Clinical Manifestations and Complications of MERSYaseen Arabi, MD, FCCP, FCCM, ATSFChairman, Intensive Care Department / Medical Director, Respiratory Services / Professor, College of Medicine, King Saud Bin Abdulaziz University for Health Sciences

Riyadh, Saudi Arabia

I have nothing to disclose.

Within the last 12 months I have not had any type of financial arrangement or affiliation with commercial interests related to the

content of this continuing education activity that requires disclosure.

Nonpaid consultations on therapeutics for MERS for Gilead Sciences, SAB Biotherapeutics, and Regeneron

DISCLOSURE

1. Epidemiology2. Clinical presentation3. Update on therapy

1. Supportive therapy: NIV, ECMO2. Adjunctive pharmacologic therapy: Steroids3. Specific pharmacologic therapies

Convalescent plasma Ribavirin/ interferon MIRACLE trial AIMS trial (SAB-301)

Outline

• Alphacoronaviruses• HCoV-229E• NL63

• Betacoronaviruses• Lineage A

• HCoV-OC43• HKU1

• Lineage B• SARS-CoV

• Lineage C• MERS-CoV

Human Coronaviruses

2468 cases851 deaths

Confirmed global cases of MERS

reported to WHO

Respiratory Symptoms

Parameters, no% MERS-SARI (N=330) Non- MERS-SARI

(N=222)

P value

Shortness of breath 247 (74.8) 154 (69.4) 0.31

Cough 227 (68.8) 141 (63.5) 0.24

Cough with sputum production 128 (38.8) 100 (45) 0.34

Bloody sputum/hemoptysis 29 (8.8) 10 (4.5) 0.05

Chest pain 66 (20) 25 (11.3) 0.009

Sore throat 46 (13.9) 13 (5.9) <0.001

Wheezing 18 (5.5) 26 (11.7) 0.008

Runny nose (rhinorrhoea) 15 (4.5) 4 (1.8) 0.02

Co-morbidities

VariablesMERS-SARI

N=330

Non-MERS-SARI

N=222P value

Diabetes with chronic complications— no. (%) 162 (49.1) 118 (53.2) 0.39

Chronic cardiac disease— no. (%) 134 (40.6) 126 (56.8) <0.001

Renal disease— no. (%) 100 (30.3) 49 (22.1) 0.06

Chronic pulmonary disease— no. (%) 46 (13.9) 84 (37.8) <0.001

Chronic neurological disease— no. (%) 36 (10.9) 57 (25.7) <0.001

Respiratory Parameters

VariablesMERS-SARI

N=330

Non-MERS-SARI

N=222P value

FiO2— median (Q1,Q3) 0.7 (0.5, 1.0) 0.5 (0.3, 0.6) <0.001

PaO2, mmHg— median (Q1,Q3) 67 (58, 85) 76 (55, 99) 0.02

PaO2/ FiO2 ratio— median (Q1,Q3) 106 (66, 160) 176 (104, 252) <0.001

Tidal volume (ml)— median (Q1,Q3) 400 (350, 440) 400 (340, 436) 0.58

Tidal volume per kg of predicted body weight (ml/kg)— median

(Q1,Q3)6.6 (5.8, 7.6) 7.1 (6.0, 8.3) 0.012

PEEP (cmH20)— median (Q1,Q3) 12 (8, 14) 8 (5, 10) <0.001

Plateau pressure (cmH20)— median (Q1,Q3) 28 (22, 30) 23 (17, 26.0) <0.001

Driving Pressure (cmH20)— median (Q1,Q3) 15 (12, 18) 15 (11, 18) 0.69

Number of quadrants with infiltrates on chest radiograph—

median (Q1,Q3)3 (2, 4) 2 (0, 3) <0.001

Extra Pulmonary Parameters During ICU Stay—No. (%)

VariableMERS SARI

N=330Non-MERS-SARI

N=222P value

Elevated ALT (> 55 U/L) — no. (%) 142/252 (56.3) 35/93 (37.6) 0.002

Elevated AST (> 34 U/L) — no. (%) 197/227 (86.8) 61/96 (63.5) <0.001

Hyperbilirubinemia (>20.5 µmol/L) — no. (%) 148/252 (58.7) 41/93 (44.1) 0.02

Leukopenia (< 4.0 x109/L) — no. (%) 58/287 (20.2) 21/204 (10.3) 0.003

Thrombocytopenia (< 150 x109/L ) — no. (%) 169/288 (58.7) 74/204 (36.3) <0.001

ICU therapies

VariablesMERS-SARI

N=330

Non- MERS-SARI

N=222P value

Non-invasive mechanical ventilation— no. (%) 100 (30.3) 67 (30.2) 0.98

Invasive mechanical ventilation— no. (%) 281 (85.2) 162 (73.0) <0.001

Oscillatory ventilation— no. (%) 26 (7.9) 0 (0) <0.001

Prone Ventilation— no. (%) 32 (9.7) 2 (0.9) <0.001

Inhaled Nitric Oxide— no. (%) 43 (13) 14 (6.3) 0.01

Extracorporeal membrane oxygenation (ECMO)—

no. (%)

19 (5.8) 2 (0.9) 0.02

Renal replacement therapy (RRT)— no. (%) 161 (48.8) 49 (22.1) <0.001

Inotropes/vasopressors— no. (%) 262 (79.4) 122 (55.0) <0.001

Variables MERS-SARI

N=330

Non- MERS-SARI

N=222

P value

Hospital mortality— no (%) 223 (67.6) 82 (36.9) <0.001

Approach to Suspected MERS

Histopathology

• Post-mortem biopsies• Lungs: necrotizing pneumonia,

diffuse alveolar damage• Kidney: acute kidney injury• Liver: portal and lobular hepatitis • Muscle: myositis with muscle

atrophic changes • Brain and heart: unremarkable

EM Studies

• Lung• Kidney• Muscle

• Of 302 MERS critically ill patients, NIV was used in 35% patients. • 92.4% of NIV patients required intubation and invasive mechanical

ventilation.• NIV patients were more likely to require inhaled nitric oxide. • The use of NIV was not independently associated with 90‐day mortality.

90-Day MortalityVariables Logistic regression

Cox proportional hazard model

Marginal structural model

OR (95% CI)

p-valueHR

(95% CI)p-value

OR (95% CI)

p value

All corticosteroids patients vs. no corticosteroids (ref)

1.87 (1.18, 2.96) 0.007 1.08 (0.80,1.46) 0.63 0.75 (0.52, 1.07) 0.12

Viral RNA Clearance With Steroids

Variables Cox proportional hazard model Joint Cox proportional MSMHR

(95% CI)p value

HR(95% CI)

p value

All corticosteroids patients vsNo corticosteroids (ref)

1.11 (0.63, 1.94) 0.73 0.35 (0.17, 0.72) 0.005

1554 EmergingInfectiousDiseases•www.cdc.gov/eid•Vol.22,No.9,September2016

RESEARCH

We explored the feasibility of collecting convalescent plas-

ma for passive immunotherapy of Middle East respiratory

syndrome coronavirus (MERS-CoV) infection by using ELI-

SA to screen serum samples from 443 potential plasma do-

nors:196patientswithsuspectedorlaboratory-confir

m

e d

MERS-CoV infection, 230 healthcare workers, and 17

household contacts exposed to MERS-CoV. ELISA-reactive

sampleswerefurthertestedbyindirectfluo r escent antibody

and microneutralization assays. Of the 443 tested samples,

12(2.7%)hadareactiveELISAresult,and9ofthe12had

reactiveindirectfluo r escent antibodyandmicroneutraliza-

tion assay titers. Undertaking clinical trials of convalescent

plasma for passive immunotherapy of MERS-CoV infection

may be feasible, but such trials would be challenging be-

causeofthesmallpoolofpotentialdonorswithsuffici ent ly

high antibody titers. Alternative strategies to identify conva-

lescent plasma donors with adequate antibody titers should

be explored, including the sampling of serum from patients

with more severe disease and sampling at earlier points

during illness.

Middle East respiratory syndrome coronavirus

(MERS-CoV) was initially identified in September

2012 when a patient in Saudi Arabia with a severe, acute

respiratory infection and acute renal failure died (1). As

of June 19, 2016, more than 1,733 MERS-CoV cases and

at least 628 associated deaths had been identified ; >80%

of the cases occurred in Saudi Arabia (2). More than 20

countries outside of the Arabian Peninsula have reported

MERS-CoV cases, and the 2015 outbreak in South Korea

with attendant mortality has reinforced concerns about in-

ternational outbreaks (3). No specific treatment has been

proven effective for MERS-CoV infection.

Convalescent plasma containing MERS-CoV–specif-

ic antibodies from recovered patients has been suggested

as a potential therapy for infected persons (4). Conva-

lescent plasma has been used to treat several other viral

infections, including those caused by the severe acute re-

spiratory syndrome coronavirus (SARS-CoV), avian in-

flu

e

nza A(H5N1) virus, and influe nza A(H1N1)pdm09 vi-

rus (5–10). A recent metaanalysis of studies using passive

immunotherapy for treatment of severe acute respiratory

infections of viral etiology suggests that the timely use of

convalescent blood products, particularly those with neu-

tralizing antibodies, results in a reduced death rate (11).

Public Health England and ISARIC (the International Se-

vere Acute Respiratory and Emerging Infection Consor-

tium) published a decision-making support tool on poten-

tial therapies for MERS-CoV that highlights convalescent

plasma and other neutralizing antibody–containing immu-

notherapeutics (e.g., hyperimmune immunoglobulins and

monoclonal antibodies) as the most promising potential

treatments for serious MERS-CoV illness and deserving

of evaluation in human clinical trial(s) (4).

However, no data support the feasibility of obtain-

ing convalescent plasma from patients who have been

exposed to MERS-CoV or recovered from infection with

the virus. Camels are the likely source for most animal-

to-human transmission and appear to have long-lasting

antibody responses; in preclinical models, such antibod-

ies appear effective in reducing the severity of pathologic

Feasibility of Using Convalescent Plasma Immunotherapy for

MERS-CoV Infection, Saudi ArabiaYaseen M. Arabi, Ali H. Hajeer, Thomas Luke, Kanakatte Raviprakash, Hanan Balkhy,

Sameera Johani, Abdulaziz Al-Dawood, Saad Al-Qahtani, Awad Al-Omari, Fahad Al-Hameed,

Frederick G. Hayden,1 Robert Fowler, Abderrezak Bouchama, Nahoko Shindo,

Khalid Al-Khairy, Gail Carson, Yusri Taha, Musharaf Sadat, Mashail Alahmadi

Authoraffili at ions: KingSaudbinAbdulazizUniversityforHealth

Sciences, King Abdullah International Medical Research

Center, Riyadh, Saudi Arabia (Y.M. Arabi, A.H. Hajeer, H. Balkhy,

S. Johani, A. Al-Dawood, S. Al-Qahtani, A. Bouchama,

K.Al-Khairy,M.Sadat,M.Alahmadi);NavalMedicalResearch

Center, Silver Spring, Maryland, USA (T. Luke, K. Raviprakash);

Alfaisal University, Riyadh (A. Al-Omari); King Saud bin

Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia

(F. Al-Hameed); University of Virginia School of Medicine,

Charlottesville, Virginia, USA (F.G. Hayden); University of Toronto,

Toronto, Ontario, Canada (R. Fowler); World Health Organization,

Geneva,Switzerland(N.Shindo);UniversityofOxfordCentrefor

Tropical Medicine, Oxford, UK (G. Carson); King Abdulaziz

Medical City, Al-Ahsa, Saudi Arabia (Y. Taha)

DOI:http://dx.doi.org/10.3201/eid2209.151164

1This author is a member of ISARIC (the International Severe

Acute Respiratory and Emerging Infection Consortium).

Number of subjects

who were tested

N= 443

Positive

RT-PCR

N=11(4.7%)

Patients with suspected or confirmed

MERS-CoV

N=196

Healthcare Workers with history of MERS-CoV

exposure

N=230

Household contact with

MERS-CoV patients

N=17

Negative

RT-PCR N=219(95.3%)

Reactive ELISA

N=4(36.4%)

Reactive ELISA

N=0(0%)

Positive

RT-PCR

N= 5(2.6%)

Negative

RT-PCR

N= 191(97.4%)

Reactive ELISA

N= 2(40%)

Reactive ELISA

N=6(3%)

Positive

RT-PCR

N=0(0%)

Negative RT-PCR

N=17(100%)

Reactive ELISA

N=0(0%)

Reactive ELISA

N=0(0%)

Day 90 Mortality

Variables Logistic regression Cox proportional hazard

regression model

Marginal structural model

aOR (95% CI) p Value aHR (95% CI) p Value aOR (95% CI) p Value

RBV/IFN versus no RBV/IFN (ref) 2.27 (1.20, 4.32) 0.01 1.52 (1.13, 2.06) 0.006 1.03 (0.73, 1.44) 0.87

RBV versus no RBV (ref) 2.02 (1.09, 3.73) 0.02 1.41 (1.04, 1.90) 0.03 1.19 (0.84, 1.68) 0.33

IFN versus no IFN (ref) 2.53 (1.32, 4.85) 0.005 1.57 (1.18, 2.09) 0.002 1.05 (0.74, 1.48) 0.80

Arabi Trials 2018

MIRACLE Trial

AIMS Trial (Phase II/III Trial)

• SAB-301 (Tc Bovine-derived Anti-MERS Immunoglobulin)• Phase II:

• Non-futility• Sample size recalculation

• Phase III:• Efficacy

2015

MERS-CoVResearch Initiatives Workshop

2016-2019

Protocol Development

2019

Site Visit

AIMS Study Program

2019

Investigators Meeting

Conclusions

• MERS cases continue to occur; it is still a severe disease• Supportive care

• NIV: caution• ECMO: possible benefit

• Adjunctive therapy: steroids only if indicated for other reasons• Ribavirin and IFN: not effective• MIRACLE trial: Ongoing• AIMS trial: in process

Thank you.