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    Topic review

    Fungal Infections in COVID-19 Patients

    Subjects: Microbiology
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    Patients with severe COVID-19, such as individuals in intensive care units (ICU), are exceptionally susceptible to bacterial and fungal infections. The most prevalent fungal infections are aspergillosis and candidemia. Nonetheless, other fungal species (for instance, Histoplasma spp., Rhizopus spp., Mucor spp., Cryptococcus spp.) have recently been increasingly linked to opportunistic fungal diseases in COVID-19 patients. These fungal co-infections are described with rising incidence, severe illness, and death that is associated with host immune response. Awareness of the high risks of the occurrence of fungal co-infections is crucial to downgrade any arrear in diagnosis and treatment to support the prevention of severe illness and death directly related to these infections. 

    1. Introduction

    Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of coronavirus disease 2019 (COVID-19), has infected millions of patients worldwide, and placed an unprecedented stress on healthcare systems [1][2][3][4]. This disease has predisposed a relatively high number of patients to acute respiratory distress syndrome, and co-infections are a frequent complication [5][6], especially with prolonged hospital stays [7]. Changes in humans’ microbiota have been recently observed in COVID-19 patients [1], with patients often being colonized or infected by microorganisms responsible for secondary infections (co-infections or superinfections), often caused by bacteria and fungal pathogens [5][7][8][9]. Indeed, several opportunistic infections following severe respiratory viral infections have been recognized in COVID-19 patients [2]—particularly, a higher incidence of fungal co-infections (Figure 1) [10][11][12]. For example, in Spain, the incidence of candidemia cases was higher in the first and second waves and lower during the third wave, also with a prevalence of invasive pulmonary aspergillosis (IPA) cases [11]. Moreover, the coronavirus-associated pulmonary aspergillosis (CAPA) showed to affect up to 30% of ventilated patients with COVID-19 admitted in intensive care units (ICU) [13], and, in a hospital in Pisa (Italy), 21.9% of 315 hospitalized patients with COVID-19 had a superinfection [14].
    Figure 1. Percentage of variation of cases of COVID-19 patients with fungal co-infections reported in 2020 and 2021 (source: PubMed).
    The main pathogens related to co-infections are reported to be Enterobacterales (44.9%), non-fermenting Gram-negative bacilli (15.6%), Gram-positive bacteria (15.6%), and fungi (5.5%) [14]. In COVID-19 patients, the most fungi related to co-infections are Aspergillus spp., Candida albicans, Candida glabrataCandida dubliniensisCandida parapsilosis sensu strictoCandida tropicalis, and Candida krusei (Pichia kudriavzevii) [8]. Moreover, these cases have been indicated as mainly primary and catheter-related infections [15].
    There is still lack of information regarding the long-term impact of secondary infections on the outcome of hospitalized COVID-19 patients [9][16]. Patients with co-infection undergoing invasive mechanical ventilation showed to be 3.8 times more likely to die than those without positive cultures [9]. In order to perform an efficient treatment and reduce mortality, it is important to make an accurate early identification [12]; however, these co-infections raise difficulties on diagnosis, treatment (including broad-spectrum antimicrobial drugs, mechanical ventilation, extracorporeal membrane oxygenation), prognosis, and even increase the disease the symptoms and mortality of COVID-19 [8][12][15][17][18][19].
    The repercussions of SARS-CoV-2 infections on future global antimicrobial resistance must be explored profoundly [3][16]. In Valencia (Spain), the antifungal consumption increased in 2020 compared to previous year, especially echinocandins, voriconazole, and isavuconazole [11]. Considering that the antimicrobials drugs for COVID-19 patients, both on and during admission, are almost all prescribed uncertainly in clinical settings, there is expected an increase in drug-resistant infections [3].
    Lastly, considering the immune response, there has been represented a host dysregulation triggered by SARS-CoV-2 infection, which has been hypothesized as a causal pathway for the increasingly reported mainly fungal (oral) manifestations associated with COVID-19 [20][21]. Additionally, the alteration in human microbiota (due to SARS-CoV-2 infection), which can also indicate the progression of COVID-19, may contribute to bacterial, fungal, or viral infections and affect the immune system [1]. In these patients, this is normally described as an increase in pro-inflammatory markers, such as IL-1, IL-6, and tumor necrosis alpha (TNF-α), less CD4 interferon-gamma expression, and a decreased number of CD4 and CD8 cells, which increase susceptibility to bacterial and fungal infections [12].

    2. Fungal Infections as a Co-Morbidity of COVID-19

    Fungal co-infections are frequent in the COVID-19 patients; therefore, its awareness is important for proper diagnosis and, subsequently, efficient treatment of the fungal co-infections for reducing morbidity and mortality. Due to a general neglected approach towards fungal tropical diseases, morbidity and mortality is expected to worsen in the context of the COVID-19 pandemic [22]. SARS related to COVID-19 disease is known to increase the risk of invasive fungal infections (IFI) [23][24]. In addition, patients suffering from endemic mycoses and COVID-19 co-infection seem to be an at-risk population and have a poor prognosis. A significant number of cases of COVID-19-associated candidiasis, aspergillosis, mucormycosis, and histoplasmosis have been reported so far from the different region of the world [22][25][26][27]. Some reports even state that COVID-19 increases the mortality rate in the patients having fungal infections, but the case reports suggest that individuals with COVID-19 are more susceptible to a fungal infection mostly because of impaired immune responses, which further increases the awareness of clinicians for more effective diagnosis and treatment [28][29].

    2.1. Candidiasis

    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].
    Table 1. Clinical characteristics of COVID-19 patients reported with candidiasis.
    Fungal Infection in COVID-19 Infection Observed Immune
    Disease Models
    Test/Diagnosis Performed COVID-19
    Antifungals Used Steroids? Outcome after Treatment References
    Candida duobushaemulonii
    Candida parapsilosisCandida lusitaniae
    pro-inflammatory markers (d-dimer, ferritin, CRP, progressive
    thrombocytosis) and neutrophilia
    Acute pulmonary
    with subarachnoid hemorrhage
    superimposed bacterial pneumonia
    CT scan, Culture,
    Blood, urine, and
    Amikacin, tigecycline,
    NR Dead [31]
    (Candida glabrata)
    C-reactive protein and interleukin 6—altered
    Type-2 diabetes
    ischemic heart disease
    stadium IV, leg amputation highly suspected bacterial superinfection
    Chest X-ray and CT scan, RT-PCR, serology,
    Caspofungin NR Dead [32]
    Candida auris (n = 10),
    Candida albicans (n = 3), Candida tropicalis (n = 1), Candida krusei (P. kudriavzevii) (n = 1)
    NA Underlying chronic conditions (e.g., hypertension, n = 7; DM, n = 6; and chronic kidney and liver disease, n = 2) MALDI-TOF and molecular identification—sequencing NR Micafungin NR Dead (n = 8) [4]
    Candida auris
    (n = 3)
    NA DM,
    hypertension, chronic renal
    failure, coronary artery
    disease, obesity
    Vitek 2 system,
    MALDI-TOF, sequencing,
    multiplex PCR
    NR Anidulafungin NR Dead [33]
    Candida auris
    (n = 12)
    NA DM (n = 6), hypertension (n = 6), multiple myeloma (n = 1),
    stem cell transplantation (n = 1), dyslipidemia (n = 1), end stage renal disease (n = 1), bladder cancer (n = 1), obesity (n = 1), systematic lupus erythematosus (n = 1)
    whole genome sequencing
    Remdesivir (n = 9), HCQ (n = 1), Amphotericin B
    n = 10 Dead (n = 6)
    Alive (n = 6)
    DM: diabetes mellitus; DTA: deep tracheal aspirate; HCQ: Hydroxychloroquine; MALDI-TOF: matrix-assisted laser desorption/ionization time-of-flight; NA: not applicable/available; NR: not reported; PCR: polymerase chain reaction.
    Both fungi and virus display highly distinctive patterns of sudden emergence, and are based on simple infection-driven, human-to-human transmission [35]. In times of SARS-CoV-2, the vigilance of multidrug-resistant Candida spp. (e.g., Candida aurisC. glabrata, and Candida duobushaemulonii [17][31][36]) is extremely important. Data regarding multidrug-resistant Candida spp. in COVID-19 patients are scarce [31]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 [37]. 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 [38]. 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 [33]. 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 [33]. 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 [39]. 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 [40]. 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 [40].
    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].

    2.2. Aspergillosis

    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.
    Table 2. Clinical characteristics of COVID-19 patients reported with aspergillosis.
    Fungal Infection in COVID-19 Infection Observed Immune Response Co-morbidity/
    Test/Diagnosis Performed COVID-19 Treatment Antifungals Used Steroids? Outcome after Treatment References
    Aspergillus spp., CAPA
    Highly permissive inflammatory response DM, CVD CT scan, Culture HCQ Azoles, liposomal amphotericin B NR Alive [43]
    Immunocompromised ARD, HT CT scan, RT-PCR, Culture, ELISA NR Voriconazole Yes
    (n = 7)
    Some alive and some dead [44]
    Aspergillus fumigatus, CAPA
    Immunocompromised DM, HT CT scan, Culture NR Isavuconazole, voriconazole No Alive [42]
    HT, coronary heart disease, obesity CT scan, RT-PCR, Culture, HCQ, meropenem, azithromycin Voriconazole Yes Dead [26]
    Low B-cell and T-cell response Severe dyspnea, hypertension, DM CT scan, RT-PCR, Serology RD, multiple antibiotics Multiple antifungals No Alive [45]
    Systemic pro-inflammatory cytokine responses Asthma, DM, Myeloma CT scan, RT-PCR, Culture, NR Voriconazole, isavuconazole, liposomal amphotericin B, caspofungin, anidulafungin Yes Some alive and some dead [46]
    High inflammatory response and immunosuppression ALL, AML RT-PCR, CT scan, Culture, Serology NR Caspofungin, fluconazole, liposomal amphotericin B, caspofungin, itraconazole No Some alive and some dead [47]
    Aspergillus spp., IA
    Acquired immunodeficiency and immunosuppression ARD Antigen, CT scan, Culture, Serology NR NR Yes Death
    (quick evolution)
    Strong deregulation of core components of innate immune and inflammatory responses RHAEM NA NA NA NA NR [49]
    ARD: acute respiratory disease/distress; ALL: acute lymphoblastic leukemia; AML: acute myeloid leukemia; CAPA: COVID-19-associated pulmonary aspergillosis; CT: computed tomography; CVD: cardiovascular disorder; ELISA: enzyme-linked immunosorbent assay; DM: diabetes mellitus; HIV: human immunodeficiency viruses; HT: hypertension; IA: invasive aspergillosis; NA: not applicable/available; NR: not reported; RHAEM: Reconstituted Human Airway Epithelial Model; RA: Rheumatoid arthritis; HCQ: Hydroxychloroquine; RD: Remdesivir; RT-PCR: real time-polymerase chain reaction.

    2.3. Histoplasmosis

    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].
    Table 3. Clinical characteristics of COVID-19 patients reported with histoplasmosis.
    Fungal Infection in COVID-19 Infection Observed Immune Response Co-morbidity/
    Test/Diagnosis Performed COVID-19 Treatment Antifungals Used Steroids? Outcome after Treatment References
    Histoplasma capsulatum
    Acquired immunodeficiency HIV CT-scan,
    Tenofovir/lamivudine and atazanavir/ritonavir
    ceftriaxone, azithromycin
    Itraconazole Yes
    Alive [27][52]
    HIV HIV CT-scan,
    Atazanavir/ritonavir, tenofovir/emtricitabine Itraconazole,
    amphotericin B deoxycholate
    No Alive [27]
    Inflammatory response NA CT-scan,
    Levofloxacin Itraconazole Yes
    Alive [53]
    NA NA CT scan,
    NA Itraconazole No Alive [54]
    Histoplasma capsulatum-like intracellular yeasts
    Acquired immunodeficiency HIV CT-scan,
    HCQ, lopinavir/ritonavir, tenofovir disoproxil fumarate/emtricitabine plus dolutegravir Amphotericin B deoxycholate,
    No Lost to follow-up [55]
    ART: antiretroviral therapy; CT: computed tomography; HIV: human immunodeficiency viruses; NA: not applicable/available; HCQ: Hydroxychloroquine; RT-PCR: real time-polymerase chain reaction.

    2.4. Mucormycosis

    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].
    Table 4. Clinical characteristics of COVID-19 patients reported with mucormycosis.
    Test/Diagnosis Performed COVID-19 Treatment Antifungals Used Steroids? Outcome after Treatment References
    None mentioned Linezolid, meropenem NA Died [67]
    Remdesivir Amphotericin B NA Died [68]
    Vascular disease
    Tocilizumab, methylprednisolone, dexamethasone Amphotericin B Methylprednisolone, dexamethasone Died [69]
    HT CT-scan,
    Hydrocortisone Amphotericin B Hydrocortisone Died [70]
    NA CT-scan,
    Remdesivir, tocilizumad, dexamethasone Amphotericin B Dexamethasone Died [71]
    Remdesivir, dexamethasone Amphotericin B Dexamethasone Died [72]
    HT CT-scan,
    HCQ, lopinavir–ritonavir Amphotericin B NA Died [73]
    Meropenem Amphotericin B Dexamethasone Alive [74]
    DM CT-scan,
    NA Amphotericin B NA Alive [75]
    NA Liposomal amphotericin B, itraconazole NA Alive [76]
    Remdesivir, dexamethasone, metformin, glipizide Amphotericin B, ceftriaxone Dexamethasone Live [77]
    DM CT-scan,
    Meropenem, oseltamivir
    tocilizumab, sitagliptin/metformin
    Amphotericin B Methylprednisolone,
    Died [69]
    DM CT-scan,
    Remdesivir, ceftriaxone, azithromycin, dexamethasone Voriconazole, liposomal amphotericin B Dexamethasone Live [78]
    DM (1 patient)
    No co-morbidity (1 patient)
    CT-scan Remdesivir, convalescent plasma,
    vancomycin, piperacillin-tazobactam
    Amphotericin B NA Live (n = 1)
    Died n = (1)
    Amphotericin B NA Died [79]
    DM (n = 8)
    CRF (n = 3)
    CT-scan Broad-spectrum antibiotics Liposomal amphotericin B Dexamethasone Died (n = 7)
    Alive (n = 4)
    (all patients)
    Systemic antifungals Glucocorticoids Died (n = 7)
    Live (n = 8)
    T2DM (4)
    T2DM with HT (1)
    HT (1)
    Kidney Disease (1)
    Tocilizumab, prednisolone,
    piperacillin/tazobac, linezolid
    Voriconazole Prednisolone Died (n = 3)
    Alive (n = 4)
    DM (21-cases)
    HT (14-cases)
    Renal failure (1-case)
    HCQ, azithromycin Caspofungin Combination of steroids All Live [76]
    DM (16) RT-PCR Corticosteroids Liposomal amphotericin B, voriconazole,
    On Steroid Alive (n = 10)
    Died n = (6)
    dexamethasone or
    methylprednisolone (7 patients); interferon (2 patient);
    remdesivir (1 patient);
    flavipiravir and HCQ (1 patient)
    Amphotericin B, posaconazole Dexamethasone or
    (n = 7)
    Live [84]
    Remdesivir, levofloxacin, dexamethasone, meropenem, vancomycin, piperacillin/tazobactam Amphotericin B, posaconazole Dexamethasone Live [85]
    No co-morbidity CT-scan,
    HCQ Amphotericin B NA Died [86]
    chronic lymphocytic leukemia
    RT-PCR NA Amphotericin B NA Died [87]
    RT-PCR NA Amphotericin B No Died [88]
    AML CT-scan,
    Amphotericin B NA Died [73]
    renal disease CT-scan,
    Remdesivir, vancomycin, cefepime Liposomal amphotericin B, posaconazole Dexamethasone Died [72]
    HF s/p OHT DM
    RT-PCR Remdesivir
    Fluconazole Methylprednisolone,
    Died [89]
    No history of any co-morbidity CT-scan,
    Tocilizumab Liposomal amphotericin B, posaconazole, isavuconazole Dexamethasone Live [90]
      Piperacillin/tazobactam, HCQ, azithromycinlopin, vir/ritonavir, prednisone
    Liposomal amphotericin B, isavuconazole, posaconazole Prednisone, Dexamethasone Live [91]
    HT RT-PCR Remdesivir, dexamethasone Amphotericin B Dexamethasone Died [92]
    (all 6 patients)
    Prednisolone, dexamethasone, methylprednisolone Amphotericin B, posaconazole Prednisolone,
    Remdesivir, interferon-alpha Systemic antifungals Systemic corticosteroid Died [94]
    T2DM, HT (2)
    T2DM (3)
    convalescent plasma,
    Liposomal amphotericin B,
    Methylprednisolone Died (n = 2)
    Alive (n = 3)
    T1DM CT-scan,
    Ceftriaxone, azithromycin,
    Amphotericin B Dexamethasone Live [71]
    HCQ, remdesivir, vancomycin, meropenem Liposomal amphotericin B,
    Prednisone Died [96]
    RT-PCR Meropenem, remdesivir, dexamethasone Liposomal amphotericin B Dexamethasone, prednisolone Died [97]
    CT: computed tomography; DM: diabetes mellitus; HIV: human immunodeficiency viruses, HT: hypertension; NA: not applicable/available; HCQ: Hydroxychloroquine; RT-PCR: real time-polymerase chain reaction; ICM: ischemic cardiomyopathy.; CKD: chronic kidney disease; AML: acute myeloid leukemia; UTI: urinary tract infections: HF; heart failure; s/p: status post; OHT: orthotopic heart transplant.

    2.5. Cryptococcus

    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).
    Table 5. Clinical characteristics of COVID-19 patients reported with cryptococcosis and other fungal infections.
    Fungal Infection in COVID-19 Infection Observed Immune Response Co-morbidity/
    Test/Diagnosis Performed COVID-19 Treatment Antifungals Used Steroids? Outcome after Treatment References
    Cryptococcus neoformans High inflammatory response and immunosuppression HAT, HBV CT-scan,
    meropenem, vancomycin Fluconazole Yes
    (tacrolimus, prednisone)
    Death [99]
    Acquired immunodeficiency and immunosuppression HIV CT-scan,
    Amphotericin B deoxycholate plus fluconazole No Death [100]
    High inflammatory response and immunosuppression Stage IV prostate cancer
    HT, colon-sigma diverticulosis
    CT-scan No Fluconazole
    Amphotericin B plus flucytosine
    Dexamethasone Death [101]
    High inflammatory response and immunosuppression HT, DM NA
    but COVID19 positive mentioned
    Tocilizumab and corticosteroids Anidulafungin,
    Methylprednisolone Death [98]
    Coccidioidomycosis (Coccidioides immitis, C. posadasii) Impaired cytokine signaling from CD4+ Th1 and cytotoxic CD8+ T-cells among patients No associated respiratory symptoms & disease CT scan, Culture, Serology NR Liposomal Amphotericin B No Alive [102]
    Coccidioidomycosis (Coccidioides immitis) Depressed cellular immunity Progressive respiratory symptoms, hypoxemia CT scan, Culture, Remdesivir Fluconazole No Alive [103]
    Pneumocystis jirovecii Cytokine release storm RA CT scan, Culture, Serology HCQ, Tocilizumab Caspofungin, ganciclovir, cefoperazone Glucocorticoids NR [104]
    Functional immune suppression related to CD4+ lymphocytopenia HIV, progressive hypoxemia RT-PCR, Culture, Serology, CT NR Trimethoprim- sulfamethoxazole NR NR [105]
    Immunocompromised ARD, DM, HT RT-PCR, Culture, Serology, HCQ, Lopinavir-ritonavir Antifungals and antibacterials Yes Some alive and some dead [106]
    Low CD4 count (35.6%) HIV CT, RT-PCR, Multiplex PCR NR Co-trimoxazole and oral prednisolone No Alive [107]
    Anemia, lymphopenia, raised C-reactive protein, immunosuppression HIV CT, RT-PCR NR Co-trimoxazole, IV pentamidine No Death [108]
    Severe depletion of CD4+ cells HIV RT-PCR, Culture, CT Emtricitabine, Ritonavir Trimethoprim-sulfamethoxazole No NR [109]
    Immunocompetent patient Recovered from COVID-19 RT-PCR, Culture, CT Enoxaparin, ceftaroline Trimethoprim-sulfamethoxazole, methylprednisolone Yes Alive [110]
    Immunocompromised patients HT, hepatic steatosis, massive lung thromboses RT-PCR, Culture, CT, Histopathology Remdesivir Trimethoprim-sulfamethoxazole, prednisone Yes Some alive and some dead [111]
    Saccharomyces cerevisiae (boulardii)
    (n = 2)
    Immunosuppression HT (first)
    Diabetes (Second)
    RT-PCR Oseltamivir
    treated with Ultra-Levure [preparation of Saccharomyces cerevisiae (boulardii)]
    Both live [112]
    Fusarium proliferatum immunocompetent diabetic patient HAT
    substituted hypothyroidism
    RT-PCR No Amphotericin B
    No Live [113]
    ARD: Acute respiratory disease/distress, CT: Computed tomography, DM: Diabetes mellitus; HIV: human immunodeficiency viruses; HT: Hypertension; IA: Invasive aspergillosis; NA: Not applicable/available; NR: Not reported; RHAEM: Reconstituted Human Airway Epithelial Model; RA: Rheumatoid arthritis; HCQ: Hydroxychloroquine; RD: Remdesivir; RT-PCR: real time-polymerase chain reaction; HBV: hepatitis B virus.

    2.6. Other Fungal Infections

    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 [109][110]. Similarly to the other cases, during these co-infections, steroids had a negative impact on COVID-19-associated fungal co-infections conditions [110][111].

    The entry is from 10.3390/jof7090720


    1. Soltani, S.; Zakeri, A.; Zandi, M.; Kesheh, M.M.; Tabibzadeh, A.; Dastranj, M.; Faramarzi, S.; Didehdar, M.; Hafezi, H.; Hosseini, P.; et al. The Role of Bacterial and Fungal Human Respiratory Microbiota in COVID-19 Patients. BioMed Res. Int. 2021, 2021, 6670798.
    2. Talento, A.F.; Hoenigl, M. Fungal Infections Complicating COVID-19: With the Rain Comes the Spores. J. Fungi 2020, 6, 279.
    3. Rawson, T.M.; Wilson, R.C.; Holmes, A. Understanding the role of bacterial and fungal infection in COVID-19. Clin. Microbiol. Infect. 2021, 27, 9–11.
    4. Chowdhary, A.; Tarai, B.; Singh, A.; Sharma, A. Multidrug-resistant Candida auris infections in critically Ill Coronavirus disease patients, India, April–July 2020. Emerg. Infect. Dis. 2020, 26, 2694–2696.
    5. Chowdhary, A.; Sharma, A. The lurking scourge of multidrug resistant Candida auris in times of COVID-19 pandemic. J. Glob. Antimicrob. Resist. 2020, 22, 175–176.
    6. Arastehfar, A.; Carvalho, A.; Nguyen, M.H.; Hedayati, M.T.; Netea, M.G.; Perlin, D.S.; Hoenigl, M. COVID-19-associated candidiasis (CAC): An underestimated complication in the absence of immunological predispositions? J. Fungi 2020, 6, 211.
    7. Kubin, C.J.; McConville, T.H.; Dietz, D.; Zucker, J.; May, M.; Nelson, B.; Istorico, E.; Bartram, L.; Small-Saunders, J.; Sobieszczyk, M.E.; et al. Characterization of Bacterial and Fungal Infections in Hospitalized Patients with Coronavirus Disease 2019 and Factors Associated with Health Care-Associated Infections. Open Forum Infect. Dis. 2021, 8, ofab201.
    8. Chen, X.; Liao, B.; Cheng, L.; Peng, X.; Xu, X.; Li, Y.; Hu, T.; Li, J.; Zhou, X.; Ren, B. The microbial coinfection in COVID-19. Appl. Microbiol. Biotechnol. 2020, 104, 7777–7785.
    9. Silva, D.L.; Lima, C.M.; Magalhães, V.C.R.; Baltazar, L.M.; Peres, N.T.A.; Caligiorne, R.B.; Moura, A.S.; Fereguetti, T.; Martins, J.C.; Rabelo, L.F.; et al. Fungal and bacterial coinfections increase mortality of severely ill COVID-19 patients. J. Hosp. Infect. 2021, 113, 145–154.
    10. Moser, D.; Biere, K.; Han, B.; Hoerl, M.; Schelling, G.; Woehrle, T.; Chouke, A. COVID-19 Impairs Immune Response to Candida albicans. Front. Immunol. 2021, 12, 1–10.
    11. Mulet Bayona, J.V.; Tormo Palop, N.; Salvador García, C.; Fuster Escrivá, B.; Chanzá Aviñó, M.; Ortega García, P.; Gimeno Cardona, C. Impact of the SARS-CoV-2 Pandemic in Candidaemia, Invasive Aspergillosis and Antifungal Consumption in a Tertiary Hospital. J. Fungi 2021, 7, 440.
    12. Bhatt, K.; Agolli, A.; Patel, M.H.; Garimella, R.; Devi, M.; Garcia, E.; Amin, H.; Domingue, C.; Del Castillo, R.G.; Sanchez-Gonzalez, M. High mortality co-infections of COVID-19 patients: Mucormycosis and other fungal infections. Discoveries 2021, 9, e126.
    13. Bienvenu, A.L.; Bleyzac, N.; Richard, J.C.; Leboucher, G. No time for pending confirmation of invasive fungal disease in critically ill COVID-19 patients-think empirical treatment. Crit. Care 2020, 24, 4–5.
    14. Falcone, M.; Tiseo, G.; Giordano, C.; Leonildi, A.; Menichini, M.; Vecchione, A.; Pistello, M.; Guarracino, F.; Ghiadoni, L.; Forfori, F.; et al. Predictors of hospital-acquired bacterial and fungal superinfections in COVID-19: A prospective observational study. J. Antimicrob. Chemother. 2020, 76, 1078–1084.
    15. Bardi, T.; Pintado, V.; Gomez-Rojo, M.; Escudero-Sanchez, R.; Azzam Lopez, A.; Diez-Remesal, Y.; Martinez Castro, N.; Ruiz-Garbajosa, P.; Pestaña, D. Nosocomial infections associated to COVID-19 in the intensive care unit: Clinical characteristics and outcome. Eur. J. Clin. Microbiol. Infect. Dis. 2021, 40, 495–502.
    16. Ansari, S.; Hays, J.P.; Kemp, A.; Okechukwu, R.; Murugaiyan, J.; Ekwanzala, M.D.; Ruiz Alvarez, M.J.; Paul-Satyaseela, M.; Iwu, C.D.; Balleste-Delpierre, C.; et al. The potential impact of the COVID-19 pandemic on global antimicrobial and biocide resistance: An AMR Insights global perspective. JAC-Antimicrobial Resist. 2021, 3, dlab038.
    17. Černáková, L.; Roudbary, M.; Brás, S.; Tafaj, S.; Rodrigues, C.F. Candida auris: A Quick Review on Identification, Current Treatments, and Challenges. Int. J. Mol. Sci. 2021, 22, 4470.
    18. Salmanton-Garcia, J.; Sprute, R.; Stemler, J.; Bartoletti, M.; Dupont, D.; Valerio, M.; Garcia-Vidal, C.; Falces-Romero, I.; Machado, M.; de la Villa, S.; et al. COVID-19-Associated Pulmonary Aspergillosis, March–August 2020. Emerg. Infect. Dis. 2021, 27, 1077–1086.
    19. Danion, F.; Letscher-Bru, V.; Guitard, J.; Sitbon, K.; Dellière, S.; Angoulvant, A.; Desoubeaux, G.; Botterel, F.; Bellanger, A.-P.; Gargala, G.; et al. High mortality of COVID-19 associated mucormycosis in France: A nationwide retrospective study. medRxiv 2021.
    20. Riad, A.; Gomaa, E.; Hockova, B.; Klugar, M. Oral candidiasis of COVID-19 patients: Case report and review of evidence. J. Cosmet. Dermatol. 2021, 20, 1580–1584.
    21. Rajendra Santosh, A.B.; Muddana, K.; Bakki, S.R. Fungal Infections of Oral Cavity: Diagnosis, Management, and Association with COVID-19. SN Compr. Clin. Med. 2021, 3, 1373–1384.
    22. Nargesi, S.; Bongomin, F.; Hedayati, M.T. The impact of COVID-19 pandemic on AIDS-related mycoses and fungal neglected tropical diseases: Why should we worry? PLoS Negl. Trop. Dis. 2021, 15, e0009092.
    23. Gangneux, J.-P.; Bougnoux, M.-E.; Dannaoui, E.; Cornet, M.; Zahar, J.R. Invasive fungal diseases during COVID-19: We should be prepared. J. Mycol. Med. 2020, 30, 100971.
    24. Verweij, P.E.; Alanio, A. Fungal infections should be part of the core outcome set for COVID-19. Lancet Infect. Dis. 2021, 21, e145.
    25. Katz, J. Prevalence of candidiasis and oral candidiasis in COVID-19 patients: A cross-sectional pilot study from the patients’ registry in a large health center. Quintessence Int. 2021, 52, 714–718.
    26. Prattes, J.; Valentin, T.; Hoenigl, M.; Talakic, E.; Reisinger, A.C.; Eller, P. Invasive pulmonary aspergillosis complicating COVID-19 in the ICU—A case report. Med. Mycol. Case Rep. 2021, 31, 2–5.
    27. Messina, F.A.; Marin, E.; Caceres, D.H.; Romero, M.; Depardo, R.; Priarone, M.M.; Rey, L.; Vázquez, M.; Verweij, P.E.; Chiller, T.M.; et al. Coronavirus Disease 2019 (COVID-19) in a Patient with Disseminated Histoplasmosis and HIV—A Case Report from Argentina and Literature Review. J. Fungi 2020, 6, 275.
    28. Seagle, E.E.; Jackson, B.R.; Lockhart, S.R.; Georgacopoulos, O.; Nunnally, N.S.; Roland, J.; Barter, D.M.; Johnston, H.L.; Czaja, C.A.; Kayalioglu, H.; et al. The landscape of candidemia during the COVID-19 pandemic. Clin. Infect. Dis. 2021, ciab562.
    29. Kayaaslan, B.; Eser, F.; Kaya Kalem, A.; Bilgic, Z.; Asilturk, D.; Hasanoglu, I.; Ayhan, M.; Tezer Tekce, Y.; Erdem, D.; Turan, S.; et al. Characteristics of candidemia in COVID-19 patients; increased incidence, earlier occurrence and higher mortality rates compared to non-COVID-19 patients. Mycoses 2021, 64, 1083–1091.
    30. Nucci, M.; Barreiros, G.; Guimarães, L.F.; Deriquehem, V.A.S.; Castiñeiras, A.C.; Nouér, S.A. Increased incidence of candidemia in a tertiary care hospital with the COVID-19 pandemic. Mycoses 2021, 64, 152–156.
    31. Awada, B.; Alam, W.; Chalfoun, M.; Araj, G.; Bizri, A.R. COVID-19 and Candida duobushaemulonii superinfection: A case report. J. Med. Mycol. 2021, 31, 101168.
    32. Posteraro, B.; Torelli, R.; Vella, A.; Leone, P.M.; De Angelis, G.; De Carolis, E.; Ventura, G.; Sanguinetti, M.; Fantoni, M. Pan-Echinocandin-Resistant Candida glabrata Bloodstream Infection Complicating COVID-19: A Fatal Case Report. J. Fungi 2020, 6, 163.
    33. De Almeida, J.N.; Brandão, I.B.; Francisco, E.C.; Almeida, S.L.R.; Oliveira Dias, P.; Pereira, F.M.; Santos Ferreira, F.; Andrade, T.S.; Miranda Costa, M.M.; Souza Jordão, R.T.; et al. Axillary Digital Thermometers uplifted a multidrug-susceptible Candida auris outbreak among COVID-19 patients in Brazil. Mycoses 2021, 64, 1062–1072.
    34. Hanson, B.M.; Dinh, A.Q.; Tran, T.T.; Arenas, S.; Pronty, D.; Gershengorn, H.B.; Ferreira, T.; Arias, C.A.; Shukla, B.S. Candida auris Invasive Infections During a COVID-19 Case Surge. Antimicrob. Agents Chemother. 2021, AAC-01146.
    35. Steele, E.J.; Gorczynski, R.M.; Lindley, R.A.; Tokoro, G.; Temple, R.; Wickramasinghe, N.C. Origin of new emergent Coronavirus and Candida fungal diseases—Terrestrial or cosmic? Cosm. Genet. Evol. 2020, 106, 75–100.
    36. Rodrigues, C.; Rodrigues, M.; Silva, S.; Henriques, M. Candida glabrata Biofilms: How Far Have We Come? J. Fungi 2017, 3, 11.
    37. Chowdhary, A.; Sharma, C.; Meis, J.F. Candida auris: A rapidly emerging cause of hospital-acquired multidrug-resistant fungal infections globally. PLOS Pathog. 2017, 13, e1006290.
    38. Di Pilato, V.; Codda, G.; Ball, L.; Giacobbe, D.R.; Willison, E.; Mikulska, M.; Magnasco, L.; Crea, F.; Vena, A.; Pelosi, P.; et al. Molecular Epidemiological Investigation of a Nosocomial Cluster of C. auris: Evidence of Recent Emergence in Italy and Ease of Transmission during the COVID-19 Pandemic. J. Fungi 2021, 7, 140.
    39. Prestel, C.; Anderson, E.; Forsberg, K.; Lyman, M.; de Perio, M.A.; Kuhar, D.; Edwards, K.; Rivera, M.; Shugart, A.; Walters, M.; et al. Candida auris Outbreak in a COVID-19 Specialty Care Unit—Florida, July–August 2020. MMWR. Morb. Mortal. Wkly. Rep. 2021, 70, 56–57.
    40. Macauley, P.; Epelbaum, O. Epidemiology and Mycology of Candidaemia in non-oncological medical intensive care unit patients in a tertiary center in the United States: Overall analysis and comparison between non-COVID-19 and COVID-19 cases. Mycoses 2021, 64, 634–640.
    41. Koehler, P.; Bassetti, M.; Chakrabarti, A.; Chen, S.C.; Colombo, A.L.; Hoenigl, M.; Klimko, N.; Lass-Flörl, C.; Oladele, R.O.; Vinh, D.C.; et al. Defining and managing COVID-19-associated pulmonary aspergillosis: The 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet. Infect. Dis. 2021, 21, e149–e162.
    42. Nasrullah, A.; Javed, A.; Malik, K. Coronavirus Disease-Associated Pulmonary Aspergillosis: A Devastating Complication of COVID-19. Cureus 2021, 31, e13004.
    43. Arastehfar, A.; Carvalho, A.; van de Veerdonk, F.L.; Jenks, J.D.; Koehler, P.; Krause, R.; Cornely, O.A.; Perlin, D.S.; Lass-Flörl, C.; Hoenigl, M. COVID-19 Associated Pulmonary Aspergillosis (CAPA)—From Immunology to Treatment. J. Fungi 2020, 6, 91.
    44. Dupont, D.; Menotti, J.; Turc, J.; Miossec, C.; Wallet, F.; Richard, J.-C.; Argaud, L.; Paulus, S.; Wallon, M.; Ader, F.; et al. Pulmonary aspergillosis in critically ill patients with Coronavirus Disease 2019 (COVID-19). Med. Mycol. 2020, 59, 110–114.
    45. Wu, S.; Yang, S.; Chen, R.; Chen, H.; Xu, Y.; Lin, B. Dynamic Immune Response Profiles and Recovery of a COVID-19 Patient with Coinfection of Aspergillus fumigatus and Other Baseline Diseases: A Case Report. OMICS A J. Integr. Biol. 2020, 24, 615–618.
    46. Armstrong-James, D.; Youngs, J.; Bicanic, T.; Abdolrasouli, A.; Denning, D.W.; Johnson, E.; Mehra, V.; Pagliuca, T.; Patel, B.; Rhodes, J.; et al. Confronting and mitigating the risk of COVID-19 associated pulmonary aspergillosis. Eur. Respir. J. 2020, 56, 2002554.
    47. Brown, L.-A.K.; Ellis, J.; Gorton, R.; De, S.; Stone, N. Surveillance for COVID-19-associated pulmonary aspergillosis. Lancet Microbe 2020, 1, e152.
    48. Schein, F.; Munoz-Pons, H.; Mahinc, C.; Grange, R.; Cathébras, P.; Flori, P. Fatal aspergillosis complicating severe SARS-CoV-2 infection: A case report. J. Mycol. Med. 2020, 30, 101039.
    49. De Lamballerie, C.N.; Pizzorno, A.; Fouret, J.; Szpiro, L.; Padey, B.; Dubois, J.; Julien, T.; Traversier, A.; Dulière, V.; Brun, P.; et al. Transcriptional Profiling of Immune and Inflammatory Responses in the Context of SARS-CoV-2 Fungal Superinfection in a Human Airway Epithelial Model. Microorganisms 2020, 8, 1974.
    50. Wheat, L.J.; Azar, M.M.; Bahr, N.C.; Spec, A.; Relich, R.F.; Hage, C. Histoplasmosis. Infect. Dis. Clin. North Am. 2016, 30, 207–227.
    51. Azar, M.M.; Hage, C.A. Clinical Perspectives in the Diagnosis and Management of Histoplasmosis. Clin. Chest Med. 2017, 38, 403–415.
    52. Basso, R.P.; Poester, V.R.; Benelli, J.L.; Stevens, D.A.; Zogbi, H.E.; da Vasconcellos, I.C.S.; Pasqualotto, A.C.; Xavier, M.O. COVID-19 associated histoplasmosis in an AIDS patient. Mycopathologia 2020, 186, 109–112.
    53. De Macedo, P.M.; Freitas, A.D.; Bártholo, T.P.; Bernardes-Engemann, A.R.; de Abreu Almeida, M.; Almeida-Silva, F.; Zancopé-Oliveira, R.M.; Almeida-Paes, R. Acute Pulmonary Histoplasmosis Following COVID-19: Novel Laboratorial Methods Aiding Diagnosis. J. Fungi 2021, 7, 346.
    54. Stasiak, C.E.S.; Nigri, D.H.; Cardoso, F.R.; de Almeida Rezende d Mattos, R.S.; Martins, P.A.G.; Carvalho, A.R.S.; de Almeida, S.A.; Rodrigues, R.S.; Rosado-de-Castro, P.H. Case Report: Incidental Finding of COVID-19 Infection after Positron Emission Tomography/CT Imaging in a Patient with a Diagnosis of Histoplasmosis and Recurring Fever. Am. J. Trop. Med. Hyg. 2021, 104, 1651–1654.
    55. Bertolini, M.; Mutti, M.F.; Barletta, J.A.E.; Falak, A.; Cuatz, D.; Sisto, A.; Ragusa, M.A.; Claros, N.O.F.; Rolón, M.J. COVID-19 associated with AIDS-related disseminated histoplasmosis: A case report. Int. J. STD AIDS 2020, 31, 1222–1224.
    56. Chakrabarti, A.; Denning, D.W.; Ferguson, B.J.; Ponikau, J.; Buzina, W.; Kita, H.; Marple, B.; Panda, N.; Vlaminck, S.; Kauffmann-Lacroix, C.; et al. Fungal rhinosinusitis. Laryngoscope 2009, 119, 1809–1818.
    57. Ferguson, B.J. Definitions of fungal rhinosinusitis. Otolaryngol. Clin. North Am. 2000, 33, 227–235.
    58. Hallur, V.; Prakash, H.; Sable, M.; Preetam, C.; Purushotham, P.; Senapati, R.; Shankarnarayan, S.A.; Bag, N.D.; Rudramurthy, S.M. Cunninghamella arunalokei a New Species of Cunninghamella from India Causing Disease in an Immunocompetent Individual. J. Fungi 2021, 7, 670.
    59. Scheckenbach, K.; Cornely, O.; Hoffmann, T.K.; Engers, R.; Bier, H.; Chaker, A.; Greve, J.; Schipper, J.; Wagenmann, M. Emerging therapeutic options in fulminant invasive rhinocerebral mucormycosis. Auris Nasus Larynx 2010, 37, 322–328.
    60. Vairaktaris, E.; Moschos, M.M.; Vassiliou, S.; Baltatzis, S.; Kalimeras, E.; Avgoustidis, D.; Pappas, Z.; Moschos, M.N. Orbital cellulitis, orbital subperiosteal and intraorbital abscess. Report of three cases and review of the literature. J. Cranio-Maxillofac. Surg. 2009, 37, 132–136.
    61. Mohindra, S.; Mohindra, S.; Gupta, R.; Bakshi, J.; Gupta, S.K. Rhinocerebral mucormycosis: The disease spectrum in 27 patients. Mycoses 2007, 50, 290–296.
    62. Munir, N.; Jones, N.S. Rhinocerebral mucormycosis with orbital and intracranial extension: A case report and review of optimum management. J. Laryngol. Otol. 2006, 121, 192–195.
    63. Deshazo, R.D. Fungal Sinusitis. Am. J. Med. Sci. 1998, 316, 39–45.
    64. Ballester, D.G.; González-García, R.; García, C.M.; Ruiz-Laza, L.; Gil, F.M. Mucormycosis of the head and neck: Report of five cases with different presentations. J. Cranio-Maxillofac. Surg. 2012, 40, 584–591.
    65. Chen, N.; Zhou, M.; Dong, X.; Qu, J.; Gong, F.; Han, Y.; Qiu, Y.; Wang, J.; Liu, Y.; Wei, Y.; et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet 2020, 395, 507–513.
    66. Yang, X.; Yu, Y.; Xu, J.; Shu, H.; Xia, J.; Liu, H.; Wu, Y.; Zhang, L.; Yu, Z.; Fang, M.; et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: A single-centered, retrospective, observational study. Lancet Respir. Med. 2020, 8, 475–481.
    67. Hanley, B.; Naresh, K.N.; Roufosse, C.; Nicholson, A.G.; Weir, J.; Cooke, G.S.; Thursz, M.; Manousou, P.; Corbett, R.; Goldin, R.; et al. Histopathological findings and viral tropism in UK patients with severe fatal COVID-19: A post-mortem study. Lancet Microbe 2020, 1, e245–e253.
    68. Werthman-Ehrenreich, A. Mucormycosis with orbital compartment syndrome in a patient with COVID-19. Am. J. Emerg. Med. 2021, 42, 264.e5–264.
    69. Mehta, S.; Pandey, A. Rhino-Orbital Mucormycosis Associated with COVID-19. Cureus 2020, 12, e10726.
    70. Do Monte Junior, E.S.; dos Santos, M.E.L.; Ribeiro, I.B.; de Oliveira Luz, G.; Baba, E.R.; Hirsch, B.S.; Funari, M.P.; de Moura, E.G.H. Rare and Fatal Gastrointestinal Mucormycosis (Zygomycosis) in a COVID-19 Patient: A Case Report. Clin. Endosc. 2020, 53, 746–749.
    71. Placik, D.A.; Taylor, W.L.; Wnuk, N.M. Bronchopleural fistula development in the setting of novel therapies for acute respiratory distress syndrome in SARS-CoV-2 pneumonia. Radiol. Case Rep. 2020, 15, 2378–2381.
    72. Mekonnen, Z.K.; Ashraf, D.C.; Jankowski, T.; Grob, S.R.; Vagefi, M.R.; Kersten, R.C.; Simko, J.P.; Winn, B.J. Acute Invasive Rhino-Orbital Mucormycosis in a Patient with COVID-19-Associated Acute Respiratory Distress Syndrome. Ophthalmic Plast. Reconstr. Surg. 2020, 37, e40–e80.
    73. Pasero, D.; Sanna, S.; Liperi, C.; Piredda, D.; Pietro Branca, G.; Casadio, L.; Simeo, R.; Buselli, A.; Rizzo, D.; Bussu, F.; et al. A challenging complication following SARS-CoV-2 infection: A case of pulmonary mucormycosis. Infection 2020, 1–6.
    74. Garg, D.; Muthu, V.; Sehgal, I.S.; Ramachandran, R.; Kaur, H.; Bhalla, A.; Puri, G.D.; Chakrabarti, A.; Agarwal, R. Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): Case Report and Systematic Review of Literature. Mycopathologia 2021, 186, 289–298.
    75. Saldanha, M.; Reddy, R.; Vincent, M.J. Title of the Article: Paranasal Mucormycosis in COVID-19 Patient. Indian J. Otolaryngol. Head Neck Surg. 2021, 1–4.
    76. Krishna, D.S.; Raj, H.; Kurup, P.; Juneja, M. Maxillofacial Infections in Covid-19 Era—Actuality or the Unforeseen: 2 Case Reports. Indian J. Otolaryngol. Head Neck Surg. 2021, 1–4.
    77. Selarka, L.; Sharma, A.K.; Rathod, G.; Saini, D.; Patel, S.; Sharma, V.K. Mucormycosis—A Dreaded Complication of Covid-19. QJM An Int. J. Med. 2021, hcab166.
    78. Johnson, A.K.; Ghazarian, Z.; Cendrowski, K.D.; Persichino, J.G. Pulmonary aspergillosis and mucormycosis in a patient with COVID-19. Med. Mycol. Case Rep. 2021, 32, 64–67.
    79. Waizel-Haiat, S.; Guerrero-Paz, J.A.; Sanchez-Hurtado, L.; Calleja-Alarcon, S.; Romero-Gutierrez, L. A Case of Fatal Rhino-Orbital Mucormycosis Associated with New Onset Diabetic Ketoacidosis and COVID-19. Cureus 2021, 13, e13163.
    80. Topcu, O.; Ozaslan, M.; Kılıc, İ.H.; Oguzkan, S.B.; Kurt, B.S.; Cay, M.; Tonus, S.S.; Bayram, A. Susceptibility of severe COVID-19 patients to rhino-orbital mucormycosis fungal infection in different clinical manifestations. Jpn. J. Ophthalmol. 2021, 65, 515–525.
    81. Fouad, Y.A.; Abdelaziz, T.T.; Askoura, A.; Saleh, M.I.; Mahmoud, M.S.; Ashour, D.M.; Ashour, M.M. Spike in Rhino-Orbital-Cerebral Mucormycosis Cases Presenting to a Tertiary Care Center During the COVID-19 Pandemic. Front. Med. 2021, 8, 645270.
    82. Zurl, C.; Hoenigl, M.; Schulz, E.; Hatzl, S.; Gorkiewicz, G.; Krause, R.; Eller, P.; Prattes, J. Autopsy Proven Pulmonary Mucormycosis Due to Rhizopus microsporus in a Critically Ill COVID-19 Patient with Underlying Hematological Malignancy. J. Fungi 2021, 7, 88.
    83. Moorthy, A.; Gaikwad, R.; Krishna, S.; Hegde, R.; Tripathi, K.K.; Kale, P.G.; Rao, P.S.; Haldipur, D.; Bonanthaya, K. SARS-CoV-2, Uncontrolled Diabetes and Corticosteroids—An Unholy Trinity in Invasive Fungal Infections of the Maxillofacial Region? A Retrospective, Multi-centric Analysis. J. Maxillofac. Oral Surg. 2021, 20, 418–425.
    84. Pakdel, F.; Ahmadikia, K.; Salehi, M.; Tabari, A.; Jafari, R.; Mehrparvar, G.; Rezaie, Y.; Rajaeih, S.; Alijani, N.; Barac, A.; et al. Mucormycosis in patients with COVID-19: A cross-sectional descriptive multicenter study from Iran. Mycoses 2021.
    85. Veisi, A.; Bagheri, A.; Eshaghi, M.; Rikhtehgar, M.H.; Kanavi, M.R.; Farjad, R. Rhino-orbital mucormycosis during steroid therapy in COVID-19 patients: A case report. Eur. J. Ophthalmol. 2021, 112067212110094.
    86. Alekseyev, K.; Didenko, L.; Chaudhry, B. Rhinocerebral Mucormycosis and COVID-19 Pneumonia. J. Med. Cases 2021, 12, 85–89.
    87. Ashour, M.M.; Abdelaziz, T.T.; Ashour, D.M.; Askoura, A.; Saleh, M.I.; Mahmoud, M.S. Imaging spectrum of acute invasive fungal rhino-orbital-cerebral sinusitis in COVID-19 patients: A case series and a review of literature. J. Neuroradiol. 2021, in press.
    88. Revannavar, S.M.; Supriya, S.P.; Samaga, L.; Vineeth, V.K. COVID-19 triggering mucormycosis in a susceptible patient: A new phenomenon in the developing world? BMJ Case Rep. 2021, 14, e241663.
    89. Maini, A.; Tomar, G.; Khanna, D.; Kini, Y.; Mehta, H.; Bhagyasree, V. Sino-orbital mucormycosis in a COVID-19 patient: A case report. Int. J. Surg. Case Rep. 2021, 82, 105957.
    90. Buil, J.B.; van Zanten, A.R.H.; Bentvelsen, R.G.; Rijpstra, T.A.; Goorhuis, B.; van der Voort, S.; Wammes, L.J.; Janson, J.A.; Melchers, M.; Heusinkveld, M.; et al. Case series of four secondary mucormycosis infections in COVID-19 patients, the Netherlands, December 2020 to May 2021. Eurosurveillance 2021, 26, 2100510.
    91. Arana, C.; Ramirez, R.E.C.; Xipell, M.; Casals, J.; Moreno, A.; Herrera, S.; Bodro, M.; Cofan, F.; Diekmann, F.; Esforzado, N. Mucormycosis associated with COVID-19 in two kidney transplant~patients. Transpl. Infect. Dis. 2021, e13652.
    92. Sharma, S.; Grover, M.; Bhargava, S.; Samdani, S.; Kataria, T. Post coronavirus disease mucormycosis: A deadly addition to the pandemic spectrum. J. Laryngol. Otol. 2021, 135, 442–447.
    93. Honavar, S.; Sen, M.; Lahane, S.; Lahane, T.; Parekh, R. Mucor in a Viral Land: A Tale of Two Pathogens. Indian J. Ophthalmol. 2021, 69, 244.
    94. Karimi-Galougahi, M.; Arastou, S.; Haseli, S. Fulminant mucormycosis complicating coronavirus disease 2019 (COVID-19). Int. Forum Allergy Rhinol. 2021, 11, 1029–1030.
    95. Kanwar, A.; Jordan, A.; Olewiler, S.; Wehberg, K.; Cortes, M.; Jackson, B.R. A Fatal Case of Rhizopus azygosporus Pneumonia Following COVID-19. J. Fungi 2021, 7, 174.
    96. Khatri, A.; Chang, K.-M.; Berlinrut, I.; Wallach, F. Mucormycosis after Coronavirus disease 2019 infection in a heart transplant recipient—Case report and review of literature. J. Med. Mycol. 2021, 31, 101125.
    97. Nehara, H.R.; Puri, I.; Singhal, V.; IH, S.; Bishnoi, B.R.; Sirohi, P. Rhinocerebral mucormycosis in COVID-19 patient with diabetes a deadly trio: Case series from the north-western part of India. Indian J. Med. Microbiol. 2021, 39, 180–383.
    98. Khatib, M.; Ahmed, A.; Shaat, S.; soliman Mohamed, A.; Nashwan, A. Cryptococcemia in a Patient with COVID-19: A Case Report. Clin. Case Rep. 2020, 9, 853–855.
    99. Passarelli, V.C.; Perosa, A.H.; de Souza Luna, L.K.; Conte, D.D.; Nascimento, O.A.; Ota-Arakaki, J.; Bellei, N. Detected SARS-CoV-2 in Ascitic Fluid Followed by Cryptococcemia: A Case Report. Compr. Clin. Med. 2020, 2, 2414–2418.
    100. Gonzalez, A.J.C.; Montenegro-Idrogo, J.J.; Vadillo, A.R.V.; Torres, M.S.; Matos, I.V.; Delgado, C.P.R. Hospital-acquired SARS-CoV-2 pneumonia in a person living with HIV. Int. J. 2020, 31, 1320–1322.
    101. Passerini, M.; Terzi, R.; Piscaglia, M.; Passerini, S.; Piconi, S. Disseminated Cryptococcosis in a Patient with Metastatic Prostate Cancer Who Died in the Coronavirus Disease 2019 (COVID-19) Outbreak. Cureus 2020, 12, e8254.
    102. Krauth, D.S.; Jamros, C.M.; Rivard, S.C.; Olson, N.H.; Maves, R.C. Accelerated Progression of Disseminated Coccidioidomycosis Following SARS-CoV-2 Infection: A Case Report. Mil. Med. 2021, usab132.
    103. Chang, C.C.; Senining, R.; Kim, J.; Goyal, R. An Acute Pulmonary Coccidioidomycosis Coinfection in a Patient Presenting with Multifocal Pneumonia with COVID-19. J. Investig. Med. High Impact Case Rep. 2020, 8, 232470962097224.
    104. Cai, S.; Sun, W.; Li, M.; Dong, L. A complex COVID-19 case with rheumatoid arthritis treated with tocilizumab. Clin. Rheumatol. 2020, 39, 2797–2802.
    105. Menon, A.A.; Berg, D.D.; Brea, E.J.; Deutsch, A.J.; Kidia, K.K.; Thurber, E.G.; Polsky, S.B.; Yeh, T.; Duskin, J.A.; Holliday, A.M.; et al. A Case of COVID-19 and Pneumocystis jirovecii Coinfection. Am. J. Respir. Crit. Care Med. 2020, 202, 136–138.
    106. Alanio, A.; Dellière, S.; Voicu, S.; Bretagne, S.; Mégarbane, B. The presence of Pneumocystis jirovecii in critically ill patients with COVID-19. J. Infect. 2021, 82, 84–123.
    107. Coleman, H.; Snell, L.B.; Simons, R.; Douthwaite, S.T.; Lee, M.J. Coronavirus disease 2019 and Pneumocystis jirovecii pneumonia: A diagnostic dilemma in HIV. AIDS 2020, 34, 1258–1260.
    108. Kelly, S.; Waters, L.; Cevik, M.; Collins, S.; Lewis, J.; Wu, M.-S.; Blanchard, T.J.; Geretti, A.M. Pneumocystispneumonia, a COVID-19 mimic, reminds us of the importance of HIV testing in COVID-19. Clin. Med. 2020, 20, 590–592.
    109. Mang, S.; Kaddu-Mulindwa, D.; Metz, C.; Becker, A.; Seiler, F.; Smola, S.; Maßmann, A.; Becker, S.L.; Papan, C.; Bals, R.; et al. Pneumocystis jirovecii Pneumonia and Severe Acute Respiratory Syndrome Coronavirus 2 Coinfection in a Patient with Newly Diagnosed HIV-1 Infection. Clin. Infect. Dis. 2020, 72, 1487–1489.
    110. Viceconte, G.; Buonomo, A.R.; Lanzardo, A.; Pinchera, B.; Zappulo, E.; Scotto, R.; Moriello, N.S.; Vargas, M.; Iacovazzo, C.; Servillo, G.; et al. Pneumocystis jirovecii pneumonia in an immunocompetent patient recovered from COVID-19. Infect. Dis. 2021, 53, 382–385.
    111. Jeican, I.I.; Inișca, P.; Gheban, D.; Tuaran, F.; Aluaș, M.; Trombitas, V.; Cristea, V.; Crivii, C.; Junie, L.M.; Albu, S. COVID-19 and Pneumocystis jirovecii Pulmonary Coinfection—The First Case Confirmed through Autopsy. Medicina 2021, 57, 302.
    112. Ventoulis, I.; Sarmourli, T.; Amoiridou, P.; Mantzana, P.; Exindari, M.; Gioula, G.; Vyzantiadis, T.A. Bloodstream Infection by Saccharomyces cerevisiae in Two COVID-19 Patients after Receiving Supplementation of Saccharomyces in the ICU. J. Fungi 2020, 6, 98.
    113. Poignon, C.; Blaize, M.; Vezinet, C.; Lampros, A.; Monsel, A.; Fekkar, A. Invasive pulmonary fusariosis in an immunocompetent critically ill patient with severe COVID-19. Clin. Microbiol. Infect. 2020, 26, 1582–1584.