Study design and population.
Two hundred eighty-six patients with previously confirmed SARS-CoV-2 infection by PCR or antigen testing who were diagnosed with long COVID at our clinic between May 2021 and December 2021 were potentially eligible for inclusion in this study.
Clinical data, such as age, sex, BMI, and COVID-19 onset, PCR-positive date, consultation day and laboratory data, including AST and ALT levels, of the selected patients were collected and summarized in our database designed for this study. In addition, medical histories of diabetes mellitus, hypertension, hyperlipidaemia, migraine, bronchial asthma, sleep apnoea syndrome, and other conditions, as well as a history of smoking were similarly recorded based on self-reported information. For the evaluation of therapeutic efficacy, 29 censored patients were excluded from the analysis. A summary of the data collected from the study patients is presented in Table 1. The study protocol was approved by the ethics committee of UnMed Clinic Motomachi, Kanagawa, Japan (authorization number: UM22-01). The review board approved and waived the need for written informed consent from the participants due to the retrospective, noninterventional nature of this study. We have read the Declaration of Helsinki and have followed the recommended guidelines in this study.
Therapeutic interventions for long COVID-related symptoms.
Because herbaceous medications are generally agents that easily ameliorate a variety of systemic symptoms, including dysautonomia, they are actively administered to most patients, depending on the manifestations.
Therapeutic options for long COVID-related symptoms in our clinic are listed in Table 6. As previously reported, hochuekkito, juzentaihoto and ninjinyoeito were administered for fatigue, and kakkonto and/or acetaminophen were administered for fever, headache/joint pain, along with some other herbal drugs 36. For smell disorder, tokishakuyakusan was prescribed according to the clinical and basic evidence of its effectiveness for olfactory dysfunction 37,38. In addition, rikkunshito, bukuryoingohangekobokuto and hangeshashinto with a proton pump inhibitor, as an acid suppressant, and/or a dopamine-2 receptor antagonist were appropriately administered for digestive manifestations, such as nausea, stomachache, abdominal fullness, diarrhoea, constipation 39,40. Based on the good results of a recent clinical trial in the UK, inhaled budesonide was actively used for pulmonary symptoms including cough, sore throat, sputum, dyspnoea, chest pain with kikyoto, carbocysteine and ambroxol hydrochloride 41. For sleep disturbance, eszopiclone and/or lemborexant, which are independent sleep aids, were palliatively introduced as needed. As a Japanese study previously successfully managed alopecia using saikokaryukotsuboreito, this herbal drug was also selected to treat alopecia in the present study 42. Last, betahistine mesilate and ryokeijyutsukanto were used to relieve dizziness symptom. We were unable to provide appropriate care for brain fog or dysgeusia.
Primary outcomes were the clinical course with a futuristic overview, evaluation of the effectiveness of treatment for each manifestation and risk factors affecting the recovery period of long COVID. Fatigue, smell disturbance, fever, headache/arthralgia, respiratory manifestations, digestive symptoms, circulatory disturbance, sleep disorder, hair loss, brain fog, and dizziness were separately assessed as distinct manifestations of long COVID in the analysis. For the validation of the recovery period, the clinical courses were divided into 4 groups: good (within a month or less), moderate (within two months), slow (within three months) and resistance (3 months or more). Clinical outcomes were measured at more than 3 months of follow-up, depending on the condition. The secondary outcome was the relationship between serum transaminase levels and fatigue determined by measuring blood samples from 164 selected patients.
Demographic and clinical data were extracted from electronic medical records. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). The chi-square test was used to compare distributions of categorical variables. Significant levels were set at p < 0.05. In the comparison of improvement of complaints after treatment, Bonferroni adjustment was conducted for each test separately to consider the number of significance tests undertaken.