Negative 40 3




7 B 22 38 Negative Negative 27 2

8 A 29 34 Negative Negative Negative 3

9 B 27 Negative Negative Negative 39 3

Mean cycle time for patients with detected influenza A … 26a 34.17a 0 0 34.4a 2b

Estimated viral load for detected influenza A, copies/mL … 5 milliona 50,000a 0 0 50,000a …

Note: Cycle number indicates real-time RT-PCR cycle number. The cycle number value is inversely proportional to the titer of virus present. aMean value calculated from patients with detectable influenza A. bMean duration.

© SHEA 2017


Nosocomial ARI Outbreaks

Nosocomial outbreaks documented in a variety of healthcare settings, including general medical wards, LTCFs, and pediatrics and oncology units

In 2009, among 1,520 hospitalized patients with pH1N1, 30 acquired influenza nosocomially

57% received antivirals, 53% received escalated care, and 27% died

Nosocomial outbreaks can also result in up to 50% attack rates in staff, staff furloughs, and increased costs for the institution

Enstone JE, et al. Emerg Infect Dis. 2011;17:592-8; Stott DJ, et al. Occup Med (Lond). 2002;52:249-53.

© SHEA 2017


Healthcare-Associated Respiratory Infections: Pediatrics

Of 96 patients, 9% died and 3% of deaths were attributed to FRI

15% (2/13) of children with influenza had been vaccinated, and 80% (4/5) of children with RSV had received

anti-RSV monoclonal antibody Vayalumkal JV, et al. Infect Control Hosp Epidemiol. 2009;30:652-8.

Redraw

Surveillance

Site No. of Cases

Surveillance

Period, Days

No. of

Patient-Days

Infections per

1,000 Patient-Days No. of Admissions

Infections per

1,000 Admissions

A 7 81 7,699 0.91 1,306 5.36

B 35 111 32,413 1.08 4,338 8.07

C 13 111 11,691 1.11 2,301 5.65

D 3 90 4,906 0.61 747 4.02

E 20 119 13,311 1.50 911 24.66

F 11 113 11,461 0.96 1,938 5.68

G 5 119 11,013 0.45 1,750 2.86

H 2 119 6,802 0.29 491 4.07

Total 96 … 99,296 0.97 13,682 7.02

Incidence of Healthcare-Acquired FRI in Patients Younger Than 18 Years Old, Canadian Nosocomial Infection Surveillance Program

Surveillance, 2005

© SHEA 2017


Healthcare-Associated Respiratory Infections: Pediatrics (cont.)

Vayalumkal JV, et al. Infect Control Hosp Epidemiol. 2009;30:652-8.

Pathogen

No. (%) of

Isolates

RSV 38 (38)

Influenza A 9 (9)

Influenza B 8 (8)

Parainfluenza 11 (11)

Adenovirus 6 (6)

Staphylococcus aureus 7 (7)

Haemophilus influenza 4 (4)

Moraxella catarrhalis 4 (4)

Streptococcus pneumoniae 3 (3)

Pseudomonas aeruginosa 2 (2)

Enterobacter cloacae 2 (2)

Other bacteria 6 (6)

= 72%

© SHEA 2017


Speciesa Total No. of Outbreaksb

Outbreaks Including Some Kind of Closure Closure Rate P Value

S aureus 223 23 10.3% NS

Hepatitis virus 150 6 4.0% .002

Pseudomonas spp 130 10 7.7% NS

Klebsiella spp 115 10 8.7% NS

Acinetobacter spp 105 24 22.9% .02

Serratia spp 94 14 14.9% NS

Enterococci 67 8 11.9% NS

Enterobacter spp 66 10 15.2% NS

Streptococci 63 18 28.6% .001

Salmonella spp 56 4 7.1% NS

Legionella spp 48 2 4.2% NS

Norovirus 34 15 44.1% < .001

Clostridium spp 34 4 11.8% NS

Aspergillus spp 25 5 20.0% NS

Influenza/parainfluenza virus 26 10 28.5% < .001

Citrobacter spp 12 3 25.0% NS

Adenovirus 11 3 27.3% NS

Shigella spp 11 4 36.4% .04

Rotavirus 27 7 25.9% .05

SARS coronavirus 12 4 33.3% NS

Total 1,561 194 12.4% —

Unit Closure Rates for Various Pathogens

Hansen S, et al. J Hosp Infect. 2007;65:348-53.

Closure Rates in Outbreaks Stratified by the Causative Pathogen (Outbreak Database, N = 1,561)

aOnly pathogens that had been reported in at least 10 outbreaks are included. bMultiple answers possible.

© SHEA 2017


Part II: MERS-CoV Outbreaks

© SHEA 2017


MERS-CoV: Saudi Arabia, 2012

60-year-old Saudi man admitted to

hospital on June 13, 2012

7-day history of fever, productive

cough, and shortness of breath

No history of cardiopulmonary or

renal disease, no long-term

medications, nonsmoker

Treatment

Oseltamivir, levofloxacin, piperacillin-

tazobactam, and micafungin

Physical Examination

Findings

BP 140/80 mm Hg

HR 117 beats/min

Temp 38.3° C

RR 20 breaths/min

Zaki AM, et al. N Engl J Med. 2012;367:1814-20.

© SHEA 2017


Immediate Steps

Data to collect and/or consider

Exposures Other ill persons

Animals

Season

Travel

How do I protect HCP, visitors, and other patients?

Isolation/cohorting

PPE

Source control

© SHEA 2017


Re-Evaluate

Data to collect and/or consider Exposures

Other ill persons

Animals

Season Travel

Do I need additional measures in place to protect HCP, visitors, and other patients? Isolation/cohorting PPE Source control

© SHEA 2017


What Now?

We have:

Atypical and severe

respiratory illness with

routine diagnostic testing not

revealing expected pathogens

Unusual finding on viral

cultures

No expected “exposures”

We should:

Send specimen for additional

testing

Ensure appropriate isolation

and PPE

Conduct a literature search

Call public health authorities

regarding other potential cases

Call colleagues regarding other

potential cases

© SHEA 2017


ProMED-mail: Saturday, September 15, 2012

A new human coronavirus was isolated from...sputum of a male patient aged

60 years old presenting with pneumonia associated with acute renal failure.

Testing with a pancoronavirus RT-PCR yielded a band at a molecular weight

appropriate for a coronavirus. The virus RNA was also tested in Dr. Ron

Fouchier's laboratory in the Netherlands and was confirmed to be a new

member of the beta group of coronaviruses, closely related to bat

coronaviruses.

© SHEA 2017


What Do We Know About Coronavirus?

Single-stranded RNA

Common cause of respiratory

virus infections

Mild infections: alpha 229E and

NL63, beta OC43

Severe infections: SARS-CoV,

MERS-CoV

Natural hosts include bats, civet

cats, dogs, and rodents

CDC. www.cdc.gov;

Graham RL, et al. Nat Rev Microbiol. 2013;11:836-48.

Membrane protein

Nucleocapsid protein

Spike protein

RNA

Envelope protein

© SHEA 2017


Sequencing MERS-CoV

Originally named HCoV-EMC

Belongs to lineage C of the

genus β-coronavirus (with

bat coronaviruses HKU4

and HKU5)

SARS-CoV is lineage B

6 human coronaviruses

indicated in red

Milne-Price S, et al. Pathog Dis. 2014;71:121-36.

δ

β

α

γ

A

B

D

C

94

80

100

100

96

88 88

100

100

100

96

83

100

100

100

100

96

BtC

oV

-HK

U7

96

© SHEA 2017


Bermingham A, et al. Euro Surveill. 2012;17:20290; Pebody RG, et al. Euro Surveill. 2012;17:20292.

MERS-CoV: England, 2012

On September 14, 2012, a patient with unexplained severe respiratory illness was transferred to intensive care in London after traveling from Qatar

Negative for specific and well-known coronaviruses

Positive for general coronavirus family

Sequence showed genus β-coronavirus with closest relationships to bat coronaviruses HKU4 and HKU5

99.5% sequence similarity to novel human coronavirus recovered from a Saudi Arabian man who died in June 2012

13 close contacts (all HCWs) with mild self-limiting respiratory illnesses

© SHEA 2017


WHO Global Alert: Sunday, September 23, 2012

WHO. www.who.int.

© SHEA 2017


MERS-CoV: Saudi Arabia (Al-Hasa), 2013

7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 1 2 3 4 5 6 7 8 9 10 11 12 13 14

0

4

2

3

4

April 2013 May 2013

No

. o

f N

ew

Ca

se

s

Acquired in Dialysis Unit, Hospital A

Acquired in Hospital B, C, or D

Acquired in ICU, Hospital A

Acquired in Ward 1, Hospital A

Acquired in Ward 2, Hospital A

Community-Acquired

Assiri A, et al. N Engl J Med. 2013;369:407-16.

© SHEA 2017


Evaluating the Situation Further

What key facts do you need to determine?

Who?

What?

Where?

When?

What is the likely transmission? Or source?

What is the incubation period? Serial interval?

What is a case?

Line list

Epidemic curve

Exposure history

© SHEA 2017


Who, What, When, Where: Al-Hasa, 2013

Important epidemiologic

findings from the Al-Hasa

outbreak

Interhospital transmission

Transmission in ICU and

crowded settings

Key individuals who spread

to many other individuals

Assiri A, et al. N Engl J Med. 2013;369:407-16.

Family Member

HCW

Patient

Confirmed Case

Probable Cause

Community

Ward 1, Hospital A

Ward 2, Hospital B

Dialysis, Hospital A

ICU, Hospital A

Ward, Hospital B

Dialysis, Hospital C

ICU, Hospital D

Ward, Hospital D

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 settings.

April

8 13

6 29 22 15

May

© SHEA 2017


Transmission Dynamics

Incubation period

The time from exposure to developing symptoms

Serial interval

The time between successive cases

Ex: the time between when the first case develops symptoms and the onset in a

secondary case

© SHEA 2017


Outbreak Transmission Dynamics: Al-Hasa, 2013

Estimated incubation period: 5.2 days (95% CI, 2.2-12.4) (SARS 4.0 days [95% CI, 1.8-10.6])

Estimated serial interval: 7.6 days (95% CI, 3.0-19.4) (SARS median 8.4 days) Assiri A, et al. N Engl J Med. 2013;369:407-16.

0 15 10 5

0.0

0.2

0.4

0.6

0.8

1.0

Days After Infection

Pro

po

rti

on

Wit

h S

ym

pto

ms

Incubation Period

0 5 10 15 20 25 30

0.0

0.2

0.4

0.6

0.8

1.0

Days After Symptom Onset in Patient

Transmitting Infection

Pro

po

rti

on

Wit

h S

ym

pto

ms

Serial Interval

© SHEA 2017


Basic Reproduction Number (R0): How Infectious Is MERS-CoV?

R0 is the number of secondary infections caused by a primary case

in an entirely susceptible population

Al-Hasa MERS-CoV R0 estimated to be in the range of 0.6-0.69

Prepandemic SARS-CoV was 0.8

Relatively small cluster sizes indicate transmission can be controlled

once the clusters are detected and interventions put in place

In the absence of controls, Rindex of clusters was in the range of 0.8-1.3

Chains of transmission were not sustained with infection control

measures

Breban R, et al. Lancet. 2013;382:694-9; Cauchemez S, et al. Lancet Infect Dis. 2014;14:50-6.

© SHEA 2017


MAR APR MAY JUN JUL AUG SEP OCT NOV DEC JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC

2012 2013

Jordan: Two deceased

patients are

retrospectively

diagnosed with MERS-

CoV (Hjawi et al 2013)

September 20, 2013: Dr. Ali

Mohamed Zaki reports the

isolation of a novel

coronavirus in a ProMED-mail

post

A family cluster in the UK

provides definitive evidence of

human-to-human transmission

(Health Protection Agency

2013)

A hospital outbreak of MERS-

CoV in Saudi Arabia forms the

largest cluster to date (Assiri

et al 2013)

October 13-18, 2013:

Almost 2 million pilgrims

gather in Saudi Arabia for

the 2013 Haij

MERS-CoV detected in

three camels in Qatar; the

animals are linked to human

cases (ProMED-mail)

MERS-COV–specific RT-

PCR assays are developed

and used for the diagnosis of

the second MERS-CoV

patient (Bermingham et al

2012; Corman et al 2012)

Erasmus Medical Center

characterizes the full genome

of MERS-CoV (van

Boheemen et al 2012)

DPP4 is established as the

cellular receptor for MERS-

CoV (Raj et al 2013)

MERS-CoV infection in

rhesus macaques fulfills

Koch’s postulates (Munster

et al 2013)

Crystal structure for MERS-

CoV bound to its receptor is

determined (Lu et al 2013;

Wang et al 2013)

MERS-CoV neutralizing

antibodies are found in Omani

camels (Reuskein et al 2013)

Treatment with

interferon alfa-2b and

ribavirin improves

outcome in MERS-

CoV–infected rhesus

macaques (Fatzarano

et al 2013)

An RNA fragment identical to MERS-CoV

is recovered from an Egyptian tomb bat

in Saudi Arabia (Mernish et al 2013)

A phylogenetic analysis of 21

MERS-CoV genomes suggests

multiple zoonotic introductions

(Cotton et al 2013)

Timeline of MERS-CoV Outbreaks (2012-2013)

Milne-Price S, et al. Pathog Dis. 2014;71:121-36.

© SHEA 2017


MERS-CoV: South Korea, 2015

A 68-year-old South Korean man developed fever and myalgia

on May 11, 2015, after returning from a business trip to the

Middle East

He was diagnosed with MERS-CoV on May 20, 2015, after

contacting approximately 600 people during his visits to health

centers

26 cases were confirmed from these initial contacts; transmission

via nosocomial infection followed after that

Korea Centers for Disease Control and Prevention. Osong Public Health Res Perspect. 2015;6:269-78.

© SHEA 2017


MERS-CoV: South Korea, 2015

Approximately one-half of the MERS-CoV cases (92/186) in South

Korea were associated with a 1,950-bed, tertiary care university

hospital

82 cases originated from one unprotected exposure

Crowded emergency department

Experimental evidence later supported the possible contribution

of MERS-CoV contamination of air and surrounding materials in

the outbreak

Park GE, et al. Ann Intern Med. 2016;165:87-93; Cho SY, et al. Lancet. 2016;388:994-1001;

Kim SH, et al. Clin Infect Dis. 2016;63:363-9.

© SHEA 2017


Environmental Contamination: South Korea, 2015

Rooms of 4 patients in 2 hospitals examined for environmental

contamination of MERS-CoV

Gathered air samples and swabbed high-touch and ventilation

surfaces for viral culture and PCR

4/7 air samples tested positive

15/68 surfaces contaminated with MERS-CoV live virus

Room, anteroom, medical equipment (bed sheets and rails, IV fluid

hangers, tables, outlets)

Many surfaces PCR-positive up to 27 days after symptom onset


© SHEA 2017


Comparison of Case and Environment: South Korea, 2015

Patient Data Environmental Data

Hospital No. Case Status

Time of Sampling for

PCR (Days After

Symptom Onset) MERS-CoV PCR Results

Environmental

Sampling

RT-PCR

From

Samples

RT-PCR

From Viral

Culture

A 1 Pneumonia on mechanical ventilation

and ECMO 22 (+) at the time of sampling Air sampling 2/2 1/2

Fomites swab 4/6 2/6

Fixed-structure swab 7/13 2/13

2 Pneumonia on mechanical ventilation 16 (+) at the time of sampling Air sampling 2/2 2/2



Elevator Fixed-structure swab 1/5 0/5

B 3 Pneumonia and bedridden 19 (-) at the time of sampling Air sampling 3/3 1/3



Elevator Fixed-structure swab 1/5 1/5


Patient Case Status and Environmental Test Results in 2 MERS-Designated Hospitals, Republic of Korea

© SHEA 2017


Why Did These Outbreaks Occur?

Surveillance and case finding are limited

Unable to identify cases in a timely fashion (diagnostic and logistics)

PCR testing can take 4 or 5 days

Serology is unreliable

Variable approaches to screening

Poor recognition of syndromes and risk factors

Spectrum of disease not identified early

Risk factors for transmission in healthcare not fully understood

© SHEA 2017


Why Did These Outbreaks Occur? (cont.)

System issues

Intrahospital transfers

Visitation and family care policies

Poor internal and external communication

Lack of transparency about outbreak facts to public health community

Isolation precautions and use of barrier precautions not followed or understood

Inadequate quantities of isolation materials

Confusion about recommendations for barrier precautions to be used (CDC vs WHO)

© SHEA 2017


Guidelines for MERS-CoV: Before the First Case Preparation

Surveillance

Education

Laboratory readiness

Communication

Planning

Case treatment

PIDAC. www.picnet.ca.

© SHEA 2017


Guidelines for MERS-CoV: Management

Accommodation

Additional precautions

Diagnosis

Communication

Education/training

Follow-up for identification of transmission

PIDAC. www.picnet.ca.

© SHEA 2017


The Science: SARS vs MERS* SARS MERS

Cumulative number of case(s) 8,098 1,905

Number of deaths 774 677

Case fatality ratio (%) 9.6% 35%

Number of countries 29 27

Total publications 2,854 475

Case reports 135 21

Clinical trials 33 1

Comparative studies 145 9

Evaluation studies 48 0

Meta-analysis 1 0

Perl TM, et al. Ann Intern Med. 2015;163:313-4; WHO. www.who.int; Arabi YM, et al. Ann Intern Med. 2014;160:389-97.

*As of 2/28/2017.

© SHEA 2017


Summary

MERS-CoV provides a recent example of an emerging pathogen that was amplified in healthcare where transmission resulted from a failure of recognition, issues with collaboration and communication, and suboptimal laboratory identification

Risk factors are not well studied (mostly observational), and case-control studies are essential

Current prevention strategies (including standard recommendations):

Early recognition and diagnosis, hand hygiene, isolation, appropriate use of and adherence to PPE, cohorting, reporting, cleaning and disinfection

Research is essential to answer key questions about transmission and risk factors for transmission

© SHEA 2017


Additional Resources

MERS Provider and Facility Preparedness Checklists. Centers for Disease

Control and Prevention.

www.cdc.gov/coronavirus/mers/preparedness/index.html

Preparedness Resources (MERS). Centers for Disease Control and

Prevention. www.cdc.gov/coronavirus/mers/preparedness/resources-

preparedness.html

MERS: Information for Healthcare Professionals. Centers for Disease Control

and Prevention. www.cdc.gov/coronavirus/mers/hcp.html

Interim Infection Prevention and Control Recommendations for Hospitalized

Patients with MERS-CoV. Centers for Disease Control and Prevention.

www.cdc.gov/coronavirus/mers/infection-prevention-control.html

http://www.cdc.gov/coronavirus/mers/preparedness/index.html

http://www.cdc.gov/coronavirus/mers/preparedness/resources-preparedness.html



http://www.cdc.gov/coronavirus/mers/hcp.html

http://www.cdc.gov/coronavirus/mers/infection-prevention-control.html





case study 1: mers-cov - society for healthcare...

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