Invasive Mucormycosis and Aspergillosis Coinfection Associated with Post-COVID-19 Pneumonia in a Tertiary Care Hospital.

Acute invasive fungal rhinosinusitis is a rare infection primarily affecting patients with co-morbidities like immunosuppression and poorly controlled diabetes. Mucormycosis is increasingly being reported in patients with SARS-CoV-2 (COVID-19). However, reports of coinfection of aspergillosis and mucormycosis involving nose, paranasal sinuses, orbit, and brain are rare in literature. We aimed to evaluate the patient demographics, clinical presentation, and management of cases presenting with mixed infection. We carried out retrospective analysis of 12 patients with confirmed diagnosis of mixed invasive fungal infections post-COVID-19 disease out of 70 cases of COVID-19-associated mucormycosis (CAM) presenting to a tertiary-level hospital in North India from May to June 2021. All patients had diabetes mellitus; the mean age was 48 years. The common presenting features were headache, nasal congestion, palatal ulcer, and vision loss accompanied by facial pain and swelling. Two patients developed cerebral abscess during the course of treatment; three patients had concurrent COVID-19 pneumonia. All patients received systemic liposomal amphotericin B and serial surgical debridements. The overall mortality rate was 16.7%. Our study demonstrates that mucormycosis and aspergillosis are angioinvasive mycoses that are clinically and radiologically identical. KOH direct mount of clinical sample showing septate hyphae should be extensively searched for aseptate hyphae after digestion and clearing of the tissue. A high index of suspicion of mixed infection post-COVID-19 and early initiation of liposomal amphotericin B followed by prompt surgical intervention can reduce the overall morbidity and mortality among patients with this condition.

A 9-gene biomarker panel identifies bacterial coinfections in culture-negative COVID-19 cases.

Confirmatory diagnosis of bacterial coinfections with COVID-19 is challenging due to the limited specificity of the widely used gold-standard culture sensitivity test despite clinical presentations. A misdiagnosis can either lead to increased health complications or overuse of antibiotics in COVID-19 patients. With a multi-step systems biology pipeline, we have identified a 9-gene biomarker panel from host blood that can identify bacterial coinfection in COVID-19 patients, even in culture-negative cases. We have also formulated a qPCR-based score that diagnoses bacterial coinfection with COVID-19 with the accuracy, specificity, and sensitivity of 0.93, 0.96, and 0.89, respectively. This gene signature and score can assist in the clinical decision-making process of necessary and timely prescription of antibiotics in suspected bacterial coinfection cases with COVID-19 and thereby help to reduce the associated morbidity and mortality.

Microbiologically confirmed infections and antibiotic-resistance in a national surveillance study of hospitalised patients who died with COVID-19, Italy 2020-2021.

BACKGROUND: Patients hospitalised for COVID-19 may present with or acquire bacterial or fungal infections that can affect the course of the disease. The aim of this study was to describe the microbiological characteristics of laboratory-confirmed infections in hospitalised patients with severe COVID-19. METHODS: We reviewed the hospital charts of a sample of patients deceased with COVID-19 from the Italian National COVID-19 Surveillance, who had laboratory-confirmed bacterial or fungal bloodstream infections (BSI) or lower respiratory tract infections (LRTI), evaluating the pathogens responsible for the infections and their antimicrobial susceptibility. RESULTS: Among 157 patients with infections hospitalised from February 2020 to April 2021, 28 (17.8%) had co-infections (≤ 48 h from admission) and 138 (87.9%) had secondary infections (> 48 h). Most infections were bacterial; LRTI were more frequent than BSI. The most common co-infection was pneumococcal LRTI. In secondary infections, Enterococci were the most frequently recovered pathogens in BSI (21.7% of patients), followed by Enterobacterales, mainly K. pneumoniae, while LRTI were mostly associated with Gram-negative bacteria, firstly Enterobacterales (27.4% of patients, K. pneumoniae 15.3%), followed by A. baumannii (19.1%). Fungal infections, both BSI and LRTI, were mostly due to C. albicans. Antibiotic resistance rates were extremely high in Gram-negative bacteria, with almost all A. baumannii isolates resistant to carbapenems (95.5%), and K. pneumoniae and P. aeruginosa showing carbapenem resistance rates of 59.5% and 34.6%, respectively. CONCLUSIONS: In hospitalised patients with severe COVID-19, secondary infections are considerably more common than co-infections, and are mostly due to Gram-negative bacterial pathogens showing a very high rate of antibiotic resistance.

Super Dominant Pathobiontic Bacteria in the Nasopharyngeal Microbiota Cause Secondary Bacterial Infection in COVID-19 Patients.

Coronavirus disease 2019 (COVID-19) is a respiratory infectious disease responsible for many infections worldwide. Differences in respiratory microbiota may correlate with disease severity. Samples were collected from 20 severe and 51 mild COVID-19 patients. High-throughput sequencing of the 16S rRNA gene was used to analyze the bacterial community composition of the upper and lower respiratory tracts. The indices of diversity were analyzed. When one genus accounted for >50% of reads from a sample, it was defined as a super dominant pathobiontic bacterial genus (SDPG). In the upper respiratory tract, uniformity indices were significantly higher in the mild group than in the severe group (P < 0.001). In the lower respiratory tract, uniformity indices, richness indices, and the abundance-based coverage estimator were significantly higher in the mild group than in the severe group (P < 0.001). In patients with severe COVID-19, SDPGs were detected in 40.7% of upper and 63.2% of lower respiratory tract samples. In patients with mild COVID-19, only 10.8% of upper and 8.5% of lower respiratory tract samples yielded SDPGs. SDPGs were present in both upper and lower tracts in seven patients (35.0%), among which six (30.0%) patients possessed the same SDPG in the upper and lower tracts. However, no patients with mild infections had an SDPG in both tracts. Staphylococcus, Corynebacterium, and Acinetobacter were the main SDPGs. The number of SDPGs identified differed significantly between patients with mild and severe COVID-19 (P < 0.001). SDPGs in nasopharyngeal microbiota cause secondary bacterial infection in COVID-19 patients and aggravate pneumonia. IMPORTANCE The nasopharyngeal microbiota is composed of a variety of not only the true commensal bacterial species but also the two-face pathobionts, which are one a harmless commensal bacterial species and the other a highly invasive and deadly pathogen. In a previous study, we found that the diversity of nasopharyngeal microbiota was lost in severe influenza patients. We named the genus that accounted for over 50% of microbiota abundance as super dominant pathobiontic genus, which could invade to cause severe pneumonia, leading to high fatality. Similar phenomena were found here for SARS-CoV-2 infection. The diversity of nasopharyngeal microbiota was lost in severe COVID-19 infection patients. SDPGs in nasopharyngeal microbiota were frequently detected in severe COVID-19 patients. Therefore, the SDPGs in nasopharynx microbiota might invade into low respiratory and be responsible for secondary bacterial pneumonia in patients with SARS-CoV-2 infection.

Antibiotic use in patients with Coronavirus disease 2019 (COVID-19): outcomes and associated factors.

OBJECTIVES: To characterise the factors, outcomes and infections associated with antibiotic use in COVID-19 patients. METHODS: Records of patients with RT-PCR-confirmed COVID-19, hospitalized at the CHU Charleroi (Belgium) between 11 March and 3 May 3 2020, were retrospectively reviewed. Factors associated with antibiotic treatment, outcomes and bacterial infections were analysed. RESULTS: Among the 164 hospitalized COVID-19 patients (median age 60.5 years [IQR] 46-79), twenty-five (15.2%) were admitted to the ICU. Twenty-six (15.9%) died in the hospital. One hundred (61%) received antibiotic treatment. Combination therapies with macrolides were more common in the early part of the study period (26/67, 38.8%). Twenty-eight patients (17.1%) had a confirmed infection, mostly of the urinary tract (18/28, 64.3%). Only 2 (1.2%) had a documented respiratory coinfection. Six of the 7 ICU infections (85.7%) were superinfections. Gram-negative bacteria were most frequently isolated. In multivariate analysis, six factors were associated with antibiotic use: being hospitalized in the ICU (OR: 4.59; 95% CI 1.07-19.71), age > 65 years (OR: 4.16; 95% CI 1.72-10.05), arrival from a nursing home (OR: 4.59; 95% CI 1.11-19.71), diabetes (OR: 4.35; 95% CI 1.26-14.93), bilateral consolidation on chest CT (OR: 9.92; 95% CI 2.40-41.06) and a C-reactive protein level > 60 mg/L (OR:2.46; 95% CI 1.13-5.37). Antibiotic treatment did not reduce the length of stay or the mortality rate. CONCLUSION: Antibiotics have been overused during the COVID-19 pandemic, despite a low rate of coinfections . Integrating the antimicrobial stewardship (AMS) programme into the COVID-19 response is essential.

The Balance of Neutrophil Extracellular Trap Formation and Nuclease Degradation: an Unknown Role of Bacterial Coinfections in COVID-19 Patients?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is leading to public health crises worldwide. An understanding of the pathogenesis and the development of treatment strategies is of high interest. Recently, neutrophil extracellular traps (NETs) have been identified as a potential driver of severe SARS-CoV-2 infections in humans. NETs are extracellular DNA fibers released by neutrophils after contact with various stimuli and accumulate antimicrobial substances or host defense peptides. When massively released, NETs are described to contribute to immunothrombosis in acute respiratory distress syndrome and in vascular occlusions. Based on the increasing evidence that NETs contribute to severe COVID-19 cases, DNase treatment of COVID-19 patients to degrade NETs is widely discussed as a potential therapeutic strategy. Here, we discuss potential detrimental effects of NETs and their nuclease degradation, since NET fragments can boost certain bacterial coinfections and thereby increase the severity of the disease.

Pneumococcal Conjugate Vaccine Protection against Coronavirus-Associated Pneumonia Hospitalization in Children Living with and without HIV.

In December 2019 a new coronavirus (CoV) emerged as a human pathogen, SARS-CoV-2. There are few data on human coronavirus infections among individuals living with HIV. In this study we probed the role of pneumococcal coinfections with seasonal CoVs among children living with and without HIV hospitalized for pneumonia. We also described the prevalence and clinical manifestations of these infections. A total of 39,836 children who participated in a randomized, double-blind, placebo-controlled clinical trial on the efficacy of a 9-valent pneumococcal conjugate vaccine (PCV9) were followed for lower respiratory tract infection hospitalizations until 2 years of age. Nasopharyngeal aspirates were collected at the time of hospitalization and were screened by PCR for four seasonal CoVs. The frequency of CoV-associated pneumonia was higher in children living with HIV (19.9%) than in those without HIV (7.6%, P < 0.001). Serial CoV infections were detected in children living with HIV. The case fatality risk among children with CoV-associated pneumonia was higher in those living with HIV (30.4%) than without HIV (2.9%, P = 0.001). C-reactive protein and procalcitonin levels were elevated in 36.8% (≥40 mg/liter) and 64.7% (≥0.5 ng/ml), respectively, of the fatal cases living with HIV. Among children without HIV, there was a 64.0% (95% CI: 22.9% to 83.2%) lower incidence of CoV-associated pneumonia hospitalizations among PCV9 recipients compared to placebo recipients. These data suggest that Streptococcus pneumoniae infections might have a role in the development of pneumonia associated with endemic CoVs, that PCV may prevent pediatric CoV-associated hospitalization, and that children living with HIV with CoV infections develop more severe outcomes.IMPORTANCE SARS-CoV-2 may cause severe hospitalization, but little is known about the role of secondary bacterial infection in these severe cases, beyond the observation of high levels of reported inflammatory markers, associated with bacterial infection, such as procalcitonin. We did a secondary analysis of a double-blind randomized trial of PCV to examine its impact on human CoV infections before the pandemic. We found that both children living with and without HIV randomized to receive PCV had evidence of less hospitalization due to seasonal CoV, suggesting that pneumococcal coinfection may play a role in severe hospitalized CoV infections.

Detection of Bacterial Coinfection in COVID-19 Patients Is a Missing Piece of the Puzzle in the COVID-19 Management in Indonesia.

Bacterial coinfection in COVID-19 patients has the potential to complicate treatments and accelerate the development of antibiotic resistance in the clinic due to the widespread use of broad-spectrum antibiotics, including in Indonesia. The surge of COVID-19 patients may worsen antibiotic overuse; therefore, information on the actual extent of bacterial coinfection in COVID-19 patients in Indonesia is crucial to inform appropriate treatment. This Viewpoint elaborates on a nascent research project focused on sequencing of swab samples to detect bacterial coinfection in COVID-19 patients in Indonesia. Supported by a L'Oréal-UNESCO For Women in Science National Fellowship, it is designed to inform better clinical management of COVID-19 in Indonesia.

Limited Utility of Procalcitonin in Identifying Community-Associated Bacterial Infections in Patients Presenting with Coronavirus Disease 2019.

The role of procalcitonin in identifying community-associated bacterial infections among patients with coronavirus disease 2019 is not yet established. In 2,443 patients of whom 148 had bacterial coinfections, mean procalcitonin levels were significantly higher with any bacterial infection (13.16 ± 51.19 ng/ml; P = 0.0091) and with bacteremia (34.25 ± 85.01 ng/ml; P = 0.0125) than without infection (2.00 ± 15.26 ng/ml). Procalcitonin (cutoff, 0.25 or 0.50 ng/ml) did not reliably identify bacterial coinfections but may be useful in excluding bacterial infection.

Metaproteomics Analysis of SARS-CoV-2-Infected Patient Samples Reveals Presence of Potential Coinfecting Microorganisms.

In this Letter, we reanalyze published mass spectrometry data sets of clinical samples with a focus on determining the coinfection status of individuals infected with SARS-CoV-2 coronavirus. We demonstrate the use of ComPIL 2.0 software along with a metaproteomics workflow within the Galaxy platform to detect cohabitating potential pathogens in COVID-19 patients using mass spectrometry-based analysis. From a sample collected from gargling solutions, we detected Streptococcus pneumoniae (opportunistic and multidrug-resistant pathogen) and Lactobacillus rhamnosus (a probiotic component) along with SARS-Cov-2. We could also detect Pseudomonas sps. Bc-h from COVID-19 positive samples and Acinetobacter ursingii and Pseudomonas monteilii from COVID-19 negative samples collected from oro- and nasopharyngeal samples. We believe that the early detection and characterization of coinfections by using metaproteomics from COVID-19 patients will potentially impact the diagnosis and treatment of patients affected by SARS-CoV-2 infection.

Bacterial and fungal coinfections in COVID-19 patients hospitalized during the New York City pandemic surge.

We observed bacterial or fungal coinfections in COVID-19 patients admitted between March 1 and April 18, 2020 (152 of 4,267, 3.6%). Among these patients, mortality was 57%; 74% were intubated; 51% with bacteremia had central venous catheters. Time to culture positivity was 6-7 days, and 79% had received prior antibiotics. Metallo-ß-lactamase-producing E. cloacae coinfections occurred in 5 patients.

COVID-19 and Fatal Sepsis Caused by Hypervirulent Klebsiella pneumoniae, Japan, 2020.

A patient in Japan with coronavirus disease and hypervirulent Klebsiella pneumoniae K2 sequence type 86 infection died of respiratory failure. Bacterial and fungal co-infections caused by region-endemic pathogens, including hypervirulent K. pneumoniae in eastern Asia, should be included in the differential diagnosis of coronavirus disease patients with acutely deteriorating condition.

Bacterial and Fungal Coinfection in Individuals With Coronavirus: A Rapid Review To Support COVID-19 Antimicrobial Prescribing.

BACKGROUND: To explore and describe the current literature surrounding bacterial/fungal coinfection in patients with coronavirus infection. METHODS: MEDLINE, EMBASE, and Web of Science were searched using broad-based search criteria relating to coronavirus and bacterial coinfection. Articles presenting clinical data for patients with coronavirus infection (defined as SARS-1, MERS, SARS-CoV-2, and other coronavirus) and bacterial/fungal coinfection reported in English, Mandarin, or Italian were included. Data describing bacterial/fungal coinfections, treatments, and outcomes were extracted. Secondary analysis of studies reporting antimicrobial prescribing in SARS-CoV-2 even in absence of coinfection was performed. RESULTS: 1007 abstracts were identified. Eighteen full texts reporting bacterial/fungal coinfection were included. Most studies did not identify or report bacterial/fungal coinfection (85/140; 61%). Nine of 18 (50%) studies reported on COVID-19, 5/18 (28%) on SARS-1, 1/18 (6%) on MERS, and 3/18 (17%) on other coronaviruses. For COVID-19, 62/806 (8%) patients were reported as experiencing bacterial/fungal coinfection during hospital admission. Secondary analysis demonstrated wide use of broad-spectrum antibacterials, despite a paucity of evidence for bacterial coinfection. On secondary analysis, 1450/2010 (72%) of patients reported received antimicrobial therapy. No antimicrobial stewardship interventions were described. For non-COVID-19 cases, bacterial/fungal coinfection was reported in 89/815 (11%) of patients. Broad-spectrum antibiotic use was reported. CONCLUSIONS: Despite frequent prescription of broad-spectrum empirical antimicrobials in patients with coronavirus-associated respiratory infections, there is a paucity of data to support the association with respiratory bacterial/fungal coinfection. Generation of prospective evidence to support development of antimicrobial policy and appropriate stewardship interventions specific for the COVID-19 pandemic is urgently required.

Secondary infections in patients hospitalized with COVID-19: incidence and predictive factors.

OBJECTIVES: The aim of our study was to describe the incidence and predictive factors of secondary infections in patients with coronavirus disease 2019 (COVID-19). METHODS: This was a cohort study of patients hospitalized with COVID-19 at IRCCS San Raffaele Hospital between 25th February and 6th April 2020 (NCT04318366). We considered secondary bloodstream infections (BSIs) or possible lower respiratory tract infections (pLRTIs) occurring 48 hours after hospital admission until death or discharge. We calculated multivariable Fine-Gray models to assess factors associated with risk of secondary infections. RESULTS: Among 731 patients, a secondary infection was diagnosed in 68 patients (9.3%); 58/731 patients (7.9%) had at least one BSI and 22/731 patients (3.0%) at least one pLRTI. The overall 28-day cumulative incidence was 16.4% (95%CI 12.4-21.0%). Most of the BSIs were due to Gram-positive pathogens (76/106 isolates, 71.7%), specifically coagulase-negative staphylococci (53/76, 69.7%), while among Gram-negatives (23/106, 21.7%) Acinetobacter baumanii (7/23, 30.4%) and Escherichia coli (5/23, 21.7%) predominated. pLRTIs were caused mainly by Gram-negative pathogens (14/26, 53.8%). Eleven patients were diagnosed with putative invasive aspergillosis. At multivariable analysis, factors associated with secondary infections were low baseline lymphocyte count (≤0.7 versus >0.7 per 109/L, subdistribution hazard ratios (sdHRs) 1.93, 95%CI 1.11-3.35), baseline PaO2/FiO2 (per 100 points lower: sdHRs 1.56, 95%CI 1.21-2.04), and intensive-care unit (ICU) admission in the first 48 hours (sdHR 2.51, 95%CI 1.04-6.05). CONCLUSIONS: Patients hospitalized with COVID-19 had a high incidence of secondary infections. At multivariable analysis, early need for ICU, respiratory failure, and severe lymphopenia were identified as risk factors for secondary infections.

A Retrospective Study of Coinfection of SARS-CoV-2 and Streptococcus pneumoniae in 11 Hospitalized Patients with Severe COVID-19 Pneumonia at a Single Center.

BACKGROUND A lethal synergism between the influenza virus and Streptococcus pneumoniae has been identified. However, bacterial coinfection is considered relatively infrequent in hospitalized patients with COVID-19, and the co-prevalence of Streptococcus pneumoniae is low. MATERIAL AND METHODS We retrospectively analyzed the clinical characteristics and outcomes of patients subsequently admitted to AMITA Health Saint Francis Hospital between March 1 and June 30, 2020, with documented SARS-CoV-2 and S. pneumoniae coinfection. RESULTS We identified 11 patients with S. pneumoniae coinfection. The median age was 77 years (interquartile range [IQR], 74-82 years), 45.5% (5/11) were males, 54.5% (6/11) were white, and 90.9% (10/11) were long-term care facility (LTCF) residents. The median length of stay was 7 days (IQR, 6-8 days). Among 11 patients, 4 were discharged in stable condition and 7 had died, resulting in an inpatient mortality rate of 64%. CONCLUSIONS At our center, 11 patients with COVID-19 pneumonia who had confirmed infection with SARS-CoV-2 were diagnosed with Streptococcus pneumoniae infection while in hospital. All patients had pneumonia confirmed on imaging and a nonspecific increase in markers of inflammation. The in-hospital mortality rate of 64% (7 patients) was higher in this group than in previous reports. This study highlights the importance of monitoring bacterial coinfection in patients with viral lung infection due to SARS-CoV-2.

SARS-CoV-2-related pneumonia cases in pneumonia picture in Russia in March-May 2020: Secondary bacterial pneumonia and viral co-infections.

BACKGROUND: We are communicating the results of investigating statistics on SARS-CoV-2-related pneumonias in Russia: percentage, mortality, cases with other viral agents, cases accompanied by secondary bacterial pneumonias, age breakdown, clinical course and outcome. METHODS: We studied two sampling sets (Set 1 and Set 2). Set 1 consisted of results of testing 3382 assays of out-patients and hospital patients (5-88 years old) with community-acquired and hospital-acquired pneumonia of yet undetermined aetiology. Set 2 contained results of 1204 assays of hospital patients (12-94 years old) with pneumonia and COVID-19 already diagnosed by molecular biological techniques in test laboratories. The results were collected in twelve Russian cities/provinces in time range 2 March - 5 May 2020. Assays were analysed for 10 bacterial, 15 viral, 2 fungal and 2 parasitic aetiological agents. RESULTS: In Set 1, 4.35% of total pneumonia cases were related to SARS-CoV-2, with substantially larger proportion (18.75%) of deaths of pneumonia with COVID-19 diagnosed. However, studying Set 2, we revealed that 52.82% patients in it were also positive for different typical and atypical aetiological agents usually causing pneumonia. 433 COVID-19 patients (35.96%) were tested positive for various bacterial aetiological agents, with Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae infections accounting for the majority of secondary pneumonia cases. CONCLUSIONS: SARS-CoV-2, a low-pathogenic virus itself, becomes exceptionally dangerous if secondary bacterial pneumonia attacks a COVID-19 patient as a complication. An essential part of the severest complications and mortality associated with COVID-19 in Russia in March-May 2020, may be attributed to secondary bacterial pneumonia and to a much less extent viral co-infections. The problem of hospital-acquired bacterial infection is exceptionally urgent in treating SARS-CoV-2 patients. The risk of secondary bacterial pneumonia and its further complications, should be given very serious attention in combating SARS-CoV-2.

Severity of Respiratory Infections With Seasonal Coronavirus Is Associated With Viral and Bacterial Coinfections.

The clinical presentation of human coronavirus (HCoV) infections in children varies strongly. We show that children with an HCoV-associated lower respiratory tract infection more frequently had respiratory syncytial virus codetected and higher abundance of Haemophilus influenzae/haemolyticus than asymptomatic HCoV carriers as well as children with a non-HCoV-associated lower respiratory tract infection. Viral and bacterial cooccurrence may drive symptomatology of HCoV-associated infections including coronavirus disease 2019.