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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.
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