Apart from general supportive care there is still no proven or licensed therapy for the management and treatment of MERC-CoV. However, since MERC-CoV is phylogenetically related to SARS and both cause ARDS [1
], treatment options that were used during the SARS outbreak are being considered for MERS-CoV management. This includes the use of interferon monotherapy which has been preferred over the use of interferon and ribavirin combination [3
]. This was based mainly on the potential harmful side effects of the combination. In addition, the use of ribavirin alone for the management of MERS-CoV infection
was also believed to be associated with an unfavorable safety profile since high doses of the drug were assumed to be needed to approach the required inhibitory concentration in vivo
It was intended to treat the first patient with PEG-IFN α2a monotherapy. However, ribavirin 400 mg every 12 hours with no loading dose was added by the initial treating physician. After taking over, the drug was not discontinued by the specialist since the dose was not high and the patient did not have contraindications for the drug. Within one week of therapy, when the condition of the patient was stable enough to allow for the collection of tracheal aspirates, MERS-CoV was undetectable in that sample (Figure 2). At this stage, it was not possible to attribute the rapid virological response of the patient to the PEG-IFN α/ribavirin combination. The patient developed the frequent hemolytic anemia known to be associated with this combination which led to the discontinuation of ribavirin nine days after its initiation. However, his situation was possible to manage with few blood transfusions
The effect of the PEG-IFN α/ribavirin combination can be more elucidated by examining the response of the second patient whose case was more complicated. This patient developed acute renal failure and progressive anemia early during the course of his MERS-CoV infection complicating the utilization of ribavirin in the therapy. Therefore, PEG-INF α2b and a brief course of intravenous corticosteroids were used as a first line therapy. However, due to his continuous deterioration and lack of clinical and virological response, IVIG was added with the intention to modify the inflammatory
response and possibly provide the patient with cross reactive antibodies against MERS-CoV. The effect of the addition of IVIG was negligible and the condition of the patient worsened even further reaching a critical stage. As a result, ribavirin was added as a desperate measure to save the patient despite contraindications. The PEG-IFN α/ribavirin combination resulted in significant clinical, radiological, and virological improvements. The tracheal aspirates became negative for MERS-CoV nine days after the addition of ribavirin (Figure 2). Interestingly, the virus was detectable again in tracheal aspirates five days later despite the continuous administration of ribavirin. It is possible the reason for this reactivation is the fading of the effect of the last dose of PEG-INF α2b which was administered ten days before, resulting in the patient receiving ribavirin monotherapy for three days. Even though this reactivation seemed to be of little clinical significance, it may indicate that monotherapy with lower doses of ribavirin is not sufficient to inhibit the replication of MERS-CoV, therefore, supporting the proposed synergistic effect of PEG-IFN α and ribavirin [4
The most important adverse reaction of the PEG-IFN α/ribavirin combination experienced in treated patients was the drop in hemoglobin
level. Few blood transfusions, in addition to erythropoietin for the second patient, were sufficient to stabilize the hemoglobin level above 9 g/dl. No life threatening side effects were witnessed.
It is interesting that the second patient responded well to the treatment even though ribavirin was added 14 days after his admission. Other published cases treated with a related combination were less successful [5
]. One reason for this inconsistency could be the early initiation of PEG-IFN α in our case which may have played an important role in enhancing the response to the combination later. Another reason is our utilization of PEG-IFN α which is possibly more effective than the standard IFN α against MERS-CoV.
Another interesting feature that should also be noticed is that the Orf1a was detectable by RT-PCR for a longer duration and in higher quantity than the upE. This may indicate that testing for the Orf1a is more sensitive than the upE for screening and following up patients (Figure 2).
Although the findings highlighted above may indicate that the of PEG-IFN α/low dose ribavirin combination is the most effective therapy for the treatment of MERS-CoV infected patients, stronger evidence is still needed for the determination of the most effective and safest treatment regimen for this infection.