Herbal Medicine for Coronavirus Disease 2019 (COVID-19) in Children: a Literature Review

Abstract

Objectives Few studies to date reviewed herbal medicines prescribed to pediatric patients with coronavirus disease 2019 (COVID-19). We aimed to summarize and analyze these herbal medicines. Methods Nine databases were searched for studies published up until November 24, 2020. Nine case reports and one case series involving 17 pediatric patients were included in the study. The clinical symptoms, interventions, outcomes, pattern identification, composition, and frequency of herbal medicine administration were analyzed. Results The symptoms of pediatric patients with COVID-19 treated with herbal medicines were mild or moderate. Herbal medicines have been used to alleviate symptoms, such as fever and cough. No adverse events were reported. All of the patients who received herbal medicines were discharged from the hospital after symptomatic relief. Pattern identification revealed that the lungs were the most affected organs. Epidemic toxins, wind, dampness, and heat were the primary etiological factors. More pediatric patients with COVID-19 were prescribed a combination of herbal and Western medicines than herbal medicines alone. The frequently used herbs include Glycyrrhizae Radix et Rhizoma, Lonicerae Flos, Scutellariae Radix, Armeniacae Semen, Citri Reticulatae Pericarpium, and Astragali Radix. Conclusions Our review can serve as a reference for the treatment of COVID-19 in children.

Ⅰ. Introduction

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)^1,2). Currently, COVID-19 is spreading rapidly worldwide, posing a serious threat to public health. As of February 1, 2021, more than 100 million confirmed cases of COVID-19 and 2 million COVID-19-attributed deaths worldwide³⁾. It has been reported that children and adolescents accounted for approximately 13% of all COVID-19 cases⁴⁾.

Pediatric COVID-19 patients are asymptomatic or have common symptoms, such as fever and cough. These symptoms may be accompanied by gastrointestinal symptoms, such as diarrhea^5,6). Children infected with COVID-19 are less likely to develop serious illnesses than adults^7,8). However, recent studies have shown that the hospitalization rates among children with COVID-19 are not low. Approximately one in three children in the United States is admitted to the intensive care unit due to COVID-19. This rate is similar to that reported for adults^9,10). In Spain, 60% of pediatric COVID-19 patients require hospitalization, and approximately 10% are admitted to the intensive care unit¹¹⁾.

No drugs have been officially approved by the United States Food and Drug Administration for the treatment of COVID-19 in children. This has led healthcare workers to use several drugs¹²⁾. Concerns have also been raised about the high rates of antibiotic prescriptions in a state of uncertainty about specific treatment options⁵⁾.

Traditionally, herbal medicines are used to prevent and treat viral infections. They have been shown to be effective for the treatment of respiratory infections¹³⁾. Many clinicians have suggested that herbal medicine is effective in preventing the spread of COVID-19^13,14). Guidelines have been published regarding the use of herbal medicines in the diagnosis and treatment of patients with mild-to-critical COVID-19¹⁵⁾. However, there are limited studies or reviews on the diagnosis and treatment of pediatric patients with COVID-19 using herbal medicine. Owing to dissimilarities in pharmacokinetics and pharmacodynamics between children and adults, the use of herbal medicines requires caution. In general, children have decreased absorption, metabolism, and excretion of drugs compared with adults¹⁶⁾. Therefore, it is necessary to analyze herbal medicine treatments for pediatric patients with COVID-19 to provide additional accurate information. By reviewing articles on the treatment of COVID-19 pediatric patients with herbal medicine, we aimed to summarize and analyze oral herbal medicines for COVID-19 in children. We analyzed these medicines in terms of single or combination therapy with Western medicine, herbal composition, pattern identification, and treatment progress.

Ⅱ. Materials and Methods

A. Search Strategy

Two authors performed a literature search of the electronic databases from inception to November 24, 2020. There were no language restrictions English databases included: PubMed, Cochrane Library, Embase (via Elsevier), Allied and Complementary Medicine Database (AMED) (via EBSCO), and Cumulative Index to Nursing and Allied Health Literature (CINAHL). The Chinese databases included the Chinese National Knowledge Infrastructure Database (CNKI) and Wanfang Database. Korean databases include the Oriental Medicine Advanced Searching Integrated System (OASIS) and the Korean Association of Medical Journal database (KoreaMed).

The searches were conducted in English, Chinese, and Korean. The following search terms were used in PubMed: (coronavirus disease 2019 OR COVID-2019 OR COVID-19 OR Coronavirus OR Coronavirus Infection* OR 2019 novel coronavirus OR 2019-nCoV OR novel coronavirus pneumonia OR NCP OR severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR novel coronavirus OR new coronavirus OR Wuhan seafood market pneumonia virus OR Wuhan coronavirus) AND (herbal medicine OR traditional medicine OR East Asian traditional medicine OR oriental medicine OR Chinese medicine OR Chinese herbal medicine OR Korean medicine OR herbal formula OR herb).

B. Inclusion and Exclusion Criteria

1. Types of Studies

Case reports or case series that used herbal medicine with or without Western medicine for COVID-19 were eligible.

2. Participants

Children and adolescents aged ≤18 years who were diagnosed with COVID-19 were included regardless of sex, race, nationality, or severity. If data on children could be extracted from a case study involving both adult and pediatric patients, the study was included in the review. However, if data on pediatric patients could not be extracted from a case study because patient information concerning adult and pediatric subjects was integrated, the study was excluded from the analysis.

3. Intervention

Any type of oral herbal medicine treatment, with or without Western medicine for COVID-19, was included. Oral herbal medicines include traditional herbal decoctions, powders, pills, ointments, and patent Chinese medicine.

4. Outcome

The primary outcomes included the following: clinical outcomes (discharge or death), conversion time to obtain negative test results for SARS-CoV-2 nucleic acids, and time to clinical recovery (abatement time of fever and duration of cough or rhinorrhea). The secondary outcomes included the following: (1) length of hospital stay, (2) total clinical effective rate = (number of cured cases + number of effective cases)/total number of cases × 100 (%), (3) pulmonary function and imaging, (4) duration of mechanical ventilation, (5) quality of life, and (6) incidence of adverse events.

C. Study Selection, Data Extraction, and Data Analyses

Two independent authors searched the databases, screened the titles and abstracts of the articles, and determined the studies that met the predefined criteria. Data from the literature were extracted independently by the authors using a standardized data extraction form. The extracted information included country name, number of trials included, clinical data on participants, interventions, and treatment outcomes. The composition of the herbal decoction prescription for each case was analyzed, and the frequency of each herbal decoction was calculated using Microsoft Office Excel 2016 (Microsoft Corporation, Redmond, WA, USA). Disagreements were discussed until consensus was reached.

D. Methodological Quality

Both authors read the papers and independently assessed their quality according to the tool for evaluating the methodological quality of case reports and case series suggested by Murad et al.¹⁷⁾. The tool comprises four domains: selection, ascertainment, causality, and reporting. These domains were evaluated using eight questions. However, questions 4 (“Were other alternative causes that may explain the observation ruled out?”), 5 (“Was there a challenge/rechallenge phenomenon?”), and 6 (“Was there a dose–response effect?”) were judged to be unrelated to our study question as they were more relevant to adverse drug events. Therefore, these three questions were excluded from the analysis. The case studies were evaluated using the remaining five questions. If all the domains were satisfied, the study was judged to be of “good quality”. If more than three domains were satisfied, the study was judged to be of “fair quality”. If one or two domains were satisfied, the study was judged to be of “poor quality”.

Ⅲ. Results

A. Literature Search and Study Characteristics

The literature search identified 10,102 studies. A total of 165 studies were included by screening the titles and abstracts of 8,780 studies after removing duplicates. Finally, 10 case studies met the predefined inclusion criteria after a review of full-text articles (Figure 1)^18-27). The characteristics of the included studies are summarized in Table 1. Nine case reports and one case series were identified. Nine studies^19-27) were published in China and one study was published¹⁸⁾ in Japan. Seven studies^21-27) were published in Chinese and three studies^18-20) were published in English. Among the ten studies, 17 cases with children met the inclusion criteria. Eleven children were boys and six were girls. Further, the age of 11 of the children was <10 years, and that of six of the children was 10–18 years. Eight children were prescribed herbal medicines alone and nine children were prescribed both herbal and Western medicines.

Table 1. Summary of the Included Studies

M, male; F, female; HM, herbal medicine; WM, Western medicine; NA, not available

Figure 1. Flowchart of the literature search and study selection

AMED, Allied and Complementary Medicine Database; CINAHL, Cumulative Index to Nursing and Allied Health Literature; CNKI, Chinese National Knowledge Infrastructure Database; OASIS, Oriental Medicine Advanced Searching Integrated System

B. Clinical Symptoms

Thirteen pediatric patients had COVID-19 symptoms, such as fever and cough^18-25) and four patients were asymptomatic^26,27). The main symptoms were fever (n = 6) and cough (n = 6)^{19,21,22,25,27)}. Other respiratory symptoms include runny nose, nasal congestion, shortness of breath, and sore throat. Taste disorders were observed in two patients¹⁸⁾. Two patients had digestive symptoms, such as diarrhea²⁰⁾ and nausea²¹⁾. The details of pediatric patients in the included studies are shown in Table 2.

Table 2. Cases of Children with COVID-19 Who Were Prescribed Herbal Medicine

y, year; mo, months; F, female; M, male; NA, not available; DH, duration of hospitalization; NR, not reported; bid, 2 times a day; tid, 3 times a day; qd, once a day; CT, computed tomography; ALT, alanine aminotransferase; AST, aspartate transaminase; CK-MB, creatine kinase myocardial band; MBT, maximum body temperature; *The date of hospitalization was calculated on the first day of hospitalization as day 0.

C. Radiologic Tests

Of the 17 included pediatric patients, 15 underwent radiologic testing^19-27); 13 underwent chest CT and two patients underwent chest radiography^21,25). However, the results were not reported for 4 patients who underwent chest computed tomography (CT)²⁷⁾. Therefore, 11 radiological test results were confirmed. Normal findings were reported in three patients^22,24). Imaging findings revealed lung marking thickening in three patients, small nodules and bronchovascular bundle thickening in one patient¹⁹⁾, and ground-glass opacities in one patient²⁷⁾. Furthermore, in three patients^20,21,23), the findings were suggestive of pneumonia.

D. Pattern Identification

The pattern identification used in the included studies was described according to the World Health Organization International Standard Terminology for Traditional Medicine²⁸⁾. Pattern identification was used in five of the 17 patients (Table 3)^20,21,23,25). Pattern identification applied in the early stage of COVID-19 was “Lung qi failing to diffuse due to wind-damp”^21,25) and “Depressed heat damaging fluid”^22,24). For the middle stage, “Damp-heat inner blocking and epidemic toxin blocking the lung”^21,25) and “Damp-heat blocking upper and middle energizer, dual deficiency of qi and yin, lung and spleen qi deficiency”^21,25) were used. In the recovery stage, “lung and spleen qi deficiencies were applied to two patients^21,25). One patient, whose stage was not specified, was diagnosed with “Epidemic toxin blocking the lung”²³⁾.

Table 3. Herbal Medicines and Pattern Identifications for Treating Pediatric Patients with COVID-19

*No description of the medication dose; NR, not reported; +etc., in the reference literature, all the herbs were not described, and were indicated as “etc. (et cetera)” ; ^†A modified Qingfei Paidu decoction excluded Ephedrae Herba (麻黃), Cinnamomi Ramulus (桂枝), Bupleuri Radix (柴胡), Asari Radix et Rhizoma (細辛), and Aurantii Fructus Immaturus (枳實) from the original decoction.

E. Intervention

1. Herbal Medicine Treatment

Herbal decoctions were prescribed to eight patients^20-22,24,27), patent medicine was prescribed to four patients^18,19,25), and both types of herbal medicines were prescribed to five patients^23,26,27) (Table 2). In total, one–seven herbal medicines were prescribed to one patient. The names and composition of the herbal decoctions are listed in Table 3.

2. Frequency of Herbs Prescribed in Herbal Decoctions

When analyzing the herbal medicines used in each case, the most frequently prescribed herb was Glycyrrhizae Radix et Rhizoma (甘草, n = 13), followed by Lonicerae Flos (金銀花, n = 9), Scutellariae Radix (黃芩, n = 9), and Armeniacae Semen (杏仁, n = 8) (Table 4, Figure 2). The therapeutic effects, properties, flavor, and channel tropism of each herb are shown in Figure 2.

Table 4. Frequency of Herbs Used in the Herbal Decoction for the COVID-19 in Children

Figure 2. Frequency of herbs used in the herbal decoction for the management of pediatric COVID-19

3. Western Medicine Treatment

Of the 17 included patients, eleven patients were given a combination of Western and herbal medicines. Western medicines prescribed with herbal medicines include recombinant human interferon-α2b (spray or injection)^22,24-27), oral antivirals (such as lopinavir/ritonavir and ribavirin tablets)^24,26,27), antibiotics (e.g., cefixime and azithromycin tablets)²⁶⁾, antitussive expectorants (such as ambroxol hydrochloride oral solution)¹⁹⁾, vitamin C tablets²⁵⁾, and probiotics²⁵⁾ (Table 2).

F. Outcomes

1. Primary Outcomes

All patients with COVID-19 (n = 17) in the included studies were discharged from the hospital after their symptoms had improved. No deaths were reported^18-27). The time of conversion to negative test results for SARS-CoV-2 nucleic acids after the intervention in symptomatic children (n = 12) ranged from five days to 1 month^18-26). One case series²⁷⁾ did not report the timeframe. The duration of the symptoms after the intervention ranged from 2 to 19 days^18,21,23-27).

2. Secondary Outcomes

The length of hospital stay in the 13 patients ranged from 6 to 24 days^{18,19,21-25,27)}. The time to improvement in chest imaging findings after the interventions in four patients ranged from 6 days to 4 weeks^19,20,23,25). In three patients reporting data on routine blood and biochemical tests, the test results were recorded as normal at 6–12 days^{19,20,23,25,26)}. No adverse events related to the herbal medicines were reported in any of the included studies. In the case of Western medicine, one patient experienced nausea and vomiting during oral antiviral therapy (lopinavir/ritonavir). Hence, the therapy was discontinued²⁴⁾. None of the studies reported outcomes, such as the total clinical effective rate, duration of mechanical ventilation, or quality of life.

G. Methodological Quality of case studies

The quality assessment of each study is presented in Table 5. Of the 10 studies, eight studies^18-21,23-26) were evaluated as having fair quality, as they fulfilled three domains, and two studies^22,27) were classified as having poor quality, as they fulfilled two domains. None of the studies met any of the four domains. Except for one study²⁷⁾, the selection domain of nine studies was not fulfilled owing to lack of clarity.

Table 5. Evaluation Results Based on the Tool for Assessing the Methodological Quality of Case Reports and Case Series

¹Do the patient(s) represent(s) the whole experience of the investigator (center) or is the selection method unclear to the extent that other patients with similar presentations may not have been reported?; ²Was the exposure adequately ascertained?; ³Was the outcome adequately ascertained?; ⁴Was the follow-up long enough for outcomes to occur?; ⁵Is the case(s) described with sufficient details to allow other investigators to replicate the research or to allow practitioners to make inferences related to their own practice?; 0 = No; 1 = Yes

Ⅳ. Discussion

The severity of COVID-19 clinical manifestations was divided into four categories: mild, moderate, severe, and critical²⁹⁾. In the included studies, the severity of symptoms in children who received herbal medicine for COVID-19 was primarily mild or moderate. There were no cases of tachypnea, shock, or respiratory failure that required mechanical ventilation. It is known that clinical symptoms in pediatric COVID-19 patients are less severe than those in adults due to reduced expression of angiotensin-converting enzyme 2 (ACE2) receptors, an infectious pathway of SARS-CoV-2^5,30). Most mild or moderate disease stages in pediatric COVID-19 patients who received herbal treatment may originate from these general clinical features. However, as only a few studies were included in this review, it may be difficult to generalize the indications for herbal treatment in pediatric COVID-19 patients to mild or moderate stages. According to randomized controlled trial studies in adults, it has been reported that the range of subjects treated with herbal medicines range between mild and critical cases³¹⁾. In epidemiological studies on COVID-19 in children in China, 2.7%-5.8% of cases were severe or critical^32-34). Therefore, additional studies are required to examine the severe and critical stages in pediatric COVID-19 patients treated with herbal medicine.

In the included cases, eight out of 11 patients showed abnormal imaging findings, such as thickening of lung tissue and bronchovascular bundles, similar to the previously reported chest X-ray features³⁵⁾. A European multicenter study of 82 medical institutions found that 47% of pediatric COVID-19 patients had radiographic findings suggestive of pneumonia and 25% had symptoms of lower respiratory tract infection³⁶⁾. These cases often require intensive care unit admission. Hence, when treating pediatric COVID-19 patients with herbs, chest imaging with X-rays and CT is required in addition to diagnostic tests for SARS-CoV-2.

Lung dysfunction is a major consequence of COVID-19 infection. However, it is necessary to carefully observe not only respiratory symptoms, but also abnormalities in other organ systems. Among pediatric COVID-19 patients treated with herbal medicine, although respiratory symptoms were mild, cases of liver and myocardial damage were observed via blood tests^19,20). Abnormal liver enzymes are common in children with COVID-19. They also serve as prognostic factors for assessing COVID-19^37,38). Cardiovascular disease is emerging as one of the most important and life-threatening complications of adult COVID-19 patients³⁹⁾. The overall severity of heart disease associated with COVID-19 infection appears to be much lower in children than in adults. However, multisystem inflammatory syndrome (MIS-C), which may occur in children during COVID-19, is associated with cardiac complications. Therefore, caution should be exercised^40,41).

All pediatric patients with COVID-19 in the included studies were discharged from the hospital after their symptoms improved. Pediatric patients with COVID-19 have a favorable prognosis and regain their health within 1–2 weeks of disease onset⁸⁾. None of the studies reported any adverse effects of herbal medicine treatments with or without Western medicine in children with COVID-19. It has been reported that mild pediatric COVID-19 patients recover 1–2 weeks after onset⁶⁾. Herbal medicine has been reported to reduce the duration of fever and hospitalization. However, there is insufficient evidence on its effect on the recovery period of pediatric COVID-19 patients³¹⁾.

The COVID-19 treatment guidelines recommend that infectious diseases be treated according to the stage of the disease and via pattern identification during herbal medicine treatment^29,42). Of the 17 patients, 5 who were treated using pattern identification were prescribed various herbal medicines according to the changes in their symptoms or based on the findings of tongue examinations^21,23-25). The lungs were the most affected organs. Epidemic toxins, wind, dampness, and heat were the main etiologies, and the pattern identification used in the studies had some similarities with those used in the article in the guideline review⁴²⁾. For example, “epidemic toxins blocking the lungs, lung, and spleen qi deficiency” were mentioned in the guideline review^21,42). In the guideline review of COVID-19 treatment, pattern identification and prescriptions were divided according to disease⁴²⁾. However, according to our study, pattern identification belonging to the stage was not fixed. For example, “lung and spleen qi deficiency” is a pattern identification used mainly in the recovery stage. However, it can also be used in the middle stage. It was reported that “Lung and spleen qi deficiency” could occur by inducing “Dual deficiency of qi and yin” due to “damp-heat” in the middle stage^21,25).

Thirteen herbs were used more than 5 times. Except Jujubae Fructus, these herbs have been frequently used to treat COVID-19^31,42-45). In particular, Lonicerae Flos, Scutellariae Radix, Forsythiae Fructus, Gypsum Fibrosum, Ephedrae Herba, and Cicadae Periostracum mainly have lung channel tropism, heat-clearing, and exterior-relieving effects, which have been associated with the classification of COVID-19 as a lung-afflicting damp-heat epidemic and the frequent use of antipyretic herbs for treatment^44,46).

The use of qi-tonifying and spleen/stomach channel tropism formed another characteristic of the prescribed herbal medicine. Therapeutic strategies for qi-tonifying and invigorating the spleen/stomach were concerned with not only treating the disease but also helping with recovery. In particular, invigorating the spleen/stomach can remove damp^47,48). Astragali Radix (7 times) and Jujubae Fructus (5 times) were warm-natured and had spleen channel tropism. Astragali Radix has been shown to tonify qi, remove sputum, and treat COVID-19-related renal damage^49,50). Astragali Radix is rarely used in other stages. However, it is often used in the recovery stage of COVID-19 patients⁴²⁾. There have been no reports of pattern identification or disease stage in patients prescribed Astragali Radix. However, the efficacy of these herbs allowed us to speculate that these pediatric COVID-19 patients were in a deficiency syndrome or stage of recovery^26,27). The frequent use of Jujubae Fructus for the treatment of pediatric COVID-19 patients was a distinct feature. Jujubae Fructus is traditionally used to tonify qi, treat blood deficiency, and improve the overall nutritional status^51,52). Jujubae Fructus was prescribed together with Astragali Radix; therefore, it could be speculated that this combination was used to tonify qi and ameliorate the deficiency syndrome in pediatric COVID-19 patients.

Glycyrrhizae Radix et Rhizoma, which was used a total of 13 times, was the most commonly used herb. This is consistent with a previous study that Glycyrrhizae Radix et Rhizoma was the most frequently used herbal medicine for all stages, including mild, moderate, severe, and recovery⁴²⁾. This is most likely because Glycyrrhizae Radix et Rhizoma has antiviral effects and is used as an adjuvant treatment in most herbal prescriptions⁴³⁾. Lonicerae Flos (nine times) has been used to prevent respiratory viral diseases since ancient times and has been found to be efficacious in the treatment of patients with H1N1 influenza virus and adenovirus infections^53,54). Additionally, a study using in silico screening showed that Lonicerae Flos binds to ACE2 to exhibit an anti-COVID-19 effect⁵⁵⁾. Furthermore, the combination of Lonicerae Flos and Forsythiae Fructus (six times) has been reported as a key herbal combination for treating COVID-19⁵⁵⁾. Forsythiae Fructus is one of the five most frequently used herbs for treating COVID-19^31,43,44). Forsythiae Fructus has been reported to be effective against viral bronchitis. Hence, its efficacy in the treatment of COVID-19 may be related to this effect⁴⁴⁾.

Scutellariae Radix (nine times) had a heat-clearing effect and could inhibit the infection of viruses and bacteria; thus, it could be used to treat upper respiratory tract infection of COVID-19^31,45). In particular, the combination of Scutellariae Radix and Glycyrrhizae Radix et Rhizoma (13 times) has been reported to act on immune disease targets⁴⁵⁾. Armeniacae Semen (eight times) is an herb used for pediatric asthma, and one guideline review reported it to be the most used herb in patients with pediatric COVID-19⁵⁶⁾. Amygdalin, the active ingredient of Armeniacae Semen, has a strong affinity for ACE2. Therefore, it is speculated that it can block the spread of SARS-CoV-2⁵⁷⁾. The combination of Armeniacae Semen and Ephedrae Herba (five times) was the most frequently used couplet medicines for the treatment of COVID-19⁵⁸⁾.

According to a review of COVID-19 guidelines, Citri Reticulatae Pericarpium (seven times) is the most frequently used herb to treat COVID-19⁴³⁾. Citri Reticulatae Pericarpium has antipyretic properties and is effective in removing phlegm^59,60). In addition, Citri Reticulatae Pericarpium is often paired with Glycyrrhizae Radix et Rhizoma (13 times) to treat respiratory problems. A combination of these two herbs has been used to treat the symptoms of fatigue and fever^43,61). Gypsum Fibrosum is mainly used for moderate and severe stages, and in particular, when high fever is confirmed, it is additionally used^31,42). Agastachis Herba was used five times, and another study reported it to be the most commonly used drug for the treatment of COVID-19⁴³⁾. Agastachis Herba has been reported to be used in the mild and moderate stages of COVID-19⁴²⁾. Puerariae Radix has an exterior-relieving effect and is often used to treat COVID-19, and the combination of Puerariae Radix and Glycyrrhizae Radix et Rhizoma is often prescribed for the treatment of COVID-19⁴⁵⁾. Cicadae Periostracum has also been frequently used to treat COVID-19 and has been reported to be used specifically for the mild stage^45,62).

More pediatric patients with COVID-19 were prescribed a combination of herbal medicines and Western medicine than herbal medicines alone (Table 2). Recombinant human interferon-α2b, antibiotics, and antivirals are primarily used in Western medicine. Compared with Western medicine alone, herbal medicine combined with Western medicine has been reported to reduce the duration of clinical symptoms, fever, and cough; improve radiological and nucleic acid tests; and increase the recovery rate. No significant difference in adverse events were observed⁶³⁾. Considering this aspect and the ethical issue that a placebo cannot be administered to a control group, it is necessary to proceed with a trial comparing the effects of a combination of herbal medicine and Western medicine with those of Western medicine alone in future clinical trials with children.

We analyzed case reports and a case series of herbal medicine treatment for pediatric COVID-19 patients. Several case studies have applied the proposed tool to methodological quality assessment^64-66). When evaluating the methodological quality of the case studies included in our study, most studies demonstrated fair quality^{18-21, 23-26)}. In the selection domain, most of the studies included in our study were judged to be unsatisfactory. There was no information on how the cases were selected and there was a possibility of selection bias¹⁷⁾. In addition, it was determined that the reporting domain was not satisfied in two of the included case studies^22,27). There is insufficient information regarding treatment and clinical processes that other researchers or clinicians can fully utilize in clinical practice.

Knowledge of the pathogenesis and treatment of pediatric COVID-19 is incomplete⁵⁾. Our review could be used as a reference for herbal medicine treatment of COVID-19 in children. However, this study had several limitations. The number of patients was small and the studies were retrospective. This makes it difficult to draw conclusions regarding the therapeutic effects and safety of herbal medicine treatment for children with COVID-19. In future studies, it is important to accumulate more cases of pediatric patients treated with herbal medicine.