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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 1  |  Issue : 4  |  Page : 118-127

Ribavirin plus interferon or oseltamivir in severe Middle East respiratory syndrome infection: A retrospective cohort study


1 Clinical Pharmacy Services, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia
2 College of Pharmacy, Northern Border University, Rafha, Saudi Arabia
3 Clinical Pharmacy Services, Prince Mohammed bin Abdulaziz Hospital, Riyadh, Saudi Arabia

Date of Submission20-Apr-2022
Date of Acceptance02-Nov-2022
Date of Web Publication31-Dec-2022

Correspondence Address:
Sulaiman A Al-Zubairy
Clinical Pharmacy Services, Johns Hopkins Aramco Healthcare, 6th Street, Gharb Al Dhahran, Dhahran 34465
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjcp.sjcp_12_22

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  Abstract 

Background: Middle East respiratory syndrome (MERS) is associated with significant mortality with no approved antiviral therapy. Objectives: The aim of this study was to compare the efficacy and safety of the combination of ribavirin and PEG-interferon α-2a (RIF), oseltamivir, and supportive care (SC) alone in MERS patients. Materials and Methods: Retrospective cohort for all patients admitted to the intensive care unit with severe symptomatic laboratory-confirmed MERS infection between September 2013 and February 2017. Patients were divided into two pairwise comparisons: RIF and oseltamivir combined (antivirals) vs. SC; and RIF vs. oseltamivir. The primary endpoint was 60-day mortality. Secondary endpoints were the requirement for mechanical ventilation (MV) and renal replacement therapy (RRT), and laboratory changes. Results: A total of 113 patients met the study inclusion criteria; 77 received antivirals (47 received RIF and 30 oseltamivir), and 36 SC. The 60-day mortality rate was 36% with antivirals vs. 50% with SC (P = 0.136), and 45% with RIF vs. 23% with oseltamivir (P = 0.092). The MV requirement was 42% with antivirals vs. 65% with SC (P = 0.083), and 54% with RIF vs. 27% with oseltamivir (P = 0.067). The RRT requirement was 29% with antivirals vs. 31% with SC (P = 0.943), and 40% with RIF vs. 14% with oseltamivir (P = 0.019). The median hemoglobin decrease with RIF was 4 g/dL vs. 1 with oseltamivir (P < 0.001); the WBC decrease with RIF was 1.3 vs. 0.2 with oseltamivir (P = 0.007); the blood glucose increase with RIF was 143 mg/dL vs. 89 with oseltamivir (P = 0.036), and the indirect bilirubin increase with RIF was 0.4 mg/dL vs. 0.3 with oseltamivir (P = 0.023). Conclusions: In this study, the use of RIF or oseltamivir in severe MERS infections did not significantly reduce 60-day mortality, nor the requirement for MV or RRT. Furthermore, the subgroup that received oseltamivir had more favorable renal, hepatic, and hematological outcomes than RIF. Larger, prospective, well-designed studies are warranted to confirm these findings.

Keywords: Antiviral, corona, coronavirus, interferon, MERS, oseltamivir, respiratory syndrome, ribavirin


How to cite this article:
Al-Zubairy SA, Alkhadhairi EK, Abuzaid MM. Ribavirin plus interferon or oseltamivir in severe Middle East respiratory syndrome infection: A retrospective cohort study. Saudi J Clin Pharm 2022;1:118-27

How to cite this URL:
Al-Zubairy SA, Alkhadhairi EK, Abuzaid MM. Ribavirin plus interferon or oseltamivir in severe Middle East respiratory syndrome infection: A retrospective cohort study. Saudi J Clin Pharm [serial online] 2022 [cited 2023 Feb 2];1:118-27. Available from: http://www.sjcp.org/text.asp?2022/1/4/118/366500


  Introduction Top


Since 2012, the World Health Organization (WHO) has reported nearly 2,500 cases of the Middle East respiratory syndrome coronavirus (MERS-CoV) infection, with a 34% mortality rate.[1] Although no antiviral therapy is approved for MERS infection, some antiviral therapies have been investigated based on cell culture and animal data, as well as experience with the severe acute respiratory syndrome (SARS) coronavirus.[2],[3],[4] Only two controlled trials have looked into the efficacy of antiviral treatment in MERS infections in humans.[5],[6] In the studies, oral ribavirin plus subcutaneous PEGylated interferon-2a (RIF) was retrospectively compared to supportive care (SC) in patients with severe MERS infection. RIF was associated with significantly improved survival at 14 days but not at 28 days in the first study (44 patients).[5] The second study, which included 349 patients, found that RIF had no effect on 90-day mortality or MERS-CoV RNA clearance.[6]

Both ribavirin and PEG-interferon are known to cause myelosuppression in chronic hepatitis-C (CHC) studies. Furthermore, some patients who received ribavirin and PEG-interferon experienced hepatic side effects. Diabetes mellitus was reported with RIF by <1% in postmarketing surveillance.[7],[8] Although RIF was used at comparable dosing in CHC studies to MERS, the duration of CHC therapy was longer (48 weeks vs. two weeks in MERS), which may have resulted in a different side effect profile.

Oseltamivir and empiric antibiotics have been used because MERS has a respiratory clinical presentation similar to influenza or bacterial pneumonia.[9] In a retrospective study of 20 SARS patients, oseltamivir was associated with better clinical outcomes than ribavirin alone,[10] but extrapolating the results of such a small SARS study to MERS patients is difficult.

Significant mortality with MERS is due not only to the virus’s virulence and a lack of effective therapy, but also to the nature of the disease, which can cause respiratory or renal failure. Mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) are two nonpharmacological treatments that have been shown to improve MERS respiratory failure. The use of ECMO was shown to improve inpatient hospital mortality in a study of 35 patients with MERS, but it was associated with a longer intensive care unit (ICU) stay and a similar overall hospital length of stay.[11] Severe MERS is notable for its impact on older men with comorbid diseases such as diabetes and a variety of lung, renal, hepatic, and cardiac conditions. We compared the efficacy and safety of RIF, oseltamivir, and SC in critically ill patients in this study.


  Patients and Methods Top


Patients

A retrospective cohort study was conducted on all patients admitted to the ICU at Prince Mohammed Bin Abdulaziz Hospital (PMAH) in Riyadh, Saudi Arabia, with a severe laboratory-confirmed MERS-CoV infection requiring ICU admission between September 2013 and February 2017. Two reverse transcription-polymerase chain reaction (RT-PCR) tests for respiratory tract samples were used to confirm MERS infection. PMAH is designated as a provincial MERS center where patients with confirmed MERS infection are transferred from other health facilities. Patients with pre-existing end-stage renal disease, pregnancy, or use of oseltamivir and RIF together were excluded. The study’s primary endpoint was 60-day mortality. Secondary endpoints were the requirement for MV and renal replacement therapy (RRT), and laboratory changes. MV was indicated based on hospital criteria for hypoxic or hypercapnic respiratory deficiencies. RRT can be either hemodialysis or continuous RRT and started as indicated by a nephrologist. Laboratory tests included blood count, blood glucose (BG), renal and hepatic tests, troponin, and blood gases. The Sequential Organ Failure Assessment (SOFA) score was used to assess organ function on admission. The score is based on different scores, one each for the respiratory, renal, cardiovascular, coagulation, hepatic, and neurological systems as well use of vasopressors.[12] Lab change was the difference between the admission value and post-therapy reported value or the latest during therapy, except for BG, which was between the baseline and average BG. For patients who received RRT, renal panel values before RRT were used if RRT was initiated after the start of antivirals. For patients who received MV, the value of blood gases before MV was used if MV was initiated after the start of antivirals.

Antiviral therapy

The RIF protocol was composed of PEG-interferon-α2a (180 μg subcutaneously once weekly for two doses) combined with ribavirin (loading dose of 2,000 mg orally followed by 10-day maintenance doses [MD] based on the CrCl). The RIF protocol was implemented in several hospitals during the MERS outbreak.[13] For CrCl >50 mL/min, ribavirin MD was 1,200 mg q8h for four days and then 600 mg q8h for six days. For CrCl 20–50, ribavirin MD was 600 mg q8h for four days and then 600 mg q6h for six days. With CrCl <20, ribavirin MD was 200 mg q6h for four days and then 200 mg q12h for six days. Alternatively, oseltamivir was dosed according to influenza dosing guidelines (75 mg orally BID), but for varying durations. Ribavirin was used in the form of Copegus 200 mg tablets; manufactured by Patheon, Canada, for Roche. PEG-interferon-α2a was in the form of Pegasys 180 µg syringes, Switzerland, Roche. Oseltamivir was in the form of Tamiflu 75 mg capsules, USA, Roche.

Statistical analysis

Patients were divided into two pairwise comparisons: RIF and oseltamivir combined (antivirals) vs. SC; and RIF vs. oseltamivir. The Kaplan-Meier curve was used to present 60-day mortality, MV, and RRT events over time, and the log-rank test was used to compare statistical differences. Event date was the day after the start of antiviral in the antivirals’ patients and post-admission in the SC group. The Fisher’s Exact test was used to compare nominal data, presented as frequencies (percentages). The t-test was used for comparing continuous normally distributed means presented with standard deviation (SD). The Mann–Whitney U test was used for nonparametric frequencies, presented as median (interquartile range [IR]). The Shapiro–Wilk test was used to test frequency normality. A significance level of 0.05 was used. Statistical tests were run via IBM SPSS Statistics software version 26. Multivariate regression was used to address potential baseline confounders. Patients who were on MV or RRT at baseline were excluded from the analysis for the MV or RRT requirement. Since oseltamivir was given in different doses, a point-biserial correlation was used to correlate dosing with mortality. The required sample size was estimated to be 345 patients based on WHO case fatalities.


  Results Top


Patients who met the inclusion criteria were 113; 77 received antivirals and 36 SC. Antivirals used were RIF (47 patients) and oseltamivir (30) and were initiated within 24 hours of admission [Figure 1]. Key baseline characteristics of patients in the study comparisons are shown in [Table 1] and [Table 2]. Median [IR] baseline BG with antivirals was 178 [132, 263] mg/dL and 148 [110, 188] mg/dL with SC (P = 0.042). Mean [SD] for the highest baseline troponin T value was 0.499 [0.411] with antivirals and 0.231 [0.56] with SC (P = 0.006). Baseline hemoglobin was 12.9 [2.4] g/dL with antivirals and 11.5 [3.1] g/dL with SC (P = 0.023). Multivariate regression of mortality with baseline BG OR [95% CI] was 1.001 [0.996, 1.006], P = 0.668; hemoglobin 0.998 [0.982, 1.015], P = 0.812; and with troponin T 0.998 [0.982, 1.015], P = 0.193.
Figure 1: Patient allocation.
ESRD = end-stage renal disease, RIF = ribavirin plus interferon (pegylated) α-2a, SC = supportive care


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Table 1: Baseline characteristics for patients who received AV vs. SC

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Table 2: Baseline characteristics for patients who received RIF vs. Oseltamivir

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The overall mortality rate was 41%. The death causes were respiratory failure (91.3%), renal complications (4.35%), and others (4.35%). The median [IR] overall post-admission death day was 13 [7, 23]. In the antiviral group, 28/77 patients [36%] died vs. 18/36 [50%] with SC (P = 0.136), and 21/47 [45%] with RIF vs. 7/30 [23%] with oseltamivir (P = 0.092). The MV requirement rate was 42% [21/50] with antivirals vs. 65% [15/23] with SC (P = 0.083), and 54% [15/28] with RIF vs. 27% [6/22] with oseltamivir (P = 0.067). The RRT requirement rate was 29% [21/72] with antivirals vs. 31% [11/36] with SC (P = 0.943), and 40% [17/43] with RIF vs. 14% [4/29] with oseltamivir (P = 0.019). ECMO was used in two RIF patients after therapy began, in addition to the two at baseline. Mortality, and MV and RRT initiation events over time are shown for antivirals vs. SC in [Figure 2] and RIF vs. oseltamivir in [Figure 3]. Of all patients, 100 (88.5%) received MV either on admission or post-therapy, and 38 (33.6%) received RRT. All patients who received RRT also received MV, and 38% of those who received MV required RRT. Logistic regression for mortality with age OR [95% CI] was 1.023 [0.977, 1.049], P = 0.084; and average BG 0.239 [0.998, 1.006], P = 0.239. Nevertheless, the mortality rate was the same for patients in age groups 18–30 and >70 years (62%). Patients with average BG <140 mg/dL had a 25% mortality rate; 140–200, 43%; 201–300, 44%; and >300, 48%. Most patients used insulin.
Figure 2: Kaplan–Meier curves for study endpoints with AV vs. SC: (A) 60-day survival, (B) requirement for MV, and (C) requirement for RRT. AV = antivirals, MV = mechanical ventilation, RRT = renal replacement therapy, SC = supportive care

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Figure 3: Kaplan–Meier curves for study endpoints with RIF vs. OSE: (A) 60-day survival, (B) requirement for MV, and (C) requirement for RRT. MV = mechanical ventilation, OSE = oseltamivir, RIF = ribavirin plus interferon (pegylated) α-2a, RRT = renal replacement therapy

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The median (IR) duration of oseltamivir therapy was four [2, 5] days, with all patients receiving 75 mg BID except two, who received 150 mg BID and 75 mg QD. The point-biserial correlation coefficient (rpb) for therapy days and mortality was –0.16, and the mean duration of therapy in survived patients was 4.2 days vs. 3.3 in those who died. rpb for requiring MV was –0.23 with an average of 4.8 therapy days in those who did not require MV vs. 3.5 in those who did. rpb for requiring RRT was –0.06 with an average of four therapy days in those who did not require RRT vs. 3.6 in those who did.

Most significant laboratory changes from baseline after treatment with antivirals vs. SC are displayed in [Table 3] and RIF vs. oseltamivir in [Table 4]. The median hemoglobin decrease with RIF was 4 g/dL vs. 1 g/dL with oseltamivir (P < 0.001); the WBC decrease with RIF was 1.3 vs. 0.2 × 109/L with oseltamivir (P = 0.007); the lymphocytes decrease with RIF was 0.4 vs. 0.1 × 109/L with oseltamivir (P < 0.001); the absolute neutrophils decrease with RIF was 1.48 vs. 0.48 × 109/L with oseltamivir (P = 0.013); the BG increase with RIF was 143 mg/dL vs. 89 mg/dL with oseltamivir (P = 0.036); the total bilirubin increase with RIF was 0.6 mg/dL vs. 0.4 mg/dL with oseltamivir (P = 0.047); the indirect bilirubin increase with RIF was 0.4 mg/dL vs. 0.3 mg/dL with oseltamivir (P = 0.023); the ALT increase with RIF was 66 vs. 10 with oseltamivir (P = 0.001); the AST increase with RIF was 37 vs. 10 with oseltamivir (P = 0.032); the serum creatinine increase with RIF was 0.9 vs. 0.2 with oseltamivir (P = 0.036); and the BUN increase with RIF was 13 vs. 4 with oseltamivir (P = 0.018). Multivariate regression for mortality with lab value changes that were significantly different between RIF and oseltamivir are presented in [Table 5].
Table 3: Most significant laboratory changes from baseline after treatment with AV vs. SC

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Table 4: Most significant laboratory changes from baseline for patients received RIF vs. OSE

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Table 5: Multivariate regression analysis of mortality with significantly different lab value changes between RIF and oseltamivir

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  Discussion Top


Research findings confirm that RIF has no clinical benefit in MERS and suggest that oseltamivir use may be associated with better outcomes. These findings are unusual because oseltamivir targets the influenza virus rather than corona. Oseltamivir activity in influenza co-infections is one possible explanation. Co-infection with various viral pathogens has been confirmed in an extensive number of patients with respiratory tract disease.[14] Another reason for the superiority of oseltamivir over RIF is the latter’s toxicity profile. RIF, similar to previous trials,[7],[8] was associated with a significant drop in hemoglobin and WBC, as well as an increase in renal and hepatic panels.

RRT was used as one of the study endpoints for therapy outcomes because MERS is characterized by renal impairment; however, only 4% of the study population died of renal complications, whereas 91% died of respiratory failure. The oseltamivir days had a strong correlation with the need for MV and mortality, and the average oseltamivir duration in survived patients was close to five days, which is the labeled influenza treatment duration. Most patients (89%) received MV at some point, and approximately one-third required RRT. More than two-thirds of MERS cases in this study were males, with a median age of 53. This population is more likely to come into contact with camels, which are thought to be MERS-CoV reservoirs. MERS was first identified in a human in Saudi Arabia’s Bisha region, close to where an Egyptian tomb bat tested positive for MERS-CoV.[15]

Because the study included ICU patients, the case fatality rate in this study (41%) was higher than the global reported rate (34%).[1] Arabi et al.[6] discovered a higher mortality rate in ICU patients, with 74% of those who received RIF dying and 62% of those who did not. MERS had a higher global case-fatality rate than SARS (11%)[16] and COVID-19 (1.1%),[17] but spread much more slowly. Saudi health authorities screened thousands of individuals with respiratory symptoms to contain the MERS outbreak.[18]

During the 42-month cohort period, patients received different treatments due to the adoption of different hospital protocols. Oseltamivir was used either as an empiric treatment until a differential diagnosis of influenza was ruled out, or earlier in the cohort when the RIF protocol was not followed. Because the RIF regimen was implemented based on SARS data,[4] a large proportion of the study patients were in the RIF group. Following that, some clinicians began to question RIF’s efficacy, and as a result, a subset of patients received only SC. Furthermore, the study’s retrospective design did not allow for an equal distribution of subjects among study groups or proper control of confounders. ECMO was started in two RIF patients at the start of therapy and two more afterward. At the time, ECMO was a relatively new approach for MERS patients, and it is possible that it was not available to all patients throughout the duration of the study. There was no control over the initial SC provided at the referring institutions because patients were referred from other facilities after MERS confirmation. There was no significant correlation between average BG and mortality; however, patients with an average BG of <140 mg/dL had a lower mortality rate (25%) than those with higher BG levels (>43%). At the time, the study sample represented approximately 6% of the 1,917 reported cases worldwide.[19] Nonetheless, a larger sample size was required to produce more valid conclusions.


  Conclusions Top


The use of RIF or oseltamivir in severe MERS infections did not reduce 60-day mortality or the need for MV or RRT in this study. Patients who received oseltamivir had better renal, hepatic, and hematological outcomes than those who received RIF. This could be due to oseltamivir activity against influenza co-infections, as well as RIF toxicity. Larger, well-designed prospective studies are warranted to confirm these findings.

Ethical policy and institutional review board statement

The PMAH Institutional Review Board granted ethical approval for this study, and patient consent was waived because the study relied on retrospective analysis of existing patient records. The authors acknowledge the use of PMAH facilities for the research data utilized in this article. The views expressed in this article are solely those of the authors and do not necessarily reflect those of PMAH.

Financial support and sponsorship

Not applicable.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
World Health Organization (WHO). Middle East Respiratory Syndrome Coronavirus (MERS-CoV); 2019. Available from: http://www.who.int/emergencies/mers-cov/en/. [Last accessed on 13 Oct 2022].  Back to cited text no. 1
    
2.
Falzarano D, de Wit E, Martellaro C, Callison J, Munster VJ, Feldmann H Inhibition of novel β coronavirus replication by a combination of interferon-α2b and ribavirin. Sci Rep 2013;3:1686.  Back to cited text no. 2
    
3.
Falzarano D, de Wit E, Rasmussen AL, Feldmann F, Okumura A, Scott DP, et al. Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV-infected rhesus macaques. Nat Med 2013;19:1313-7.  Back to cited text no. 3
    
4.
Momattin H, Mohammed K, Zumla A, Memish ZA, Al-Tawfiq JA Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV): Possible lessons from a systematic review of SARS-CoV therapy. Int J Infect Dis 2013;17:e792-8.  Back to cited text no. 4
    
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Omrani AS, Saad MM, Baig K, Bahloul A, Abdul-Matin M, Alaidaroos AY, et al. Ribavirin and interferon alfa-2a for severe Middle East respiratory syndrome coronavirus infection: A retrospective cohort study. Lancet Infect Dis 2014;14: 1090-5.  Back to cited text no. 5
    
6.
Arabi YM, Shalhoub S, Mandourah Y, Al-Hameed F, Al-Omari A, Al Qasim E, et al. Ribavirin and interferon therapy for critically ill patients with Middle East respiratory syndrome: A multicenter observational study. Clin Infect Dis 2020;70:1837-44.  Back to cited text no. 6
    
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Copegus Tablet, Film Coated (ribavirin) [prescribing information]. South San Francisco, CA: Genentech USA; 2015.  Back to cited text no. 7
    
8.
Pegasys (peginterferon alfa-2a) [product monograph]. Mississauga, ON: Hoffmann-La Roche Limited; 2015.  Back to cited text no. 8
    
9.
Alraddadi BM, Watson JT, Almarashi A, Abedi GR, Turkistani A, Sadran M, et al. Risk factors for primary middle east respiratory syndrome coronavirus illness in humans, Saudi Arabia, 2014. Emerg Infect Dis 2016;22:49-55.  Back to cited text no. 9
    
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Hsu LY, Lee CC, Green JA, Ang B, Paton NI, Lee L, et al. Severe acute respiratory syndrome (SARS) in Singapore: Clinical features of index patient and initial contacts. Emerg Infect Dis 2003;9:713-7.  Back to cited text no. 10
    
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Alshahrani MS, Sindi A, Alshamsi F, Al-Omari A, El Tahan M, Alahmadi B, et al. Extracorporeal membrane oxygenation for severe Middle East respiratory syndrome coronavirus. Ann Intensive Care 2018;8:3.  Back to cited text no. 11
    
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Lambden S, Laterre PF, Levy MM, Francois B The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care 2019;23:374.  Back to cited text no. 12
    
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Chong YP, Song JY, Seo YB, Choi JP, Shin HS; Rapid Response Team. Antiviral treatment guidelines for Middle East respiratory syndrome. Infect Chemother 2015;47:212-22.  Back to cited text no. 13
    
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Stefanska I, Romanowska M, Donevs.ki S, Gawryluk D, Brydak LB Co-infections with influenza and other respiratory viruses. Adv Exp Med Biol 2013;756:291-301.  Back to cited text no. 14
    
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Memish ZA, Mishra N, Olival KJ, Fagbo SF, Kapoor V, Epstein JH, et al. Middle East respiratory syndrome coronavirus in bats, Saudi Arabia. Emerg Infect Dis 2013;19:1819-23.  Back to cited text no. 15
    
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Chan-Yeung M, Xu RH SARS: Epidemiology. Respirology 2003;8:S9-14.  Back to cited text no. 16
    
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Johns Hokins University (JHU), 2020. Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineering at JHU. Available from: https://coronavirus.jhu.edu/map.html. [Last accessed on 13 Oct 2022].  Back to cited text no. 17
    
18.
Memish ZA, Al-Tawfiq JA, Makhdoom HQ, Al-Rabeeah AA, Assiri A, Alhakeem RF, et al. Screening for Middle East respiratory syndrome coronavirus infection in hospital patients and their healthcare worker and family contacts: A prospective descriptive study. Clin Microbiol Infect 2014;20:469-74.  Back to cited text no. 18
    
19.
WHO, 2017. Middle East respiratory syndrome coronavirus (MERS-CoV) - Disease Outbreak News 10 March 2017. Available from: https://www.who.int/csr/don/10-march-2017-mers-saudi-arabia/en/. [Last accessed on 25 Nov 2021].  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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