Challenges of the Global COVID-19 Pandemic and Invasive Fungal Pathogens in SARS-COV-2 Associations: A Dangerous Relationship

Background: COVID-19 is a rapidly transmissible pneumonia-like illness caused by SARS-CoV-2 that out broke in China in 2019 and is currently circulating worldwide. In the current context of the SARS-CoV-2 pandemic, complications are observed in clinical settings for the treatment of severe COVID-19 disease in nosocomial settings, due to cases of fungal co-infections. Objective: To carry out a review on fungal infections associated with respiratory infections caused by COVID-19 (Sars-Cov-2


COVID-19 is a rapidly transmissible pneumonia-like illness caused by SARS-
CoV-2 that out broke in the city of Wuhan in China in December 2019 and is currently circulating across the planet. In 2021, it already accounted for millions of people infected with the severe acute respiratory syndrome virus (SARS-CoV-2) [1]. As the COVID-19 pandemic has evolved, increasing concerns have been reported about invasive fungal infections, particularly with the use of potent immunosuppressive drugs to treat immune storms in patients with severe illness from this infection [2].
Fungal infections have been reported as a complication of severe COVID-19, impairing the clinical course of patients hospitalized in hospital intensive care settings [3]. Fungal nosocomial infections are being related due to the permanence of hospitalized patients, causing concern due to the experience of the pandemic caused by the COVID-19 disease, having relevance in critically ill patients affected by the disease [4].
In the context of a severe acute respiratory syndrome, in patients infected with SARS-COV-2 (COVID- 19), patients may require intensive care, using for prolonged periods, these devices and broad-spectrum medications, increase the risk of fungal infections secondary.
The current pandemic, known as SARS-CoV-2 (COVID-19) which causes Severe Acute Respiratory Syndrome, according to WHO (World Health Organization) panel records, the disease has already affected more than 635,000 people with cases confirmed, resulting in more than 6 million deaths worldwide. Brazil ranks fifth among countries in number of cases of the disease (35 million), behind the United States (97 million), India (44.6 million) and France (36.3 million). In addition, the number of deaths in Brazil (more than 688,000) is the second highest in the world ranking, after the USA [5]. and Alphacoronavirus (α-CoV) [6].
Six CoVs are known to infect humans, but two of them are capable of causing respiratory syndrome: SARS-CoV and MERS-CoV, however other species of CoVs cause mild respiratory disease in humans (HCoV-HKV1, HCoV-OC43, HCoV-NL63 and HCoV-229E).
The rapidly changing virus. The first variant of Sars-CoV-2, called D614G, was identified in early 2020, and is considered the most infectious genotype in humans. In December, the English strain B. allergic symptoms may occur due to non-infectious mechanisms [10].
The main infectious agent, when it comes to opportunistic infections associated with co-infections, is Aspergillus fumigatus, a filamentous fungus, which causes several forms of the disease, however, the most serious is the invasive pulmonary one; evolving to fatal pneumonia if not treated [11]. Aspergillosis can also be caused by the following agents: A. flavus, A. terreus and A. niger. Chong [12], define COVID-19-associated pulmonary aspergillosis (CAPA) as the most common infection of the symptoms of invasive pulmonary aspergillosis. The  symptoms are fever resistant to antibiotic therapy, pleural pain and cough, however, the symptomatology can be nonspecific [9].
As the world struggles to cope with the deadly effects of COVID-19, a new threat known as "black fungus" has appeared around the world. The disease is rare but can be serious worldwide, with a high incidence of damage reported in India. Fungi of the order Mucorales, can be acquired by sporongiodosporic inhalation due to food contamination or traumatic inoculation, their agents belong to the genera Rhizopus, Lichtheimia, Apophysomyces, Rhizomucor, Mucor, Cunninghamella and Syncephalastrum [13]. According to Prakash and Chakrabarti [14], patients with uncontrolled diabetes mellitus are associated with the onset of mucormycosis, in patients with hematological malignancy, organ transplant recipients, iron overload and large skin lesions, among others. This infection can still affect the rhino-orbito-cerebral region (ROC), pulmonary, cutaneous, gastrointestinal region, and may be disseminated, with the most frequent clinical manifestations, the ROC and pulmonary forms [15].
Another group of extreme importance is the yeasts of the genus Candida. These fungi are part of the microbiota of humans and animals, and when immunity deficiency occurs these organisms proliferate developing the fungal infection candidiasis that can cause infections in the bloodstream (Candidemia). The most infectious species to humans are: Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis and Candida krusei and more currently the emerging species in certain parts of the world: Candida auris, informs us the CDC [16].
The risk factors for an invasive infection in the bloodstream, both for yeast species of the genus Candida, are similar: use of broad-spectrum antibiotics, diabetes, prolonged use of venous catheters, breathing tubes, long stay in intensive care and invasive procedures all make Candida spp. and other fungi, with high rates of morbidity and mortality, further worsening the situation of individuals who are immunosuppressed [16] [17].

Methodology
About 102 articles were initially selected for the description of this review. Data were collected using PUBMED, SCIELO, GOOGLE ACADÊMICO, BIRREME, SCIENCE DIRECT and SPRINGER LINK databases from 2021 to 2022, using the terms: Co-infections, COVID-19, Aspergillosis, Candida, Mucormycosis, Fungal infections, Coronavirus and SARS-CoV-2, with articles that provided information that correlated fungal infections with COVID-19 disease.
A total of 80 articles were identified through the initial database search. We excluded articles due to lack of information or publications that did not report primary data. For the selection of articles, we related COVID- 19

Results
In the search in order to answer the questions, through the descriptors, 37 articles were identified, of which they were selected in the year 2020 (7, 18.92%) and in the years 2021 and 2022 (15,40.54%) respectively. The results reported in this study are associated with factors and hospitalized patients who developed fungal diseases after and during COVID-19.
According to the records presented in our series, in We investigated that relative to host age; fungal infections associated with SARS-CoV-2 were shown to have a more pronounced effect in the older age group. The incidence of co-infections according to the authors' reports, the ages reported were between 1 year (younger age) and 88 years (older age). Most cases involved male patients, females ranked second ( Table 1).
The elderly, mostly male, aged between 55 and 77 years, were diagnosed with more comorbidities, including neutropenia, diabetes mellitus, structural lung disease and/or using mechanical ventilation, corticosteroids or immunomodulators for the treatment of COVID-19. Reports of pulmonary and respiratory infections (11,29.7%) were the most common, followed by cases of pneumonia (8,21.6%) and then blood infections (7, 18.9%) (

Discussion
SARS-CoV-2 is, today, a public health obstacle in the world and it is of extreme importance, all attention to the problems that the virus has caused. Based on research, co-infections of the virus with other microorganisms may hinder the clinical practice of patients affected by COVID-19 [18]. Severe illness from COVID-19 is associated with increased pro-inflammatory cytokines, interleukin (IL)-1, IL-6 and tumor necrosis factor alpha, reduced expression of CD4-interferon-gamma, CD4 and CD8 T cells, which increase susceptibility to fungal infections [19]. The association of opportunistic systemic mycoses with COVID-19, reported, can cause relevant damage to the already compromised immune system and aggravate the state of patients who are debilitated, due to comorbidities and the use of corticosteroid therapies in the treatment of the disease, which may lead to risks of an unwanted case evolution [4]. The treatment of these two co-associated infections is complex and requires attention and palliative care. Immunomodulatory drugs, including corticosteroids and cytokine blockers, are options to combat hyperinfection caused by the virus [20] the likely decrease in the immune system and defense cells (lymphocytes) damaged by SARS-CoV-2 seems to be associated with the emergence of co-infections [18]. According to Hoenigl and collaborators [20], these drugs hinder the activation of innate and adaptive antimicrobial responses and exacerbate existing underlying diseases, therefore, they represent important predisposing factors for secondary fungal infections and side effects on susceptibility to fungal infections, because fungi are an extremely neglected public health problem with few treatment options.
Although current studies focus on the intestinal microbiota, signaling the genera Candida, Malassezia, Aspergillus, Epicocum, Sccharomyces, Alternaria and Cladosporium, as the most common intestinal fungi in infections [21] [24]. Other infrequent opportunistic pathogenic fungi that cause pulmonary infections also need to be considered, such as Mucor spp. and Cryptococcus spp. [25]. More recently, zygomycetes have emerged as important fungal pathogens, especially in the severely immunocompromised host [24].
Although other yeast-like and filamentous fungal agents have also been reported, in cases with COVID-19 such as Trichosporon spp., Histoplasma spp., Coccidioides spp., Paracoccidioides spp., Fusarium spp., Cladosporium spp., Alternaria spp., Penicillium spp. at lower frequencies in this pandemic scenario. British researchers [26], in their studies, demonstrated that Candida albicans, C. glabrata, Aspergillus flavus, A. fumigatus, both from respiratory samples, also indicated with probability analysis, that COVID-19 patients-19 with co-infection became more likely to die than those who did not have co-infection, mentioning the growing reports in Europe of pulmonary aspergillosis associated with COVID- CAPA. COVID-19-associated pulmonary aspergillosis (CAPA) is a disease that requires prolonged ICU treatment due to the high mortality rate; records provided by researchers indicate that in France, 33% of patients with COVID-19 in the ICU were affected by CAPA, and in Germany, it affected up to 26% of patients [28].
The CDC (Centers of Disease Control and Prevention) informs that Aspergillus and mucorales, both are fungal groups that are virtually impossible to avoid contact with, as people inhale their spores, harmful to a weakened immune system, causing infections in the lungs and sinuses nasal passages with chances of spreading to other parts of the body [4].
Tavares [4], emphasize that patients with serious severity of COVID-19 with severe inflammation, dysregulation of the microbiota and treatment with antibiotics, often early, in addition to immunosuppressive drugs, leave the individual prone to mycoses such as Candida spp., Aspergillus spp. and Mucorales; being corroborated by ANVISA's technical note [15] which says there are cases of fungal infections in demand for growth in patients who acquire the severe form of the COVID-19 disease in intensive care, as is the case with invasive aspergillosis and mucormycosis.
We must take into account that in the SARS-CoV-2 pandemic, Severe Acute Respiratory Syndrome; the microbiological co-infection associated with the COVID-19 disease has led individuals to the need for hospitalization and hospital treatment, with opportunistic fungal co-infections. According to Severo [36] mucormycosis is an opportunistic fungal infection that usually does not course with disease in immunocompetent individuals, having clinical manifestations due to the state of the host, associated with diseases and when it appears it usually has a rapid evolution. Mucormycosis is the rarest type of fungal infection in order of importance after candidiasis and aspergillosis.
Mucormycosis depends on some basic conditions of the patient, predominantly in the male population and is associated with diabetes and oncological disease, plus the interaction of steroids, causing greater immunosuppression and the high glycemic rates triggered by diabetes mellitus, making these patients even more susceptible patients to the opportunism of zygomycosis [4]. in view of the already existing dissemination of mucormycosis common in that country, as well as the increasing prevalence of diabetes mellitus in the Indian population, this being a risk factor for the onset of infection, showing that species of the genus Rhizopus were more frequently observed in rhino-orbito-cerebral forms, with 46% of fatal cases [37]. Reports of 35 cases of mucormycosis were described by Nazari [27] that presented rhino-orbito-cerebral manifestations (91.43%) and rhinosinusitis (8.57%) distributed in rhino-sino-orbital infections (48.57%), rhino-orbital (20%), sinus-orbital (14.29%), orbital (5.71%) and rhino-sino-orbital (5.71%) orbital-cerebral involvement (2.86%). Definitive identification of Rhizopus oryzae (=R. arrhizus).

Reports of immunosuppression in cases of SARS-CoV
Research carried out in 2021 [38] showed that the increased use of corticosteroids in diabetic patients undergoing treatment for COVID-19 helps in uncontrolled glucose levels, favoring the appearance of fungi of the order Mucorales, as well as evidenced that in Brazil, patients with diabetes affected by COVID-19 more often needed intensive care units.
In India, cases of mucormycosis, called black fungus, have been associated with a range of pre-existing health conditions, including diabetes mellitus, iron overload, cancer, organ transplantation, kidney failure, acquired immunodeficiency syndrome (AIDS) and therapy immunosuppressant [13] [14] [39]. According to reports by an Emirati researcher [40]; overuse of steroids for COVID-19 patients has likely been the cause of the rise in the rare fungal disease. The infection stems from reduced immune response and capacity as a result of the steroids used to limit the immune system's overreaction to the infection.
In Brazil, Bonates [41] reported a case of mucormycosis in a male patient from Manaus/Brazil, diabetic, presenting diabetic ketoacidosis and ocular infection, who tested immunoglobulin G (IgG) positive for SARS CoV-2, presenting flu-like symptoms; the patient had necrosis in the region of the nose, orbits and palate and died, and the sequencing test showed 99% similarity with Rhizopus oryzae. In Brazil, Munhoz [42], presented a case of rhino-orbito-cerebral mucormycosis in a diabetic patient hospitalized for COVID-19 whose diagnosis was confirmed by identifying the agent Rhizopus microsporus var. microsporus.
Indian researchers in 2022 [39] reported 102 cases of mucormycosis, being treated for COVID-19. The patients had diabetes mellitus and severe diabetic ketoacidosis, favoring fungal opportunism by filamentous zygomycetes in cases of maxillary necrosis, sinus-orbito-nasal involvement and pulmonary infections. Amphotericin-B, posaconazole and isavuconazole are the antifungals used in the treatment of mucormycosis or black fungus.
Silva and researchers [43] correlating co-infections and mortality, the rates found were higher in male patients compared to females, and older age contri- A similar situation occurred in Iran. Hypertension, cardiovascular diseases, diabetes mellitus and chronic kidney diseases were the underlying diseases reported in cases of co-infections with fungal entities linked to COVID-19. Patients were admitted to the ICU, mechanically ventilated and received antibiotics and corticosteroids. No antifungal was recommended and the patients died [27]. For Chen and associates [18], the intestinal balance can be altered in co-in fection, triggering infection and stimulation of the immune system to a more pronounced inflammation and, if a co-infection increases the level of systemic inflammation, this increases the severity of the disease, reducing the patient's healing time. These researchers, in their sample, highlighted the main fungal species: Aspergillus spp, Candida albicans, C. glabrata, C. dubliniensis, C. parapsilosis sensu stricto, C. tropicalis and C. krusei.
Linked to COVID-19, cases of the yeast emerging as one of the most infectious agents, Candida auris, are becoming more routine, possibly the pandemic may be favoring the spread of this species of Candida in hospital environments.
Almeida-Jr and collaborators [44] presented cases of C. auris in Brazil, in the city of Salvador in December 2020, showing that the colonized were in the same intensive care unit to treat COVID-19 and, molecular analyzes showed that the strains found in Brazil they were phylogenetically related to the South Asian clade (Clade 1), considering that the patients had no history of traveling abroad.
Other reported cases occurred in New Delhi, India, 15 cases of COVID-19 associated candidemia (CAC) in ICU patients; Candida auris, C. albicans, C. tropicalis and C. krusei were identified; most of those colonized by Candida auris were male and aged between 66 -88 years and had underlying diseases such as hypertension, diabetes mellitus, kidney disease and chronic liver disease and half of the patients affected by C. auris required mechanical ventilation due to severity of COVID-19 [45]. Another peculiar case reported in India, by Bhagali [46], of a male patient who developed retinitis caused by Candida albicans after infection with SARS-CoV-2; this patient was diabetic and hypertensive and needed to use corticosteroids to treat COVID-19. In Brazil, a report of 60 strains of C. parapsilosis resistant to the azole fluconazole and tolerant to echinocandins caused an outbreak of candidemia among patients with COVID-19 in a Brazilian ICU; reported and discussed by Daneshia and collaborators [47]. Vitale and researchers [35] listed the yeasts that were associated with co-infections in COVID-19 and found Candida species fungemia reported in 149 cases. The most frequently isolated species from blood cultures were C. albicans, C. auris, C. glabrata, C. tropicalis, C. parapsilosis, C. dubliniensis, C. orthopsilosis and C. krusei (=Pichia kudriavzevii) and also Trichosporon asahii, Saccharomyces cerevisiae, Rhodotorula mucilaginosa and Cryptococcus neoformans. In Iran, researchers pointed out those older and female patients were more affected by Candida yeast infections and COVID-19 infections. Cases included oropharyngeal candidiasis (62.35%), pulmonary candidiasis (29.41%), candidemia (7.06%) and endocarditis (1.18%), isolating in these records, C. albicans, the most common species, followed by C. glabrata, C. dubliniensis, C. tropicalis, C. parapsilosis and C. krusei [27].
Rodriguez and colleagues [48], reported cases of fungemia in inpatients with SARS-CoV-2 at 4 institutions in Colombia in 2020; these patients received therapy with Beta-Lactam antibiotics and steroids, many used a central venous catheter and had a prolonged time in the intensive care unit and developed fungemia due to Candida auris, C. albicans, C. tropicalis, C. parapsilosis, C. orthopsilosis, C. glabrata and Trichosporon asahii.
Incidentally, this last fungal agent, in recent times, has been showing its invasive capacity to cause serious fungal infections. The genus Trichosporon is known for its capacity for superficial colonization; however some species have shown pathogenic potential for systemic infections. This fungal agent has changed from a rare opportunistic pathogen to a group of microorganisms that has been causing alarm and concern worldwide, mainly due to its profile of resistance to antifungal agents.
Trichosporon asahii is a highly resistant emerging pathogen with considerable mortality, particularly in critically ill patients and immunocompromised individuals [2]. Rodriguez in casuistry [48] reported 20 cases of T. asahii fungemia in patients with COVID-19, with a reported overall mortality of 60% in this cohort.
Benelli and researchers [50] reported a case of a patient with bloodstream infection by T. asahii in a critically ill patient with COVID-19 associated with Acinetobacter baumanii. Almeida-Jr. [51], described 5 critical patients with COVID-19 who developed fungemia by T. asahii, who presented risk conditions: central venous catheter, previous exposure to broad-spectrum antibiotics, previous therapy with echinocandin and previous prolonged corticosteroid therapy. More currently, Cronyn [52] reported urinary infection in a male patient with severe COVID-19, isolating the co-infection agent T. asahii, treated with fluconazole and voriconazole, and finally, a case of associated brain abscess to Coronavirus Disease 2019 caused by a rare species of basidiomycete of the genus Trichosporon, T. dohaense affecting a diabetic patient who received systemic corticosteroids for the treatment of COVID-19 [53]. Another fungal organism also present in co-infections associated with patients with severe COVID-19 was the genus Cryptococcus. Recently, cryptococcal infections have emerged as a concern after association with COVID-19 infection (CACI), because Cryptococcus spores can remain dormant in human hosts, because cryptococcal infections are considered incurable, their fungal cells can remain dormant for many years and relapse occurs when the host becomes immunocompromised [54], which can lead to invasive cryptococcosis and disse-DOI: 10.4236/aim.2023. 131001 14 Advances in Microbiology mination in contexts of corticosteroid use, immunosuppressive therapy, endocrine and metabolite disorders, and blood and cancerous malignancies [55].
Infection by Cryptococcus spp. was reported in severe COVID-19 patients associated with pulmonary infection and followed by cryptococcal meningitis in 13 reports described by Regalla and colleagues [56]. Of 212,479 hospitalized patients with COVID-19; 65 patients were diagnosed with cryptococcosis, with cases of cerebral cryptococcosis, pulmonary cryptococcosis and disseminated cryptococcosis. Twenty-one patients had HIV infection in reports described by US researchers [57]. Chan and reseachers [58] reported 18 cases of COVID-19 infections associated with cryptococcosis, isolating C. neoformans and C. laurentii in their case series; these researchers, in summary, emphasized that COVID-19-associated cryptococcosis is uncommon; however, it may be underestimated due to underdiagnosis. In the same year, Roesch and collaborators [59] reported a case of a female patient, where conventional results did not detect the presence of comorbidities. Pathology demonstrated a collection of histiocytes, neutrophils, and necrotic debris, and pathology stains were positive for Cryptococcus fungal organisms, leading to a secondary lung cryptococcal infection. Alegre-Gonzales [60] in Spain, reported disseminated infection by C. neoformans, in a male patient with immunosuppression, affected by COVID-19, with fatal outcome.
Still other fungal entities are also involved in cases of patient infections associated with the serious situation involving COVID-19. Fusarium, a plant pathogen, has crossed the species barrier, has become a common pathogen that infects immunocompromised, transplant patients, and rarely infects healthy individuals. A case of fusariosis and COVID-19, associated with pulmonary infection, was reported by Damani [61] in a healthy, non-critical patient.
Fusarium and Scedosporium belong to a heterogeneous group of filamentous fungi defined as infections called hyalohyphomycosis. Cases of severe pulmonary fusariosis associated with the COVID-19 virus have been reported F. incarnatum, F. fujikuroi, F. equiseti and F. solani in Iran [62] and a rare case of pulmonary infection due to Scedosporium occurred in Chile, described by John and researchers [63].
Another case of this type of infection was reported by Poignon [64] in a case of pulmonary fusariosis described in a diabetic patient with severe COVID-19 due to F. proliferatum, in France, and a case of invasive fusariosis, which occurred in Argentina, by F. verticillioides in a previously immunocompetent and critically ill patient with severe COVID-19 pneumonia [65].
In a Middle Eastern country, cases of pulmonary fusariosis in two men and four women with positive BAL galactomannan (GM) tests were reported in cases of COVID-19. The causative agents, including F. incarnatum, F. fujikuroi, F. equiseti and F. solani detected in bronchoalveolar lavage (BAL) culture [27].
Histoplasmosis is a global systemic mycosis highly endemic in certain regions of the Americas, including Brazil. The acute form of histoplasmosis usually occurs after exposure of more than one individual to a common environmental  [71].
Also in that country, Texas/USA researchers [72] that coincided with the COVID-19 infection identified 60 cases of coccidioidomycosis. The investigators reported that seven of these patients developed clinically progressive coccidioidomycosis, and reported that corticosteroid intakes were considered a risk factor for the development of the fungal disease.
Finally, record of Paracoccidioides mycosis, associated with the case of COVID-19, reported by Macedo and collaborators [73]. PCM is a systemic fungal disease that occurs in Latin America and is most prevalent in South America.
Infection begins in the lungs after inhaling active forms of Paracoccidioides spp.
that affected young patient, male, 19 years old, with weight loss and scattered lymph nodes throughout the body, according to a case report.
COVID-19 still has a high prevalence worldwide. It is important for studies that evaluate the occurrence and frequency of association with and its impact on therapeutic modification and on the respiratory condition [30]. It is clear that Immune alterations in patients with SARS, MERS and FLU (influenza), especially alterations in the subsets of peripheral blood T lymphocytes, contribute to the understanding of the characteristics, diagnosis, monitoring, prevention and treatment of the disease [75]. According to Iranian researchers, Almasi and Mohammadipanah [76] there are two factors that address drug discovery to develop a new drug for SARS-CoV-2. Drug retargeting, screening molecular databases using drug modeling tools, and screening compound libraries in antiviral assays are current major approaches to finding potential agents for SARS-CoV-2 therapy. Much progress in understanding SARS-CoV-2 and molecular details of its lifecycle, followed by the identification of new therapeutic targets, is needed to lead to an efficient approach to anti-SARS-CoV-2 drug discovery.
In fact, the association of COVID-19 infection and fungal infections brings great problems to patients affected by these two diseases, depending on the im-

Conclusions
This review aims to raise awareness of the importance of early detection and treatment of fungal infections, as mortality rates are high in patients with COVID-19, or even those with other immunosuppression conditions. It is necessary to accurately identify risk factors associated with secondary infections in each diagnosed patient to ensure optimal clinical outcomes.
It is important to keep in mind strategies and protocols to define more efficient and personalized treatments for COVID-19 patients, due to the emergence of fungal coinfections and the complexity that they can cause in the course of the disease, to allow safer interventions for patients, resulting in better treatment results.
It is also worth remembering that the growing cases of co-infections associated with fungi, the cases of mucormycosis that occurred in India, or even the rise of emerging fungi such as Candida auris, a multiresistant fungus, presented the SARS-CoV-2, and has shown their multiple abilities to infect and cause clinical emergency damage.
Frequent monitoring of co-infections acquired in the community and in hospital environments should be constant, serving as a surveillance for the scientific and medical community for cases of superinfections, raising awareness about the possibility of fungal co-infections, conscious use of antifungal drugs, which are often scarce in certain places, become essential factors, which aim to reduce delays in diagnosis and treatment, in order to help prevent serious illness and death from these infections.