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      The use of Traditional Chinese Medicines to treat SARS-CoV-2 may cause more harm than good

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      Pharmacological Research
      Elsevier Ltd.

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          Abstract

          Dear Sirs, We wish to reply to the article entitled “Traditional Chinese medicine for COVID-19 treatment” published in this journal by Ren et al. [1]. The article expounds the benefit of Traditional Chinese Medicine (TCM) for the treatment of the illness called COVID-19 resulting from the novel coronavirus SARS-CoV-2, stating, “clinical practice results showed that traditional Chinese medicine (TCM) plays significant role in the treatment of COVID-19, bringing new hope for the prevention and control of COVID-19” and that “early intervention of TCM can effectively prevent the disease from transforming into severe and critical disease” [1]. The authors in particular recommend the use of the qingfei paidu decoction (QPD) which contains a large number of primary constituents, outlined in the article [1]. The quoted efficacy of this compound is a cure rate of “over 90 %” [1]. Although this figure sounds impressive, when compared to the current mortality rate attributed to the novel coronavirus, of between 1–3 %, its suggested therapeutic effect may be no better than placebo. We note the authors are not alone in promoting a role of TCM in the treatment of COVID-19, with the use of TCM appearing in recent guidelines derived from the initial epicentre of the disease in Wuhan China [2]. We wish to highlight significant concerns regarding the association between traditional herbal medicines and severe, non-infective interstitial pneumonitis and other aggressive pulmonary syndromes, such as diffuse alveolar haemorrhage and ARDS which have emerged from Chinese and Japanese studies particularly during the period 2017−2019. Initially the association between traditional herbal therapies and pneumonitis was based on isolated case reports. These included hypersensitivity pneumonitis associated with the use of traditional Chinese or Japanese medicines such as Sai-rei-to, Oren-gedoku-to, Seisin-renshi-in and Otsu-ji-to (9 references in supplemental file). Larger cohorts and greater numbers now support this crucial relationship. In a Japanese cohort of 73 patients, pneumonitis development occurred within 3 months of commencing traditional medicine in the majority of patients [3], while a large report from the Japanese Ministry of Health, Labor and Welfare, described more than 1000 cases of lung injury secondary to traditional medications, the overwhelming majority of which (852 reports) were described as ‘interstitial lung disease [4]. Currently the constituent of traditional herbal medicines which is considered most likely to underlie causation of lung disease is Scutellariae Radix also known as Skullcap or ou-gon, which has been implicated through immunological evidence of hypersensitivity as well as circumstantial evidence, being present in all of those medicines outlined above [3]. Notably, skullcap is a constituent of QPD as used and described in the paper by Ren et al. relating to COVID-19 [1]. Scutellariae Radix-induced ARDS and COVID-19 disease share the same characteristic chest CT changes such as ground-glass opacities and airspace consolidation, therefore distinguishing between lung injury due to SARS-CoV-2 and that secondary to TCM may be very challenging. The potential for iatrogenic lung injury with TCM needs to be acknowledged [5]. Morbidity and mortality from COVID-19 are almost entirely related to lung pathology [6]. Factors which impose a burden on lung function such as chronic lung disease and smoking are associated with increased risk for a poor outcome. Severe COVID-19 may be associated with a hypersensitivity pneumonitis component responsive to corticosteroid therapy [7]. Against this background the use of agents with little or no evidence of clinical efficacy and which have been significantly implicated in causing interstitial pneumonitis that could complicate SARS-CoV-2 infection, should be considered with extreme caution. In conclusion, the benefits of TCM in the treatment of COVID-19 remain unproven and may be potentially deleterious. We recognise that there is currently insufficient evidence to prove the role of TCM in the causation of interstitial pneumonitis, however the circumstantial data is powerful and it would seem prudent to avoid these therapies in patients with known or suspected SARS-CoV-2 infection, until the evidence supports their use. Declaration of Competing Interest There are no conflicts to declare.

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          Clinical Characteristics of Coronavirus Disease 2019 in China

          Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)
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            A rapid advice guideline for the diagnosis and treatment of 2019 novel coronavirus (2019-nCoV) infected pneumonia (standard version)

            In December 2019, a new type viral pneumonia cases occurred in Wuhan, Hubei Province; and then named “2019 novel coronavirus (2019-nCoV)” by the World Health Organization (WHO) on 12 January 2020. For it is a never been experienced respiratory disease before and with infection ability widely and quickly, it attracted the world’s attention but without treatment and control manual. For the request from frontline clinicians and public health professionals of 2019-nCoV infected pneumonia management, an evidence-based guideline urgently needs to be developed. Therefore, we drafted this guideline according to the rapid advice guidelines methodology and general rules of WHO guideline development; we also added the first-hand management data of Zhongnan Hospital of Wuhan University. This guideline includes the guideline methodology, epidemiological characteristics, disease screening and population prevention, diagnosis, treatment and control (including traditional Chinese Medicine), nosocomial infection prevention and control, and disease nursing of the 2019-nCoV. Moreover, we also provide a whole process of a successful treatment case of the severe 2019-nCoV infected pneumonia and experience and lessons of hospital rescue for 2019-nCoV infections. This rapid advice guideline is suitable for the first frontline doctors and nurses, managers of hospitals and healthcare sections, community residents, public health persons, relevant researchers, and all person who are interested in the 2019-nCoV.
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              Traditional Chinese medicine for COVID-19 treatment

              1 Summary The current 2019-nCoV outbreak is moving rapidly [1], the cumulative number of confirmed cases in mainland China has reached 80151, with 47,204 (58.89 %) cured cases and 2943 (3.67 %) deaths as of 2-Mar-2020, and no specific drug has been discovered for Coronavirus Disease 2019 (COVID-19). However, a number of clinical practice results showed that traditional Chinese medicine (TCM) plays significant role in the treatment of COVID-19, bringing new hope for the prevention and control of COVID-19. TCM has a long history and played an indispensable role in the prevention and treatment of several epidemic diseases. During the SARS epidemic in 2003, the intervention of TCM has also achieved remarkable therapeutic effect. During the treatment period of COVID-19, more than 3100 medical staff of TCM were dispatched to Hubei province, and TCM scheme was included in the guideline on diagnosis and treatment of COVID-19 [2], and TCM experts fully participate in the whole rescue process. The decoction, Chinese patent medicine, acupuncture and other characteristic therapy of TCM was comprehensively employed, mainly treated based on syndrome differentiation. Specific TCM wards were set up, and established the designated hospital, moreover, TCM team participates in treatment collectively. Currently, the total number of confirmed cases treated by TCM has reached 60,107 [3]. In 102 cases of mild symptoms treated with TCM, the clinical symptom disappearance time was shortened by 2 days, the recovery time of body temperature was shortened by 1.7 days, the average length of stay in hospital was shortened by 2.2 days, the improvement rate of CT image was increased by 22 %, the clinical cure rate was increased by 33 %, 27.4 % reduction in the rate of common to severe cases and 70 % increase in lymphocyte.3 In addition, in the treatment of severe patients with TCM, the average length of stay in hospital and the time of nucleic acid turning negative has been shortened by more than 2 days. From current treatment results, TCM based on an over-all symptoms of 2019-nCoV pneumonia patients, has suggested to prescribe prescription that are likely to be effective, such as qingfei paidu decoction (QPD), gancaoganjiang decoction, sheganmahuang decoction, qingfei touxie fuzheng recipe, etc. QPD which consisted of Ephedrae Herba, Glycyrrhizae Radix et Rhizoma Praeprata cum Melle, Armeniacae Semen Amarum, Gypsum Fibrosum, Cinnamomi Ramulus, Alismatis Rhizoma, Polyporus, Atractylodis Macrocephalae Rhizoma, Poria, Bupleuri Radix, Scutellariae Radix, Pinelliae Rhizoma Praepratum cum Zingibere et Alumine, Zingiberis Rhizoma Recens, Asteris Radix et Rhizoma, Farfarae Flos, Belamcandae Rhizoma, Asari Radix et Rhizoma, Dioscoreae Rhizoma, Aurantii Fructus Immaturus, Citri Reticulatae Pericarpium, and Pogostemonis Herba, has been promoted as a general prescription in the diagnosis and treatment plan of COVID-19 in China [2]. Among the 701 confirmed cases treated by QPD, 130 cases were cured and discharged, clinical symptoms of 51 cases disappeared, 268 cases of symptoms improved, and 212 cases of stable symptoms without aggravation [3]. The effective cure rate of QPD against COVID-19 is over 90 %. According to the theory of TCM, the target organ location of COVID-19 is the lung, and the etiology attribute is “damp and toxin plague”. The network pharmacology analysis showed that QPD has an overall regulatory effect via multi-component and multi-target. The primary site of pharmacological action is the lung, as 16 herbs to lung meridian, which indicated that the decoction is mainly specific for lung diseases. In addition, it can play the role of dehumidification through the rise and fall of the spleen and stomach, and exhibited the protection for heart, kidney and other organs. Among the potential targets screen, most of them co-expressed with ACE-2, the receptor of COVID-19, indicating the potential improvement of COVID-19. It can inhibit the replication of COVID-19 by acting on multiple ribosomal proteins. COVID-19 can lead to strong immune response and inflammatory storm [4]. Functional enrichment analysis showed that QPD could inhibit and alleviate excessive immune response and eliminate inflammation by regulating immune related pathway and cytokine action related pathway [5]. Furthermore, through the prediction of molecular docking, it was found that patchouli alcohol, ergosterol and shionone in the formula had better anti−COVID-19 effect, which provided new molecule structures for new drug development [6]. Here, we take one highly suspected COVID-19 patient treated with TCM as a case example to show its effectiveness [7]. The male patient was on a business trip in Wuhan for several days before the onset of the disease. During the admission period, fever and cough were repeated, and respiratory rales of both lungs were not obvious. Western medicine was used firstly, including orally take oseltamivir phosphate capsule, intravenous infusion of ganciclovir, aerosol inhalation of recombinant human interferon a1b, etc. Although the nucleic acid test was negative, the results of chest CT showed that the fusion of two lung ground glass shadows was enlarged and the density was increased, which was more advanced than that of admission (Fig. 1 a-1c). As the serious illness, combined with the patient's performance of damp-heat syndrome, and the heat is more serious than damp, QPD was added for treatment. On the night of administration, the body temperature dropped to 36.2 ℃, and then tended to be normal. After 6 days of treatment, chest CT was better than before, tracheobronchial shadow was normal, and inflammation was obviously absorbed (Fig. 1d). The patient had no fever or asthenia, coughing occasionally, and the rales of two lungs were weaker than before. After discharge, continue to take 7 doses of the prescription, occasionally cough, no special discomfort was found. The clinical symptoms and imaging examination of the patients improved significantly after the treatment, reflecting the advantages of TCM. Fig. 1 Comparison of chest CT results of patients. (a), chest CT on January 24; (b), chest CT on January 28; (c), chest CT on January 30; (d), chest CT on February 4. Fig. 1 TCM has own characteristics such as holistic concept, balance of Yin and Yang, syndrome differentiation and treatment, strengthening the body resistance to eliminate pathogenic factors. TCM has thousands of years of experience in regulating the body and enhancing the resistance to epidemic diseases, with unique insights and prevention and control experience. For mild and common patients, the early intervention of TCM can effectively prevent the disease from transforming into severe and critical disease. In the severe cases, TCM has won time for rescuing them by improving symptoms (http://www.scio.gov.cn/xwfbh/xwbfbh/wqfbh/42311/42560/index.htm). Treatment practice of COVID-19 showed that early intervention of TCM is important way to improve cure rate, shorten the course of disease, delay disease progression and reduce mortality rate. Furthermore, the reason why TCM works is not only to inhibit the virus, but might block the infection, regulate the immune response, cut off the inflammatory storm, and promote the repair of the body. Moreover, the prevention and control measures of COVID-19 fully reflect the ideology of “preventive treatment of disease”. Apart from the epidemic diseases recorded in the Han Dynasty should be isolated, the preventive measures of TCM also include psychology, sports, diet, medication, etc. In the next prevention and control work of COVID-19, it should give full play to the advantages of TCM in syndrome differentiation and the whole therapeutic effect, reduce the complications as well as death rate. Besides, the scientific research should also be carried out on the TCM with definite curative effective of COVID-19, to comprehensively evaluating its action mechanism and in-depth understanding COVID-19. Declaration of Competing Interest There are no conflicts to declare.
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                Author and article information

                Contributors
                Journal
                Pharmacol Res
                Pharmacol. Res
                Pharmacological Research
                Elsevier Ltd.
                1043-6618
                1096-1186
                3 April 2020
                3 April 2020
                : 104776
                Affiliations
                [a ]Dept. of Immunology and Infectious Diseases, Sydney Children’s Hospital, Sydney, Australia
                [b ]School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia
                [b ]School of Women’s and Children’s Health, University of New South Wales, Sydney, Australia
                [c ]Dept. of Respiratory Medicine, Sydney Children’s Hospital, Sydney, Australia
                Author notes
                [* ]Corresponding author at: Dept. of Immunology and Infectious Diseases, Sydney Children’s Hospital, Sydney, Australia. paul.gray1@ 123456health.nsw.gov.au
                Article
                S1043-6618(20)30906-3 104776
                10.1016/j.phrs.2020.104776
                7129235
                32251726
                889e6e86-1775-4240-8cfe-576f9119b035
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 13 March 2020
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                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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