Takayama et al. reported a case of pneumonia treated by Kampo medicine gokoto (case 17). A 52-year-old male patient presented with cough, sputum, and joint pain. Chest radiography revealed interstitial shadow in the right lung that was diagnosed as moderate stage I COVID-19. After administration of gokoto, a Kampo medicine for cough and sputum, for symptom relief, cough and sputum improved within 4 days. Takayama et al. also reported 5 cases (cases 18-22) of COVID-19-related olfactory disorder treated by kakkontokasenkyushin'i. The symptoms improved within 3-5 days after administration of kakkontokasenkyushin'i. Kakkontokasenkyushin'i can be used for treating nasal congestion, rhinitis, and inflammation in the nasal mucosa. Olfactory disorder in COVID-19 has been reported to be associated with inflammation and congestion, especially in the olfactory bulb and olfactory cleft. They concluded that kakkontokasenkyushin'i may be considered as a treatment alternative for the olfactory disorder related to COVID-19.
On the other hand, some reports have suggested the clinical efficacy of Chinese medicine in COVID-19. Ke et al. have reported the efficacy of Lianhua Qingwen (LH) capsules in patients with COVID-19, using a multi-center, prospective, randomized controlled trial. Certain LH components overlap in the Kampo medicine maoto or maotokasekko that were administered to cases 1-4, 6-11, and 14-22, as shown in Tables 1, 2. The efficacy of LH was compared between conventional treatment alone or in combination with LH for 14 days. The rate of recovery of symptoms including fever, fatigue, and cough was significantly shortened by LH administration. Zheng et al. reported that LH treatment modulates the inflammatory process, exerts antiviral effects and repairs lung injury in the network pharmacology analysis of the therapeutic mechanisms of LH in COVID-19.
Furthermore, a national retrospective registry study reported by Lihua et al. suggested that QFPDT was associated with a substantially lower risk of in-hospital mortality. Modified QFPDT in Japan was administered to cases 10, 11, 15, and 16, as shown in Tables 1, 2. Although these reports have revealed the efficacy of traditional medicine, further clinical trials are required to evaluate the efficacy of Kampo medicine on COVID-19-related symptoms and conditions.
The JSOM has prepared a research project for clinical trials of Kampo medicine in patients with COVID-19, some of which are currently in progress. Table 3 shows the list of the clinical studies being planned or conducted in the JSOM projects. In particular, studies one through three are referred to as an Integrative Management in Japan for Epidemic Disease (IMJEDI).
Study 1 is a multi-centered, randomized trial to test our hypothesis that the Kampo medicine, hochuekkito, has a preventive effect on the symptoms of COVID-19 among healthy hospital workers. While we hope for an effective and widely available vaccine, the efficacy of the current vaccines has not been shown in a large number of patients. Furthermore, the efficacy of the vaccines may be reduced if SARS-CoV-2 persistently and consistently undergoes mutations. The possible mechanisms of the preventive effect of hochuekkito (bu Zhong yi qi tang) against COVID-19 have reported by Takayama et al.. Thus, clinical trials are being conducted to assess the efficacy of Kampo medicine for preventing COVID-19. Medical staff, overextended from the increase in critical patient care and the other circumstances involved with the COVID-19 pandemic, are thought to have decreased immunity along with physical and mental health issues. Furthermore, they are at an increased risk of infection when providing medical care. Therefore, we considered it necessary to verify the effectiveness of Kampo medicine in preventing illness among staff members who continue to provide medical care despite these challenges.
Study 2 is a multi-centered, retrospective, observational study to investigate the efficacy of the actual treatment (conventional and Kampo medicine) in patients with mild-to-moderate or even suspected COVID-19. Several clinical trials on antiviral drugs are currently in progress; however, evidence on its efficacy remains limited. Kampo medicine has a long history of repeated use in viral epidemics and was also used during the Spanish influenza pandemic, approximately 100 years ago. Several cases of COVID-19 treated with Kampo medicine have already been reported. The next step in establishing Kampo medicine as a treatment strategy for COVID-19 is organizing a clinical study with a large number of cases. In Japan, many COVID-19 patients are treated with a combination of Kampo medicine and Western medicine, and an observational study that would collect data from a multi-center setting would be ideal.
Study 3 is a multi-centered, randomized trial to test our hypothesis that additional administration of Kampo medicines kakkonto and shosaikotokakikyosekko is more effective in relieving symptoms and preventing the onset of severe infection in mild-to-moderate COVID-19 patients compared to those treated with conventional treatment alone. The symptoms and signs associated with acute infectious diseases were categorized into six-stage patterns in the original concept of Kampo medicine described in the Shanhanlun, which is a traditional Asian medical textbook of infectious diseases written by Zhan Zhongjing. The Shanhanlun explains that infectious diseases progress through six-stage patterns: early, middle, and late yang patterns and early, middle, and late yin patterns. Characteristic symptoms are chill and fever in the early yang pattern, alternating chill and fever with respiratory and intestinal symptoms in the middle yang pattern, and marked fever with thirst in the late yang pattern. The symptoms also include coldness with intestinal symptoms in the early yin pattern, coldness with marked fatigue in the middle yang pattern, and coldness with circulation failure with disturbance of consciousness in the late yang pattern. To study the efficacy and safety of Kampo medicines for COVID-19 patients, it is necessary to focus on a certain type of Kampo medicine. COVID-19 symptoms include chills, fever, muscle pain, joint pain, nasal congestion and discharge, sore throat, a cough producing sputum, loss of appetite, diarrhea, impaired smell and taste, and malaise, which progress from the early yang pattern to the middle and late yang patterns described in Shanhanlun. The type of Kampo formula depends on the stage of clinical manifestation: mao formula in the early yang pattern, saiko formula in the middle yang pattern, and sekko in the late yang pattern. A combination of mao formula, saiko formula, and sekko is an ideal choice for treating diseases such as COVID-19, which transition from the early to the middle and late yang patterns in the Kampo concept. Thus, these combinations were included in saikatsugekito, which was used for the Spanish flu, and case series have already reported the use of saikatsugekito for COVID-19. Saikatsugekitois applied in combination with kakkonto and shosaikotokakikyosekko under the permissions of the national health insurance. The possible mechanisms of saikatsugekito against SARS-CoV-2 and COVID-19 have been reported by Arita et al..
While study 4 is a multi-centered, prospective, observational study to investigate the efficacy of Kampo medicines in patients with COVID-19-related sequelae. After the stabilization of COVID-19 patients, continued support for recovery and management of sequelae is needed. Future research interests include epidemiological investigations of sequelae and case series that summarize the experience of patients who used Kampo medicine for treatment.