A Review on Candidiasis and Opportunistic Mycosis in Human and Animals

DOI : 10.7176/JNSR/9-9-01 Publication date :May 31 st 2019 INTRODUCTION CANDIDIOSIS Candida albicans (C. albicans) is part of the normal microbial flora in human beings and domestic animals, and is associated with the mucous surfaces of the oral cavity, gastrointestinal tract and vagina. Immune dysfunction can allow C. albicans to switch from a commensal to a pathogenic organism capable of infecting a variety of tissues and causing a possibly fatal systemic disease (Traynor and Huffnagle, 2001). Mucosal infection is the most usual form of the disease but cutaneous lesions are seen on occasion (Lehmann, 1985). In cattle, as a consequence of the abundant use, and occasional abuse, of antibiotics in the treatment of mastitis, there is a selection of flora, mainly members of the genus Candida, that are new etiological agents of these processes, which are initially difficult to diagnose because their presence is not expected. Candidiasis in birds is related to malnutrition and stress, generally produced by the same strains that are found naturally on the food plants of these animals. Arthritis caused by yeasts in horses is relatively frequent as a consequence of contamination of wounds or after surgical treatment. In pigs, candidiasis usually takes the form of digestive alterations in young animals, and is usually related to problems that predispose to the disease, like treatment with antibiotics (Garcia and Blanco, 2000). C. albicans is a common causative agent of stomatitis in the dog (Jadhav and Pal, 2006). Although fungi need pre deponent factors to produce the disease, it is known that saprophytic colonization of the mucous membrane by C. albicans does not need the host to be immune compromised, since it is detected in immune competent individuals (Garcia and Blanco, 2000).

2001a). A few cases of pulmonary involvement and later dissemination have been reported in dogs (Clercx et al., 1996). Aspergillosis of the air passages is also frequently reported in birds, and certain species of Aspergillus have been known to infect insects (Geiser, 2009). Etiology Aspergillus was first described in 1729 and receives its name due to its resemblance to an aspergillum used to sprinkle holy water. A member of the family Trichocomaceae, Aspergillus species are closely related to another mold, Penicillium. However, identification of the causative organism responsible for most infections is usually not difficult, with four species responsible for the majority of illnesses. A. fumigatus is responsible for more than 90% of invasive disease in some reviews, with Aspergillus flavus (A. flavus), Aspergillus terreus (A. terreus), and Aspergillus niger (A. niger) responsible for the majority of remaining invasive aspergillosis cases (Patterson et al., 2000).

Host risk factors
Risk factors for invasive aspergillosis may be associated with the changes in macrophage and neutrophil function, which may explain why infection mainly affects bone marrow and solid organ transplant recipients, Intensive Care Unit (ICU) patients, post-operative patients, those with chronic pulmonary diseases, patients with AIDS and patients on immune modulating drugs (TNF-α inhibitors), neutropenic patients, or those who have received corticosteroid treatment. Other risk group is patients with chronic granulomatous disease, drug user, patients with sarcoidosis, severe burn patients and alcoholics (Ascioglu et al., 2002). Aspergillus can also develop when no risk factors are present. Thus, cases have been explained of community-acquired pneumonia due to Aspergillus in apparently immune competent patients (Franquet et al., 2001) but it is likely that the patients had some undetected defect in macrophage and neutrophil function that allowed invasive infection to develop.
Malnutrition, vitamin deficiencies (especially vitamin A), long term antibiotic use, age (young or old) also contributes to the presentation of the disease, as well as trauma, dusty environments, lead poisoning and irritants of the airways like smoke of cigarette or ammonia (Washburn et al., 1990).

Pathogenesis Virulence factors
Aspergilli produce catalase, an enzyme that breaks down hydrogen peroxide (H2O2) to water and oxygen. The strong association of aspergillosis with chronic granulomatous disease (CGD) (Cohen et al., 1981) provides indirect evidence that catalase is a virulence factor. A. fumigatus produces gliotoxin, a metabolite in the epipolythiodioxopiperazine family with a broad range of immunosuppressive properties. Gliotoxin inhibits macrophage phagocytosis (Eichner et al., 1986), as well as T-cell activation and proliferation. It induces DNA fragmentation and programmed cell death (apoptosis) in macrophages by mechanisms apparently distinct from its antiphagocytic properties (Waring, 1990). It is not known whether clinically significant amounts of gliotoxin are produced in human disease. In a case report, concentrations of gliotoxin approximately 100 times greater than that needed for in vitro effects were found in a bovine udder infected with A.fumigatus (Bauer et al., 1989). In addition to gliotoxin, A. fumigatus produces an 18-kDa cytotoxin that acts by cleaving a phosphodiester bond of the 28S rRNA of eukaryotic ribosomes (Smith et al., 1993). Host defense Antigen release evokes production of IgE, IgG and IgA antibody against the A.fumigatus and intense production of nonspecific total IgE. IgE mediated mast cell degranulation in the bronchi release mediators that would cause bronchospasm as well as permeability changes in the epithelium. Eosinophilic chemotactic factors cause pulmonary and peripheral blood eosinophilia IgG-A.fumigatus, IgA-A.fumigatus also causes activation of complement in the bronchi. It has been demonstrated that there occurs hyper releasability of histamme from basophils of ABPA patients (Ricketti et al., 1983).

Preventive Measures
In developed countries, where regulations allow higher aflatoxin concentrations in animals, the agricultural industries have developed alternative approaches chemoprotection and enterosorption to limit biologically effective exposure without the high cost of preventing contamination. Chemoprotection is based on manipulating the biochemical processing of aflatoxin to ensure detoxification rather than preventing biological exposure. Enterosorption is based on the approach of adding a binding agent to food to prevent the absorption of the toxin while the food is in the digestive tract; the combined toxin-sorbent is then excreted in the feces. This approach has been used extensively and with great success in the animal feeding industry. (Williams et al., 2004).
It has been shown that HEPA filtration can reduce or even eliminate Aspergillus spores from the air (Comet et al., 1999). Caring for high-risk patients in rooms supplied with HEPA-filtered air has helped to prevent the acquisition of this infection within the hospital (Oren et al., 2001), provided certain technical requirements are met. Components of a protected hospital environment should include a well-sealed room, HEPA filtration of incoming air, directed (or laminar) airflow within the room, positive room air pressure relative to the corridor, and high rates of room air exchange (Center for Disease Control and Prevention, 1997)

CRYPTOCOCCOSIS
Cryptococcosis is a rare fungal infection produced by inhalation of encapsulated yeast called Cryptococcus neoformans. C. neoformans can be found worldwide in soil, pigeon/bird, cat, dog, fox, monkey, cattle, horse, goat, and many other mammals' feces (www.doctorfungus.org, 2008). Recently, a differentiation has been made between two species, Cryptococcus gattii (C.gattii) and C. neoformans. This differentiation was made on the basis of genetic variation and a lack of evidence for genetic recombination between both gene types (Duncan et al., 2006a, b). These genetic differences are consistent with differences in habitat, geographical distribution and, most importantly, in pathogenicity and the effectiveness of the response of the host immune system. C.neoformans infects predominantly immune compromised hosts, while C. gattii has not been associated with a suppressed immune system (Duncan et al.,2006a,b) and is mostly found on eucalyptus trees and in the soil Duncan et al.,2006a).
The primary route of entry for Cryptococcus is via the lungs, where the fungus may establish a primary infection. If the initial pulmonary infection is not controlled, the fungus can disseminate to other organs and the central nervous system, resulting in fatal cryptococcal meningoencephalitis Aguirre et al., 2004;Chen et al., 2007).
Human disseminated cryptococcosis has two unusual features that distinguish it from other disseminated fungal infections. First, patients have cryptococcal polysaccharide antigen in their body fluids, and detection of this is useful in diagnosis of the disease. Second, there is a limited inflammatory response in tissues harbouring C. neoformans. One could interpret these findings to mean that individuals with the highest levels of cryptococcal polysaccharide in their body fluids simply had higher number of organisms in their tissues and therefore were the most likely not to respond to antifungal therapy. Another interpretation could be that the cryptococcal polysaccharide had an adverse effect on host defence mechanisms, thus allowing a progressive disease, concluding that cryptococcal polysaccharide in the bloodstream exacerbates disease (Clemons et al., 2000).
Clinical cryptococcosis has been reported worldwide in many animal species. It is the most common systemic fungal infection in cats and is often described in dogs (Duncan et al., 2006b). In cats, C. neoformans is most commonly isolated from immunosuppressed individuals, whereas C. gattii is considered as primary pathogen because it infects immune competent hosts, even in areas where the organism is endemic (Duncan et al., 2006a). In other animal species, cryptococcosis can appear to be related to immune depression, although not always. Then, have been described outbreaks of ovine and caprine cryptococcosis with respiratory signs, and without immune depression situation detected in those animals . In these cases, respiratory symptoms associated with cachexia were the predominant clinical picture; liver and brain involvement was also documented ( Baro et al., 1998).
Cryptococcosis may occur in horses as a disseminated cryptococcal infection with osteomylitis of both the axial and appendicular skeleton produced by C.gattii. The administration of corticoids led to clinical deterioration due to immune modulating effects. Administration of systemic corticoids occurred after lesions had appeared; however, the horse deteriorated significantly after corticosteroid treatment (Lenard et al., 2007). Etiology Cryptococcus spps. are fungi in the Division Basidiomycota. Although there are more than 30 species of Cryptococcus, only two organisms -C. neoformans and C. gattii (previously C. neoformans var. gattii)commonly affect humans and animals. Other species including C. laurentii, C. albidus, C. uzbekistanensis, C. adeliensis, C. curvatus, C. magnus, C. humicolus, C. luteolus, C. macerans, C. flavescens and C. uniguttulatus have been found in clinical cases; however, this is rare. Of the latter group of organisms, C. laurentii and C. albidus have been described most often in people (The Center for Food Security and Public Health, 2013). Host risk factors C. neoformansis also an opportunistic pathogen, which can cause cryptococcosis in patients with HIV infection and HIV-negative patients with immunological conditions predisposing to this fungal infection, such as a history of systemic corticosteroid therapy, immunosuppressive treatments, organ transplant, chronic organ failure (liver, lung, and kidney), malignancy, rheumatic diseases, systemic lupus erythematosus and diabetes mellitus (Casadevall et al., 2008). Pathogenesis Virulence Factors C. gattii and C. neoformans share many attributes that increase their ability to invade and survive in a host organism (Ellerbroek et al., 2004). The main virulence factors identified in C. gattii to date include an outer polysaccharide capsule, melanin, mannitol, extracellular proteinase, products of the laccase pathway, superoxide dismutase, phospholipases, urease, and the STE12 transcription factor (a homologue of Saccharomyces cerevisiae STE12) that is present only in the mating type (Chang et al., 2000). Other properties of C. gattii contribute to its infectivity such as its ability to grow at physiological temperature (Sorrel, 2001) its tolerance of low pH and elevated salt levels (Kidd et al., 2007), and its ability to switch capsular phenotype (Jian et al., 2006).  Vol.9, No.9, 2019 Host defenses Clearance of Cryptococcus infection requires the development of a Th1-type CMI and the subsequent pulmonary recruitment and activation of leukocytes. The leukocytic infiltrate in response to cryptococcal infection includes a mix of myeloid and lymphoid cells, all of which are capable of inhibiting the growth of, or killing, the organism in vitro (Romani, 2004).
Neutrophils and macrophages are the two phagocytic cells in the natural host defence that are most likely to be responsible for clearing the cryptococcal cells from the tissues. There was very little inflammatory response, i.e. influx of neutrophils, lymphocytes and macrophages, into infected host tissues (Clemons et al., 2000).
In this Th1-CMI, IFN-g, TNF-a, IL-2, IL-12, IL-15, IL-18, monocyte chemotactic protein-1, macrophage inflammatory protein-1a and nitric oxide have been shown to have important roles in murine models. GM-CSF plays a complex role in the development of anticryptococcal immunity in the lungs: it is required for early recruitment of leukocytes into the lung, movement of recruited leukocytes into the alveolar space and the formation of inflammatory foci in the lungs (Chen et al., 2007).
The Th2 cytokines IL-4 and IL-5 were not secreted at significantly higher levels in Cryptococcus-infected brains of immune mice compared to control mice (Uicker et al., 2005). CD4+ T-cells are critical for the control of Cryptococcus. An antigen-specific CD4+ T cell response occurs when the T cell receptor recognizes processed antigen fragments presented by MHC Class II. Then CD4+ T cells secrete cytokines and proliferate . Nevertheless, in the lung, both CD4+ andCD8+ T cells are required to clear the cryptococcal infection. If yeasts escape and colonize the brain, rapid proliferation leads to serious central nervous system disease. Work with severe T cell and B cell-deficient combined immune deficient mice and wild-type controls has demonstrated a CD4+ T cell-mediated resistance to cryptococcal organisms that colonize the brain. Depletion of CD8+ T cells had no detectable effect on T cell-mediated resistance in brain in vivo. In contrast, CD8+ T cells play a welldefined and important role in containment of pulmonary infection (Aguirre et al., 2004).

Preventive measures
There is no vaccine available for cryptococcosis; thus, prevention through environmental condition control is vital. Reduction of aerosolization of the C. neoformans is key and should be done wetting or chemically disinfecting a region, then removing large accumulations of bird/animal droppings. Corticosteroid medications usage should be minimized to prevent cryptococcosis due to their tendency of exacerbating compromised patients conditions (http://www.aidsmap.com/en/news; McCarthy, 2006).

FUSARIOSIS
Fusarium spp.are important infectious filamentous fungi, second only to Aspergillus spp. These fungi are ubiquitous in the environment and are found in the soil and air. Interestingly, Fusarium spp. are primarily known as plant pathogens but can also infect humans and animals, causing superficial, locally invasive, and disseminated disease. (Nucci and Anaissie, 2007). Infection is mainly through inhalation of airborne conidia or via breaks in the skin due to trauma and/or burns. Fusarium spp. also produces toxins that can cause food poisoning through the consumption of toxin-contaminated food (Dignani & Anaissie, 2004).
In humans, Fusarium species cause a broad spectrum of infections, including superficial (such as keratitis and onychomycosis), locally invasive, or disseminated infections, with the last occurring almost exclusively in severely immunocompromised patients . Fusarium species may also cause allergic diseases (sinusitis) in immunocompetent individuals (Wickern, 1993) and mycotoxicosis in humans and animals following ingestion of food contaminated by toxin-producing Fusarium spp.  Etiology More than 100 species of Fusarium have been identified, but only a few cause infections in humans (Alastruey et al., 2008). Fusarium solani (F.solani) is the most frequent cause of invasive disease (in approximately half of all cases), followed by F. oxysporum, F. moniliforme (previously F. verticillioides), and F. proliferatum (Torres et al., 2011). Other species that rarely cause infections in humans include F. dimerum, F. chlamidosporum, F. sacchari, F. antophilum and others. Fusarial keratitis is most commonly caused by F. solani (Doczi et al., 2004), whereas fusarial onychomycosis is most commonly caused by F. oxysporum ( Brilhante et al., 2005;Godoy et al., 2004;Ninet et al., 2005).

Host risk factors
Neutropenia is one of the most important risk factors for acquiring fusariosis. Patients undergoing Heamtopoetic Stem Cell Transplantation(HSCT) or solid organ transplantation, those with hematological malignancies or acquired immune deficiency syndrome (AIDS) and those taking pharmacological immunosuppressant therapies are at high risk for fusariosis. (Nucci et al., 2004& Enoch et al., 2006.

Pathogenesis Virulence Factors
Fusarium species possess several virulence factors, including the ability to produce mycotoxins, including trichothecenes, which suppress hum oral and cellular immunity and may also cause tissue breakdown. In addition, Fusarium species have the ability to adhere to prosthetic material and to produce proteases and collagenases .

Host Defenses
The innate immunity plays a major role in the defense against mold infections (Shoham& Levitz, 2005). Macrophages and neutrophils damage fusarial hyphae, and their effect is primed by gamma interferon, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF) (Gaviria et al., 1999), and interleukin-15 (Winn et al., 2005). The importance of T-cell defenses against Fusarium is illustrated by the occurrence of disseminated fusariosis in non-neutropenic HSCT recipients (Nucci et al., 2004). These patients have severe T-cell immunodeficiency caused by multiple therapies for their underlying disease and for graft-versus-host disease (GvHD). Further supporting the importance of T-cell immunity and phagocytes is the major impact of corticosteroid therapy on the outcome of fusariosis, as shown by the much higher death rate among recipients of such therapy than among patients who were not receiving corticosteroids (Nucci et al., 2003).

Preventive measures
General preventive measures that should be employed in patients at significant risk of invasive fusariosis, such as patients with hematologic malignancies undergoing induction chemotherapy or hematopoietic cell transplantation, include: Avoidance of activities associated with skin breakdown, avoidance of contact of areas of skin breakdown with tap water., Careful examination for and treatment of onychomycosis and paronychia and surgical debridement of infected wounds prior to commencing anti-cancer therapies, delaying severely immunosuppressive therapies until areas of skin breakdown are healed, when possible. (Nucci & Anaissie, 2007;.
Following appropriate air and water precautions during periods at risk. These include use of a high efficiency particulate air filter and positive pressure isolation rooms, avoiding contact with reservoirs of Fusarium spp, such as tap water, and having showers cleaned thoroughly prior to use by high-risk patients (Anaissie et al.,2001;.

PNEUMOCYTIS
Pneumocystis carinii (P.carinii) is an opportunistic and widespread fungus found in the lungs of humans and other mammals. It can be the cause of severe pneumonia, especially in humans suffering from AIDS (Cailliez et al., 1991). In the veterinary literature P. carinii pneumonia (PCP) has been reported in foals1, (Tanaka et al., 1994) (especially Arabian foals with inherited severe combined immunodeficiency, in pigs, (Kondo et al., 1993) and in domestic goats. Only a few cases of P. carinii pneumonia have been reported in dogs, and most commonly among young animals (Furuta et al., 1994). P. carinii was considered as a group of heterogeneous populations, genetically isolated from each other, that have undergone a prolonged process of genetic and functional adaptation to each mammalian species (Dei-Cas, 2000).
Further genetic analysis has shown that Pneumocystis isolated from different species has significant differences in gene sequence and chromosomes. This has prompted nomenclature changes and P. carinii is now reserved for the rat pathogen, P.carinii f.sp. muris for the murine pathogen, and P. jiroveci for the human pathogen (Steele et al., 2005). It may be that this situation will be repeated in different animal species, like the description of the genetically different P. canis in dog (English et al., 2001). Pneumocystis pneumonia is a well-recognized major opportunistic infection in HIV-positive individuals, and is growing in importance in HIV-negative patients undergoing immunosuppressive treatment for malignancy, connective tissue disease or organ transplantation.
In the veterinary field, Pneumocystis has been described as producing pneumonia in dogs, causing serious pulmonary alterations. Pneumocystis is important in horses, where treatment with immunosuppressive drugs, like corticoids, is a relatively frequent practice in animals.
Dedicated to sport, originating a pneumonic process with bronchoneumonic diffuse image. In pigs, this fungus gives rise to pneumonic processes, affecting animals 7-11 weeks old, with lung damage that includes a decrease of the size of the pulmonary septa with infiltration of mononuclear cells and appearance of exudates in the alveoli. This focal pneumonia evolves toward a diffuse pneumonia, very similar to what happens with this disease in children (Cavallini et al., 2007). Pneumocystis infects hosts by a respiratory route, and animal-to-animal airborne transmission has been clearly established (Dumoulin et al., 2000). In humans, the persistence of Pneumocystis in the lung is a limited-time phenomenon inversely related to immunological improvement. A normal immune response completely eradicates Pneumocystis from the host. However, immunocompetent hosts can be parasitized transiently by Pneumocystis: increased titres of Pneumocystis antibodies were detected in hospital staff in close contact with Pneumocystis pneumonia patients, and immunocompetent experimental hosts were parasitized transiently by Pneumocystis after close contact with hosts developing pneumonia by this fungus (Dei-Cas, 2000).

Etiology
Pneumocystis organisms were first reported and named P.carinii in the beginning of last century after recognition that pneumocystis organisms in different mammals are different, in1994 an interim trinomial name change was adopted with the name P. carinii f.sp hominis for pneumocystis infecting humans and P.carinii f.sp. carinii for one of the two species infecting rats (The Pneumocystis Workshop, 1994). Finally, in 2002, by the recognition of its genetic and functional distinctness, human pneumocystis organism was renamed Pneumocystis jiroveci, in honour of Otto Jirovec, who is credited for describing the microbe in humans (Frenkel, 1999;Stringer et al., 2002).

Host risk factors
Although not fully characterized, the known risk factors for P.jirovecii infection include impaired immunity because of HIV infection, hematologic malignancies, and connective tissue disorders (Roblot et al., 2002). Pathogenesis Host defense A host defense against Pneumocystis is indistinguishable from that observed for other medically important fungal pathogens of the lung (Steele et al., 2005). As with fungal pathogens such as A. fumigatus, C.neoformans and Histoplasma capsulatum(H. capsulatum), alveolar macrophages are an essential component of the immune response against Pneumocystis and are ultimately responsible for clearing this fungus from the lungs ( He et al.,2003;Steele et al., 2005). CD4+ T cells are absolutely critical for resolution of Pneumocystis, having an essential role in the recruitment and activation of effector cells against the organism. CD8+ T cells by themselves do not aid clearance of Pneumocystis from the lungs (Dei-Cas, 2000; IFN-ᵞ is not absolutely required for clearing Pneumocystis from the lungs but is required for modulating the inflammation (Dei-Cas, 2000). B cells and/or Pneumocystis-specific antibody are important for clearance of Pneumocystis from the lungs. Antibodies against Pneumocystis are reported to be readily detectable in the early years of life, at ages similar to that reported for other pathogenic fungi such as C. albicans and C. neoformans (Goldman et al., 2001;Steele et al., 2005), and most data suggest that the organism is widely encountered in nature and that antibody production is part of the natural host response, predominantly of the IgG class, but also IgM. In this sense, many ELISA-based assays have been developed and employ a wide variety of Pneumocystis preparations and antigens to detect the presence of Pneumocystis-specific antibodies (Steele et al., 2005).

Preventive Measures
Adults and adolescents who have HIV infection (including pregnant women and those on HAART) should receive Chemoprophylaxis against PCP if they have a CD4+ T-lymphocyte count of less than 200/μL or a history of or pharyngeal candidiasis (Phair et al., 1990). Persons who have a CD4+ T-lymphocyte percentage of less than 14% or history of an acquired immunodeficiency syndrome (AIDS)-defining illness but do not otherwise qualify should be considered or prophylaxis (Kaplan et al., 1998). When monitoring the CD4+ T-lymphocyte count at least every 3 months is not possible, initiation of chemoprophylaxis at a CD4+ T-lymphocyte count of greater than 200 but less than 250 cells/μL also should be considered (CDC, 1989).