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.