Post Covid-19 Sinonasal Candidiasis: A Crisis Within the Pandemic.

The aim of this study was to find out the association of sinonasal candidiasis and Covid-19 infection. A prospective observational study was conducted at a tertiary care centre from April to September 2021, involving all patients with invasive candidiasis of the paranasal sinuses having a history of Covid-19 infection. A total of 18 patients of covid associated sinonasal candidiasis among the 475 cases of fungal rhinosinusitis were studied. All patients had involvement of nose and sinuses and 2 patients had orbital involvement with no loss of vision, while 3 had intracranial extensions and 1 had pulmonary involvement. Mandible was involved in 1 patient alone, while the maxilla and palate were involved in 5 patients. 15 patients were hypertensive, 12 diabetics and 1 had aplastic anaemia. Cultures showed that 8 patients had C. parapsilosis, 5 had C. albicans, 3 had C. tropicalis and 2 had mixed fungal infections. All patients underwent surgical debridement and antifungal administration. They were followed up for a minimum of 3 months. There was only one mortality (with aplastic anaemia), rest 17 were disease free at the time of writing this article. This is perhaps the first case series of post covid sinonasal candidiasis in the world. Invasive sinonasal candidiasis is a newer sequela of COVID-19 infection. Uncontrolled diabetes and over-zealous use of steroids at the time of Covid-19 are few of the known risk factors. Early surgical intervention and anti-fungal treatment should be sought for management.

Factors Associated with Outcome in Patients Managed for Invasive Fungal Infections at the Infectious Diseases Department of a Tertiary Care Hospital

Objective: To look for the factors associated with outcomes in patients managed for invasive fungal infections at the Infectious Diseases Department of a Tertiary Care Hospital Study Design: Comparative cross-sectional study Place and Duration of Study: Department of Infectious Diseases, Pak Emirates Military Hospital, Rawalpindi Pakistan,from Apr 2021 to Sep 2022. Methodology: A total of 90 patients with a different types of invasive fungal infections diagnosed by consultant infectious diseases were recruited. First, they were given standard treatment for fungal infection;they were diagnosed as per guidelines. Then, they were followed up for one month to look for an outcome. Results: Out of 90 patients with invasive fungal infections included in the study, 62(68.8%) had a good outcome, while 28(31.2%) had a poor outcome. The mean age of the patients recruited in our study was 39.54±6.27 years. Of all the participants, 65(72.2%) patients were male, while 25(27.8%) were female. Statistical analysis revealed that poorly controlled diabetes, COVID-19 infection and HIV positive were statistically significantly associated with poor outcomes in our study participants (p-value<0.05). Conclusion: The Considerable number of patients with invasive fungal infections had a poor outcome in our study. The presence of poorly controlled diabetes, COVID-19 infection and being HIV positive were the factors associated with poor outcomes in our study participants.

Evaluation of risk factors, clinico-radiographic presentations of COVID-associated mucormycosis in the maxillofacial region reporting to a tertiary care dental facility.

Purpose: To evaluate the prevalence of risk factors associated with COVID-associated mucormycosis (CAM) in the maxillofacial region with emphasis on clinical and radiological characteristics of the disease reporting to the dentists. Methods: Archival records of the patients diagnosed with rhino-cerebral mucormycosis through histopathology or culture, were screened and 266 records were included. These records were divided into three groups-previously diabetic (PD, n = 122), recently diagnosed diabetic (RD, n = 105) and non-diabetic (ND, n = 39). All the records were evaluated and compared among the three groups for the duration of presentation, history of co-existing medical conditions, the association of treatment given during COVID-19, and the clinical and radiographic presentations of the disease. Results: The results confirmed uncontrolled diabetes mellitus as the major risk factor for the disease. The prevalence of steroid administration was lower in our study in contrast to previous literature. The risk factors and treatment rendered during COVID-19 did not differ significantly among the three groups (p > 0.05). The findings indicate that the disease was milder and progressed more slowly in the ND group, both clinically and radiographically, and it had close resemblance to odontogenic infection. Conclusion: Patients with early CAM mimicked the odontogenic infection and were more likely to report in a dental setup. Hence, a multidisciplinary and holistic management approach is necessary.

Rhino-orbital mucormycosis in a Mexican patient with COVID-19: Case report.

BACKGROUND: A variety of bacterial and fungal co-infections may be attributed to the coronavirus disease 2019 (COVID-19), particularly in people who already have a medical condition such diabetes mellitus or those who received large dosages of steroids. CASE REPORT: We described a 52-year-old diabetic man who was receiving high doses of dexamethasone and antibiotics while receiving ambulatory care for COVID-19 pneumonia. His anterior rhinoscopy revealed a necrotic scab, and a sample confirmed Mucor spp. He underwent surgery and was given amphotericin as a result of the severity of the condition, palpebral ptosis, and right ocular palsy he was experiencing. The patien ́s progression was satisfactory. CONCLUSIONS: pre-existing diabetes mellitus, previous steroid and antimicrobial use, as well as SARS-CoV-2 infection are some of the risk factors associated with Mucor spp. infection. Prompt detection of mucormycosis is important in the management of these affected patients.

ANTECEDENTES: A la enfermedad por coronavirus (COVID-19) se le han atribuido diversas coinfecciones bacterianas y fúngicas, especialmente en sujetos con enfermedades preexistentes (diabetes mellitus) o en quienes han recibido altas dosis de corticosteroides. REPORTE DE CASO: Paciente masculino de 52 años, con antecedente de diabetes mellitus, quien recibió altas dosis de dexametasona y antibióticos mientras recibía atención ambulatoria por neumonía secundaria a COVID-19. La rinoscopia anterior reveló una costra necrótica, y una muestra de exudado confirmó la coexistencia de Mucor spp. Debido a la complicación del cuadro clínico, ptosis palpebral y parálisis ocular derecha, se le administró anfotericina B y fue intervenido quirúrgicamente. La evolución del paciente fue satisfactoria. CONCLUSIONES: La diabetes mellitus preexistente, el consumo de corticosteroides y antimicrobianos, además de la infección por SARS-CoV-2 son factores de riesgo asociados con la infección por Mucor spp. Es importante la detección oportuna de mucormicosis en el tratamiento de estos pacientes.

Pneumocystis jirovecii Infections Among COVID-19 Patients: A Case Series and Literature Review.

Background: Pneumocystis jirovecii pneumonia (PCP) is a serious, emerging complication of coronavirus disease 2019 (COVID-19). Methods: We performed a systematic review of published cases. We describe 6 new cases of PCP/COVID-19 coinfection. Among our cases (n = 6) and those in the literature (n = 69) with available data, the median age (interquartile range [IQR]) was 59 (44-77) years (n = 38), 72% (47/65) were male, and the mortality rate was 30.9% (21/68). Results: Long-term corticosteroid use was noted in 45.1% (23/51), advanced HIV infection (defined as a CD4 count <200 cells/µL) in 17.6% (9/51), and antineoplastic chemotherapy in 13.7% (7/51), consistent with known PCP risk factors. Notably, 56.7% (38/47) had verifiable risk factors for PCP (high-dose corticosteroids, immunosuppressive therapy, and HIV infection) before COVID-19 infection. A median absolute lymphocyte count (IQR) of 0.61 (0.28-0.92) ×103 cells/mm3 (n = 23) and CD4 count (IQR) of 66 (33-291.5) cells/mm3 (n = 20) were also discovered among the study population. Conclusions: These findings suggest a need for greater attention to PCP risk factors among COVID-19 patients and consideration of PCP prophylaxis in these high-risk populations.

Incidence, risk factors and pre-emptive screening for COVID-19 associated pulmonary aspergillosis in an era of immunomodulant therapy.

PURPOSE: COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential benefit of a pre-emptive screening strategy for CAPA in ICUs in the Netherlands/Belgium during immunosuppressive COVID-19 treatment. MATERIALS AND METHODS: A retrospective, observational, multicentre study was performed from September 2020-April 2021 including patients admitted to the ICU who had undergone diagnostics for CAPA. Patients were classified based on 2020 ECMM/ISHAM consensus criteria. RESULTS: CAPA was diagnosed in 295/1977 (14.9%) patients. Corticosteroids were administered to 97.1% of patients and interleukin-6 inhibitors (anti-IL-6) to 23.5%. EORTC/MSGERC host factors or treatment with anti-IL-6 with or without corticosteroids were not risk factors for CAPA. Ninety-day mortality was 65.3% (145/222) in patients with CAPA compared to 53.7% (176/328) without CAPA (p = 0.008). Median time from ICU admission to CAPA diagnosis was 12 days. Pre-emptive screening for CAPA was not associated with earlier diagnosis or reduced mortality compared to a reactive diagnostic strategy. CONCLUSIONS: CAPA is an indicator of a protracted course of a COVID-19 infection. No benefit of pre-emptive screening was observed, but prospective studies comparing pre-defined strategies would be required to confirm this observation.

Yeast Bloodstream Infections in the COVID-19 Patient: A Multicenter Italian Study (FiCoV Study).

Fungemia is a co-infection contributing to the worsening of the critically ill COVID-19 patient. The multicenter Italian observational study FiCoV aims to estimate the frequency of yeast bloodstream infections (BSIs), to describe the factors associated with yeast BSIs in COVID-19 patients hospitalized in 10 hospitals, and to analyze the antifungal susceptibility profiles of the yeasts isolated from blood cultures. The study included all hospitalized adult COVID-19 patients with a yeast BSI; anonymous data was collected from each patient and data about antifungal susceptibility was collected. Yeast BSI occurred in 1.06% of patients, from 0.14% to 3.39% among the 10 participating centers. Patients were mainly admitted to intensive or sub-intensive care units (68.6%), over 60 years of age (73%), with a mean and median time from the hospitalization to fungemia of 29 and 22 days, respectively. Regarding risk factors for fungemia, most patients received corticosteroid therapy during hospitalization (61.8%) and had a comorbidity (25.3% diabetes, 11.5% chronic respiratory disorder, 9.5% cancer, 6% haematological malignancies, 1.4% organ transplantation). Antifungal therapy was administered to 75.6% of patients, mostly echinocandins (64.5%). The fatality rate observed in COVID-19 patients with yeast BSI was significantly higher than that of COVID-19 patients without yeast BSI (45.5% versus 30.5%). Candida parapsilosis (49.8%) and C. albicans (35.2%) were the most fungal species isolated; 72% of C. parapsilosis strains were fluconazole-resistant (range 0-93.2% among the centers). The FiCoV study highlights a high prevalence of Candida BSIs in critically ill COVID-19 patients, especially hospitalized in an intensive care unit, a high fatality rate associated with the fungal co-infection, and the worrying spread of azole-resistant C. parapsilosis.

Split-bolus, single-phase contrast enhanced CT: a one-stop shop for invasive fungal sinusitis.

Contrast-enhanced magnetic resonance imaging is considered the imaging modality of choice for invasive fungal sinusitis (IFS); however, it is not feasible to perform emergency CEMRI especially in the setting of COVID-19. The CECT protocol for evaluation of suspected IFS can be modified by using split-bolus, single-phase CT as it provides an optimal soft tissue demonstration of sinonasal disease; extrasinus spread to orbit, and intracranial involvement along with simultaneous opacification of the internal carotid artery and cavernous sinus. The extent of bone erosion can also be well delineated on the multiplanar reconstructions (MPRs) in the bone window. Further a structured reporting format can help provide optimal surgical guidance in cases of IFS.

Mucorales/Fusarium Mixed Infection in Hematologic Patient with COVID-19 Complications: An Unfortunate Combination.

Hematological diseases, especially those causing severe neutropenia, represent the main factor in the development of invasive fungal infections (IFIs). Furthermore, COVID-19 has been considerably associated with IFIs due to immunological dysregulation, prolonged hospitalization in intensive care units, and immunomodulatory therapies. Opportunistic molds are correlated with elevated morbidity and mortality rates in these patients, due to immune impairment, diagnostic complexity, and therapeutic challenges. Among opportunistic fungal infections, the Mucorales and Fusarium species are considered particularly aggressive, especially during severe neutropenia. A mixed Mucorales/Fusarium infection has been rarely described in scientific literature. Herein, we report a case of Mucorales and Fusarium co-infection in a patient with acute leukemia whose clinical history was also complicated by COVID-19. Herein, we report a challenging case in order to encourage the clinical suspicion of combined fungal infections in immunosuppressed patients, performing a punctual microbiological diagnosis, and promptly administering the correct empiric and targeted antifungal therapy.

Increased deaths from fungal infections during the COVID-19 pandemic-National Vital Statistics System, United States, January 2020-December 2021.

BACKGROUND: COVID-19-associated fungal infections cause severe illness, but comprehensive data on disease burden are lacking. We analyzed US National Vital Statistics System (NVSS) data to characterize disease burden, temporal trends, and demographic characteristics of persons dying from fungal infections during the COVID-19 pandemic. METHODS: Using NVSS's January 2018-December 2021 Multiple Cause of Death Database, we examined numbers and age-adjusted rates (per 100,000 population) of fungal deaths by fungal pathogen, COVID-19 association, demographic characteristics, and year. RESULTS: Numbers and age-adjusted rates of fungal deaths increased from 2019 (n = 4,833, rate 1.2, 95% confidence interval [CI] 1.2-1.3) to 2021 (n = 7,199, rate: 1.8, 95% CI = 1.8-1.8); of 13,121 fungal deaths during 2020-2021, 2,868 (21.9%) were COVID-19-associated. Compared with non-COVID-19-associated fungal deaths (n = 10,253), COVID-19-associated fungal deaths more frequently involved Candida (n = 776 [27.1%] versus n = 2,432 [23.7%]) and Aspergillus (n = 668 [23.3%] versus n = 1,486 [14.5%]) and less frequently involved other specific fungal pathogens. Fungal death rates were generally highest in non-White and non-Asian populations. Death rates from Aspergillus infections were approximately two times higher in the Pacific US census division compared with most other divisions. CONCLUSIONS: Fungal deaths increased during 2020-2021 compared with previous years, primarily driven by COVID-19-associated fungal deaths, particularly those involving Aspergillus and Candida. Our findings may inform efforts to prevent, identify, and treat severe fungal infections in COVID-19 patients, especially in certain racial/ethnic groups and geographic areas.

Perturbations of immune landscape in COVID-19 associated mucormycosis.

BACKGROUND: A rise in secondary fungal infections during the COVID-19 pandemic necessitates a deeper understanding of the associated immunological perturbations. OBJECTIVES: To evaluate the clinical and immunological characteristics observed in patients with COVID-19 associated mucormycosis (CAM) infection. PATIENTS/ METHODS: Cases of mucormycosis with or post-COVID-19 infection were compared with cases of acute COVID-19 and convalescent COVID-19. Lymphocyte subsets, cytokines and other laboratory markers were compared between the groups. RESULTS: The frequency of proposed risk factors for CAM was diabetes mellitus (77%), recent history of steroid use (69%) and hypoxia during COVID-19 infection (52%). Iron metabolism was dysregulated in CAM patients with low TIBC and total iron. Further, CAM was accompanied with lymphopenia with drastic reduction in B cell counts; however, plasmablasts were not altered. Further, CAM patients had low immunoglobulin levels and antibodies specific to mucor peptide did not increase in CAM suggesting dysfunction in B-cell response. There was increase in activated effector cytotoxic CD8 T cells and NK cells in CAM compared with COVID-19 infection and healthy controls. Among T helper cells, Tregs were reduced and Th-1 frequency was increased in CAM compared with COVID-19 infection. A distinct cytokine signature was evident in CAM with increase in IL-1ß, IFN-γ, IL-6, IL-22, IL-17A, IL-10, IL-2, IL-8, IL-7, IL-21 and GM-CSF. CONCLUSION: This is the first study on immunophenotyping in CAM suggesting the need for long-term monitoring of B-cell function after SARS-CoV-2 in patients with dysregulated glycaemic control and the possible benefit of therapeutic supplementation with intravenous immunoglobulins in CAM.

Rhino-Orbital and Breast Mucormycosis After COVID-19: A Case Report

The recent rise of Invasive Fungal Infections (IFI), especially mucormycosis in COVID-19 patients, is further complicating the outcomes. Here, we present a case of concomitant rhino-orbital and breast mucormycosis after COVID-19. To the best of our knowledge, this is the first case of breast mucormycosis after COVID-19. © 2022 Seventh Sense Research Group®

[Impact of the first year of the COVID-19 pandemic on the epidemiology of invasive infections (bacteremia) in the hospitals of the Assistance Publique-Hôpitaux de Paris]. / Impact de la première année de la pandémie de COVID-19 sur l'épidémiologie des infections invasives (bactériémies) dans les hôpitaux de l'Assistance Publique­Hôpitaux de Paris.

Introduction: The COVID-19 pandemic has led to a massive influx of patients suffering from severe forms of the disease into hospitals, often requiring intensive care (vascular catheters, ventilation, etc.) which exposes them to high risks of nosocomial infections, particularly invasive infections (bacteremia). Method: The impact of the COVID-19 pandemic on the epidemiology of bacteremia in 2020 was analysed in 25 hospitals of the Assistance Publique-Hôpitaux de Paris (AP-HP, approximately 14,000 beds, covering the Île-de-France region). Up to a quarter of patients admitted to AP-HP during the March-April period (peak of the 1st wave) were infected with COVID-19. The incidence over 100 admissions of bacteraemia increased overall compared to previous years: by 24% in March 2020 and by 115% in April. Results: The evolution of the incidence of bacteremia was not the same for 2 groups of microorganisms with very different ecologies. For the "hospital" type microorganisms classically responsible for nosocomial infections, the incidence increased significantly in March-April 2020: Klebsiella pneumoniae (×2.3), Pseudomonas aeruginosa (×2.4), Staphylococcus aureus (×2.4), enterococci (×3.4), yeasts (×2.7). Two thirds of the bacteremias caused by these microorganisms were considered as acquired during hospitalization. Importantly, there was also a sharp increase in the incidence of bacteremia caused by antibiotic-resistant strains. The antibiotics used as indicators were the 3rd generation cephalosporins (3GCs), major antibiotics in the treatment of serious infections used for monitoring bacterial resistance in Europe. For example, the incidence of bacteremia with 3GC-resistant strains increased threefold in April 2020 for K. pneumoniae. During the same period, the consumption of 3GC increased sharply in the same hospitals (+131% in March and +148% in April). For Streptococcus pneumoniae (pneumococcus) and Streptococcus pyogenes (group A hemolytic streptococcus), two pathogens responsible for mainly community and respiratory-transmitted infections, the pandemic had the opposite effect. There was a decrease in incidence in 2020 by 34% and 28% respectively for these two species, particularly in the spring when strict containment, physical distancing and mask-wearing measures were in place. A slight re-emergence of infections with these two species occurred in the summer of 2020 after the relaxation of prevention measures. In contrast to what was seen above, 4/5 of the bacteremias caused by these two species were considered as community-acquired. Conclusion: The COVID-19 pandemic which had a strong impact on hospital management and social organization in the general population, had opposite impacts on the incidence of bacteremia depending on the pathogens and their mode of transmission.

Clinical Phenotypes of COVID-19 Associated Mucormycosis (CAM): A Comprehensive Review.

A mucormycosis surge was reported during the COVID-19 pandemic in India. A literature search until 14 July 2022, with the aim of updating COVID-19-associated mucormycosis (CAM), identified 663 studies and 88 met inclusion criteria (8727 patients). India reported 8388 patients, Egypt 208 and Europe 40. Rhino-orbito-cerebral mucormycosis (ROCM) was identified among 8082 (98.3%) patients, followed by 98 (1.2%) with pulmonary. In India, 82.6% of patients had diabetes mellitus, with 82% receiving corticosteroids. In Europe, 75% presented pulmonary CAM, 32.5% had diabetes and 40% were immunocompromised. CAM was identified at a median of 17.4 days (IQR 7.5 days) post COVID-19 diagnosis, and PCR was performed in five studies. Rhino-orbital invasion is clinically obvious, while cerebral involvement presents with cavernous sinus thrombosis, meningitis and cerebrovascular disease. Symptoms of pulmonary CAM usually overlap with severe COVID-19 pneumonia. High-dose liposomal Amphotericin B (and early surgical debridement in ROCM) are the mainstay of therapy. The median mortality rate was estimated to be 21.4% (IQR 31.9%), increased by the presence of pulmonary (80% (IQR 50%) or cerebral involvement (50% (IQR 63.9%). In summary, different CAM clinical phenotypes need to be distinguished, influenced by geographical presentation. Opportunities exist for diagnosis and therapy optimization, based on earlier high-dose antifungal therapy, early source control, strict glycemic control and restriction of steroids to COVID-19 patients with oxygen requirements.

Agents of mucormycosis outbreak associated with COVID-19

Mucormycosis is a life-threatening infection. Mucormycetes causes a wide range of diseases, including pneumonia, rhinosinusitis, internal organ spread, gastrointestinal tract involvement, and skin and soft tissue infection. It infects predominantly with hematological malignancies, transplantation, immunocompromised, and diabetes mellitus patients. The most severe type of the disease is a disseminated disease, which is linked to significant immunosuppression. Currently, this disease is more prevalent in the COVID-19 pandemic because of erroneous steroid use and untreated diabetes. However, there is a scarcity of study and information on the COVID-19 and mucormycosis connection. According to the latest research, mucormycosis cases are rising in developed and developing nations, and only a few therapies are available. The exact burden of mucormycosis is unclear;however, it is likely to be greater than recorded instances due to mucormycosis epidemiological changes. As a result of the delay in identifying this severe illness, appropriate antifungal medications are delayed, resulting in significant morbidity and death. A few drugs are underclinical trials for their efficacy. Other obstacles to treat patients are lack of reliable diagnostic non-invasive tests. This review article draws the attention of its readers and clinicians towards the agents of mucormycosis and discuss the various cases to manage this fungal infection.

Association of COVID-19 with Rhino-Cerebral Mucormycosis: An Observational Study.

Mucormycosis is becoming more common in patients infected with or recovering from COVID-19 under the current situation. However, there is a scarcity of research on a specific group of COVID-19 individuals who are predisposed to mucormycosis. As a result, a retrospective observational study was undertaken to assess the possible connection of mucormycosis with COVID-19. The goal was also to investigate the link between diabetes mellitus, mucormycosis and COVID-19. The occurrence and severity of the disease among the case records were assessed using signs and symptoms, investigations conducted during COVID-19, and serological test results. Patients were classified as previously known diabetics, recently diagnosed diabetics, or non-diabetics based on their history of pre-existing DM and HBA1c levels at the time of reporting for mucormycosis. The findings show that mild COVID-19-infected patients and non-diabetic patients have a high incidence of COVID-19-associated mucormycosis (CAM). As a result, all clinicians participating in the care of COVID-infected patients must be aware of the significant risk of secondary mucormycosis in the post-recovery phase, even in those with mild or moderate symptoms.

Cirrhosis and fungal infections-a cocktail for catastrophe: A systematic review and meta-analysis with machine learning.

OBJECTIVES: We evaluated the magnitude and factors contributing to poor outcomes among cirrhosis patients with fungal infections (FIs). METHODS: We searched PubMed, Embase, Ovid and WOS and included articles reporting mortality in cirrhosis with FIs. We pooled the point and relative-risk (RR) estimates of mortality on random-effects meta-analysis and explored their heterogeneity (I 2 ) on subgroups, meta-regression and machine learning (ML). We assessed the study quality through New-Castle-Ottawa Scale and estimate-asymmetry through Eggers regression. (CRD42019142782). RESULTS: Of 4345, 34 studies (2134 patients) were included (good/fair/poor quality: 12/21/1). Pooled mortality of FIs was 64.1% (95% CI: 55.4-72.0, I 2 : 87%, p < .01), which was 2.1 times higher than controls (95% CI: 1.8-2.5, I 2 :89%, p < .01). Higher CTP (MD: +0.52, 95% CI: 0.27-0.77), MELD (MD: +2.75, 95% CI: 1.21-4.28), organ failures and increased hospital stay (30 vs. 19 days) were reported among cases with FIs. Patients with ACLF (76.6%, RR: 2.3) and ICU-admission (70.4%, RR: 1.6) had the highest mortality. The risk was maximum for pulmonary FIs (79.4%, RR: 1.8), followed by peritoneal FIs (68.3%, RR: 1.7) and fungemia (55%, RR: 1.7). The mortality was higher in FIs than in bacterial (RR: 1.7) or no infections (RR: 2.9). Estimate asymmetry was evident (p < 0.05). Up to 8 clusters and 5 outlier studies were identified on ML, and the estimate-heterogeneity was eliminated by excluding such studies. CONCLUSIONS: A substantially worse prognosis, poorer than bacterial infections in cirrhosis patients with FIs, indicates an unmet need for improving fungal diagnostics and therapeutics in this population. ACLF and ICU admission should be included in the host criteria for defining IFIs.

Challenges in Diagnosing COVID-19-Associated Pulmonary Aspergillosis in Critically Ill Patients: The Relationship between Case Definitions and Autoptic Data.

Critically ill COVID-19 patients can develop invasive pulmonary aspergillosis (CAPA). Considering the weaknesses of diagnostic tests/case definitions, as well as the results from autoptic studies, there is a debate on the real burden of aspergillosis in COVID-19 patients. We performed a retrospective observational study on mechanically ventilated critically ill COVID-19 patients in an intensive care unit (ICU). The primary objective was to determine the burden of CAPA by comparing clinical diagnosis (through case definitions/diagnostic algorithms) with autopsy results. Twenty patients out of 168 (11.9%) developed probable CAPA. Seven (35%) were females, and the median age was 66 [IQR 59-72] years. Thirteen CAPA patients (65%) died and, for six, an autopsy was performed providing a proven diagnosis in four cases. Histopathology findings suggest a focal pattern, rather than invasive and diffuse fungal disease, in the context of prominent viral pneumonia. In a cohort of mechanically ventilated patients with probable CAPA, by performing a high rate of complete autopsies, invasive aspergillosis was not always proven. It is still not clear whether aspergillosis is the major driver of mortality in patients with CAPA.

Therapeutic Drug Monitoring of Antifungal Agents in Critically Ill Patients: Is There a Need for Dose Optimisation?

Invasive fungal infections are an important cause of morbidity and mortality, especially in critically ill patients. Increasing resistance rates and inadequate antifungal exposure have been documented in these patients, due to clinically relevant pharmacokinetic (PK) and pharmacodynamic (PD) alterations, leading to treatment failure. Physiological changes such as third spacing (movement of fluid from the intravascular compartment to the interstitial space), hypoalbuminemia, renal failure and hepatic failure, as well as common interventions in the intensive care unit, such as renal replacement therapy and extracorporeal membrane oxygenation, can lead to these PK and PD alterations. Consequently, a therapeutic target concentration that may be useful for one patient may not be appropriate for another. Regular doses do not take into account the important PK variations in the critically ill, and the need to select an effective dose while minimising toxicity advocates for the use of therapeutic drug monitoring (TDM). This review aims to describe the current evidence regarding optimal PK/PD indices associated with the clinical efficacy of the most commonly used antifungal agents in critically ill patients (azoles, echinocandins, lipid complexes of amphotericin B, and flucytosine), provide a comprehensive understanding of the factors affecting the PK of each agent, document the PK parameters of critically ill patients compared to healthy volunteers, and, finally, make recommendations for therapeutic drug monitoring (TDM) of antifungals in critically ill patients.