Discussions
To the best of our knowledge, this is the first report indicating that combination antiviral therapy consisting of lopinavir/ritonavir and favipiravir might prove beneficial for patients with COVID-19. These agents relieved life-threatening lung injury in Case 1, 3 and in the other case provided early negative RT-PCR for SARS-CoV-2 results from a nasal swab specimen on day 7 after the initiation of antiviral therapy.
Although approximately 80% of COVID-19 patients have been reported to have mild disease1,2, the mortality rate of COVID-19 has so far been reported to range from 1.4% to 15%1-3; and the case-fatality rate of patients classified as critical, such as Case 1, has been reported to be 49.0%1. While the causes of death from these reports2,3 were unclear, the acute respiratory distress syndrome might have been related to disease severity. The histopathological features of COVID-19–induced lung injury resemble those of the Severe Acute Respiratory Syndrome (SARS) and Middle Eastern Respiratory Syndrome4. A higher incidence of physician-diagnosed pneumonia was observed in patients with severe disease than in those with less severe disease, and 3.4% of all COVID-19 patients progressed to acute respiratory distress syndrome afterward2. Thus, the establishment of predictive markers for the degree of disease severity, followed by the appropriate treatment for severely ill patients, are urgent priorities. We think that this report might be valuable with regard to these issues (predictive markers and life-saving treatment).
The protease inhibitor lopinavir/ritonavir, which is approved for the treatment of human immunodeficiency virus-1 infection, was reported to be effective for 5 patients with COVID-19 in Singapore. They all were cured5. However, a randomized controlled trial to verify whether severe COVID-19 patients get clinical improvement to receive lopinavir/ritonavir in China reported no benefit6. Favipiravir, which is being stockpiled for use as a countermeasure for novel influenza, functions as a chain terminator at the site of the incorporation of viral RNA and reduces the viral load. The agent resembles a nucleoside analogue, functioning as a purine homologue, and therefore inhibits viral RNA synthesis7. It has broad spectrum activity against RNA viruses such as the Ebola virus, Lassa virus, rabies, and the virus that causes severe fever with thrombocytopenia syndrome7,8. An open-label nonrandomized control study reported COVID-19 patients treated by favipiravir showed significantly higher improvement in chest imaging and faster viral clearance than those treated by lopinabir/ritonavir9.
Commonly reported adverse reactions to lopinavir/ritonavir have included diarrhea, nausea, vomiting, hypertriglyceridemia, and hypercholesterolemia10. The adverse reactions to favipiravir include teratogenicity, increased blood levels of uric acid, diarrhea, and neutropenia. Hypertriglyceridemia and hypercholesterolemia were observed in Case 1. Although there are no safety data on the simultaneous use of lopinavir/ritonavir plus favipiravir, based on the kinetic mechanisms of the agents, the drug-drug interactions appear to be minimal10. Immediately after termination of favipiravir medication in Case 3, transient febrile reaction was observed. Although it is not easy to distinguish infectious-fever from iatrogenic drug fever, it makes us suggest the importance to remember the chemical fever even in antiviral therapy.
The progression of COVID-19 seems to be associated with a ‘cytokine storm’, which is also true of SARS and Middle Eastern Respiratory Syndrome. Elevated ferritin levels and lymphocytopenia seemed to be an accurate reflection of the severity of COVID-19 in our 3 patients, based on their clinical courses (Fig. 1). COVID-19 patients who needed admission to intensive care unit had less lymphocyte counts than counterpart3. Our findings suggest that IL-6 and TNF-α which were reflected by the serum CRP and ferritin level, has a central role in the progression of COVID-19, as opposed to IFN-γ(Table 1). Chaolin H et al . reported that a patient with severe COVID-19 had high concentrations of GCSF, IP10, MCP1, MIP1A and TNF-α, which led to activation of T-helper 1 cells3. On the other hand, they also reported increased secretion of T-helper 2 cytokines3. The ferritin, CRP and β2-microglobulin levels decreased in Case 1 and 3 after the administration of favipiravir. These findings suggest that favipiravir not only reduces the levels of inflammatory cytokines in vitro, but might also reduce the levels in vivo7. Furthermore, earlier therapy onset may have needed to avoid lung sequela now that chest CT findings at post-treatment suggests remaining pulmonary fibrosis(Fig. 2). According to the radiological study11,12, COVID-19 must leave pulmonary scars like SARS13,14.
This case series has limitations. First, we described only 3 patients. Second, they may have improved without any antiviral therapy. Third, the unavoidable delay to the diagnosis of COVID-19 impedes the ability to determine when we should initiate antiviral therapy.
In conclusion, the combination therapy of lopinavir/ritonavir plus favipiravir might be a treatment option for patients with COVID-19. Serum ferritin levels and lymphocytopenia are promising markers for disease severity and disease progression that are commonly available in general clinical practice.