Background
Fungal co-infection is a recognised complication of respiratory virus infections, increasing morbidity and mortality, but can be readily treated if diagnosed early. An increasing number of small studies describing aspergillosis in COVID-19 patients with severe respiratory distress are being reported, but comprehensive data is lacking. The aim of this study was to determine the incidence, risk factors and impact of invasive fungal disease in adult COVID-19 patients with severe respiratory distress.
Methods
An evaluation of a national, multi-centre, prospective cohort evaluation of an enhanced testing strategy to diagnose invasive fungal disease in COVID-19 intensive care patients. Results were used to generate a mechanism to define aspergillosis in future COVID-19 patients.
Results
One-hundred and thirty-five adults (median age: 57, M/F: 2·2/1) were screened. The incidence was 26.7% (14.1% aspergillosis, 12·6% yeast infections). The overall mortality rate was 38%; 53% and 31% in patients with and without fungal disease, respectively (P: 0.0387). The mortality rate was reduced by the use of antifungal therapy (Mortality: 38·5% in patients receiving therapy versus 90% in patients not receiving therapy (P: 0.008). The use of corticosteroids (P: 0.007) and history of chronic respiratory disease (P: 0.05) increased the likelihood of aspergillosis.
Conclusions
Fungal disease occurs frequently in critically ill, mechanically ventilated COVID-19 patients. The survival benefit observed in patients receiving antifungal therapy implies that the proposed diagnostic and defining criteria are appropriate. Screening using a strategic diagnostic approach and antifungal prophylaxis of patients with risk factors will likely enhance the management of COVID-19 patients.
The rates of Pneumocystis pneumonia (PcP) are increasing in the HIV-negative susceptible population. Guidance for the prophylaxis and treatment of PcP in HIV, haematology, and solid-organ transplant (SOT) recipients is available, although for many other populations (e.g., auto-immune disorders) there remains an urgent need for recommendations. The main drug for both prophylaxis and treatment of PcP is trimethoprim/sulfamethoxazole, but resistance to this therapy is emerging, placing further emphasis on the need to make a mycological diagnosis using molecular based methods. Outbreaks in SOT recipients, particularly renal transplants, are increasingly described, and likely caused by human-to-human spread, highlighting the need for efficient infection control policies and sensitive diagnostic assays. Widespread prophylaxis is the best measure to gain control of outbreak situations. This review will summarize diagnostic options, cover prophylactic and therapeutic management in the main at risk populations, while also covering aspects of managing resistant disease, outbreak situations, and paediatric PcP.
Management of invasive aspergillosis has been improved by biomarker assays, but limited accessibility and batch testing limit the impact. Lateral flow assays (LFA) are a simple method for use outside specialist centers, provided performance is acceptable. The objective of this study was to determine the performance of the recently released IMMY sona Aspergillus LFA when testing serum samples. The study took the form of a retrospective, anonymous case/control study comprising 179 serum samples from 136 patients with invasive fungal disease, previously documented using recently revised internationally accepted definitions. The LFA was performed following the manufacturer’s instructions using a cube reader to generate a galactomannan index (GMI). Performance parameters were determined, and receiver operator characteristic (ROC) analysis was used to identify an optimal threshold. Concordance with the Bio-Rad Aspergillus Ag assay (GM-EIA) was performed. At the recommended positivity threshold (GMI ≥ 0.5), LFA sensitivity and specificity were 96.9% (31/32) and 98% (98/100), respectively. ROC analysis confirmed the optimal threshold and generated an area under the curve of 0.9919. Qualitative agreement between LFA and GM-EIA was 89.0%, generating a Kappa statistic of 0.698, representing good agreement, with most discordance arising due to false-negative GM-EIA samples that were positive by LFA. The median GMI generated by the LFA was significantly greater than that generated by the GM-EIA. The IMMY sona Aspergillus LFA, when used with a cube reader, provides a rapid alternative to the well-established GM-EIA, potentially detecting more GM epitopes and enhancing sensitivity.
Aspergillus fumigatus
is a ubiquitous mold that can cause severe infections in immunocompromised patients, typically manifesting as invasive pulmonary aspergillosis (IPA). Adaptive and innate immune cells that respond to
A. fumigatus
are present in the endogenous repertoire of patients with IPA but are infrequent and cannot be consistently isolated and expanded for adoptive immunotherapy. Therefore, we gene-engineered
A. fumigatus
–specific chimeric antigen receptor (Af-CAR) T cells and demonstrate their ability to confer antifungal reactivity in preclinical models in vitro and in vivo. We generated a CAR targeting domain AB90-E8 that recognizes a conserved protein antigen in the cell wall of
A. fumigatus
hyphae. T cells expressing the Af-CAR recognized
A. fumigatus
strains and clinical isolates and exerted a direct antifungal effect against
A. fumigatus
hyphae. In particular, CD8
+
Af-CAR T cells released perforin and granzyme B and damaged
A. fumigatus
hyphae. CD8
+
and CD4
+
Af-CAR T cells produced cytokines that activated macrophages to potentiate the antifungal effect. In an in vivo model of IPA in immunodeficient mice, CD8
+
Af-CAR T cells localized to the site of infection, engaged innate immune cells, and reduced fungal burden in the lung. Adoptive transfer of CD8
+
Af-CAR T cells conferred greater antifungal efficacy compared to CD4
+
Af-CAR T cells and an improvement in overall survival. Together, our study illustrates the potential of gene-engineered T cells to treat aggressive infectious diseases that are difficult to control with conventional antimicrobial therapy and support the clinical development of Af-CAR T cell therapy to treat IPA.
Infection in people with multiple sclerosis (MS) is of major concern, particularly for those receiving disease-modifying therapies. This article explores the risk of infection in people with MS and provides guidance—developed by Delphi consensus by specialists involved in their management—on how to screen for, prevent and manage infection in this population.
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