Therapeutic options for Middle East respiratory syndrome coronavirus (MERS-CoV)--possible lessons from a systematic review of SARS-CoV therapy.

The Middle East Respiratory Syndrome coronavirus (MERS-CoV) has been detected in a number of countries in the Middle East and Europe with an apparently high mortality rate. It is phylogenetically related to the SARS coronavirus and has also been associated with severe respiratory illness as well as nosocomial transmission in healthcare settings. Current international recommendations do not support any specific therapies; however, there are a number of agents, which were used during the SARS epidemic of 2003. It is possible that these might be active against the related MERS coronavirus. We have reviewed the literature on the safety and efficacy of therapies used in patients with SARS with a view to their potential use in patients with MERS-CoV infections.

Introduction

Coronaviruses are RNA viruses which usually cause mild upper respiratory illnesses. The emergence of SARS (severe acute respiratory Syndrome) MERS (Middle east respiratory syndrome) has focussed global attention on the clinical significance of cornaviruses.

The current Middle East Respiratory Syndrome Novel coronavirus (MERS-CoV) was first isolated in June 2012 from the respiratory tract of a businessman in the Bisha area of Saudi Arabia, who subsequently died of pneumonia and renal failure. As of 28 July 2013 MERS-CoV has caused 91 laboratory confirmed cases and 46 deaths, representing a high case fatality rate of 50%. The high case fatality rate is likely related to the pattern of the disease as we probably are seeing only the tip of the iceberg of critically ill and admitted patients. The high fatality rate is likely to decline as milder clinical cases emerge. Similar to SARS, common symptoms in patients with MERS-CoV include fever, cough, shortness of breath, and gastrointestinal symptoms. Most patients have had pneumonia and the majority was reported to have multiple co-morbid conditions.3, 4

The rapid deployment of effective therapeutics is a high priority as there is currently no specific therapy or vaccine for MERS-CoV. The clinical experience from SARS suggests that a number of interventions including ribavirin with and without corticosteroids, interferon alfa with corticosteroids, ribavirin with lopinavir and ritonavir, and convalescent plasma may improve the outcome in patients but the data are not conclusive.

The purpose of this review is first to summarize the effectiveness of these treatments, in an attempt to identify a therapeutic approach that could help select the most appropriate therapeutic options for patients with MERS-CoV infections.

Methods

We systematically searched the literature databases (PubMed, Science Direct and the Cochrane database) for published studies. We used the key words “SARS”, “coronavirus”, in combination with “treatment”, human studies, randomized controlled trials (RCT), prospective or retrospective cohort designs, case-control designs, or case series; agents included were ribavirin, interferon, Lopinavir and ritonavir (LPV/r), and convalescent plasma. We exclude corticosteroid studies as this was beyond the scope of this review and the management of severe pneumonia has been well covered in the WHO guideline.

Data extracted from these publications include: authors name, publication year, type of study, level of evidence, sample size, interventions dose, duration, indication, route, and time of administration, number of patients, and efficacy and safety outcome of these interventions. The outcomes of interest included mortality rate, measures of morbidity and adverse effects. The outcomes reported in the selected studies included death, mechanical ventilation, improvement of symptoms, admission to the intensive care unit, infectious complications, successful discharge and adverse effects.

Assessment of study quality

The clinical studies were all critically appraised. Aspects that were assessed included study design, the possibility of bias in the selection of the control group and treatment allocation, and whether the treatment regimen and reporting of outcomes were consistent. The studies were tabulated and summarized in a narrative way, and were grouped by the treatment strategy. We categorized each article depending on which drug was used. We tabulated results as type of study, dose, duration, time of administration, and indication of medication, number of patients included in that study, plus the final outcomes.

The studies were scored using the US Preventive Services Task Force scoring system, where Level of Evidence.

LOE, I: Evidence obtained from at least one properly designed randomized controlled trial.

Level II-1: Evidence obtained from well-designed controlled trials without randomization.

Level II-2: Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.

Level II-3: Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence.

Level III: Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

Results

We identified 54 studies about SARS or coronavirus and we included 19 studies only. We excluded 35 studies since 14 of them were in vitro studies, 15 corticosteroid studies, and 6 were non-therapeutic studies. Overall, we analyzed 19 studies, nine used ribavirin alone or with interferon (Table 1 )8, 9, 10, 11, 12, 13, 14, 15, 16, two used lopinavir and ritonavir (Table 2 )17, 18, six used convalescent plasma (Table 3 )19, 20, 21, 22, there was one study of Interferon alpha (Table 4 ) and one study comparing Interferon alpha versus ribavirin. Summaries of the different studies are presented in Table 1, Table 2, Table 3, Table 4.

Table 1

Summary of Ribavarin Therapy in the treatment of SARS patients

Table 2

Lopinavir/Ritonavir studies

Table 3

Convalescent Plasma studies

Table 4

Interferon alpha studies

Discussion

There has been a lot of concern worldwide about the emergence of the MERS-CoV. Although infection control, molecular diagnostics and international public health have improved considerably since the 2003 SARS epidemic, there are still no proven or licensed therapies for any coronavirus infection. The high mortality associated with MERS-CoV led us to conduct this systematic review to summarize the available options for treatment for novel coronavirus infection based on previous reports of therapy of SARS, a related coronavirus.

The most commonly used agent was the broad spectrum antiviral ribavirin. There were seven reports of the use of ribavirin in SARS patients although only four reported control groups. The mortality benefit was inconsistent with mortality rates of between 5% and 42.8%,8, 9, 10, 11, 12, 13, 14 two studies showed improvements of symptoms in 71.4%-80% of patients, and ICU admission rates of 13%-20%.8, 9 The major problem with ribavirin was the significant incidence of adverse events especially hemolysis which was reported in 68.5%.

The timing of the start of antiviral agents is important in most virus infections. One study compared oseltamivir versus ribavirin and showed no obvious response to ribavirin, however, the treatment were started after 10-14 days of symptoms which might have led to the poorer outcomes.

There was only one randomized controlled trial: this compared ribavirin versus interferon-1α and showed no advantage of ribavirin over interferon in patients with SARS. In addition, there were observational studies comparing Interferon-1α with untreated controls. Interferon led to improvements in clinical and laboratory parameters compared with control patients. However, there was no standard regime used and adverse events were not well documented.

The addition of lopinavir/ritonavir to ribavirin regimen was associated with improved clinical outcome and reduces the death rate comparing to ribavirin regimen alone in observational studies.17, 18 These studies are detailed in Table 2.

Few studies addressed the effect of convalescent plasma.19, 20, 21, 22 These studies were mainly case reports which limit the generalizability of their findings. In three studies of SARS patients, patients in the plasma group had a shorter hospital stay (58.3% -73.4% versus 15.6%- 19%; P < 0.001)21, 22 and lower mortality than the comparator group (0%- 12.5% versus 17% 23.8%).19, 21, 22

Intriguingly, an in vitro study showed that convalescent plasma from SARS patients might contain cross-reactive antibodies against other beta-coronavirus including MERS-CoV. Of 28 sera, 7 (25%) had antibodies anti-MERS-CoV neutralizing antibodies at low titers. Convalescent sera was recommended in a recent study by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). Cross- reactive antibodies may be present in convalescent plasma from SARS patients against other beta-coronavirus and may be associated with a better outcome, reduced mortality, and shorter hospital stay.19, 20, 21, 22 There are considerable technical hurdles to overcome before convalescent sera can be widely recommended as a therapeutic agent in the modern era. Currently, there is a need to establish a serology test to diagnose patients with mild disease and thus identify those patients as possible donors of convalescent sera.

We conclude that the use of ribavirin may improve the outcome and reduce mortality as shown in a number of studies. One of the reasons for the failure of ribavirin in some reports may have been the timing for the use of ribavirin, after 6-14 days of symptom,11, 14, 16 compared to studies which showed benefits when ribavirin was started within 48 hours of hospitalization or after diagnosis of SARS was established.8, 9, 12, 13The major limitation of Ribavarin is its significant toxicity at the doses used to treat patients with SARS. Although the addition of lopinavir/ritonavir to ribavirin appeared to have a better outcome in patients with SARS.17, 18 There are reports that lopinavir/ritonavir is not active in vitro against the MERS-CoV. Other in vitro studies have failed to yield potent therapeutic agents despite a search including DPP4 inhibitors.

Among the limitations of this review are the heterogeneity of the reviewed studies in terms of the wide range of treatment dosages, frequency, and route of administration, duration, and timing of administration. The reported treatment effects should be interpreted with caution due to the lack of randomized, controlled trials.

Also, while we have drawn on the SARS literature, and SARS is a closely related virus, there are clearly differences between SARS and the MERS-CoV and the data might not be able to be directly extrapolated to MERS-CoV infected patients. The use of the discussed agents would require monitoring hematological and biochemical parameters during treatment to detect and prevent adverse effects associated with therapy. Possible dosages of discussed agents especially with unavailability of intravenous ribavarin are listed in Table 5 . The table also includes the possible dosage of pegelated interferon-α (PegIFN—α) that is commonly used in the treatment of hepatitis C virus infection. PegIFN-α was 50-100 times more effective in vitro for MERS-CoV than SARS-CoV. The long half-life of PegIFN-α and the associated adverse effects calls for extra attention for the use of shorter-acting interferon. The use of interferon therapy with ribavirin is not recommended in patients with hepatitis C virus infection and renal dysfunction (Clcr <50 mL/minute).

Table 5

Possible dosages and schedule of therapeutic agents for MERS-CoV Infection

With the emergence of MERS-CoV and the lack of high quality clinical evidence to support recommendations for the use of available therapeutic options, there is a clear need for developing protocols to be used in randomized-controlled trials in order to determine the most effective therapies for this novel emerging pathogen.