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38 Gonda et al. | Journal of Clinical and Translational Research 2024; 10(1): 33-51
their D-dimer and BNP levels surpassed the standard values at Indeed, vaccines can induce secretory IgA antibodies and
the time of admission, requiring anticoagulants for thrombosis are effective. However, there is still an urgent need for antiviral
prevention. It has been reported that thrombosis can be induced drugs with potent activity to defend against the emerging
in patients with COVD-19. However, the current findings show SARS-CoV-2 variants for which existing vaccines may be less
that fibrinogen and FDP levels remain high after infection, but effective. Certainly, early treatment with molnupiravir reduced
they became lower than before infection, although not within the the risk of hospitalization or death in unvaccinated adults at risk
standard values, after 14 days of molnupiravir administration. for COVID-19 (Funded by Merck Sharp and Dohme; MOVe-
Furthermore, concomitant administration of CAM improved OUT ClinicalTrials.gov number, NCT04575597) [37]. As an
coagulation factor elevation and intravascular coagulation, and early treatment for patients with COVID-19, molnupiravir
venous thromboembolism and pulmonary thromboembolism administration is therapeutically effective, but there is the
were not observed in the target patients. This might be the reason potential for co-infection or potentially life-threatening recurrence
why no patients from the current cohort died of COVID-19 and in patients after treatment. The need for highly synergistic agent
were successfully discharged from the hospital. integrating molnupiravir is also becoming increasingly important.
Based on our results, IgA and sIL2R are potential predictive factors. To control for confounding factors, we investigated the number
Uninfected individuals had significantly higher IgA levels and lower of vaccinations in rehabilitation patients who were uninfected
sIL2R levels than infected individuals. This can be one of the reasons despite being quarantined with other COVID-19 patients. As
why there were no new infection cases even after 14 days although the a result, uninfected patients received fewer vaccinations than
rehabilitation patients had had close contact with COVID-19-positive those with COVID-19. Therefore, in this study, vaccination was
roommates in a closed ward (Figure 3). In addition, molnupiravir excluded as a confounding factor, and blood biomarkers were
administration sustained the effect of IgM even on day 14, but analyzed for their capacity, without the influence of vaccination,
molnupiravir plus CAM administration resulted in higher IgG levels to prevent COVID-19 deterioration.
on day 14. Although there was no significant difference, CAM might Our results show that IgA levels increased when molnupiravir
maintain humoral immunity even after 10 days of administration. was co-administered with CAM. CAM effects are not limited
SARS-CoV-2, the virus that causes COVID-19, infects cells on to only anti-inflammatory [38]. Molnupiravir plus CAM may
mucosal surfaces. Serum-neutralizing antibody responses are variable, alter and improve the clinical course of patients with COVID-19
and neutralizing antibodies appear to be generally low in patients with infection, at least through an indirect mechanism that relies on
COVID-19. Potent IgG antibodies neutralize the virus, but secretory several variable anti-inflammatory and/or immunomodulatory
antibody responses such as IgA, which can affect initial viral spread effects in addition to its well-known antibacterial activity.
and transmissibility across mucosa, may be of particular value for Compared to uninfected patients, IgA may be a predictive factor
defense against SARS-CoV-2 [33]. This result is consistent with the for the improvement of COVID-19 infection, and sIL2R may be a
effect of molnupiravir plus CAM administration, i.e., increase in IgA predictive factor for the prevention of secondary infection.
and decrease in sIL2R (Figure 3). There are several limitations in this study. First, the present work
Molnupiravir (MK-4482, EIDD-2801) is a promising broad- is essentially an exploratory retrospective study. There is no previous
spectrum experimental antiviral agent developed by Merck & Co. clinical evidence evaluating the therapeutic efficacy of molnupiravir
It was originally developed to treat influenza infections because it and CAM against COVID-19, and the sample size was based on the
exerts antiviral activity through RNA-dependent RNA polymerase to feasible number of consented patients who were hospitalized. Second,
induce huge numbers of copy errors. Molnupiravir has demonstrated without knowing DDI, many antivirals and anti-inflammatory drugs
potent in vitro antiviral activity with low cytotoxicity and high have been approved to treat COVID-19 patients, but potential DDIs
resistance barrier against positive-sense RNA viruses, including that can enhance the safety and efficacy of molnupiravir and CAM
SARS-CoV-2 [34]. When the pandemic began, molnupiravir was in remain elusive [39]. Third, the target sample size of this study is
pre-clinical development for the treatment of seasonal influenza but small. Fourth, uninfected patients who could not be transferred
has evolved into a potential agent for the prevention and treatment were managed in a closed ward and inspection was performed on
of COVID-19 [35]. Influenza infections occur year-round on the both the infected and uninfected individuals, but there might be a
main island, and we have reported that the non-infected individuals bias in terms of examination date. Furthermore, bias from patients
had higher IgA levels than the influenza-infected individuals [36]. and attending physicians cannot be completely avoided. Fifth,
IgA levels in nasal discharge and alveolar lavage fluid, which were this study was conducted only at medical institutions on the main
markedly decreased when anti-influenza drugs were administered island of Okinawa and included only Japanese patients undergoing
alone, significantly recovered to high levels when the drug was rehabilitation treatment. Sixth, macrolides increase the risk of some
administered in combination with CAM, a macrolide with immuno- cardiac side effects, especially in the elderly. These constraints have
modulating effects. In addition, IgA production was significantly limited generalization of the current set of findings.
enhanced by nearly 10-fold in patients who were co-administered 5. Conclusion
with CAM, although it was not observed after the administration of
anti-influenza drugs alone [9]. CAM combined administration may D-dimer, IgA, and sIL2R are potential predictive factors of
increase IgA, which is low in the human body, by encouraging its COVID-19 severity in patients with mild-to-moderate symptoms
production, as observed in this study. receiving molnupiravir plus CAM.
DOI: https://doi.org/10.36922/jctr.00075