Introduction
2377 confirmed cases were in Macao by the end of 2022 due to the pandemic of COVID-19, accounting for 0.35% of local total population [
1]. High dense population in small area is the major feature of Macao demography, a total population of over 680,000 is counted on the area of 32.9 square kilometers (density of over 20,000 people per kilometer) [
2], which is extremely higher than that of Chinese mainland, easily bringing convenience for the COVID-19 virus effective dissemination [
3]. In addition, as a well-known tourist and harbor region, considerable short-term population mobility is typical here. According to the statistical yearbook of Macao in year 2022, apart from the over 80% of tourists from Chinese mainland, ones from Hongkong, Taiwan and abroad make up of the rest parts of visitors, and their average sojourn time is usually less than one week [
4]. Although Macao government restricted entry and exit at the border during the outbreak and kept strict records of the fever status of each person, the daily basic population motility and import/export trade continued to pose a challenge to the tracking and control of the epidemic [
5].
As a heavily mutated COVID-19 strain, Omicron variant had spread worldwide and led to severe acute respiratory syndrome for infected patients [
6]. Different from the epidemic strain in Chinese mainland, the main subvariant of Omicron raged locally was BA.5.1 in Macao, which originated directly from the evolutionary branch of Omicron BA.2. Owing to the higher transmission rate than other subvariants, BA.5.1 infected a large number of populations in a quite short time, inducing systemic and upper respiratory symptoms, such as fever, runny nose, sore throat, fatigue and so on [
7]. Thus, the wide employment of antiviral drugs sprung up according to the guidelines issued by National Health Commission of the People’s Republic of China and World Health Organization (WHO) [
8,
9]. However, there remains limitations on these drugs treatment. For example, the adverse events, such as diarrhea, nausea and dizziness were non-negligible [
10,
11]. In the safety research on Molnupiravir and Nirmatrelvir-Ritonavir, it showed that the above adverse reactions accounted for 1% to 2% of participates in the treatment group [
12]. Additionally, it was unknown whether these drugs still had ideal efficacy against the novel mutations in the future [
13].
The investigation suggested that 90% of Chinese patients infected by COVID-19 received Chinese medicines treatment [
14]. Recent study demonstrated Chinese medicines could decrease the proportion of severe case progressing by 55%, as well as the mortality rate of severe or critical patients by 49% [
15]. Among these medicines, early in 2020, Lianhua Qingwen (LHQW) capsule was designated as one of the commonly recommended drugs against COVID-19 by National Health Commission of the People’s Republic of China [
16]. In fact, there were series of Chinese proprietary medicines employed during pandemic, and most of them were the symptomatic treatment [
14]. For example, LHQW capsule was mainly applied for the symptoms of sore throat, fever, and muscle soreness, while another common medicine, Huoxiang Zhengqi (HXZQ) capsule was used to alleviate asthenia with gastrointestinal discomfort, such as vomiting and diarrhea.
Apart from the Chinese medicine treatment, due to the wide variability and the strong immune escape ability, the infected patients had a higher risk of re-infection [
17]. Hence, the vaccination is an essential option to reduce the corresponding health risks. Updated to the end of 2022, over one million times of vaccination were registered, and over six hundred thousand people were vaccinated [
1]. One report from the United States suggested that authorized mRNA vaccines were highly effective among working-age adults on preventing COVID-19 infection, which ameliorated the viral RNA load, fever symptoms and the duration of illness [
18]. Meanwhile, according to domestic research, inoculation of COVID-19 inactivated vaccine had a significant effect on attenuating the severity rate of elderly people over 60 years old [
19]. However, the exact statistical reports of Chinese proprietary medicine treatment and vaccination in Macao are still lacking. Therefore, we retrospected the situation of a group of subjects who were quarantined in local hotels due to COVID-19 infection from June to August 2022, and collected their baseline information, including Chinese proprietary medicine treatment and vaccination history. Besides, we also recorded their cycle threshold (Ct) values, as well as symptoms from the beginning of quarantine and followed up after they left the quarantine environment. Patients took Chinese proprietary medicine under the guidance of Chinese Medicine doctors, and all medication information was tracked and uploaded by qualified personnel. In the present study, we mainly discussed two kinds of common Chinese proprietary medicines, the effects of LHQW and HXZQ capsules on COVID-19 infected patients, along with the vaccination, in order to provide a factual and statistical basis for the future epidemic control and therapeutic policies in Macao.
Discussion
The present study, to our knowledge, for the first time deciphered the Chinese proprietary medicine and vaccination effects on indices related to COVID-19 and prognosis from the lens of statistical analysis in Macao. Here, we observed that over half of patients were female, of which, people engaged in service industry, such as tourism, gambling, retail, and catering, accounted for a high proportion. These findings were consistent with current reports in Hong Kong [
22] and Egypt [
23]. The proportion of service employee in quarantined patients may be derived from the local industrial structure, as the tertiary industry is the local pillar industry [
24]. In terms of personal habits, more of the quarantine subjects were those who never took physical exercises. This was quite reasonable as a spectrum of epidemiological studies had declared that regular physical activity was associated with a lower risk of COVID-19 infection [
25,
26], moreover, the cardiopulmonary benefits brought by exercise could reduce the possibility of being hospitalized due to COVID-19 [
27,
28]. Meanwhile, nutrients in the proper and healthy diet could effectively reduce oxidative stress and inflammation, which particularly vital during the COVID-19 crisis [
29]. Conversely, irritating diet, such as fried food, has been demonstrated to increase the systemic inflammation [
30] which is very disadvantageous to coronavirus struggle [
29,
31]. In our study, we found that nearly 60% of participants preferred irritating food (581, 59.5%), among which, fried food and strong coffee were favored by more patients than spicy food and strong tea (fried food preference, 44.8%; strong coffee, 52.0%, Additional file
1: Table S2).
In addition, at the beginning of quarantine, over half of the patients showed fever and cough. However, after quarantine and medication, these systemic and upper respiratory symptoms were evidently ameliorated. We also observed that middle dose of LHQW had the significant protective efficacy in promoting Ct value turning negative. In fact, research on LHQW, HXZQ and western medicine showed that the combination treatment of these drugs against COVID-19 had the potential of reducing the rate of progression to severe cases and improve patient prognosis [
32].Specifically, as the symptomatic treatment from Chinese proprietary medicine, LHQW has been recommended to treat mild or moderate COVID-19 by the Evidence-Based Medicine Chapter of the China International Exchange and Promotive Association for Medical and Health Care (CPAM) and the Chinese Research Hospital Association (CRHA) [
33,
34]. Two population studies on LHQW combined with regular treatment showed that patients with COVID-19 suffered less from fever, cough, and weakness [
35,
36], which were different from our findings. We suspected that it may result from the too-small sample size of patients who did not take LHQW capsules (894 patients with symptoms at the beginning, 7.6% of them not LHQW administrated) and we did not control the independent variable intentionally, making the causality result on drug using leading to symptoms alteration weak. However, the effect of LHQW on patients’ Ct value turning negative did help us find the potential of this drug on COVID-19 treatment, which aligned to the positive report of LHQW functioning on anti-virus replication of SARS-CoV-2 [
37]. Additionally, pertaining to the target prediction of LHQW, research displayed that the highly enriched targets were related to inflammation and oxidative stress response, such as the interleukin-17 (IL-17) pathway and the nuclear factor kappa-B (NF-κB) pathway [
38]. The component study on LHQW also showed that bioactive ingredients such as quercetin, naringenin, β-sitosterol, luteolin, and stigmasterol may target on regulating androgen receptor (AR), myeloperoxidase (MPO), epidermal growth factor receptor (EGFR), insulin and aryl hydrocarbon receptor (AHR) gene expression against COVID-19 [
39]. Taken together, our study confirmed the potential efficacy of the Chinese proprietary medicine through the self-control of patients, nevertheless, the possibility of self-recovery could not be ruled out in the present analysis, and therefore brought a challenging causality between drug treatment and Ct value alteration, which is the limitation in the study due to the lack of control group. Hence, the present study suggested the potential positive association between the Chinese proprietary medication and COVID-19 related index, but not the direct causal relationship of these two variables.
Vaccination has been the focal point since the pandemic onset. Most of the authorized vaccine performed well in the prevention of severe cases of COVID-19 [
40]. In our study, patients with certain characteristics, especially engaged in healthcare and over 60 years old, were prone to receive vaccination. Being at high risk of exposure to virus [
41], 28.99% of medical staff was reported to be infected in the very first COVID-19 pandemic of Zhongnan Hospital Affiliated to Wuhan University. Meanwhile, according to the related report from WHO, by April 2020, a total of 22,703 COVID-19 cases have been documented over 52 countries worldwide. However, under the heavy burden of epidemic [
42], there still remained high level of vaccine hesitancy among healthcare staff in some countries [
43,
44], on the contrary, our study found the inclination of vaccination in medical staff, which may be owing to good publicity and authentic information on the role of inoculation [
43]. Moreover, during the Omicron wave in Shanghai since March 2022, older age has been demonstrated as the risk factor of severe or critical case, and among which, fully vaccinated shortened the viral shedding time, thus evidently protect patients from severe infections [
21], meanwhile, multiple times of vaccination were able to further prevent symptomatic diseases, and might play a protective role in the resistance of future variants [
45]. By far, three years on from the administration of the first experimental COVID-19 vaccine doses to human in March 2020, and 18 vaccines have been designated for employment [
40]. There are several main types of vaccine platforms, including mRNA, inactivated virus, viral vector and protein subunit [
46‐
49]. In the present study, patients inoculated with inactivated virus vaccine (CNBG) and mRNA vaccine accounted for the highest proportion. We also found that two times of CNBG, coupled with one time of mRNA exhibited a better efficiency in reducing Ct positive rate during 20 days of quarantine. In fact, this kind of mixed inoculation is now very common all over the world. Study suggested the population vaccinated with Oxford-AstraZeneca (viral vector vaccine) the first time and Pfizer-BioNTech (mRNA vaccine) the second time triggered 11.5 folds in higher anti-spike response of immunoglobulin G (IgG) and IgA than those received both times of AstraZeneca [
50]. Similar reports from Britain [
51] and Spain [
52] have affirmed the value of mixed inoculation.
With the continuous liberalization of prevention policy on COVID-19, the normalization of the pandemic has been infiltrated into various areas in China. As a result, the prognosis of infection has become a great concern in the whole society. Adverse prognostic events were often related to severe cases [
53]. Recent evidence revealed that cardiovascular involvement and inflammation were highly associated with poor prognosis and mortality [
54‐
58]. In addition, neurological symptoms, such as headache, fatigue, and loss of olfactory sensation, as well as gastrointestinal reactions, were common adverse prognostic events [
59,
60]. In the present study, we found that symptoms after quarantine were positively associated with prognosis, rather than initial symptoms. Intriguingly, patients’ subjective evaluation about medication displayed negative correlation with prognosis symptoms, meaning more positive self-evaluation, less prognostic symptoms, which was similar to one health quality study on patients with intensive care unit admission. This study illustrated that health perception scores at 2 months after admission was positively associated with that at 12 months after admission [
61].
As to the limitation of the present study, there were many covariates that could have influenced the progression of COVID-19 as well as medication or vaccination which were unmeasured here, such as the underlying disease of patients, especially cardiopulmonary involvement, the corresponding indices like clinical lung function tests, chest Ct scanning were lack [
62,
63]. Patients with underlying medical conditions, especially those with longstanding infections, chronic metabolism disorder, or cancer, are more likely to suffer from more severe symptoms, thus leading to ineffective medication, or longer medicating duration and higher drug doses. Other covariates like education and economic levels, are also engaged in obscuring the association of drug administration and COVID-19 progression [
64], as patients with higher education and economic level may more acknowledge the significance of instant quarantine and positive medicating, and hence, more easily being enrolled in our survey and resulting in the occurrence of bias. We admitted the weakness inherited in retrospective study, including the difficulty of re-collecting specific information, such as the previously unmeasured confounders, like the prevalence of underlying diseases and economic income levels. Most notably, due to the lack of human control of the independent variable, this type of study cannot directly determine the causal relationship between the independent variable and the dependent variable but can only provide clues to correlations. As for the limitation of self-control, we realize that it may introduce bias in the selection of the study population. For example, the patients included in the study were mainly Macao native, who, due to the high population density and mobility of people in the area, may have a higher probability of being exposed to viral strains, which may affect the accuracy of the conclusions we draw, and therefore the conclusions we obtain are cautious.
Taken together, the present study manifested that the mixed vaccination provided the possibility to accelerate the discharge of COVID-19 patients, and the treatment of Chinese proprietary medicine brought new opportunities for remission of the disease, which implied that mixed inoculation and necessary medication remain pivotal tools for prevention and palliation during epidemic, and importantly, whether current strains will mutate and local epidemics will change remains to be seen, hence, more effective vaccines and drugs are still needed, and more rigorous, large-sample, controlled-variable, population-based prospective studies of these prophylactic and therapeutic approaches should be conducted [
65,
66]. Moreover, considering the difference of demographic characteristics of Macao, compared with Chinese mainland, such as the higher population density and mobility, site-specific prevention and control strategies should also be adapted over time as this novel evidence emerges in the future.
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