Coronavirus disease 2019 (COVID-19), which was first reported in December 2019, has become a global pandemic, resulting in considerable morbidity and mortality in 187 countries and regions worldwide, especially in patients with underlying diseases, such as kidney diseases (Naicker et al., 2020). Previous studies reported that 2.15–11% patients receiving maintenance hemodialysis (HD) were susceptible to COVID-19, and HD centers have been high-risk settings during the epidemic in China (Xiong et al., 2020; Zou et al., 2020). Because of the large number of patients visiting the HD centers, there is an increased risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Traditional Chinese medicine (TCM) has accumulated experience of several decades in the treatment of pandemic and endemic diseases with multi-component, multi-target, and multi-effect modes of action. Currently, TCM is frequently used in combination with Western medicine for the treatment of kidney disease and has shown multiple treatment effects with low toxicity and few adverse effects. An open-label trial reported that Ren Shen Yang Rong Tang could decrease chronic inflammation and increase the quality of life in HD patients (Hsiao et al., 2015). In addition, TCM uremic clearance granule could significantly relieve clinical symptoms, reduce the level of inflammatory factors and antioxidative stress, and have a certain effect on renal anemia, calcium and phosphorus metabolism disorders, and other complications (Bai et al., 2021).

The association between HD-associated COVID-19 and the risk of mortality is unclear. Our study retrospectively analyzed data from Wuhan Third Hospital Guanggu Branch, Wuhan, China. We aimed to describe the clinical, laboratory, and radiological characteristics; TCM symptom scores; treatment; and outcomes in HD patients confirmed to have SARS-CoV-2 infection, and to compare these factors in patients who received Western medicine and those who received a combination of Western medicine and TCM. We hope our study will provide the global community with information about clinical features and treatment of hemodialysis-associated COVID-19.

The demographic and baseline clinical characteristics of the patients were similar in the two groups (Table 1).

Symptom severity in the patients at baseline was similar in the two groups (Table 2).

Figure 1 shows the outcomes in the two groups. The mortality rate was significantly lower in the TG than in the CG, and the cure rate was significantly higher (p = 0.011). As shown in Table 3, there were 19 moderate cases, six severe cases, and six critical cases in the TG. However, two critical patients died, and patients in all moderate cases and severe cases were cured and discharged, showing that the recovery rate was higher in the moderate and severe groups. Moreover, we found that there were 12 cases of cold-damp obstruction of the lung pattern, 11 cases of epidemic toxin blocking lung pattern, and 7 cases of internal blockage and external desertion pattern in the TG. Two patients with internal blockage and external desertion pattern died, and the other two categories of patients were cured and discharged. This suggests that early Chinese medicine intervention for COVID-19 may be more effective in the treatment and prognosis of patients (Table 4).

`Patients treated with a combination of TCM and Western medicine showed a significantly greater increase in albumin, and a significantly greater reduction in CRP, d-dimer, and LDH than those in the CG. After treatment, the d-dimer levels were lower and albumin was higher in the TG (both p < 0.05) (Figure 2).

As shown in Figure 3, TCM symptom scores were significantly reduced after treatment in both groups. The improvement in anorexia was significantly more obvious in the TG than in the CG (p ≤ 0.001).

Table 5; Figure 4 show the admission chest CT scan findings in the two groups of patients and the CT scan findings on absorption of lung lesions after treatment, respectively.

Table 6 shows clinical adverse events reported in the two groups. Before TCM treatment, four patients had mild liver injury. In terms of liver function (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and direct bilirubin [DBIL]) before and after treatment in the TG, liver function returned to normal after treatment in one patient and remained mild in two patients, and one patient died. The remaining patients were had normal liver function before and after TCM treatment, and their ALT and AST values did not change (p > 0.05). Although there was a significant difference in DBIL before and after treatment in the TG (p < 0.05), the indicators were within the normal range, suggesting that there were no serious drug-related adverse reactions during TCM treatment.

SARS-CoV-2 affects the lungs, causing a lingering disease that is difficult to cure (WANG et al., 2020). Some studies (Ji et al., 2020; Shah et al., 2020) have shown that most patients present with a slow onset, long incubation period, and mild symptoms. However, in the later stages of the disease, some patients develop phlegm-stasis, which presents as obstruction of the lung, epidemic toxin-blocking lung, and internal blockage and external desertion patterns on CT. The clinical manifestations are fever, cough, expectoration, fatigue, chest distress, shortness of breath, and other symptoms. Complications include severe pneumonia, acute respiratory failure, and myocardial damage. A previous study (Guan et al., 2020) showed that fever and cough are the main symptoms and vomiting and diarrhea are minor symptoms. In this study, the main clinical manifestations of HD patients with COVID-19 were fatigue, dry cough, anorexia, fever, and dyspnea, which may be difficult to distinguish from other common symptoms of ordinary HD patients.

Albumin, which is synthesized by the liver, is the main serum protein component of the human body, which maintains osmotic pressure and resists infection and oxidation (Caraceni et al., 2016; Zaccherini and Bernardi, 2019). Pretorius et al. (Pretorius et al., 2013) reported that the decrease in serum albumin can increase the risk of infection and thrombosis and cause major cardiovascular adverse events. In our study, the serum albumin level of the patients in the TG was higher than that in the CG after treatment with TCM. The clinical manifestations of HD patients are often fatigue and anorexia, accompanied by anemia. The TCM used in our study improved the clinical symptoms and serum albumin levels; however, further research is needed on the specific mechanisms. In addition, CRP and LDH were lower in the TG after treatment. CRP is the main indicator for evaluating systemic inflammatory response. LDH is an important biochemical indicator of the body’s response to tissue cell hypoxia and blood perfusion, which could be used as a detection index for disease severity and prognosis.

HD patients often show varying degrees of micro-inflammation, which may reduce the patient’s immune function and increase the risk of infection. Xing Ren (Prunus armeniaca L.) and Ma Huang (EH) can promote the synthesis of lung surfactants and have anti-inflammatory, bacteriostatic, and antiviral effects. Wei Xiaolu (Xiaolu, 2013) reported that the main medicinal ingredient of Huo Xiang (Pogostemon cablin [Blanco] Benth.) is patchouli oil, which could act as an anti-adenovirus, probably by destroying viral genes and preventing viral adsorption. It has been confirmed that the immune system dysfunction and chronic infections in ESRD cause multiple complications. Frequent HD causes insufficient blood perfusion in the kidneys, affecting the body’s electrolyte balance, calcium and phosphorus absorption, and toxin clearance (Vanitha et al., 2016). An increase in inflammatory factors in the patient’s serum aggravate the infection, which is obviously related to the severity of the disease. Therefore, it is important to enhance the host’s immunity and suppress the inflammatory response in patients (Kato et al., 2008; Wehmeyer et al., 2013). The Ma Xing Shi Gan Decoction (Hsieh et al., 2012) provides effective anti-inflammatory, anti-influenza, and immune-enhancing effects, and provides oseltamivir-like anti-influenza virus ceramide enzyme activity, and downregulates the secretion and expression of interferon (IFN)-α/β in macrophages infected by influenza (Zhang et al., 2019). We found that TCM can effectively reduce CRP and LDH, reduce inflammation, and promote inflammation absorption. The diagnosis and treatment guidelines mention that continuous renal replacement therapy is used to treat critically ill patients to remove cytokines and other inflammatory mediators (Zaccherini and Bernardi, 2019). Hemodialysis can eliminate most inflammatory mediators and cytotoxic substances that cause increased permeability of the blood vessel wall, and this may have affected the improvement in inflammatory indicators in the TG. Uremia is associated with widespread impairment of lymphocyte and granulocyte functions, and an abnormal immune system may change such patients’ response to SARS-CoV infection (Zhou et al., 2017). EH has been used in Asian traditional herbal medicine to cure bronchial asthma, cold, flu, chills, fever, headache, nasal congestion, and cough (Soni et al., 2004). EH contains two main active constituents, ephedrine and pseudoephedrine, which are potent sympathomimetic drugs that stimulate α-, β1-, and β2-adrenoceptors (Ma et al., 2007). However, legal restrictions regarding ephedrine products exist in several Western countries. As of 2004, the US food and drug association received more than 18,000 adverse reports from people using ephedrine to treat asthma, colds, allergies, and various other diseases (Soni et al., 2004). However, EH is one of the herbal medicines from TCM that was successfully used for the treatment of SARS-CoV-infected patients in the 2002/2003 SARS epidemic; thus, the antiviral activity of EH is separable from its adverse effects (Mantani et al., 1999; Liu et al., 2012; Wang et al., 2014; Wei et al., 2019; Luo et al., 2020). Currently, EH extract is ranked third in terms of priority treatment for COVID-19 in China (Oesch et al., 2021).

A study of 1,099 confirmed COVID-19 patients found that among 173 severe patients, 23.7% had hypertension, 16.2% had diabetes, 5.8% had coronary heart disease, and 2.3% had cerebrovascular disease (Guan et al., 2020). We found that hypertension accounts for the highest proportion of chronic underlying diseases, suggesting that patients with hypertension may be more susceptible to SARS-CoV-2. SARS-CoV and SARS-CoV-2 mainly bind to target cells through angiotensin-converting enzyme 2 (ACE2), which can be expressed in the epithelial cells of the lung, intestine, kidney, and blood vessels; promote the expression of ACE2 (Li et al., 2017); and improve the susceptibility of the body to SARS-CoV-2. ACE2 (Wan et al., 2020; Wrapp et al., 2020) seems to be unrelated to infectivity, but it has an impact on disease severity in terms of lung, heart, and kidney function. SARS-CoV-2 infection can affect the lung, myocardium, kidney, liver, digestive tract, pancreas, brain, and other organs, increasing the severity and fatality in COVID-19 patients. However, the above theory is not supported by large-scale clinical data. The latest research shows that the key receptor of the new coronavirus—ACE2—is nearly 100 times higher in the kidneys than in the lungs, especially the proximal tubules (Dai et al., 2020). The kidney may be one of the main targets of the virus, and kidney damage may eventually lead to multiple organ failure and death. However, the characteristics of kidney damage related to the new coronavirus infection need to be investigated further. It has been reported (Yang et al., 2017) that HD can stimulate the ACE/Ang II/AT1R axis (Angiotensin Converting Enzyme/Angiotensin II/Angiotensin Receptor 1) in the circulation of patients with cardiovascular disease, thereby reducing the activity of the ACE2/Ang- (Ureña, 2008; Hsiao et al., 2015; Naicker et al., 2020; National Health Commissio, 2020; Xiong et al., 2020; Zou et al., 2020; Bai et al., 2021)/Mas axis and reducing the concentration of ACE2.

COVID-19 is a major global human threat that has turned into a pandemic. Although specific therapeutic agents or vaccines for COVID-19 are available, this novel coronavirus has specifically high morbidity in elderly and comorbid populations. Therefore, all measures must be taken to decelerate, if not to eradicate the pandemic and to control the unmanageably high incidence rates. According to the clinical manifestations of patients, TCM or integrated Chinese and Western medicine interventions can adjust the body’s immune function and stimulate the body’s ability to resist disease. According to the report of National Administration of Traditional Chinese Medicine, 214 COVID-19 patients in four Chinese provinces were treated with Qing Fei Pai Du Tang with an overall effectivity rate ≥90%. Among them, the symptoms of most patients (≥60%) were markedly improved, while illness of others (30%) was stabilized (Zhong et al., 2020). Thereafter, 701 COVID-19 patients were treated with Qing Fei Pai Du Tang in ten provinces in China. The result showed that 130 patients (18.5%) were completely cured, 268 patients (38.2%) showed improvement in symptoms, and 212 patients stabilized after treatment. In the treatment of confirmed and suspected COVID-19 patients, the Lian Hua Qing Wen Capsule (LHQWC) was shown to markedly relieve major symptoms, such as fever and cough, and promote recovery (Yang et al., 2020). Moreover, LHQWC was shown to significantly inhibit SARS-COV-2 replication, affect virus morphology, and exert anti-inflammatory activity in vitro (Runfeng et al., 2020).

SARS-CoV-2 infection presents a special threat to patients on dialysis, and death is deemed to be due to cardiovascular causes and not directly due to the infection. One HD center in Wuhan reported 37 cases of COVID-19 among 230 HD patients (16.1%) and four cases among 33 staff members (12.1%). Dialysis patients with COVID-19 had less lymphopenia, lower serum levels of inflammatory cytokines, and milder clinical disease than other patients affected by SARS-CoV-2 infection (Centers for Disease Contr, 2020). Other studies (Guan et al., 2020; Biarnés-Suñé et al., 2021) reported that elderly patients and patients with comorbidities might be at an increased risk of death if they contract COVID-19. Patients with end-stage renal disease and undergoing maintenance HD are at a greater risk of viral transmission because of impaired immune function and high comorbidity (Dalrymple and Go, 2008; Kato et al., 2008; Butler et al., 2020). Moreover, they are exposed to frequent and repetitive potentially infectious risk factors during regular HD treatment (Sarnak and Jaber, 2000). In this study, each patient was immediately admitted to the isolation ward and received supplemental oxygen through a face mask. The control group was given Arbidol as antiviral therapy, and ceftriaxone sodium/tazobactam sodium injection plus moxifloxacin as antibiotics. Considering renal failure, maintenance HD (two times per week) was administered and restrictions on water intake were enforced to attenuate kidney burden. Albumin and globulin were administered for hypoproteinemia. On the basis of the abovementioned treatment, in addition to the formula recommended in the guide, we also used proprietary Chinese medicines, such as Liuwei Dihuang pills, Huoxiang Zhengqi powder, Jinguishenqi pills, Sijunzi decoction, and according to the patient’s condition in the TG. The mortality rate of the patients in our study was 18.9%. Most patients who died were elderly patients with multiple underlying diseases, such as hypertension, diabetes, coronary heart disease, cerebrovascular disease, and malignancy, and a duration of HD of more than 5 years. Although there was no obvious difference in CT scans between the TG and CG, the cure rate was higher and mortality rate was lower in the TG than in the CG, suggesting that TCM may have a potential role in relieving complications and improving patient survival.

However, the question as to whether patients receiving HD are at a higher risk of mortality from COVID-19 and the mechanisms behind the positive effects of TCM remain to be analyzed in larger clinical studies in future. Further double-blinded, prospective, randomized controlled trials are needed to fully evaluate the effect of TCM in many patients receiving HD.

In summary, TCM and Western medicine both have their own advantages. The integration of TCM and Western medicine might be an effective and feasible solution for curing COVID-19, and more clinical research is needed to confirm this.