Treatment outcomes for patients with Middle Eastern Respiratory Syndrome Coronavirus (MERS CoV) infection at a coronavirus referral center in the Kingdom of Saudi Arabia

Coronaviruses cause a spectrum of illness from asymptomatic disease to respiratory failure. Early reports of coronavirus infections suggested that most infections were mild until the 2003 SARS epidemic that was associated with significant morbidity and mortality [1]. In September 2012, a novel coronavirus was identified in a 60-year old man in Saudi Arabia [2]. A second case was identified in a Qatari patient hospitalized in the United Kingdom [3]. The two coronaviruses were genetically identical and similar to isolates obtained from bats [4]. In July 2013, the coronavirus study group named this new virus Middle East respiratory syndrome coronavirus (MERS–CoV) [5].

As of December 21, 2015, there have been 1625 cases worldwide with 586 deaths [6]. The epidemiology and clinical manifestations of this disease have described a spectrum of illness from asymptomatic infection to severe respiratory failure and death. The overall mortality rate remains at 37 % [7‐15]. Importantly, there are no known effective treatments. In 2014 there was an increase in MERS-CoV cases reported from the Jeddah region of Saudi Arabia. To describe the changing epidemiology and outcomes, we report the clinical features and treatment outcomes of patients admitted to a regional referral hospital in Jeddah, Saudi Arabia.

MERS-CoV is an emerging disease for which the initial epidemiology has been described, but in-depth clinical studies and the role of therapy in incompletely understood. While the clinical features for MERS-CoV have been described in several large case series [6‐14], there is a paucity of literature on therapy. Our results from a relatively large number of patients demonstrate similar clinical features and mortality to previous studies [6‐14]. In our cohort, treatment with beta interferon and mycophenolate mofetil may be predictive of survival, but the greatest predictor of survival is the severity of illness on presentation.

Improved diagnostics have demonstrated an expanded spectrum of disease that includes less severe cases than previously reported. We now understand that MERS-CoV causes an acute respiratory disease syndrome and one third of patients present with gastrointestinal symptoms [14]. Fever has been seen in 62–87 % of patients, cough in 55–87 %, and gastrointestinal symptoms in 26–35 %. Seventy-six to 96 % percent of patients have had comorbid illnesses, most commonly chronic renal failure, diabetes and heart disease [7‐15]. This may be partially related to the epidemiology of increased disease transmission in healthcare settings rather than a true host risk factor. Laboratory findings have been non-specific and consistent with other viral infections. Thrombocytopenia (75 %) and lymphopenia (58 %) have been commonly described in these patients [7, 9‐13, 15]. Forty three percent had acute kidney injury [7, 11‐13, 17] and 76–100 % had CXR abnormalities with bibasilar infiltrates as the most common finding [8‐13, 15, 18]. The outcomes in these more severely ill patients remain poor. Between 50–90 % required ICU care [10, 11, 13, 15] and 67–100 % in the ICU setting required invasive ventilation for a median of 7–16 days [8, 10, 12]. In addition to mechanical ventilation, several patients have received extracorpeal membrane oxygenation (ECMO) to support ventilation. From non-randomized data from the World Health Organization, five out of six patients receiving ECMO died [9]. Fifty-eight to 75 % required renal replacement therapy [11, 12, 17] and 30–60 % of hospitalized patients died [7‐15]. The severity of illness can be partially explained by the widespread lung disease caused by MERS-CoV and it appears that mortality in those patients requiring intensive care is extremely high. Although no autopsy data is available, in explanted lung, infection with MERS-CoV causes widespread infection and alveolar disease [19, 20].

The clinical features in our cohort similarly also show a high proportion of patients with fever (96 %) and cough (80.4 %) shortness of breath (90 %), and almost one third of patients (29.4 %) with gastrointestinal symptoms. Our cohort consisted of ill patients with hypotension (15.7 %), tachypnea (76.9 %) and hypoxia (33 %). Thirty seven percent required ICU care and 10 patients received ECMO. Similar to previous results, all of the patients who received ECMO died [9].

There is no known effective treatment for MERS CoV. Many compounds have been screened in vitro for possible activity against this coronavirus [21‐24], however, the in vivo efficacy has not been subjected to clinical investigation.

In vitro data suggests that MERS-CoV inhibits host interferon production through various molecular pathways [25‐30] mycophenic acid, the active agent of prodrug mycophenolate mofetil, and cyclosporine strongly inhibit MERS coronavirus in human and monkey cell lines even more so than they inhibit SARS coronavirus [24, 31‐33]. Interferon alpha and interferon beta reduce MERS coronavirus replication in explanted lung tissue [19]. In vivo, comparing host response in two patients with MERS coronavirus and differing outcomes, the patient who was able to clear MERS CoV infection was able to mount an interferon response and the patient who died had low levels of interferon alpha suggesting a therapeutic role for interferon [34]. The combination of interferon alpha and ribavirin has been used successfully in rhesus monkeys infected with MERS coronavirus [35], and in a few small case series [36‐38]. Beta-interferon seems to be an even more potent inhibitor of MERS coronavirus in vitro [19] [24, 31‐33]. One small study with exceptionally high mortality rates using interferon beta for treatment found no difference in mortality between interferon beta use and interferon alpha use [39]. Our data, albeit from a retrospective cohort support the findings that interferon beta is associated with a decrease in mortality.

There are limited data on the efficacy of treatment regiments for this virulent disease. We present data from a retrospective cohort of ill patients with Mers-CoV and the results of the evaluation of the clinical efficacy of beta interferon beta, alpha interferon, ribavirin and mycophenolate mofetil in addition to routine supportive care. Forty five percent of patents (23 patients) received interferon beta and in this cohort, sixteen percent of patients received interferon alpha (8 patients) and 37 % of patients (9 patients) received ribavirin, either in conjunction with interferon alpha or interferon beta, and 8 patient received mycophenolate mofetil. Patients receiving beta interferon and mofetil had improved survival, however this was confounded by the severity of illness on presentation for beta interferon. All of the patients who received mycophenolate mofetil survived however because of the small number, we could not analyze the independent efficacy of mycophenolate mofetil.

While this is a relatively large series of MERS-CoV cases, the primary limitation of our study is that it is a retrospective review of cases and not a randomized trial and thus subject to confounding as seen in our cohort. We used a modified APACHE 2 score without all of the clinical variables, which may have underestimated the association of severity of illness with reduced survival. Importantly, the mortality in patients receiving additional therapies that modulate the immune response was low. All of the eight patients who received mycophenolate mofetil in our study survived. Hence, it may be reasonable to further study this agent in controlled trials.

This observational study investigates novel treatment options like beta interferon and mycophenolate mofetil for MERS-CoV in humans which have in vitro activity. Our cohort demonstrated severity of illness is an important effect modifier and needs to be considered in evaluating novel agents. To better assess the efficacy of these therapies, international prospective randomized trials with adequate numbers of patients are needed to further evaluate the impact of these treatments in addition to routine supportive care when compared to other treatment options.