One of the major complications of severe COVID-19 cases are yeast infections. They are mainly caused primarily by Candida spp., which are associated with a high mortality rate, due to a longer ICU stay, catheterization, and broad-spectrum antibiotic use [6] (Table 1). Nucci et al. observed stable incidence of candidemia in their hospital during an 18-year period (1.3 episodes per 1000 admissions), but since March 2020, an increase in cases diagnosed with candidemia was noticed [30]. Compared with non-COVID-19 patients, COVID-19 patients with candidemia were more likely to be under mechanical ventilation [30]. Katz et al. evaluated the association between COVID-19 and oral and systemic candidiasis [25]. Generally, candidiasis was significantly associated with increased risk for COVID-19, whereas oral candidiasis showed an insignificant trend [25].

Both fungi and virus display highly distinctive patterns of sudden emergence, and are based on simple infection-driven, human-to-human transmission [31]. In times of SARS-CoV-2, the vigilance of multidrug-resistant Candida spp. (e.g., Candida auris, C. glabrata, and Candida duobushaemulonii [17,32,33]) is extremely important. Data regarding multidrug-resistant Candida spp. in COVID-19 patients are scarce [32]. C. auris, an emerging pathogen known for a reduced susceptibility to antifungals, is spread across all continents [5], and it is easily transmitted between healthcare professionals. Both C. auris and SARS-CoV-2 have been found on hospital surfaces including on bedrails, intravenous (IV) poles, beds, air conditioner ducts, windows, and hospital floors [5]. Hospital-acquired C. auris infections in coronavirus disease patients may lead to adverse outcomes and additional strain on healthcare resources [34]. Moreover, the standard COVID-19 critical care of using mechanical ventilation and protracted ventilator-assisted management makes these patients potentially susceptible to colonization and infections by C. auris [5]. For example, during April–July 2020 in New Delhi (India), C. auris accounted for two-thirds of cases, and the case-fatality rate was very high (60%) [4]. In a phylogenetic molecular clock study (Genoa, Italy), Di Pilato and colleagues showed that all C. auris isolates were resistant to amphotericin B, voriconazole, and fluconazole at a high level, owing to mutations in ERG11 (K143R) and TACB1 (A640V) genes. Critically, C. auris could be easily spread because of the COVID-19 pandemic [35]. After the first C. auris-colonized case was diagnosed in a COVID-19 patient in ICU at a hospital in Salvador, Brazil, a multidisciplinary team conducted a local C. auris prevalence investigation [36]. Remarkably, findings revealed that among body swabs collected from 47 patients, eight samples from the axillae were positive for C. auris. Contaminated axillary monitoring thermometer helped to C. auris dissemination. Re-use of these devices must imply a careful disinfection or they should be replaced by other temperature monitoring methods [36]. Moreover, in 2020, the Florida Department of Health was alerted to three C. auris bloodstream infections and one urinary tract infection (UTI) in four patients with COVID-19 who had received care in the same COVID-19 ICU ward [37]. A report from in a tertiary academic center (United States, May 2014 to October 2020) showed that in an entire sample (non-COVID-19 and COVID-19 groups), C. albicans accounted for a minority of isolates collected [38]. Compared to non-COVID-19 patients with candidemia, COVID-19 patients had lower ICU admission sequential organ failure assessment score, but longer ICU stays and central venous catheter dwell times at candidemia detection [38].

Surveillance data assessed differences in candidemia patients with and without a prior COVID-19 diagnosis [28]. COVID-19 patients with candidemia lacked established underlying conditions associated with candidemia but had two times the mortality rate versus candidemia patients without COVID-19 [28]. Over a two-year period, patients followed in the ICU of Ankara City Hospital, Turkey, were divided into pre-pandemic and pandemic periods [29]. In multivariate logistic regression analysis, corticosteroid use, presence of sepsis, and age older than 65 years were independent risk factors for mortality in candidemia patients [29]. Indeed, candidemia with high mortality is reported as a more serious problem for COVID-19 patients due to its increased and earlier incidence, and a higher rate of mortality [28,29].

Aspergillosis is one of the most common opportunistic fungal co-infections caused by some Aspergillus spp., which particularly affects immunocompromised persons, such as COVID-19 patients. It critically affects the respiratory system, leading to a mild/serious lung infection, known as pulmonary aspergillosis, a serious form of aspergillosis, which becomes worse over time and does not have an effective treatment [26,41]. Clinical characteristics of the COVID-19 patients co-infected with aspergillosis can be analyzed in Table 2. Based on the available literature, it is suggested to keep a low threshold to investigate for COVID-19 associated pulmonary aspergillosis (CAPA), since an early detection and respective treatment may significantly improve outcomes. Moreover, prolonged courses of steroids should not be given unless further conclusive evidence is available [42], because steroids suppress the immune system, making the patient more susceptible to secondary infections. A rapid and aggressive treatment approach with judicious use of steroids while treating co-infections turns out to be the best possible outcome and solution.

Histoplasmosis is a systemic mycosis, highly endemic in certain regions of America and Asia, including Brazil and India. It is caused by a dimorphic fungus, Histoplasma capsulatum, which predominately occurs in soil containing large amounts of bird or bat droppings. The infection occurs through the inhalation of fungal microconidia after perturbation of these environmental sources [50]. Similarly to aspergillosis, the disease is usually associated with immunosuppressive conditions, clinically presenting severe acute disseminated forms. Underlying lung disorders can predispose individuals to chronic pulmonary histoplasmosis, whereas acute and subacute pulmonary forms mainly occur in healthy individuals after a large fungal inoculum inhalation [50,51]. These clinical forms are less known, often misdiagnosed as bacterial pneumonia and pulmonary tuberculosis (Table 3). In the case of this particular fungal disease, it was indicated that most patients who received steroids for COVID-19 treatment developed histoplasmosis (Table 3). Histoplasmosis is mainly associated with COVID-19 patients with AIDS, and there are very few studies on the co-infection of H. capsulatum and COVID-19 [27,52]. Actually, the important findings were all patients of COVID-19 having co-infection of H. capsulatum survived after antifungal treatment with amphotericin B and itraconazole (Table 3) [27,52,53,54,55].

The presence of hyphal infiltration of sinus tissue and a temporal course of less than four weeks defines mucormycosis [56,57]. The most common species related to mucormycosis are Rhizopus spp. and Mucor spp., but recently, a new Cunninghamella species, Cunninghamella bigelovii, was described [58]. Clinically, rhino-cerebral mucormycosis (RCM) can have atypical symptoms and signs that are similar to complicated sinusitis, such as crusting, nasal blockage, facial pain, proptosis and chemosis, edema, ptosis, and even ophthalmoplegia, as well as fever and headache and symptoms of intracranial extension [59,60]. A black eschar can be found on the hard palate or in the nasal cavity, but it is not typical [61,62]. Mycotic infiltration of blood vessels, thrombosis with vasculitis, acute neutrophilic infiltrate, bleeding, and tissue infarction are all histological characteristics [63].

Without early treatment and identification, this illness may advance quickly, with reported death rates of 50–80%, due to intra-orbital and cerebral complications. Even with timely treatment of underlying illnesses, diagnosis, and surgical intervention, therapy is frequently ineffective, resulting in infection spread and eventually death [64].

Recently, there has been a shift in the occurrence of sinus mucormycosis infection, and patients have been identified more often. A dramatic increase in cases of invasive fungal sinusitis, especially mucormycosis, has occurred in the past months, with many patients needing drastic surgical operations to treat this illness [65,66]. The use of steroids to control COVID-19 may be directly related to the suppression in immunity; thus, it also allows the colonization of opportunistic fungi, leading to mucormycosis, during any stages of the disease (Table 4) [23].

Cryptococcus neoformans is also related to a very serious opportunistic infection in immunocompromised patients. It has been reported that C. neoformans can infect COVID-19 patients. Mohamad Y et al. described the importance of early suspicion of C. neoformans infections in patients with immunocompromised state, considering that Cryptococci patients have a high risk of mortality [98]. In the current perspective, the use of immunosuppressive drugs should be justified and to be alert for infections such as C. neoformans, which can cause sepsis and mortality [98]. Studies have shown that almost all patients with COVID-19 having co-infection of C. neoformans did not survive, even after treatment with fluconazole and amphotericin B (Table 5).

Some other types of fungal infections have also been reported along with COVID-19. This is the case of Coccidioides immitis and Pneumocystis jirovecii (Table 5). Although co-infection with P. jirovecii is considered life-threatening, according to recent publications, patients improved clinically when treated with common drugs, such as trimethoprim–sulfamethoxazole [99,100]. Similarly to the other cases, during these co-infections, steroids had a negative impact on COVID-19-associated fungal co-infections conditions [100,101].