Keywords
MERS - Middle East respiratory syndrome coronavirus - epidemiology - control measures
- transmission - Saudi Arabia
Emerging infectious diseases continue to be of a significant importance worldwide
with the potential to cause major outbreaks and global pandemics. In 2002, the world
had witnessed the appearance of the severe acute respiratory syndrome coronavirus
(SARS-CoV) in China.[1]
[2] And about a decade later, a new and emerging coronavirus was described in a patient
from Saudi Arabia.[3]
[4] The virus was identified as a novel coronavirus and later was named the Middle East
respiratory syndrome coronavirus (MERS-CoV).[5] These two coronaviruses shared multiple similarities in the epidemiology, clinical
presentations, and posed challenges in prevention and management.[6]
[7] For any new emerging zoonotic pathogen, there are five stages in the evolution to
cause diseases limited to humans. In stage 1, the pathogen is confined to the animal
host; in stage 2, human infections occur as a result of animal contacts; in stage
3, there is a limited human-to-human transmission; stage 4, there are multiple outbreaks
with human-to-human transmission; and stage 5, infections occur within humans.[8] In this review, we describe the epidemiology, clinical features, and outcome of
both SARS and MERS-CoV.
The SARS-CoV and MERS-CoV
The SARS-CoV and MERS-CoV
SARS-CoV and MERS-CoV are enveloped positive strand RNA betacoronaviruses. The first
coronavirus was isolated from humans in 1965 and was cultivated on human ciliated
embryonal tracheal cells.[9] Coronaviruses are enveloped, and positive stranded RNA viruses classified as a family
within the Nidovirales order. There are four genera: α, β, gamma, and delta, and human
coronaviruses belong to the α or the β genera.[10] In 2002, SARS-CoV outbreak was described and the virus was 50 to 60% identical and
distantly related to known coronaviruses.[11] The newly described virus was able to cause disease in macaques with a similar spectrum
of disease.[12] While the MERS-CoV belongs to lineage C betacoronavirus and emerged in September
2012 and continuous to cause sporadic cases and clusters of disease mostly in the
Arabian Peninsula.[13]
SARS Outbreak Evolution and Clinical Characteristics
SARS Outbreak Evolution and Clinical Characteristics
The initial description of the SARS outbreak was announced in November 2002 through
non-official reports of the occurrence of an outbreak of respiratory illness in Guangdong
Province, China,[14] and few months later, this was reported to the World Health Organization (WHO).
Analysis of the virus showed a point-source outbreak.[15] The disease was recognized due to the occurrence of a cluster of atypical pneumonias
occurring in Vietnam, Hong Kong, Canada, United States, and Singapore.[1]
[16]
[17]
[18]
[19]
[20]
[21]
[22]
[23] All cases were linked to a patient who stayed in hotel M in Hong Kong, and subsequently,
patients traveled from Hong Kong to Ireland, Vietnam, Singapore, United States, and
Canada.[24] This outbreak involved 30 countries in 6 continents and caused a total of 8,098
cases with a case fatality rate of 9.5%.[25] The clinical spectrum of the disease ranged from mild to severe disease requiring
mechanical ventilation.[26] The clinical picture followed an initial febrile illness, followed by a period of
improvement then a clinical deterioration.[27]
[28]
[29] The need for intensive care unit (ICU) care was described in 17 to 30% of SARS patients.[28]
[29]
[30] In another study, 15% of SARS patients required mechanical ventilation.[27] Patients also had extra-respiratory symptoms such as diarrhea.[31] It was interesting to note that health care workers (HCWs) constituted 21% of all
SARS cases.[32]
[33]
[34] The disease was associated with 10% case fatality rate,[35] and the presence of diabetes mellitus and other comorbidities was associated with
increased fatality rates.[30] SARS was thought to cause milder disease in children with no fatalities.[36] One reason for the rapid spread of SARS was the occurrence of superspreaders.[35] Superspreading event is described as the ability of certain individuals to infect
a disproportionately large number of secondary patients relative to a typical infectious
individual.
The origin of the SARS virus is thought to be animal and a similar virus was isolated
from Himalayan palm civets (Paguma larvata), raccoon dogs (Nyctereutes procyonoides), and from a Chinese ferret badger (Melogale moschata).[37] In addition, antibodies against SARS-CoV were found among wild animal traders in
Guangdong Province.[37]
[38] A seroprevalence of 72.7% was well known among those with trading history involving
P. larvata.[38] Although most patients with SARS had symptomatic disease, there are few seroprevalence
studies and one study showed that 124 (12%) of 1,030 individuals were positive by
ELISA and 0.19% by the SARS-specific immunofluorescence assay (IFA).[39] In another study, seroprevalence among HCWs was 2.3%[40] and a meta-analysis showed an overall seroprevalence of 0.10%.[41] There were no approved therapeutic or preventative options for SARS, while a variety
of therapeutic agents were used.[42] SARS human cases disappeared abruptly by June 2003 with no approved vaccine or therapeutic
agents developed or applied.
MERS-CoV Evolution and Origin of the Virus
MERS-CoV Evolution and Origin of the Virus
The first case of MERS-CoV was reported in a businessman who lived in Bisha, Kingdom
of Saudi Arabia (KSA) who presented to health care with pneumonia in early June 2012
and on transfer to a hospital in Jeddah, he rapidly succumbed to death within 10 days
of diagnosis with multiorgan failure. The virus was later isolated and reported in
September 2012 as the newly emerging MERS-CoV. As of January 2020, there have been
a total of 2,468 cases of human MERS-CoV cases reported to WHO from 27 countries.
More than 80% of cases have been reported from the Arabian Peninsula with KSA being
the most affected country. There have been 851 reported mortalities with an overall
case fatality rate of MERS-CoV estimated at 35% ([Fig. 1]). The exact origin of MERS-CoV is not known. However, MERS-CoV is likely to have
originated from bats based on the isolation of other lineage C β-coronaviruses closely
related to MERS-CoV and the isolation of a bat coronavirus that resembles MERS-CoV.
Throat swabs, urine, feces, and serum samples were collected from wild bats in the
KSA including the area where the first MERS-CoV patient had lived and worked. A 190-nucleotide
fragment of the RNA-dependent RNA polymerase region of MERS-CoV genome was detected
in one fecal pellet from an Egyptian tomb bat (Taphozous perforates).[43] The amplified sequence was identical to that of the MERS-CoV sequence from the first
index human case.[43] The one-humped dromedaries (Camelus dromedarius) had been linked to MERS-CoV ([Fig. 2]). Multiple studies showed high prevalence of MERS-CoV antibodies in dromedary camels
in the Arabian Peninsula, North Africa, and Eastern Africa.[44]
[45]
[46]
[47]
[48]
[49]
[50] In addition, studies have shown that MERS-CoV antibodies were present in stored
camel sera as early as early 1990s, suggesting the presence of MERS-CoV in dromedaries
for over 20 years before its first description in humans.[50]
[51]
[52] MERS-CoV antibodies were detected more commonly among camels > 2 years of age compared
with younger camels.[46]
[52]
[53]
[54] In addition, MERS-CoV was detected from respiratory tract samples by reverse transcriptase
polymerase chain reaction (RT-PCR) in oronasal and fecal samples from dromedary camels
in the Arabian Peninsula.[52]
[53]
[54]
[55]
[56]
[57]
[58] In contrast to the MERS-CoV antibodies, juvenile camels shed more MERS-CoV as detected
by PCR.[52]
[53]
[54]
[55] In addition, viable MERS-CoV was isolated in cell cultures from nasal and fecal
samples from dromedary camels.[54]
[57]
[59]
[60]
[61] There had been studies documenting the isolation of similar and near-identical MERS-CoV
strains from epidemiologically linked humans and dromedary camels.[61]
[62]
[63] In addition, sequence of the MERS-CoV spike, ORF3–4a, and nucleocapsid regions were
identical from asymptomatic contacts and their camels.[64] The most recent common ancestor of all human MERS-CoV was found phylogenetically
to date to the end of the year 2010.[65] In addition, animal reservoir is geographically dispersed.[66]
[67]
Fig. 1 Epicurve of confirmed global cases of MERS-CoV from September 2012 to July 16, 2019.
MERS-CoV, Middle East respiratory syndrome coronavirus; WHO, World Health Organization.
Fig. 2 Camels: a possible intermediary source of Middle Eastern respiratory syndrome coronavirus.
Clinical Features and Laboratory Findings
Clinical Features and Laboratory Findings
The clinical and laboratory presentations of SARS-CoV and MERS-CoV are similar with
some minor differences highlighted in [Table 1]. The clinical picture of MERS-CoV cases ranges from asymptomatic to severe cases.
In many cases, the presenting symptoms are respiratory and 33% of patients have gastrointestinal
symptoms such as vomiting and diarrhea.[68]
[69]
[70]
[71]
[72]
[73] Most hospitalized MERS-CoV patients present with fever, cough, and shortness of
breath with clinical and radiological evidence of pneumonia.[70]
[71]
[72]
[74] It seems that severe disease is a characteristic of primary cases, immunocompromised,
and those with underlying comorbidities namely diabetes, kidney, and heart disease.
In severe cases, there are multiple complications including respiratory and renal
failure, acute liver injury, cardiac arrhythmias, and coagulopathy.[69]
[70]
[73]
[75] There are few studies which showed no predictive signs or symptoms to differentiate
patients with community-acquired pneumonia from those with MERS-CoV infection.[72]
[76] The median incubation period was 5.2 days (95% confidence interval [CI], 1.9–14.7),
and the serial interval was 7.6 days (95% CI, 2.5–23.1).[69] The median time to hospitalization, ICU admission, mechanical ventilation, and death
were 5, 7, and 11 days, respectively.[69]
[77] MERS-CoV carries a high case fatality rate (28.6–63.6%) specially among elderly
patients with several comorbidities, while in young healthy patients, they present
with mild to no symptoms.[71]
[78] One study found a lower case fatality rate similar to the rate reported in patients
from South Korea of 9%.[79]
[80] The variability of the case fatality rates may be related to host factors, associated
comorbidities, care provided, and yet unidentified factors.[78] In addition, the case fatality rate is inversely related to the percentage of asymptomatic
cases as the percentage of these patients increased to 29%, and the case fatality
rate decreased to 30%.[70]
[71]
[77]
[81]
[82]
[83] In addition, the case fatality rate is higher among critically ill patients[76]
[78]
[79]
[80] comparing between MERS-CoV and non-MERS-CoV patients in relation to age, clinical,
and laboratory features.[72]
[76]
[84]
[85]
[86] In KSA, extensive testing for MERS-CoV is being done over the past 6 years with > 50,000
patients presenting to emergency care with respiratory symptoms being screened for
MERS-CoV each year with a very low yield of 0.7% being positive.[87] This excessive testing is applied in combination with a visual triage in all emergency
rooms of all health care facilities (governmental and private) utilizing a clinical
score cutoff of > 4 for MERS-CoV infection showing sensitivity and specificity of
74.1 and 18.6%, respectively, in predicting MERS-CoV diagnosis.[88]
Table 1
Comparison of demographic, clinical, and laboratory features between MERS-CoV and
SARS-CoV
|
MERS-CoV[8]
[36]
[37]
[38]
[39]
|
SARS-CoV[1]
[28]
[40]
|
|
Date of first case report (place)
|
April 2012 (Jordan)
|
November 2002 (China)
|
|
June 2012 (first KSA case)
|
|
|
Incubation period
|
Mean: 5.2 d (95% CI: 1.9–14.7)
|
Mean: 4.6 d (95% CI: 3.8–5.8)
|
|
Range: 2–13 d
|
Range: 2–14 d
|
|
|
Serial interval
|
7.6 d
|
8.4 d
|
|
Age group
|
|
Adults
|
98%
|
93%
|
|
Children
|
2%
|
5–7%
|
|
Age (y): range, median
|
Range: 1–94; median: 50
|
Range: 1–91; mean: 39.9
|
|
Mortality
|
|
CFR—overall
|
41.8%
|
9.6%
|
|
CFR in patients with comorbidities
|
13.3%
|
1–2%
|
|
Time from onset to death
|
Median 11.5 d
|
Mean 23.7d
|
|
Sex (M, F)
|
M: 64.5%, F: 35.5%
|
M: 43%, F: 57%
|
|
Presenting symptoms
|
|
Fever >38°C
|
98%
|
99–100%
|
|
Chills/rigors
|
87%
|
15–73%
|
|
Cough
|
83%
|
62–100%
|
|
Dry
|
56%
|
29–75%
|
|
Productive
|
44%
|
4–29%
|
|
Hemoptysis
|
17%
|
0–1%
|
|
Headache
|
11%
|
20–56%
|
|
Myalgia
|
32%
|
45–61%
|
|
Malaise
|
38%
|
31–45%
|
|
Shortness of breath
|
72%
|
40–42%
|
|
Nausea
|
21%
|
20–35%
|
|
Vomiting
|
21%
|
20–35%
|
|
Diarrhea
|
26%
|
20–25%
|
|
Sore throat
|
14%
|
13–25%
|
|
Rhinorrhea
|
6%
|
2–24%
|
|
Comorbidities
|
76%
|
10–30%
|
|
Diabetes
|
10%
|
24%
|
|
Chronic renal disease
|
13%
|
2–6%
|
|
Chronic heart disease
|
7.5%
|
10%
|
|
Malignancy
|
2%
|
3%
|
|
Hypertension
|
34%
|
19%
|
|
Obesity
|
17%
|
N/A
|
|
Smoking
|
23%
|
17%
|
|
Viral hepatitis
|
Not known
|
27%
|
|
Laboratory results
|
|
CXR abnormalities
|
100%
|
94–100%
|
|
Lymphopenia (<1.5 × 109/L)
|
32%
|
68–85%
|
|
Leukopenia (<4.0 × 109/L)
|
14%
|
25–35%
|
|
Thrombocytopenia (<140 × 109/L)
|
36%
|
40–45%
|
|
Elevated LDH
|
48%
|
50–71%
|
|
Elevated ALT
|
11%
|
20–30%
|
|
Elevated AST
|
14%
|
20–30%
|
|
Ventilatory support required
|
80%
|
14–20%
|
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CFR,
case fatality rate; CI, confidence interval; CXR, chest X-ray; KSA, Kingdom of Saudi
Arabia; LDH, lactate dehydrogenase; MERS-CoV; Middle East respiratory syndrome coronavirus;
SARS-CoV, severe acute respiratory syndrome coronavirus.
Source: Reproduced with permission from Hui et al.[161]
Predictors of 30-day mortality included factors such as age > 65 years, being a non-HCW,
the presence of preexisting comorbidities, presentation with severe disease, hospital-acquired
infections, and corticosteroid use.[70]
[89]
[90]
[91] The use of continuous renal replacement therapy and extracorporeal membrane oxygenation
(ECMO) were additional risk factors for increased fatality.[91]
[92]
[93] However, one study showed ECMO lowering in-hospital death.[94]
Laboratory Tests
The diagnosis of MERS-CoV infection relies on the confirmation by real-time reverse
transcriptase PCR of respiratory tract samples. Lower respiratory samples provide
better yield and is the sample source of choice for testing.[95]
[96] However, a single negative test should not rule out infection and a repeat testing
is indicated as some patients may have intermittent positive tests.[97] Serologic testing for MERS-CoV utilizes IFA, serum neutralization, or protein microarray
assays to detect MERS-CoV antibodies.[98] The utility of serodiagnosis relies on two serum samples taken 14 days or more apart.
Serodiagnosis begins with a screening ELISA or IFA and a confirmatory neutralization
assay.[99]
[100]
[101] Testing for MERS-CoV by PCR detected the virus in the patient serum, urine, and
feces but at a much lower level than those found in the lower respiratory tract.[102] Patients with MERS-CoV infection had abnormal laboratory findings including: leukopenia,
lymphopenia, thrombocytopenia, and elevated hepatic enzymes.[68]
[71]
[72]
[76]
[103] A risk analysis showed that the following were associated with increased risk of
death: presence of comorbidity (relative risk [RR] = 3), male gender (RR = 1.6), exposure
to dromedary camels (RR = 1.6), and consumption of camel milk (RR = 1.5).[104] Overall, over the past 7 years, 50% of MERS-CoV cases reported to WHO were associated
with human-to-human transmission in hospitals. Among 61 MERS-CoV patients presenting
with MERS-CoV in 2017, 9 (15%) were associated with a hospital outbreak, 10 (16%)
were household contacts, and 42 (69%) were sporadic cases. Of the 42 sporadic cases,
50% had camel contact.[105] In an outbreak investigation of a cluster of MERS cases in a nonhealth care–associated
setting, 18 (2.2%) of 828 contacts were positive for MERS-CoV infections.[106] This rate was similar to household contact study of 4.3%.[101]
Intrahospital Transmission
Intrahospital Transmission
Health care–associated infection is the hallmark of the transmission of MERS-CoV between
patients and from patients to HCWs.[69]
[70]
[74]
[81]
[107]
[108]
[109]
[110]
[111]
[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120]
[121]
[122]
[123] Of the factors contributing to intrahospital transmission is the occurrence of superspreading
events. In the outbreak in the Republic of Korea, three patients were epidemiologically
connected to 73% of the transmissions and each infected 23, 28, and 85 individuals.[124] In addition, superspreader phenomena also occurred in the first reported outbreak
in Al-Hasa, Saudi Arabia.[69] A recent systematic review outlined the contributing factors to health care–associated
MERS-CoV transmissions and included: absent physical barriers between beds, inadequate
isolation of suspected MERS patients, lack of isolation and negative pressure rooms,
unfamiliarity and underrecognition of MERS infection, insufficient compliance with
infection control measures, aerosol generating procedures, presence of multiple friends
and family members in the patient's room, and the phenomena of “medical shopping.”[125] HCWs may act as contributors to the spread of MERS-CoV infection. In one study,
MERS-CoV PCR was positive in 4.5% among exposed HCWs[126] and another study showed 15 (1.3%) of 1,169 HCWs were positive by PCR and 5 (0.68%)
of 737 HCWs were positive by serology.[127] Other studies showed none of 38 HCWs was positive by serology[128] and none of 48 contacts was positive.[129] In Korea, 36 (19.9%) of 181 confirmed MERS-CoV cases were HCWs.[130] However, studies had showed that most positive HCWs were asymptomatic or had mild
disease.[131] Although major hospital outbreaks were thought to be linked to intrahospital transmission
of MERS-CoV, MERS-CoV genome sequence in these outbreaks showed multiple introductions
of the virus with human-to-human transmissions.[66]
[67]
[69] There were three distinct MERS-CoV genotypes.[67]
Seasonality of MERS-CoV
The emergence of MERS-CoV had led to many speculations regarding the seasonality of
this disease and initially thought to occur mostly in March–May and September–November.[81]
[132]
[133] One reason for such a significant increase in April–May 2014 was a large outbreak
in Jeddah, Saudi Arabia.[107] However, seasonal variation may be the result of seasonality in the calving of dromedaries
in November and March.[10]
[44]
[46]
[48]
[52]
[55]
[77]
[82]
[83]
[134] Such a concept was studied and it was found that the prevalence of MERS-CoV was
higher in camels in the winter (71.5%) than the summer season (6.2%).[135] Looking at all MERS-CoV cases from 2012 to 2016, the mean monthly cases were higher
in the winter and summer months.[136] Evaluation of cases from January 2013 and December 2017 included a total of 2,025
cases and showed a noteworthy decrease in the annual cases in 2016 to 2017.[137] Of all the 2,025 cases, 38.2% occurred in the Spring and 36.4% occurred in the Summer.[137] However, there was no variation on the number of cases per year, and either per
month or per season.[137]
Therapeutic Options
Currently, there is no approved therapy for MERS-CoV infection. Studies showed superiority
of interferon (IFN)-β compared with other IFN types[138] and that polyethylene glycol IFN-α had excellent cytopathic inhibitory effect.[139] In addition, the combination of INF-α2b and ribavirin showed augmentation of action
and lower concentrations of IFN-α2b and ribavirin were required.[140] However, the data from clinical use of these two agents in retrospective studies
showed no therapeutic advantages of these on survival of patients.[42]
[141]
[142]
[143]
[144]
[145] A retrospective analysis showed that using INF to treat patients with positive MERS-CoV
RT-PCR was associated with a case fatality rate of 90% compared with 44% in those
with negative MERS-CoV RT-PCR test.[68] Another study showed survival rates of 78.3, 75, and 68.4% using IFN-β, IFN-α, and
ribavirin, respectively.[146] The use of the antiretroviral therapy for MERS-CoV was tried using pegylated IFN,
ribavirin, and lopinavir/ritonavir[143] and another eight patients received mycophenolate mofetil and the latter patients
survived.[146] A randomized controlled trial using a combination of lopinavir–ritonavir and IFN-β1b
is being conducted.[147]
Seroprevalence of MERS-CoV
Seroprevalence of MERS-CoV
Although MERS-CoV PCR testing is the main methodology for the diagnosis of MERS-CoV
infection, serologic tests confirmed 8 (6.4%) of 124 Jordanian contacts who were positive.[119] Seroprevalence of 356 abattoir workers and blood donors found that 8 (2.2%) were
weakly positive by immunofluorescence assay (IFA), and none was had positive neutralization
titers.[148] A seroprevalence study found none of 268 children with respiratory tract infections
to be positive.[149] In an evaluation of 280 household contacts, 12 (4.3%) were probable cases by serology.[101] However, in a population-based survey of 10,000 samples, the seroprevalence was
0.15% and the camel shepherd and abattoir workers had 17- and 26-fold increase in
seroprevalence in comparison to the general population.[150]
Infection Control
MERS-CoV is stable in the environment and can survive on plastic and steel for up
to 48 hours at lower temperature and humidity. However, MERS-CoV is less viable at
higher temperature and humidity.[151] This finding was confirmed by another study where a temperature of 65°C had a strong
negative effect on viral infectivity compared with a temperature of 25°C.[152] In the hospital setting, WHO advocates contact and droplet precautions with airborne
isolation when dealing with aerosol-generating procedures.[153]
[154] However, both the United States and the European Centre for Disease Prevention and
Control recommend the use of airborne infection isolation precautions.[155]
MERS and Camel Connections
MERS and Camel Connections
In a recent study from Egypt, Senegal, Tunisia, Uganda, Jordan, Saudi Arabia, and
Iraq, MERS-CoV was detected in camels using either PCR or serology.[156] The positivity rate using PCR ranged from 0% in Uganda, Jordan, and Iraq to 3.1%
in Saudi Arabia, 5.5% in Senegal, and 8.2% in Egypt.[156] It was shown that seropositivity is very high (84.5%) among tested camels compared
with PCR positivity of 3.8%.[157] Studies from Saudi Arabia showed either no significant difference in seropositivity
of MERS-CoV in camels in different regions[156] or had detected variable seropositivity to MERS-CoV (37–100%).[158] It is worth mentioning that Somalia and Sudan are the main source of imported camels
into Saudi Arabia.[156]
The seroprevalence of MERS-CoV is lower (30.3%) in juvenile camels (<2 years of age)
compared with adult camels (82.6%)[156] as described in the previous studies.[53] Also, the detection rate of MERS-CoV RNA by PCR is higher in adults (16.1%) compared
with juvenile camels (1.7%).[156] What is unusual is the ability of MERS-CoV to causes reinfection of camels in the
presence of antibodies.[56]
[156] Another important finding of MERS-CoV in camels is that camels rarely show signs
of infection.[156]
[159] Although it has been postulated that drinking camel milk is one of the key sources
of infection in the Arabian peninsula, a study found no MERS-CoV in the urine of naturally
infected camels.[160]
Conclusion
Emerging respiratory viruses, specially MERS-CoV, continue to challenge the public
health infrastructure of countries of the Arabian Peninsula with the risk of transmission
and outbreaks in other countries though travel. Although it is still debated by some,
bats appear to be the common natural source of both SARS and MERS. There are considerable
similarities in the clinical features of both MERS-CoV and SARS-CoV, but MERS tends
to progress much faster to respiratory failure than SARS. Although SARS-CoV clinical
cases disappeared since mid-2003, both MERS-CoV and SARS-CoV are still listed as priority
pathogens by the WHO research and development blueprint. The case fatality rate of
MERS-CoV is much higher and likely related to older age and comorbid illness of the
sporadic cases. Several gaps continue in our knowledge about disease prevention and
treatment, and more studies are needed to understand the pathogenesis, viral kinetics,
mode of disease transmission, any other intermediary source, and treatment options
of MERS to guide public health infection control measures and treatment.
