Risk of infection in patients with hidradenitis suppurativa on biologics or other immunomodulators: a systematic review and meta-analysis.

Hidradenitis suppurativa (HS) is a painful skin condition that significantly affects patients' quality of life. Biologic agents, including anti-TNF agents and IL-17 inhibitors, have shown promise as treatment options for HS. However, there is concern about the increased risk of infections associated with these therapies. We conducted a systematic review and meta-analysis following PRISMA and MOOSE guidelines. We searched PubMed and Embase until February 1, 2023. The primary outcome of interest was the incidence of any infectious complications. Secondary outcomes included serious and opportunistic infections in HS patients treated with biologics or other immunomodulators. Twenty-four studies met our inclusion criteria, comprising 1,696 patients. The pooled incidence rate for any infection was 24.2%, primarily consisting of mild respiratory and skin infections. Subgroup analysis based on the mechanism of action (MOA) showed a pooled incidence of 7.77% for anti-IL1, 14.24% for anti-PDE4, and 21.96% for anti-TNF. Notably, patients receiving anti-IL17 had the highest incidence rate of infection at 33.6%, but the relative risk compared to placebo was not significantly elevated (0.99, 95% CI: 0.86-1.14). Serious infections were rare, with pooled incidences of 0.39% for anti-IL17 and 0.03% for anti-TNF. Opportunistic infections were infrequent, with 10 reported cases, including eight oral candidiasis, one cryptosporidiosis, and one Blastocystis hominis infection. The use of biologic therapies in HS patients does not significantly increase the risk of infectious complications. Additionally, the occurrence of serious or opportunistic infections in HS patients treated with biologics appears to be minimal.

Association of the Streptococcus bovis/Streptococcus equinus Complex With Colorectal Neoplasia: A Systematic Review and Meta-analysis.

Background: Invasive infection with Streptococcus bovis/Streptococcus equinus complex (SBSEC) bacteria is associated with underlying colorectal neoplasia. However, the link between intestinal or fecal colonization with SBSEC isolates or antibody responses to SBSEC members and colorectal cancer is not thoroughly investigated in the literature. Methods: We searched the PubMed, EMBASE, and Web of Science databases for case-control studies as well as retrospective or prospective cohort studies reporting an association between SBSEC bacteria and colorectal neoplasia. Results: We identified 22 studies (15 case-control and 7 cohort) that met our inclusion criteria. Among the cohort studies, patients with SBSEC bacteremia were 3.73 times more likely to have underlying colorectal cancer compared with individuals with no bacteremia (relative risk [RR], 3.73; 95% CI, 2.79-5.01), whereas the risk of underlying colorectal adenoma in patients with SBSEC bacteremia was not significantly increased (RR, 5.00; 95% CI, 0.83-30.03). In case-control studies, patients with colorectal cancer were 2.27 times more likely to have evidence of intestinal or fecal colonization with SBSEC isolates (odds ratio [OR], 2.27; 95% CI, 1.11-4.62) and immunoglobulin G (IgG) antibody responses to SBSEC antigens (OR, 2.27; 95% CI, 1.06-4.86) compared with controls. Patients with colorectal adenoma were not more likely to be colonized with SBSEC isolates compared with controls (OR, 1.12; 95% CI, 0.55-2.25). Conclusions: Apart from the well-established association of SBSEC bacteremia and underlying colorectal cancer, intestinal or fecal colonization with SBSEC isolates and IgG antibody responses to SBSEC antigens were higher in patients with colorectal cancer compared with controls. Neither bacteremia from SBSEC isolates nor colonization with SBSEC bacteria was associated with underlying colorectal adenoma.

Incidence of serious infections in patients with ANCA-associated vasculitis receiving immunosuppressive therapy: A systematic review and meta-analysis.

Introduction: Rituximab and azathioprine are used to induce or maintain remission in patients with ANCA-associated vasculitis (AAV). We evaluated the incidence of serious infections and infection-related deaths in patients with AAV treated with rituximab and azathioprine, during the maintenance of remission period. Methods: We searched PubMed and EMBASE for randomized clinical trials (RCTs) and observational studies evaluating immunosuppressive agents in patients with AAV. We defined serious or severe infections according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The study was registered on PROSPERO (CRD42022366269). Results: From 1,265 abstracts, we identified 21 studies (7 RCTs and 14 observational), with relevant data. We included data from 1,284 and 2,938 individuals for assessment in our primary and secondary outcomes, respectively. The overall cumulative incidence of serious infections was 15.99% (CI 95%: 6.95-27.53%) during the total follow-up period (induction and maintenance) and 7.62% (CI 95%: 4.43-11.43%) during the maintenance period. Additionally, we found a 0.49% overall case fatality rate (CI 95%: 0.02-1.37%) and a 0.09% infection-related mortality rate (CI 95%: 0.00-0.51%) during maintenance treatment. Notably, we found a 14.61% (CI 95%: 10.19-19.61%) cumulative incidence of serious infections among patients who received rituximab and a 5.93% (CI 95%: 1.19-13.26%) cumulative incidence of serious infections among patients who received azathioprine during maintenance. Moreover, the cumulative incidence of serious infections during the total follow-up period (induction and maintenance) was 20.81% (CI 95%:4.56-43.70%) for the combination of cyclophosphamide and azathioprine and 14.12% (CI 95%: 5.20-26.00%) for rituximab. Discussion: The cumulative incidence of serious infections during total follow-up and maintenance was within expected limits, while fatal infections during maintenance treatment were uncommon. Additionally, treatment with rituximab for both induction and maintenance did not exceed the anticipated by previous studies incidence of serious infections. Clinical practice and long-term follow up data are needed to corroborate these findings. Systematic review registration: Identifier: PROSPERO (CRD42022366269).

Biological Evaluation of the Antibacterial Retinoid CD437 in Cutibacterium acnes Infection.

Acne vulgaris is a complex skin disease involving infection by Cutibacterium acnes, inflammation, and hyperkeratinization. We evaluated the activity of the retinoid 6-[3-(adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) and 16 other retinoid analogs as potential anti-C. acnes compounds and found that CD437 displayed the highest antimicrobial activity with an MIC against C. acnes (ATCC 6919 and HM-513) of 1 µg/mL. CD437 demonstrated an MBC of 2 µg/mL compared to up to 64 µg/mL for the retinoid adapalene and up to 16 µg/mL for tetracycline, which are commonly used clinically to treat acne. Membrane permeability assays demonstrated that exposure of C. acnes ATCC 6919 to CD437 damaged the integrity of C. acnes ATCC 6919 bacterial membranes, and this finding was confirmed with scanning electron microscopy. Additionally, CD437 downregulated the expression of C. acnes ATCC 6919 virulence factors, including the genes encoding Christie-Atkins-Munch-Petersen factor 1 (CAMP1), CAMP2, glycerol-ester hydrolase B (GehB), sialidase B, and neuraminidase. In a mouse skin infection model of C. acnes ATCC 6919, topical treatment with CD437 ameliorated skin lesions and reduced the bacterial burden in situ (P < 0.001). In human NHEK primary cells, CD437 reduced the transcriptional levels of the coding genes for inflammatory cytokines (interleukin-1α, ~10-fold; interleukin-6, ~20-fold; interleukin-8, ~30-fold; and tumor necrosis factor-alpha, ~6-fold) and downregulated the transcriptional levels of KRT10 (~10-fold), FLG (~4-fold), and TGM1 (~2-fold), indicating that CD437 can diminish inflammation and hyperkeratinization. In summary, CD437 deserves further attention for its dual function as a potential acne therapeutic that potentially acts on both the pathogen and the host.

Prevalence and Characteristics of Nonalcoholic Fatty Liver Disease and Fibrosis in People Living With HIV Monoinfection: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: Liver disease remains a leading cause of morbidity and mortality among people living with HIV (PLWH). Emerging data suggest that PLWH are at high risk for developing nonalcoholic fatty liver disease (NAFLD). The aim of this review is to examine the current literature and provide an accurate estimate of the prevalence of NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis, and identify potential risk factors for NAFLD in PLWH. METHODS: We searched PubMed and Embase databases to identify studies reporting the prevalence of NAFLD and/or fibrosis in PLWH monoinfection. We performed a random effects meta-analysis of proportions to estimate the pooled prevalence of NAFLD, NASH, and fibrosis among PLWH monoinfection. We also examined potential risk factors for NAFLD by comparing characteristics of PLWH monoinfection with and without NAFLD. RESULTS: A total of 43 studies, reporting data for 8230 patients, met our eligibility criteria and were included in the meta-analysis. Based on imaging studies the overall pooled prevalence of NAFLD and moderate liver fibrosis (METAVIR ≥ F2) among PLWH monoinfection was 33.9% (95% confidence interval [CI], 29.67%-38.39%), and 12.00% (95% CI, 10.02%-14.12%), respectively. Based on biopsy studies, prevalence of NASH and significant liver fibrosis (stage ≥F2 on histology) was 48.77% (95% CI, 34.30%-63.34%) and 23.34% (95% CI, 14.98%-32.75%), respectively. Traditional metabolic syndrome and HIV-related factors were associated with NAFLD in PLWH. CONCLUSIONS: Our study confirms that the burden of NAFLD, NASH, and fibrosis is high among PLWH monoinfection. Prospective longitudinal studies are needed to delineate NAFLD, NASH, and fibrosis risk factors, and identify early interventions and new therapies for NAFLD in this population.

Cumulative Incidence and Relative Risk of Infection in Patients With Multiple Myeloma Treated With Anti-CD38 Monoclonal Antibody-Based Regimens: A Systematic Review and Meta-analysis.

Background: Patients with multiple myeloma are at higher risk for infections due to disease pathogenesis and administered therapies. The purpose of this study was to estimate the risk for any grade and severe infections associated with the use of anti-CD38 monoclonal antibodies in patients with multiple myeloma. Methods: We searched PubMed and EMBASE for randomized controlled trials (RCTs) that included patients with multiple myeloma who received CD38-targeting monoclonal antibody regimens and reported outcomes of infection and performed a random-effects meta-analysis to estimate the relative risk for infections. Results: After screening 673 citations, we retrieved 17 studies providing data on 11 RCTs. Overall, the included reports evaluated 5316 patients (2797 in the intervention arm and 2519 in the control arm). The relative risk (RR) for both any grade or severe infections was 1.27 (95% CI, 1.17-1.37 and 1.14-1.41, respectively). The cumulative incidence of any grade infections for patients who received anti-CD38 agents was 77% (95% CI, 68%-86%), while for severe infections it was 28% (95% CI, 23%-34%). Patients treated with anti-CD38 agents had a 39% higher risk for any grade pneumonia (RR, 1.39; 95% CI, 1.12-1.72) and a 38% higher risk for severe pneumonia (RR, 1.38; 95% CI, 1.09-1.75). For upper respiratory tract infections, the relative risk was 1.51 and 1.71 for any grade and severe infections, respectively. Regarding varicella-zoster virus (VZV) reactivation, we found no evidence of increased risk (RR, 3.86; 95% CI, 0.66-22.50). Conclusions: Patients with multiple myeloma treated with regimens that included an anti-CD38 monoclonal antibody were at higher risk for any grade or severe infections without an associated higher mortality rate during the follow-up period of the retrieved studies. No evidence of increased risk for VZV reactivation was noted, but there was a significant association between CD38-targeting treatment and pneumonia risk. Increased surveillance for infections, development of effective prophylactic strategies, and studies with long follow-up are needed for patients with multiple myeloma treated with anti-CD38-based regimens.

Targeted therapies in CLL/SLL and the cumulative incidence of infection: A systematic review and meta-analysis.

Background: Patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) are prone to infections. Aims: Provide a pooled estimate of the cumulative incidence for infections that fulfilled the criteria associated with severe infectious adverse events for grade 3 or higher (including pneumonia, febrile neutropenia and sepsis) in patients who receive targeted therapies. Methods: We searched PubMed and EMBASE for randomized controlled trials (RCT) that included patients with CLL/SLL who received targeted therapies and performed a random-effects meta-analysis to estimate the cumulative incidence of infections. Results: Of 2,914 studies screened, we retrieved 31 which evaluated 11,660 patients. The pooled cumulative incidence of infections for patients who received treatment regimens based on a BTK inhibitors was 19.86%. For patients who received treatment based on rituximab and second generation anti-CD20 monoclonal antibodies, the pooled cumulative incidence of infections was 19.85 and 13.46%, respectively. Regarding PI3K inhibitor-based regimens the cumulative incidence of severe infections was 30.89%. BCL-2 inhibitors had a cumulative incidence of infections of 17.49% while lenalidomide and alemtuzumab had an incidence of 13.33 and 45.09%, respectively. The cumulative incidence of pneumonia ranged from 3.01 to 8.45% while febrile neutropenia ranged from 2.68 to 10.80%. Regarding sepsis, the cumulative incidence ranged from 0.9 to 4.48%. Conclusion: Patients with CLL/SLL who receive targeted therapies may develop severe infections at significant rates that, in addition to disease stage and other complications, depend on the mechanism of action of the used drug. Surveillance for infections and development of effective prophylactic strategies are critical for patients with CLL/SLL who receive targeted therapies. Systematic Review Registration: [https://systematicreview.gov/], identifier [registration number].

The incidence of opportunistic infections in patients with psoriatic arthritis treated with biologic and targeted synthetic agents: A systematic review and meta-analysis.

Background: Biologic (bDMARD) and targeted synthetic (tsDMARD) disease-modifying anti-rheumatic drugs have broadened the treatment options and are increasingly used for patients with psoriatic arthritis (PsA). These agents block different pro-inflammatory cytokines or specific intracellular signaling pathways that promote inflammation and can place patients at risk of serious infections. We aimed to review the incidence of opportunistic infections (OIs) in patients with PsA who were treated with these agents. Methods: We searched PubMed and EMBASE through 14 April 2022 for randomized clinical trials evaluating bDMARD or tsDMARD in the treatment of PsA. Trials were eligible if they compared the effect of a bDMARD or tsDMARD with placebo and provided safety data. We used the Revised Cochrane risk-of-bias tool to assess the risk of bias among trials, and stratified the studies by mechanism of action (MOA) of the agents studied. Results: We included 47 studies in this analysis. A total of 17,197 patients received at least one dose of an agent of interest. The cumulative incidence of OIs by MOA was as follows: 1) JAK inhibitors: 2.72% (95% CI: 1.05%-5.04%), 2) anti-IL-17: 1.18% (95% CI: 0.60%-1.9%), 3) anti-IL-23: 0.24% (95% CI: 0.04%-0.54%), and 4) anti-TNFs: 0.01% (95% CI: 0.00%-0.21%). Based on their MOA, these agents are known to increase the risk of certain serious infections. The cumulative incidence of herpes zoster infection following treatment with JAK inhibitors (JAKi) was 2.53% (95% CI: 1.03%-4.57%) and the cumulative incidence of opportunistic Candida spp. infections following treatment with anti-IL-17, was 0.97% (95% CI: 0.51%-1.56%). Conclusion: The overall incidence of OIs among patients with PsA who were treated with biologic and targeted synthetic agents is low. However, careful monitoring is warranted for specific OIs such as herpes zoster infection following JAKi treatment, mucocutaneous candidiasis following anti-IL-17 treatment, and Mycobacterium tuberculosis infection following anti-TNF treatment.

Clinical Outcomes Associated with SARS-CoV-2 Co-Infection with Rhinovirus and Adenovirus in Adults-A Retrospective Matched Cohort Study.

(1) Background: Respiratory co-infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses are common, but data on clinical outcomes and laboratory biomarkers indicative of disease severity are limited. We aimed to compare clinical outcomes and laboratory biomarkers of patients with SARS-CoV-2 alone to those of patients with SARS-CoV-2 and either rhinovirus or adenovirus. (2) Methods: Hospitalized patients co-infected with SARS-CoV-2 and rhinovirus and patients co-infected with SARS-CoV-2 and adenovirus were matched to patients infected with SARS-CoV-2 alone. Outcomes of interest were the cumulative incidences of mechanical ventilation use, intensive care unit (ICU) admission, 30-day all-cause mortality, and 30-day all-cause readmission from the day of discharge. We also assessed differences in laboratory biomarkers from the day of specimen collection. (3) Results: Patients co-infected with SARS-CoV-2 and rhinovirus, compared with patients infected with SARS-CoV-2, had significantly greater 30-day all-cause mortality (8/23 (34.8%) vs. 8/69 (11.6%), p = 0.02). Additionally, median alanine transaminase (13 IU/L vs. 24 IU/L, p = 0.03), aspartate transaminase (25 IU/L vs. 36 IU/L, p = 0.04), and C-reactive protein (34.86 mg/L vs. 94.68 mg/L, p = 0.02) on day of specimen collection were significantly lower in patients co-infected with SARS-CoV-2 and rhinovirus in comparison to patients infected with SARS-CoV-2 alone. Clinical outcomes and laboratory markers did not differ significantly between patients with SARS-CoV-2 and adenovirus co-infection and patients with SARS-CoV-2 mono-infection. (4) Conclusion: SARS-CoV-2 and rhinovirus co-infection, compared with SARS-CoV-2 mono-infection alone, is positively associated with 30-day all-cause mortality among hospitalized patients. However, our lack of significant findings in our analysis of patients with SARS-CoV-2 and adenovirus co-infection may suggest that SARS-CoV-2 co-infections have variable significance, and further study is warranted.

Identification and Functional Analysis of Cytokine-Like Protein CLEC-47 in Caenorhabditis elegans.

A variety of effector proteins contribute to host defense in Caenorhabditis elegans. However, beyond lytic enzymes and antimicrobial peptides and proteins, little is known about the exact function of these infection-related effectors. This study set out to identify pathogen-dependent cytokine-like molecules, focusing on C-type lectin domain-containing proteins (CLECs). In total, 38 CLECs that are differentially regulated in response to bacterial infections have been previously identified by microarray and transcriptome sequencing (RNA-seq) analyses in C. elegans. We successfully cloned 18 of these 38 CLECs and chose to focus on CLEC-47 because, among these 18 cloned CLECs, it was the smallest protein and was recombinantly expressed at the highest levels in prokaryotic cells examined by SDS-PAGE. Quantitative real-time PCR (qRT-PCR/qPCR) showed that the expression of clec-47 was induced by a variety of Gram-positive bacterial pathogens, including Enterococcus faecium, Staphylococcus aureus, and Cutibacterium acnes, but was suppressed by the Gram-negative bacteria Klebsiella pneumoniae and Pseudomonas aeruginosa. By expressing CLEC-47 in HEK 293 cells, we showed that CLEC-47 is released into the culture media, which the Golgi apparatus inhibitors (brefeldin A [BFA] and GolgiStop) could block. Purified recombinant CLEC-47 (maltose binding protein [MBP]-CLEC-47-His) did not display antimicrobial activity against ESKAPE pathogen isolates but bound directly to murine macrophage J774A.1 cells. Recombinant CLEC-47 attracted and recruited J774A.1 cells in a chemotaxis assay. In addition, qPCR studies and enzyme-linked immunosorbent assays (ELISAs) showed that CLEC-47 activates J774A.1 cells in a dose- and time-dependent manner to express the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), IL-6, and Macrophage Inflammatory Protein 2 (MIP-2). Moreover, C. elegans, fed with CLEC-47-expressing Escherichia coli, demonstrated enhanced expression of several antimicrobial proteins (CNC-1, CNC-2, CPR-1, and CPR-2) as well as the detoxification protein MTL-1. These data suggest that CLEC-47 functions as a novel cytokine-like signaling molecule and exemplify how the study of infection-related effectors in C. elegans can help elucidate the evolution of immune responses. IMPORTANCE A variety of effector proteins contribute to host defense in the nematode Caenorhabditis elegans. However, little is known about the exact function of these infection-related effectors beyond lytic enzymes and antimicrobial peptides and proteins. This study set out to identify pathogen-dependent cytokine-like molecules, and we focus on the C-type lectin domain-containing proteins (CLECs). Our data suggest that CLEC-47 functions as a novel cytokine-like signaling molecule and exemplify how the study of infection-related effectors in nematodes can help elucidate the evolution of immune responses.

Biocidal and biocompatible hybrid nanomaterials from biomolecule chitosan, alginate and ZnO.

Biocidal activity and biocompatibility of nanomaterials (NMs) are crucial for healthcare applications. This study aims to develop biocidal hybrid NMs with high inhibition rates to control multidrug-resistant bacterial infection compared to conventional antibiotics. Herein, ZnO, chitosan-ZnO (CZnO) and alginate-ZnO (AZnO) NMs were synthesized via a simple one-pot technique. The one-pot process facilitates the efficiency of a chemical reaction whereby a reactant is subjected to successive chemical reactions in just one step. The resulted NMs bio-physicochemical features were analyzed using various analytical methods. The bactericidal and bacteriostatic mechanism of NMs strongly depends on the production of reactive oxygen species in NMs, due to their size, large surface areas, oxygen vacancies, ion release, and diffusion ability. The antibacterial potential of the NMs was tested against methicillin-resistant Staphylococcus aureus. The inhibition zone disclosed that the AZnO possessed an excellent antibacterial activity compared to ZnO and CZnO. Furthermore, toxicity studies revealed that the AZnO demonstrated low toxicity to the HepG2 cell lines. These results confirmed that the AZnO hybrid nanomaterials are promising futuristic biocidal agents suitable for the clinical and healthcare industries.

Antifungal Activity of the Phenolic Compounds Ellagic Acid (EA) and Caffeic Acid Phenethyl Ester (CAPE) against Drug-Resistant Candida auris.

Candida auris is an emerging healthcare-associated fungal pathogen that has become a serious global health threat. Current treatment options are limited due to drug resistance. New therapeutic strategies are required to target this organism and its pathogenicity. Plant polyphenols are structurally diverse compounds that present a vast range of biological properties. In the present study, plant-derived molecules ellagic acid (EA) and caffeic acid phenethyl ester (CAPE) were investigated for their antifungal and antivirulence activities against Candida auris. We also tested against C. albicans. The minimum inhibitory concentration (MIC) for EA ranged from 0.125 to 0.25 µg/mL and for CAPE ranged from 1 to 64 µg/mL against drug-resistant C. auris strains. Killing kinetics determined that after 4 h treatment with CAPE, there was a complete reduction of viable C. auris cells compared to fluconazole. Both compounds might act by modifying the fungal cell wall. CAPE significantly reduced the biomass and the metabolic activity of C. auris biofilm and impaired C. auris adhesion to cultured human epithelial cells. Furthermore, both compounds prolonged the survival rate of Galleria mellonella infected by C. auris (p = 0.0088 for EA at 32 mg/kg and p = 0.0028 for CAPE at 4 mg/kg). In addition, EA at 4 µg/mL prolonged the survival of C. albicans-infected Caenorhabditis elegans (p < 0.0001). CAPE was not able to prolong the survival of C. albicans-infected C. elegans. These findings highlight the antifungal and antivirulence effects of EA and CAPE against C. auris, and warrant further investigation as novel antifungal agents against drug-resistant infections.

The Anti-Biofilm Efficacy of Caffeic Acid Phenethyl Ester (CAPE) In Vitro and a Murine Model of Oral Candidiasis.

Candida albicans is the main fungal species associated with the development of oral candidiasis. Currently, therapeutic options for these infections are limited by the adverse effects of antifungal drugs and by the emergence of drug resistant strains. Thus, the development of new antifungal agents is needed for the prevention and treatment of oral Candida infections. Caffeic acid phenethyl ester (CAPE) is a natural compound from propolis polyphenolic groups that exhibits many pharmacological properties. In this study, we investigated whether CAPE can have antifungal and immunomodulatory effects on oral candidiasis. Preliminary tests to assess the antifungal activity of CAPE were performed using the Minimum Inhibitory Concentration (MIC) assay that demonstrated inhibition in a range from 16 to 32 µg/mL, confirming its antifungal activity on several C. albicans strains isolated from the oral cavity. Subsequently, we analyzed Candida spp biofilms formed in vitro, in which CAPE treatment at 5 x MIC caused a reduction of 68.5% in the total biomass and ~2.60 Log in the viable cell count (CFU/mL) in relation to the untreated biofilm (p<0.0001). Next, RNA was extracted from untreated and CAPE-treated biofilms and analyzed by real-time qPCR. A series of genes analyzed (ALS1, ECE1, EPA1, HWP1, YWP1, BCR1, BGR1, CPH1, EFG1, NDT80, ROB1, TEC1, UME6, SAP2, SAP5, PBL2, and LIP9) were downregulated by CAPE compared to the untreated control group (p<0.0001). In in vivo studies using Galleria mellonella, the treatment with CAPE prolonged survival of larvae infected by C. albicans by 44.5% (p < 0.05) and accompanied by a 2.07-fold increase in the number of hemocytes. Flow cytometry revealed the most prominent increases were in types P2 and P3 hemocytes, granular cells, which phagocytize pathogens. In addition, CAPE treatment decreased the fungal load in the hemolymph and stimulated the expression of antifungal peptide genes such as galiomicin and gallerimycin. The antifungal and immunomodulatory activities observed in G. mellonella were extended to a murine model of oral candidiasis, in which CAPE decreased the levels of C. albicans colonization (~2 log CFU/mL) in relation to the untreated control group. In addition, CAPE treatment significantly reduced pseudomembranous lesions, invasion of hyphae on epithelium surfaces, tissue damage and inflammatory infiltrate (p < 0.05). CAPE was also able to increase the expression of ß-defensin 3 compared to the infected and untreated group by 3.91-fold (p < 0.0001). Taken together, these results show that CAPE has both antifungal and immunomodulatory effects, making it a promising natural antifungal agent for the treatment and prevention of candidiasis and shows impact to oral candidiasis.

BMI and pneumonia outcomes in critically ill covid-19 patients: An international multicenter study.

OBJECTIVE: Previous studies have unveiled a relationship between the severity of coronavirus disease 2019 (COVID-19) pneumonia and obesity. The aims of this multicenter retrospective cohort study were to disentangle the association of BMI and associated metabolic risk factors (diabetes, hypertension, hyperlipidemia, and current smoking status) in critically ill patients with COVID-19. METHODS: Patients admitted to intensive care units for COVID-19 in 21 centers (in Europe, Israel, and the United States) were enrolled in this study between February 19, 2020, and May 19, 2020. Primary and secondary outcomes were the need for invasive mechanical ventilation (IMV) and 28-day mortality, respectively. RESULTS: A total of 1,461 patients were enrolled; the median (interquartile range) age was 64 years (40.9-72.0); 73.2% of patients were male; the median BMI was 28.1 kg/m2 (25.4-32.3); a total of 1,080 patients (73.9%) required IMV; and the 28-day mortality estimate was 36.1% (95% CI: 33.0-39.5). An adjusted mixed logistic regression model showed a significant linear relationship between BMI and IMV: odds ratio = 1.27 (95% CI: 1.12-1.45) per 5 kg/m2 . An adjusted Cox proportional hazards regression model showed a significant association between BMI and mortality, which was increased only in obesity class III (≥40; hazard ratio = 1.68 [95% CI: 1.06-2.64]). CONCLUSIONS: In critically ill COVID-19 patients, a linear association between BMI and the need for IMV, independent of other metabolic risk factors, and a nonlinear association between BMI and mortality risk were observed.

Impact of Influenza Infection Among Adult and Pediatric Populations With Hematologic Malignancy and Hematopoietic Stem Cell Transplant: A Systematic Review and Meta-Analysis.

PURPOSE: Influenza is increasingly recognized as a leading cause of morbidity and mortality in patients with hematologic malignancies and recipients of hematopoietic stem cell transplantation (HSCT). However, the impact of influenza on this population has not been previously evaluated in a systematic review. This study systematically reviewed and summarized the outcomes of influenza infection as to in-hospital influenza-related mortality, development of lower respiratory tract infection and acute respiratory distress syndrome, need for hospitalization, intensive care unit admission, and mechanical ventilation. METHODS: We conducted a systematic search of literature using the PubMed and EMBASE databases for articles published from January 1989 through January 19, 2020, reporting laboratory-confirmed influenza in patients of any age with hematologic malignancies and HSCT. Time from transplantation was not included in the search criteria. The impact of antiviral therapy on influenza outcomes was not assessed due to heterogeneity in antiviral treatment provision across the studies. Patients with influenza-like illness, solid-tumor cancers, or nonmalignant hematologic diseases were excluded from the study. A random-effects meta-analysis was performed to estimate the prevalences and 95% CIs of each outcome of interest. A subgroup analysis was carried out to assess possible sources of heterogeneity and to evaluate the potential impact of age on the influenza infection outcomes. Heterogeneity was assessed using the I2 statistic. FINDINGS: Data from 52 studies providing data on 1787 patients were included in this analysis. During seasonal epidemics, influenza-related in-hospital mortality was 16.60% (95% CI, 7.49%-27.7%), with a significantly higher death rate in adults compared to pediatric patients (19.55% [95% CI, 10.59%-29.97%] vs 0.96% [95% CI, 0%-6.77%]; P < 0.001). Complications from influenza, such as lower respiratory tract infection, developed in 35.44% of patients with hematologic malignancies and HSCT recipients, with a statistically significant difference between adults and children (46.14% vs 19.92%; P < 0.001). However, infection resulted in a higher hospital admission rate in pediatric patients compared to adults (61.62% vs 22.48%; P < 0.001). For the 2009 H1N1 pandemic, no statistically significant differences were found between adult and pediatric patients when comparing the rates of influenza-related in-hospital mortality, lower respiratory tract infection, and hospital admission. Similarly, no significant differences were noted in any of the outcomes of interest when comparing H1N1 pandemic with seasonal epidemics. IMPLICATIONS: Regardless of influenza season, patients, and especially adults, with underlying hematologic malignancies and HSCT recipients with influenza are at risk for severe outcomes including lower respiratory tract infection and in-hospital mortality.

Mortality in mechanically ventilated patients with COVID-19: a systematic review.

Introduction: The use of mechanical ventilation associated with acute hypoxemic respiratory failure, the most common complication in critically ill COVID-19 patients, defines a high risk population that requires specific consideration of outcomes and treatment practices.Areas covered: This review evaluates existing information about mortality rates and effectiveness of antiviral, immune-modulating, and anticoagulation treatments in COVID-19 patients who received mechanical ventilation. The mortality rate and follow-up periods in patients receiving mechanical ventilation ranged widely. Antivirals, including remdesivir and convalescent plasma, have shown no definitive mortality benefit in this population despite positive results in other COVID-19 patients. Dexamethasone was associated with an absolute reduction in 28-day mortality by 12.3% (95% CI, 6.3 to 17.6), after adjusting for age. Reduced mortality has been demonstrated with tocilizumab use alongside corticosteroids. Evidence is inconclusive for therapeutic anticoagulation, and further studies are needed to determine the comparative benefit of prophylactic anticoagulation.Expert opinion: Significant variation and high mortality rates in mechanically ventilated patients necessitate more standardized outcome measurements, increased consideration of risk factors to reduce intubation, and improved treatment practices. Anticoagulation and dexamethasone should be incorporated in the treatment of patients receiving invasive mechanical ventilation, while more rigorous studies are required for other potential treatments.

In inpatients with COVID-19, none of remdesivir, hydroxychloroquine, lopinavir, or interferon ß-1a differed from standard care for in-hospital mortality.

SOURCE CITATION: Pan H, Peto R, Henao-Restrepo AM, et al. Repurposed antiviral drugs for Covid-19-interim WHO Solidarity Trial results. N Engl J Med. 2020. [Epub ahead of print.] 33264556.

Readmissions among patients with COVID-19.

BACKGROUND: Hospital readmissions are associated with poor patient outcomes and increased health resource utilisation. The need to study readmission patterns is even bigger during a pandemic because the burden is further stretching the healthcare system. METHODS: We reviewed the initial hospitalisation and subsequent readmission for 19 patients with confirmed COVID-19 in the largest statewide hospital network in Rhode Island, US, from March 1st through April 19th, 2020. We also compared the characteristics and clinical outcomes between readmitted and non-readmitted patients. RESULTS: Of the 339 hospitalised patients with COVID-19, 279 discharged alive. Among them, 19/279 were readmitted (6.8%) after a median of 5 days. There was a significantly higher rate of hypertension, diabetes, chronic pulmonary disease, liver disease, cancer and substance abuse among the readmitted compared with non-readmitted patients. The most common reasons of readmissions happening within 12 days from discharge included respiratory distress and thrombotic episodes, while those happening at a later time included psychiatric illness exacerbations and falls. The length of stay during readmission was longer than during index admission and more demanding on healthcare resources. CONCLUSION: Among hospitalised patients with COVID-19, those readmitted had a higher burden of comorbidities than the non-readmitted. Within the first 12 days from discharge, readmission reasons were more likely to be associated with COVID-19, while those happening later were related to other reasons. Readmissions characterisation may help in defining optimal timing for patient discharge and ensuring safe care transition.

Medicare Part D Spending on Drugs Prescribed by Oncologists: Temporal Trends and Regional Variation.

PURPOSE: Drug cost is a significant factor in the ever-increasing expenditures for cancer health care. METHODS: We used Medicare Part D administrative data to explore prescribing patterns and attributed drug costs of oncologists from 2013 to 2017. We highlighted regional variation in spending and potential associations. We used the location quotient (LQ) to measure the relative concentration of oncologists compared with the national average by hospital referral regions. Costs were reported in 2017 US dollars (inflation adjusted) for cross-year comparisons. RESULTS: Oncology's share in Part D spending showed an uninterrupted increasing trend. In 2017, oncologists prescribed medicines with $12.8 billion in Part D costs (8.3% of all Part D payments), which exceeded 2013 costs by $7.3 billion, when their claim payments were $5.5 billion (5.0% of all Part D payments). Oncology contributed a higher annual growth in Part D drug costs compared with all other providers (15.1% and 3.1%, respectively, for 2017). The top 3 drugs increased cost by approximately $3.5 billion from 2013 to 2017. Across hospital referral regions, the oncologists' Part D share varied (median in 2017, 7.7%; interquartile range, 6.2%-9.3%) and was higher across regions where oncologists had an LQ significantly > 1 (mostly in areas with centers that excel in cancer care) and lower for an LQ significantly < 1 (median, 9.7% v 6.2%, respectively; P < .001). CONCLUSION: Oncology increased its share in Part D drug spending, disproportionately to all other providers, with regional differences partially moderated by the oncology workforce and quality of cancer care.

The cost-effectiveness of empirical antibiotic treatments for high-risk febrile neutropenic patients: A decision analytic model.

PURPOSE: Febrile neutropenia has a significant clinical and economic impact on cancer patients. This study evaluates the cost-effectiveness of different current empiric antibiotic treatments. METHODS: A decision analytic model was constructed to compare the use of cefepime, meropenem, imipenem/cilastatin, and piperacillin/tazobactam for treatment of high-risk patients. The analysis was performed from the perspective of U.S.-based hospitals. The time horizon was defined to be a single febrile neutropenia episode. Cost-effectiveness was determined by calculating costs and deaths averted. Cost-effectiveness acceptability curves for various willingness-to-pay thresholds (WTP), were used to address the uncertainty in cost-effectiveness. RESULTS: The base-case analysis results showed that treatments were equally effective but differed mainly in their cost. In increasing order: treatment with imipenem/cilastatin cost $52,647, cefepime $57,270, piperacillin/tazobactam $57,277, and meropenem $63,778. In the probabilistic analysis, mean costs were $52,554 (CI: $52,242-$52,866) for imipenem/cilastatin, $57,272 (CI: $56,951-$57,593) for cefepime, $57,294 (CI: $56,978-$57,611) for piperacillin/tazobactam, and $63,690 (CI: $63,370-$64,009) for meropenem. Furthermore, with a WTP set at $0 to $50,000, imipenem/cilastatin was cost-effective in 66.2% to 66.3% of simulations compared to all other high-risk options. DISCUSSION: Imipenem/cilastatin is a cost-effective strategy and results in considerable health care cost-savings at various WTP thresholds. Cost-effectiveness analyses can be used to differentiate the treatments of febrile neutropenia in high-risk patients.