key: cord-0962590-zgc2z891
authors: Shen, Pan; Li, Jing; Tu, Shenghao; Wu, Yanran; Peng, Yongtiao; Chen, Gang; Chen, Chao
title: Positive effects of Lianhuaqingwen granules in COVID-19 patients: a retrospective study of 248 cases
date: 2021-05-21
journal: J Ethnopharmacol
DOI: 10.1016/j.jep.2021.114220
sha: 48e24eda9acfd307f508dada2b28eabbf7d2107a
doc_id: 962590
cord_uid: zgc2z891

ETHNOPHARMACOLOGICAL RELEVANCE: Lianhuaqingwen (LHQW) is a Chinese medicine, developed from appropriate addition and reduction of combined traditional Chinese medicine (TCM) Yinqiao San and Maxing Shigan decoction. LHQW has been used in routine influenza treatment for decades and plays a role in a broad-spectrum therapy on various influenza viruses. Aims of the study: The therapeutic effects of LHQW in coronavirus disease 2019 (COVID-19) have not been fully elucidated. A retrospective study was conducted in patients with COVID-19 to evaluate the influence of LHQW on laboratory results related to the disease, and to provide evidence for the clinical practice of TCM. MATERIALS AND METHODS: We retrospectively collected 248 patients who met the moderate type COVID-19 diagnostic criteria, and received treatment in Tongji Hospital. Patients were divided into control (158 cases, standard treatment) and LHQW treatment (90 cases, standard treatment combined with LHQW) groups according to the different treatments administered. All laboratory data were obtained after 5–7 days’ treatment. RESULTS: In this study, the average patient age was 58.95 years and 131 patients were male. The two groups were comparable in demographic characteristics, symptoms, and treatment. Compared with in the control group, D-dimer and erythrocyte sedimentation rate were significantly lower in the LHQW treatment group (2.47±4.67 vs. 1.68±3.61; 44.47±30.24 vs. 35.39±27.43; both P<0.05). Lymphocyte counts, albumin and hemoglobin levels were higher in the LHQW treatment group than those in the control group (1.00±0.46 vs. 1.13±0.5; 34.39±5.2 vs. 35.71±4.76; 127.03±16.58 vs. 131.11±14.66; both P<0.05). CONCLUSION: The study showed that LHQW significantly improved laboratory results of patients with COVID-19 and could be effectively applied alongside standard treatment of patients with moderate type COVID-19, providing preliminary clinical research evidence for the use of TCM in treatment of this disease.

Coronavirus disease has become a major epidemic that seriously endangers human health and public safety all over the world. A newly emerged coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been recognized as being responsible for the occurrence of this disease (Pascarella et al., 2020) . Similar to the other two highly pathogenic coronaviruses, SARS-CoV and MERS-CoV, SARS-CoV-2 can cause severe respiratory disorders and high mortality (Nkengasong, 2020) . By 1st May, 2021, more than 150 million confirmed cases of COVID-19 had been reported globally, including 2 million deaths, and a continuing increase is predicted. This disease inflicts enormous health, economic, and social crises, with no country escaping its effects.

At present, it is important to develop potential antiviral agents; however, these treatment strategies will take months, even years, to become available . In 2003, patients with SARS who received traditional Chinese medicine (TCM) treatment had shorter hospital stays and fewer steroid-related side effects . The application of TCM can contribute to effective treatment as a complementary and alternative measure, reducing the rate of severe illness and death.

From the start of the COVID-19 outbreak in Wuhan, Chinese physicians have adopted a combination of TCM and Western medicine (Ling, 2020) , and the application of Lianhuaqingwen granules (LHQW) combined with standard treatment appears to be beneficial. LHQW is a Chinese medicine comprising 13 herbs, developed from appropriate addition and deletion of combined Yinqiao San and Maxing Shigan J o u r n a l P r e -p r o o f decoctions. Yinqiao San, derived from the traditional Wenbing Tiaobian, was mainly administered in the treatment of "warm disease" characterized by clinical symptoms including cough, fever and headache. Maxing Shigan decoction, stemming from the classical monograph Shanghan Lun, was typically used against diseases including measles, influenza, bronchitis, and pneumonia (Hsieh et al., 2012) . LHQW has been used in routine influenza treatment for decades, and plays a role in broad-spectrum curative therapy for various influenza viruses, such as H7N9 and H1N1 Ding et al., 2017) . Lin et al. reported that LHQW significantly decreased the Visual Analog Scale and Sino-Nasal Outcome Test-22 scores in chronic rhinosinusitis patients in comparison with placebo group. Histologic changes in nasal mucosa were significantly improved only in LHQW group, including alveolar septum thickening, capillary congestion, interstitial edema, which might be associated with the levels of malonaldehyde, glutathione peroxidase, and super oxide dismutase, played significant roles in pathogenesis of lung injury. CD4 + and CD8 + T cells were decreased in the LHQW treatment group, but not in placebo group . In a prospective randomized controlled trial, the recovery rate was significantly higher in the LHQW therapy group compared with the control group (91.5% vs. 82.4%) in patients with COVID-19 (Hu et al., 2020) . In a system review of COVID-19 (Liu et al., 2021) , patients treated by LHQW combined with standard treatment have a higher overall effective rate and CT recovery rate compared with others treated by standard methods.

Also, patients treated by LHQW combined with standard treatment have a lower incidence of diarrhea.

J o u r n a l P r e -p r o o f LHQW is usually used as a supplementary therapeutic agent, which is considered to relieve symptoms, improve drug efficacy, shorten the course of the disease, and reduce the proportion of severe cases. LHQW can be used alone in some diseases with chronic airway inflammation and mild type of COVID-19 or other acute respiratory inflammation. A study demonstrated that LHQW treatment alone control the inflammation in nasal mucosa and result in the improvement of chronic rhinosinusitis . In this study, a retrospective study was performed to provide evidence for treatment of moderate COVID-19 with LHQW. (1) suspected cases with one of the following etiological evidences: a) RT-PCR assay for SARS-CoV-2 RNA; b) viral gene sequence is highly homologous to SARS-CoV-2;

(2) moderate severity of disease, indicated by fever and respiratory symptoms with radiological findings consistent with pneumonia; J o u r n a l P r e -p r o o f

(3) patients age over 18 years.

Exclusion criteria consisted of the following:

(1) patients with severe or critical COVID-19, requiring mechanical ventilation;

(2) patients with acute respiratory disease not caused by SARS-CoV-2, but resulting from basic diseases such as primary immunodeficiency or acquired immunodeficiency disease, abnormal lung development, severe pulmonary interstitial disease, bronchiectasis, congenital respiratory tract malformation, congenital heart disease and gastroesophageal reflux disease;

(3) patients with asthma requiring daily treatment, respiratory bacterial infections, including acute tracheobronchitis, sinusitis, and other respiratory tracts diseases that may affect outcome;

(4) previous or present disorders that may affect outcome, including: malignant disease, severe liver disease, severe renal insufficiency or continuous renal replacement therapy, blood disease, and organ transplantation;

(5) pregnant or lactating women;

(6) allergy to the ingredients of LHQW;

(7) participation in other clinical trials within the last 6 months;

(8) patients who received other medications, in addition to standard treatment and LHQW.

The standard treatment comprised the following: (1) patients were restricted to bed rest and adequate nutrient intake, especially in terms of calories, was provided along with careful monitoring of water and electrolyte balance to maintain internal environment stability; (2) closely monitoring of vital signs and oxygen saturation, with provision of effective oxygen therapy; (3) according to patients' conditions, monitoring of blood, and urine tests, c-reactive protein (CRP), coagulation function, biochemical indicators (liver enzyme, renal function, myocardial enzyme), arterial blood gas analysis, and chest CT-imaging; (4) 

We retrospectively reviewed medical records and clinical data for enrolled patients with moderate severity COVID-19 pneumonia from Tongji Hospital. All laboratory data were obtained after 5-7 days' treatment, including blood cell count, biochemical parameters, inflammation parameters, and coagulation function. 

Differences in demographic characteristics (except age) between the two groups were analyzed by Chi square test; age was analyzed by T test. The Mann-Whitney U test was applied to assess differences in blood cell count, biochemical parameters, inflammation parameters and coagulation function between the two groups. All data analyses were performed with SPSS version 16.0(SPSS Inc. Chicago, IL). P<0.05

was considered statistically significant.

As shown in Table 1 

As shown in Table 2 , compared with in the control group, LC ( Figure 1A ) and HGB ( Figure 1B ) in blood routine analysis were significantly increased in the LHQW treatment group (P<0.05), while no significant difference was found between the two groups in terms of NC, PLT, EC, and WBC (P>0.05).

As shown in Table 3 , blood biochemistry demonstrated that ALB ( Figure 1C ) was higher in the LHQW treatment group compared with in the control group (P<0.05).

However, no significant differences in ALT, AST, LDH, GLB, CR, UREA, MB, CK-MB, eGFR, HCO3, and NT-proBNP were found between the two groups.

As shown in Table 4, differences in hs-CRP, IL-1β, TNF-α, IL-2R, IL-6, IL-8, IL-10, ferroprotein, and PCT between the two groups were not statistically significant (P>0.05). However, ESR was significantly higher in the control group compared with in the LHQW treatment (P<0.05) ( Figure 1D ).

As shown in Table 5 , D-dimer in the control group was significantly higher than that in the LHQW treatment group (P<0.05) ( Figure 1E ). However, no significant differences in PT, PTA, INR, APTT, FIB, and TT were found between the two groups.

In this study, we aimed to retrospectively identify differences in clinical indicators among patients receiving TCM in addition to standard Western treatments for COVID-19, to provide evidence for the efficacy of TCM in this disease. Overall, treatment with LHQW for 5-7 days resulted in significant improvements in LC, ESR, D-dimer, ALB and HGB in patients with COVID-19.

SARS-CoV-2 causes damage to the respiratory tract, heart, nervous system, esophagus, urinary bladder, kidney, and jejunum (Li and De Clercq, 2020; Zou et al., 2020) . Susceptibility to SARS-CoV-2 infection may be related to efficiency of binding to angiotensin converting enzyme 2. Currently, the main therapeutic approach The mechanism behind the observed decrease in ALB in patients with COVID-19 remains unclear, but may be related to increased catabolism of ALB, decreased synthesis or insufficient intake, and abnormal distribution after viral infection. Hypoproteinemia observed in patients with viral pneumonia could also be J o u r n a l P r e -p r o o f related to the above factors . Hypoproteinemia caused by fever and insufficient protein intake during COVID-19 is closely related to the course of disease, with a longer course signifying, a greater the possibility of hypoproteinemia.

Pathologic anatomy showed that COVID-19 mainly caused inflammatory reactions characterized by injury of the deep airways and alveoli. Substantial quantities of fluid, fibrin exudate, and transparent membrane formation were observed in alveoli.

Pulmonary exudation and hypoproteinemia suggest the possibility of capillary leakage syndrome, but this is often accompanied by systemic edema, which is different from the presentation of COVID-19 and requires further study. LHQW plays a role in correcting ALB and HGB levels, which may be related to improving the airway microenvironment, regulating the immune response, and controlling symptoms such as fever and anorexia.

As a classic TCM prescription for treating respiratory diseases, LHQW is the only approved TCM used in the treatment of influenza and SARS. Studies have shown that honeysuckle and forsythia had therapeutic effects on COVID-19 by blocking multiple binding sites of angiotensin converting enzyme II and SARS-CoV-2 in humans (Niu et al., 2020) . Rhodiola and its active ingredients could improve hypoxia and blood oxygen partial pressure, with significant positive effects on pulmonary hypoxia caused by pathological damage, relieving edema, and inhibiting inflammation of lung tissue. In a randomized, double-blind, multi-center clinical trial of influenza (H1N1) in 2009 (Duan et al., 2011) , compared with the oseltamivir phosphate treatment group, no significant differences were found in the frequency of J o u r n a l P r e -p r o o f viral nucleotide transversion and remission of all influenza symptoms in patients treated with LHQW capsules. LHQW was superior to oseltamivir phosphate in reducing fever and relieving cough, muscle soreness, fatigue, and other symptoms.

These findings provided evidence for the antiviral effects of LHQW.

The inflammatory cytokine storm has been identified as an over-defensive response to various viruses, which can cause diffuse lung injury and lead to severe disease (Xu et al., 2020) . In a recent study (Runfeng et al., 2020) , the authors found that LHQW significantly inhibited SARS-COV-2 replication and reduced excessive expression of pro-inflammatory cytokines (IL-6, TNF-α and macrophage chemokine protein-1). LHQW also effectively reduced the expression of IL-1β, IL -2, and IL-13 and attenuated lung injury associated with inflammatory cell infiltration. These findings suggest that LHQW protects against SARS-CoV-2 and may be a potentially effective agent for controlling COVID-19. This study had some limitations. It should be noted that the sample size was small, and there was no comparison between the treatment efficiency and the rate of severe illness between the LHQW group and the control group. Finally, there is a lack of research regarding indicators and symptoms of LHQW side effects. In the future, prospective, double-blind, randomized controlled clinical studies are needed to further assess the clinical efficacy of LHQW.

LHQW has shown therapeutic effects in COVID-19 by improving LC, ALB, and HGB and reducing ESR and D-dimer. Considering the efficacy profiles, LHQW could be a potential agent for the treatment of COVID-19.

None.

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J o u r n a l P r e -p r o o f Abbreviation: ALT, alanine aminotransferase; AST, aspartate aminotransferase; TP, total protein; ALB, albumin; GLB, globulin; LDH, lactate dehydrogenase; CR, creatinine; UREA, urea nitrogen; eGFR, estimated glomerular filtration rate; MB, myohemoglobin; CK-MB, creatine kinase-muscle/brain; NT-proBNP, N-terminal prohormone brain natriuretic peptide.*p < 0.05 is considered statistically significant. Abbreviation: ESR, erythrocyte sedimentation rate; hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin-6; PCT, procalcitonin; IL-2R, Interleukin-2 receptor; IL-8, interleukin-8; IL-10, interleukin-10; TNF-α, tumor necrosis factor α.*p < 0.05 is considered statistically significant. Abbreviation: PT, prothrombin time; PTA, prothrombin activity; INR, Internationally standardized ratio; FIB, fibrinogen; APTT, activated partial prothrombin time; TT, thrombin time.*p < 0.05 is considered statistically significant.J o u r n a l P r e -p r o o f