Phytochemicals with antifungal compounds derived from plants.
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More than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\\n\\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\\n\\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\\n\\nAdditionally, each book published by IntechOpen contains original content and research findings.
\\n\\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\\n\\n\\n\\n
\\n"}]',published:!0,mainMedia:null},components:[{type:"htmlEditorComponent",content:'
Simba Information has released its Open Access Book Publishing 2020 - 2024 report and has again identified IntechOpen as the world’s largest Open Access book publisher by title count.
\n\nSimba Information is a leading provider for market intelligence and forecasts in the media and publishing industry. The report, published every year, provides an overview and financial outlook for the global professional e-book publishing market.
\n\nIntechOpen, De Gruyter, and Frontiers are the largest OA book publishers by title count, with IntechOpen coming in at first place with 5,101 OA books published, a good 1,782 titles ahead of the nearest competitor.
\n\nSince the first Open Access Book Publishing report published in 2016, IntechOpen has held the top stop each year.
\n\n\n\nMore than half of the publishers listed alongside IntechOpen (18 out of 30) are Social Science and Humanities publishers. IntechOpen is an exception to this as a leader in not only Open Access content but Open Access content across all scientific disciplines, including Physical Sciences, Engineering and Technology, Health Sciences, Life Science, and Social Sciences and Humanities.
\n\nOur breakdown of titles published demonstrates this with 47% PET, 31% HS, 18% LS, and 4% SSH books published.
\n\n“Even though ItechOpen has shown the potential of sci-tech books using an OA approach,” other publishers “have shown little interest in OA books.”
\n\nAdditionally, each book published by IntechOpen contains original content and research findings.
\n\nWe are honored to be among such prestigious publishers and we hope to continue to spearhead that growth in our quest to promote Open Access as a true pioneer in OA book publishing.
\n\n\n\n
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\r\n\r\n\tThis book will cover recent progress in the field of BCI and the challenges for extraction of the human decisions out of brain signals. The presented topics will include neuroscience, recording BCI Signals, signal processing, artifact reduction, machine learning, invasive and noninvasive methods and applications of BCI and ethics.
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However, the impact of these “opportunistic” diseases on human health is not widely highlighted [2]. Due to this, research related to fungi occurs slowly compared to those caused by other pathogens.
Among the different mycotic infections, those caused by Candida and Cryptococcus are the most threatening due to severity of the disease and higher worldwide occurrence [3]. The pathogenicity of fungal infections proceeds in well-organized steps. For example, Candida cell surface adhesion factors first promote its adherence to host surface, followed by releasing of various hydrolytic enzymes and other virulence factors for invasion and damage of the host tissues [4].
Candida species can cause a variety of infections from the mildest to the most severe being candidemia the most frequent hospital infection accounting for up to 15% of bloodstream infections. Candida species are the main causative agents in 50–70% of systemic fungal infections [5].
Cryptococcus species are other yeasts of medical importance, with more than 39 species, among which Cryptococcus gattii and Cryptococcus neoformans are the most clinically relevant [6, 7, 8]. However, other species such as Cryptococcus albidus and Cryptococcus laurentii are emerging pathogens involved in several types of infections [6, 9, 10, 11].
These yeasts are present in several environmental niches, such as woody sites (decomposing tree trunks, mainly eucalyptus, and soil), vegetable remains, domestic dust, and bird excrement, more precisely in Columba livia [12, 13, 14]. The source of the infection is exogenous and occurs primarily by inhalation or by direct inoculation into the tissue after trauma of desiccated spores or yeasts. It is believed that the only source of infection is environmental, since there are no reports of transmission between animals and humans or between humans [15].
The main virulence factors of Cryptococcus species are growth capacity at 37°C, polysaccharide capsule, melanin synthesis, and production of urease and antioxidant enzymes, causing primary or opportunistic cryptococcosis, such as pulmonary, cutaneous, and meningitis diseases [6, 8, 13, 16, 17, 18, 19]. Cryptococcosis is the third opportunistic infection associated with AIDS [20].
In addition to delays in yeast diagnosis, there is currently a limited antifungal armamentarium in use against yeast diseases including only four chemical classes: polyenes, triazoles, echinocandins, and flucytosine. Antifungals act by binding specific components of fungal plasma membrane or its biosynthetic pathways or even cell wall components [21]. However, most of the antifungal agents used in the clinic is fungistatic and often led to the development of resistance by fungal species. Modern early antifungal treatment strategies, such as prophylaxis and empirical and preemptive therapy, result in long-term exposure to antifungal agents, which is a major driving force for the development of resistance.
Among the available antifungal agents, azoles are the preferred and most frequently used drugs for treatment of Candida and Cryptococcus infections. Fluconazole (FLZ), a type of azole, is often preferred in treatments of Candida infections because of its low cost and toxicity, in addition to availability in varied formulations [22]. However, there are many reports that described resistance development among Candida species, especially in relation to azoles.
Infectious Diseases Society of America recommends the treatment of cryptococcosis through FLZ and amphotericin B (AMB) with or without combination with 5-flucytosine (5-FC), followed by prolonged maintenance with fluconazole. Other azole compounds such as itraconazole (ITC), voriconazole, and posaconazole may be used as an alternative to FLZ in cases of contraindication or inefficacy of the latter [23, 24]. However, there has been a progressive increase in isolates of Cryptococcus spp. resistant to FLZ, which complicates the management of cryptococcal meningitis [25]. On the other hand, AMB and 5-FC are not available in all countries and are, respectively, nephrotoxic and hepatotoxic, limiting the anti-cryptococcal therapeutic [24].
Considering the limited availability of antifungals in use and the emergence of resistance, the control of Candida and Cryptococcus infections is a challenge in the modern clinic. In this way there is a continuous need for the search for new substances with new mechanisms of action with the aim of developing novel broad spectrum antifungal drugs with better efficacy.
In this way, plants stand out as the major producers of promising substances, the phytochemicals. Identification of new molecules with antifungal potential for the manufacture of new drugs, more effective and less toxic, is essential to facing the challenge. The use of phytochemicals alone or in combination with traditional drugs represents an important alternative to conventional therapy. The combination of drugs usually requires lower doses of antimicrobials. This reduction might lead to a toxicity decrease, which results in a higher tolerance to the antimicrobial by the patient.
In the last two decades, fungal infections have shown a significant increment. In addition to the increase in the number of patients with compromised immune system, factors such as increasing number of patients using catheters, the use of broad-spectrum antibiotics, the rising number of patients requiring organ transplantations, as well as those with hematological malignancies and diabetes also contribute to this phenomenon [26, 27].
Even though fungal infections cause significant amount of human morbidity and mortality, the impact of these “opportunistic” diseases on human health is not widely highlighted [2]. Due to this, the research into the pathophysiology of human fungal infections is slow in comparison to other disease-causing pathogens. Recently, an editorial published in the journal Nature Microbiology [28] ratified the importance of not neglecting fungi. The call proposed a reflection on fungi and how these microorganisms have been neglected, even with studies already consolidated showing their medical relevance.
The most frequent fungal diseases affecting populations in the world are candidiasis [29, 30, 31, 32, 33, 34] and cryptococcosis [8, 20, 25]. There are several types of candidiasis as mucosal candidiasis, cutaneous candidiasis, onychomycosis, systemic candidiasis [35, 36], and pulmonary candidiasis. An important fact is that candidiasis is an infection that can affect both immunocompromised and healthy people [37, 38]. Candidemia is the most relevant and prevalent nosocomial fungal infection associated with a high mortality rate (up to 49%) in patients with a compromised immune system [39, 40]. The association of Candida with bloodstream infections depends on patient’s condition, age, and geographic region. Candidemia is such an important infection that in 10–40% of cases, it is associated with sepsis or septic shock [41].
Candida albicans continues to be the most prevalent species isolated from fungal infections [27, 42, 43, 44]. However, the prevalence of other Candida species has increase substantially. These species are C. parapsilosis, C. tropicalis, C. krusei, C. glabrata, C. guilliermondii, C. orthopsilosis, C. metapsilosis, C. famata, and C. lusitaniae [44, 45, 46].
Candida species presents high degree of flexibility, being able to grow in extremely different environments regarding to the availability of nutrients, temperature variation, pH, osmolarity, and amount of available oxygen [47]. This fact associated with the high resistance capacity of species to antifungals, their virulent features, and capability of forming biofilms with other species [48, 49] makes the genus Candida a serious risk to human health [50]. Thus, Candida species are highly adaptable and possess numerous strategies to survive in conditions that can affect their overgrowth and alter their susceptibility profiles.
Cryptococcus spp. may remain latent in the lungs, leading to asymptomatic infection, or may cause multifocal lung disease. The latency period of Cryptococcus can range from 6 weeks to more than 1 year after inhalation [51]. The fungus presents neurotrophism and can migrate to the central nervous system (CNS) through hematogenous dissemination and, when crossing the blood-brain barrier, can cause meningoencephalitis [13, 18]. Episodes of mental confusion in patients with cryptococcosis have been described [52, 53]. Neurocryptococcosis is the most severe form of the disease with high mortality rates in the absence of adequate treatment [18, 23]. The mortality due to cryptococcosis is higher than the mortality caused by tuberculosis and similar to that caused by malaria [54].
Another clinical manifestation is cutaneous cryptococcosis, which is rare and usually secondary to hematogenous dissemination. Cutaneous lesions are characterized by an infiltrative plaque of a solid tumor mass that can present ulcerative and necrotic lesion [17]. Pulmonary and cutaneous lesions due to nodular features may be misdiagnosed as tumor lesions [55]. In addition to the respiratory tract, CNS and skin, other sites may be affected: prostate, eyes, adrenal glands, lymph nodes, bone marrow, and liver [51].
Until now, there are three proposals to explain fungal neurotropism. The first is that neuronal substrates present in the basal ganglia promote cryptococcal growth and survival, and, thus, perivascular spaces may serve as a niche for Cryptococcus, as described by [56] in a healthy female patient who had evidence of Cryptococcus infection within the perivascular spaces of the parenchyma. The second proposal describes that it is possible that there are specific neuronal receptors that can attract Cryptococcus to the CNS [57]. The third hypothesis, one of the most widespread, is that the fungus uses neurotransmitters such as dopamine that aids in the synthesis of melanin [19, 57, 58].
Besides the clinical importance of fungal infections caused by theses pathogenic yeasts, interestingly, climatic abnormalities due to phenomena such as La Niña and El Niño have recently been described as important in the distribution and occurrence of mycoses in countries influenced by them [59].
In the last two decades, there has been an increasing, but limited, discovery of antifungal agents [47]. These include azoles, such as fluconazole, itraconazole, ketoconazole (KTC), miconazole, and clotrimazole, polyenes (amphotericin B [AMB] and nystatin), allylamines, thiocarbamates, morpholines, 5-fluorocytosine, and echinocandins (for instance, caspofungins) [21]. However, fungal cells and human cells are eukaryotic, so antifungal compounds target both cell types, resulting in considerable side effects in patients and fewer available targets for drug action. Antifungals target three cellular components of fungi (Figure 1). Azoles inhibit ergosterol biosynthesis by interfering with the enzyme lanosterol 14-α-demethylase in endoplasmic reticulum of the fungal cell. This enzyme is involved in the transformation of lanosterol into ergosterol, a component that is part of the plasma membrane structure of the fungus (Figures 1 and 2). Thus, as the concentration of ergosterol is reduced, the cell membrane structure is altered, thereby inhibiting fungal growth [60].
Mechanisms of action of some traditional antifungal agents on cellular targets. Azoles inhibit the ergosterol synthesis in the endoplasmic reticulum of the fungal cell by interfering with the enzyme lanosterol 14-α-demethylase. Polyenes act by binding to ergosterol present at the cell membrane. Echinocandins inhibit (1,3) β-d-glucan synthase, thereby preventing glucan synthesis.
Specific point of action of antifungal drugs in the ergosterol biosynthesis pathway.
Azoles comprise a five-member azole ring containing two (imidazole) or three nitrogen atoms (triazole) attached to a complex side chain [61, 62]. Imidazoles include KTC, miconazole, econazole, and clotrimazole, and triazoles include FLZ, ITC, voriconazole (synthetic triazole derivative of FLZ of second generation), and posaconazole (hydroxylated analog of itraconazole) [63].
AMB and nystatin bind to ergosterol causing the disruption of the membrane structure and promoting extravasation of intracellular constituents such as ions and sugars and, consequently, cell death [21] (Figure 1).
Pyrimidine analogs include 5-fluorocytosine and 5-fluorouracil (5FU). The first has fungistatic properties and enters the fungal cell through cytosine permease, inhibiting the thymidylate-synthetase enzyme and interfering with DNA. 5-fluorouracil, which in turn can be phosphorylated to 5-fluorodeoxyuridine monophosphate, can be incorporated into RNA molecules [63]. Due to toxicity [64]; stronger side effects, such as hepatic impairment; interference with bone marrow function; and rapid occurrence of resistance especially among Candida species, the clinical use of 5-FC is preferred in association with AMB [65, 66]. In addition, the nephrotoxicity and hepatotoxicity of AMB and 5-FC, respectively, and the unavailability of these antifungals in many countries have limited their use in cryptococcal therapeutic [24].
Host’s immunity, type of infection, site of origin of the samples, toxicity, bioavailability of the drug, and the sensitivity/resistance profile of the isolates interfere in the choice of the type of agent to be used [22]. AMB is considered the gold standard drug for most mycoses that affect patients at risk [67], although it has high toxicity. Azoles have fungistatic properties that affect cell growth and proliferation [65]. Among azoles, KTC was one of the firsts to emerge and was the first alternative to AMB [68]. Currently, FLZ is the drug of choice for most Candida and Cryptococcus infections [64] and is the most recommended antifungal agent for use in invasive candidiasis [47, 49].
For cryptococcosis, the choice of treatment depends on the patient’s immunological status and mainly on the clinical of the disease, if it is just a pulmonary manifestation or if the infection is systemic. Fluconazole is recommended in cases of lung disease with mild to moderate symptoms. Amphotericin B with or without combination with 5-flucytosine is the recommended therapy for more serious infections such as meningoencephalitis, followed by prolonged maintenance with fluconazole [23, 24].
Although azoles are generally well-tolerated, they have limitations such as hepatotoxicity and the emergence of resistance among fungal isolates [69] which provide motivation for improving this class of antifungal agents [68]. For instance, alterations in triazole molecule gave rise to voriconazole (structurally related to FLZ) and posaconazole (related to ITC), both available for systemic therapy [66].
Echinocandins, which include caspofungin, micafungin, and anidulafungin, are a new class of antifungals and have fungicidal effects in all Candida species [66]. They inhibit (1,3) β-d-glucan synthase, thereby preventing glucan synthesis, which is present in the cell membrane of fungi (Figure 1). As this drug acts on the wall structure of the fungus, it has the advantage of a lower side effect in animal cells [47].
Allylamines (terbinafine and naftifine) and thiocarbamates inhibit the enzyme squalene epoxidase, which participates in the synthesis of ergosterol and is encoded by the ERG1 gene (Figure 2). This activity leads to membrane rupture and accumulation of squalene. Allylamine effects can also prevent the production of other sterol derivatives.
To minimize toxicity and resistance, some pharmacological strategies were developed. The preparation and use of new antifungal formulas (liposomal AMB (Ambisome®), AMB lipid complexes (Abelcet®), AMB colloidal dispersions (Amphocil®/Amphotech®), and AMB lipid nanosphere formulations and β-cyclodextrin itraconazole) are one strategy [68]. Others include combination therapies of antifungal compounds (e.g., AMB + 5-FC, FLZ + 5-FC, AMB + FLZ, caspofungin + liposomal AMB, and caspofungin + FLZ) and nanostructuring of conventional antifungal agents [70, 71, 72, 73].
However, all traditional antimycotic drugs have at least one restriction related to their use. Some do not have a broad spectrum of action or are fungistatic. Others have high toxicity and low bioavailability with significant side effects [74]. Therefore, limitations of treatment and drug resistance associated with pathogenicity of the clinical isolates support the urgent need to identify substances that are more effective, with new mechanisms of action in the fight against Candida and Cryptococcus infections.
Most antifungals target sterols or the enzymes that synthesize them. However, the fungistatic nature of many of these antifungals and emergence of clinical drug resistance limits their success. Increased drug resistance in fungi is a problem that cannot be avoided, particularly for FLZ, which is the preferred antifungal for treating yeast infections [75].
The number of people at risk for fungal infections has been increasing, resulting in an increased use of antifungal agents, even as prophylaxis. Thus, besides the existence of some non-albicans Candida (NAC) species presenting inherent resistance to azoles, higher minimum inhibitory concentrations (MICs) for antifungals against C. albicans strains have been observed [76]. The World Health Organization (2014) categorizes antimicrobial resistance as that developed by the microorganism to an antimicrobial drug, which was initially effective in treatment of such infections. Low-dose prophylactic administration of azole derivatives, such as FLZ, for prolonged periods to prevent the occurrence of opportunistic infections in immunosuppressed patients also results in resistant phenotypes [27, 75]. Therapeutic failures and empiric treatment are facts which are likely to collaborate to the increased incidence of fungal infections.
In the last decade, a number of new clinical problems have arisen, requiring new guidelines regarding the treatment of cryptococcosis, mainly because clinical data have suggested that cryptococcal strains have become more resistant to drugs [23, 25]. Some relates say that clinical Cryptococcus isolates are frequently less susceptible to fluconazole than environmental isolates. However, Chowdhary et al. [77] evaluated the susceptibility profile of environmental and clinical strains of C. gattii and observed that environmental samples were less susceptible to fluconazole, itraconazole, and voriconazole in comparison to clinical isolates.
Heteroresistance is also a worrying phenomenon. It consists of the ability of a subpopulation of microorganism to adapt to high concentrations of the drug, resulting in resistant homogenous populations. However, heteroresistant strains return to the initial phenotype when the stimulus with the drug is withdrawn [78].
Some mechanisms for cellular and molecular resistance to FLZ in yeasts are described. In Candida and Cryptococcus, the first is related to the induction of multidrug pumps, which decrease the concentration of drug available in the intracellular compartment of yeast cells. Various genes belonging to the ATP-binding cassette superfamily or to the major facilitator superfamily encode efflux pumps were identified in C. albicans. Overexpression of some transporter genes or of their regulated genes can confer cross-resistance to various azoles [21]. In C. gattii and C. neoformans, AFR1, MDR1, and AFR2 genes encode ABC transporters that expel the azole out of the fungal cell, thereby causing resistance to these drugs [79].
A second mechanism of resistance involves modification of the target enzyme encoded by the ERG11 gene, also known as cytochrome P450 lanosterol 14-α-demethylase (Cyp51). Mutations in this gene prevent azoles from binding to enzyme sites. Another mechanism of resistance is related to mutations in the ERG3 gene which does not convert 14-α-methylfecosterol into 14-α-methyl-3,6-diol in the ergosterol synthesis pathway. This substitution causes azoles to have no fungistatic effects on the fungal cell membrane [21].
Transcriptional regulation is also important for the development of resistance mechanisms. YAP1, a protein, is important for the mechanism of C. neoformans heteroresistance to fluconazole and oxidative stress. Mutant strains of C. neoformans that lost protein YAP1 became hypersensitive to a variety of oxidizing agents and mainly to fluconazole [80].
Resistance to polyenes (AMB) in fungus is less common and in C. albicans is associated with the substitution of ergosterol with a precursor molecule or a general reduction of sterols in the plasma membrane [81]. Reduction of membrane ergosterol renders Cryptococcus neoformans and Aspergillus spp. less susceptible to amphotericin B [82]. Enzymes encoded by ERG3 and ERG2 genes participate in ergosterol biosynthesis and have the main alterations related to AMB resistance because mutations in their genes modify ergosterol content required for the action of polyenes [83].
The main resistance mechanism to echinocandins is related with point mutations in gene that encodes the major subunit of the glucan synthase enzyme (Fks subunit) (Figure 1) and can provide resistance to all echinocandin [84]. Other Candida species also present this resistance mechanism such as C. tropicalis, C. parapsilosis, C. glabrata, C. krusei, C. guilliermondii, and C. dubliniensis [85, 86].
Resistance to 5-FC can be of two types: primary, occurring via cytosine permease (encoded by the FCY2 gene) whose mutation decreases drug uptake [87], and secondary, related to alterations in cytosine deaminase (encoded by FCY1) or uracil phosphoribosyltransferase (encoded by FUR1) activities. Cytosine permease is responsible by conversion of 5-FC to 5-fluorouridine or to 5-fluorouridine monophosphate (5-FUMP) [88]. Resistance is easily developed in fungal isolates from patients who are receiving the drug. However, other molecular mechanisms related to resistance to 5-FC must exist because most of them have not been observed in C. albicans [89].
The increase in the drug-resistant Candida and Cryptococcus strains to commercial antifungals has caught the attention of clinicians and researchers to medicinal plant products (commonly referred as phytochemicals). The use of phytochemicals with greater antifungal potential and different mechanisms of action may be useful in reducing the phenomenon of resistance. Lately, they have become a significant alternative for discovery of commercially viable, economically cheaper, and safe phytomedicines.
Global Action Fund for Fungal Infections (GAFFI), an international organization working to reduce infections and deaths associated with fungi, has reported that approximately 300 million people in the world suffer from a serious fungal infection every year and that among them over 1.35 million deaths are registered [90].
Despite the introduction of new and novel antifungal drugs, their production and impact are slow, and the development of antifungal resistance has forced the attention of researchers toward herbal products, mainly phytochemicals, in search of development of safe and economically viable antifungals.
Populations around the world have used folk medicine as an alternative therapy for various disorders. Currently, many species have been extensively studied in an attempt to discover new biologically active compounds with novel structures and mechanism of action for the development of new drugs.
Medicinal plants are commonly preferred because of their wide level of functional chemical groups with comparatively poor toxic substances, low-cost extracts, fewer side effects, and easy accessibility to people. Various bioactive compounds have been abundantly found such as phytochemicals.
Leaves, as well as the seeds and fruits of plants, have higher levels of phenolic compounds. The concentration of these compounds also depends on the nature of the chemical used as solvent in the extraction process as well as on the growth and storage conditions [91].
The biological activity of plant products has been evaluated against fungi. The ethanol extract, Lonicera japonica aerial parts, a medicinal plant of folk medicine of China that used to treat some diseases, showed a very strong antimicrobial activity against Candida species and potent wound healing capacity [92]. Methanolic extract of Lannea welwitschii leaves was antimicrobial against clinical yeasts. A preliminary phytochemical screening of extracts revealed tannins, flavonoids, alkaloids, and glycosides as compounds [93]. Pyrostegia venusta crude flower extracts, fractions, and pure compounds showed an effective broad spectrum antifungal activity [94].
An extract of Piper betle leaves inhibited the growth of Candida species [95], and four different extracts of Strychnos spinosa showed anti-Candida activity [96]. Hydro-methanolic extracts of leaves from Juglans regia and Eucalyptus globulus and methanol extract of Cynomorium coccineum demonstrated excellent antimycotic property against Candida strains [91, 97]. Akroum [98] showed antifungal activity in an acetylic extract of Vicia faba against C. albicans in vitro and reduced mortality rates in Candida-infected mice that were treated with the extract.
Berberine, a protoberberine-type isoquinoline alkaloid isolated from the roots, rhizomes, and stem bark of natural herbs, such as Berberis aquifolium, Berberis vulgaris, Berberis aristata, Hydrastis canadensis, Phellodendron amurense, Coptis chinensis, and Tinospora cordifolia, was described as powerful reducer of the viability of in vitro biofilms formed by fluconazole-resistant Candida tropicalis cells [99].
Ethanolic and aqueous extracts from different plants from Brazilian Cerrado commonly used in folk medicine such as Eugenia dysenterica and Pouteria ramiflora were promising against C. tropicalis, C. famata, C. krusei, C. guilliermondii, and C. parapsilosis. A phytochemical screening of active extracts from these plants disclosed as main components flavonoids and catechins [100]. Crude extract and fractions (n-butanolic and ethyl acetate ones) from Terminalia catappa leaves showed antifungal properties against Candida spp.; hydrolysable tannins (punicalin, punicalagin), gallic acid (GA), and flavonoid C-glycosides were the active components found in butanolic fraction [101].
Bottari et al. [102] determined the antimicrobial activity of the aqueous and ethanolic leaf extracts of Carya illinoensis. Both extracts had MIC values against seven Candida reference strains between 25 and 6.25 mg/mL. Phenolic acids (gallic acid and ellagic acid), flavonoids (rutin), and tannins (catechins and epicatechins) were likely responsible, in part, for the activity against Candida strains. Further, the extracts inhibited the production of C. albicans germ tubes.
Several woody plant produce medicinal phytochemicals such as polyphenols that are low molecular weight naturally occurring organic compounds containing one or more phenolic groups [103]. Further, polyphenols perform various substantial functions in plant physiology and, therefore, can be found, in lesser or greater quantity, in all of them.
Phenolic acids, flavonoids, tannins, and coumarins are some examples of phenolic compounds found in and extracted from medicinal plants [104] (Table 1). Research has shown that polyphenols have potentially healthy effects in humans, working primarily as anticancer, antihypertensive, anti-allergen, anti-inflammatory, antioxidant, and antimicrobial agents. The antimicrobial activity of polyphenols has been extensively investigated mainly against bacteria [104]. Nevertheless, the antifungal activity of most of the phenolic compounds remains unknown. There are few studies on the mechanism of action of the substance, cytotoxicity, the synergism with traditional antifungals drugs, and their anti-virulence activities.
Phytochemicals | Bioactive compounds | Properties | Plant sources |
---|---|---|---|
Flavonoids | Flavan-3-ol | Against Candida | Syzygium cordatum |
Baicalein, gallotannin | Against Candida | Scutellaria baicalensis | |
Coumarins | Ulopterol | Against M. canis | Skimmia laureola |
Prenyletin; prenyletin-methyl-ether | Against T. rubrum; T mentagrophytes | — | |
Osthenol | C. albicans, Fusarium solani, A. fumigatus | — | |
5,8-Dihydroxyumbelliprenin | T. interdigitale, M. gypseum | Ferula foetida | |
Saponins | Colchiside | Phytopathogenic fungi | Dipsacus asper roots |
Terpenes or terpenoids | Triterpenes | Against dermatophytes | Ethyl acetate leaf extract of Satureja khuzestanica |
Lectins | Lectins | Fusarium oxysporum | Seed from native Amazon species |
Tannins | Punicalagin Punicalin | Against Candida spp. | Terminalia catappa |
Punicalagin | T. mentagrophytes; T. rubrum; M. canis; M. gypseum | Punica granatum | |
Ellagic acid, gallagic acid, punicalins, punicalagin | C. albicans, Cryptococcus neoformans, Aspergillus fumigatus | Punica granatum | |
Lambertianin C, sanguiin H-6 | Geotrichum candidum | Rubus idaeus |
Phytochemicals with antifungal compounds derived from plants.
Those with the most promising antifungal activity isolated from natural sources include flavonoids, tannins, coumarins, quinones, lignans, and neolignans [105] (Table 1).
Flavan-3-ols, flavonols, and tannins have received the most attention among the known polyphenols, attributable to their large spectrum of efficacy and high antimicrobial property. Structurally, flavonoids are aromatic compounds with 15 carbon atoms (C15) on their basic skeleton; they consist in tricyclic phenolic compounds with two aromatic rings on their structure (C6–C3–C6) [105]. Flavonoids are a class of natural compounds with several known protective activities, including antifungal activity. The flavonoids include subclasses such as chalcones, flavones, isoflavones, flavonols, flavanols (flavan-3-ol), and anthocyanidins [106].
The activity of flavonols such as quercetin, myricetin, and kaempferol has been described in C. albicans. For instance, quercetin, myricetin, and kaempferol from propolis have showed activity against Candida species [107]. The flavanol subclass (flavan-3-ol) and gallotannin, extracted from Syzygium cordatum, also showed inhibitory properties on the growth of C. albicans [108]. Serpa et al. [109] isolated baicalein, belonging to a subclass of flavones, from Scutellaria baicalensis, and induced apoptosis in C. albicans (Table 1), and apigenin, a flavone isolated from propolis, showed antifungal potential. Flavonoids as much as coumarins and lignans have shown an antifungal potential against several species of dermatophytes [105].
Other important groups of polyphenolic compounds present in various plant parts, such as the roots, flowers, leaves, fruits, and seeds, are tannins. They are divided into hydrolyzable (ellagitannins) and condensed tannins (proanthocyanidins) and gallotannins [110]. They have the ability to precipitate macromolecules such as proteins [111] as well as have antimicrobial properties. However, the mechanisms underlying the antimicrobial action of tannins in different microorganisms are still under investigation [111].
Ellagitannins constitute a complex class of polyphenols characterized by one or more hexahydroxydiphenoyl (HHDP) which can be linked in various ways to the glucose molecule [112]. Ellagic acid, gallagic acid, punicalins, and punicalagins isolated from ethyl acetate and butanolic fractions of Punica granatum revealed antifungal activity against C. albicans, Cryptococcus neoformans, and Aspergillus fumigatus [113] (Table 1).
Ellagitannins isolated from Ocotea odorifera, a plant commonly used in Brazil in folk medicine, have a potential against C. parapsilosis [114]. Two ellagitannins isolated from raspberry (Rubus idaeus L.) fruit, lambertianin C and sanguiin H-6, showed fungistatic activity both in vitro and in situ against Geotrichum candidum [115]. Dos Santos et al. [111] verified that encapsulated tannins from Acacia mearnsii have moderate activity against Aspergillus niger (ATCC 9642) and C. albicans (ATCC 34147).
Coumarins have a C6-C3 skeleton, possessing an oxygen heterocycle as part of the C3 unit [105]. These compounds are known to play a role in disease and pest resistance, as well as UV tolerance. The antifungal activity of 40 coumarins was tested against reference strains of Candida albicans, Aspergillus fumigatus, and Fusarium solani, but among them only osthenol showed the most effective antifungal activity (Table 1). The authors argue that the action of osthenol can be related to the presence of an alkyl group at C-8 position [116].
Another coumarin derivative, 4-acetetatecoumarin, was effective in inhibiting Aspergillus spp., acting on the factors of virulence and affecting the structure of the fungal wall. Diversinin, a coumarin isolated from the petroleum ether extract of Baccharis darwinii, demonstrated antifungal activity against T. rubrum, T. mentagrophytes, and M. gypseum, being fungicidal. Another coumarin derivative, 5,8-dihydroxyumbelliprenin, isolated from Ferula foetida, was active against M. gypseum and Trichophyton interdigitale [105] (Table 1).
Phenylpropanoids are other naturally occurring compounds categorized as coumarins, phenylpropanoic acid, and lignans frequently studied for their anti-Candida properties [117]. Navarro-Garcia et al. [118] and Raut et al. [119] found that a coumarin (scopoletin) and two phenylpropanoic acids (salicylaldehyde and anisyl alcohol) have antifungal property against C. albicans, with MICs of 25, 31, and 31 μg/mL, respectively.
Shahzad et al. [103] observed the effectiveness of pyrogallol and curcumin (CUR) against various C. albicans clinical isolates. In addition, curcumin inhibited the adhesion capability of cells and demonstrated anti-biofilm activity. Curcumin is a flavonoid found in turmeric (Curcuma longa L.). Pure curcumin had potential activity against Cryptococcus gattii both in vitro and in vivo [120]. According to Ferreira et al. [121], the essential oil from Curcuma longa L. can reduce the colony diameter, germination, and sporulation of Aspergillus flavus.
Alalwan et al. [122] undertook a series of adsorption experiments with varying concentrations of curcumin and showed that 50 μg/mL could prevent adhesion of C. albicans SC5314 to denture materials. Curcumin-silver nanoparticles also showed potential anticandidal activity against fluconazole-resistant Candida species isolated from HIV patients with MIC range of 31.2–250 μg/mL [123].
Gallic acid is a polyphenol natural compound found in many medicinal plant species that has been shown to have anti-inflammatory and antibacterial properties. GA was found to have a broad spectrum of antifungal activity against dermatophyte and Candida strains. Authors verified that GA reduced the activity of sterol 14-α-demethylase P450 (CYP51) and squalene epoxidase in the T. rubrum membrane.
Teodoro et al. [124] demonstrated that acetone fraction from Buchenavia tomentosa aqueous extract and its major compound gallic acid had the ability to inhibit reference strains C. albicans ATCC 18804 and Candida albicans SC 5314 adherence and to disrupt 48 h-biofilm.
In the eagerness to research and develop new substances to suppress the development of pathogenic fungi from natural plant substances, knowledge about the biological activities of essential oils has been growing. Essential oils’ pharmacological activities, mainly related to their complex chemical composition and high concentrations of phenols, make these compounds particularly interesting for both the treatment and the prevention of fungal infections. Natural phenolic substances are among the most antifungal active substances present in essential oils, generally showing low toxic effects in animals [125]. They consist in a complex mixture of monoterpene and sesquiterpene hydrocarbons and oxygenated derivatives such as alcohols, aldehydes, ketones, and phenylpropanoids.
Essential oils are also called volatile oils or ethereal oils, as they have a high degree of evaporation when exposed to air. The presence of terpenes contributes to the complex constitution with the action against microorganisms being directly related to this characteristic [126]. Since ancient times, Mondello et al. [127] proposed that tea tree oil could be used in antifungal therapy, because it showed efficacy against multidrug-resistant Candida species in vitro and against mucosal candidiasis in vivo; they have also showed that terpinen-4-ol was the main substance presented in the oil which contribute to the anticandidal activity.
Several oils have demonstrated activity against Candida species. Sharifzadeh et al. [128] observed that essential oils from Trachyspermum ammi have anticandidal effects against isolates resistant to FLZ. Herbal essences from Foeniculum vulgare, Satureja hortensis, C. cyminum, and Zataria multiflora were tested against C. albicans. Essential oils from Z. multiflora showed the best anticandidal activity [129].
Carica papaya essential oils have inhibitory effects against Candida species, detected by agar diffusion and microdilution assays [130]. Minooeianhaghighi et al. [131] verified that a combination of essential oils from Cuminum cyminum and Lavandula binaludensis showed growth inhibition of C. albicans isolates, at very low concentrations (between 3.90 and 11.71 μg/mL). Essential oils from Cymbopogon nardus have also shown antimicrobial potential against Candida species, with inhibition of hyphal growth in C. albicans at concentrations between 15.8 and 1000 μg/mL. This oil also inhibited growth of filamentous fungus from the environment. Main compounds of C. nardus essential oil were the oxygen-containing monoterpenes: citronellal, geranial, geraniol, citronellol, and neral [126]. In addition to inhibiting biofilm formation [132], essential oils from Artemisia judaica have been shown to inhibit the formation of germination tubes in C. albicans and have shown that at a very low concentration (0.16 μL/mL), it inhibited 80% of Candida filamentation. Kose et al. [133] demonstrated the fungicidal potential of essential oils from Centaurea baseri against Candida species, with an MIC of 60 μg/mL.
Among the monoterpenes there is thymol (2-isopropyl-5-methylphenol) [134]. It is the most abundant constituent in essential oils from Thymus vulgaris (thyme) [135] and the major component of essential oils from Origanum vulgare (oregano) [136]. Thymol showed antifungal activity, fungistatic and fungicidal one, against Candida strains. Authors verified an MIC of 39 μg/mL against C. albicans and C. krusei and MIC of 78 μg/mL against C. tropicalis. Probably thymol acts by binding to ergosterol in the plasma membrane, thereby increasing ion permeability and resulting in cell death because an eightfold increase (from 39.0 to 312.5 μg/mL) in thymol MIC values against C. albicans was seen in the presence of exogenous ergosterol. A combination of thymol and nystatin resulted in synergy [137].
Terpenoids have shown synergistic effects with FLZ, so it may be useful as a candidate antifungal chemotherapeutic agent. In addition, terpenoids exhibit a very good antimycotic activity of filamentous-form growth of C. albicans at nontoxic concentrations [138]. Further, in experiments realized by [139], rubiarbonol G, a triterpenoid from Rubia yunnanensis, showed potent antimicrobial activity against C. albicans, with an MIC of 10.5 μg/mL.
The antifungal potential of terpenes, geraniol, and citronellol has been investigated previously, with effective inhibitory activity against C. albicans [138] and filamentous fungi of the Aspergillus species [140]. In addition, Mesa-Arango et al. [67] showed that oxygenated monoterpenes in the citral chemotype, such as geraniol, citral, and citronellal, have antifungal activity against C. parapsilosis, C. krusei, Aspergillus flavus, and Aspergillus fumigatus.
Terpenes’ anti-biofilm activity and the efficacy of thymol, geraniol, and carvacrol in the treatment of Candida infections associated with the use of hospital devices have been related [141]. Effects of carvacrol on Candida cells can be associated with alterations in the cytoplasmic membrane and induction of apoptosis [108].
Although the process of discovering bioactive molecules is complex and time-consuming, involving isolation, identification, and optimization of pharmacokinetic and pharmacodynamic properties, as well as the selection of lead compounds for further drug development, data related here showed that plants are a promising source of active molecules with antifungal properties. Biological assays have shown that plant extracts or essential oils and their bioactivity molecules inhibit ATCC and clinical strains of fungi species, including those with resistance to drugs employed in medical practice. In addition, some are able to inhibit and control the main virulence factors of fungi species, such as the formation and proliferation of hyphae and filamentation and, more importantly, the eradication of mature biofilms.
Eugenol (4-allyl-2-methoxyphenol) is a phenolic compound and the main constituent of the essential oil isolated from the Eugenia caryophyllata. There are reports of some pharmacological effects of eugenol, such as antifungal and antibacterial agent, and its anti-Candida action seems to be related to the generation of oxidative stress concomitantly with lipid peroxidation of the cell membrane of Candida albicans yeast and the generation of reactive oxygen species [142]. Eugenol also showed antifungal effects against both Cryptococcus gattii and C. neoformans cells by causing morphological alterations, changes of cellular superficial charges, and oxidative stress. Thymol and carvacrol can represent alternative, efficient, and cost effective drugs for anti-biofilm therapy for Cryptococcus species.
Eugenol showed activity against Alternaria spp. and P. chrysogenum, by agar diffusion method [143] and, along with other monoterpenes such as carvacrol and isoeugenol, exhibited strong antifungal activity against Rhizopus stolonifer and Absidia coerulea [144].
Resistance mechanisms are developed by fungi to the treatment with conventional drugs in addition to toxic side effects to human cells showed by these drugs; researchers’ efforts in developing new strategies to improve treatment effectiveness of fungal infection are growing, with an interest in plants and folklore medicine.
The knowledge about synergistic effects of plant extracts or their compounds with traditional agents is nowadays a type of study that has aroused interest. Some in vitro screening assays have evidenced that plant extracts are less toxic than existing antifungal agents and, in combination with them, could reduce toxicity and increase antifungal potential [21, 145].
Accordingly, combination antifungal therapy offers the possibility of broadening the spectrum of drug activity, reducing toxicity, and decreasing fungal resistance [146].
Although combination of medications requires a careful evaluation of the synergistic, antagonistic, and agonist properties of the drugs involved [147], the use of drug combinations in treatment of infections by fungi is a common preferred strategy clinically. In many cases of fungal infection, combination therapy has been used successfully [21]. For some examples, see Table 2.
Combination of antifungals | Target | References |
---|---|---|
AMP B + posaconazole AMP B + caspofungin AMP B + fluconazole | Candida biofilms Candida biofilms Cryptococcosis in murine model | [148] [54] [149] |
Micafungin + fluconazole Micafungin + voriconazole Micafungin + AMP B Micafungin + isavuconazole | Candida infections | [150] [151] [152] |
Flucytosine + voriconazole | Candida infections | [148] |
Minocycline + fluconazole | Candida albicans biofilms | [148] |
Posaconazole + caspofungin | Candida infections | [153] [154] |
Terbinafine + azole | Candida growth | [155] [156] |
Echinocandin + azole | Invasive candidiasis | [157] |
AMP B + flucytosine | Invasive candidiasis | [158] |
Natamycin + 5-fluorouracil | Fusarium species ocular isolates | [159] |
Various regimes of combinatorial antifungal therapy showing better efficacy in combination than that of independent drugs (adapted from [21]).
AMP B: amphotericin B.
There are two main hypotheses about the type of interaction resulting from the combination of fluconazole and amphotericin B, based on the mechanisms of action of these drugs. In the theory of depletion, the interaction between fluconazole and amphotericin B would result in antagonism due to pre-exposure to fluconazole, which would lead to depletion of the membrane ergosterol, and thus there would be a decrease in the available sites for amphotericin B. In the second theory, the synergism, amphotericin B would lead to the formation of pores, which would facilitate the greater access of azole to the intracellular space, which by inhibiting the enzymes involved in ergosterol biosynthesis would increase the antimicrobial efficacy. According to these theories, the combination of fluconazole and amphotericin B could involve different interactions [160, 161, 162].
Considering the difficulties regarding to the treatment of candidiasis and cryptococcosis, the combination of antifungals represents an important alternative to conventional therapy. The synergistic effects of drugs are primarily attributable to cell wall damage by one antifungal. Thus, this component potentiates the activity of other drugs exactly against some constituent of plasma membrane. Alternatively, compromised cell wall with an increased permeability could facilitate movement of drugs across the cell membrane to their targets. Or, the synergistic action of different drugs occurs because they act on different targets of the same pathway, which can happen, for example, with the combination of azoles and allylamines.
The objective of this strategy is to maximize the antifungal effects. Tangarife-Castaño et al. [163] reported synergy between essential oils or plant extracts associated with antifungal drugs when used as anti-C. albicans agents. The best synergistic effects were obtained from the combination between itraconazole and P. bredemeyeri extract against C. albicans.
Synergistic potential was observed when methanolic extract of T. catappa leaves was combined with nystatin or AMB against reference strains of C. albicans, Candida neoformans, C. glabrata, Candida apicola, and Trichosporon beigelii [164]. The combination showed maximum synergy against C. apicola.
Santos et al. [165] related synergistic antifungal activity of an ethanol extract of Hyptis martiusii in combination with metronidazole against C. albicans, C. krusei, and C. tropicalis. Avijgan et al. [166] reported a potent synergistic effect between an Echinophora platyloba ethanolic extract and itraconazole or FLZ against isolates of C. albicans from vaginal secretions of patients with recurrent vulvovaginitis, significantly lowering the concentrations of both substances.
A combination between thymol and nystatin was found to have synergistic effects against Candida species [137], reducing the MICs of both products by 87.4%. Synergism was observed between a water insoluble fraction from U. tomentosa bark and terbinafine, as well as between it and FLZ against seven resistant isolates of C. glabrata and C. krusei [167]. Synergistic effects led to cell damage, and authors demonstrated, through differential scanning calorimetry and infrared analysis, that intermolecular interactions between the extract components and either terbinafine or FLZ occurring outside the cell wall are likely responsible for synergistic effects observed between substances.
Subfraction combinations of Terminalia catappa, Terminalia mantaly, and Monodora tenuifolia showed synergistic interactions against C. albicans, C. glabrata, C. parapsilosis, and C. neoformans isolates. Synergistic combination between M. tenuifolia and T. mantaly subfractions also showed fungicidal effects against most tested strains [168].
The combination therapy with curcumin and fluconazole was the most effective among the treatments tested against Cryptococcus gattii. The association was able to reduce the fungal burden and damage on lung tissues of infected mice and to eliminate the fungal burden in the brain, enhancing the survival of mice with C. gattii-induced cryptococcosis [120].
Methanolic extract of Buchenavia tetraphylla is a great source of antimicrobial compounds and enhanced the action of FLZ against different C. albicans isolates from vaginal secretions as well as azole-resistant isolates. The extract increased the action of FLZ in most strains through additive (20% of strains) or synergistic (60% of strains) effects [169].
Kumari et al. [170] investigated the effect of six essential oil compounds sourced from oregano oil (carvacrol), cinnamon oil (cinnamaldehyde), lemongrass oil (citral), clove oil (eugenol), peppermint oil (menthol), and thyme oil (thymol) against three infectious forms: planktonic cells, biofilm formation, and preformed biofilm of C. neoformans and C. laurentii. The anti-biofilm activity of the tested compounds was in the order thymol > carvacrol > citral > eugenol = cinnamaldehyde > menthol. The three most potent compounds thymol, carvacrol, and citral showed best anti-biofilm activity at a much lower concentration against C. laurentii. In the presence of these potent compounds, assays revealed the absence of extracellular polymeric matrix, reduction in cellular density, and alteration in the surface morphology of biofilm cells. In addition they were the most efficient in terms of human safety in keratinocyte-Cryptococcus spp. co-culture infection model suggesting that thymol, carvacrol, and citral can be further exploited as cost-effective and nontoxic anti-cryptococcal drugs.
The lectin pCramoll from Cratylia mollis, a native forage plant endemic to the semiarid region of Brazil (caatinga biome), showed an immunomodulatory effect and a synergism in combination with fluconazole, increasing the survival of animals with cryptococcosis caused by C. gattii and improving aspects of morbidity present in the progression of cryptococcosis [171].
Thymol exhibited synergistic effects when combined with fluconazole against clinical species of Candida, enhancing the antifungal potential of the drug and decreasing the concentration required for the effect [172]. Zaidi et al. [173] found that methanolic extract of leaves of Ocimum sanctum in combination with fluconazole showed higher antifungal potential and synergistic activity against resistant Candida spp. than methanolic extract or fluconazole when used alone.
Essential oils were also recently proposed to increase drug effectiveness. Lavandula and Rosmarinus essential oils were selected as antiproliferative agents to compound lipid nanoparticles for clotrimazole delivery in treatment of Candida skin infections. Authors confirmed the potential anti-Candida activity of the selected oils due to their interaction with membrane permeabilization. In addition, in vitro studies against Candida albicans, Candida krusei, and Candida parapsilosis showed an increase of the antifungal activity of clotrimazole-loaded nanoparticles prepared with Lavandula or Rosmarinus, thus confirming that nanostructured lipid carriers (NLC) containing these essential oils represent a promising strategy to improve drug effectiveness against topical candidiasis [174].
A novel therapeutic strategy that has been adopted is photodynamic therapy (PDT). It is based on the interaction between a nontoxic photosensitizer and a safe source of visible light at a low intensity; the combination of these two factors in the presence of oxygen leads to the development of reactive oxygen species (ROS) which are toxic and cause oxidative damage to microorganism cells [175]. Curcumin associated with LED light was an efficient strategy against biofilms of C. dubliniensis isolates [176]. The uptake of CUR by yeast cells and its penetration through the biofilm were accompanied by confocal laser scanning microscopy. Daliri et al. [177] have assessed the effect of curcumin- and methyl blue-mediated PDT in combination with different laser exposure parameters on C. albicans colonies. They verified that the 460-nm laser in combination with CUR has the maximum antifungal efficiency against C. albicans.
Although we have described herein many in vitro studies examining synergistic effects among potential antifungal biomolecules and traditional antifungal agents, the mechanisms underlying these synergistic effects are poorly understood. Randomized and controlled analyses have been performed with the objective of verifying the efficacy and risks of using traditional antifungal combinations; however, the results are poor and contradictory. High cost to conduct these strategies, reduced number of clinical cases, and the existence of confusing variables are factors that contribute to the obtaining of vague and non-reproducible results.
Therefore, it is extremely relevant to examine carefully possible synergism between new phytocompounds and conventional antimycotic drugs in order to obtain more insight. Understanding the cellular action of each substance in the combination process is also a key step in inferring ways to employ strategy in the clinic. A lack of consensus in the medical clinic emphasizes the need to conduct further clinical trials using combinations of antifungals. The experiments and results addressed herein support further investigation of new plant constituents with antifungal properties and the efficacy of combination therapies involving phytocomponents and traditional antifungal agents as an important start for the development of unusual and original antifungal therapies.
The increase in Candida and Cryptococcus infections is alarming leading to high rates of morbidity and mortality worldwide. Concomitantly with the increase in fungal infections, species emerged, and the resistance phenomenon increased so that the available antifungal arsenal becomes irrelevant in the face of the problem. In addition, there are limitations manifested by some antifungal agents such as fungistatic character, severe toxicity, and renal dysfunction. Therefore, it is crucial to develop new drugs as alternative therapies that are potentially active against Cryptococcus and Candida. Plants are considered abundant and safe sources of phytochemicals endowed with many biological activities. Several polyphenols have been isolated and studied in relation to their anti-yeast and anti-virulence activities and may be useful in obtaining promising, efficient, and cost-effective drugs for the inhibition of Candida and Cryptococcus infections. Many phytosubstances are extremely effective in combination therapy with traditional or other phytochemicals, which can be further exploited to lead to novel drug therapies against recalcitrant infections.
Authors thank Ceuma University for their contribution to the work.
The authors declare no competing interests.
Following the initial description of the physiologically corrective operation for tricuspid atresia by Fontan and Baudet [1] and Kreutzer and his associates [2] almost simultaneously, such surgery was widely adapted by most pediatric cardiologists and pediatric cardiac surgeons. This concept of bypassing the right ventricle (RV) was further extended to manage other cardiac defects with a functionally single ventricle.
The original surgery as described by Fontan and Baudet [1] consisted of (1) end-to-end anastomosis of superior vena cava (SVC) with the right pulmonary artery (PA) (classical Glenn procedure [3]), (2) connection of the separated right PA to the right atrium (RA) either directly or through an aortic homograft, (3) closure of the defect in the atrial septum, (4) insertion of a pulmonary valve homograft into the orifice of the inferior vena cava (IVC), and (5) ligation of the main PA, to entirely bypass the RV. On the basis of the procedures performed, one must infer that Fontan’s concept was to use the right atrium as a pumping chamber; therefore, he inserted a prosthetic valve into the IVC and right atrial-pulmonary artery junction.
On the contrary, Kreutzer et al. [2] anastomosed the right atrial appendage to the PA directly or by a pulmonary homograft and closed the ASD. Neither a Glenn procedure was performed nor a prosthetic valve was inserted in the IVC. Kreutzer’s view appears to be that the RA does not function as a pump and that the left ventricle functions as a suction pump in the system.
The surgical procedure as generally performed appears to shadow Kreutzer’s principle, and consequently, I have used the term “Fontan-Kreutzer operation” to describe this procedure [4, 5, 6, 7, 8]. However, because of priority of publication and more common usage in the literature, I will use the term “Fontan operation” in this chapter.
In this review, I will discuss the evolution of the Fontan concepts, the indications for Fontan operation, the Fontan procedure as used currently, and the results of old and current types of Fontan.
A number of modifications of the aforementioned surgery were made by these [1, 2] and other groups of investigators [9, 10] in the field. In this section, these concepts/procedures will be reviewed.
During the first 20 years after Fontan’s [1] and Kruetzer’s [2] description of the procedure, a number of modifications of the surgery were undertaken by several surgeons, as extensively reviewed and referenced elsewhere [9, 10]. In general, there was a consensus that there is no need for a classic Glenn anastomosis and that a prosthetic valve is not necessary in the IVC. Detailed review of these papers revealed that four major types of Fontan operations were being performed for physiologic correction of tricuspid atresia. These include (1) RA-PA anastomosis, direct or through a non-valved conduit; (2) RA-PA anastomosis through a valved conduit; (3) RA-RV anastomosis, direct or non-valved anastomosis; and (4) RA-RV anastomosis through a valved conduit.
In order to understand the advantages of one operation over the other, 17 papers published as of December 1990 that have documented adequate information to evaluate mortality and reoperation rates for each of the four types of Fontan surgery were reviewed. Pooled data from these 17 articles and statistical comparisons were presented in Tables I–IV for the interested reader [9]. This analysis revealed that atriopulmonary (RA-PA) connection appears to be better than atrioventricular (RA-RV) anastomosis and direct connection is better than valved or non-valved conduit anastomosis. Nevertheless, atrioventricular valved (homograft) conduit anastomosis appears to have advantages of (1) restoring a four-valved, four-chambered, biventricular heart and (2) lower right atrial pressure than with atriopulmonary connection. Based on these data [9, 10], the following conclusions were drawn: (1) direct atriopulmonary connection for children with tricuspid atresia with normally related great arteries and a small (<30% of normal) right ventricle without trabecular right ventricular component and for patients who had tricuspid atresia with transposition of the great arteries and (2) atrioventricular valved (homograft) conduit anastomosis for patients with tricuspid atresia and normally related great arteries but with a right ventricular size greater than 30% of normal and a trabecular right ventricular component [9, 10].
Bidirectional cavopulmonary anastomosis is a modified version of classic Glenn procedure in which the upper end of the divided SVC is anastomosed end to side to the right PA without disconnecting the latter from the main PA. Thus, the SVC blood is diverted into both the right and left PAs, justifying the term, “bidirectional.”
Experimental bidirectional cavopulmonary anastomosis was first studied by Haller et al. [11] in animal models, and its first clinical use was described by Azzolina et al. [12] in 1972. Other investigators [13, 14, 15, 16, 17] later applied this technique to palliate complex heart defects with decreased pulmonary blood flow. Hemodynamic advantages of the bidirectional Glenn procedure are improvement of effective pulmonary blood flow, decrease in total pulmonary blood flow, and reduction of left ventricular volume overloading. In addition, preservation of continuity of the pulmonary artery is an added advantage and may help facilitate a low-risk Fontan procedure. When both right and left SVCs are present, bilateral bidirectional Glenn shunts should be performed, especially if the bridging innominate vein is absent or small. Based on our own experience and that published in the literature [13, 14, 15, 16, 17], the author recommended serious consideration in employing bidirectional cavopulmonary anastomosis as an interim palliative procedure for patients who are at an increased risk for the Fontan procedure [9, 10].
Puga et al. [18] positioned a patch inside the right atrium to divert the IVC blood into the PAs; they had good results in the 12 patients that they used this technique. This was later called lateral tunnel and was widely used until extra-cardiac conduits came into vogue.
To better understand the valve-less atriopulmonary anastomosis type of Fontan, de Leval et al. [19] performed hydrodynamic studies and found that (1) the right atrium is not an efficient pump in non-valved atriopulmonary connections, (2) pulsations in a non-valved circulation truly generate turbulence with consequent decrease in net flow, and (3) energy losses occur in the non-pulsatile chambers, corners, and obstructions. In an attempt to address these deficiencies, they developed a procedure which they named “total cavopulmonary connection.” In this procedure, they connected the divided SVC, end to side, to the undivided right pulmonary artery (bidirectional Glenn), and the IVC blood is diverted through a composite intra-atrial tunnel (with the use of posterior wall of the right atrium as posterior wall of the tunnel) into the cardiac end of the divided superior vena cava, which in turn was connected to the PA. They felt that technical simplicity, maintenance of low right atrial and coronary sinus pressure, and reduction of risk of atrial thrombus formation are advantages of this type of operation. They performed this procedure on 20 patients and observed two early deaths and one late death. Postoperative hemodynamic studies were performed in 10 of the survivors which indicated good results. They recommended this type of operation for patients with a non-hypertrophied right atrium. While the total cavopulmonary connection was initially devised for patients with complex atrial anatomy and/or systemic venous anomalies, it has since been used extensively for all types of cardiac anatomy with one functioning ventricle and irrespective of venous anomalies.
Subsequent experimental studies by Sharma and his associates [20] indicated that complete or minimal offset between the orifices of the SVC and IVC into the right pulmonary artery decreases energy losses.
Marcelletti et al. [21, 22] used an interposition extra-cardiac conduit from the IVC to the PA in place of lateral tunnel used in total cavopulmonary connection in 1990. Subsequently, most surgeons adopted this modification of total cavopulmonary connection, and currently extra-cardiac conduits are used in most Fontan operations.
Since the vast majority of patients requiring Fontan operation present as neonates or in the early infancy, palliative procedures are performed at the time of presentation, and subsequently (at 12–18 months of age) the Fontan operation is undertaken. A considerable mortality (~16%) was seen with primary Fontan surgery, largely related to the impact of rapid changes in ventricular geometry and development of ventricular diastolic dysfunction. The concept of further staging the procedure by performing bidirectional Glenn procedure around 6 months of age followed by final Fontan between 12 and 18 months of age was introduced in early 1990s [23, 24]. Performing the Fontan procedure in stages appears to decrease overall mortality, most likely related to improving the ventricular function by correction of the afterload mismatch that is associated with one-stage Fontan procedure. At the current time, most centers prefer staged Fontan with bidirectional Glenn initially, followed later by extra-cardiac conduit diversion of the inferior vena caval blood into the PA.
In 1978, Choussat et al. proposed several criteria for performing Fontan operation [25]. Many cardiologists and surgeons have modified these criteria. Patients not meeting these criteria were deemed to be at a higher risk for a poor prognosis following a Fontan operation than patients who are within the limits of the set criteria. For the high-risk group, several investigators have proposed the concept of leaving a small atrial septal defect (ASD) open to facilitate decompression of the right atrium [26, 27, 28]. Laks et al. advocated closure of the atrial defect by constricting the preplaced suture in the postoperative period [28], while Bridges et al. [27] used a transcatheter closure method at a later date.
Higher cardiac output and significant decreases in the postoperative pleural effusions and systemic venous congestion were noted after a fenestrated Fontan procedure. In addition, the duration of hospitalization appears to have decreased. Nonetheless, these beneficial effects are at the expense of mild arterial hypoxemia and potential for paradoxical embolism.
While the fenestrated Fontan procedure was initially designed for patients at high risk for Fontan surgery, it has since been used in patients with modest or even low risk. Although rare, reports of cerebrovascular or other systemic arterial embolic events occurring after a fenestrated Fontan operation tend to contraindicate the use of fenestrations in patients with low or usual risk. In following years, fenestrated Fontan have been routinely used at most institutions. Some data indicate that routine fenestration is not necessary [29].
Patients who have undergone a fenestrated Fontan operation or patients who have a residual atrial defect, despite correction, may have clinically significant right-to-left shunt causing varying degrees of hypoxemia. These residual defects should be closed not only to address arterial desaturation but also for prevention of paradoxical embolism [30, 31]. Although two types of fenestration closure, namely, constriction of the preplaced suture in the postoperative period [26, 28] and device closure later [27] were described, device closure is opted at most institutions. Closure of such defects can be performed by using transcatheter techniques [32, 33, 34, 35]. The procedure is usually performed 6–12 months following fenestrated Fontan procedure. Although a number of devices have been used in the past [32, 33, 34, 35], at the present time, Amplatzer septal occluders are the most commonly used devices to accomplish such closures.
The indications for opting for a Fontan operation are patients who have one functioning ventricle. At first, patients with tricuspid atresia were selected for this procedure [1, 2]. Shortly thereafter, patients with double-inlet left (single) ventricle were added to the indications for Fontan [36]. Following description of surgical palliation of hypoplastic left heart syndrome (HLHS) by Norwood et al. [37, 38] in the early 1980s, HLHS became the major lesion requiring Fontan operation. Subsequently, mitral atresia (with normal aortic root), unbalanced atrioventricular septal defects (AVSDs), pulmonary atresia with intact ventricular septum with markedly hypoplastic right ventricle, and other complex heart defects with one functioning ventricle were selected for Fontan surgery.
Attempts to insert prosthetic ventricular septum for single ventricle patients met with problems, leading to abandoning such procedures. Thereafter, Fontan became a preferred treatment method. With reasonably good results of Fontan, the pendulum swung so that any patient who could not undergo complete repair became a candidate for Fontan.
A middle of the road method, the so-called one-and-one-half ventricle repair was developed for patients with pulmonary atresia with intact ventricular septum with modest-sized right ventricle. In this procedure, a bidirectional Glenn procedure to divert the SVC flow into the PA is performed and allows the small right ventricle to pump the IVC blood into the pulmonary circuit, and the patent foramen ovale is closed. It is generally considered to be a better option than Fontan, although, to my knowledge, there are no comparative studies to assess this issue.
Because of relatively high mortality rates (17.0–31.7%) [39, 40] and low actuarial survival rates (66.5% at 5 years and 64.4% at 15 years) [41] for unbalanced AVSD patients following Fontan, a number of institutions attempted single stage or staged biventricular repair or conversion from single ventricle (Fontan) to biventricular repair [39, 42, 43, 44, 45, 46, 47]. Detailed analysis by Nathan et al. [39] suggested that the biventricular repair and conversion from single ventricle (Fontan) to biventricular repair groups had reasonably similar mortality rates and a similar need for cardiac transplantation, but these parameters were lower than those seen in the Fontan palliation cohort.
Cardiac transplantation is a surgical alternative in the management of HLHS [48] and other single ventricle lesions. While heart transplantation was used at several institutions initially for HLHS, because of non-availability of donor hearts, most institutions have reverted to the Norwood/Fontan route. In addition, following successful cardiac transplantation, multiple medications for the prevention of graft rejection, frequent outpatient visits and periodic endomyocardial biopsy, to recognize rejection very early, are necessary in the management of these children. At the present time, cardiac transplantation is used for patients failing Fontan operation at a limited number of institutions.
As reviewed above, since the original description in the early 1970s, the Fontan procedure has undergone numerous modifications, and, at the present time it is best described as staged total cavopulmonary connection (TCPC) with an extra-cardiac conduit and fenestration. It is performed in three stages.
The majority, if not all, of patients who require Fontan operation (see Section 3. Indications for Fontan Operation) present during the neonatal and early infancy period, and the Fontan cannot be performed at that time because of naturally high PA pressure and high pulmonary vascular resistance (PVR). Therefore, Fontan, by necessity, becomes a multistage procedure. These babies should receive palliative intervention to allow them to reach the age and size to undergo successful Fontan surgery. The type of palliation is largely dependent upon the hemodynamic disturbance produced by multiple defects associated with a given congenital heart defect (CHD).
In neonates with decreased pulmonary blood flow, the ductus arteriosus should be kept open by administration of prostaglandin E1 (PGE1) intravenously at a dose of 0.05–0.1 mcg/kg/min. Once the O2 saturation improves, the dosage of PGE1 is gradually reduced to 0.02–0.025 mcg/kg/min to minimize the side effects of the prostaglandins. Following stabilization and diagnostic studies, as necessary to confirm the diagnosis, a more permanent way of providing pulmonary blood flow should be instituted. A number of methods to augment pulmonary blood flow have been used over the years [49, 50]. These include subclavian artery to ipsilateral PA anastomosis (classic Blalock-Taussig shunt), descending aorta to the left PA anastomosis (Potts shunt), ascending aorta to the right PA anastomosis (Waterston-Cooley shunt), SVC to right PA anastomosis, end-to-end (classic Glenn shunt), enlargement of the ventricular septal defect (VSD), formalin infiltration of the wall of the ductus arteriosus, central aortopulmonary fenestration or expanded polytetrafluoroethylene (Gore-Tex; W. L. Gore and Associates, Inc., Newark, Delaware) shunt, Gore-Tex interposition graft between the subclavian artery and the ipsilateral PA (modified Blalock-Taussig shunt), balloon pulmonary valvuloplasty, and stent implantation into the ductus arteriosus. Currently modified Blalock-Taussig (BT) shunt [51] by insertion of a Gore-Tex graft between the subclavian artery to the ipsilateral PA (Figure 1a) is performed by most surgeons to address pulmonary oligemia. More recently connecting the RV outflow tract with the PA via non-valve Gore-Tex graft is being used at several institutions to palliate pulmonary oligemia. Placement of a stent in the ductus arteriosus [52, 53, 54] and balloon pulmonary valvuloplasty (if the predominant obstruction is at the pulmonary valve level) [55, 56, 57] are other available options to augment the pulmonary blood flow.
Stage I Fontan. Selected frames form cineangiograms in two different babies; the first with pulmonary oligemia who received Blalock-Taussig (BT) shunt (a) and the second with pulmonary plethora who had pulmonary artery banding (PB) (b). C, catheter; LPA, left pulmonary artery; RPA, right pulmonary artery (Reproduced from [30]).
In babies with increased pulmonary blood flow, optimal anti-congestive measures should be started immediately. Once the congestive heart failure (CHF) is adequately addressed, PA banding (Figure 1b) is performed [58] irrespective of control of CHF.
Infants with near normal pulmonary blood flow with O2 saturations in the low 80s do not need intervention and are clinically followed until Stage II.
Neonates with hypoplastic left heart syndrome usually have Norwood palliation (Figure 2) [37, 59] in the neonatal period; in this operation, the following procedures are performed: (1) the main pulmonary artery and the aorta are anastomosed together; additional prosthetic material is used as needed; (2) the pulmonary circulation receives blood supply by connecting the aorta to the PA via a modified BT shunt [51] (Figure 2b); (3) atrial septum is excised to allow unhindered blood flow from the left to the atrium; and (4) ductal tissue is removed, and coarctation of the aorta, if present is repaired. Some surgeons use alternative Sano shunt [60], connecting the RV outflow tract to the PA (Figure 2c) instead of BT shunt.
Stage I Fontan for hypoplastic left heart syndrome. Selected frames from cineangiograms demonstrating Norwood operation in which the neoaorta (NAo) and hypoplastic aorta (HAo) perfuse the coronary arteries (CAs) as shown in (a), Blalock-Taussig (BT) shunt as illustrated in (b) and Sano shunt as depicted in (c). (b) and (c) are from two different babies. LPA, left pulmonary artery; RPA, right pulmonary artery (Reproduced from [30]).
In patients with inter-atrial obstruction, it should be relieved either by transcatheter methodology or by surgery as deemed appropriate for a given clinical scenario. If there is associated coarctation of the aorta, it should also be relieved. Some patients with double-inlet left ventricle may have significant obstruction at the level of bulboventricular foramen [61]. Similarly some babies with tricuspid atresia with transposition of the great arteries may have obstruction at the VSD level, causing obstruction to systemic blood flow [61, 62]. Such babies require Damus-Kaye-Stansel (connection of the aorta to the PA) [63] along with a BT shunt. Inter-atrial obstruction may be present frequently in babies with mitral atresia and single ventricle [64]. In such babies, predictable fall in PVR occurs following balloon or surgical relief of inter-atrial obstruction [64]; consequently, PA banding should be undertaken without hesitation at the time of relieving the atrial septal obstruction, so as to reduce the probability for CHF, lower the PVR and PA pressure, prevent pulmonary vascular obstructive disease (PVOD), and pave the way for Fontan approach [64].
Irrespective of the type of palliative surgery in the neonatal period, bidirectional Glenn procedure [12, 13, 14, 17, 23], namely, anastomosis of the SVC to the right PA, end-to-side (Figure 3) is performed around the age of 6 months. The previously performed BT or Sano shunt is ligated at the same time. Although performing the procedure at 6 months is generally adopted, it can be performed as early as 3 months provided normalcy of PA pressure and anatomy can be documented.
Stage II of Fontan. Selected frames from cineangiograms in two different children illustrating bidirectional Glenn operation in which the superior vena cava is anastomosed to the right pulmonary artery (RPA). Unobstructed flow from the SVC to the right (RPA) and left (LPA) pulmonary arteries is clearly seen. (Reproduced from [30]).
In patients with persistent left SVC, bilateral bidirectional Glenn (Figure 4) is undertaken especially in patients with a small or absent left innominate vein. A bidirectional Glenn procedure may also be performed for patients with infrahepatic interruption of the IVC with azygos or hemiazygos continuation, and such a procedure is called a Kawashima procedure by some authorities.
Stage II Fontan. Selected frames from cineangiograms in a different child than shown in Figure 3, illustrating bilateral bidirectional Glenn operation. (a) Superior vena caval angiogram demonstrates immediate visualization of the right pulmonary artery (RPA). Un-opacified blood flow from persistent left SVC (PLSVC) is indicated by the arrow in (a). (b) PLSVC angiogram illustrates rapid opacification of the left pulmonary artery (LPA). Un-opacified blood from the right SVC is shown by the arrow in (b). Flow from the respective SVCs into the pulmonary arteries is clearly seen (Reproduced from [30]).
Prior to the bidirectional Glenn procedure, normal PA pressures and adequate size of the branch PAs should be ensured by cardiac catheterization and cineangiography. Echo-Doppler or other imaging studies (magnetic resonance imaging [MRI] or computed tomography [CT]) is advocated at some institutions.
If PA stenosis is present, it may be addressed with balloon angioplasty or stent implantation, as deemed appropriate, or it may be addressed during the bidirectional Glenn procedure. Atrioventricular valve regurgitation, aortic coarctation, subaortic obstruction, and other abnormalities should also be repaired/addressed at the time of this operation.
During the final Stage III, the IVC flow is diverted into the PA along with creation of a fenestration. We arbitrarily divided [30] these procedures into Stage IIIA (diversion of IVC into the PA) and Stage IIIB (closure of the fenestration).
In the final Stage III, the total cavopulmonary connection is achieved by diverting the IVC flow into the PA either by a lateral tunnel [18, 65] or by an extra-cardiac, non-valved conduit (Figures 5 and 6) [21, 22]; the procedure is usually performed between the ages of 1 and 2 years, usually 1 year following the bidirectional Glenn procedure. Most surgeons seem to prefer extra-cardiac conduit to accomplish this final stage of Fontan. The majority of surgeons construct a fenestration, 4–6 mm in size, between the conduit and the atria (Figures 5 and 6) [27]. While the creation of fenestration during the Fontan operation was initially proposed for high-risk patients [27, 28], most surgeons now seem to prefer fenestration, since fenestration during the Fontan improves mortality rate and reduces morbidity during the immediate postoperative period [30].
Selected cine frames in posteroanterior (a) and lateral (b) views, demonstrating Stage IIIA Fontan procedure diverting the inferior vena caval flow into the pulmonary arteries via a non-valve conduit (Cond). Flow across the fenestration (fen) is shown by arrows in (a) and (b). HV, hepatic veins; LPA, left pulmonary artery; PG, pigtail catheter in the descending aorta; RPA, right pulmonary artery.
Selected cine frames in posteroanterior (a) and lateral (b) views in a different patient to the one shown in Figure 5, demonstrating Stage IIIA Fontan procedure diverting the inferior vena caval (IVC) flow into the pulmonary arteries via a non-valve conduit (Cond). Flow across the fenestration (fen) is shown by arrows in (a) and (b). Abbreviations are the same as those in Figure 5.
Cardiac catheterization and selective cineangiography are usually performed shortly prior to Fontan conversion in order to assess the PA anatomy and pressures, trans-pulmonary gradient, PVR, and ventricular end-diastolic pressure and to assure that they are normal prior to proceeding with Fontan completion. At some institutions, MRI is used for this assessment instead of catheterization and angiography; however, the author’s preference is catheterization. During this catheterization, any significant collateral vessels that are present are also transcatheter-occluded by most cardiologists.
In the final stage, Stage IIIB, the fenestration is closed (Figures 7b, 8b, and 9B and C) by transcatheter methodology [27, 30, 31, 32, 33, 34, 35], usually 6–12 months after Fontan Stage, IIIA. In the past, most devices used to occlude ASDs [32, 33, 34, 35] were employed for this purpose, but at the present time, Amplatzer septal occluders are the most commonly used devices to accomplish such closures. If there are any other residual shunts, they should also be occluded (Figure 10) by device closure.
Stage IIIB. (a) Selected frames from cineangiograms in anteroposterior projection illustrating Stage IIIA of the Fontan operation in which the inferior vena caval (IVC) flow is diverted into the pulmonary arteries by a non-valve conduit (Cond). The fenestration (fen) is shown by the arrow in (a). (b) Closure of the fenestration with an Amplatzer septal occluder device (D) is shown with an arrow in (b). HV, hepatic veins; LPA, left pulmonary artery; RPA, right pulmonary artery (Reproduced from [30]).
Stage IIIB. (a) Selected frames from cineangiograms in lateral view of the same patient illustrated in Figure 5 showing Stage IIIA of the Fontan operation in which the inferior vena caval (IVC) flow is diverted into the pulmonary arteries by a non-valve conduit (Cond). The fenestration (fen) is shown by the arrow in (a). (b) Closure of the fenestration with an Amplatzer septal occluder device (D) is shown with an arrow in (b). (Stage IIIB). Reproduced from [30].
(A) Selected cine frame from a Fontan conduit cineangiogram in anteroposterior view, demonstrating tubular fenestration (Tu fen) with opacification of the left atrium (LA). (B) The Tu fen is closed with an Amplatzer vascular plug (AVP). (C) A follow-up conduit cineangiogram after AVP implantation, showing complete occlusion of the Tu fen. TEE, transesophageal probe.
(A) A selected cineangiographic frame showing the Fontan conduit in lateral view, demonstrating a residual shunt (RS) at the superior aspect of the conduit (Cond). (B) The RS was occluded with an Amplatzer septal occluder device (AD); the residual shunt is no longer seen. TEE, transesophageal echo probe.
In children who have one functioning ventricle requiring Fontan correction, the systemic and pulmonary circulations work in-parallel in place of the usual in-series circulation. A fragile equilibrium between the two circulations must be preserved so that adequate systemic and pulmonary perfusions are maintained. There is substantial interstage mortality ranging from 5 to 15% [66, 67, 68] which may be due to restrictive atrial communication, obstruction of the aortic arch, blockage of the shunt, distortion of the PAs, atrioventricular valve insufficiency, or a combination thereof [66]. Intercurrent illnesses such as dehydration, respiratory tract illness, or fever disturb this balance and make the patients to become critically ill and have been blamed for interstage mortality [66, 68]. The surgically created BT and Sano shunts may also get thrombosed producing severe hypoxemia [69]. Indeed, these abnormalities produce significant interstage mortality [67]; these appear to occur more frequently between Stages I and II than between Stages II and III. Consequently, extreme vigilance in managing these patients should be maintained by the caregiver [68, 70]; even trivial illnesses must be aggressively monitored and addressed as appropriate.
Immediate and follow-up results of both older and current types of Fontan will be reviewed in this section.
The results of original Fontan [1, 2] and its earlier modifications, namely, RA-to-PA or RA-to-RV anastomosis either directly or via valved or non-valved conduits, revealed high initial mortality rates. The initial mortality rates ranged from 10 to 26% [9, 10, 71, 72]. Furthermore, the postoperative stay in the intensive care setting was prolonged.
The initial mortality following staged, total cavopulmonary connection has decreased remarkably [73, 74, 75, 76, 77, 78]. Patients who had total cavopulmonary connection without fenestration had initial mortality rates ranging from 8 to 10.5% [73, 74, 75], while subjects who had total cavopulmonary connection with fenestration had slightly lower (4.5–7.5%) initial mortality rates [76, 77, 78].
In one large single institutional study examining the results of 500 consecutive Fontan surgery patients [77], early failure was associated with high (≥19 mm Hg) mean PA pressure, young age at surgery, heterotaxy syndrome, a right-sided tricuspid valve as systemic atrioventricular valve, distorted pulmonary arteries, an atriopulmonary connection, no Fontan fenestration, and longer cardiopulmonary bypass time.
These investigators also observed that a significant improvement in morbidity and mortality from early (first quartile—early failures: 27.1%) to the more recent time (last quartile—early failures: 7.5%) occurred [77]. This progress appears to be related to increasing surgical and intensive care experience as well as to more recently introduced Fontan modifications.
Long-term follow-up results were also poor with older types of Fontan [9, 10]. The late mortality rates varied from 1 to 11%, and when early and late mortality rates were combined, they varied between 11 and 25%. The need for reoperations was present in 1–11% of patients. Factors adversely influencing late mortality and reoperation rates are earlier calendar year of operation, age of patient at the time of surgery, type of prior palliative procedures, hypoplasia, distortion or obstruction of PAs, subaortic obstruction, significant mitral valve insufficiency, elevated PA pressure or resistance, decreased left ventricular function, increased left ventricular muscle mass, asplenia syndrome, and others [9, 10].
Following the introduction of staged cavopulmonary anastomosis (both lateral tunnel and extra-cardiac conduit diversion of IVC blood to the PA), the long-term outcomes have improved. In one study in which results of follow-up for 10.2 ± 0.6 years of 196 patients were examined, the estimated Kaplan-Meier survival was 93 and 91% at 5 and 10 years, respectively [79]. An equally impressive finding was freedom from supraventricular arrhythmias in 96 and 91% of patients at 5 and 10 years following surgery. In a different study, the actuarial survival 15 years following surgery was 85% [80]. But, late re-interventions were necessary in 12.7% of patients. When lateral tunnel and extra-cardiac conduit types of Fontan were compared, the outcomes were found to be similar for both groups [81, 82].
Using fenestration during Fontan appears to improve early mortality and morbidity, particularly demonstrated in high-risk patents [83]. A more recent analysis in a smaller group of patients did not demonstrate significant advantage of fenestrated Fontan over the non-fenestrated [84]. However, the general consensus is that using fenestration during Fontan decreases mortality and morbidity during the postoperative period [30, 76, 77, 78].
Periodic follow-up following Fontan is generally recommended. These patients are evaluated at 1, 6, and 12 months after Stage IIIB (device closure of fenestration) and yearly thereafter. During the follow-up, platelet-inhibiting doses of aspirin 2–5 mg/kg/day in children or clopidogrel 75 mg/day in adults to prevent thrombus formation and angiotensin-converting enzyme inhibitors for afterload reduction are generally prescribed. Electrocardiograms and echocardiograms are generally performed during evaluation of these patients with additional imaging studies, as indicated. Any abnormalities, as and when detected, are addressed.
During follow-up, a number of complications were reported, and these include arrhythmias, obstructed Fontan pathways, cyanosis, paradoxical emboli, thrombi, development of collateral vessels, and protein loosing enteropathy [30, 31, 85]. These complications appear to be more frequent with older types of Fontan than with the currently used staged, total cavopulmonary connection with extra-cardiac conduit and fenestration. When such complications develop, they should be promptly investigated and treated. In the ensuing paragraphs, a brief review of some of these complications will be presented.
Arrhythmias were more frequently seen in patients with old Fontan (atriopulmonary connection) than with staged TCPC. The observed arrhythmias were typically atrial arrhythmias, namely, atrial flutter/fibrillation and supraventricular tachycardia. Initially, anti-arrhythmic medications are used to control the rhythm disturbance. This should be followed by hemodynamic and angiographic assessment to identify obstructive lesions in the Fontan pathways. The obstructive lesions should be treated with balloon angioplasty, stent, or surgery, as applicable. Continued rhythm abnormality calls for radiofrequency ablation. Although the success rate of radiofrequency ablation is high in 80% range [86], rates of recurrence range from 30 to 40%. In subjects who have resistant arrhythmias, reducing the atrial mass, switch to TCPC with concomitant Maize procedure is advisable [87]. A few patients develop atrioventricular block or sick sinus syndrome which may require pacemaker implantation. Fortunately, ventricular arrhythmias are less frequent.
Obstructions in Fontan circulation may occur. Obstructive lesions in the SVC or IVC may arise but are less frequently seen. However, branch pulmonary artery stenoses may be seen more often. Obstructions within the lateral tunnel or extra-cardiac conduit are also uncommon, but may occur due to thrombus formation and will be addressed in the section on “Thrombus formation.” In the presence of signs and symptoms indicative of obstruction in the Fontan pathway, prompt investigation to confirm such obstruction should be made. While echo studies are useful in young children, poor echo windows in adolescents and adults may require MRI and CT, and/or angiographic studies to confirm or exclude such obstructive lesions. If the obstructive lesions are detected, they should be promptly relieved by balloon angioplasty or stent implantation (Figure 11) [88]. Surgery may be needed in rare occasions.
Selected frames from cineangiograms of the pulmonary artery in posteroanterior view illustrating normal right pulmonary artery (RPA) and narrowed (arrow) left pulmonary artery (LPA) prior to (a) and after (b) stent (arrow) placement in an adolescent who had Fontan surgery several years earlier (Reproduced from [88]).
Sometimes connections between lateral tunnel and extra-cardiac conduit on the one hand and the atrium on the other persist. These residual defects and intentionally created Fontan fenestrations result in right-to-left shunt because the pressure in the Fontan conduit is higher than that of the atrial pressures. These residual defects will result in arterial desaturation and may become the site of paradoxical embolism with consequential transient ischemic attacks (TIAs), cerebrovascular accidents (CVAs), and systemic emboli. These residual defects as well as Fontan fenestrations should be occluded by transcatheter techniques to return O2 saturations to normal and decrease the likelihood for paradoxical embolism [30, 32, 33, 83, 88, 89]. Amplatzer septal occluder (St. Jude Medical, Inc., St Paul, MN) is currently most common device used to accomplish this (Figures 7,8, and 10). Tubular fenestrations may be closed with Amplatzer vascular plug devices (St. Jude Medical, Inc.) (Figure 9). Test occlusion of the residual defect or fenestration is suggested to ensure that adequate cardiac output is maintained following defect occlusion [89, 90], especially if the procedure is performed shortly after fenestrated Fontan. Late follow-up results of fenestration closure are good [33].
There is a tendency for thrombus formation in the Fontan pathway; the reported prevalence was 15–30% [91, 92]. Regrettably the usual transthoracic echo-Doppler evaluation may not discover these thrombi. However, transesophageal echocardiography, MRI, or CT studies may be necessary to detect these thrombi. In an attempt to prevent thrombus formation in the Fontan circuit, thromboprophylaxis is commonly recommended; both warfarin and aspirin have been utilized in the past for this purpose. A multicenter, randomized trial was conducted to compare the efficacy of these two drugs; results showed less than optimal results with both drugs and no significant difference between the two regimens [93]. In the author’s experience, most children are prescribed with aspirin for thromboprophylaxis which may be switched to clopidogrel (Plavix) as the children approach adulthood.
Despite seemingly adequate thromboprophylaxis, some patients develop thrombosis of the Fontan conduits (Figure 12A). We initially employ thrombus dissolving drug therapy (tPA, heparin, etc.). If the thrombi do not resolve, we have employed stenting of the conduit to compress the thrombi against the conduit wall [94]. An example from our experience is shown in Figure 12.
(A) Selected frame from a cineangiogram of a Fontan conduit in lateral view, illustrating a thrombus (arrow in (A)). (B) and (C) position of a stent (St) before (B) and after (C) its complete expansion. (D) Cineangiographic frame demonstrating the widely patent stent after stent deployment. Also, note the residual shunt (RS) at the superior aspect of the conduit (seen in (A) and (D)). The RS was occluded with an Amplatzer septal occluder device (AD) shortly after the cine shown in (D). (F) A follow-up cineangiogram 1 year later shows the continued patency of the conduit with no RS. TEE, transesophageal echo probe (Reproduced from [94]).
Systemic venous to pulmonary venous and systemic arterial to pulmonary arterial collateral vessels may develop in some patients after the Fontan procedure [88, 95]. These may develop both shortly after the procedure and during late follow-up. Systemic venous to pulmonary venous collateral vessels produce arterial hypoxemia. In addition, they may also become potential sites for paradoxical embolism. Systemic arterial to pulmonary arterial (or venous) collateral vessels produce left ventricular volume overload. These abnormal vessels should be transcatheter-occluded with coils, vascular plugs, and ductal occluding devices depending upon the size and accessibility. Examples from the author’s experience of occluding these vessels are shown in Figures 13–16 [88, 95, 96].
(a) Selected frame from a left innominate vein (L inn) cineangiogram in posteroanterior view demonstrating an anomalous vein (AV) opacifying the atrial mass (not marked). (b) Following occlusion with Gianturco coil (arrow), the AV is completely occluded and the systemic arterial saturation improved (Reproduced from [88]).
(A) Selected frame from a cineangiogram in lateral view with the catheter positioned at the superior vena cava/azygos junction illustrating a fistula which results in opacification of the left atrium (LA). (B) The fistula was occluded with an Amplatzer vascular plug (arrow—AVP) with some residual flow. (C) Follow-up SVC injection shows complete occlusion by the AVP (Reproduced from [96]).
(A) Selected cine frame from an internal mammary artery (IMA) cineangiogram in the lateral view, demonstrating multiple small collateral vessels arising from the pericardiophrenic (PCP) branch, which resulted in a significant levophase (not shown). (B) Following occlusion with a Gianturco coil (C), there is complete occlusion of this vessel (Reproduced from [95]).
(A) Selected cine frame from a right subclavian artery (RSA) cineangiogram showing branches (white arrows) of the thyrocervical (TC) trunk which supplied a number of small vessels, giving a good degree of levophase. (B) Complete occlusion occurred following the implantation of a Gianturco coil (C) (Reproduced from [95]).
Protein losing enteropathy (PLE) is a grave long-term complication of Fontan with a prevalence of 11.1% in older types of Fontan [85, 97]. However, the incidence appears to have come down to 1.2% with staged TCPC [85, 98]. The reason for development of PLE is not understood. Intestinal protein loss secondary to lymphatic distension which in turn may be due to elevated pressure in systemic veins is considered to be a pathogenic mechanism. But, PLE has been seen even in patients with “normal” Fontan circuit pressures. Therefore, the true cause of PLE remains a mystery. The symptoms and signs of PLE are diarrhea, edema, ascites, and/or pleural effusions. Laboratory abnormalities include reduced serum albumin and elevated fecal alpha-1 antitrypsin levels. The PLE diagnosis may be confirmed with technetium 99m-labeled human serum albumin scintigraphy [99].
Because of high mortality rate seen with PLE, speedy diagnosis and implementing aggressive management strategies are important [85]. At first, supportive therapy such as medium-chain triglycerides diet, infusion of intravenous albumin, and replacement of immunoglobulins should be undertaken. Obstructive lesions in the Fontan pathway should be scrutinized, and aortopulmonary connections should be screened for. If identified, they should be treated with appropriate transcatheter measures. Surgical therapy is indicated if they cannot be adequately addressed with transcatheter intervention. A variety of other treatment regimens, including prednisone, elementary diet, calcium replacement, regular high-molecular-weight heparin, low-molecular-weight heparin, somatostatin, high-dose spironolactone, sildenafil, and resection of localized intestinal lymphangiectasia, have been utilized in the past with varying degrees of success [85].
Following a short trial of any of the above treatment modes, largely on the basis of the cardiologist’s preference, a more definitive treatment methods such as lessening the conduit pressure by creating a fenestration between the conduit and the atrium [99, 100, 101], converting atriopulmonary type of Fontan to TCPC [87, 102, 103], instituting sequential atrioventricular pacing [104, 105], and performing cardiac transplantation [106, 107, 108] should all be considered. Again, it is essential to emphasize that timely treatment should be instituted as soon as PLE is identified [85]. Fortunately, the need for use of these methods has progressively diminished since the wide use of staged TCPC.
Since the initial description of the Fontan operation in the early 1970s by Fontan, Kruetzer, and their associates, several modifications have been introduced. These include avoiding classic Glenn anastomosis; not using a prosthetic valve in the IVC; RA-PA anastomosis, direct or through a non-valved conduit; RA-PA anastomosis through a valved conduit; RA-RV anastomosis, direct or non-valved anastomosis; RA-RV anastomosis through a valved conduit; bidirectional Glenn procedure (cavopulmonary anastomosis); lateral tunnel; total cavopulmonary connection; extra-cardiac conduit, staged Fontan; fenestrated Fontan; and closure of Fontan fenestration. Currently staged, total cavopulmonary connection with extra-cardiac conduit and fenestration has become the most commonly used multistage surgery in accomplishing the Fontan.
The indications for Fontan are patients who have one functioning ventricle, and these include tricuspid atresia, double-inlet left ventricle, HLHS, mitral atresia with normal aortic root, unbalanced AVSDs, pulmonary atresia with intact ventricular septum with markedly hypoplastic right ventricle, and other complex heart defects with one functioning ventricle. Recently there has been a trend for biventricular repair, particularly for patients with unbalanced AVSDs.
Stage I consists of performing palliative procedures on the basis of pathophysiology of the defect complex at presentation, usually in the neonatal period. Stage II involves performing a bidirectional Glenn procedure (diversion of the superior vena caval blood flow into both lungs) usually at about the age of 6 months. During stage IIIA diversion of the IVC blood flow into the lungs, usually by an extra-cardiac conduit plus a fenestration, usually at about the age of 2 years. Stage IIIB consists of transcatheter closure of the fenestration 6–12 months after Stage IIIA.
Both the immediate and follow-up results have remarkably improved, both in terms of mortality and morbidity, following the introduction of staged total cavopulmonary connection with extra-cardiac conduit and fenestration with subsequent catheter closure of Fontan fenestration. Complications do occur during follow-up, and they should be addressed as and when they are detected.
The author declares no conflict of interest.
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