Site-based comparative analysis of sample collection through direct biopsy and nasal swab collection for early diagnosis of post-COVID rhinomaxillary fungal infection using KOH mounting – A Retrospective Cohort study. (preprint)

AIM To perform site-based comparative analysis for samples collected from the nasal region and Oral cavity subjected to microscopic detection of fungal hyphae in KOH mount in a group of patients with rhinomaxillary mucormycosis. Method: ology - 40 patients full-filled eligibility criteria. The diagnostic outcome of detection of fungal hyphae from the KOH samples obtained was the primary endpoint of the study. Based on this, the samples were grouped into 3 groups viz- Oral, Nasal and Both. The secondary outcome was to check if there was any diagnostic delay in these three groups of patients Results: The mean number of days for delayed diagnosis for oral site involvement was 56.33 ± 37.53, for Nasal involvement was 32.86 ± 19.53 and for both oral & nasal involvement was 22.00 ± 12.94. This difference was statistically significant at p=0.03. The mean delay in diagnosis was significantly less when both oral & nasal regions are involved as compared to the only oral region involved at P=0.01. Conclusion: - To avoid the chance of delayed diagnosis or false-negative results its best to collect samples from both nasal tissues and the most representative site in the dentoalveolar segment depending on the extensiveness of the disease.

Impairment of host adaptive immune response to Candida albicans infection: an in-silico insight on SARS-CoV-2 conspiracy (preprint)

Recent evidence reported that SARS-CoV-2 infections might trigger serious consequences in otherwise asymptomatic Candida albicans infections. To elucidate the mechanism of such co-infections, we have reconstructed Protein-protein interaction network (PPIN res )with the upregulated genes in blood of C. albicans infected asymptomatic patients and identified 55 Core Genes (CGs). Functional enrichment of CGs evidenced their potential to resist fungal infection. With CGs, Gene Regulatory Network (GRN res ) was reconstructed with TF-TF, TF-CG, CG-CG interactions and it exhibited 7 Articulation Points (APs). Mapping these TF-CG interactions with DEGs of COVID-19 revealed that 460 TF-CG pairs and 4 APs are downregulated. Subsequently, functional and pathway enrichment analysis of these gene pairs was performed. Our overall results suggest that weakening of adaptive immune response might pave the path for C. albicans superinfections in COVID-19 patients.

Pulmonary Giant Cavitary Coccidioides With Fungal Ball and Hemoptysis.

Coccidioidomycosis (CM) is a fungal disease that results from inhalation of spores of Coccidioides immitis and C posadasii. If symptomatic, disease primarily manifests as community-acquired pneumonia; however, additional pulmonary manifestations such as pleural effusion, empyema, and cavitation may occur. Diabetic patients have an increased risk of severe and cavitary CM. Cavitary disease may erode vasculature and pulmonary parenchyma leading to further complications. Furthermore, chronic cavities can become colonized as well and develop superimposed infections. This is a case of cavitary CM in uncontrolled diabetic nonadherent to treatment presenting with hemoptysis and mycetoma.

Post-COVID-19 chronic pulmonary aspergillosis in an immunocompetent woman with a history of pulmonary tuberculosis: a case report (preprint)

Previously treated pulmonary tuberculosis and Corona Virus Disease -2019 predispose to CPA and other pulmonary fungal diseases due to residual lung damage. We report a case of CPA in a 63-years-old Cameroonian woman with a history of PTB, 13 months after suffering from COVID-19 and treated with itraconazole 100mg.

Autopsy findings after long-term treatment of COVID-19 patients with microbiological correlation.

Between April and June 2020, i.e., during the first wave of pandemic coronavirus disease 2019 (COVID-19), 55 patients underwent long-term treatment in the intensive care unit at the University Hospital of Regensburg. Most of them were transferred from smaller hospitals, often due to the need for an extracorporeal membrane oxygenation system. Autopsy was performed in 8/17 COVID-19-proven patients after long-term treatment (mean: 33.6 days). Autopsy revealed that the typical pathological changes occurring during the early stages of the disease (e.g., thrombosis, endothelitis, capillaritis) are less prevalent at this stage, while severe diffuse alveolar damage and especially coinfection with different fungal species were the most conspicuous finding. In addition, signs of macrophage activation syndrome was detected in 7 of 8 patients. Thus, fungal infections were a leading cause of death in our cohort of severely ill patients and may alter clinical management of patients, particularly in long-term periods of treatment.

Repurposing Benzbromarone as Antifolate to Develop Novel Antifungal Therapy for Candida Albicans (preprint)

Fungal infections in humans are responsible for mild to severe infections resulting in the systemic effects responsible for a large amount of mortality. The invasive fungal infections are having similar symptomatic effects to those of COVID-19. The COVID-19 patients are immunocompromised in nature and have a high probability of developing severe fungal infections resulting in the development of further complications. The existing antifungal therapy is having associated problems related to the development of drug resistance, sub-potent in nature, and the presence of undesirable toxic effects. The fungal dihydrofolate reductase is an essential enzyme involved in the absorption of dietary folic acid and its conversion into tetrahydrofolate, which is a coenzyme required for the biosynthesis of the fungal nucleotides. Thus, in the current study, an attempt has been made to identify potential folate inhibitors of Candida albicans by a computational drug repurposing approach. Benzbromarone is identified as a potential anti-folate agent based upon the molecular docking simulation-based virtual screening followed by the molecular dynamic simulation of the macromolecular complex for the development of a novel therapy for the treatment of candidiasis.

Aspergillus Tracheobronchitis in COVID-19 ARDS Patients – A Cohort Study (preprint)

Background: Coronavirus disease 2019 (COVID-19) acute respiratory distress syndrome patients are at risk for fungal infections, especially aspergillosis and mucormycosis. COVID-19-associated pulmonary aspergillosis (CAPA) is differentiated in a pulmonary form and Aspergillus tracheobronchitis (ATB). During the first wave of the pandemic, bronchoscopy for diagnosing Aspergillus superinfections was rarely performed in COVID-19 patients, so that detailed on data on ATB in CAPA patients is scarce. We analyzed prevalence and mortality of tracheobronchitis in patients with CAPA.Methods: We conducted a retrospective, single-centre study at the 14-bed intensive care unit (ICU) of the Department I of Internal Medicine of the University Hospital of Cologne, Germany from March 2020 to February 2021. CAPA patients were identified by twice weekly analysis of tracheal aspirates for Aspergillus growth, Aspergillus DNA (PCR) and galactomannan combined with serum galactomannan testing. In case of positive results, bronchoscopy with the examination of trachea and lower airways and bronchoalveolar lavage followed.Findings: A total of 69 COVID-19 patients were admitted to the ICU, with 17 patients developing probable CAPA. All CAPA patients received bronchoscopy resulting in a clinical diagnosis of tracheobronchitis in 8 patients with signs of tracheal lesions, pseudomembranes or vulnerable bloody trachea. Seven bronchoalveolar lavages revealed culture and eight PCR positivity for Aspergillus fumigatus. In 7 of 8 tracheobronchitis patients, bronchoalveolar lavage samples tested positive for galactomannan antigen optical density index of >0.5. The overall mortality of CAPA patients was 52.9% and the overall mortality of ATB patients was 75%.Interpretation: Our data indicate a substantial prevalence of tracheobronchitis in this single-center cohort of CAPA patients. To facilitate early diagnosis bronchoscopic tracheal examination is crucial as computed tomography lacks diagnostic accuracy to enable timely initiation of therapy.Funding Information: This work was in part supported by the German Registry of COVID-19 Autopsies (www.DeRegCOVID.ukaachen.de), funded by the Federal Ministry of Health (ZMVI1-2520COR201), and the project DEFEAT PANDEMICs, funded by the Federal Ministry of Education and Research (01KX2021).Declaration of Interests: PK reports grants or contracts from German Federal Ministry of Research and Education and the State of North Rhine-Westphalia; Consulting fees Ambu GmbH, Gilead Sciences, Noxxon N.V. and Pfizer Pharma; Honoraria for lectures from Akademie für Infektionsmedizin e.V., Ambu GmbH, Astellas Pharma, BioRad Laboratories Inc., European Confederation of Medical Mycology, Gilead Sciences, GPR Academy Ruesselsheim, medupdate GmbH, MedMedia, MSD Sharp & Dohme GmbH, Pfizer Pharma GmbH, Scilink Comunicación Científica SC and University Hospital and LMU Munich; Participation on an Advisory Board from Ambu GmbH, Gilead Sciences, Pfizer Pharma; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other non-financial interests from Elsevier, Wiley and Taylor & Francis online outside the submitted work. SvS none. JGB reports scientific grants and travel expenses from Kite/Gilead outside the submitted work. FF has a clinician scientist position supported by the deans office, medical faculty, University of Cologne. JSG none. FP none. BB reports honoraria, travel expenses and advisory role from/for Astellas, Celgene, Johnson & Johnson, Kite/Gilead, MSD, Novartis, Pfizer, Takeda and financing of scientific research by Astellas, Celgene, Kite/Gilead, MSD and Takeda outside the submitted work. DAE received honoraria from Sanofi and TAKEDA outside the submitted work. ASV reports travel grants from Gilead Sciences outside the submitted work. OK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead and Pfizer and receipt of equipment, materials, drugs, medical writing, gifts or other services by Pfizer, MSD, Basilea, Gilead, Virotech and Wako Fujifilm outside the submitted work. PB none. MK reports payment or honoraria for lectures, presentations or speakers bureaus by Gilead, MSD and Pfizer outside the submitted work. OAC reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer, Scynexis; Consulting fees from Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, Matinas, MedPace, Menarini, Molecular Partners, MSG-ERC, Noxxon, Octapharma, PSI, Scynexis, Seres; Honoraria for lectures from Abbott, Al 344 Jazeera Pharmaceuticals, Astellas, Grupo Biotoscana/United Medical/Knight, Hikma, MedScape, MedUpdate, Merck/MSD, Mylan, Pfizer; Payment for expert testimony from Cidara; Participation on a Data Safety Monitoring Board or Advisory Board from Actelion, Allecra, Cidara, Entasis, IQVIA, Jannsen, MedPace, Paratek, PSI, Shionogi; A pending patent currently reviewed at the German Patent and Trade Mark Office; Other interests from DGHO, DGI, ECMM, ISHAM, MSG-ERC, Wiley outside the submitted work.Ethics Approval Statement: Patients with CAPA were included in the FungiScope® global registry for emerging invasive fungal infections (https://www.clinicaltrials.gov; National Clinical Trials identifier NCT01731353), which was approved by the local ethics committee of the University of Cologne, Cologne, Germany (identifier 05-102).

Superinfections in critically ill COVID-19 patients - an association with Dexamethasone? (preprint)

BacgroundSuper-infections in COVID-19 patients with acute respiratory distress syndrome (ARDS) on mechanical ventilation were initially reported to be rare. Little is known of their incidence after dexamethasone was introduced as standard care. We aimed to determine the incidence and characteristics of superinfections in mechanically ventilated COVID-19 patients during the course of the COVID-19 pandemic, and explore the possible impact of the introduction of dexamethasone as standard therapy. MethodsIn this national, multi-center, observational, retrospective study we included patients ≥ 18 years admitted from March 1 st 2020 to January 31 st 2021 with polymerase chain reaction (PCR)-confirmed SARSCoV-2 infection treated with invasive mechanical ventilation. Data was collected from electronic health records. Patient characteristics, clinical findings, microbiology, length of stay and 90-day survival were examined with backwards stepwise multiple regression. Results155 patients (115 men, mean age 62 years, range 26-84 years) were included. 73 patients (47%) had a total of 101 superinfections where pneumonia dominated (70%). Superinfections were more commonly observed in patients receiving dexamethasone (67% vs 30%, p<0.0001), and in patients with pre-existing autoimmune disease (18% vs 5%, p<0.01). Invasive fungal infections were reported exclusively in dexamethasone-treated patients [9/72 (13%) vs 0/83 (0%), p<0.0001]. There was no difference in 90-day survival between patients with and patients without superinfections (64% versus 73%, p=0.238). In multiple regression analysis, superinfection was associated with dexamethasone use [OR 5.35 (2.62–11.35), p<0.001], pre-existing autoimmune disease [OR 4.90 (1.50–19.4), p=0.008] and higher lymphocyte count at the time of admission [OR 2.31 (1.23–4.86), p=0.009]. ConclusionIn critically ill COVID-19 patients receiving invasive ventilation, introduction of dexamethasone as standard of care was strongly and independently associated with superinfections. A focus on this complication is warranted when studying alternative anti-inflammatory therapy.

Tocilizumab in Critically Ill COVID-19 Patients: An Observational Study (preprint)

Tocilizumab is one of the IL-6 antagonists hypothesized to decrease the inflammatory response in the cytokine storm, postulated to be one of the mechanisms behind development of ARDS in COVID-19 patients. The objective of our study was to determine the response of tocilizumab in patients suffering from SARS-CoV-2 by analyzing the clinical parameters and inflammatory markers. A single-arm observational study was conducted from March 15, 2020, to March 15, 2021. The clinical outcomes in terms of mortality, weaning from mechanical ventilator, improvement in laboratory parameters including inflammatory cytokines and length of hospital stay were documented. Reduction in values of inflammatory markers and patients discharged home in stable condition was defined as improvement after tocilizumab administration. A total of 514 patients received tocilizumab. Critically sick patients 333 (64.8%) constituted he majority of study population. 363 (70.6%) patients were discharged home. Overall mean length of stay was found to be 11.50 ± 8.4 days. There was significant difference in length of stay of patients who required invasive mechanical ventilation as compared to those who were kept only on supplemental oxygen ( p <0.05) . Patients who were discharged showed significant improvement in all inflammatory markers and neutrophil to lymphocyte ratio as compared to those who expired ( p <0.05). 21 (4.1%) patients had a positive blood culture while 57 (11.1%) had a positive tracheal aspirate. In conclusion, tocilizumab is a reasonable therapeutic option for worsening COVID-19 pneumonia by decreasing the need for mechanical ventilation. However, its use is associated with significant adverse events including secondary bacterial and fungal infections.

Effect of The “Normalized Epidemic Prevention And Control Requirements” On Hospital-Acquired And Community-Acquired Infections In China (preprint)

Background: No studies have yet reported the effect of prevention and control measures, which were implemented to combat COVID-19, on the prevention and control of common HAIs. We aimed to examine the effect of the “Normalized Epidemic Prevention and Control Requirements” (implemented in May 2020) by comparison of hospital-acquired infections (HAIs) and community-acquired infections (CAIs) in China during 2018, 2019, and 2020. Methods: : Data of inpatients before and after implementation of new requirements were retrospectively analyzed, including infection rate, use of alcohol-based hand cleaner, anatomical sites of infections, pathogen species, infection by multi-drug-resistant species, use of different antibiotics, and antibiotic use density. Results: : The HAI rate was significantly higher in 2020 than in 2018 and 2019 ( P< 0.05), and the CAI rate was significantly higher in 2019 and 2020 than in 2018 ( P <0.001). Lower respiratory tract infections were the most common HAI during all years, with no significant changes over time. Lower respiratory tract infections were also the most common CAI, but were significantly more common in 2018 and 2019 than 2020 ( P <0.001). There were no changes in upper respiratory tract infections among HAIs or CAIs. Most HAIs and CAIs were from Gram-negative bacteria, and the percentages of fungal infections were greater in 2019 and 2020 than 2018. MRSA infections were more common in 2020 than in 2018 and 2019 ( P< 0.05). The utilization rate and usage days of antibiotics decreased over time ( P <0.001), the culture rate of microbial specimens before antibiotics usage increased over time ( P <0.001), but antibiotic use density remained steady over time. Conclusions: : The new prevention and control requirements provided important benefits during the COVID-19 pandemic. However, their effects on HAIs were not obvious.

Pneumonia Caused by Lichtheimia Ramosa During the COVID-19 Pandemic in Hubei Province, China：A Case Report and Literature Review (preprint)

Background: Mucor infection cannot be ignored in patients with pulmonary shadowing with cavitation .This paper reports a case of mucormycosis during the COVID-19 pandemic in Hubei Province, China. Case PresentationA anesthesiology doctor was initially diagnosed as COVID-19 due to changes in lung imaging. Later Lichtheimia ramose was found by Metagenomic next generation sequencing (mNGS) in the Bronchoalveolar lavage fluid (BALF).After adjusting amphotericin B for anti-infective treatment, the patient's infection lesions were shranked and the symptoms were significantly relieved. ConclusionThe diagnosis of invasive fungal infections is very difficult, mNGS can make an accurate pathogenic diagnosis of invasive fungal diseases for the clinic and provide a basis for clinical treatment.

COVID-19 and Mucormycosis: The Double Edge Sword (preprint)

Background: and aim India has declared mucormycosis as an epidemic. The incidence rate is rising day by day as there are more than 29000 cases in 28 states until March 2021. COVID-19 is already burdening the health care system, and post-COVID mucormycosis leads to mortality and morbidity in patients treated with COVID-19. This article aims to understand the various complications of mucormycosis and how it is impacting COVID-19 infected patients. Methods A thorough literature search was performed using PubMed, Google Scholar, and Embase from May 2021 to June 2021. The authors selected the articles based on relevance. Mucormycosis, black fungus, fungal infection, COVID-19, pathogenesis, corticosteroids, treatment, antifungals were the major keywords searched. Secondary resources included from the published news articles. Results Through the literature, we observed that patients after COVID-19 are more vulnerable to these fungal infections, especially immunocompromised patients, patients with long-term steroid use, and uncontrolled diabetes. This review enlightens the manifestations, pathogenesis, and various treatment and anticipation policies for mucormycosis. Conclusion Awareness about the possibility of the disease is necessary to reduce the delay of diagnosis and timely treatment to prevent further implications of the disease. In addition, prevention of the disease with strict follow-up measures with sanitation and hygiene maintenance is also essential.

[CT Characteristics of Consolidation Type of Pulmonary Cryptococcosis in Immunocompetent Patients].

Objective To analyze the CT characteristics of consolidation type of pulmonary cryptococcosis in immunocompetent patients,and thus improve the diagnosis of this disease. Methods A total of 20 cases with consolidation-type pulmonary cryptococcosis confirmed by pathological examinations were studied.Each patient underwent breath-hold multislice spiral CT,and 10 patients underwent contrast enhanced CT.The data including lesion number,lesion distribution,lesion density,performance of enhanced CT scan,accompanying signs,and prognosis were analyzed. Results The occurrence rates of single and multiple lesions were 80.0%(n=16)and 20.0%(n=4),respectively.In all the 16 multiple-lesion patients,the occurrence rate of unilateral lobar distribution was 56.0%(n=9).The 76 measurable lesions mainly presented subpleural distribution(71.1%,n=54)and lower pulmonary distribution(75.0%,n=57).A total of 39 lesions were detected in the 10 patients received contrast enhanced CT,in which 31 lesions(79.5%)showed homogeneous enhancement,34 lesions(87.2%)showed moderate enhancement,and all the lesions manifested angiogram sign.Consolidation lesions were accompanied by many CT signs,of which air bronchogram sign had the occurrence rate of 63.2%(n=48),including types Ⅲ(n =37)and Ⅳ(n=11).Other signs included halo signs(43/76,56.6%),vacuoles or cavities(9/76,11.8%),pleural thickening(14/20,70.0%),and pleural effusion(2/20,10.0%).After treatment,the lesions of 7 patients were basically absorbed and eventually existed in the form of fibrosis. Conclusions The lesions in the immunocompetent patients with consolidation type of pulmonary cryptococcosis usually occur in the lower lobe and close to the pleura,mainly presenting unilateral distribution.The CT angiogram signs,proximal air bronchogram signs,and halo signs are the main features of this disease,which contribute to the diagnosis.

COVID-19: CRISPR/Cas-like System of nsp3 Promotes the Mutant Recombination and Drug Resistance (preprint)

Patients with novel coronavirus pneumonia usually suffer from bacterial and fungal infections, and the drug resistance problem caused by the pandemic is becoming more and more serious. Simultaneously, the SARS-COV-2 virus has a rapid mutation phenomenon, and somegene coding regions by mutation and recombination may be related to the drug resistance of the virus. Therefore, studying the relationship between the co-infection of bacteria and fungi and the evolution of SARS-COV-2 has important guiding significance for preventing a pandemic. We found that the SARS-COV-2 virus's nsp3 protein had a CRISPR/Cas 9 (II-B)-like function by searching for conserved domains. The system could target and edit the negative-strand RNA of SARS-COV-2. We speculated that the crRNA (CRISPR RNA) produced by the CRISPR/Cas system of Pseudomonas aeruginosa carried the genetic information of the conserved domains of bacteriophages and Pseudomonas, including drug resistance. After the phage lysed the Pseudomonas, the crRNA was released and attached to the fungal spores, and then invaded the patient's cells along with the spores or hyphae. nsp3 synthesized and assembled 4Fe-4S, iron-containing molecules bound to the cas4 domain, in the mitochondria of phagocytes. The iron came from hemoglobin attacked by the SARS-COV-2 virus protein. The nsp3 protein bound the crRNA in the phagocytic cytoplasm. It targeted the negative-strand RNA of SARS-COV-2, inserting conserved domain gene fragments into the negative-strand RNA through editing and splicing. Since the Cas protein had no codon checking function, the cutting and splicing would destroy the protein-coding information in the original RNA coding region, causing mutation and recombination of the SARS-COV-2 virus genome. If crRNA carried the drug resistance gene fragments of bacteria or phage, SARS-COV-2 would have similar drug resistance. Because of the growing problem of drug resistance in COVID-19 patients, we should pay attention to preventing fungi and bacteria co-infection. Avoid the CRISPR/Cas-like system of the novel coronavirus to cause rapid mutation and recombination and increased the drug resistance problem of SARS-COV-2.

Influenza- and COVID-19-associated pulmonary aspergillosis: are the pictures different? (preprint)

Background: Invasive pulmonary aspergillosis (IPA) in intensive care unit patients is a major concern, in particular for those with acute respiratory distress syndrome (ARDS). As observed previously for influenza-associated ARDS, the SARS-CoV-2 pandemic has shown a high proportion of COVID-19 patients with ARDS to be at risk of developing invasive fungal diseases.MethodsWe used the new international definitions of influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) to compare the demographic, clinical, biological and radiological aspects of IAPA and CAPA in a monocentric retrospective study.ResultsAmong the 120 ARDS patients included, we observed equivalent prevalence of IPA in Influenza and COVID-19 populations: 17 IAPA (23.9%) and 10 CAPA (20.4%). There were no significant differences in demographic or admission characteristics between patients with and without IPA. Kaplan-Meier curves showed significantly higher 90-day mortality for IPA patients overall (p = 0.032), whereas mortality did not differ between CAPA and IAPA. The duration of mechanical ventilation was higher for IPA patients (23 days [IQR 17–40] than those without (17 days [IQR 9–25], p  = 0.038). Patients with COVID-19 and influenza associated ARDS treated with corticosteroids were more likely to develop IPA. Radiological findings of IPA in both populations using the new criteria increased sensitivity but with still poor specificity. Nonetheless, they also showed interesting differences between IAPA and CAPA with a higher proportion of features suggestive of IPA in IAPA patients. Lastly, therapeutic drug monitoring also appeared challenging since a wide proportion of IPA patients had low plasma voriconazole concentrations, with a significant higher delay to reach voriconazole concentrations > 2mg/L in CAPA versus IAPA patients ( p  = 0.045).ConclusionsICU patients presenting with ARDS during COVID-19 are very similar to those with severe influenza pneumonia in terms of prevalence of IPA and outcome, while CAPA is mainly favored by advanced age irrespective of the background. The dramatic consequences on the patients' prognosis emphasize the need for a better awareness in these particular populations. Larger prospective studies may help in designing the most well-adapted personalized management to prevent IPA, which represents a high burden of death in severe COVID-19 and Influenza pneumonia.

State-of-the-art review of secondary pulmonary infections in patients with COVID-19 pneumonia.

BACKGROUND: The incidence of secondary pulmonary infections is not well described in hospitalized COVID-19 patients. Understanding the incidence of secondary pulmonary infections and the associated bacterial and fungal microorganisms identified can improve patient outcomes. OBJECTIVE: This narrative review aims to determine the incidence of secondary bacterial and fungal pulmonary infections in hospitalized COVID-19 patients, and describe the bacterial and fungal microorganisms identified. METHOD: We perform a literature search and select articles with confirmed diagnoses of secondary bacterial and fungal pulmonary infections that occur 48 h after admission, using respiratory tract cultures in hospitalized adult COVID-19 patients. We exclude articles involving co-infections defined as infections diagnosed at the time of admission by non-SARS-CoV-2 viruses, bacteria, and fungal microorganisms. RESULTS: The incidence of secondary pulmonary infections is low at 16% (4.8-42.8%) for bacterial infections and lower for fungal infections at 6.3% (0.9-33.3%) in hospitalized COVID-19 patients. Secondary pulmonary infections are predominantly seen in critically ill hospitalized COVID-19 patients. The most common bacterial microorganisms identified in the respiratory tract cultures are Pseudomonas aeruginosa, Klebsiella species, Staphylococcus aureus, Escherichia coli, and Stenotrophomonas maltophilia. Aspergillus fumigatus is the most common microorganism identified to cause secondary fungal pulmonary infections. Other rare opportunistic infection reported such as PJP is mostly confined to small case series and case reports. The overall time to diagnose secondary bacterial and fungal pulmonary infections is 10 days (2-21 days) from initial hospitalization and 9 days (4-18 days) after ICU admission. The use of antibiotics is high at 60-100% involving the studies included in our review. CONCLUSION: The widespread use of empirical antibiotics during the current pandemic may contribute to the development of multidrug-resistant microorganisms, and antimicrobial stewardship programs are required for minimizing and de-escalating antibiotics. Due to the variation in definition across most studies, a large, well-designed study is required to determine the incidence, risk factors, and outcomes of secondary pulmonary infections in hospitalized COVID-19 patients.

Fatal disseminated aspergillosis in an immunocompetent patient with COVID-19 due to Aspergillus ochraceus.

Aspergillus infection is a well-known complication of severe influenza and severe acute respiratory syndrome coronavirus (SARS-CoV), and these infections have been related with significant morbidity and mortality even when appropriately diagnosed and treated. Recent studies have indicated that SARS-CoV-2 might increase the risk of invasive pulmonary aspergillosis (IPA). Here, we report the first case of Aspergillus ochraceus in a SARS-CoV-2 positive immunocompetent patient, which is complicated by pulmonary and brain infections. Proven IPA is supported by the positive Galactomannan test, culture-positive, and histopathological evidence. The patient did not respond to voriconazole, and liposomal amphotericin B was added to his anti-fungal regimen. Further studies are needed to evaluate the prevalence of IPA in immunocompetent patients infected with SARS-CoV-2. Consequently, testing for the incidence of Aspergillus species in lower respiratory secretions and Galactomannan test of COVID-19 patients with appropriate therapy and targeted anti-fungal therapy based on the primary clinical suspicion of IPA are highly recommended.

Occurrence of Invasive Pulmonary Fungal Infections in Patients with Severe COVID-19 Admitted to the ICU.

Rationale: Whether severe coronavirus disease (COVID-19) is a significant risk factor for the development of invasive fungal superinfections is of great medical interest and remains, for now, an open question.Objectives: We aim to assess the occurrence of invasive fungal respiratory superinfections in patients with severe COVID-19.Methods: We conducted the study on patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related pneumonia admitted to five ICUs in France who had respiratory and serum sampling performed for specific screening of fungal complications.Measurements and Main Results: The study population included a total of 145 patients; the median age was 55 years old. Most of them were male (n = 104; 72%), were overweight (n = 99; 68%), and had hypertension (n = 83; 57%) and diabetes (n = 46; 32%). Few patients presented preexisting host risk factors for invasive fungal infection (n = 20; 14%). Their global severity was high; all patients were on invasive mechanical ventilation, and half (n = 73, 54%) were on extracorporeal membrane oxygenation support. Mycological analysis included 2,815 mycological tests (culture, galactomannan, ß-glucan, and PCR) performed on 475 respiratory samples and 532 sera. A probable/putative invasive pulmonary mold infection was diagnosed in 7 (4.8%) patients and linked to high mortality. Multivariate analysis indicates a significantly higher risk for solid organ transplant recipients (odds ratio, = 4.66; interquartile range, 1.98-7.34; P = 0.004). False-positive fungal test and clinically irrelevant colonization, which did not require the initiation of antifungal treatment, was observed in 25 patients (17.2%).Conclusions: In patients with no underlying immunosuppression, severe SARS-CoV-2-related pneumonia seems at low risk of invasive fungal secondary infection, especially aspergillosis.