Analysis of MicroRNA Cargo in Circulating Extracellular Vesicles from HIV-Infected Individuals with Pulmonary Hypertension.

The risk of developing pulmonary hypertension (PH) in people living with HIV is at least 300-fold higher than in the general population, and illicit drug use further potentiates the development of HIV-associated PH. The relevance of extracellular vesicles (EVs) containing both coding as well as non-coding RNAs in PH secondary to HIV infection and drug abuse is yet to be explored. We here compared the miRNA cargo of plasma-derived EVs from HIV-infected stimulant users with (HIV + Stimulants + PH) and without PH (HIV + Stimulants) using small RNA sequencing. The data were compared with 12 PH datasets available in the GEO database to identify potential candidate gene targets for differentially altered miRNAs using the following functional analysis tools: ingenuity pathway analysis (IPA), over-representation analysis (ORA), and gene set enrichment analysis (GSEA). MiRNAs involved in promoting cell proliferation and inhibition of intrinsic apoptotic signaling pathways were among the top upregulated miRNAs identified in EVs from the HIV + Stimulants + PH group compared to the HIV + Stimulants group. Alternatively, the downregulated miRNAs in the HIV + Stimulants + PH group suggested an association with the negative regulation of smooth muscle cell proliferation, IL-2 mediated signaling, and transmembrane receptor protein tyrosine kinase signaling pathways. The validation of significantly differentially expressed miRNAs in an independent set of HIV-infected (cocaine users and nondrug users) with and without PH confirmed the upregulation of miR-32-5p, 92-b-3p, and 301a-3p positively regulating cellular proliferation and downregulation of miR-5571, -4670 negatively regulating smooth muscle proliferation in EVs from HIV-PH patients. This increase in miR-301a-3p and decrease in miR-4670 were negatively correlated with the CD4 count and FEV1/FVC ratio, and positively correlated with viral load. Collectively, this data suggest the association of alterations in the miRNA cargo of circulating EVs with HIV-PH.

Longitudinal multicompartment characterization of host-microbiota interactions in patients with acute respiratory failure.

Critical illness can significantly alter the composition and function of the human microbiome, but few studies have examined these changes over time. Here, we conduct a comprehensive analysis of the oral, lung, and gut microbiota in 479 mechanically ventilated patients (223 females, 256 males) with acute respiratory failure. We use advanced DNA sequencing technologies, including Illumina amplicon sequencing (utilizing 16S and ITS rRNA genes for bacteria and fungi, respectively, in all sample types) and Nanopore metagenomics for lung microbiota. Our results reveal a progressive dysbiosis in all three body compartments, characterized by a reduction in microbial diversity, a decrease in beneficial anaerobes, and an increase in pathogens. We find that clinical factors, such as chronic obstructive pulmonary disease, immunosuppression, and antibiotic exposure, are associated with specific patterns of dysbiosis. Interestingly, unsupervised clustering of lung microbiota diversity and composition by 16S independently predicted survival and performed better than traditional clinical and host-response predictors. These observations are validated in two separate cohorts of COVID-19 patients, highlighting the potential of lung microbiota as valuable prognostic biomarkers in critical care. Understanding these microbiome changes during critical illness points to new opportunities for microbiota-targeted precision medicine interventions.

Novel Approach to Exploring Protease Activity and Targets in HIV-associated Obstructive Lung Disease using Combined Proteomic-Peptidomic Analysis.

Background: Obstructive lung disease (OLD) is increasingly prevalent among persons living with HIV (PLWH). However, the role of proteases in HIV-associated OLD remains unclear. Methods: We combined proteomics and peptidomics to comprehensively characterize protease activities. We combined mass spectrometry (MS) analysis on bronchoalveolar lavage fluid (BALF) peptides and proteins from PLWH with OLD (n=25) and without OLD (n=26) with a targeted Somascan aptamer-based proteomic approach to quantify individual proteases and assess their correlation with lung function. Endogenous peptidomics mapped peptides to native proteins to identify substrates of protease activity. Using the MEROPS database, we identified candidate proteases linked to peptide generation based on binding site affinities which were assessed via z-scores. We used t-tests to compare average forced expiratory volume in 1 second per predicted value (FEV1pp) between samples with and without detection of each cleaved protein and adjusted for multiple comparisons by controlling the false discovery rate (FDR). Findings: We identified 101 proteases, of which 95 had functional network associations and 22 correlated with FEV1pp. These included cathepsins, metalloproteinases (MMP), caspases and neutrophil elastase. We discovered 31 proteins subject to proteolytic cleavage that associate with FEV1pp, with the top pathways involved in small ubiquitin-like modifier mediated modification (SUMOylation). Proteases linked to protein cleavage included neutrophil elastase, granzyme, and cathepsin D. Interpretations: In HIV-associated OLD, a significant number of proteases are up-regulated, many of which are involved in protein degradation. These proteases degrade proteins involved in cell cycle and protein stability, thereby disrupting critical biological functions.

Hepatitis C Virus Clearance and Diffusing Capacity for Carbon Monoxide in Women With and Without Human Immunodeficiency Virus.

Hepatitis C virus (HCV) infection is associated with extrahepatic effects, including reduced diffusing capacity of the lungs. It is unknown whether clearance of HCV infection is associated with improved diffusing capacity. In this sample of women with and without human immunodeficiency virus, there was no association between HCV clearance and diffusing capacity.

Genetic architecture of inbreeding depression may explain its persistence in a population of wild red deer.

Inbreeding depression is of major concern in declining populations, but relatively little is known about its genetic architecture in wild populations, such as the degree to which it is composed of large or small effect loci and their distribution throughout the genome. Here, we combine fitness and genomic data from a wild population of red deer to investigate the genomic distribution of inbreeding effects. Based on the runs of homozygosity (ROH)-based inbreeding coefficient, FROH, we use chromosome-specific inbreeding coefficients (FROHChr) to explore whether the effect of inbreeding varies between chromosomes. Under the assumption that within an individual the probability of being identical-by-descent is equal across all chromosomes, we used a multi-membership model to estimate the deviation of FROHChr from the average inbreeding effect. This novel approach ensures effect sizes are not overestimated whilst maximising the power of our available dataset of >3000 individuals genotyped on >35,000 autosomal SNPs. We find that most chromosomes confer a minor reduction in fitness-related traits, which when these effects are summed, results in the observed inbreeding depression in birth weight, survival and lifetime breeding success. However, no chromosomes had a significant detrimental effect compared to the overall effect of inbreeding, indicating no major effect loci. We conclude that in this population, inbreeding depression is likely the result of multiple mildly or moderately deleterious mutations spread across all chromosomes, which are difficult to detect with statistical confidence. Such mutations will be inefficiently purged, which may explain the persistence of inbreeding depression in this population.

Subphenotypes of self-reported symptoms and outcomes in long COVID: a prospective cohort study with latent class analysis.

OBJECTIVE: To characterise subphenotypes of self-reported symptoms and outcomes (SRSOs) in postacute sequelae of COVID-19 (PASC). DESIGN: Prospective, observational cohort study of subjects with PASC. SETTING: Academic tertiary centre from five clinical referral sources. PARTICIPANTS: Adults with COVID-19 ≥20 days before enrolment and presence of any new self-reported symptoms following COVID-19. EXPOSURES: We collected data on clinical variables and SRSOs via structured telephone interviews and performed standardised assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via quantitative PCR. OUTCOMES MEASURES: Description of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA) and relationship with viral load. RESULTS: We analysed baseline data for 214 individuals with a study visit at a median of 197.5 days after COVID-19 diagnosis. Participants reported ever having a median of 9/16 symptoms (IQR 6-11) after acute COVID-19, with muscle-aches, dyspnoea and headache being the most common. Fatigue, cognitive impairment and dyspnoea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3 (1-6)) than those ever experienced (p<0.001). Unsupervised LCA of symptoms revealed three clinically active PASC subphenotypes: a high burden constitutional symptoms (21.9%), a persistent loss/change of smell and taste (20.6%) and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p<0.001) as well as referral source for enrolment. Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes. CONCLUSIONS: We identified three distinct PASC subphenotypes. We highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.

Influence of Impaired Diffusing Capacity and Sleep-disordered Breathing on Nocturnal Hypoxemia and Health Outcomes in Men with and without Human Immunodeficiency Virus.

Rationale: Nocturnal hypoxemia is common in sleep-disordered breathing (SDB) and is associated with increased morbidity and mortality. Although impaired diffusing capacity of the lung for carbon monoxide (DlCO) is associated with daytime hypoxemia, its influence on SDB-related nocturnal hypoxemia is not known. Objectives: To characterize the effects of DlCO impairment on SDB-related nocturnal hypoxemia and associated health outcomes. Methods: Data from a multicenter cohort of men with and without human immunodeficiency virus (HIV) infection, with concomitant measures of DlCO and home-based polysomnography (n = 544), were analyzed. Multivariable quantile regression models characterized associations between DlCO and several measures of SDB-related hypoxemia (e.g., total sleep time with oxygen saturation as measured by pulse oximetry [SpO2] < 90% [T90]). Structural equation models were used to assess associations of impaired DlCO and SDB-related hypoxemia measures with prevalent hypertension and type 2 diabetes. Results: DlCO impairment (<80% predicted) was associated with sleep-related hypoxemia. Participants with severe SDB (apnea-hypopnea index ⩾ 30 events/h) and impaired DlCO had higher T90 (median difference, 15.0% [95% confidence interval (CI), 10.3% to 19.7%]) and average SDB-related desaturation (median difference, 1.0 [95% CI, 0.5 to 1.5]) and lower nadir SpO2 (median difference, -8.2% [95% CI, -11.4% to -4.9%]) and average SpO2 during sleep (median difference, -1.1% [95% CI, -2.1% to -0.01%]) than those with severe SDB and preserved DlCO. Higher T90 was associated with higher adjusted odds of prevalent hypertension (odds ratio, 1.39 [95% CI, 1.14 to 1.70]) and type 2 diabetes (odds ratio, 1.25 [95% CI, 1.07 to 1.46]). Conclusions: DlCO impairment in severe SDB was associated with sleep-related hypoxemia, prevalent hypertension, and type 2 diabetes. Assessment of SDB should be considered in those with impaired DlCO to guide testing and risk stratification strategies.

The effect of sexual behavior on HIV-1 seroconversion is mediated by the gut microbiome and proinflammatory cytokines.

The association between HIV-1 seroconversion and gut dysbiosis is well documented, and its association with sexual activity is also widely recognized. However, it is not known whether the gut dysbiosis mediates the effects of high-risk sexual behavior on HIV-1 seroconversion. In this report we focused on men who engaged in high-risk sexual behavior where they had receptive anal intercourse with multiple men. We demonstrate that proinflammatory cytokines, sCD14 and sCD163, and gut microbiota mediate the effects of this high-risk sexual behavior on subsequent HIV seroconversion. We discovered changes in the gut microbial ecology, prior to seroconversion, both in terms of the composition as well as inter-relationships among the commensal species. Furthermore, these changes correlate with future HIV seroconversion. Specifically, as the number of sexual partners increased, we discovered in a "dose-response" manner, a decrease in the abundance of commensal and short-chain fatty acid-producing species, A. muciniphila, B. caccae, B. fragilis, B. uniformis, Bacteroides spp., Butyricimonas spp., and Odoribacter spp, and an increase in proinflammatory species Dehalobacterium spp. and Methanobrevibacter spp. These changes were also observed among subsequent HIV seroconverters. Interestingly, we also discovered a reduction in correlations among these commensal and short-chain fatty acid producing bacteria in a "dose-response" manner with the number of sexual partners. Our mediation analysis not only provides a conceptual model for the disease process but also provides clues for future clinical interventions that will manipulate the gut microbiota to treat high-risk subjects to prevent HIV seroconversion.

The salivary microbiota of patients with acute lower respiratory tract infection-A multicenter cohort study.

The human microbiome contributes to health and disease, but the oral microbiota is understudied relative to the gut microbiota. The salivary microbiota is easily accessible, underexplored, and may provide insight into response to infections. We sought to determine the composition, association with clinical features, and heterogeneity of the salivary microbiota in patients with acute lower respiratory tract infection (LRTI). We conducted a multicenter prospective cohort study of 147 adults with acute LRTI presenting to the emergency department of seven hospitals in three states (Pennsylvania, Michigan, and Ohio) between May 2017 and November 2018. Salivary samples were collected in the emergency department, at days 2-5 if hospitalized, and at day 30, as well as fecal samples if patients were willing. We compared salivary microbiota profiles from patients to those of healthy adult volunteers by sequencing and analyzing bacterial 16-rRNA. Compared to healthy volunteers, the salivary microbiota of patients with LRTI was highly distinct and strongly enriched with intestinal anaerobes such as Bacteroidaceae, Ruminococcaceae, and Lachnospiraceae (e.g., mean 10% relative abundance of Bacteroides vs < 1% in healthy volunteers). Within the LRTI population, COPD exacerbation was associated with altered salivary microbiota composition compared to other LRTI conditions. The largest determinant of microbiota variation within the LRTI population was geography (city in which the hospital was located).

Noninvasive diagnosis of secondary infections in COVID-19 by sequencing of plasma microbial cell-free DNA.

Secondary infection (SI) diagnosis in severe COVID-19 remains challenging. We correlated metagenomic sequencing of plasma microbial cell-free DNA (mcfDNA-Seq) with clinical SI assessment, immune response, and outcomes. We classified 42 COVID-19 inpatients as microbiologically confirmed-SI (Micro-SI, n = 8), clinically diagnosed-SI (Clinical-SI, n = 13, i.e., empiric antimicrobials), or no-clinical-suspicion-for-SI (No-Suspected-SI, n = 21). McfDNA-Seq was successful in 73% of samples. McfDNA detection was higher in Micro-SI (94%) compared to Clinical-SI (57%, p = 0.03), and unexpectedly high in No-Suspected-SI (83%), similar to Micro-SI. We detected culture-concordant mcfDNA species in 81% of Micro-SI samples. McfDNA correlated with LRT 16S rRNA bacterial burden (r = 0.74, p = 0.02), and biomarkers (white blood cell count, IL-6, IL-8, SPD, all p < 0.05). McfDNA levels were predictive of worse 90-day survival (hazard ratio 1.30 [1.02-1.64] for each log10 mcfDNA, p = 0.03). High mcfDNA levels in COVID-19 patients without clinical SI suspicion may suggest SI under-diagnosis. McfDNA-Seq offers a non-invasive diagnostic tool for pathogen identification, with prognostic value on clinical outcomes.

A common single nucleotide polymorphism is associated with inflammation and critical illness outcomes.

Acute inflammation is heterogeneous in critical illness and predictive of outcome. We hypothesized that genetic variability in novel, yet common, gene variants contributes to this heterogeneity and could stratify patient outcomes. We searched algorithmically for significant differences in systemic inflammatory mediators associated with any of 551,839 SNPs in one derivation (n = 380 patients with blunt trauma) and two validation (n = 75 trauma and n = 537 non-trauma patients) cohorts. This analysis identified rs10404939 in the LYPD4 gene. Trauma patients homozygous for the A allele (rs10404939AA; 27%) had different trajectories of systemic inflammation along with persistently elevated multiple organ dysfunction (MOD) indices vs. patients homozygous for the G allele (rs10404939GG; 26%). rs10404939AA homozygotes in the trauma validation cohort had elevated MOD indices, and non-trauma patients displayed more complex inflammatory networks and worse 90-day survival compared to rs10404939GG homozygotes. Thus, rs10404939 emerged as a common, broadly prognostic SNP in critical illness.

Prognostic Insights from Longitudinal Multicompartment Study of Host-Microbiota Interactions in Critically Ill Patients.

Critical illness can disrupt the composition and function of the microbiome, yet comprehensive longitudinal studies are lacking. We conducted a longitudinal analysis of oral, lung, and gut microbiota in a large cohort of 479 mechanically ventilated patients with acute respiratory failure. Progressive dysbiosis emerged in all three body compartments, characterized by reduced alpha diversity, depletion of obligate anaerobe bacteria, and pathogen enrichment. Clinical variables, including chronic obstructive pulmonary disease, immunosuppression, and antibiotic exposure, shaped dysbiosis. Notably, of the three body compartments, unsupervised clusters of lung microbiota diversity and composition independently predicted survival, transcending clinical predictors, organ dysfunction severity, and host-response sub-phenotypes. These independent associations of lung microbiota may serve as valuable biomarkers for prognostication and treatment decisions in critically ill patients. Insights into the dynamics of the microbiome during critical illness highlight the potential for microbiota-targeted interventions in precision medicine.

Prognostic Insights from Longitudinal Multicompartment Study of Host-Microbiota Interactions in Critically Ill Patients.

Critical illness can disrupt the composition and function of the microbiome, yet comprehensive longitudinal studies are lacking. We conducted a longitudinal analysis of oral, lung, and gut microbiota in a large cohort of 479 mechanically ventilated patients with acute respiratory failure. Progressive dysbiosis emerged in all three body compartments, characterized by reduced alpha diversity, depletion of obligate anaerobe bacteria, and pathogen enrichment. Clinical variables, including chronic obstructive pulmonary disease, immunosuppression, and antibiotic exposure, shaped dysbiosis. Notably, of the three body compartments, unsupervised clusters of lung microbiota diversity and composition independently predicted survival, transcending clinical predictors, organ dysfunction severity, and host-response sub-phenotypes. These independent associations of lung microbiota may serve as valuable biomarkers for prognostication and treatment decisions in critically ill patients. Insights into the dynamics of the microbiome during critical illness highlight the potential for microbiota-targeted interventions in precision medicine.

Aiming to Improve Equity in Lung Health: Sex and Gender.

Sex and gender impact risk factors, presentations of, and response to therapy in lung diseases such as chronic obstructive pulmonary disease, asthma, lung cancer, interstitial lung disease, and obstructive sleep apnea. Many physicians lack training in the impact of sex and gender on lung disease, resulting in diagnostic delays. Scales and indices taught in the health care system are largely validated in male populations, thereby limiting their application to females. For transgender and lesbian, gay, bisexual, transgender, and questioning + patients, high rates of bias in health care may limit patients' willingness to seek health care.

HIV-associated lung disease.

Lung disease encompasses acute, infectious processes and chronic, non-infectious processes such as chronic obstructive pulmonary disease, asthma and lung cancer. People living with HIV are at increased risk of both acute and chronic lung diseases. Although the use of effective antiretroviral therapy has diminished the burden of infectious lung disease, people living with HIV experience growing morbidity and mortality from chronic lung diseases. A key risk factor for HIV-associated lung disease is cigarette smoking, which is more prevalent in people living with HIV than in uninfected people. Other risk factors include older age, history of bacterial pneumonia, Pneumocystis pneumonia, pulmonary tuberculosis and immunosuppression. Mechanistic investigations support roles for aberrant innate and adaptive immunity, local and systemic inflammation, oxidative stress, altered lung and gut microbiota, and environmental exposures such as biomass fuel burning in the development of HIV-associated lung disease. Assessment, prevention and treatment strategies are largely extrapolated from data from HIV-uninfected people. Smoking cessation is essential. Data on the long-term consequences of HIV-associated lung disease are limited. Efforts to continue quantifying the effects of HIV infection on the lung, especially in low-income and middle-income countries, are essential to advance our knowledge and optimize respiratory care in people living with HIV.

Pulmonary Function and Quality of Life in Aging Men With and Without HIV from the Multicenter AIDS Cohort Study.

People living with HIV have greater pulmonary function impairments and decreased health-related quality of life (HRQoL) compared to uninfected peers. We examined whether pulmonary impairment was associated with HRQoL or respiratory health status. Using Multicenter AIDS Cohort Study data (2017-2019), associations between outcomes [HRQoL (36-Item Short Form Survey) and respiratory health status (St. George's Respiratory Questionnaire)] with pulmonary impairment [diffusing capacity for carbon monoxide (DLCO) and forced expiratory volume in 1 s (FEV1), defined as <80% predicted for both] were examined. Adjusted analyses utilized linear and zero-inflated beta regression, the latter summarized by odds ratio (OR) and quotient ratios (QRs). We also considered whether the subset of adjustment variables age, HIV serostatus, or smoking modified the relationships examined. Of 1048 men, 55% had HIV, with median age 57 [interquartile range (IQR) = 48, 64] years and 1.2 (IQR = 0, 18.1) smoking pack-years. Impaired DLCO, but not impaired FEV1, was significantly associated with lower physical HRQoL [-2.71 (-4.09, -1.33); -1.46 (-3.45, 0.54), respectively]. Pulmonary impairment was associated with higher odds of any St. George's Respiratory Questionnaire (SGRQ) (total score) limitation [DLCO OR = 1.53 (1.15, 2.04); FEV1 OR = 2.48 (1.16, 5.30)] and was elevated in individuals with more severe SGRQ limitations [DLCO QR = 1.13 (0.94, 1.36); FEV1 QR = 1.27 (0.98, 1.64)]. HIV did not modify any associations examined. Age modified the DLCO and any respiratory limitation (SGRQ symptom score) association for every 10 mL CO/min/mmHg decrease in DLCO [age 30 OR = 1.03 (0.51, 2.08); age 50 OR = 1.85 (1.27, 3.85); and age 70 OR = 3.45 (2.00, 5.88)]. Similarly, age modified the DLCO and any respiratory limitation (SGRQ total score) association. FEV1 associations with SGRQ and HRQoL scores were similar across all ages. Impaired pulmonary function was associated with lower HRQoL and greater respiratory impairments. Future studies can determine if interventions aimed at preserving pulmonary function are effective in improving HRQoL and respiratory health among aging men with and without HIV.

Distinct profiles of host responses between plasma and lower respiratory tract during acute respiratory failure.

Current plasma-based subphenotyping approaches in acute respiratory failure represent host responses at a systemic level but do not capture important differences in lower respiratory tract biology https://bit.ly/40kTdDG.

Haemophilia joint health score (HJHS) usage, patterns and outcome data in patients with haemophilia A and haemophilia B in Australia: A descriptive study using the Australian Bleeding Disorders Registry (ABDR).

INTRODUCTION: Assessment of joint health is an essential component of haemophilia management. A variety of clinical tools have been developed to standardise this assessment process. One such tool, the Haemophilia Joint Health Score (HJHS), is embedded for use within the Australian Bleeding Disorders Registry (ABDR). This provides a unique opportunity to analyse patterns of tool usage as well as associations between scores, demographics and clinical outcome factors. AIMS: To characterise clinician practices regarding use of HJHS in routine clinical assessment of persons with haemophilia (PWH), to examine relationships between HJHS, and age, inhibitor status and body mass index (BMI), and to identify potential barriers to HJHS tool usage. METHODS: A national, retrospective study was conducted using data extracted from the ABDR between 2014 and 2020, complemented by a qualitative questionnaire exploring haemophilia treatment centre (HTC) structure, resourcing and clinician perspectives about HJHS. RESULTS: 28.1% (622/2220) of PWH had at least one HJHS recorded in the ABDR during the defined study period (546 haemophilia A, 76 haemophilia B). HJHS were recorded more in children than adults and performed more in severe than non-severe haemophilia. Multivariate analysis demonstrated significant association of age, severity and inhibitor status with HJHS. No association was identified between BMI and HJHS. Qualitative surveys revealed significant variation in physiotherapy funding, availability and methods of tool use between HTCs. CONCLUSION: This study provides valuable insights into joint health assessment in Australia. It improved our understanding of factors influencing long-term joint outcomes. Practical limitations of HJHS tool were also discussed.

Respiratory Fungal Communities are Associated with Systemic Inflammation and Predict Survival in Patients with Acute Respiratory Failure.

Rationale: Disruption of respiratory bacterial communities predicts poor clinical outcomes in critical illness; however, the role of respiratory fungal communities (mycobiome) is poorly understood. Objectives: We investigated whether mycobiota variation in the respiratory tract is associated with host-response and clinical outcomes in critically ill patients. Methods: To characterize the upper and lower respiratory tract mycobiota, we performed rRNA gene sequencing (internal transcribed spacer) of oral swabs and endotracheal aspirates (ETA) from 316 mechanically-ventilated patients. We examined associations of mycobiome profiles (diversity and composition) with clinical variables, host-response biomarkers, and outcomes. Measurements and Main Results: ETA samples with >50% relative abundance for C. albicans (51%) were associated with elevated plasma IL-8 and pentraxin-3 (p=0.05), longer time-to-liberation from mechanical ventilation (p=0.04) and worse 30-day survival (adjusted hazards ratio (adjHR): 1.96 [1.04-3.81], p=0.05). Using unsupervised clustering, we derived two clusters in ETA samples, with Cluster 2 (39%) showing lower alpha diversity (p<0.001) and higher abundance of C. albicans (p<0.001). Cluster 2 was significantly associated with the prognostically adverse hyperinflammatory subphenotype (odds ratio 2.07 [1.03-4.18], p=0.04) and predicted worse survival (adjHR: 1.81 [1.03-3.19], p=0.03). C. albicans abundance in oral swabs was also associated with the hyperinflammatory subphenotype and mortality. Conclusions: Variation in respiratory mycobiota was significantly associated with systemic inflammation and clinical outcomes. C. albicans abundance emerged as a negative predictor in both the upper and lower respiratory tract. The lung mycobiome may play an important role in the biological and clinical heterogeneity among critically ill patients and represent a potential therapeutic target for lung injury in critical illness.