key: cord-0781208-c4db7bj0
authors: Ding, Hong; Deng, Wenjun; Ding, Lingling; Ye, Xiaoqun; Yin, Shanye; Huang, Weishan
title: Glycyrrhetinic acid and its derivatives as potential alternative medicine to relieve symptoms in nonhospitalized COVID‐19 patients
date: 2020-06-05
journal: J Med Virol
DOI: 10.1002/jmv.26064
sha: e5bdb4069e94e831527dd440c77f6b9995e7c098
doc_id: 781208
cord_uid: c4db7bj0

SARS‐CoV‐2 is highly infectious, and infection by this virus results in COVID‐19, manifesting predominantly symptoms in the lower respiratory system. Detection of viral genomic materials by RT‐PCR is the gold standard for diagnosis. Suspected COVID‐19 patients who had a documented history of exposure and exhibited symptoms, but did not have positive PCR test results, were generally self‐quarantined with prescriptions aiming to help attenuate their symptoms. These prescriptions are however neither specific nor highly effective for COVID‐19 treatment. Given the rapidly growing pandemic and the overwhelmed medical system, the number of self‐quarantined patients is increasing. There is an urgent need of alternative medicine to help patients relieve symptoms during self‐quarantine, and to potentially help increase their chances of survival and recovery from the infection. We report here a case of severe COVID‐19 that never had a positive PCR test result during disease progression but was confirmed with antibody test post recovery. This patient was self‐quarantined and received diammonium glycyrrhizinate (DG), a steroid‐like molecule, in combination with vitamin C as alternative medicine. This patient went through severe COVID‐19 but eventually recovered upon the implementation of this treatment regimen, suggesting potential therapeutic effects of DG as alternative medicine to help relieve COVID‐19 symptoms.

regimen, suggesting potential therapeutic effects of DG as alternative medicine to help relieve COVID-19 symptoms.

alternative medicine, antibody test positive, COVID-19, PCR test negative, prolonged symptoms 1 | BACKGROUND Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is highly infectious, 1 even when the patients show no or minor symptoms. 2 Infection by SARS-CoV-2 causes a broad spectrum of diseases that affects multiple organs including the lung, nervous system, heart, digestive system, kidney and others. 3 The resultant coronavirus disease 2019 (COVID-19) manifests predominantly symptoms in the lower respiratory system, typically presented as viral pneumonia. Detection of viral genomic materials is the gold standard for diagnosis. Standard operation procedures use pharyngeal swabbing samples from the upper respiratory system, which may miss the anatomic location of viral replication, leading to false negative diagnostic result. 4 The unexpected pandemic outbreak also resulted in deprivation of medical resources in the peak phase in areas that did not have sufficient preparation and/or resources. Suspected COVID-19 patients who had documented history of exposure and exhibited symptoms, but did not have positive polymerase chain reaction (PCR) test results, were generally self-quarantined. Some patients had a contact history with a confirmed COVID-19 patient but did not have typical viral pneumonia symptoms or fever, and so did not get selected for PCR testing. Given the rapidly growing pandemic and the overwhelmed medical system, a number of patients with typical COVID-19 symptoms could not be hospitalized, even if they were tested positive by PCR. The combination of the false negative rate of PCR testing, the biased pre-screening procedure for patients to get tested, and hospital space limitation results in an increasing number of nonhospitalized COVID-19 patients. These patients are generally self-quarantined with prescriptions for alternative medicine to help ameliorate their symptoms.

Most of the prescribed alternative medicines are, however, neither specific nor highly effective for COVID-19 treatment. There is an urgent need of alternative medicine to help patients relieve symptoms during self-quarantine, and possibly to help increase their chances of survival and recovery from the infection.

The outbreak of COVID-19 in Wuhan, China, in January 2020, was the first strike on public health system by SARS-CoV-2. 5 Patients infected with COVID-19 had a high chance of developing severe pneumonia and acute respiratory distress syndrome (16%-17%) and the mortality rate was high (4.3%-11%). 3, [5] [6] [7] Hospitalization became the only possible way for severe COVID-19 patients to receive medical supports and treatment against symptoms. The unexpected outbreak with a rapidly growing patient number placed a significant demand of medical resources, and so hospitals in Wuhan prioritized hospitalization for severe patients with positive PCR test results until mid-February. A number of patients in Wuhan had documented contact histories with confirmed COVID-19 patients and also showed respiratory symptoms, however unfortunately, their upper respiratory system did not have viral loads that were high enough to pass the PCR test threshold, and so they did not have a positive PCR test result to qualify for hospitalization in January and early February in Wuhan. Our medical team tracked and helped treat a number of these nonhospitalized COVID-19 patients.

Here, we report a case of nonhospitalized COVID-19 that never had a positive PCR test result during disease progression and recovery.

This patient was confirmed as a COVID-19 case, by SARS-CoV-2specific antibody test post recovery. This severe COVID-19 patient was self-quarantined and received diammonium glycyrrhizinate (DG), a marketed Chinese traditional medicine with a steroid-like effect, in combination with vitamin C (VC) as alternative medicine. Upon implementation of this treatment regimen, the patient's symptoms were significantly relieved and eventually recovered. In this article, we aim to report more details of this encouraging case and bring DG to the table for discussion about its potential as an alternative medicine to attenuate COVID-19 symptoms in nonhospitalized patients. Of note, this case is not a clinical trial, and we decided to share this information with the hope of increasing treatment options for patients who cannot be "diagnosed" with PCR test, are turned down by hospitals and have to seek alternative medicine for COVID-19 symptoms.

We have received consent from the patient to report this case. Table 1) .

CT scan revealed bilateral distribution of patchy shadows and groundglass opacity ( Figure 1B, upper panel) , typical hallmark of viral pneumonia. On January 29th, sera test for IgM antibodies against common respiratory viruses that may induce viral pneumonia, including influenza A, influenza B, adenovirus, respiratory syncytial virus, parainfluenza, and mumps, all of which returned negative results (Table 1) . We also ruled out recent infections by mycoplasma pneumoniae and chlamydia pneumoniae, since IgM tests for these pathogens returned negative results as well (Table 1) . Given the patient's history of contact with confirmed COVID-19 patients and her typical COVID-19 symptoms, the most possible infection at the time was SARS-CoV-2.

However, the patient was tested negative by RT-PCR for SARS-CoV-2 using samples collected via oropharyngeal swabbing, on January 28th and This patient with suspected COVID-19 was sent home for selfquarantine. Our medical team continued to follow-up and treat this patient during her quarantine at home.

Given that the medicines prescribed in the hospital failed to relieve the patient's symptoms and started to trigger side effects, and that and on February 6th, the patient stopped feeling fatigued ( Figure 1B ).

In about a week, all severe symptoms were resolved, and the patient's appetite improved to the level comparable to her regular appetite. After eight consecutive days with the DG+VC treatment regimen, on February 10th (day 30), the treatment was discontinued as the patient stopped reporting any discomforts.

We continued to monitor the patient's conditions. In follow-up tests, she was tested negative for SARS-CoV-2 by RT-PCR on 

Thus far for COVID-19, there are no pharmacological treatment regimens of proven efficacy. Immunopathology is a leading cause of morbidity and mortality in severe COVID-19 patients. 9 There is an urgent need for treatment regimens that can manage inflammation and tissue damages associated with severe COVID-19, to reduce mortality and buy time for the immune system to clear the virus from the patients.

During the initial COVID-19 outbreak in Wuhan, corticosteroid has been used in hospitals to suppress lung inflammation in COVID-19 patients, 10 however, multiple side effects have been observed. Moreover, recent studies suggested limited clinical benefits of corticosteroid, yet the evidence for this remains largely circumstantial. 11, 12 Here we report DG, a marketed Chinese traditional medicine with a steroid-like effect, in combination with VC as a potential antiinflammatory treatment to relieve severe symptoms from COVID-19. DG is the active ingredient in the traditional Chinese medicinal herb licorice.

It is metabolized into glycyrrhetinic acid, which has a chemical structure similar to that of corticosteroid ( Figure 1A) and thus functions as a glucocorticoid-like drug, which may help provide immune regulation against cytokine storm and reduce inflammation, although might be less stringent than steroids. 13 DG has been used in the clinics for over 20 years in China and Japan as an antiviral and anti-inflammatory drug against hepatitis with few reported side effects, likely via its function in F I G U R E 1 Diammonium glycyrrhizinate+vitamin C as a potential treatment to relieve COVID-19 symptoms. A, Chemical structures of diammonium glycyrrhizinate and corticosteroid are shown. B, Symptoms and treatments of the patient outlined accordingly to days post symptom onset since Jan 12th, 2020 modulating the levels of expression of IL-6 and IL-10. 14 Our previous results also supported its safety and protective effects against colitis using rat models. 15 In an LPS-induced lung acute injury model in mice, DG exhibited potent anti-inflammatory efficacy and attenuated lung injury. 16 Furthermore, DG has protective effects against Aβ 1-42 -induced neurotoxicity. 17 Last but not the least, it has been demonstrated that glycyrrhizic acid derivatives have antiviral activity against SARS-CoV infection in Vero cells. 18 Our article here reports a case of nonhospital COVID-19 that showed significantly positive responses to DG treatment.

Although the exact functions of DG against SARS-CoV-2 infection and the associated immunopathology await further investigations, it is possible that the therapeutic effects of DG observed in this severe COVID-19 patient were a combinatory result of the antiviral and antiinflammatory effects of DG in the respiratory and neurological systems.

Given these encouraging pharmacological effects and the demonstrated safety, as well as the low cost and wide availability of DG and VC, we suggest that a combination of these might be a good candidate for alternative medicine against COVID-19. Implementation of this treatment regimen might worth more attention, and further investigations in clinical trials can be considered to validate its effects in relieving severe symptoms and reducing mortality of COVID-19 in a larger cohort. For suspected COVID-19 patients who cannot be hospitalized and have no venues for COVID-19 specific prescriptions, we suggest that the combination of DG and VC may be a promising candidate as an alternative medicine to help relieve severe symptoms of COVID-19 during self-quarantine. 8 

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Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing

Clinical features of patients infected with 2019 novel coronavirus in Wuhan

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COVID-19 diagnostic process in mainland China: The math beyond pneumonia

COVID-19: immunopathology and its implications for therapy

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Inhaled corticosteroids and COVID-19: a systematic review and clinical perspective

Redeploying plant defences

Diammonium glycyrrhizinate, a component of traditional Chinese medicine Gan-Cao, prevents murine T-cell-mediated fulminant hepatitis in IL-10-and IL-6-dependent manners

Protective effects of glycyrrhizic acid by rectal treatment on a TNBS-induced rat colitis model

Monoammonium glycyrrhizinate inhibited the inflammation of LPSinduced acute lung injury in mice

Diammonium glycyrrhizinate upregulates PGC-1alpha and protects against Abeta1-42-induced neurotoxicity

Antiviral activity of glycyrrhizic acid derivatives against SARS-coronavirus

Glycyrrhetinic acid and its derivatives as potential alternative medicine to relieve symptoms in nonhospitalized COVID-19 patients

The authors thank the patient who volunteered to participate in this study and nurses and doctors who helped with tests, medical consulting, and discussions. Research related to signaling pathways regulating airway immunopathology and strategies of therapeutic development in the authors' laboratories is supported in part by grants from the National Institutes of Health (R56AI146226, R21AI137822, and P20GM130555-6610).

Weishan Huang receives research support from MegaRobo Technologies Corporation. The other authors claim no conflict of interests.

HD, WD, SY, and WH designed research and analyzed data; HD, WD, LD, and XY collected data; SY and WH wrote the manuscript.

http://orcid.org/0000-0002-1330-1131