Fungal Lung Disease.

Fungal lung disease encompasses a wide spectrum of organisms and associated clinical conditions presenting a significant global health challenge with type and severity determined by underlying host immunity and infecting fungal strain. The most common group of diseases are associated with the filamentous fungus Aspergillus spp. and include allergic bronchopulmonary aspergillosis (ABPA), sensitization, aspergilloma, and chronic and invasive pulmonary aspergillosis. Fungal lung disease remains epidemiologically heterogenous and is influenced by geography, environment, and host comorbidities. Diagnostic modalities continue to evolve and now include novel molecular assays and biomarkers, however, persisting challenges include achieving rapid and accurate diagnosis, particularly in resource-limited settings and in differentiating fungal infection from other pulmonary conditions. Treatment strategies for fungal lung diseases rely mainly on antifungal agents, however, the emergence of drug-resistant strains poses a substantial global threat and adds complexity to existing therapeutic challenges. Emerging antifungal agents and increasing insight into lung mycobiome via may offer fresh and personalized approaches to diagnosis and treatment, while innovative methodologies are required to mitigate drug resistance and adverse effects of treatment. This state-of-the-art review describes the current landscape of fungal lung disease, highlighting key clinical insights, current challenges, and emerging approaches for its diagnosis and treatment.

Outcomes in patients receiving continuous monitoring of vital signs on general wards: A systematic review and meta-analysis of randomised controlled trials.

Objective: The timely identification of deterioration on general wards is crucial to patient care with each hour of delay independently associated with increased risk of death. The introduction of continuous monitoring of patient vital signs on general wards, currently not standard care, may improve patient outcomes. Our aim was to investigate whether patients on general wards receiving continuous vital signs monitoring have better outcomes than patients receiving usual care. Methods: Meta-analysis of randomised controlled trials comparing non-critical care patients receiving continuous monitoring of vital signs to usual care. We searched Medline, Embase, and Web of Science, and assessed risk of bias with version 2 of the Cochrane risk-of-bias tool for randomised trials. In addition to measures related to the early detection of deterioration, we planned to present all patient outcomes reported by the clinical trials included. Results: We included seven trials involving 1284 participants. There were no statistically significant differences in the four outcomes pooled. Comparing continuously monitored to normal care, the pooled odds for hospital mortality, major event/complication, and HDU/ICU admission was 0.95 (95% CI 0.59-1.53, p = 0.84; 660 participants, 3 studies), 0.71 (95% CI 0.38-1.31, p = 0.27; 948 participants, 4 studies) and 0.82 (95% CI 0.25-2.67, p = 0.74; 655 participants, 4 studies), respectively. The mean difference for length of stay was 2.12 days lower (95% CI -5.56 to 1.32, p = 0.23; 1034 participants, 6 studies). Conclusion: We found no significant improvements in outcomes for patients continuously monitored compared to usual care. Further research is needed to understand what modalities of continuous monitoring may influence outcomes and investigate the implications of a telepresence service and multi-parameter scoring system. Registration: PROSPERO CRD42023458656.

Health in a Virtual Environment (HIVE): A Novel Continuous Remote Monitoring Service for Inpatient Management.

The aim of this study was to describe the implementation of a novel 50-bed continuous remote monitoring service for high-risk acute inpatients treated in non-critical wards, known as Health in a Virtual Environment (HIVE). We report the initial results, presenting the number and type of patients connected to the service, and assess key outcomes from this cohort. This was a prospective, observational study of characteristics and outcomes of patients connected to the HIVE continuous monitoring service at a major tertiary hospital and a smaller public hospital in Western Australia between January 2021 and June 2023. In the first two and a half years following implementation, 7541 patients were connected to HIVE for a total of 331,118 h. Overall, these patients had a median length of stay of 5 days (IQR 2, 10), 11.0% (n = 833) had an intensive care unit admission, 22.4% (n = 1691) had an all-cause emergency readmission within 28 days from hospital discharge, and 2.2% (n = 167) died in hospital. Conclusions: Our initial results show promise, demonstrating that this innovative approach to inpatient care can be successfully implemented to monitor high-risk patients in medical and surgical wards. Future studies will investigate the effectiveness of the program by comparing patients receiving HIVE supported care to comparable patients receiving routine care.

A phase I clinical trial assessing the safety, tolerability, and pharmacokinetics of inhaled ethanol in humans as a potential treatment for respiratory tract infections.

Background: Current treatments for respiratory infections are severely limited. Ethanol's unique properties including antimicrobial, immunomodulatory, and surfactant-like activity make it a promising candidate treatment for respiratory infections if it can be delivered safely to the airway by inhalation. Here, we explore the safety, tolerability, and pharmacokinetics of inhaled ethanol in a phase I clinical trial. Methods: The study was conducted as a single-centre, open-label clinical trial in 18 healthy adult volunteers, six with no significant medical comorbidities, four with stable asthma, four with stable cystic fibrosis, and four active smokers. A dose-escalating design was used, with participants receiving three dosing cycles of 40, 60%, and then 80% ethanol v/v in water, 2 h apart, in a single visit. Ethanol was nebulised using a standard jet nebuliser, delivered through a novel closed-circuit reservoir system, and inhaled nasally for 10 min, then orally for 30 min. Safety assessments included adverse events and vital sign monitoring, blood alcohol concentrations, clinical examination, spirometry, electrocardiogram, and blood tests. Results: No serious adverse events were recorded. The maximum blood alcohol concentration observed was 0.011% immediately following 80% ethanol dosing. Breath alcohol concentrations were high (median 0.26%) following dosing suggesting high tissue levels were achieved. Small transient increases in heart rate, blood pressure, and blood neutrophil levels were observed, with these normalising after dosing, with no other significant safety concerns. Of 18 participants, 15 completed all dosing cycles with three not completing all cycles due to tolerability. The closed-circuit reservoir system significantly reduced fugitive aerosol loss during dosing. Conclusion: These data support the safety of inhaled ethanol at concentrations up to 80%, supporting its further investigation as a treatment for respiratory infections.Clinical trial registration: identifier ACTRN12621000067875.

OPTIMA: An Open-Label, Noncomparative Pilot Trial of Inhaled Molgramostim in Pulmonary Nontuberculous Mycobacterial Infection.

Rationale: Inhaled granulocyte-macrophage colony-stimulating factor (GM-CSF) has been proposed as a potential immunomodulatory treatment for nontuberculous mycobacterial (NTM) infection.Objectives: This open-label, noncomparative pilot trial investigated the efficacy and safety of inhaled GM-CSF (molgramostim nebulizer solution) in patients with predominantly treatment-refractory pulmonary NTM infection (Mycobacterium avium complex [MAC] and M. abscessus [MABS]), either in combination with ongoing guideline-based therapy (GBT) or as monotherapy in patients who had stopped GBT because of lack of efficacy or intolerability.Methods: Thirty-two adult patients with refractory NTM infection (MAC, n = 24; MABS, n = 8) were recruited into two cohorts: those with (n = 16) and without (n = 16) ongoing GBT. Nebulized molgramostim 300 µg/d was administered over 48 weeks. Sputum cultures and smears and clinical assessments (6-min-walk distance, symptom scores, Quality of Life-Bronchiectasis Questionnaire score, and body weight) were collected every 4 weeks during treatment and 12 weeks after the end of treatment. The primary endpoint was sputum culture conversion, defined as three consecutive monthly negative cultures during the treatment period.Results: Eight patients (25%) achieved culture conversion on treatment (seven [29.2%] patients with MAC infection, one [12.5%] patient with MABS infection); in four patients, this was durable after the end of treatment. Of the 24 patients with MAC infection, an additional 4 patients had a partial response, converting from smear positive at baseline to smear negative at the end of treatment, and time to positivity in liquid culture media increased. Two of these patients sustained negative cultures from the end of treatment. Other clinical endpoints were unchanged. Serious adverse events were mainly pulmonary exacerbations or worsening NTM infection. Three deaths, not treatment related, were reported.Conclusions: In this population of patients with severe NTM disease, molgramostim was safe and well tolerated. Sputum culture conversion rates for patients with MAC infection (29.2%) were greater than reported for similar refractory MAC cohorts managed with GBT alone. Less benefit was seen for MABS infection. No serious safety concerns were identified. Further evaluation in a larger cohort is warranted.Clinical trial registered with www.clinicaltrials.gov (NCT03421743).

Clinical trials of pneumonia management assess heterogeneous outcomes and measurement instruments.

OBJECTIVES: To inform clinical practice guidelines, randomized controlled trials (RCTs) of the management of pneumonia need to address the outcomes that are most important to patients and health professionals using consistent instruments, to enable results to be compared, contrasted, and combined as appropriate. This systematic review describes the outcomes reported in clinical trials of pneumonia management and the instruments used to measure these outcomes. STUDY DESIGN AND SETTING: Based on a prospective protocol, we searched MEDLINE/PubMed, Cochrane CENTRAL and clinical trial registries for ongoing or completed clinical trials evaluating pneumonia management in adults in any clinical setting. We grouped reported outcomes thematically and classified them following the COMET Initiative's taxonomy. We describe instruments used for assessing each outcome. RESULTS: We found 280 eligible RCTs of which 115 (41.1%) enrolled critically ill patients and 165 (58.9%) predominantly noncritically ill patients. We identified 43 distinct outcomes and 108 measurement instruments, excluding nonvalidated scores and questionnaires. Almost all trials reported clinical/physiological outcomes (97.5%). Safety (63.2%), mortality (56.4%), resource use (48.6%) and life impact (11.8%) outcomes were less frequently addressed. The most frequently reported outcomes were treatment success (60.7%), mortality (56.4%) and adverse events (41.1%). There was significant variation in the selection of measurement instruments, with approximately two-thirds used in less than 10 of the 280 RCTs. None of the patient-reported outcomes were used in 10 or more RCTs. CONCLUSION: This review reveals significant variation in outcomes and measurement instruments reported in clinical trials of pneumonia management. Outcomes that are important to patients and health professionals are often omitted. Our findings support the need for a rigorous core outcome set, such as that being developed by the European Respiratory Society.

Severe community-acquired pneumonia in the post COVID-19 era.

PURPOSE OF REVIEW: The aim was to examine and summarize the most recent published literature in the last years stating the advances for treatment options and adjunctive therapies in patients hospitalized with severe community-acquired pneumonia (sCAP). Search was performed in PubMed, including observational studies, randomized controlled trials, systematic reviews and meta-analyses, and international guidelines. RECENT FINDINGS: Regardless of a large number of published CAP guidelines, most of their recommendations are based on low-level evidence.Viruses have an increasing role as sCAP etiology with an impact on mortality. Accordingly, it is imperative to strengthen the demand for vaccines and newer antivirals. Considering an early monitoring of the immune response in patients with severe Influenza, may help to evaluate a personalized immunomodulatory strategy. Despite growing evidence, the use of corticosteroids as an adjunctive therapy in bacterial sCAP continues to be controversial. SUMMARY: Mortality due to sCAP still remains undesirably high. This fact strengthens the need for more high-quality research to increase evidence. It also highlights the need for clinicians to be aware of the level of evidence of the stated recommendations, taking this into consideration before decision making.

Impact of air pollution on respiratory microbiome: A narrative review.

BACKGROUND: Respiratory microbiome composition depends on an intricate balance between host characteristics, diet, and environmental factors. Some studies indicate a bidirectional relationship between respiratory microbiota and disease. Air pollution is consistently associated with increased respiratory morbidity and mortality in different populations and across different ages. The aim of this review was to report a summary of the evidence regarding the impact of air pollution on the upper and lower respiratory tract microbiome. METHODS: A literature search from interaction between air pollution and respiratory microbiome was performed (2010-2022). RESULTS: Sixteen studies demonstrated changes in microbiome with both environmental and household air pollution. Increasing levels of air pollutants are associated with lower relative abundance of Corynebacterium and increasing levels of pathogen colonization, such as Haemophilus influenzae, Moraxella catarrhalis, Streptococcus pneumoniae and Pseudomonas aeruginosa and Acinetobacter baumannii, altering the incidence and clinical course of respiratory infections. This ultimately leads to an excess of morbidity and mortality due to antimicrobial resistance. CONCLUSION: Changes of air pollution on the respiratory microbiome may influence respiratory infections in critical care. Use of probiotics may restore the diversity of baseline microbiome, preventing infections by resistant organisms in the critical care setting. Using protective equipment decreased the effect of air pollutants on increasing potentially pathogenic microorganisms.

Expert Review on Nonsurgical Management of Parapneumonic Effusion: Advances, Controversies, and New Directions.

Parapneumonic effusion and empyema are rising in incidence worldwide, particularly in association with comorbidities in an aging population. Also driving this change is the widespread uptake of pneumococcal vaccines, leading to the emergence of nonvaccine-type pneumococci and other bacteria. Early treatment with systemic antibiotics is essential but should be guided by local microbial guidelines and antimicrobial resistance patterns due to significant geographical variation. Thoracic ultrasound has emerged as a leading imaging technique in parapneumonic effusion, enabling physicians to characterize effusions, assess the underlying parenchyma, and safely guide pleural procedures. Drainage decisions remain based on longstanding criteria including the size of the effusion and fluid gram stain and biochemistry results. Small-bore chest drains appear to be as effective as large bore and are adequate for the delivery of intrapleural enzyme therapy (IET), which is now supported by a large body of evidence. The IET dosing regimen used in the UK Multicenter Sepsis Trial -2 has the most evidence available but data surrounding alternative dosing, concurrent and once-daily instillations, and novel fibrinolytic agents are promising. Prognostic scores used in pneumonia (e.g., CURB-65) tend to underestimate mortality in parapneumonic effusion/empyema. Scores specifically based on pleural infection have been developed but require validation in prospective cohorts.

Impact of macrolide treatment on long-term mortality in patients admitted to the ICU due to CAP: a targeted maximum likelihood estimation and survival analysis.

INTRODUCTION: Patients with community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU) have high mortality rates during the acute infection and up to ten years thereafter. Recommendations from international CAP guidelines include macrolide-based treatment. However, there is no data on the long-term outcomes of this recommendation. Therefore, we aimed to determine the impact of macrolide-based therapy on long-term mortality in this population. METHODS: Registered patients in the MIMIC-IV database 16 years or older and admitted to the ICU due to CAP were included. Multivariate analysis, targeted maximum likelihood estimation (TMLE) to simulate a randomised controlled trial, and survival analyses were conducted to test the effect of macrolide-based treatment on mortality six-month (6 m) and twelve-month (12 m) after hospital admission. A sensitivity analysis was performed excluding patients with Pseudomonas aeruginosa or MRSA pneumonia to control for Healthcare-Associated Pneumonia (HCAP). RESULTS: 3775 patients were included, and 1154 were treated with a macrolide-based treatment. The non-macrolide-based group had worse long-term clinical outcomes, represented by 6 m [31.5 (363/1154) vs 39.5 (1035/2621), p < 0.001] and 12 m mortality [39.0 (450/1154) vs 45.7 (1198/2621), p < 0.001]. The main risk factors associated with long-term mortality were Charlson comorbidity index, SAPS II, septic shock, and respiratory failure. Macrolide-based treatment reduced the risk of dying at 6 m [HR (95% CI) 0.69 (0.60, 0.78), p < 0.001] and 12 m [0.72 (0.64, 0.81), p < 0.001]. After TMLE, the protective effect continued with an additive effect estimate of - 0.069. CONCLUSION: Macrolide-based treatment reduced the hazard risk of long-term mortality by almost one-third. This effect remains after simulating an RCT with TMLE and the sensitivity analysis for the HCAP classification.

A multiple comorbidities mouse lung infection model in ApoE­deficient mice.

Acute pneumonia is characterised by a period of intense inflammation. Inflammation is now considered to be a key step in atherosclerosis progression. In addition, pre-existing atherosclerotic inflammation is considered to play a role in pneumonia progression and risk. In the present study, a multiple comorbidities murine model was used to study respiratory and systemic inflammation that results from pneumonia in the setting of atherosclerosis. Firstly, a minimal infectious dose of Streptococcus pneumoniae (TIGR4 strain) to produce clinical pneumonia with a low mortality rate (20%) was established. C57Bl/6 ApoE -/- mice were fed a high-fat diet prior to administering intranasally 105 colony forming units of TIGR4 or phosphate-buffered saline (PBS). At days 2, 7 and 28 post inoculation (PI), the lungs of mice were imaged by magnetic resonance imaging (MRI) and positron emission tomography (PET). Mice were euthanised and investigated for changes in lung morphology and changes in systemic inflammation using ELISA, Luminex assay and real-time PCR. TIGR4-inoculated mice presented with varying degrees of lung infiltrate, pleural effusion and consolidation on MRI at all time points up to 28 days PI. Moreover, PET scans identified significantly higher FDG uptake in the lungs of TIGR4-inoculated mice up to 28 days PI. The majority (90%) TIGR4-inoculated mice developed pneumococcal-specific IgG antibody response at 28 days PI. Consistent with these observations, TIGR4-inoculated mice displayed significantly increased inflammatory gene expression [interleukin (IL)-1ß and IL-6] in the lungs and significantly increased levels of circulating inflammatory protein (CCL3) at 7 and 28 days PI respectively. The mouse model developed by the authors presents a discovery tool to understand the link between inflammation related to acute infection such as pneumonia and increased risk of cardiovascular disease observed in humans.

How to use biomarkers of infection or sepsis at the bedside: guide to clinicians.

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. In this context, biomarkers could be considered as indicators of either infection or dysregulated host response or response to treatment and/or aid clinicians to prognosticate patient risk. More than 250 biomarkers have been identified and evaluated over the last few decades, but no biomarker accurately differentiates between sepsis and sepsis-like syndrome. Published data support the use of biomarkers for pathogen identification, clinical diagnosis, and optimization of antibiotic treatment. In this narrative review, we highlight how clinicians could improve the use of pathogen-specific and of the most used host-response biomarkers, procalcitonin and C-reactive protein, to improve the clinical care of patients with sepsis. Biomarker kinetics are more useful than single values in predicting sepsis, when making the diagnosis and assessing the response to antibiotic therapy. Finally, integrated biomarker-guided algorithms may hold promise to improve both the diagnosis and prognosis of sepsis. Herein, we provide current data on the clinical utility of pathogen-specific and host-response biomarkers, offer guidance on how to optimize their use, and propose the needs for future research.