2014 Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection

Clinical Course and Outcomes of Critically Ill Patients With MiddleEast Respiratory Syndrome Coronavirus InfectionYaseen M. Arabi, MD; Ahmed A. Arifi, MD; Hanan H. Balkhy, MD; Hani Najm, MD; Abdulaziz S. Aldawood, MD; Alaa Ghabashi, MD;Hassan Hawa, MD; Adel Alothman, MB; Abdulaziz Khaldi, MD; and Basel Al Raiy, MD

Background: Since September 2012, 170 confirmed infections withMiddle East respiratory syndrome coronavirus (MERS-CoV) havebeen reported to the World Health Organization, including 72deaths. Data on critically ill patients with MERS-CoV infection arelimited.

Objective: To describe the critical illness associated withMERS-CoV.

Design: Case series.

Setting: 3 intensive care units (ICUs) at 2 tertiary care hospitals inSaudi Arabia.

Patients: 12 patients with confirmed or probable MERS-CoVinfection.

Measurements: Presenting symptoms, comorbid conditions, pul-monary and extrapulmonary manifestations, measures of severity ofillness and organ failure, ICU course, and outcome are described, asare the results of surveillance of health care workers (HCWs) andpatients with potential exposure.

Results: Between December 2012 and August 2013, 114 patientswere tested for suspected MERS-CoV; of these, 11 ICU patients(10%) met the definition of confirmed or probable cases. Three of

these patients were part of a health care–associated cluster that alsoincluded 3 HCWs. One HCW became critically ill and was the 12thpatient in this case series. Median Acute Physiology and ChronicHealth Evaluation II score was 28 (range, 16 to 36). All 12 patientshad underlying comorbid conditions and presented with acute se-vere hypoxemic respiratory failure. Most patients (92%) had ex-trapulmonary manifestations, including shock, acute kidney injury,and thrombocytopenia. Five (42%) were alive at day 90. Of the520 exposed HCWs, only 4 (1%) were positive.

Limitation: The sample size was small.

Conclusion: MERS-CoV causes severe acute hypoxemic respira-tory failure and considerable extrapulmonary organ dysfunctionand is associated with high mortality. Community-acquired andhealth care–associated MERS-CoV infection occurs in patients withchronic comorbid conditions. The health care–associated clustersuggests that human-to-human transmission does occur with un-protected exposure.

Primary Funding Source: None.

Ann Intern Med. 2014;160:389-397. www.annals.orgFor author affiliations, see end of text.This article was published online first at www.annals.org on 28 January 2014.

In September 2012, a new coronavirus was isolatedfor the first time from a patient in Saudi Arabia, who

presented with acute pneumonia and renal failure (1).The virus was identified as a human �-coronavirus andwas subsequently named “Middle East respiratory syn-drome coronavirus” (MERS-CoV) (2). Since then, 170laboratory-confirmed cases of infection with MERS-CoVhave been reported to the World Health Organization,including 72 deaths (3). The disease has a high fatality rateand has several clinical features that resemble the infectioncaused by the severe acute respiratory syndrome coronavi-rus (SARS-CoV) (4). As such, there has been concern thatthe virus has the potential to cause a pandemic. Worldknowledge about this virus is accumulating, but data oncritically ill patients infected with MERS-CoV are limited.

We describe the clinical course and outcomes of 12critically ill patients with MERS-CoV admitted to 3 inten-sive care units (ICUs) in 2 tertiary hospitals in SaudiArabia.

METHODS

The study was approved by the Institutional ReviewBoard of the National Guard Health Affairs, Riyadh, SaudiArabia, and consent was not required.

SettingThe Saudi Arabian National Guard Health Affairs

serves close to 1 million individuals of the Saudi ArabianNational Guard soldiers and their dependents through aprimary, secondary, and tertiary health care system thatincludes 4 tertiary care hospitals and more than 90 primaryhealth care clinics. We report on critically ill patients withMERS-CoV infection from 1 ICU (a medical–surgicalICU referred to as “ICU 1”) at King Abdulaziz Hospital,Al-Ahsa, and from 2 ICUs (a medical–surgical ICU and acardiac ICU, referred to as “ICU 2” and “ICU 3,” respec-tively) at King Abdulaziz Medical City, Riyadh. AlthoughICU 2 and ICU 3 are located in the same hospital, they arein geographically separate locations and have limited staffcrossover.

Both hospitals have board-certified intensivists whotreat patients in closed medical–surgical ICUs and provideconsultations to patients in the cardiac ICU as required.

See also:

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The hospitals are accredited by the Joint Commission In-ternational and have Infection Prevention and Controlprograms that work collaboratively with the ICU staff.Hand-hygiene compliance in the ICUs for 2012 was 85%to 98%, and the influenza vaccination rate among healthcare workers (HCWs) was 83%.

Since the first case of MERS-CoV was identified inSaudi Arabia in September 2012, the National Guard hos-pitals along with all other health care facilities in SaudiArabia implemented the guidelines for testing of suspectedcases and screening (surveillance of potential exposures) forMERS-CoV according to Ministry of Health directives.The multidisciplinary outbreak committee was reactivatedto manage the current MERS-CoV outbreak. The infec-tion control precautions for suspected MERS-CoV in-cluded placement of patients in a single-bed negative-pressure room and the use of personal protectiveequipment (N-95 mask, gown, and gloves) by HCWs.This study includes all cases encountered from December2012, the date of the first suspected case, until August2013. The first confirmed case of MERS-CoV was in May2013 in Al-Ahsa and in June 2013 in Riyadh. The timeframe overlaps with that of a previously reported case se-ries, and the authors cannot entirely exclude the possibilitythat 1 or 2 of the patients in the current report have beenincluded in the previous case series.

PatientsInfection with MERS-CoV was suspected in patients

presenting with acute respiratory illness and chest radio-graphs suggestive of pneumonia and the acute respiratorydistress syndrome (ARDS), especially if the patient re-quired ICU admission. Suspected cases were tested for

MERS-CoV with real-time polymerase chain reaction(RT-PCR), using the recommended sampling technique(nasopharyngeal swab and tracheal aspirates or bronchoal-veolar lavage in intubated patients). In suspected cases withnegative RT-PCR results, the test was repeated at the dis-cretion of the treating physician. The HCWs and ICUpatients who were potentially exposed to MERS-CoV weresystematically screened. Samples were tested at the regionalreference laboratory of the Saudi Arabian Ministry ofHealth and the hospital laboratory at King Abdulaziz Med-ical City, Riyadh, as described elsewhere (5). The RT-PCRamplification targeted both the upstream E protein (upEgene) and ORF1a for confirmation.

DefinitionsWe included all patients admitted to ICUs with con-

firmed or probable MERS-CoV infection as defined by theWorld Health Organization (6). A confirmed case was de-fined as a suspected case with a positive result for MERS-CoV on RT-PCR. A probable case was defined as asuspected case if the RT-PCR result for MERS-CoV wasunavailable, negative, or inconclusive in a patient with anepidemiologic link to a patient with confirmed MERS-CoV (6).

Data on demographic characteristics, contact historywith a MERS-CoV confirmed case patient, underlyingcomorbid conditions, presenting symptoms, and radio-graphic findings were collected from the medical records.On the day of intubation, we assessed severity of illness byusing Acute Physiology and Chronic Health Evaluation IIscores and Sequential Organ Failure Assessment (SOFA)scores (7). On days 1, 3, 7, and 14 of intubation, wedocumented laboratory and ventilator variables and arterialblood gases. Leukopenia was defined as leukocyte countless than 4.0 � 109 cells/L, lymphopenia as a lymphocytecount less than 1.5 � 109 cells/L, and thrombocytopeniaas a platelet count less than 140 � 109 cells/L. Aspartateaminotransferase and alanine aminotransferase levels wereconsidered elevated if they were more than twice the upperreference limit (34 U/L and 55 U/L, respectively).

We recorded the time course of the patient’s illness,microbiological test results, and treatments received. Wealso recorded the following outcomes: duration of mechan-ical ventilation, ICU length of stay, and survival to ICUdischarge, at day 28 and at day 90.

Role of the Funding SourceThis study did not receive external funding.

RESULTS

During the 9-month study period in the 2 hospitals,114 patients were suspected of having and were tested forMERS-CoV infection (Figures 1 and 2). Of these, 10 ICUpatients (9%) met the definition of confirmed cases, and1 (1%) was a probable case. Among these cases, 8 werecommunity-acquired, and 3 occurred in patients in ICU 3

Context

Middle East respiratory syndrome coronavirus (MERS-CoV)is an emerging pathogen with a clinical spectrum that isnot yet fully delineated.

Contribution

Twelve hospitalized patients found to have MERS-CoVinfection all required intensive care, including mechanicalventilation. Underlying comorbid disease was present in allpatients. Extrapulmonary involvement was common. Vari-ous treatments were tried. Mortality was high. Three caseswere nosocomially acquired, and 1 health care worker wasamong the case patients.

Caution

A small case series may not be representative of all pa-tients presenting to hospitals with MERS-CoV infection.

Implication

Additional information on optimal management ofMERS-CoV infection is urgently needed.

—The Editors

Original Research Course and Outcomes of Critically Ill Patients With MERS-CoV Infection

390 18 March 2014 Annals of Internal Medicine Volume 160 • Number 6 www.annals.org


(the cardiac ICU) who were part of a health care–associ-ated cluster that included HCWs. In the latter patients, theinitial hospitalization was for aortic valve replacement, cor-onary artery bypass graft surgery, or pericardiectomy forconstrictive pericarditis. All of the hospitalized patientswith confirmed MERS-CoV infection required ICU ad-mission.

In addition, 23 cardiac ICU patients were screened aspart of active surveillance because of possible contact withconfirmed HCW cases; all tested negative. The surveillancealso included 520 HCWs who were screened for MERS-CoV; only 4 (1%) were positive. Three of the infections inHCWs occurred as a part of the health care–associatedMERS-CoV cluster. These HCWs were nurses reported tohave had exposure, without the use of personal protectiveequipment, to patients who were subsequently confirmedto have MERS-CoV infection. Only 1 of the HCWs (pa-tient L), who had asthma, became severely ill and requiredICU admission and is fully described in this series alongwith the other 11 patients. The other HCWs were mildlysymptomatic or asymptomatic and were managed at homeuntil the RT-PCR result was negative. Figure 1 shows thedistribution of these cases between the 2 hospitals in Al-Ahsa and Riyadh.

Clinical PresentationThe demographic and clinical characteristics of the 12

critically ill patients with confirmed or probable MERS-CoV infection are shown in Table 1 and Appendix Tables1 to 3 (available at www.annals.org). The median age ofthe patients was 59 years (range, 36 to 83 years). Eightpatients (67%) were male.

The presenting symptoms were mainly those of lowerrespiratory tract infection (dyspnea in 11 patients [92%],cough in 10 [83%], and fever in 8 [67%]); in contrast,symptoms of upper respiratory tract infection were infre-quent (Table 1). The median interval from onset of symp-toms to the emergency department visit was 1 day; to ICUadmission, 2 days; and to intubation, 4.5 days (range for alltime frames, 0 to 33 days). Figure 3 summarizes the timecourse of disease.

The median Acute Physiology and Chronic HealthEvaluation II score was 28 (range, 16 to 36), and the me-dian SOFA score was 9 (range, 3 to 12). Each patient hadat least 1 comorbid condition (Table 1); the median num-ber of comorbid conditions was 3 (range, 1 to 6). Animalexposure was documented for 2 patients; in both instances,the animals (a camel and a domestic cat) were not appar-ently ill.

Respiratory Manifestations and SupportAcute severe hypoxemic respiratory failure was the

prominent feature of the presentation, and all patients re-quired invasive mechanical ventilation (Table 2). Beforeintubation, 5 patients had received a failed trial of nonin-vasive positive-pressure ventilation (NIPPV). Chest radiog-raphy at the time of intubation showed airspace changes

that ranged from unilateral lobar to bilateral diffuse in-volvement consistent with ARDS (Appendix Figure, avail-able at www.annals.org). Chest computed tomography wasperformed in 3 patients and confirmed the same patterns(Figure 4).

All patients received intravenous sedation, and 4(33%) patients received neuromuscular blockade. Becauseof refractory hypoxemia, nitric oxide was used in 6 (50%)patients, prone positioning in 3 (25%), and high-frequency oscillation ventilation (HFOV) in 2 (17%) asrescue therapy. No patient was treated with extracorporealmembrane oxygenation. The median duration of mechan-ical ventilation was 16 days (range, 4 to 30 days). Trache-ostomy was performed in 3 patients (25%).

Nonrespiratory Manifestations and SupportEleven patients (92%) had at least 1 extrapulmonary

manifestation. Individual organ components of the SOFAscore are shown in Appendix Table 3 (available at www.annals.org).

Circulatory

Vasopressors were required in 8 patients (67%) on day1 and in 11 patients (92%) during the ICU stay. Echocar-diography was performed in 11 patients, and all showed noacute change in myocardial function.

Renal

Acute kidney injury that required renal replacementtherapy occurred in 7 patients (58%).

Figure 1. Map of the Kingdom of Saudi Arabia showing the2 study hospitals, the number of suspected and confirmedMERS-CoV infections in patients, and the number of HCWsscreened and cases confirmed in HCWs.

Jordan

KAMC-Riyadh

Iraq

IranKuwait

Bahrain

RiyadhQatar

UAE

Oman

Yemen

Red Sea

Medina

Jeddah Mecca

Dammam

Al-Hasa

Al Taif

Number of involved ICUs: 2Patients with suspected MERS-CoV: 91Patients with confirmed or probable

MERS-CoV: 8HCWs screened for MERS-CoV: 376HCWs with confirmed MERS-CoV: 3HCWs with MERS-CoV requiring ICU: 1

KAH-Al-Hasa

Number of involved ICUs: 1Patients with suspected MERS-CoV: 23Patients with confirmed MERS-CoV: 3HCWs screened for MERS-CoV: 144HCWs with confirmed MERS-CoV: 1HCWs with MERS-CoV requiring ICU: 0

ICU 1 is located in Al-Ahsa and ICU 2 and ICU 3 in Riyadh. HCW �health care worker; ICU � intensive care unit; KAH � King AbdulazizHospital; KAMC � King Abdulaziz Medical City; MERS-CoV � Mid-dle East respiratory syndrome coronavirus; UAE � United ArabEmirates.

Original ResearchCourse and Outcomes of Critically Ill Patients With MERS-CoV Infection

www.annals.org 18 March 2014 Annals of Internal Medicine Volume 160 • Number 6 391






Hepatic

The aspartate aminotransferase level was elevated in 6patients on day 1 and in 8 patients during the ICU stay.The alanine aminotransferase level was elevated in 2 pa-tients on day 1 and in 5 patients during the ICU stay.

Hematologic

Nine patients (75%) had lymphopenia on day 1, and11 (92%) had it during the ICU stay. Thrombocytopeniawas noted in 2 patients on day 1 and in 7 patients (58%)during the ICU stay.

Gastrointestinal

Diarrhea was noted in 2 patients. Three patients hadacute abdomen during the ICU stay. One patient, who haddiabetes and peripheral vascular disease, developed isch-emic bowel; abdominal computed tomography revealedpneumatosis intestinalis, and the patient required hemico-lectomy. The other 2 patients had negative laparotomies.

Microbiological InvestigationsOne patient was co-infected with methicillin-resistant

Staphylococcus aureus and influenza B and another withStreptococcus pneumoniae.

Figure 5 shows the results of sequential RT-PCR test-ing. Eleven patients had positive results. Infection with

MERS-CoV was considered probable in 1 patient becauseof high clinical suspicion and an epidemiologic link to aconfirmed positive MERS-CoV case that was identified af-ter he had died; hence, no test was performed for thispatient.

Antimicrobial Therapy, Corticosteroids, and IntravenousImmunoglobulin

All patients received broad-spectrum antimicrobials,and 7 patients (58%) received oseltamivir empirically.None of the patients received ribavirin or interferon-�.Low-dose hydrocortisone (�300 mg/d) was given to 5 pa-tients (42%) for shock and methylprednisolone (120 to1000 mg/d) was given to 5 other patients (42%). Onepatient received intravenous immunoglobulin and high-dose corticosteroids for thrombocytopenia, with an im-provement in platelet count.

OutcomesAmong the 12 patients, 7 (58%) were alive at day 28,

5 (42%) were alive at ICU discharge, and 5 (42%) werealive at day 90. The median ICU length of stay was 30days (range, 7 to 104 days). The median hospital length ofstay was 41 days (range, 8 to 96 days), excluding 1 patientwho was still in the hospital at the time of submission.Table 3 summarizes other outcomes.

Figure 2. Study flow diagram.

Persons tested orscreened for MERS-CoV

(n = 657)

Patients withsuspected MERS-CoV

(n = 114)

Patients screened aspart of active surveillance

(n = 23)

HCWs tested orscreened for MERS-CoV

(n = 520)

Symptomatic HCW with confirmedMERS-CoV isolated at home

(n = 1)

Confirmed cases ofMERS-CoV(n = 10)*

Probable cases ofMERS-CoV

(n = 1)*

Negative resultsfor MERS-CoV

(n = 23) HCWs positivefor MERS-CoV

(n = 4)

HCWs negativefor MERS-CoV

(n = 516)

Asymptomatic HCWs withMERS-CoV isolated at home

(n = 2)

Symptomatic HCW withMERS-CoV admitted to the ICU

(n = 1)*

HCW � health care worker; ICU � intensive care unit; MERS-CoV � Middle East respiratory syndrome coronavirus.* Cases described in this report.




DISCUSSION

We report on 12 critically ill patients with confirmedor probable MERS-CoV infection. Among these cases were3 cardiac ICU patients who were part of a health care–associated MERS-CoV cluster in 1 ICU. This cluster alsoincluded 3 HCWs, one of whom became critically ill. Allcritically ill patients had underlying comorbid conditionsand developed acute respiratory failure that was character-ized by severe hypoxemia and illness, a high incidence ofextrapulmonary manifestations, and a high mortality rate.

The clinical features of MERS-CoV disease observedin our patients bear some resemblance to those in criticallyill patients with disease caused by SARS-CoV (5). For ex-ample, patients with MERS-CoV infection presented withacute hypoxemic respiratory failure requiring invasive me-chanical ventilation, therapy with NIPPV frequently failedin these patients, and they often had severe hypoxemianecessitating rescue therapy.

However, our case series also demonstrates some im-portant differences from SARS-CoV infection. All of ourpatients had underlying comorbid conditions, includingasthma, diabetes, renal failure, cardiac disease, recent sur-gery, or heart failure. This high prevalence of comorbidconditions may be explained in part by the high prevalenceof diabetes and hypertension in the Saudi population.However, it also strongly suggests that patients withsuch conditions are susceptible hosts for MERS-CoV.There were no hospitalized patients with MERS-CoV in-fection outside the ICU, which differs from a Canadianstudy of SARS in which only 19% of patients were criti-cally ill (8).

To date, the diagnostic characteristics of MERS-CoVon RT-PCR, including the sensitivity and negative predic-tive value, are unknown. A negative result could be related

Table 1. Characteristics of Patients With Confirmed orProbable Middle East Respiratory Syndrome CoronavirusInfection

Variable Value (n � 12)

Median age (range), y 59 (36–83)Men, n (%) 8 (67)Median body mass index (range), kg/m2 31.8 (21.6–46.1)Median time from onset of symptoms to presentation

in the emergency department (range), d*1 (0–33)

Median time from onset of symptoms to ICUadmission (range), d

2 (0–33)

Median time from onset of symptoms to intubation(range), d

4.5 (0–33)

Health care worker, n (%) 1 (8)Health care–associated infection, n (%) 3 (25)Country of origin, n (%)

Saudi Arabia 9 (75)Pakistan 1 (8)Philippines 1 (8)Egypt 1 (8)

APACHE II score 28 (16–36)Smokers, n (%) 4 (33)Presenting symptoms, n (%)

Dyspnea 11 (92)Cough 10 (83)Fever (temperature �38 °C) 8 (67)Myalgia or arthralgia 3 (25)Headache 2 (17)Diarrhea 2 (17)Weakness 2 (17)Wheezing 2 (17)Sputum production 2 (17)Rhinorrhea 1 (8)Nausea 1 (8)Blood in sputum 1 (8)Sore throat 1 (8)

Comorbid conditions, n (%)Diabetes 8 (67)Hypertension 6 (50)Renal insufficiency 5 (42)Myocardial infarction 4 (33)Cardiac surgery 3 (25)Cerebrovascular accident 3 (25)Obesity 3 (25)Congestive heart failure 2 (17)Peripheral vascular disease 2 (17)Asthma 1 (8)Dialysis dependency 1 (8)Kidney and liver transplant 1 (8)Malignant melanoma 1 (8)Neuromuscular disease 1 (8)Valvular disease 1 (8)

APACHE � Acute Physiology and Chronic Health Evaluation; ICU � intensivecare unit.* Excluding health care–associated infections.

Figure 3. Timeline of the clinical course of the studypatients.

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Intubation

Hospital discharge

Death

26 M

ay 20

13

13 Ju

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13

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19 Ju

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The beginning of the solid lines refers to the onset of MERS-CoV symp-toms. The different line colors indicate the 3 different intensive careunits (ICU 1 in Al-Ahsa and ICU 2 and ICU 3 in Riyadh). The dashedline indicates the time in the hospital before the onset of MERS-CoVsymptoms in patients with health care–associated infection. Patient Gwas still in the hospital as of 9 January 2014. ICU � intensive care unit;MERS-CoV � Middle East respiratory syndrome coronavirus.




to timing of the test in the disease course; variable viralshedding; and, most important, sample quality and tech-nique, as well as transportation time to the reference labo-ratory. In 2 of our patients, the result remained positive forseveral weeks, and it seems that a persistent positive resultmay not necessarily be associated with worse outcome orinfectiousness to others.

Use of a lung protective strategy with a small tidalvolume is the mainstay of management of ARDS (9). Re-cent studies showed significant survival benefit with pronepositioning and neuromuscular blockade in patients withARDS (10, 11). Although the use of inhaled nitric oxide inpatients with severe ARDS causes a transient improvementin oxygenation, it has not been shown to improve survivaland may be harmful (12). Of note, in vitro studies have

shown that nitric oxide inhibits the replication cycle ofSARS-CoV (13). The clinical therapeutic relevance of thisfinding to MERS-CoV infection is unknown.

The routine early use of HFOV in ARDS is not rec-ommended because 2 recent trials showed no benefit andpossible harm (14, 15). However, HFOV may still have arole as a rescue therapy, which was the case in our patients.There have been concerns about aerosol generation andpossible increased risk for disease transmission with HFOV(16). A study examining SARS transmission to HCWs didnot show an association between HFOV and staff infec-tion, but the sample size was insufficient to exclude sec-ondary transmission with HFOV (17). In our patients, weused filtered circuits because it has been suggested to re-duce transmission (18).

Table 2. Physiologic and Laboratory Variables of Patients on Days 1, 3, 7, and 14

Variable Day 1 (n � 12) Day 3 (n � 12) Day 7 (n � 10) Day 14 (n � 7)

Median FIo2 (range) 0.8 (0.4–1.0) 0.6 (0.3–1.0) 0.6 (0.3–1.0) 0.6 (0.4–1.0)Median tidal volume (range), mL 450 (259–551) 412 (262–573)* 374 (314–460)* 432 (338–522)*Median PEEP (range), cm H2O 10 (5–14) 12 (5–18)* 14 (5–16)* 11 (8–14)*Median peak pressure (range), cm H2O 30 (20–36)* 32 (21–39)* 31 (24–36)* 31 (21–39)*Median mean airway pressure (range), cm H2O 16 (11–22) 19 (13–30) 22 (8–30) 20 (13–23)†Median respiratory rate (range), breaths/min 24 (15–35) 26 (5–32) 27 (3–35) 25 (14–32)*Median arterial blood gas values (range)

pH 7.3 (7.1–7.4) 7.3 (7.2–7.4) 7.3 (7.2–7.4) 7.3 (7–7.5)PaCO2, mm Hg 46 (33–72) 49 (31–345) 57 (38–70) 52 (36–69)PaO2, mm Hg 69 (39–248) 67 (47–216) 78 (51–112) 65 (58–93)Bicarbonate, mEq/L 22 (15–28) 23 (20–33) 26 (20–34) 28 (18–42)

Median PaO2–FIO2 ratio (range) 88 (76–413) 108 (52–360) 111 (55–299) 115 (69–205)Median oxygenation index value (range) 0.16 (0.02–0.54) 0.16 (0.04–0.38) 0.18 (0.03–0.52) 0.12 (0.07–0.24)Mode of ventilation, n (%)

Assist-control ventilation 11 (91.6) 10 (83.3) 9 (90) 6 (85.7)Synchronized intermittent mandatory ventilation 1 (8.3) 1 (8.3) 0 (0) 0 (0)High-frequency oscillatory ventilation 0 (0) 1 (8.3) 1 (10) 1 (14.3)

Median mean arterial pressure (range), mm Hg 63 (54–72) 63 (48–67) 64 (52–100) 64 (59–70)Median systolic blood pressure (range), mm Hg 97 (80–129) 103 (64–124) 102 (74–175) 112 (80–129)Median heart rate (range), beats/min 109 (88–140) 101 (77–122) 102 (76–121) 115 (79–144)Median central venous pressure (range), cm H2O 14 (9–18)‡ 11 (4–19)† 11 (8–16)† 12 (8–18)*Median dopamine dosage (range), �g/kg per min 0 (0–10) 0 (0–5) 0 (0–0)* 0 (0–0)Median norepinephrine dosage (range), �g/kg per min 0.01 (0–0.50) 0.02 (0–0.70) 0.10 (0–0.77) 0 (0–1)Median lactate level (range), mmol/L§ 1.2 (0.4–4.8)† 1.8 (0.6–20.1)† 2 (0.7–14.7)‡ 1.7 (0.2–19.6)*Median creatinine concentration (range)�

�mol/L 162 (41–1118) 142 (39–870)* 120.5 (48–343) 110 (40–415)mg/dL 1.83 (0.46–12.66) 1.61 (0.44–9.85) 1.36 (0.54–3.88) 1.24 (0.45–4.70)

Median AST level (range), U/L¶ 72 (21–230)* 141 (15–1281)‡ 77 (18–205)‡ 161 (24–823)†Median ALT level (range), U/L** 49 (12–163)* 32 (5–224)‡ 39 (5–87)‡ 130 (6–768)†Median bilirubin level (range)††

�mol/L 13 (7–35)* 26 (12–118)‡ 18 (7–185)‡ 3 (8–102)†mg/dL 0.76 (0.40–2.04) 1.52 (0.70–6.90) 1.05 (0.40–0.88) 0.17 (0.47–5.96)

Median platelet count (range), � 109 cells/L‡‡ 209 (109–497)* 122 (53–466)† 255 (18–314)* 119 (8–364)Median leukocyte count (range), � 109 cells/L§§ 8.9 (1.0–20.5) 8.7 (4.2–19.6) 17.8 (6.1–23.7) 9.6 (5.6–39.7)Median lymphocyte count (range), � 109 cells/L�� 0.9 (0.3–2.7)* 0.6 (0.4–1.9)* 0.8 (0.5–1.7)* 1.1 (0.4–2)*Median SOFA score (range) 9 (3–12) 9 (4–13) 7 (0–14) 5 (0–14)

ALT � alanine aminotransferase; AST � aspartate aminotransferase; PEEP � positive end-expiratory pressure; SOFA � Sequential Organ Failure Assessment.* Missing 1 value.† Missing 2 values.‡ Missing 3–5 values.§ Normal range, 0.5–2.2 mmol/L.� Normal range, 50–98 �mol/L (0.56–1.11 mg/dL).¶ Normal range, 5–34 U/L.** Normal range, 5–55 U/L.†† Normal range, 3.4–20.5 �mol/L (0.20–1.20 mg/dL).‡‡ Normal range, 150–400 � 109 cells/L.§§ Normal range, 4.0–11.0 � 109 cells/L.�� Normal range, 1.0–4.4 � 109 cells/L.




Extracorporeal membrane oxygenation was used dur-ing the SARS and H1N1 influenza epidemics. However, itwas not used in any of our patients because of the presenceof multiple comorbid conditions, thrombocytopenia, andextrapulmonary involvement.

Data are limited on the use of NIPPV in viral pneu-monia in general. Although its use in acute lung injury isassociated with early physiologic improvement, it has notbeen shown to decrease the need for intubation or to re-duce mortality. In fact, it may increase adverse effects (19).Furthermore, NIPPV is associated with aerosol generationand may increase disease transmission (16). Five of ourpatients were treated with NIPPV initially; all eventuallyrequired invasive ventilation.

The use of corticosteroids in viral pneumonia andARDS remains controversial. The evidence for corticoste-roid use in other severe viral pneumonias, includingvaricella zoster, H1N1, and SARS, is also insufficient (20–22). A retrospective cohort study showed that thecorticosteroid-treated patients with SARS had a 20.7-foldincrease in mortality and ICU admission (23). The poten-tial benefit of corticosteroids in ARDS may be limited tothe fibroproliferative phase of the disease (24), patientswith ARDS and shock (25), or use of low-dose corticoste-roids (26). A randomized, controlled trial found that theuse of methylprednisolone for persistent ARDS was asso-ciated with improvement in physiologic end points but didnot reduce mortality. In fact, patients who started methyl-prednisolone therapy more than 2 weeks after the onset ofARDS had increased risk for death (27). Whether there isa specific role for corticosteroids in MERS-CoV is un-known. The potential role of ribavirin and interferon-� for

Figure 4. Computed tomography images from 3 patients,showing bilateral airspace disease.

Figure 5. Results of sequential real-time polymerase chainreaction.

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–– –– –– ––

–– –– ––

The red circles indicate a positive result for MERS-CoV; green circlesindicate negative results. The open circle indicates that patient H did notundergo testing because he was a probable MERS-CoV case patient.ICU � intensive care unit; MERS-CoV � Middle East respiratory syn-drome coronavirus.




the treatment of MERS-CoV is drawn from limited use inpatients with SARS and from in vitro studies on SARS-CoV (28–30).

The pathogenesis of organ dysfunction in MERS-CoVis unknown. A striking finding in our cases is the highincidence of extrapulmonary manifestations, including cir-culatory, renal, hepatic, and hematologic. It remains to bestudied whether the main pathogenic mechanism of organdysfunction is related to cytokine dysregulation, given thehigh prevalence of lymphopenia in our patients. Otherpossible mechanisms include direct viral invasion; the viruswas recovered from urine and stool in one report (31). Theresponse of severe thrombocytopenia to intravenous im-munoglobulin in one of our patients suggests a possibleautoimmune mechanism.

Acute kidney injury requiring renal replacement ther-apy occurred in our patients more often than has beenreported in SARS. Renal replacement therapy was requiredin 58% of our patients, compared with 5% of critically illpatients during the SARS epidemic in Canada (8). Thehigh prevalence may be related to preexisting comorbidconditions, such as diabetes, old age, and hypertension.The isolation of MERS-CoV from urine in one studysuggests the possibility of direct viral involvement of thekidneys (31).

The low rate of transmission among HCWs in ourstudy is consistent with previous reports from the King-dom of Saudi Arabia and the United Kingdom (32–34).We believe that the low rate of transmission to HCWs wasrelated to effective infection control, lack of susceptiblehosts, and poor adaptability of the virus to human trans-mission observed in this emerging pathogen thus far. How-ever, it is clear from the health care–associated cluster thathuman-to-human transmission occurs with unprotectedexposure. Therefore, there is a concern that MERS-CoVmay become highly infectious to humans with sustained

human-to-human transmissibility. In such an event, alongwith the high pathogenicity of the virus, MERS-CoV willbecome a major public health threat worldwide (35).

Given the high mortality rate of this emerging infec-tion and the lack of evidence for specific therapies, ourfindings call for an urgent collaborative study to examinetherapeutic options, such as convalescent plasma or ribavi-rin, interferon, or other novel drugs (36).

In conclusion, MERS-CoV infection causes severe re-spiratory and substantial nonpulmonary organ dysfunc-tions and has a high mortality rate. Community-acquiredand health care–associated MERS-CoV infection occurs inpatients with chronic comorbid conditions. Transmissionto HCWs seems to be low, although human-to-humantransmission does occur with unprotected exposure.

From King Saud bin Abdulaziz University for Health Sciences, Riyadh,and King Abdulaziz Hospital, Al-Ahsa, Kingdom of Saudi Arabia.

Acknowledgment: The authors thank the members of the Departmentof Clinical Nursing and the Infection Prevention and Control Program,King Abdulaziz Medical City, Riyadh, Saudi Arabia, for their assistance.They also thank the following persons: From the King Saud bin AbdulazizUniversity for Health Sciences, Riyadh: Sameera Johani, MD, Division ofMicrobiology, Pathology & Laboratory Medicine; Abdullah Ghamdi,MD, Department of Cardiac Sciences; Ghassan A. Al-Ghamdi, MD,Intensive Care Department and Assistant Professor, College of Medicine;Saqib I. Dara, MD, Intensive Care Department; Raed A. Hijazi, MD,Emergency Medicine; Olivia A. Trinidad, RRT, Edgardo Tabhan, RRT,and Charina Olay, RRT, all Respiratory Therapist I, Respiratory Ser-vices. From the King Abdulaziz Hospital, Al-Ahsa: Yusri Taha, MD, andMohammed Ayman El Gammal, MD, Infectious Diseases, Departmentof Medicine and Abdulsalam Al-Aithan, MD, Pulmonary & IntensiveCare Medicine. From the Imam Abdulrahman Bin Faisal Hospital, Dam-mam: Wafa Nasser, MD, Infection Prevention and Control Program.

Potential Conflicts of Interest: None disclosed. Forms can be viewed atwww.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum�M13-2486.

Reproducible Research Statement: Study protocol, statistical code, anddata set: Available from Dr. Arabi (e-mail, [email protected]).

Requests for Single Reprints: Yaseen M. Arabi, MD, Intensive CareDepartment, College of Medicine, King Saud bin Abdulaziz Universityfor Health Sciences, Mail Code 1425, PO Box 22490, Riyadh 11426,Kingdom of Saudi Arabia; e-mail, [email protected].

Current author addresses and author contributions are available atwww.annals.org.

References1. Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, Fouchier RA.Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. NEngl J Med. 2012;367:1814-20. [PMID: 23075143]2. Lu L, Liu Q, Du L, Jiang S. Middle East respiratory syndrome coronavirus(MERS-CoV): challenges in identifying its source and controlling its spread.Microbes Infect. 2013;15:625-9. [PMID: 23791956]

Table 3. Main Interventions and Outcomes

Variable Value

Noninvasive positive-pressure ventilation, n (%) 5 (42)Invasive ventilation, n (%) 12 (100)Neuromuscular blockade, n (%) 4 (33)High-frequency oscillation ventilation, n (%) 2 (17)Nitric oxide, n (%) 6 (50)Prone positioning, n (%) 3 (25)Barotrauma, n (%) 2 (17)Vasopressors, n (%) 11 (92)Renal replacement therapy, n (%) 7 (58)Tracheostomy, n (%) 3 (25)Median duration of mechanical ventilation (range), d 16 (4–30)Alive at day 28, n (%) 7 (58)Alive at day 90, n (%) 5 (42)ICU survival, n (%) 5 (42)Median ICU length of stay (range), d 30 (7–104)Median hospital length of stay (range), d 41 (8–96)*

ICU � intensive care unit.* One patient is still in the hospital.




http://www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-2486


mailto:[email protected]


3. World Health Organization. Global alert and response. Middle East respira-tory syndrome coronavirus (MERS-CoV)—update. 27 December 2013. Ac-cessed at www.who.int/csr/don/2013_12_27/en/index.html on 9 January 2014.4. Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S,et al. Clinical features and virological analysis of a case of Middle East respiratorysyndrome coronavirus infection. Lancet Infect Dis. 2013;13:745-51. [PMID:23782859]5. Assiri A, Al-Tawfiq JA, Al-Rabeeah AA, Al-Rabiah FA, Al-Hajjar S, Al-Barrak A, et al. Epidemiological, demographic, and clinical characteristics of 47cases of Middle East respiratory syndrome coronavirus disease from Saudi Arabia:a descriptive study. Lancet Infect Dis. 2013;13:752-61. [PMID: 23891402]6. World Health Organization. Global alert and response. Revised interim casedefinition for reporting to WHO—Middle East respiratory syndrome coronavi-rus (MERS-CoV). 3 July 2013. Accessed at www.who.int/csr/disease/coronavirus_infections/case_definition/en on 9 January 2014.7. Vincent JL, Moreno R, Takala J, Willatts S, De Mendonca A, Bruining H,et al. The SOFA (Sepsis-related Organ Failure Assessment) score to describeorgan dysfunction/failure. On behalf of the Working Group on Sepsis-RelatedProblems of the European Society of Intensive Care Medicine. Intensive CareMed. 1996;22:707-10. [PMID: 8844239]8. Fowler RA, Lapinsky SE, Hallett D, Detsky AS, Sibbald WJ, Slutsky AS,et al; Toronto SARS Critical Care Group. Critically ill patients with severe acuterespiratory syndrome. JAMA. 2003;290:367-73. [PMID: 12865378]9. Ventilation with lower tidal volumes as compared with traditional tidal vol-umes for acute lung injury and the acute respiratory distress syndrome. The AcuteRespiratory Distress Syndrome Network. N Engl J Med. 2000;342:1301-8.[PMID: 10793162]10. Guerin C, Reignier J, Richard JC, Beuret P, Gacouin A, Boulain T, et al;PROSEVA Study Group. Prone positioning in severe acute respiratory distresssyndrome. N Engl J Med. 2013;368:2159-68. [PMID: 23688302]11. Papazian L, Forel JM, Gacouin A, Penot-Ragon C, Perrin G, Loundou A,et al; ACURASYS Study Investigators. Neuromuscular blockers in early acuterespiratory distress syndrome. N Engl J Med. 2010;363:1107-16. [PMID:20843245]12. Afshari A, Brok J, Møller AM, Wetterslev J. Inhaled nitric oxide for acuterespiratory distress syndrome and acute lung injury in adults and children: asystematic review with meta-analysis and trial sequential analysis. Anesth Analg.2011;112:1411-21. [PMID: 21372277]13. Akerstrom S, Gunalan V, Keng CT, Tan YJ, Mirazimi A. Dual effect ofnitric oxide on SARS-CoV replication: viral RNA production and palmitoylationof the S protein are affected. Virology. 2009;395:1-9. [PMID: 19800091]14. Ferguson ND, Cook DJ, Guyatt GH, Mehta S, Hand L, Austin P, et al;OSCILLATE Trial Investigators; Canadian Critical Care Trials Group. High-frequency oscillation in early acute respiratory distress syndrome. N Engl J Med.2013;368:795-805. [PMID: 23339639]15. Young D, Lamb SE, Shah S, MacKenzie I, Tunnicliffe W, Lall R, et al;OSCAR Study Group. High-frequency oscillation for acute respiratory distresssyndrome. N Engl J Med. 2013;368:806-13. [PMID: 23339638]16. Tran K, Cimon K, Severn M, Pessoa-Silva C, Conly J. Aerosol-generatingprocedures and risk of transmission of acute respiratory infections: a systematicreview. CADTH Technol Overv. 2013;3:e3201. [PMID: 23463843]17. Fowler RA, Guest CB, Lapinsky SE, Sibbald WJ, Louie M, Tang P, et al.Transmission of severe acute respiratory syndrome during intubation and me-chanical ventilation. Am J Respir Crit Care Med. 2004;169:1198-202. [PMID:14990393]18. Sweeney AM, Lyle J, Ferguson ND. Nursing and infection-control issuesduring high-frequency oscillatory ventilation. Crit Care Med. 2005;33(3 Suppl):S204-8. [PMID: 15753729]19. Delclaux C, L’Her E, Alberti C, Mancebo J, Abroug F, Conti G, et al.Treatment of acute hypoxemic nonhypercapnic respiratory insufficiency with

continuous positive airway pressure delivered by a face mask: a randomized con-trolled trial. JAMA. 2000;284:2352-60. [PMID: 11066186]20. Mer M, Richards GA. Corticosteroids in life-threatening varicella pneumo-nia. Chest. 1998;114:426-31. [PMID: 9726725]21. Gomersall CD. Pro/con clinical debate: steroids are a key component in thetreatment of SARS. Pro: Yes, steroids are a key component of the treatmentregimen for SARS. Crit Care. 2004;8:105-7. [PMID: 15025770]22. Brun-Buisson C, Richard JC, Mercat A, Thiebaut AC, Brochard L;REVA-SRLF A/H1N1v 2009 Registry Group. Early corticosteroids in severeinfluenza A/H1N1 pneumonia and acute respiratory distress syndrome. Am JRespir Crit Care Med. 2011;183:1200-6. [PMID: 21471082]23. Auyeung TW, Lee JS, Lai WK, Choi CH, Lee HK, Lee JS, et al. The useof corticosteroid as treatment in SARS was associated with adverse outcomes: aretrospective cohort study. J Infect. 2005;51:98-102. [PMID: 16038758]24. Meduri GU, Headley AS, Golden E, Carson SJ, Umberger RA, Kelso T,et al. Effect of prolonged methylprednisolone therapy in unresolving acute respi-ratory distress syndrome: a randomized controlled trial. JAMA. 1998;280:159-65. [PMID: 9669790]25. Annane D, Sebille V, Bellissant E; Ger-Inf-05 Study Group. Effect of lowdoses of corticosteroids in septic shock patients with or without early acute respi-ratory distress syndrome. Crit Care Med. 2006;34:22-30. [PMID: 16374152]26. Tang BM, Craig JC, Eslick GD, Seppelt I, McLean AS. Use of corticoste-roids in acute lung injury and acute respiratory distress syndrome: a systematicreview and meta-analysis. Crit Care Med. 2009;37:1594-603. [PMID:19325471]27. Steinberg KP, Hudson LD, Goodman RB, Hough CL, Lanken PN, HyzyR, et al ; National Heart, Lung, and Blood Institute Acute Respiratory DistressSyndrome (ARDS) Clinical Trials Network. Efficacy and safety of corticoste-roids for persistent acute respiratory distress syndrome. N Engl J Med. 2006;354:1671-84. [PMID: 16625008]28. Morgenstern B, Michaelis M, Baer PC, Doerr HW, Cinatl J Jr. Ribavirinand interferon-beta synergistically inhibit SARS-associated coronavirus replicationin animal and human cell lines. Biochem Biophys Res Commun. 2005;326:905-8. [PMID: 15607755]29. Kuri T, Weber F. Interferon interplay helps tissue cells to cope with SARS-coronavirus infection. Virulence. 2010;1:273-5. [PMID: 21178452]30. Paragas J, Blatt LM, Hartmann C, Huggins JW, Endy TP. Interferonalfacon1 is an inhibitor of SARS-corona virus in cell-based models. Antiviral Res.2005;66:99-102. [PMID: 15911026]31. Drosten C, Seilmaier M, Corman VM, Hartmann W, Scheible G, Sack S,et al. Clinical features and virological analysis of a case of Middle East respiratorysyndrome coronavirus infection. Lancet Infect Dis. 2013;13:745-51. [PMID:23782859]32. Memish ZA, Zumla AI, Al-Hakeem RF, Al-Rabeeah AA, Stephens GM.Family cluster of Middle East respiratory syndrome coronavirus infections.N Engl J Med. 2013;368:2487-94. [PMID: 23718156]33. Memish ZA, Zumla AI, Assiri A. Middle East respiratory syndrome corona-virus infections in health care workers. N Engl J Med. 2013;369:884-6. [PMID:23923992]34. Health Protection Agency (HPA) UK Novel Coronavirus InvestigationTeam. Evidence of person-to-person transmission within a family cluster of novelcoronavirus infections, United Kingdom, February 2013. Euro Surveill. 2013;18:20427. [PMID: 23517868]35. Perlman S. The Middle East respiratory syndrome—how worried should webe? MBio. 2013;4. [PMID: 23963179]36. Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA. Ther-apeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)—possible lessons from a systematic review of SARS-CoV therapy. Int J In-fect Dis. 2013;17:e792-8. [PMID: 23993766]




http://www.who.int/csr/don/2013_12_27/en/index.html

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


Clinical Course and Outcomes of Critically Ill Patients With MiddleEast Respiratory Syndrome Coronavirus InfectionYaseen M. Arabi, MD; Ahmed A. Arifi, MD; Hanan H. Balkhy, MD; Hani Najm, MD; Abdulaziz S. Aldawood, MD; Alaa Ghabashi, MD;Hassan Hawa, MD; Adel Alothman, MB; Abdulaziz Khaldi, MD; and Basel Al Raiy, MD

Background: Since September 2012, 170 confirmed infections withMiddle East respiratory syndrome coronavirus (MERS-CoV) havebeen reported to the World Health Organization, including 72deaths. Data on critically ill patients with MERS-CoV infection arelimited.

Objective: To describe the critical illness associated withMERS-CoV.

Design: Case series.

Setting: 3 intensive care units (ICUs) at 2 tertiary care hospitals inSaudi Arabia.

Patients: 12 patients with confirmed or probable MERS-CoVinfection.

Measurements: Presenting symptoms, comorbid conditions, pul-monary and extrapulmonary manifestations, measures of severity ofillness and organ failure, ICU course, and outcome are described, asare the results of surveillance of health care workers (HCWs) andpatients with potential exposure.

Results: Between December 2012 and August 2013, 114 patientswere tested for suspected MERS-CoV; of these, 11 ICU patients(10%) met the definition of confirmed or probable cases. Three of

these patients were part of a health care–associated cluster that alsoincluded 3 HCWs. One HCW became critically ill and was the 12thpatient in this case series. Median Acute Physiology and ChronicHealth Evaluation II score was 28 (range, 16 to 36). All 12 patientshad underlying comorbid conditions and presented with acute se-vere hypoxemic respiratory failure. Most patients (92%) had ex-trapulmonary manifestations, including shock, acute kidney injury,and thrombocytopenia. Five (42%) were alive at day 90. Of the520 exposed HCWs, only 4 (1%) were positive.

Limitation: The sample size was small.

Conclusion: MERS-CoV causes severe acute hypoxemic respira-tory failure and considerable extrapulmonary organ dysfunctionand is associated with high mortality. Community-acquired andhealth care–associated MERS-CoV infection occurs in patients withchronic comorbid conditions. The health care–associated clustersuggests that human-to-human transmission does occur with un-protected exposure.

Primary Funding Source: None.

Ann Intern Med. 2014;160:389-397. www.annals.orgFor author affiliations, see end of text.This article was published online first at www.annals.org on 28 January 2014.

In September 2012, a new coronavirus was isolatedfor the first time from a patient in Saudi Arabia, who

presented with acute pneumonia and renal failure (1).The virus was identified as a human �-coronavirus andwas subsequently named “Middle East respiratory syn-drome coronavirus” (MERS-CoV) (2). Since then, 170laboratory-confirmed cases of infection with MERS-CoVhave been reported to the World Health Organization,including 72 deaths (3). The disease has a high fatality rateand has several clinical features that resemble the infectioncaused by the severe acute respiratory syndrome coronavi-rus (SARS-CoV) (4). As such, there has been concern thatthe virus has the potential to cause a pandemic. Worldknowledge about this virus is accumulating, but data oncritically ill patients infected with MERS-CoV are limited.

We describe the clinical course and outcomes of 12critically ill patients with MERS-CoV admitted to 3 inten-sive care units (ICUs) in 2 tertiary hospitals in SaudiArabia.

METHODS

The study was approved by the Institutional ReviewBoard of the National Guard Health Affairs, Riyadh, SaudiArabia, and consent was not required.

SettingThe Saudi Arabian National Guard Health Affairs

serves close to 1 million individuals of the Saudi ArabianNational Guard soldiers and their dependents through aprimary, secondary, and tertiary health care system thatincludes 4 tertiary care hospitals and more than 90 primaryhealth care clinics. We report on critically ill patients withMERS-CoV infection from 1 ICU (a medical–surgicalICU referred to as “ICU 1”) at King Abdulaziz Hospital,Al-Ahsa, and from 2 ICUs (a medical–surgical ICU and acardiac ICU, referred to as “ICU 2” and “ICU 3,” respec-tively) at King Abdulaziz Medical City, Riyadh. AlthoughICU 2 and ICU 3 are located in the same hospital, they arein geographically separate locations and have limited staffcrossover.

Both hospitals have board-certified intensivists whotreat patients in closed medical–surgical ICUs and provideconsultations to patients in the cardiac ICU as required.

See also:

PrintEditorial comment. . . . . . . . . . . . . . . . . . . . . . . . . . 432

Annals of Internal Medicine Original Research

© 2014 American College of Physicians 389



The hospitals are accredited by the Joint Commission In-ternational and have Infection Prevention and Controlprograms that work collaboratively with the ICU staff.Hand-hygiene compliance in the ICUs for 2012 was 85%to 98%, and the influenza vaccination rate among healthcare workers (HCWs) was 83%.

Since the first case of MERS-CoV was identified inSaudi Arabia in September 2012, the National Guard hos-pitals along with all other health care facilities in SaudiArabia implemented the guidelines for testing of suspectedcases and screening (surveillance of potential exposures) forMERS-CoV according to Ministry of Health directives.The multidisciplinary outbreak committee was reactivatedto manage the current MERS-CoV outbreak. The infec-tion control precautions for suspected MERS-CoV in-cluded placement of patients in a single-bed negative-pressure room and the use of personal protectiveequipment (N-95 mask, gown, and gloves) by HCWs.This study includes all cases encountered from December2012, the date of the first suspected case, until August2013. The first confirmed case of MERS-CoV was in May2013 in Al-Ahsa and in June 2013 in Riyadh. The timeframe overlaps with that of a previously reported case se-ries, and the authors cannot entirely exclude the possibilitythat 1 or 2 of the patients in the current report have beenincluded in the previous case series.

PatientsInfection with MERS-CoV was suspected in patients

presenting with acute respiratory illness and chest radio-graphs suggestive of pneumonia and the acute respiratorydistress syndrome (ARDS), especially if the patient re-quired ICU admission. Suspected cases were tested for

MERS-CoV with real-time polymerase chain reaction(RT-PCR), using the recommended sampling technique(nasopharyngeal swab and tracheal aspirates or bronchoal-veolar lavage in intubated patients). In suspected cases withnegative RT-PCR results, the test was repeated at the dis-cretion of the treating physician. The HCWs and ICUpatients who were potentially exposed to MERS-CoV weresystematically screened. Samples were tested at the regionalreference laboratory of the Saudi Arabian Ministry ofHealth and the hospital laboratory at King Abdulaziz Med-ical City, Riyadh, as described elsewhere (5). The RT-PCRamplification targeted both the upstream E protein (upEgene) and ORF1a for confirmation.

DefinitionsWe included all patients admitted to ICUs with con-

firmed or probable MERS-CoV infection as defined by theWorld Health Organization (6). A confirmed case was de-fined as a suspected case with a positive result for MERS-CoV on RT-PCR. A probable case was defined as asuspected case if the RT-PCR result for MERS-CoV wasunavailable, negative, or inconclusive in a patient with anepidemiologic link to a patient with confirmed MERS-CoV (6).

Data on demographic characteristics, contact historywith a MERS-CoV confirmed case patient, underlyingcomorbid conditions, presenting symptoms, and radio-graphic findings were collected from the medical records.On the day of intubation, we assessed severity of illness byusing Acute Physiology and Chronic Health Evaluation IIscores and Sequential Organ Failure Assessment (SOFA)scores (7). On days 1, 3, 7, and 14 of intubation, wedocumented laboratory and ventilator variables and arterialblood gases. Leukopenia was defined as leukocyte countless than 4.0 � 109 cells/L, lymphopenia as a lymphocytecount less than 1.5 � 109 cells/L, and thrombocytopeniaas a platelet count less than 140 � 109 cells/L. Aspartateaminotransferase and alanine aminotransferase levels wereconsidered elevated if they were more than twice the upperreference limit (34 U/L and 55 U/L, respectively).

We recorded the time course of the patient’s illness,microbiological test results, and treatments received. Wealso recorded the following outcomes: duration of mechan-ical ventilation, ICU length of stay, and survival to ICUdischarge, at day 28 and at day 90.

Role of the Funding SourceThis study did not receive external funding.

RESULTS

During the 9-month study period in the 2 hospitals,114 patients were suspected of having and were tested forMERS-CoV infection (Figures 1 and 2). Of these, 10 ICUpatients (9%) met the definition of confirmed cases, and1 (1%) was a probable case. Among these cases, 8 werecommunity-acquired, and 3 occurred in patients in ICU 3

Context

Middle East respiratory syndrome coronavirus (MERS-CoV)is an emerging pathogen with a clinical spectrum that isnot yet fully delineated.

Contribution

Twelve hospitalized patients found to have MERS-CoVinfection all required intensive care, including mechanicalventilation. Underlying comorbid disease was present in allpatients. Extrapulmonary involvement was common. Vari-ous treatments were tried. Mortality was high. Three caseswere nosocomially acquired, and 1 health care worker wasamong the case patients.

Caution

A small case series may not be representative of all pa-tients presenting to hospitals with MERS-CoV infection.

Implication

Additional information on optimal management ofMERS-CoV infection is urgently needed.

—The Editors




(the cardiac ICU) who were part of a health care–associ-ated cluster that included HCWs. In the latter patients, theinitial hospitalization was for aortic valve replacement, cor-onary artery bypass graft surgery, or pericardiectomy forconstrictive pericarditis. All of the hospitalized patientswith confirmed MERS-CoV infection required ICU ad-mission.

In addition, 23 cardiac ICU patients were screened aspart of active surveillance because of possible contact withconfirmed HCW cases; all tested negative. The surveillancealso included 520 HCWs who were screened for MERS-CoV; only 4 (1%) were positive. Three of the infections inHCWs occurred as a part of the health care–associatedMERS-CoV cluster. These HCWs were nurses reported tohave had exposure, without the use of personal protectiveequipment, to patients who were subsequently confirmedto have MERS-CoV infection. Only 1 of the HCWs (pa-tient L), who had asthma, became severely ill and requiredICU admission and is fully described in this series alongwith the other 11 patients. The other HCWs were mildlysymptomatic or asymptomatic and were managed at homeuntil the RT-PCR result was negative. Figure 1 shows thedistribution of these cases between the 2 hospitals in Al-Ahsa and Riyadh.

Clinical PresentationThe demographic and clinical characteristics of the 12

critically ill patients with confirmed or probable MERS-CoV infection are shown in Table 1 and Appendix Tables1 to 3 (available at www.annals.org). The median age ofthe patients was 59 years (range, 36 to 83 years). Eightpatients (67%) were male.

The presenting symptoms were mainly those of lowerrespiratory tract infection (dyspnea in 11 patients [92%],cough in 10 [83%], and fever in 8 [67%]); in contrast,symptoms of upper respiratory tract infection were infre-quent (Table 1). The median interval from onset of symp-toms to the emergency department visit was 1 day; to ICUadmission, 2 days; and to intubation, 4.5 days (range for alltime frames, 0 to 33 days). Figure 3 summarizes the timecourse of disease.

The median Acute Physiology and Chronic HealthEvaluation II score was 28 (range, 16 to 36), and the me-dian SOFA score was 9 (range, 3 to 12). Each patient hadat least 1 comorbid condition (Table 1); the median num-ber of comorbid conditions was 3 (range, 1 to 6). Animalexposure was documented for 2 patients; in both instances,the animals (a camel and a domestic cat) were not appar-ently ill.

Respiratory Manifestations and SupportAcute severe hypoxemic respiratory failure was the

prominent feature of the presentation, and all patients re-quired invasive mechanical ventilation (Table 2). Beforeintubation, 5 patients had received a failed trial of nonin-vasive positive-pressure ventilation (NIPPV). Chest radiog-raphy at the time of intubation showed airspace changes

that ranged from unilateral lobar to bilateral diffuse in-volvement consistent with ARDS (Appendix Figure, avail-able at www.annals.org). Chest computed tomography wasperformed in 3 patients and confirmed the same patterns(Figure 4).

All patients received intravenous sedation, and 4(33%) patients received neuromuscular blockade. Becauseof refractory hypoxemia, nitric oxide was used in 6 (50%)patients, prone positioning in 3 (25%), and high-frequency oscillation ventilation (HFOV) in 2 (17%) asrescue therapy. No patient was treated with extracorporealmembrane oxygenation. The median duration of mechan-ical ventilation was 16 days (range, 4 to 30 days). Trache-ostomy was performed in 3 patients (25%).

Nonrespiratory Manifestations and SupportEleven patients (92%) had at least 1 extrapulmonary

manifestation. Individual organ components of the SOFAscore are shown in Appendix Table 3 (available at www.annals.org).

Circulatory

Vasopressors were required in 8 patients (67%) on day1 and in 11 patients (92%) during the ICU stay. Echocar-diography was performed in 11 patients, and all showed noacute change in myocardial function.

Renal

Acute kidney injury that required renal replacementtherapy occurred in 7 patients (58%).

Figure 1. Map of the Kingdom of Saudi Arabia showing the2 study hospitals, the number of suspected and confirmedMERS-CoV infections in patients, and the number of HCWsscreened and cases confirmed in HCWs.

Jordan

KAMC-Riyadh

Iraq

IranKuwait

Bahrain

RiyadhQatar

UAE

Oman

Yemen

Red Sea

Medina

Jeddah Mecca

Dammam

Al-Ahsa

Al Taif

Number of involved ICUs: 2Patients with suspected MERS-CoV: 91Patients with confirmed or probable

MERS-CoV: 8HCWs screened for MERS-CoV: 376HCWs with confirmed MERS-CoV: 3HCWs with MERS-CoV requiring ICU: 1

KAH-Al-Ahsa

Number of involved ICUs: 1Patients with suspected MERS-CoV: 23Patients with confirmed MERS-CoV: 3HCWs screened for MERS-CoV: 144HCWs with confirmed MERS-CoV: 1HCWs with MERS-CoV requiring ICU: 0

ICU 1 is located in Al-Ahsa and ICU 2 and ICU 3 in Riyadh. HCW �health care worker; ICU � intensive care unit; KAH � King AbdulazizHospital; KAMC � King Abdulaziz Medical City; MERS-CoV � Mid-dle East respiratory syndrome coronavirus; UAE � United ArabEmirates.








Hepatic

The aspartate aminotransferase level was elevated in 6patients on day 1 and in 8 patients during the ICU stay.The alanine aminotransferase level was elevated in 2 pa-tients on day 1 and in 5 patients during the ICU stay.

Hematologic

Nine patients (75%) had lymphopenia on day 1, and11 (92%) had it during the ICU stay. Thrombocytopeniawas noted in 2 patients on day 1 and in 7 patients (58%)during the ICU stay.

Gastrointestinal

Diarrhea was noted in 2 patients. Three patients hadacute abdomen during the ICU stay. One patient, who haddiabetes and peripheral vascular disease, developed isch-emic bowel; abdominal computed tomography revealedpneumatosis intestinalis, and the patient required hemico-lectomy. The other 2 patients had negative laparotomies.

Microbiological InvestigationsOne patient was co-infected with methicillin-resistant

Staphylococcus aureus and influenza B and another withStreptococcus pneumoniae.

Figure 5 shows the results of sequential RT-PCR test-ing. Eleven patients had positive results. Infection with

MERS-CoV was considered probable in 1 patient becauseof high clinical suspicion and an epidemiologic link to aconfirmed positive MERS-CoV case that was identified af-ter he had died; hence, no test was performed for thispatient.

Antimicrobial Therapy, Corticosteroids, and IntravenousImmunoglobulin

All patients received broad-spectrum antimicrobials,and 7 patients (58%) received oseltamivir empirically.None of the patients received ribavirin or interferon-�.Low-dose hydrocortisone (�300 mg/d) was given to 5 pa-tients (42%) for shock and methylprednisolone (120 to1000 mg/d) was given to 5 other patients (42%). Onepatient received intravenous immunoglobulin and high-dose corticosteroids for thrombocytopenia, with an im-provement in platelet count.

OutcomesAmong the 12 patients, 7 (58%) were alive at day 28,

5 (42%) were alive at ICU discharge, and 5 (42%) werealive at day 90. The median ICU length of stay was 30days (range, 7 to 104 days). The median hospital length ofstay was 41 days (range, 8 to 96 days), excluding 1 patientwho was still in the hospital at the time of submission.Table 3 summarizes other outcomes.

Figure 2. Study flow diagram.

Persons tested orscreened for MERS-CoV

(n = 657)

Patients withsuspected MERS-CoV

(n = 114)

Patients screened aspart of active surveillance

(n = 23)

HCWs tested orscreened for MERS-CoV

(n = 520)

Symptomatic HCW with confirmedMERS-CoV isolated at home

(n = 1)

Confirmed cases ofMERS-CoV(n = 10)*

Probable cases ofMERS-CoV

(n = 1)*

Negative resultsfor MERS-CoV

(n = 23) HCWs positivefor MERS-CoV

(n = 4)

HCWs negativefor MERS-CoV

(n = 516)

Asymptomatic HCWs withMERS-CoV isolated at home

(n = 2)

Symptomatic HCW withMERS-CoV admitted to the ICU

(n = 1)*

HCW � health care worker; ICU � intensive care unit; MERS-CoV � Middle East respiratory syndrome coronavirus.* Cases described in this report.




DISCUSSION

We report on 12 critically ill patients with confirmedor probable MERS-CoV infection. Among these cases were3 cardiac ICU patients who were part of a health care–associated MERS-CoV cluster in 1 ICU. This cluster alsoincluded 3 HCWs, one of whom became critically ill. Allcritically ill patients had underlying comorbid conditionsand developed acute respiratory failure that was character-ized by severe hypoxemia and illness, a high incidence ofextrapulmonary manifestations, and a high mortality rate.

The clinical features of MERS-CoV disease observedin our patients bear some resemblance to those in criticallyill patients with disease caused by SARS-CoV (5). For ex-ample, patients with MERS-CoV infection presented withacute hypoxemic respiratory failure requiring invasive me-chanical ventilation, therapy with NIPPV frequently failedin these patients, and they often had severe hypoxemianecessitating rescue therapy.

However, our case series also demonstrates some im-portant differences from SARS-CoV infection. All of ourpatients had underlying comorbid conditions, includingasthma, diabetes, renal failure, cardiac disease, recent sur-gery, or heart failure. This high prevalence of comorbidconditions may be explained in part by the high prevalenceof diabetes and hypertension in the Saudi population.However, it also strongly suggests that patients withsuch conditions are susceptible hosts for MERS-CoV.There were no hospitalized patients with MERS-CoV in-fection outside the ICU, which differs from a Canadianstudy of SARS in which only 19% of patients were criti-cally ill (8).

To date, the diagnostic characteristics of MERS-CoVon RT-PCR, including the sensitivity and negative predic-tive value, are unknown. A negative result could be related

Table 1. Characteristics of Patients With Confirmed orProbable Middle East Respiratory Syndrome CoronavirusInfection

Variable Value (n � 12)

Median age (range), y 59 (36–83)Men, n (%) 8 (67)Median body mass index (range), kg/m2 31.8 (21.6–46.1)Median time from onset of symptoms to presentation

in the emergency department (range), d*1 (0–33)

Median time from onset of symptoms to ICUadmission (range), d

2 (0–33)

Median time from onset of symptoms to intubation(range), d

4.5 (0–33)

Health care worker, n (%) 1 (8)Health care–associated infection, n (%) 3 (25)Country of origin, n (%)

Saudi Arabia 9 (75)Pakistan 1 (8)Philippines 1 (8)Egypt 1 (8)

APACHE II score 28 (16–36)Smokers, n (%) 4 (33)Presenting symptoms, n (%)

Dyspnea 11 (92)Cough 10 (83)Fever (temperature �38 °C) 8 (67)Myalgia or arthralgia 3 (25)Headache 2 (17)Diarrhea 2 (17)Weakness 2 (17)Wheezing 2 (17)Sputum production 2 (17)Rhinorrhea 1 (8)Nausea 1 (8)Blood in sputum 1 (8)Sore throat 1 (8)

Comorbid conditions, n (%)Diabetes 8 (67)Hypertension 6 (50)Renal insufficiency 5 (42)Myocardial infarction 4 (33)Cardiac surgery 3 (25)Cerebrovascular accident 3 (25)Obesity 3 (25)Congestive heart failure 2 (17)Peripheral vascular disease 2 (17)Asthma 1 (8)Dialysis dependency 1 (8)Kidney and liver transplant 1 (8)Malignant melanoma 1 (8)Neuromuscular disease 1 (8)Valvular disease 1 (8)

APACHE � Acute Physiology and Chronic Health Evaluation; ICU � intensivecare unit.* Excluding health care–associated infections.

Figure 3. Timeline of the clinical course of the studypatients.

Pati

ent

ICU

1

Date

Hospital admission

Intubation

Hospital discharge

Death

26 M

ay 20

13

13 Ju

ne 20

13

1 July

2013

19 Ju

ly 20

13

6 Aug

ust 2

013

24 A

ugus

t 201

3

11 Se

ptem

ber 2

013

29 Se

ptem

ber 2

013

17 O

ctobe

r 201

3

31 O

ctobe

r 201

3

A

B

C

ICU

2

D

E

FG

ICU

3

H

I

JK

L

The beginning of the solid lines refers to the onset of MERS-CoV symp-toms. The different line colors indicate the 3 different intensive careunits (ICU 1 in Al-Ahsa and ICU 2 and ICU 3 in Riyadh). The dashedline indicates the time in the hospital before the onset of MERS-CoVsymptoms in patients with health care–associated infection. Patient Gwas still in the hospital as of 9 January 2014. ICU � intensive care unit;MERS-CoV � Middle East respiratory syndrome coronavirus.




to timing of the test in the disease course; variable viralshedding; and, most important, sample quality and tech-nique, as well as transportation time to the reference labo-ratory. In 2 of our patients, the result remained positive forseveral weeks, and it seems that a persistent positive resultmay not necessarily be associated with worse outcome orinfectiousness to others.

Use of a lung protective strategy with a small tidalvolume is the mainstay of management of ARDS (9). Re-cent studies showed significant survival benefit with pronepositioning and neuromuscular blockade in patients withARDS (10, 11). Although the use of inhaled nitric oxide inpatients with severe ARDS causes a transient improvementin oxygenation, it has not been shown to improve survivaland may be harmful (12). Of note, in vitro studies have

shown that nitric oxide inhibits the replication cycle ofSARS-CoV (13). The clinical therapeutic relevance of thisfinding to MERS-CoV infection is unknown.

The routine early use of HFOV in ARDS is not rec-ommended because 2 recent trials showed no benefit andpossible harm (14, 15). However, HFOV may still have arole as a rescue therapy, which was the case in our patients.There have been concerns about aerosol generation andpossible increased risk for disease transmission with HFOV(16). A study examining SARS transmission to HCWs didnot show an association between HFOV and staff infec-tion, but the sample size was insufficient to exclude sec-ondary transmission with HFOV (17). In our patients, weused filtered circuits because it has been suggested to re-duce transmission (18).

Table 2. Physiologic and Laboratory Variables of Patients on Days 1, 3, 7, and 14

Variable Day 1 (n � 12) Day 3 (n � 12) Day 7 (n � 10) Day 14 (n � 7)

Median FIo2 (range) 0.8 (0.4–1.0) 0.6 (0.3–1.0) 0.6 (0.3–1.0) 0.6 (0.4–1.0)Median tidal volume (range), mL 450 (259–551) 412 (262–573)* 374 (314–460)* 432 (338–522)*Median PEEP (range), cm H2O 10 (5–14) 12 (5–18)* 14 (5–16)* 11 (8–14)*Median peak pressure (range), cm H2O 30 (20–36)* 32 (21–39)* 31 (24–36)* 31 (21–39)*Median mean airway pressure (range), cm H2O 16 (11–22) 19 (13–30) 22 (8–30) 20 (13–23)†Median respiratory rate (range), breaths/min 24 (15–35) 26 (5–32) 27 (3–35) 25 (14–32)*Median arterial blood gas values (range)

pH 7.3 (7.1–7.4) 7.3 (7.2–7.4) 7.3 (7.2–7.4) 7.3 (7–7.5)PaCO2, mm Hg 46 (33–72) 49 (31–345) 57 (38–70) 52 (36–69)PaO2, mm Hg 69 (39–248) 67 (47–216) 78 (51–112) 65 (58–93)Bicarbonate, mEq/L 22 (15–28) 23 (20–33) 26 (20–34) 28 (18–42)

Median PaO2–FIO2 ratio (range) 88 (76–413) 108 (52–360) 111 (55–299) 115 (69–205)Median oxygenation index value (range) 0.16 (0.02–0.54) 0.16 (0.04–0.38) 0.18 (0.03–0.52) 0.12 (0.07–0.24)Mode of ventilation, n (%)

Assist-control ventilation 11 (91.6) 10 (83.3) 9 (90) 6 (85.7)Synchronized intermittent mandatory ventilation 1 (8.3) 1 (8.3) 0 (0) 0 (0)High-frequency oscillatory ventilation 0 (0) 1 (8.3) 1 (10) 1 (14.3)

Median mean arterial pressure (range), mm Hg 63 (54–72) 63 (48–67) 64 (52–100) 64 (59–70)Median systolic blood pressure (range), mm Hg 97 (80–129) 103 (64–124) 102 (74–175) 112 (80–129)Median heart rate (range), beats/min 109 (88–140) 101 (77–122) 102 (76–121) 115 (79–144)Median central venous pressure (range), cm H2O 14 (9–18)‡ 11 (4–19)† 11 (8–16)† 12 (8–18)*Median dopamine dosage (range), �g/kg per min 0 (0–10) 0 (0–5) 0 (0–0)* 0 (0–0)Median norepinephrine dosage (range), �g/kg per min 0.01 (0–0.50) 0.02 (0–0.70) 0.10 (0–0.77) 0 (0–1)Median lactate level (range), mmol/L§ 1.2 (0.4–4.8)† 1.8 (0.6–20.1)† 2 (0.7–14.7)‡ 1.7 (0.2–19.6)*Median creatinine concentration (range)�

�mol/L 162 (41–1118) 142 (39–870)* 120.5 (48–343) 110 (40–415)mg/dL 1.83 (0.46–12.66) 1.61 (0.44–9.85) 1.36 (0.54–3.88) 1.24 (0.45–4.70)

Median AST level (range), U/L¶ 72 (21–230)* 141 (15–1281)‡ 77 (18–205)‡ 161 (24–823)†Median ALT level (range), U/L** 49 (12–163)* 32 (5–224)‡ 39 (5–87)‡ 130 (6–768)†Median bilirubin level (range)††

�mol/L 13 (7–35)* 26 (12–118)‡ 18 (7–185)‡ 3 (8–102)†mg/dL 0.76 (0.40–2.04) 1.52 (0.70–6.90) 1.05 (0.40–0.88) 0.17 (0.47–5.96)

Median platelet count (range), � 109 cells/L‡‡ 209 (109–497)* 122 (53–466)† 255 (18–314)* 119 (8–364)Median leukocyte count (range), � 109 cells/L§§ 8.9 (1.0–20.5) 8.7 (4.2–19.6) 17.8 (6.1–23.7) 9.6 (5.6–39.7)Median lymphocyte count (range), � 109 cells/L�� 0.9 (0.3–2.7)* 0.6 (0.4–1.9)* 0.8 (0.5–1.7)* 1.1 (0.4–2)*Median SOFA score (range) 9 (3–12) 9 (4–13) 7 (0–14) 5 (0–14)

ALT � alanine aminotransferase; AST � aspartate aminotransferase; PEEP � positive end-expiratory pressure; SOFA � Sequential Organ Failure Assessment.* Missing 1 value.† Missing 2 values.‡ Missing 3–5 values.§ Normal range, 0.5–2.2 mmol/L.� Normal range, 50–98 �mol/L (0.56–1.11 mg/dL).¶ Normal range, 5–34 U/L.** Normal range, 5–55 U/L.†† Normal range, 3.4–20.5 �mol/L (0.20–1.20 mg/dL).‡‡ Normal range, 150–400 � 109 cells/L.§§ Normal range, 4.0–11.0 � 109 cells/L.�� Normal range, 1.0–4.4 � 109 cells/L.




Extracorporeal membrane oxygenation was used dur-ing the SARS and H1N1 influenza epidemics. However, itwas not used in any of our patients because of the presenceof multiple comorbid conditions, thrombocytopenia, andextrapulmonary involvement.

Data are limited on the use of NIPPV in viral pneu-monia in general. Although its use in acute lung injury isassociated with early physiologic improvement, it has notbeen shown to decrease the need for intubation or to re-duce mortality. In fact, it may increase adverse effects (19).Furthermore, NIPPV is associated with aerosol generationand may increase disease transmission (16). Five of ourpatients were treated with NIPPV initially; all eventuallyrequired invasive ventilation.

The use of corticosteroids in viral pneumonia andARDS remains controversial. The evidence for corticoste-roid use in other severe viral pneumonias, includingvaricella zoster, H1N1, and SARS, is also insufficient (20–22). A retrospective cohort study showed that thecorticosteroid-treated patients with SARS had a 20.7-foldincrease in mortality and ICU admission (23). The poten-tial benefit of corticosteroids in ARDS may be limited tothe fibroproliferative phase of the disease (24), patientswith ARDS and shock (25), or use of low-dose corticoste-roids (26). A randomized, controlled trial found that theuse of methylprednisolone for persistent ARDS was asso-ciated with improvement in physiologic end points but didnot reduce mortality. In fact, patients who started methyl-prednisolone therapy more than 2 weeks after the onset ofARDS had increased risk for death (27). Whether there isa specific role for corticosteroids in MERS-CoV is un-known. The potential role of ribavirin and interferon-� for

Figure 4. Computed tomography images from 3 patients,showing bilateral airspace disease.

Figure 5. Results of sequential real-time polymerase chainreaction.

Pati

ent

ICU

1

A

B

C

ICU

2

D

E

FG

ICU

3

H

I

JK

L

Day0

++

3 6 9 12 15 18 21 24 27 30

++

++ ++ ++ ++

––

++ ++ ––

++

++ –– –– ––++

++

++

++ ++ ++ ++

++

––

–– –– –– ––

–– –– ––

The red circles indicate a positive result for MERS-CoV; green circlesindicate negative results. The open circle indicates that patient H did notundergo testing because he was a probable MERS-CoV case patient.ICU � intensive care unit; MERS-CoV � Middle East respiratory syn-drome coronavirus.




the treatment of MERS-CoV is drawn from limited use inpatients with SARS and from in vitro studies on SARS-CoV (28–30).

The pathogenesis of organ dysfunction in MERS-CoVis unknown. A striking finding in our cases is the highincidence of extrapulmonary manifestations, including cir-culatory, renal, hepatic, and hematologic. It remains to bestudied whether the main pathogenic mechanism of organdysfunction is related to cytokine dysregulation, given thehigh prevalence of lymphopenia in our patients. Otherpossible mechanisms include direct viral invasion; the viruswas recovered from urine and stool in one report (31). Theresponse of severe thrombocytopenia to intravenous im-munoglobulin in one of our patients suggests a possibleautoimmune mechanism.

Acute kidney injury requiring renal replacement ther-apy occurred in our patients more often than has beenreported in SARS. Renal replacement therapy was requiredin 58% of our patients, compared with 5% of critically illpatients during the SARS epidemic in Canada (8). Thehigh prevalence may be related to preexisting comorbidconditions, such as diabetes, old age, and hypertension.The isolation of MERS-CoV from urine in one studysuggests the possibility of direct viral involvement of thekidneys (31).

The low rate of transmission among HCWs in ourstudy is consistent with previous reports from the King-dom of Saudi Arabia and the United Kingdom (32–34).We believe that the low rate of transmission to HCWs wasrelated to effective infection control, lack of susceptiblehosts, and poor adaptability of the virus to human trans-mission observed in this emerging pathogen thus far. How-ever, it is clear from the health care–associated cluster thathuman-to-human transmission occurs with unprotectedexposure. Therefore, there is a concern that MERS-CoVmay become highly infectious to humans with sustained

human-to-human transmissibility. In such an event, alongwith the high pathogenicity of the virus, MERS-CoV willbecome a major public health threat worldwide (35).

Given the high mortality rate of this emerging infec-tion and the lack of evidence for specific therapies, ourfindings call for an urgent collaborative study to examinetherapeutic options, such as convalescent plasma or ribavi-rin, interferon, or other novel drugs (36).

In conclusion, MERS-CoV infection causes severe re-spiratory and substantial nonpulmonary organ dysfunc-tions and has a high mortality rate. Community-acquiredand health care–associated MERS-CoV infection occurs inpatients with chronic comorbid conditions. Transmissionto HCWs seems to be low, although human-to-humantransmission does occur with unprotected exposure.

From King Saud bin Abdulaziz University for Health Sciences, Riyadh,and King Abdulaziz Hospital, Al-Ahsa, Kingdom of Saudi Arabia.

Acknowledgment: The authors thank the members of the Departmentof Clinical Nursing and the Infection Prevention and Control Program,King Abdulaziz Medical City, Riyadh, Saudi Arabia, for their assistance.They also thank the following persons: From the King Saud bin AbdulazizUniversity for Health Sciences, Riyadh: Sameera Johani, MD, Division ofMicrobiology, Pathology & Laboratory Medicine; Abdullah Ghamdi,MD, Department of Cardiac Sciences; Ghassan A. Al-Ghamdi, MD,Intensive Care Department and Assistant Professor, College of Medicine;Saqib I. Dara, MD, Intensive Care Department; Raed A. Hijazi, MD,Emergency Medicine; Olivia A. Trinidad, RRT, Edgardo Tabhan, RRT,and Charina Olay, RRT, all Respiratory Therapist I, Respiratory Ser-vices. From the King Abdulaziz Hospital, Al-Ahsa: Yusri Taha, MD, andMohammed Ayman El Gammal, MD, Infectious Diseases, Departmentof Medicine and Abdulsalam Al-Aithan, MD, Pulmonary & IntensiveCare Medicine. From the Imam Abdulrahman Bin Faisal Hospital, Dam-mam: Wafa Nasser, MD, Infection Prevention and Control Program.

Potential Conflicts of Interest: None disclosed. Forms can be viewed atwww.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum�M13-2486.

Reproducible Research Statement: Study protocol, statistical code, anddata set: Available from Dr. Arabi (e-mail, [email protected]).

Requests for Single Reprints: Yaseen M. Arabi, MD, Intensive CareDepartment, College of Medicine, King Saud bin Abdulaziz Universityfor Health Sciences, Mail Code 1425, PO Box 22490, Riyadh 11426,Kingdom of Saudi Arabia; e-mail, [email protected].

Current author addresses and author contributions are available atwww.annals.org.

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Table 3. Main Interventions and Outcomes

Variable Value

Noninvasive positive-pressure ventilation, n (%) 5 (42)Invasive ventilation, n (%) 12 (100)Neuromuscular blockade, n (%) 4 (33)High-frequency oscillation ventilation, n (%) 2 (17)Nitric oxide, n (%) 6 (50)Prone positioning, n (%) 3 (25)Barotrauma, n (%) 2 (17)Vasopressors, n (%) 11 (92)Renal replacement therapy, n (%) 7 (58)Tracheostomy, n (%) 3 (25)Median duration of mechanical ventilation (range), d 16 (4–30)Alive at day 28, n (%) 7 (58)Alive at day 90, n (%) 5 (42)ICU survival, n (%) 5 (42)Median ICU length of stay (range), d 30 (7–104)Median hospital length of stay (range), d 41 (8–96)*

ICU � intensive care unit.* One patient is still in the hospital.






mailto:[email protected]


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http://www.who.int/csr/don/2013_12_27/en/index.html



Current Author Addresses: Drs. Arabi, Aldawood, and Al Raiy: Inten-sive Care Department, College of Medicine, King Saud bin AbdulazizUniversity for Health Sciences, Mail Code 1425, PO Box 22490, Riyadh11426, Kingdom of Saudi Arabia.Drs. Arifi, Najm, and Khaldi: Department of Cardiac Sciences, KingSaud bin Abdulaziz University for Health Sciences, Mail Code 1404, POBox 22490, Riyadh 11426, Kingdom of Saudi Arabia.Dr. Balkhy: Infection Prevention & Control Department, King Saud binAbdulaziz University for Health Sciences, Mail Code 2034, PO Box22490, Riyadh 11426, Kingdom of Saudi Arabia.Drs. Ghabashi and Hawa: Pulmonary & Intensive Care Medicine, KingAbdulaziz Hospital, Mail Code 312, PO Box 2477, Al-Ahsa 31982,Kingdom of Saudi Arabia.Dr. Alothman: Infectious Diseases, Department of Medicine, King Saudbin Abdulaziz University for Health Sciences, Mail Code 1443, PO Box22490, Riyadh 11426, Kingdom of Saudi Arabia.

Author Contributions: Conception and design: Y.M. Arabi, A.A. Arifi,H.H. Balkhy, H. Najm, A.S. Aldawood, A. Khaldi.Analysis and interpretation of the data: Y.M. Arabi, A.A. Arifi, H.H.Balkhy, H. Najm, A.S. Aldawood, A. Alothman.Drafting of the article: Y.M. Arabi, A.A. Arifi, H.H. Balkhy, A. Gha-bashi, H. Hawa, B. Al Raiy.Critical revision for important intellectual content: Y.M. Arabi, A.A.Arifi, H.H. Balkhy, H. Najm, H. Hawa, A. Alothman, B. Al Raiy.Final approval of the article: Y.M. Arabi, A.A. Arifi, H.H. Balkhy, A.S.Aldawood, A. Ghabashi, A. Alothman, A. Khaldi.Provision of study materials or patients: Y.M. Arabi, A.A. Arifi, H.H.Balkhy, H. Najm, A.S. Aldawood, A. Ghabashi, H. Hawa, A. Khaldi.Statistical expertise: Y.M. Arabi.Administrative, technical, or logistic support: Y.M. Arabi, A.S. Alda-wood, B. Al Raiy.Collection and assembly of data: Y.M. Arabi, A.A. Arifi, H.H. Balkhy,A.S. Aldawood, A. Ghabashi, H. Hawa, A. Khaldi, B. Al Raiy.

Annals of Internal Medicine

www.annals.org 18 March 2014 Annals of Internal Medicine Volume 160 • Number 6


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18 March 2014 Annals of Internal Medicine Volume 160 • Number 6 www.annals.org


Appendix Table 2. Physiologic and Laboratory Variables on Day 1 and During the ICU Stay

Patient Shock Elevated ASTLevel

Elevated ALTLevel

Thrombocytopenia Leukopenia Lymphopenia Alive atDay 14

Alive at ICUDischarge

Day 1 ICU Day 1 ICU Day 1 ICU Day 1 ICU Day 1 ICU Day 1 ICU

A � � � � – – – – – – � � – –B � � � � – – – – – – – � � –C � � – – – – – � – – � � � �D � � � � – – – – – – � � � �E – � – � – � – � – – � � – –F � � – – – – � � � � � � � �G � � � � – � – � – – � � � �H – – – – – – – � � � � � � –I � � � � � � – – – – � � – –J � � � � � � � � � � � � – –K – � – � – � – � – – – � � –L – � – – – – – – – – – – � �

� � yes; – � no; ALT � alanine aminotransferase; AST � aspartate aminotransferase; ICU � intensive care unit.

Appendix Table 3. SOFA Score, by Study Day

Variable Median SOFA Score (Range)

Day 1 Day 3 Day 7 Day 14

Respiration 4 (2–4) 3 (2–4) 3 (1–4) 3 (2–4)Platelet count 0 (0–1) 1 (0–3) 0 (0–4) 1 (0–4)Bilirubin level 0 (0–2) 0 (0–3) 0 (0–3) 0 (0–3)Hypotension 3 (0–4) 2 (0–4) 3 (0–4) 3 (0–4)Glasgow Coma Scale score 0 (0–0) 0 (0–0) 0 (0–0) 0 (0–0)Creatinine concentration 2 (0–4) 1 (0–4) 0 (0–3) 1 (0–4)

Total 9 (3–12) 9 (4–13) 7 (0–14) 5 (0–14)

SOFA � Sequential Organ Failure Assessment.

www.annals.org 18 March 2014 Annals of Internal Medicine Volume 160 • Number 6


Appendix Figure. Chest radiographs from the 12 patientswith Middle East respiratory syndrome coronavirus infectionon the day of intubation, demonstrating airspace diseasethat ranged from lobular to bilateral lung involvement.

18 March 2014 Annals of Internal Medicine Volume 160 • Number 6 www.annals.org


Documents

2014 Clinical Course and Outcomes of Critically Ill Patients With Middle East Respiratory Syndrome Coronavirus Infection