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34 Gonda et al. | Journal of Clinical and Translational Research 2024; 10(1): 33-51
SARS-CoV-2 PCR test, among patients with mild-to-moderate 2. Methods
symptoms before respiration failure takes place. At the height of
the COVID-19 pandemic, the hospitalization rates for patients 2.1. Study design
with severe infections were high; naturally, the mild-to-moderate A total of 156 patients who were hospitalized in a rehabilitation
cases were asked to self-quarantine at home. Therefore, an ward from May 2022 to July 2022 were recruited in this study. Of
approach to treating COVID-19 patients with mild-to-moderate the 156 patients, 4 severe COVID-19 patients were transferred
symptoms is essential. to other hospitals where endotracheal intubation and ventilator
Molnupiravir has been proven to be a well-tolerated, direct- treatment were available. We administered molnupiravir (800 mg
acting oral antiviral agent that prevents symptom progression twice daily for 5 days) to 124 mild-to-moderate COVID-19 patients
in patients with mild-to-moderate COVID-19 [1,2]. Given the (Supplementary Data 1). Chest X-ray, computed tomography,
context of rapid spread of infection among hospitalized patients and bacteriological examination were performed to detect the
in isolation and closed wards, oral molnupiravir serves as an ideal occurrence of secondary infection. A respiratory physician
medication due to the ease of administration [3,4]. However, diagnosed 87 secondary infections and administered antibiotics
even if molnupiravir is administered in mild-to-moderate based on the results of bacterial sensitivity test. Fifty four of the
cases, the possibility of deterioration cannot be avoided if a 124 patients had mycoplasma infection, Gram-positive coccal
secondary infection occurs. In this study, we selected patients infection, pneumococcal infection, or Haemophilus influenza
with macrolide-susceptible bacteria among the patients with infection and received CAM (400 mg twice daily for 3 days). Of
secondary infections. the 124 patients, 33 received antibiotics other than CAM. Twenty
Macrolide (clarithromycin or azithromycin) antibiotics were eight of the 156 patients were negative for COVID-19 despite
incorporated in the treatment regimen in the early stages of the being quarantined with other COVID-19-positive patients and
COVID-19 pandemic, especially considering that they may have were not treated with any drugs for COVID-19 (Figure 1).
anti-inflammatory effects. Macrolides have been extensively
researched as broad adjunctive therapy for COVID-19 due to its 2.2. Laboratory examinations
immunostimulant abilities [5]. Adding clarithromycin (CAM) Nucleic acid detection tests and antigen tests were performed
or azithromycin to the therapeutic protocols for COVID-19 in accordance with the “Guidelines for Pathogen Testing of Novel
could be beneficial for early control of fever and early PCR- Coronavirus Infectious Disease (COVID-19) March 17, 2022,
negative conversion in mild COVID-19 cases [6]. It has been Version 5.1” published by the Ministry of Health, Labor and
reported the first COVID-19-positive patient who recovered Welfare of Japan [12]. Real-time RT-PCR was performed to detect
from the symptoms after the use of chloroquine and CAM SARS-CoV-2 nucleic acids using GeneFinder™ COVID-19 PLUS
was reported in Colombia [7]. CAM has immunomodulatory RealAmp Kit and ELITe InGenius instrument. Antigen qualitative
®
properties superior to those of azithromycin [8] and enhances tests were conducted using the SARS CoV-2 Rapid Antigen Test
antiviral secretory-IgA production and neutralizing activities Nasal kit (SD BIOSENSOR, Roche; REF: 9901-NCOV-03G;
through the induction of IgA class switching recombination [9]. LOT: QCO 3811951). During hospitalization, blood samples
Interleukin (IL)-6 and IL-2 trigger cytokine release syndrome were collected on the 5 day and 14 day from the start of oral
th
th
observed in severe cases of COVID19. CAM significantly molnupiravir administration at the time of infection according to
inhibited the production of IL-6 by dendritic cells and the doctor’s instruction. Blood biomarkers were assessed using an
significantly decreased IL-2 productions [10]. The results of automated hematology analyzer. Uninfected patients were assumed
The ACHIEVE Open-Label Single-Arm Trial demonstrated to be infected when their roommates started taking molnupiravir,
that early CAM treatment leads to clinical improvement in and their blood was collected for medical assessment, considering
patients with moderate COVID-19 [11]. the possibility of infection from infected patients in the same
At present, there is no evidence regarding therapeutic room. To investigate predictive factors of molnupiravir plus
effect of molnupiravir combined with CAM on blood CAM combination therapy in COVID-19 patients, the following
biomarkers in COVID-19 patients. Thus, the aim of this biomarkers were measured: lactate dehydrogenase (LDH) [13],
study is to investigate blood biomarkers in patients with total cholesterol, triglyceride [14], uric acid [15], creatinine [16],
mild-to-moderate COVID-19, compounded by secondary potassium [17], white blood cells (WBC), hemoglobin (Hb) [18],
infection with macrolide-sensitive bacteria, who were treated platelet (PLT) [13], C-reactive protein (CRP) [19], neutrophils,
with molnupiravir followed by administration of CAM. At lymphocytes [20], neutrophil–lymphocyte ratio (NLR) [21],
the same time, blood biomarkers were also evaluated for fibrinogen [22], fibrin degradation product (FDP) [23],
COVID-19-negative patients, who were used as controls D-dimer [24], prothrombin time-international normalized ratio
in this study despite being quarantined together with other (PT-INR) [25], creatinine phosphokinase (CPK) [26], brain
COVID-19 patients. In addition, we compared the degree natriuretic peptide (BNP) [27], IgG [28], IgA [29], IgM [30], and
of sequelae 12 months after the COVID-19 treatment with soluble IL-2 receptor (sIL2R) [31]. Cutoff values are listed in
molnupiravir plus CAM or molnupiravir alone. Supplementary Data 2 and 3.

DOI: https://doi.org/10.36922/jctr.00075