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How to treat and control Coronavirus
This guide might be useful for Nurses and Doctors in Italy. Just press the translate button at top of page to change to Italian.

MERS-CoV antiviral treatment guidelines
Key question 1. Which patients should be administered antivirals?
However, because patients with MERS show a high mortality rate (approximately 36% in reports from the Middle East, and 19% in the South Korean epidemic), antiviral treatment can be actively considered since their efficacy has been confirmed in laboratory studies and they have shown some degree of efficacy in retrospective clinical studies.
In MERS-CoV infection, the important risk factors factors for death are old age (>50-65 years, depending on the study), underlying diseases (cardiac disease, chronic pulmonary dis- ease, diabetes, chronic renal disease, etc.), bilateral pneumonia, and low cycle threshold (Ct) values in real-time reverse transcription polymerase chain reaction at diagnosis [6-10]. The risk factors predicting progression to severe disease are also similar [7, 9, 10]. In data analyzing 108 patients during the South Korean epidemic, age >50 years and shortness of breath were significant risk factors on multivariate analysis, while on univariate analysis, underlying diseases and bilateral pneumonia were also associated with death (unpublished data). In a retrospective study by Omrani et al. [5], antiviral treatment significantly improved 14-day survival in patients with severe MERS requiring mechanical ventilation. Therefore, in patients with risk factors for death or progression to severe MERS, active antiviral treatment is recommended.
Retrospective cohort studies have shown that there are also cases of healthy medical workers or patients without underlying diseases who die or progress to severe disease [10, 11]. An analysis of 108 domestic patients with MERS showed the deaths of two patients without any particular underlying dis- eases (unpublished data). Therefore, even in patients without underlying diseases, if there are clear symptoms or signs of pneumonia, antiviral treatment should be considered as long as the risk of adverse effects is not considered high.
Key question 2. When is the most appropriate time for antiviral administration?
In retrospective studies of the effects of antiviral treatment for MERS-CoV infection, it is highly likely that the therapeutic effects of antivirals were unclear because the majority of patients were critically ill due to severe pneumonia and multiorgan failure [5, 12]. Also, looking at several observational studies of SARS-CoV treatment, there was no therapeutic effect in reports in which antiviral treatment (ribavirin) was started at 6-14 days after after the onset of symptoms, but there was a
  • Although the role of antivirals in the treatment of MERS or the similar disease SARS have not been clearly proven, considering the high mortality and morbidity rates, antiviral treatment should be considered in addition to the appropriate supportive care (BIII).
  • Important risk factors predicting the progression to severe disease and death include old age, underlying dis- eases (cardiac disease, chronic pulmonary disease, diabetes, chronic renal disease, etc.), breathing difficulties, and bilateral pneumonia (II). When such risk factors are present in confirmed or suspected MERS-CoV cases, active antiviral treatment is recommended (BIII).
  • Even in patients without risk factors related to the progression to severe disease or death, respiratory failure and multi-organ failure may develop rapidly (III). There- fore, in patients with suspected or confirmed MERS- CoV infection with symptoms (fever or shortness of breath) or pulmonary infiltrate on a chest x-ray, antiviral treatment is recommended as long as the risk of adverse effects is not too high (BIII).
During the SARS epidemic of 2002-2003, antivirals such as interferon-α, ribavirin, and lopinavir/ritonavir were used in a large number of patients, and the results were reported in cohort studies. However, there was no clear conclusion about the efficacy of antivirals [4]. There is a serious lack of clinical data to demonstrate the effects of antiviral treatment in patients with MERS. The data that exists were derived from retrospective cohort studies including a small number of patients, and they do not show a clear therapeutic effect [5, 6]. In one retrospective study analyzing the effects of antiviral treatment in 44 patients with MERS, the 14-day survival rate of the treatment group was significantly higher than that of the control group (70% vs. 29%, P = 0.004), but there was no significant
• Antiviral administration should be considered as soon as possible after diagnosis (BIII).
therapeutic effect in reports in which antivirals were administered within 48 hours of hospitalization or a SARS diagnosis [4, 13, 14]. Considering all of these facts, a therapeutic effect of antivirals against MERS-CoV can only be expected when the treatment is administered as soon as possible after diagnosis.
Key question 3. Which antiviral regimens can be used in South Korea?
There are currently no antiviral drugs with a clearly proven clinical effect in the treatment of MERS-CoV infection. Antiviral studies reported to date have mostly been laboratory studies, and so the actual clinical data for the use of antivirals are limited. There are data from animal experiments and a small amount of clinical data for type 1 interferon, ribavirin, and lopinavir/ritonavir. Type 1 interferons include interferon-α2a, -α2b, and -β1a. In an animal experiment in rhesus macaques, a combination regimen of interferon-α2b and ribavirin showed clinical improvements and reduced severity [15]. There have been clinical case reports of patients who improved after combination therapy with interferon-α2b and ribavirin [16]. However, room remains for debate due to the lack of sufficient clinical studies on combination therapy us- ing type 1 interferon and ribavirin. In one retrospective comparative analysis of cases treated with ribavirin + interfer- on-α2a or interferon-β1a, neither regimen was effective [6]. In another retrospective clinical study of the effects of a combination regimen of interferon-α2a and ribavirin, 14 of 20 patients (70%) who received this treatment survived beyond 14 days, whereas only seven of 24 patients (29%) in the non-treat- ment group survived, seemingly demonstrating an effect of the combination regimen (P = 0.004). However, the interpretation
  • Acombinationregimenoftype1interferon+ribavirin+ lopinavir/ritonavir is recommended for antiviral thera- py (BIII).
  • The use of ribavirin alone is not recommended for anti- viral therapy, whereas combined administration with type 1 interferon is recommended (AIII).
  • In cases in which it is difficult to use ribavirin for antiviral therapy, a combination regimen of type 1 interferon + lopinavir/ritonavir should be considered first (AIII).
  • The dose of ribavirin for MERS-CoV treatment has not been standardized, but the drug can be used at the same doses as in previous clinical trials or the treatment of other respiratory viruses. Dose adjustment may be re- quired in patients showing signs of a decline in renal function (AIII) (Table 2).
Table 2. Antiviral treatment for MERS-CoV
a
b (CrCl 20-50 mL/min)
MedicationNormal renal function (CrCl > 50 mL/min)
Impaired renal functionHemodialysis or CrCl < 20 mL/min
A. Ribavirin, high dosec
B. Interferon-α2a
f D. Convalescent plasma
2,000 mg po loading dose → 1,200 mg po q8h for 4 days → 600 mg po q8h for 4-6 days
180 μg per week for 2 weeks
300-500 mL of full plasma (3-5 mL/kg)
2,000 mg po loading dose → 600 mg po q8h for 4 days → 200 mg po q8h for 4-6 days
Same dose
2,000 mg po loading dose → 200 mg po q6h for 4 days → 200 mg po q12h for 4-6 days
Same dose
d
e
Ribavirin, alternative intermediate dose2,000 mg po loading dose → 10 mg/kg po q8h for 10 days
2,000 mg po loading dose → 200 mg po q8h for 10 days
2,000 mg po loading dose → 200 mg po q12h for 10 days
g
C. Lopinavir/ritonavirLopinavir/ritonavir 400 mg/ 100 mg po q12h for 10 days
Same dose
Same dose
aIn the case of adverse effects caused by ribavirin, the dose should be reduced or its use should be suspended. bIf continuous renal replacement therapy is being administered, the ribavirin dose should be adjusted according to the plasma removal rate, and when calculation is difficult, consider using a dose that maintains the creatinine clearance rate (CrCl) at 20-50 mL/min. cThis is the dose typically used in the treatment of severe acute respiratory syndrome coronavirus or Middle East respiratory syndrome. dThis is a reduced dose due to concerns of adverse effects caused by ribavirin, such as cytopenia or hemolytic anemia. Based on the evidence that ribavirin + interferon-α combination therapy shows a synergistic effect in vitro , this follows the dose typically used for the treatment of respiratory syncytial virus treatment to ensure safety. eIn dialysis patients or those with severe renal dysfunction, use of ribavirin is usually not recommended due to concerns of fatal hemolytic anemia. Therefore, if ribavirin is to be used, the patient should be closely monitored for hemolytic anemia and other major adverse effects. fPegylated interferon-α2a (Pegasys®; Roche Pharmaceuticals) is administered by subcutaneous injection (SC). It can be replaced by interferon-β1a (Rebif®, 44 μg SC three times per week). Although there have been no clinical trials using interferon-α2b (Pegintron®), its administration can be considered at the treatment dose for hepatitis C, which is 1.5 μg/kg SC once per week. gLopinavir/ritonavir (Kaletra®) is mostly metabolized by the liver, so care should be taken in patients with severe liver dysfunction.
tion of the results remains under debate because there was no statistically significant difference for 28-day mortality, with the treatment group showing 30% survival and the non-treatment group showing 17% survival (P = 0.054) [5]. Both studies have limited ability to provide statistical proof due to the small number of patients. However, since there was an overall trend for improvement in the type 1 interferon + ribavirin combination therapy group, until the lack of an effect has been shown conclusively, combination therapy is recommended. Evidence for the use of lopinavir/ritonavir as an antiviral for MERS-CoV infection is based on its efficacy in the treatment of SARS-CoV [17, 18]. In an animal experiment of common marmosets, the administration of lopinavir/ritonavir alone significantly re- duced the numbers of MERS-CoV colonies in the lungs com- pared to the non-treatment group, and this effect was identi- cal to that of interferon-β1b [19]. Indeed, one report showed that patients administered lopinavir/ritonavir at the same time as type 1 interferon + ribavirin combination therapy showed improved viremia after 2 days [20]. Hence, if possible, the use of lopinavir/ritonavir in addition to type 1 interferon + ribavirin combination therapy is recommended. As for type 1 interferons, in vitro studies showed a stronger effect of inter- feron-β than interferon-α. Moreover, of these options, the me- dian effective inhibitory concentration (EC50) to maximum se- rum concentration ratio of interferon-β1b was lower than those of interferon-α2a, interferon-α2b, and interferon-β1a [21, 22]. However, because clinical studies are lacking, no particu- lar type 1 interferon can yet be concluded to be superior to the others [6].
In one in vitro study, ribavirin and interferon-α2b separately inhibited MERS-CoV proliferation [23]. However, MERS-CoV proliferation was not inhibited at the typical concentrations of ribavirin used clinically, and inhibition was only confirmed at concentrations that show toxicity in humans [21]. Therefore, monotherapy with ribavirin at typical doses is expected to show a reduced clinical effect. Nevertheless, when interfer- on-α2b and ribavirin are administered in combination, they showed a synergistic effect and a reduced dose of ribavirin was required [23]. Therefore, its combined administration with interferon is recommended.
As mentioned above, lopinavir/ritonavir was comparable with interferon β1b in an animal experiment of common mar- mosets [19]. Hence, in cases in which ribavirin cannot be used due to renal dysfunction or other adverse effects, monothera- py with interferon-β1b or lopinavir/ritonavir can be consid- ered. Nevertheless, since there are still no antivirals with a clearly proven clinical effect for the treatment of MERS-CoV
infection, as long as there are no contraindications, a combi- nation regimen of type 1 interferon + lopinavir/ritonavir should first be considered.
There are no studies of the dose-dependent differences in therapeutic efficacy for ribavirin in the treatment of MERS- CoV infection. Hence, the dose used in the retrospective study of Omrani et al. [5] is recommended. This dose is the same as that typically used in SARS-CoV treatment [13]. However, if there are concerns about ribavirin-induced adverse effects, including cytopenia and hemolytic anemia, a reduced dose could be used. This reduced dose is based on the synergistic effect of combined type 1 interferon + ribavirin in an in vitro study, and it follows the dose used in the treatment of respira- tory syncytial virus to ensure safety [24]. Nevertheless, since the suppression of virus proliferation showed a dose-depen- dent pattern in an in vitro study, the dose choice needs to be carefully considered [22, 25]. Dose adjustment is required for ribavirin according to renal function, so creatinine clearance (CrCl) requires monitoring throughout treatment. As there is an increased risk of adverse effects if renal function declines, care must be taken.
Key question 4. How long should antiviral drugs be administered?
Antiviral treatment was previously administered for 10-14 days in patients with SARS-CoV infection; accordingly, the same antiviral treatment duration has been applied for patients infected with MERS-CoV [5, 6, 13, 26]. In a retrospective cohort study of patients 16 years old with MERS-CoV pneumonia in Saudi Arabia, when combined interferon-α2a and ribavirin treatment was continued for 10-14 days, 14-day sur- vival increased significantly [5]. Although the difference did not reach statistical significance, 28-day survival showed a positive trend in the treatment group also. However, even after approximately 10 days of antiviral therapy, MERS-CoV remained detectable in the respiratory secretions of some pa-tients for up to 2-3 weeks [6]. Since the clinical significance of this finding is unclear, further studies are required for the appropriate duration of antiviral treatment. Treatment extension can be considered when immune deficiency leads to persistent viral shedding, whereas if a patient shows rapid recovery and there are concerns about adverse drug effects, the antiviral treatment duration might be shortened. Antiviral treatment is generally recommended for 10-14 days
• Antiviraltreatmentisgenerallyrecommendedfor10-14 days in patients with MERS-CoV infection (BIII).

should be decided according to the patient’s condition.
Key question 5. Should antiviral drugs be used by pregnant women?
Pregnant women are conventionally considered a high-risk group for the progression to severe disease or death, and a case was reported of stillbirth in the second trimester of pregnancy for a woman infected with MERS-CoV [27]. Of the anti- viral drugs recommended, ribavirin is in Category X for safety in pregnant women, while lopinavir/ritonavir and type 1 in- terferon are in Category C. Given the lack of clinical studies on antiviral treatment in pregnant women, it is difficult to recommend these drugs. Considering the physiological adaptations to pregnancy in pregnant women, conservative treatment should be provided [28]. When treating pregnant women in- fected with human immunodeficiency virus (HIV), the preferred protease inhibitor is lopinavir/ritonavir [29]. Among type 1 interferons, there is evidence supporting the safe use of interferon-β1a, which is used to treat multiple sclerosis, in pregnant women. Although one report showed that the incidence of spontaneous abortion increased in pregnant women who used interferon-β1a, there was no statistically significant difference with the incidence in control individuals [30, 31]. Therefore, the use of antiviral drugs can be considered after a comparison of risks and benefits of the drugs. Possible antiviral treatment would be combination therapy with interfer- on-β1a and lopinavir/tironavir, but there is no case report of this being used in pregnant women with MERS. Any decision to use antiviral drugs requires the consideration of ethical is- sues and a consultation with an obstetric specialist.
Key question 6. What are the adverse reactions and points of caution for different antiviral drug classes?
Of 110 patients infected with SARS-CoV, hemolytic anemia reportedly occurred in 67 patients (61%) during ribavirin treatment [32]. This could occur 3-5 days after the start of treatment, and on average occurred 10 days after the start of treatment. It mostly occurred when the dose exceeded a normal dose of 1,000-2,000 mg, so it could occur at the doses used to treat MERS-CoV. Hence, during ribavirin use, changes in hemoglobin, bilirubin, haptoglobin, and reticulocyte levels require close monitoring. If hemolytic anemia does occur, a dose reduction or cessation should be considered; if neces- sary, the use of lopinavir/ritonavir instead of ribavirin could be considered. Dose reduction is required in the case of impaired renal function, and ribavirin use is not recommended for patients on dialysis or those with severe renal dysfunction due to concerns of fatal hemolytic anemia. Other common adverse effects of ribavirin include bradycardia (<55/min), hy- pomagnesemia, and hypocalcemia [33]. In addition, since rib- avirin shows teratogenicity, male and female patients should both use contraception for 6 months after treatment [34].
Fatigue and flu-like symptoms can occur during type 1 in- terferon use; in these cases, the patient should be given sup- portive care [34]. Care is required since 20% of patients taking type 1 interferons show anemia, leukopenia, and thrombocy- topenia due to bone marrow suppression. If anemia does occur, the ribavirin dose first needs to be reduced or ceased if it is administered in combination, and if there is still no im- provement, the use of recombinant erythropoietin can be considered. If leukopenia or thrombocytopenia occurs, the interferon dose needs to be reduced in accordance with the manufacturer’s recommendations [35, 36].
Key questions 7. Are there any other drugs with an antiviral effect against MERS-CoV?
Mycophenolic acid, chloroquine, chlorpromazine, and loperamide have a demonstrated antiviral effect against MERS- CoV in laboratory tests, and amiodarone had an antiviral ef- fect against SARS-CoV infection (III). In addition to an immunosuppressive action through the inhibition of T/B lymphocyte differentiation, mycophenolic acid is known to show a broad antiviral effect against West Nile, Japanese encephalitis, yellow fever, dengue, and chikungunya viruses in in vitro animal experiments. Some authors have suggested the possi-
• Type 1 interferon can cause myeloid dysfunction, so CBC changes must be closely monitored. If anemia, leukopenia, or thrombocytopenia occurs, dose reduction or cessation should be considered (BIII).
• Considering the physiological adaptations to pregnancy, pregnant women should be treated conservatively. Any decision to use antiviral drugs requires the consideration of ethical issues and a consultation with an ob- stetric specialist (AIII).
• Care must be taken to prevent the occurrence of hemolytic anemia when using ribavirin, while changes in complete blood count (CBC), reticulocyte, haptoglobin, and bilirubin levels should be monitored closely. If he- molytic anemia occurs, dose reduction or cessation should be considered (AIII).

bility of clinical trials of the short-term use of mycophenolic acid and interferon-β1b in combination against MERS-CoV infection by lowering its EC50 value [37]. Chloroquine inhibit- ed MERS-CoV replication at an EC50 of 3.0 μM, and it is pre- dicted to inhibit infection in the early stages. Chlorpromazine suppresses viral invasion in the early stages by inhibiting clathrin-mediated endocytosis, and it is predicted to have an antiviral effect by inhibiting other later processes. Loperamide has also been suggested as a possible treatment since it inhib- its two other coronaviruses at low micromolar concentrations (4-6 μM) [38, 39]. The effects of amiodarone on MERS-CoV in- fection have not been confirmed, but it is known to inhibit SARS-CoV proliferation at the post-endosomal level by alter- ing the endocytic pathway, so it is predicted to have a similar effect against MERS-CoV infection [40]. One key functional receptor during host cell infection by MERS-CoV is the trans- membrane protein dipeptidyl peptidase 4 (DPP4). Adenosine deaminase is a protein that binds to DPP4, thereby competing with MERS-CoV for DPP4 binding, and it has been confirmed to act as an antagonist to MERS-CoV infection in vitro [41]. DPP4 breaks down incretin through its enzymatic function, and the DPP4 inhibitor gliptin, which is used as a hypoglyce- mic agent, interferes with this enzymatic action. Therefore, DPP4 inhibitors (such as gliptin) may not interfere with MERS-CoV binding to DPP4, nor experimental studies have been conducted to date.
Key question 8. Does convalescent plasma therapy help?
There is insufficient evidence to ascertain the safety and efficacy of convalescent plasma therapy in patients with MERS- CoV infection, but SARS-CoV treatment experiences would be helpful. According to the results of a meta-analysis examining eight observational studies of convalescent plasma therapy in patients with SARS-CoV infection, mortality rates were lower when patients were given the treatment and no major adverse effects were reported [42]. In terms of convalescent plasma administration timing, when a subgroup analysis was per- formed on 48 patients, the results were only positive when the treatment was given within 14 days of symptom onset [42].
Also, in an analysis of 80 patients with SARS in Hong Kong who were treated with convalescent plasma, treatment timing was significantly earlier for the group with positive results compared to the group with poor results (11.7 days vs. 16.0 days, P = 0.012) [43].
Considering the hypothesis that an inappropriate antibody response could lead to poor clinical results in MERS-CoV infection, convalescent plasma therapy could help some pa- tients with severe disease. In fact, in serum collected from patients who died of MERS-CoV infection, no specific antibodies were detected in the serum collected on the 26th and 32nd days after infection [11]. Convalescent plasma therapy in patients with MERS-CoV infection could be performed experimentally with the patient’s consent (or a guardian’s consent, in cases in which the patient lacks the capacity to give consent) in patients with severe disease that is refractory to anti-viral therapy. Considering SARS-CoV treatment experiences to date, the appropriate timing for treating MERS-CoV infection with convalescent plasma therapy is likely to be within 2 weeks after the disease onset [4].
Key question 9. What about other adjuvant therapies?
The long-term use of high-dose steroids can cause adverse effects such as the development of opportunistic infections, avascular necrosis, secondary bacterial infections, and persistent viral replication, and since its efficacy is has not been clearly proven for SARS, its routine use in MERS patients should be avoided [4, 29, 44, 45]. However, in a state of severe shock requiring vasopressors, the administration of low-dose steroids may be considered [46]. In patients with severe SARS, high-dose steroids were often used when fever persisted or respiratory failure/radiological findings worsened, but it has been difficult to evaluate the efficacy [4, 46]. Some authors ex- pressed the opinion that the combined administration of steroids and antiviral drugs would be helpful in some special cases, such as those of acute respiratory distress syndrome caused by SARS-CoV infection [46, 47]. If high-dose steroids are to be used in patients with MERS-CoV infection, step- down dosing of methylprednisolone can be considered as has been used in SARS treatment [48].
Since there is a lack of evidence of the efficacy of intravenous immunoglobulin (IVIG), its routine use for the treatment of MERS is not recommended. Moreover, on rare occasions, IVIG can lead to acute renal failure or thrombosis. Although one study compared the effects of antiviral therapy and IVIG in patients with SARS, its result was inconclusive [4].
  • Convalescent plasma therapy could be administered experimentally for patients with severe MERS-CoV infection that is refractory to antiviral drugs (BIII).
  • The appropriate time for convalescent plasma therapy in patients with MERS-CoV infection is within 2 weeks after disease onset (BIII).
In one analysis, pneumonia was confirmed in 60% of 108 patients during the South Korean MERS-CoV infection epi- demic (unpublished data). Although the majority of these cases are thought to be viral pneumonia, further data are needed to show how many of these cases actually had concur- rent bacterial pneumonia. According to the previous report, there are cases of MERS accompanied by other viruses such as parainfluenza, rhinovirus, influenza virus, and herpes simplex virus. Some mechanically-ventilated patients were com- plicated by secondary bacterial pneumonia, which was caused by Klebsiella pneumoniae, Staphylococcus aureus, or Acinetobacter spp. [1]. Antibacterial treatment for the combined bacterial pneumonia should be determined according to the patient’s clinical condition.