key: cord-272306-92rz2byz
authors: Morra, Mostafa Ebraheem; Van Thanh, Le; Kamel, Mohamed Gomaa; Ghazy, Ahmed Abdelmotaleb; Altibi, Ahmed M.A.; Dat, Lu Minh; Thy, Tran Ngoc Xuan; Vuong, Nguyen Lam; Mostafa, Mostafa Reda; Ahmed, Sarah Ibrahim; Elabd, Sahar Samy; Fathima, Samreen; Le Huy Vu, Tran; Omrani, Ali S.; Memish, Ziad A.; Hirayama, Kenji; Huy, Nguyen Tien
title: Clinical outcomes of current medical approaches for Middle East respiratory syndrome: A systematic review and meta‐analysis
date: 2018-04-17
journal: Rev Med Virol
DOI: 10.1002/rmv.1977
sha: 
doc_id: 272306
cord_uid: 92rz2byz

Middle East respiratory syndrome (MERS) is a respiratory disease caused by MERS coronavirus. Because of lack of vaccination, various studies investigated the therapeutic efficacy of antiviral drugs and supportive remedies. A systematic literature search from 10 databases was conducted and screened for relevant articles. Studies reporting information about the treatment of MERS coronavirus infection were extracted and analyzed. Despite receiving treatment with ribavirin plus IFN, the case fatality rate was as high as 71% in the IFN‐treatment group and exactly the same in patients who received supportive treatment only. Having chronic renal disease, diabetes mellitus and hypertension increased the risk of mortality (P < .05), and chronic renal disease is the best parameter to predict the mortality. The mean of survival days from onset of illness to death was 46.6 (95% CI, 30.5‐62.6) for the IFN group compared with 18.8 (95% CI, 10.3‐27.4) for the supportive‐only group (P = .001). Delay in starting treatment, older age group, and preexisting comorbidities are associated with worse outcomes. In conclusion, there is no difference between IFN treatment and supportive treatment for MERS patients in terms of mortality. However, ribavirin and IFN combination might have efficacious effects with timely administration and monitoring of adverse events. Large‐scale prospective randomized studies are required to assess the role of antiviral drugs for the treatment of this high mortality infection.

tions range from supportive to antiviral therapy. Two in vitro studies suggested a possible efficacious effect of interferon alpha-2b and ribavirin in the treatment of MERS infection. 10, 11 Consequently, the investigators further examined the efficacy of these drugs in an animal study. 12 Potential benefits of these antiviral treatments in both in vitro and animal studies persuaded clinicians to question the feasibility and applicability of such an approach in humans. Therefore, we aimed to recapitulate the evidence from all human published data about MERS clinical management in a systematic review and metaanalysis, to summarize the efficacy and safety of current applied therapeutics and define risk factors associated with outcomes. As a result, we may provide a better approach to more compatible management of fatal consequences of MERS infections and the risk imposed by recent outbreaks in densely populated areas.

Our study was performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. 13 We developed a protocol of methods and registered it in the international prospective register of systematic reviews (PROS-PERO) (reference, CRD42015024819). In June 2015, we conducted a systematic search of 10 After removing duplicates, three trained reviewers were assigned to independently screen the titles and abstracts of all references generated from the aforementioned search strategy on the basis of the following inclusion and exclusion criteria. Inclusion criteria were (a) any study that gives information about the treatment of MERS-CoV infection, (b) all types of study designs were included, and (c) no restriction was made with respect to language, age, and area. Exclusion criteria were (a) data that could not be reliably extracted, (b) data sets considered as overlapping, (c) studies published before 1/1/2012, (d) book chapter, thesis, letter, conference paper, poster, or editorial, and (e) animal or in vitro studies. Three reviewers compared their screening results and discussed the differences. A consensus was reached through discussion.

Extracted data included publication year, year of research, country and city of the patients, year of subject recruitment, study design, participant enrollment, data collection method, baseline characteristics before treatment, diagnostic method of MERS-CoV, time from admission to treatment start, treatment for MERS-CoV, and outcome survival. This work was conducted by 2 investigators evaluating the references independently, and all disagreements were discussed to reach a consensus from supervisors.

The quality of included clinical data was assessed using (CARE) statement for case reports 14 and the 9 metrics tool for nonrandomized studies. 15 Three reviewers were assigned to assess each included reference independently.

Mortality rates were treated as dichotomous variables with their respective 95% confidential intervals (CI). Statistical heterogeneity was assessed using the I 2 statistic 16, 17 and assumed to be influential when I 2 was greater than 50% or P ≤ .1. 18, 19 A fixed-effect model was used because there was no evidence of heterogeneity between studies. Meta-analysis was performed using data analysis and statistical software (STATA) that was developed by StataCorp. Fisher exact (or chi-square, as appropriate) and Mann-Whitney U tests were used for the categorical and continuous variables, respectively. The classification and regression tree (CART) model was used to identify independent variables that predict mortality outcome. 20 Invasive ventilation and renal replacement therapy were also chosen as the outcomes in the CART model because of direct correlation with severity and mortality. 20 All possible variables were extracted to build CART (Table S4 

A total of 1095 references were retrieved. Upon screening them regarding inclusion and exclusion criteria from Section 2, eleven references were included for data extraction and analysis. [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] Additionally, 5 references were identified through manual search. 7-9,32,33 So a total of 16 studies were eligible for selection as shown in Figure 1 .

Of the 16 studies including 116 patients, 10 were case reports, [7] [8] [9] 21, 24, 25, 28, 30, 31, 33 2 were case series, 23,26 and 4 were observational studies. 22, 27, 29, 32 Saudi Arabia was the country of origin for patients in 13 studies, and the rest were from France, Greece, and Qatar. Detailed characteristics of patients in our included articles are presented in Table 1 .

Eight studies used specific antiviral treatment 21, 22, 25, 26, [28] [29] [30] 32 while 7 studies used supportive treatment (including invasive ventilation, prone position, renal replacement therapy, vasopressors, corticosteroids, immunoglobulins, and oseltamivir). 7-9,23,24,31, 33 Omrani et al 27 used both specific antiviral treatment and supportive treatment. The specific antiviral treatments were IFN (alpha-2a, alpha-2b, and beta-1a), ribavirin, and several others including tenofovir, emtricitabine, lopinavir, and ritonavir. Among 116 patients recruited, 29 were reported with detailed information regarding baseline characteristics, comorbidities, treatments, outcomes, and some with survival time, which was subsequently used to perform univariable analysis and Kaplan-Meier survival curves (Table S4 , Found in the Supporting Information).

Hemodialysis dependency appeared in higher frequency in the IFN group than in the supportive-only group (P = .025). Conversely, renal replacement therapy and vasopressors were used more often in the supportive-only group than in the IFN group (P = .019) ( Table 2 ).

The quality of 10 case reports [7] [8] [9] 21, 24, 25, 28, 30, 31, 33 and 2 case series 23, 26 was assessed using the CARE checklist (Table S1 , Found in the Supporting Information). All of them contained an introduction and described the importance of the case in the abstract, main introduction section, demographics and symptoms of the patients, significant The quality of 4 observational studies 22, 27, 29, 32 was assessed using the 9 metrics tool 15 (Table S2 , Found in the Supporting Information).

Three of them had a score 23,27,29 of 5 of 9 as they described study design, characteristics of the patient population, inclusion criteria, method quality, and MERS diagnosis. However, none of the 3 studies described data collection method, assignment method of patients, exclusion criteria, and interpretation.

Treatment with antiviral drugs, other than oseltamivir, was reported in 9 studies. IFNs (IFN alpha-2a, alpha-2b, or beta-1a) in combination with ribavirin were the common remedies used in all 9 studies. IFN beta-1a was used in 2 studies (n = 12), both of which used a dose of 44 μg/wk for treatment. 28, 29 Ribavirin administration was started with a loading dose followed by subsequent doses in all 9 studies. The loading dose was 2000 mg for all studies while 400 mg in one study of AlGhamdi et al. 21 The subsequent doses, however, were variable among studies and ranged between 400 and 3600 mg/d. The frequency of administration of ribavirin was 3 doses per day in 2 studies 22, 30 and 2 doses per day in another 3 studies. 21, 28, 29 Duration of treatment with ribavirin was also variable and ranged between 5 and 26 days. The subsequent oral ribavirin dose was adjusted according to the calculated creatinine clearance in 3 studies. [25] [26] [27] However, the duration of treatment (8-10 days) and the loading dose (2000 mg) used in the 3 studies were similar, regardless of creatinine clearance (Table S3 , Found in the Supporting Information).

In addition to treatment with IFN and ribavirin, the treatment regimen in Shalhoub et al 28 included treatment with tenofovir/ 

Regarding mortality, studies with more than 2 cases were included in the meta-analysis. The pooled proportion of mortality was 0.714 (0.618-0.795) from 8 studies including 106 MERS patients (Figure 2 ).

In 68 patients received IFN treatment, the mortality rate was high (71%) in spite of receiving treatment with ribavirin plus IFN (alpha-2a, alpha-2b, or beta-1a). Likewise, the mortality rate was high in patients who received supportive treatment only (71%, n = 48). There was no statistical significant mortality difference when comparing mortality of both groups (P = 1) ( 

There was a significant difference between death and survival in patients with chronic renal disease (CRD 

The modeling tool, CART, identified CRD as the best parameter to predict mortality ( Figure 3A ). The performance of the decision tree tool that classified mortality outcome was at an accuracy of 72.4%, sensitivity of 52.9%, specificity of 100%, PPV of 100%, and NPV of 60%.

In addition, treatment with inotropes was exhibited as the best parameter to predict renal replacement therapy outcome ( Figure 3B ). The performance of the decision tree tool that classified renal replacement therapy outcome was at an accuracy of 86.2%, sensitivity of 66.67%, specificity of 95%, PPV of 85.7%, and NPV of 86.4%. No significant results were detected regarding the invasive ventilation outcome.

Survival time from admission to death was compared for IFN-treated (n = 30) and for non-IFN (supportive care only, n = 14) patients. All 44 cases died within 80 days after hospital admission ( Figure 4A ). Only one female case treated with IFN was eliminated from analysis because the patient remained intubated when the original study ended. However, she had met death criteria; thus, she was included The difference between the 2 groups was statistically significant (P = .001) ( Figure 4B ). The longer survival period from onset to death was simply attributed to the duration between onset and admission. 

Our systematic review highlights the significance of age and period between the illness onset and start of antiviral therapy in MERS cases' prognostic assessment. Our results revealed that younger age and 

There is no evidence of any difference between IFN treatment and supportive treatment for MERS patients in terms of mortality. The ribavirin and IFN combination might have promising effects where therapy can be started promptly and adverse effects monitored carefully; a randomized controlled trial is required to assess this possibility.

Concerning prognostic factors, delayed treatment, older age, and accompanying comorbidities such as hypertension, DM, chronic kidney disease, and dialysis dependence are associated with worse outcomes.

Because of high fatality, the seriousness of this newly emerging disease, and a limited number of available cases, we believe there is an urgent need for large-scale clinical trials on the efficacy of antiviral treatment of MERS-CoV infections.

The authors declare no competing interests. ORCID Ahmed Abdelmotaleb Ghazy http://orcid.org/0000-0002-9145-7115

Nguyen Tien Huy http://orcid.org/0000-0002-9543-9440

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