4 Discussion
In Japan, COVID-19 was authorized as a designated infectious disease.
After infection is confirmed, reporting and admission/isolation are
required. In Aomori Prefecture (population: 1,250,000 persons), where
our hospital is located, 35 patients with SARS-CoV-2 virus infection
have been confirmed. At our hospital, as a medical institution
designated for infectious diseases, 14 patients were
hospitalized/treated. Criteria for discharge at that time included the
absence of fever (37.5°C or higher), confirmation of a negative reaction
on PCR testing ≥24 hours after the confirmation of respiratory symptom
relief, and additional confirmation of a negative reaction after ≥24
hours.[8] In this study, C/T was administered to 4 patients admitted
to our hospital; symptoms reduced in all patients during the process of
virus-disappearance confirmation using PCR testing according to the
criteria for discharge. In Cases 1 to 3, negative reactions on two
consecutive sessions were not obtained through 8, 3, and 4 sessions of
PCR testing, respectively. In Cases 1 and 3, negative reactions were
obtained on two consecutive sessions of PCR testing after the start of
C/T administration. In Case 4, negative reactions were obtained on the
2nd and 3rd sessions of PCR testing
after the start of C/T administration, leading to discharge. On the
other hand, in Case 2, positive reactions were detected on two
consecutive sessions of PCR testing after the start of C/T
administration and the dose of C/T was increased 2-fold. Subsequently,
negative reactions were obtained on two consecutive sessions of PCR
testing, leading to discharge. The mean interval from the start of C/T
administration until the criteria for discharge were met was 9.8 days,
being shorter than the pre-administration course. Concerning SARS-CoV-2
virus infection, it was reported that some patients required a long
period until negative reactions on PCR testing were obtained. At Fujita
Health University Okazaki Medical Center, 90 pathogen carriers without
symptoms were investigated, and the median interval until negative
reactions on PCR testing were obtained was 9 days, whereas ≥15 days were
required in 11 (12%) of the 90 subjects.[9] According to a report
from China, when comparing the results between patients with and without
symptoms (n=37 each), the antibody titer was significantly lower in the
latter, and the median period during which the virus was detected in the
former and latter was 14 and 19 (maximum: 45 days) days, respectively,
being significantly different.[10] In the 4 patients treated at our
hospital, the antibody test was not conducted, but all patients had a
mild status and negative reactions on two consecutive sessions of PCR
testing were not confirmed before C/T administration, especially in
those aged ≥90 years; antibody production may have been low. C/T was
reported to stimulate influenza antibody production in elderly persons
with malnutrition. This suggests that C/T also improved the antibody
production capacity in patients with SARS-CoV-2 virus infection, aiding
in virus elimination. If C/T had not been administered, a longer period
may have been required until obtaining negative reactions. This was
deduced from the results in a small number of patients. In the future, a
prospective study involving a larger number of patients must be
conducted.
The course of Case 2 suggests that double-dose administration played a
role in the negative reactions; therefore, an initial dose of 2
packs/day may be appropriate. A sufficient dose should be examined in
the future, but a previous study suggested the safety of administration
at 3 packs/day with no adverse reactions.[11]
Furthermore, C/T reduces invasiveness. Several studies reported that C/T
reduced inflammation after high-intensity exercise loading in athletes,
inhibiting a reduction in NK activity and improving the
condition.[12-14] A study regarding perioperative C/T administration
to patients who underwent surgery for gastric cancer noted early
recovery from fever, inhibition of increased energy consumption, early
normalization of IL-6/CRP, and early recovery from a reduction in the
lymphocyte count ratio.[15] An experiment using a mouse small
intestine manipulation model also yielded similar results, in addition
to inhibition of a reduction in the small intestinal mucosa glutathione
level and early behavioral recovery.[16] Furthermore, experiments
using rats demonstrated that C/T administration reduced the mortality
rates after reperfusion following ischemia, in an
intraperitoneally-LPS-treated peritonitis model and after systemic
irradiation.[17-19] Excessive secretion of inflammatory cytokines
(cytokine storm), including IL-6, may be involved in severe COVID-19;
C/T administration may also play a role in severe-status prevention and
early reduction of inflammation.[20] Therefore, the use of C/T
earlier than the timing of administration in our patients, i.e.,
immediately after infection, should be examined.
Recently N-Acethylcysteine(NAC), a precursor of glutathion, has been
suggested to prevent COVID-19 associated cytokine storm and acute
respiratory distress syndrome by inhibition of IL-6, IL-8, and
TNF-α.[21] In addition, NAC blocks angiotensin-converting enzyme
2(ACE2), which is a receptor of SARS-CoV-2 spike protein.[22] This
may attenuate penetration of SARS-CoV-2 into cells. The authors
speculated that NAC may play an adjuvant role in the treatment of severe
COVID-19 cases and in the control of its lethal complication, as well as
pulmonary and cardiovascular adverse events. Thus, C/T may be
alternative of NAC.
In addition, C/T was reported to prevent the common cold; 173 healthy
adults were divided into C/T- and placebo-treated groups, and 5-week
observation was conducted.[23] In the placebo-treated group, 23
(27.1%) of 85 subjects had the common cold, whereas 10 (11.4%) of 88
subjects in the C/T-treated group had it, demonstrating a significant
difference (p=0.011). And the cumulative duration of disease was 59 days
in the placebo-treated group and 18 days in the C/T-treated group,
demonstrating a significant difference (p=0.002). These results suggest
the preventive effects of C/T administration on COVID-19. If a vaccine
is developed, C/T administration at the time of vaccination may
stimulate antibody production, furthering its preventive effects.
To confirm the effects of C/T on COVID-19 patients, prospective clinical
studies are needed. When taking C/T for prevention, it is a food, being
more available than drugs. Its total volume is 1.5 g, being small;
therefore, adherence is favorable, which will be advantageous.