Middle East Respiratory Syndrome (MERS) Nashaat S. Hamza, M.D

Hospital Gran-RoundApril 22nd2014

Objectives• Where did the virus come from?

• How were patients exposed?

• Are certain people at risk?

• How is it transmitted?

• what is the incubation period?

• For how long will patients be infectious?

• Is there a risk from certain animals or other reservoir?

• HCWs one of the commonest fears is will they become infected and if so will they infect their loved ones at home

Journal of Infection and Public Health (2013) 6, 317—318

Introduction

• Coronaviruses are a large family of viruses that cause illness in humans & animals.

• It causes illnesses ranging from common cold to SARS

• This novel coronavirus, first detected in April 2012

• It is a new virus that has not been seen in humans before.

• In most cases, it has caused severe disease.

• Death has occurred in 35-50% of cases

• Globally: WHO: a total of 211 laboratory-confirmed cases, of which 88 deaths

Coronaviruses are medium-sized, enveloped, positive-stranded RNA viruses whose name derives from their characteristic crown-like appearance in electron micrographs

Life Cycle

L. Lu et al. / Microbes and Infection 15 (2013) 625e629

Epidemiology

Morbidity and Mortality Weekly Report

The index case was a patient in Jeddah, who was hospitalized with

pneumonia in June 2012. The patient developed (ARDS) and AKI and died

First caseInitial X-ray and 2 days later

TransmissionReservoir: Remains unclear

Proven person-person transmission

Hospital Epidemic

• In April 2013, a cluster of 23 confirmed cases and 11 probable cases of MERS-CoV was detected in Al-Hasa.

• Almost all cases were directly linked to person-to-person exposure, most of them in the hemodialysis (9 cases) or ICU (4 cases) in a single hospital.

• There were only 2 proven cases in healthcare workers, and only 3 family members (all of whom had visited the hospital) were proven infected despite a survey of over 200 household contacts

• Possible modes of transmission may include droplet and contact transmission.

• Studies of transmissibility and epidemic potential suggests that MERS-CoV does not yet have pandemic potential.

Assiri A, N Engl J Med. 2013;369(5):407

Assiri A, N Engl J Med. 2013;369(5):407

Family Cluster

• A cluster occurred in October and November 2012 in 4 men in one family in Riyadh, Saudi Arabia, 2 of whom died

• None of the 24 other family members who lived with the infected patients or 124 healthcare workers who had contact with them became ill

Memish ZA, N Engl J Med. 2013;368(26):2487

Z.A. Memish et al International Journal of Infectious Diseases xxx (2014) e1–e6

International Journal of Infectious Diseases xxx (2014) e1–e6

During a 3 month period, June to August 2013, there were 12 positive MERS-CoV cases reported from the Hafr Al-Batin KSA (host an annual camel festival).

Detailed epidemiological, clinical and genomic study

The genetic data indicated that at least two of the infected contacts could not have been directly infected from the index patient and alternate source should be considered. Camels appear as the likely.

Hospital Transmission Nil with percussions

Emerging Infectious Diseases • www.cdc.gov • Vol. 20, No. 4, April 2014

None of HCW got infected

No Hajj associated Coronavirus infections in 2013

In KSA or Abroad

Clinical Microbiology and Infection, Volume 20 Number 4, April 2014

Reservoir

• MERS-CoV is thought to be of animal origin & related to several bat coronaviruses.

• It is likely that some infections occur via intermittent zoonotic transmission or possibly via an environmental source

Case definitions

• A confirmed case: laboratory testing now requires a positive PCR of two, specific genomic targets or a single positive target with sequencing of a second.

• CDC’s definition of a probable

Morbidity and Mortality Weekly Report

Probable case• 3 combinations of clinical, epidemiological and laboratory criteria can define a

probable case:

• 1-A person with a febrile acute respiratory illness + clinical, radiological, (pneumonia or ARDS) AND Testing for MERS-CoV is unavailable or negative on a single inadequate specimen ANDThe patient has a direct epidemiologic-link with a confirmed MERS-CoV case.

• 2-A person with a febrile acute respiratory illness with clinical ANDAn inconclusive MERS-CoV laboratory test AND A 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.

• 3-A person with an acute febrile respiratory illness of any severity ANDAn inconclusive MERS-CoV laboratory test (that is, a positive screening test without confirmation) AND The patient has a direct epidemiologic-link with a confirmed MERS-CoV case2.

http://www.who.int/csr/disease/coronavirus_infections/case_definition/en/index.html

CLINICAL MANIFESTATIONS

• Incubation period: in one study of 23 individuals, the median incubation period was 5.2 days (95% CI 1.9-14.7 days).

• In one secondary case that occurred in a patient in France who, the incubation period was estimated at 9 to 12 days.

• WHO and CDC recommend that an evaluation for MERS-CoV be considered in individuals with a syndrome of MERS who returned from travel to the Arabian peninsula or neighboring countries within the past 14 days

Underlying medical conditions

• In a study of 47 patients in Saudi Arabia, 45 (96 %) had underlying comorbidities

• DM(68 %), HTN (34 %), IHD (28 %), and CKD(49 %)

• One patient was on chronic glucocorticoids.

• In a study of 12 critically ill patients with MERS-CoV infection, each individual had at least one comorbid condition; the median number of comorbid conditions was 3 (range 1 to 6)

• The high rate of comorbidities reported must be interpreted with caution, since DM is very common in KSA,

Assiri A, N Engl J Med. 2013;369(5):407

Clinical features

•  Most patients have been severely ill with pneumonia and ARDS, and some have had AKI

• Many patients have required MV and & ECMO.• Other S/S: GI (anorexia, N/V, abdominal pain,

diarrhea), pericarditis, and DIC.

18 March 2014 Annals of Internal Medicine Volume 160 • Number

clinical findings were observed among 47

• ●Fever (>38°C) – 46 patients (98 %)

• ●Cough – 39 patients (83 %)

• ●Shortness of breath – 34 patients (72 %)

• ●Hemoptysis – 8 patients (17 %)

• ●Sore throat – 10 patients (21 %)

• ●Myalgias – 15 patients (32 %)

• ●Diarrhea – 12 patients (26 %)

• ●Vomiting – 10 patients (21 %)

• ●Abdominal pain – 8 patients (17 %)

• ●Abnormal chest x-ray – 47 patients (100 %)

Assiri A, N Engl J Med. 2013;369(5):407

Many asymptomatic carriers

• As an example, the Saudi MOH screened >3000 close contacts of case patients using RT-PCR: nasopharyngeal swabs and identified seven healthcare workers were positive

• 2 were asymptomatic and five of whom had mild URI

Laboratory abnormalities

• leukopenia (14 %), lymphopenia (34 %), lymphocytosis (11 %),

• Thrombocytopenia (36 %)• Elevated AST (15 %), ALT (11 %), LDH (49 %) • Few had anemia, • Some patients: progressive renal failure • DIC

Assiri A, N Engl J Med. 2013;369(5):407

SPECIMENS COLLECTION: RESPIRATORY SPECIMENS

• BAL, tracheal aspirate, pleural fluid :

• Sputum:

• B. Upper respiratory tract:

Diagnosis: PCR is the Gold standard

• Three rRT-PCR assays for routine detection of MERS-CoV have been developed. Currently described tests are an assay targeting a region upstream of the E protein gene (upE) and assays targeting the open reading frame 1b (ORF 1b) and the open reading frame 1a (ORF 1a)

• In some cases, sequencing should be performed for confirmation.

G Lu et al. Nature 000, 1-5 (2013)

The overall structure of MERS-CoV RBD.

Presence of other organisms should not exclude MERS-CoV

• CDC has changed its guidance to indicate that testing for MERS-CoV and other respiratory pathogens* can be conducted simultaneously and that positive results for another respiratory pathogen should not necessarily preclude testing for MERS-CoV.

MMWR / September 27, 2013 / Vol. 62 / No. 38

Serology• The CDC has developed a two-stage approach, ELISA for screening followed

by an indirect immunofluorescence test or microneutralization test for confirmation

• Any positive test by a single serologic assay should be confirmed with a neutralization assay. There are limited data on the sensitivity and specificity of antibody tests for MERS-CoV.

• According to the WHO, cases with a positive serologic test in the absence of PCR testing or sequencing are considered probable cases

TREATMENT• In cell culture and animal experiments, (nterferon (IFN)-alpha-2b and

ribavirin) appears promising

• In a study of rhesus macaques, two groups of three monkeys were inoculated with the virus; one group was treated with subcutaneous IFN-alpha-2b plus intramuscular ribavirin beginning eight hours after inoculation and the other group was not treated

• The treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia & lower concentrations of serum and lung pro-inflammatory markers, fewer viral genome copies, and fewer severe histopathologic changes in the lungs.

• Combination therapy with IFN-alpha-2b and ribavirin was started a median of 19 days following admission in five critically ill patients in KSA:None of the patients responded to therapy and all died of their illness.

EXPERIENCE FROM SARS

H. Al-Momattin et al. / International Journal of Infectious Diseases 17 (2013)

Ribavirin Didn't improve outcome in SARS

Vaccine development

•  There is no licensed vaccine for MERS-CoV

• An experimental candidate MERS-CoV vaccine based on the major surface spike protein using recombinant nanoparticle technology.

• Other candidate vaccines that are being studied include a full-length infectious cDNA clone of the MERS-CoV

Late therapy in

International Journal of Infectious Diseases 20 (2014) 42–46

OUTCOME• As of March 27, 2014, 86 of 206 patients with laboratory-

confirmed MERS-CoV infection (42 percent) have died.

• Because individuals with mild symptoms are less likely to be evaluated than patients with severe disease, those with MERS-CoV and mild disease might be underrepresented in published reports

• The reported case-fatality rate might therefore be an overestimate.

• In a study of 47 patients with MERS-CoV in Saudi Arabia, case-fatality rates rose with increasing age, from 39 % in < 50 years of age, to 48 % in those < 60 years of age, to 75 % >60 years or older

Travelers evaluation

• Health-care providers in the United States should continue to evaluate patients for MERSCoV infection if they develop fever and pneumonia or acute respiratory distress syndrome (ARDS) within 14 days after traveling from countries in or near the Arabian peninsula. Providers also should evaluate patients for MERS-CoV infection if they have ARDS or fever and pneumonia, and have had close contact with a recent traveler from this area who has fever and acute respiratory illness.

MMWR / September 27, 2013 / Vol. 62 / No. 38

Saudi Arabia Ministry of Health has made special recommendations

• Following groups should postpone their Hajj and Umrah this year 2013:

• People over 65 years old

• Children under 12 years old

• Pregnant women

• People with chronic diseases (such as heart disease, kidney disease, diabetes, or respiratory disease)

• People with weakened immune systems

• People with cancer or terminal illnesses

Duration of isolation precautions for novel

coronavirus (nCoV) infection• The duration of infectivity for nCoV infection is unknown.

• Also little information is currently available on viral shedding and the potential for transmission of nCoV.

• While Standard Precautions should continue to be applied always, additional isolation precautions should be used during the duration of symptomatic illness and continued for 24 hours after the resolution of symptoms.

Thank You