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.