Systematic Review: Guideline-Based Approach for the Management of Asthma and Subtypes via Chinese Medicine

Background Asthma is a chronic condition that results in the inflammation and narrowing of airways, often clinically presenting as wheeze and shortness of breath. Little is known of the mechanisms of action (MOA) of herbs used to treat asthma. The aim of this study is to review existing data regarding known MOA of traditional Chinese medicine which will aid in the understanding of possible interactions between Western drugs and Chinese herbs as well as the standardization of management via a proposed guideline to improve patient safety and possible synergism in the long term. Methods We searched through 5 databases for commonly prescribed herbs and formulas for asthma and narrowed down the search to identify the underlying MOA of individual herbs that could specifically target asthma symptoms. We included studies that stated the MOA of individual herbs when used for treating symptoms of asthma, excluding them if they are described as part of a formula. Results A total of 26 herbs commonly prescribed for asthma with known mechanism of action were identified. Herbs used for asthma were found to have similar MOA as that for drugs. Based on existing GINA guidelines, a guideline is proposed which includes a total of 5 steps depending on the severity of asthma and the herbs' MOA. 16 formulas were subsequently identified for the management of asthma, which consist of 12 “stand-alone” and 4 “add-on” formulas. “Stand-alone” formulas used independently for asthma generally follow the GINA guidelines but do not proceed beyond step 3. These formulas consist mainly of beta-agonist and steroid-like effects. “Add-on” formulas added as adjunct to “stand-alone” formulas, however, mainly act on T helper cells or have steroid-like effects. Conclusion Through the understanding of MOA of herbs and their respective formulas, it will ensue greater patient safety and outcomes.


Introduction
ere has been an increasing trend in the use of complementary and alternative medicine (CAM) [1] since its acknowledgement by the World Health Organization (WHO) in 2018 [2]. Herbs are being used by 75% of the people in the world for their basic healthcare needs [3]. Despite the dominance of Western evidence-based medicine in healthcare settings, people occasionally seek traditional Chinese medicine (TCM) treatments, a widely used form of CAM, for medical conditions such as chronic pain and allergies, including, but not limited to, asthma.
Asthma is a heterogeneous disease that is characterized by chronic, reversible airway inflammation that involves eosinophil granulocytes, mast cells, T cells, and an array of cytokines. As curative treatments for asthma are still not available, patients are increasingly seeking CAM for add-on treatments, resulting in growing concerns over the concomitant use of Western medicine and CAM herbs [4]. Furthermore, most CAM herbs used for asthma have unknown mechanism of actions (MOA).
is could potentially lead to dangerously high concentration of constituents with the same MOA, which may lead to severe side effects.
While Western doctors typically manage asthma using the Global Initiative for Asthma (GINA) guidelines based on the disease severity, TCM adopts a less guideline-based and more individualized therapy via a holistic view of the patient's pathophysiology, resulting in a discrepancy in herbal prescribing between TCM physicians [5]. With increasing scientific evidence to support the use of TCM for asthma [6], it is crucial for both medical doctors and TCM physicians to be aware of the potential risks that come with the simultaneous use of prescribed drugs and herbal medicine.
is review aims to categorise commonly used herbs and empirical prescriptions of TCM based on known MOA of Western medicines to allow both Western and TCM physicians to have a better understanding of how drugs and herbs interact. is will hopefully lead to increased patient safety and possible synergism in the long run, giving patients more choices for an individually tailored treatment and better treatment outcomes.

Types of Studies.
All studies eliciting the mechanism of action of a specific herb in the context of asthma, regardless of the model. Studies which involved the use of multiple herbs simultaneously (i.e., formulas) were excluded.

Electronic Searches.
For this review, we searched EMBASE, PubMed, CENTRAL, Wanfang, and China National Knowledge Infrastructure (CNKI).

Identifying the Herbs.
We first conducted a search to identify herbs which are currently commonly prescribed by TCM physicians by identifying systematic reviews on frequently used herbs or formulas and extracted the relevant herbs from the formulas, using the terms "asthma AND TCM OR Traditional Chinese Medicine OR alternative medicine" in EMBASE, PubMed, CENTRAL, Wanfang, and CNKI ( Figure 1). e list was subsequently confirmed with a senior TCM physician specialising in TCM Formula-logy.
We then extracted the Latin and Mandarin names of the herbs used and identified those used primarily for the treatment of asthma, before searching electronic databases for their mechanisms of action ( Figure 2). Herbs prescribed for supportive treatment were excluded.

Data Collection and Analysis
2.5.1. Selection of Studies. Four review authors (TJ, L, RS, and RM) independently reviewed the titles, abstracts, and keywords of all records retrieved to determine the studies to be assessed. We retrieved full articles for further assessment if the information given suggested that the study: (1) Discussed asthma (2) And administered any of 26 Chinese herbs identified through the initial search A fifth review author (LH) acted as arbiter and resolved any differences in opinion.

Data Analysis.
We first identified the herbs relevant to treating asthma by the formulas which contain them, for reference purposes (Table 1). We then categorised the herbs according to their mechanisms of action (Table 2), plotted a schematic representation of the herbs on the asthma immunopathological pathway (Figure 3), and then compared them against GINA guidelines to identify clinical situations where herbs could see the potential use ( Figure 4).

Results of the Search to Identify Herbs of Interest.
Our initial searches in online databases identified 6843 studies, of which 128 systematic reviews were relevant to our topic, yielding 55 herbs (Figure 1).

Included Herbs.
Of the 55 herbs, 26 were used primarily for asthma treatment.

In vitro
(1) Anti-inflammatory Suppress NO production Inhibit production of PGE2, IL-6, IL-1B Inhibit expression of iNOS and COX-2 by inhibition of NF-KB activation (2) Signalling blockade Prevent activation of MAPK signalling cascade via inhibition of phosphorylation of c-Jun N-terminal kinases, extracellular signal-regulated kinases, and p38 (3) Bronchodilation Activate of B2-adrenoceptors

Lepidium apetalum
In murine models (1) Anti-inflammatory Reduce expression of type 2 cytokines Inhibit differentiation and activation of 2 cytokines Evidence-Based Complementary and Alternative Medicine

Magnolia officinalis
In murine models (1) Anti-inflammatory Inhibit IL-4, IL-6, and IL-17 Decrease serum MDA level Increase SOD and GSH-Px/p-JNK, NF-κB, caspase-3, and cH2 Ax levels Inhibition of the PI3 K/Akt signalling pathway by TLR2 and TLR4 receptors-Steroid-like activities of asthma. Based on known mechanisms, the herbs were divided broadly into beta-adrenergic agonist, steroid-like, anticholinergics, PDE antagonist, leukotriene antagonist, and herbs with monoclonal effects or those affecting signalling pathways (Table 2). e schematic representation on how herbs act on the immunopathological pathways of asthma is depicted in Figure 3. e herbs act mainly on IL-4, IL-5, IL-13, and IL-17A and T cells on asthmatic pathways, which act to mobilize inflammatory cells, tissue repair, and remodelling, causing bronchial hyperreactivity and induction of chemokines.

Proposed Guidelines in Relation to GINA Guidelines.
e proposed guidelines (Figure 4), based on existing GINA guidelines, describe a stepwise approach to treating asthma, where increments in medication are made if existing treatment is insufficient for controlling a patient's symptoms [95].
Step 2 involves the addition of a low dose of corticosteroids.
is can be achieved by adding Magnolia officinalis to the existing herbs or possibly by substituting them with Glycyrrhiza uralensis alone.
Step 3 involves increasing the dose of the beta-2adrenoreceptor agonist to a moderate-high dose and either using a medium dose of corticosteroid or adding a leukotriene receptor antagonist (LTRA) to the lowdose corticosteroid. Pheretima aspergillum is an LTRA and could potentially be useful.
Step 4 involves the addition of either an anticholinergic or an LTRA or increasing to a moderate dose of corticosteroid, whichever was not undertaken during step

Frequently Prescribed TCM Formulas in Asthma.
A total of 16 formulas were identified as frequently prescribed for asthma (Table 3), of which 12 were "stand-alone formulas" which are usually prescribed independently and 4 were "add-on formulas" which are used in addition to "stand-  Evidence-Based Complementary and Alternative Medicine alone formulas" during an acute exacerbation [96]. e MOA of the herbs identified in the formulas was analysed, which demonstrated that "stand-alone formulas" contain herbs with beta-agonist, steroid-like effects or leukotriene antagonist mechanisms, or a combination of beta-agonist and steroid-like effects/leukotriene antagonist. However, "add-on formulas" only had either steroid-like effects or regulated T helper cells.

Mechanism of Action of Herbs and Concomitant Use of
Drugs and Herbs. Despite theoretical differences between TCM and Western medicine, research is increasingly suggesting that herbal medicines have similar MOA to that of Western medicines (Table 1). e understanding of MOA allows characterisation of herbs in relation to Western medicines and improves prescription methods of TCM physicians. For example, TCM physicians will be able to select herbs with beta-agonist effects in patients presenting with acute asthma. It also allows minimisation of possible interactions between herbs and drugs if taken concurrently, and the use of readily available antidotes should occur. Recent research showed that up to 33.6% of patients in the United Kingdom consume both herbal and prescription medicine together [97].
is could result in overdose or interactions when herbs and drugs with similar MOA be consumed concurrently [98,99]. Herbs such as Gypsum fibrosum and Zingiberis rhizoma which have no known MOA should not be used concurrently with Western medicines to prevent the occurrence of any unknown side effects.

Standardization of TCM Management of Asthma.
TCM physicians traditionally adopt a "Syndrome-Based" approach in diagnosing patients which is determined by the symptoms of the patient, looks of the tongue, and character of the pulse [100]. "Syndrome-Based" approach means that patients with the same diagnosis given by Western doctors might be diagnosed as different syndromes by TCM physicians, and as such, different management would be given. It is also a relatively subjective approach depending on the consulting physician(s) [101]. It would likely result in differences in outcomes for patients.
rough the understanding of the underlying MOA of each herb used for asthma, a proposed guideline (Figure 4) can thus be formulated based on existing GINA guidelines [95]. is would ensure a standardized uniform outcome for patients regardless of "syndromes" characterized by TCM physicians and prevent herbs with repetitive or unknown MOA from being prescribed.
Unlike drugs, herbs are usually consumed orally, and their duration of effect has not been elicited. e proposed guideline takes into account the differences in the mode of administration and durations of the effect of herbs despite the similarity in MOA. Similar to existing GINA guidelines, prescription will be stepwise and incremental according to   the severity of their asthma, from step 1 to 5. Worsening of symptoms warrants moving up the ladder, and dose reductions can be made if symptoms improve. is will ensure adequate herbs with appropriate MOA and dosage are prescribed.

Phenotype Specific Asthma erapeutic Targeting of Herbs.
In addition to the standard therapeutic MOA for asthma, herbs also seem to regulate the activity of inflammatory cells and cytokines by acting on particular pathways in the immunopathology of asthma ( Figure 3). is aids not only in understanding of the way herbs work but can also be used to target a particular phenotype of asthma, e.g., downregulation of IgE in allergen-induced asthma. Biologics such as omalizumab, which targets specific cytokines, have long been employed in the management of asthma. Herbs with similar effects could potentially be employed in a similar fashion as biologics. e therapeutic interventions for different phenotypes include IL-17 antagonist (neutrophilic asthma), IL-4/13 antagonist and anti-IgE (allergen-induced asthma), corticosteroids and IL-5 antagonist (idiopathic eosinophilic asthma), and leukotriene antagonist (aspirin exacerbated asthma) [102].
Herbs which target certain phenotypes through their effect on cytokines (Table 2) should be added after standardized therapy has been given and phenotypic assessment has been conducted, in line with GINA guidelines. is serves as an individualised management for patients with different asthmatic phenotypes and will lead to improved treatment outcomes.

Analysis of TCM Formulas Used for Asthma.
Herbs are typically prescribed in various combinations as "TCM formulas," rather than individually. ey can be broadly divided into "Stand-alone formulas" which can be used independently for diseases and "Add-on Formulas" which are usually added as adjuvants to "Stand-alone formulas" to enhance their therapeutic effects (Table 3). Interestingly, the analysis of "Stand-alone Formulas" has shown that despite the differences in herbs used, formulas generally consist of herbs with β-agonist and steroid-like effects as recommended by GINA guidelines [95]. On the other hand, "Addon Formulas" consist of herbs with steroid-like effects or assist in the regulation of T helper cells. However, none of the formulas have proceeded beyond step 3 of the GINA guidelines which could involve the addition of anticholinergics or leukotriene antagonists. In addition, some formulas consist of several herbs with the same MOA, e.g., Ma Xing Shi Gan Tang which comprises of Ephedra sinica Stapf and Glycyrrhiza uralensis, both of which exerts the β-agonistic effect and Gui Zhi Jia Hou Po Xing Ren Tang which is made up of Magnolia officinalis and Glycyrrhiza uralensis, both of which exert steroid-like effects. Unknowingly, Ma Xing Shi Gan Tang could result in arrhythmias as a result of excessive β-adrenergic activity, while Gui Zhi Jia Hou Po Xing Ren Tang could result in iatrogenicinduced Cushing syndrome, one of the well documented side effects of steroids especially in systemic steroids administration [103]. Gui Zhi Jia Hou Po Xing Ren Tang should therefore be avoided and let alone as an "Add-on Formula;" as the "Stand-alone Formula," it is added onto and might already consist of steroidal elements. In addition, one of the existing formulas (Dong Shi Zhi Chuan Ji Ben Fang) also proceeded to include herbs with leukotriene antagonist activity without first including herbs with steroidlike effects as per GINA guidelines. is will likely result in the suboptimal management of patients with asthma.

Conclusion
With a rising number of patients seeking TCM [104], it is paramount for TCM physicians to understand the underlying MOA of herbs. is will allow the standardization of prescribing and result in a more guideline-based approach. In line with this approach, herbs with repetitive or unknown MOA should be avoided to reduce the risk of side effects. Both TCM physicians and doctors should also be wary of possible herb-drug interactions. A guideline-based approach will also allow greater continuity of care should a patient wish to transfer between TCM and Western medicine and prevent under or overmedication. However, patients should still seek the advice of their doctors prior to stopping medications.
Further research on Gypsum fibrosum and Zingiberis rhizoma to identify their underlying MOA is recommended.

Data Availability
e data used to support the findings of this study are available online.

Disclosure
Wong L. H. and Tay L. are the co-first authors.

Conflicts of Interest
e authors declare that there are no conflicts of interest.