A Review of South African Traditional Medicinal Plants Used for Treating Fungal Coinfections in COVID-19 Patients with Respiratory Diseases

Abstract

Fungal infections are still most prevalent in the South African population. Fungal respiratory infections and diseases are the cause of severe clinical challenges and mortality in patients with compromised immune systems. Clinical signs of coronavirus disease of 2019 (COVID-19) such as lung injury, hyperglycemia due to diabetes, host iron and zinc depletion, hypoxia, immunosuppression, steroid therapy, and long-term hospitalization predispose patients to opportunistic fungal infections. Fungal pathogens, including Cryptococcus, Aspergillus, and Candida species, cause coinfections in patients infected with (COVID-19), and this has a negative impact on the patients’ pharmacological management goals. Cryptococcus, Aspergillus, and Candida species cause respiratory infections and illnesses including pneumonia, pulmonary aspergillosis, pulmonary candidiasis, and pulmonary cryptococcosis. South African traditional medicinal plants have been used in the treatment of respiratory symptoms and diseases caused by these fungal pathogens. Medicinal plants contain secondary metabolites possessing antifungal activity against Cryptococcus, Aspergillus, and Candida species. Moreover, medicinal plants are cheaper and easily accessible and are believed to be safe. This review documents the use of South African traditional medicinal plants including Artemisia absinthium, Artemisia afra, Dicoma anomala, Felicia species, Mentha species, Ruta graveolens, and Seasia erosa in the treatment of fungal infections and diseases caused by these pathogens.

1. Introduction

Coronavirus disease of 2019 (COVID-19) patients with asymptomatic, mild, moderate, severe, and critical disease states are at risk of developing coinfection with pathogenic fungal species including Aspergillus, Candida, and Cryptococcus [1, 2]. Research reports suggest that COVID-19 predisposes patients to fungal, and other viral coinfections, and superinfections [3]. Concurrently occurring coinfections pose a massive challenge because it complicates diagnoses and COVID-19 management [3]. COVID-19 by severe acute respiratory coronavirus 2 (SARS-CoV-2) [1, 2, 3, 4] causes respiratory symptoms such as shortness of breath, fever, fatigue, runny nose, headache, chest pain, congestion, anosmia, ageusia, sore throat, confusion, and vomiting [3, 5, 6], similar to those caused by Aspergillus, Candida, and Cryptococcus species infections [3]. An estimated 15% of COVID-19 patients admitted to the hospital’s intensive care units (ICU) become coinfected by Aspergillus [7]. Aspergillus causes pulmonary aspergillosis including allergic bronchopulmonary aspergillosis (ABPA), chronic pulmonary aspergillosis (CPA), and invasive pulmonary aspergillosis (IPA) [8]. COVID-19-associated pulmonary aspergillosis (CAPA) is reported to have a 52% death rate [9]. Aspergillus fumigatus/A. fumigatus and A. flavus are the most common Aspergillus species causing coinfection in COVID-19 patients [4]. Conducted cohort studies on COVID-19-associated pulmonary aspergillosis have described its incidence to be between 2 and 33% [2, 10]. Aspergillosis is treated by the antifungal drug class, triazoles [1, 11], voriconazole, and isavuconazole being the first-line therapies [7, 9]. However, there are challenges associated with treatment therapy including the occurrence of azole-resistant A. fumigatus [11] and drug-drug interactions associated with the use of voriconazole, which lead to increased cardiotoxic effects of anti-SARS-CoV-2 agents [1]. The study conducted on COVID-19 patients who were severely and critically ill has revealed that dexamethasone is associated with increased pulmonary aspergillosis risk and death [12]. COVID-19-associated candidiasis (CAC) has occurred in various hospitals across countries [3]. CAC is an opportunistic infection caused by fungal species of Candida genus [3, 13]. Studies conducted in various countries, including the UK, Italy, Egypt, China, Iran, India, Gharbia, and Cairo, have revealed that Candida species including C. albicans, C. tropicalis, C. glabrata, C. auris, and C. parapsilosis are implicated in CAC [4, 13, 14]. Treatment of Candida infections includes azoles, echinocandin, Amphotericin B, and its liposomes [15]. However, there is an emergence of multidrug-resistant Candida species, including C. glabrata, C. auris, inherently resistant C. krusei, C auris-resistant fluconazole, and Amphotericin B, and fluconazole-resistant C. parapsilosis and C. tropicalis [4, 15]. Moreover, COVID-19 patients receiving treatment therapy, including tocilizumab, interferon type 1β, and lopinavir-ritonavir, are at an elevated risk of developing coinfections with Candida spp. [16]. Chloroquine, hydroxychloroquine, azithromycin, and protease inhibitors can cause direct myocardial toxicity, arrhythmias, and death [1]. COVID-19 patients coinfected with human immunodeficiency virus (HIV) or those with compromised immune systems are at risk of developing cryptococcosis [15]. The literature reveals a growing number of cryptococcosis cases in COVID-19 patients who were receiving corticosteroids and immunomodulators [17, 18, 19]. Pulmonary cryptococcosis is caused by two cryptococcal pathogenic species, namely C. neoformans and C. gattii [20, 21]. The recommended treatment therapy for cryptococcosis includes initial treatment with Amphotericin B in combination with flucytosine, followed by maintenance therapy with fluconazole [15, 22]. However, fluconazole-resistant Cryptococcus has been reported, and there is also an increased risk of antifungal toxicity [19]. Phytotherapy is an important solution for treating respiratory infections and diseases in adults and children [23]. Research reports that medicinal plants contain a variety of active secondary metabolites including alkaloids, saponins, and terpenoids with antifungal activity [24]. In South Africa (SA), the majority of people utilize traditional medicinal plants (TMPs) more than Western medicines because TMPs are cheaper, widely available, and considered to be more effective [25]. South African TMPs such as Artemisia absinthium, Artemisia afra, Dicoma anomala, Felicia species, Mentha species, Ruta graveolens, and Searsia erosa have been shown to possess antifungal activity against fungal pathogens, including Cryptococcus, Aspergillus, and Candida species [19, 26, 27, 28, 29].

2. South African traditional medicinal plants used in the treatment of respiratory diseases caused by fungal pathogens

2.1 Artemisia species

Artemisia is the most widely distributed genus belonging to the Asteraceae family [26, 27]. It consists of over 500 plant species of small herbs and shrubs, which are classified as annual, biennial, and perennial natural plants [27, 30]. These plants are used as traditional medicines [26]. Among all 500 Artemisia species, two species, Artemisia afra and Artemisia absinthium are the most used in SA [30]. Artemisia afra Jacq. ex Willd (Figure 1), also known as Wilde als in Afrikaans, African wormwood in English, Lengana in Sesotho, Umhlonyane in isiXhosa, and Mhlonyane in isiZulu, is a South African medicinal plant commonly used to treat respiratory symptoms and conditions such as bronchitis, asthma, colds, coughs, fever, pneumonia, sore throat, chills, whooping cough and headache [6, 19, 28, 30, 31]. A. afra is also used in combination with other TMPs such as E. globulus and Lippia asperifolia as prophylaxis for lung inflammation and to treat influenza [28]. The crude extract of A. afra has shown antifungal activity against Candida albicans, Cryptococcus neoformans, and Aspergillus species including Aspergillus ochraceus, Aspergillus niger, and Aspergillus parasiticus (Table 1) [19, 28, 32]. The leaves of A. afra contain numerous phenolic compounds with antimicrobial activity [33]. A. afra methanolic crude extract contains scopoletin, betulinic acid, and acacetin with good antimicrobial activity [34]. Other secondary metabolites including alkaloids, tannins, saponins, steroids, cardiac glycosides, and anthraquinones, are found in the crude extract and essential oil of A. afra [35]. Toxicity testing results of A. afra extract on McCoy fibroblast cell lines indicated moderate toxicity [19]. A. absinthium (Figure 2), also known as Wormwood, Green ginger, Absinthium, or Absinthe in English, is used traditionally to treat fever [27, 29]. However, when used for a long period, A. absinthium is reported to be responsible for the central nervous system associated-adverse effects in patients such as convulsions, hallucination, and insomnia [27]. It contains secondary metabolites including lactones, terpenoids, flavonoid glycosides, organic acids, tannins, and phenols [27]. Moreover, A. absinthium has antifungal activity against C. albicans, A. niger, and A. flavus (Table 1) [29]. A. absinthium is reported to be nontoxic when tested on Wistar Hannover rats for 13 weeks [77].

Figure 1.

Artemisia afra.

South African TMPs	Venicular names	Traditional uses in respiratory conditions	Inhibited fungal pathogens implicated in coinfections in COVID-19 patients	Secondary metabolites responsible for the antifungal activity
Artemisia afra	Wild als, African wormwood, Lengana, Umhlonyane, Mhlonyane [6, 19, 28, 30, 31]	Asthma, bronchitis, colds, coughs, sore throat, chills, fever headaches, lung, inflammation, influenza, whooping cough, pneumonia [6, 19, 28, 30, 31]	C. albicans, C. neoformans [19, 28, 32]	Phenolic compounds, scopoletin, betulinic acid, acacetin, alkaloids, tannins, saponins, steroids, cardiac glycosides, anthraquinones [33, 34, 35]
Artemisa absinthium	Wormwood, Green ginger, Absinthium, Absinthe [27, 29]	Fever [29]	C. albicans, A. niger, A. flavus [27, 29]	Lactones, terpenoids, flavonoids, flavonoid glycosides, organic acids, tannins, phenols [27]
Dicoma anomala	Fever bush, Hloenya, Maagbitterwortel, Inyongana, Isihlabamakho-ndlwane [36, 37]	Cold, cough, fever, sore throat [36, 37, 38]	C. albicans, A. niger; [36, 39]	Phenolic acids, flavonoids, tannins, saponins, triterpene, phytosterols, acetylenic compounds, sesquiterpene, lactones, diterpene [40]
Felicia muricata	White Felicia, Ihbosisi [41, 42, 43]	Headaches, fever [41, 43, 44, 45]	A. niger, A. flavus [41]	Phenols, proanthocyanidins, flavonols, sesquiterpene, lactones, triterpenoids flavonoids [41, 46]
Mentha spicata	Spearmint, brown mint, Garden mint, Lady’s mint, Imboza [47, 48]	Asthma, cold, fever, flu [48, 49, 50]	A. niger, C. neoformans, C. albicans [48, 51, 52, 53]	Biopeptides, flavonoids, tannins, sterols, polyphenols, sterols, triterpenes, glycosides [53, 54]
Mentha longifolia	Wild mint, Horsemint, Silver mint, Koena, Inxina, Inzinziniba [49, 55, 56, 57, 58, 59]	Common cold, cough, sore throat, fever, headache, flu [60, 61]	C. albicans; C. glabrata, A. flavus, A. fumigatus, A. niger [55, 57, 62]	Flavonoids, ceramides, cinnamates, ester, ketones, monoterpenes, phenols, polyene, sesquiterpenes [60]
Ruta graveolens	Ruta, rue, Garden rue, Herb of grace, Wynruit [63, 64, 65, 66]	Fever, headache, colds, influenza [64, 66]	C. albicans, C. tropicalis; C. parapsilopsis, C. glabrata; A. flavus, A. fumigatus,; A. niger; C. neoformans; [67, 68, 69, 70]	Coumarins, coumarin dimers, dihydrofuranocoumarins, quinolone, furoquinoline, dihydrofuroquinoline, phenolic acids, alkaloids, flavonoids [71]
Searsia erosa	Broom karee, Besembos, Tśilabele [68, 72, 73]	Colds [72, 73]	C. neoformans [74]	Alkaloids, flavonoids, terpenoids, saponins, tannins [74]
Searsia lancea	African sumuc, Willow rhus, [68]	Colds, influenza [68]	A. flavus [75]	Flavonoids, tannins, phenols [76]
Searcia natalensis	Natal rhus [76]	Influenza [76]	C. albicans, A. Niger [75]	epicatechin, 3β-sitosterol, 3β-sitosterol glucoside stigmasterol, lupeol [75]

Table 1.

Traditional medicinal plants used in respiratory diseases caused by fungal pathogens causing coinfections in COVID-19 patients.

Figure 2.

Artemisia absinthium.

2.2 Dicoma anomala

Dicoma anomala (Figure 3) is a herbaceous plant belonging to the Asteraceae family of plants [36, 37]. It is known as Maagbitterwortel in Afrikaans, Fever bush in English, Hloenya in Sesotho, Inyongana in isiXhosa, and Isihlabamakhondlwane in isiZulu [36, 37]. In SA, Dicoma anomala is distributed in various provinces including the Free State, Limpopo, Gauteng, Northwest, Northern Cape, and Kwazulu natal [36, 38, 78]. Two subspecies, Dicoma anomala and Dicoma gerrardi are found in SA [37]. Dicoma anomala is used traditionally to treat respiratory symptoms and diseases including coughs, colds, and fever [36, 37, 38]. It has antifungal activity against C. albicans, and A. niger (Table 1) [36, 39]. Dicoma anomala produces bioactive compounds including phenolic acids, flavonoids, tannins, saponins, triterpenes, phytosterols, acetylenic compounds, sesquiterpene, lactones, and diterpene [40]. Results of acute and subchronic oral toxicity assessment of aqueous root extract of Dicoma anomala in rats for 14-day acute and 90-day subchronic toxicity testing have revealed that Dicoma anomala is not toxic at 0.5 to 2000 mg/kg [39]. Dicoma anomala dichloromethane: Methanol extract was found to be nontoxic at concentrations below 200 μg/ml when tested on Chang liver cells [79].

Figure 3.

Dicoma anomala.

2.3 Felicia muricata

The genus Felicia consists of small shrubs of 85 known species of annual and perennial herbaceous plants [80]. Felicia muricata (Figure 4) is an aromatic herb belonging to the Asteraceae family [41, 42]. It is known as white Felicia in English and Ihbosisi or Ubosisi in isiXhosa [41, 42, 43]. Felicia muricata is widely distributed in SA, and in the Eastern Cape province, it is used traditionally to treat respiratory symptoms including headaches and fever [41, 43, 44, 45]. It has antifungal activity against Aspergillus species including A. niger and A. flavus (Table 1) [41]. Felicia muricata contains secondary metabolites including phenols, proanthocyanidins, flavonols, sesquiterpene lactones, triterpenoids, and flavonoids [41, 46]. The study conducted in Wistar rats using Felicia muricata aqueous leaf extract at 50, 100, and 200 mg/kg body weight for 14 days revealed that the plant is mildly toxic and safe for oral use, and requires further investigation [81].

Figure 4.

Felicia muricata.

2.4 Mentha species

Genus Mentha is a perennial and annual plant belonging to the Lamiaceae family [82, 83]. Mentha spicata (Figure 5) is also known as Spearmint, Brown mint, Garden mint, Lady’s mint in English, and Imboza in isiXhosa [47]. It is a creeping rhizomatous and perennial herb cultivated in various tropical to temperate regions including SA [47]. Mentha spicata is used traditionally to treat respiratory symptoms and conditions such as asthma, flu, cold, and fever [48, 49, 50]. It has antifungal activity against A. niger, Cryptococcus neoformans, and Candida albicans (Table 1) [48, 51, 52, 53]. Mentha extracts and oils contain biopeptides responsible for their antifungal activity [54, 84]. Mentha spicata contains secondary metabolites including flavonoids, tannins, sterols, polyphenols, sterols, triterpenes, and glycosides [53]. Toxicity investigational study of Mentha spicata methanolic extract in mice using 500, 1000, 2000, and 5000 mg/kg for 24 hours to 14 days revealed that the plant is safe for oral administration [53]. Mentha longifolia (Figure 6), also known as Wild mint, Silver mint, and Horsemint in English, Koena in Sesotho, Inxina, and Inzinziniba in isiXhosa, is naturally present in SA [49, 55, 56, 57, 58, 59]. It is traditionally used to treat respiratory conditions including the common cold, cough, sore throat, headache, flu, and fever [60, 61]. Mentha longifolia has antifungal activity against Candida albicans, Candida glabrata, A. flavus, A. fumigatus, and A. niger (Table 1) [55, 57, 62]. The essential oil of Mentha longifolia contains a terpenoid and methanol, that has fungistatic and fungicidal activities [85]. Mentha longifolia possesses other secondary metabolites such as flavonoids, ceramides, cinnamates, ester, ketones, monoterpenes, phenols, polyene, and sesquiterpenes [60]. A toxicity testing study of Mentha longifolia methanolic extract in rats revealed that the acute oral dose was nontoxic [86].

Figure 5.

Mentha spicata.

Figure 6.

Mentha longifolia.

2.5 Ruta graveolens

Ruta graveolens (Figure 7) belongs to the Rutaceae family [63]. It is commonly known as Ruta, Rue, Garden rue, and Herb of grace in English, and Wynruit in Afrikaans [63, 64, 65, 66]. Ruta graveolens is distributed worldwide including in SA [64, 66]. It is used traditionally to treat respiratory symptoms and diseases including fever, headache, colds, and influenza [64, 66]. Ruta graveolens has antifungal activity against Candida albicans, Candida tropicalis, Candida parapsilosis, Candida glabrata, Aspergillus flavus, Aspergillus fumigatus, and Cryptococcus neoformans (Table 1) [67, 68, 69, 70]. The essential oil of Ruta graveolens contains ketones responsible for antimicrobial activity [67]. Ruta graveolens is rich in bioactive compounds including coumarins, coumarin dimers, dihydrofuranocoumarins, quinolone, furoquinoline, dihydrofuroquinoline, phenolic acids, alkaloids, and flavonoids [71]. Toxicity investigation of Ruta graveolens in Wistar rats has shown that the plant’s seeds extract at 50 mg/kg/day was not toxic after oral administration for 4 weeks [87].

Figure 7.

Ruta graveolens.

2.6 Seasia species

The genus Searsia (previously known as Rhus) belongs to the family Anacardiaceae. It is widely distributed in tropics and subtropics areas globally mostly in the African continent, especially southern Africa [88, 89]. Most Searsia species such as Searsia erosa, Searsia divaricate, Searsia lancea, Searcia natalensis, and Searsia undulata are traditionally used to treat respiratory illnesses including colds, influenza, and microbial infections [68, 90]. Searsia species have pharmacological activities including anti-inflammatory, anticancer, antiviral, antimalarial, antidiarrheal, and antioxidant activities [91]. Searsia erosa (Figure 8), also known as Broom karee, Besembos in English, and Tśilabele in Sesotho [68, 72, 73], is used traditionally to treat respiratory diseases including colds [72, 73]. It has antifungal activity against Cryptococcus neoformans (Table 1) [74]. Aqueous extracts of Searsia erosa were found to be nontoxic when tested using the brine shrimp lethality assay [74]. Searsia lancea (Figure 9) also known as African sumuc, and Willow rhus in English is used to treat colds and influenza [68]. It contains bioactive compounds including flavonoids, tannins, and phenols [75]. Searsia lancea has antifungal activity against A. flavus (Table 1) [76]. Searsia natalensis (Figure 10), also known as Natal rhus in English is used to treat influenza [76], possesses secondary metabolites including epicatechin, 3β-sitosterol, 3β-sitosterol, glucoside stigmasterol, lupeol [75]. Searsia natalensis has antifungal activity against C. albicans and A. Niger [75]. There are no studies documenting the toxicity analysis of reported Searsia species, and further studies are warranted to determine the safety of these medicinal plants.

Figure 8.

Searsia erosa.

Figure 9.

Searsia lancea.

Figure 10.

Searsia natalensis.

Table 1 shows the traditional use of South African TMPs in respiratory conditions including, asthma, bronchitis, colds, coughs, sore throat, headaches, lung inflammation, influenza, chills, whooping cough, pneumonia, and fever [6, 19, 28, 29, 30, 31, 63, 70, 85]. These TMPs are also reported to possess antifungal activity against Aspergillus, Candida, and Cryptococcus species, which are implicated in coinfections with COVID-19.

3. Conclusions

This review has summarized TMPs commonly used in the treatment of respiratory diseases caused by fungal pathogens such as Aspergillus, Candida, and Cryptococcus species implicated in coinfection in COVID-19 patients. Artemisia absinthium, Artemisia afra, Dicoma anomala, Felicia species, Mentha species, Ruta graveolens, and Searsia erosa have been used in SA for the treatment of respiratory symptoms and diseases including asthma, bronchitis, colds, coughs, sore throat, headaches, lung inflammation, influenza, chills, whooping cough, pneumonia, fever, and flu. These TMPs contain secondary metabolites responsible for their antifungal activities. In vitro and in vivo toxicity studies have confirmed that these TMPs are nontoxic for oral administration. However, further testing using animal models and clinical studies are required to profile the pharmacokinetics and pharmacodynamics of these TMPs before recommendations to use in coinfections in COVID-19 patients.

Acknowledgments

We acknowledge the Central University of Technology, Department of Health Sciences and Walter Sisulu University, Department of Internal Medicine and Pharmacology, and National Research Foundation (Black Academics Advancement Programme).

Conflict of interest

The authors declare no conflict of interest.