Gut Mycobiome and Asthma.

This review explores the 'gut-lung axis' in asthma with a focus on commensal fungal organisms. We explore how changes to the intestinal commensal fungal community composition alter lung immune function. We comprehensively review available studies that have profiled the composition of the gut mycobiome in adults and children with asthma, and discuss mechanisms of gut-lung interactions that have been described in animal models of asthma. Studies indicate that intestinal fungal dysbiosis, such as an increased abundance of certain fungi like Candida, can elevate the risk of asthma in children and exacerbate it in adults. This effect is mediated through various pathways: the host immune system's sensing of dysbiosis via C-type lectin receptors (e.g., Dectin-2), the impact of pro-inflammatory fungal metabolites (e.g., 12,13-diHOME, prostaglandin E2), and the role of lung immune cells (e.g., group 2 innate lymphoid cells [ILC2], M2 macrophages). We also describe strategies for modulating the gut mycobiome as potential therapies for severe asthma. The review concludes by emphasizing the necessity for further research into the role of the gut mycobiome in asthma to deepen our understanding of these complex interactions.

The intestinal commensal fungus Wallemia mellicola enhances asthma in mice through Dectin-2.

Overgrowth of the fungus Wallemia mellicola in the intestines of mice enhances the severity of asthma. Wallemia mellicola interacts with the immune system through Dectin-2 expressed on the surface of myeloid and intestinal epithelial cells. Using Dectin-2-deficient mice, we show that the interaction of W. mellicola with Dectin-2 is essential for the gut-lung pathways, enhancing the severity of asthma in mice with W. mellicola intestinal dysbiosis. These findings offer better insight into dysbiosis-associated inflammation and highlight the role pattern recognition receptors have in immune recognition of commensal fungi in the gut, leading to alterations in immune function in the lungs.

Safety, feasibility, and impact on the gut microbiome of kefir administration in critically ill adults.

BACKGROUND: Dysbiosis of the gut microbiome is frequent in the intensive care unit (ICU), potentially leading to a heightened risk of nosocomial infections. Enhancing the gut microbiome has been proposed as a strategic approach to mitigate potential adverse outcomes. While prior research on select probiotic supplements has not successfully shown to improve gut microbial diversity, fermented foods offer a promising alternative. In this open-label phase I safety and feasibility study, we examined the safety and feasibility of kefir as an initial step towards utilizing fermented foods to mitigate gut dysbiosis in critically ill patients. METHODS: We administered kefir in escalating doses (60 mL, followed by 120 mL after 12 h, then 240 mL daily) to 54 critically ill patients with an intact gastrointestinal tract. To evaluate kefir's safety, we monitored for gastrointestinal symptoms. Feasibility was determined by whether patients received a minimum of 75% of their assigned kefir doses. To assess changes in the gut microbiome composition following kefir administration, we collected two stool samples from 13 patients: one within 72 h of admission to the ICU and another at least 72 h after the first stool sample. RESULTS: After administering kefir, none of the 54 critically ill patients exhibited signs of kefir-related bacteremia. No side effects like bloating, vomiting, or aspiration were noted, except for diarrhea in two patients concurrently on laxatives. Out of the 393 kefir doses prescribed for all participants, 359 (91%) were successfully administered. We were able to collect an initial stool sample from 29 (54%) patients and a follow-up sample from 13 (24%) patients. Analysis of the 26 paired samples revealed no increase in gut microbial α-diversity between the two timepoints. However, there was a significant improvement in the Gut Microbiome Wellness Index (GMWI) by the second timepoint (P = 0.034, one-sided Wilcoxon signed-rank test); this finding supports our hypothesis that kefir administration can improve gut health in critically ill patients. Additionally, the known microbial species in kefir were found to exhibit varying levels of engraftment in patients' guts. CONCLUSIONS: Providing kefir to critically ill individuals is safe and feasible. Our findings warrant a larger evaluation of kefir's safety, tolerability, and impact on gut microbiome dysbiosis in patients admitted to the ICU. TRIAL REGISTRATION: NCT05416814; trial registered on June 13, 2022.

The human gut microbiome in critical illness: disruptions, consequences, and therapeutic frontiers.

With approximately 39 trillion cells and over 20 million genes, the human gut microbiome plays an integral role in both health and disease. Modern living has brought a widespread use of processed food and beverages, antimicrobial and immunomodulatory drugs, and invasive procedures, all of which profoundly disrupt the delicate homeostasis between the host and its microbiome. Of particular interest is the human gut microbiome, which is progressively being recognized as an important contributing factor in many aspects of critical illness, from predisposition to recovery. Herein, we describe the current understanding of the adverse impacts of standard intensive care interventions on the human gut microbiome and delve into how these microbial alterations can influence patient outcomes. Additionally, we explore the potential association between the gut microbiome and post-intensive care syndrome, shedding light on a previously underappreciated avenue that may enhance patient recuperation following critical illness. There is an impending need for future epidemiological studies to encompass detailed phenotypic analyses of gut microbiome perturbations. Interventions aimed at restoring the gut microbiome represent a promising therapeutic frontier in the quest to prevent and treat critical illnesses.

Dysbiosis of the intestinal fungal microbiota increases lung resident group 2 innate lymphoid cells and is associated with enhanced asthma severity in mice and humans.

BACKGROUND: The gut-lung axis is the concept that alterations of gut microbiota communities can influence immune function in the lungs. While studies have explored the relationship between intestinal bacterial dysbiosis and asthma development, less is understood about the impact of commensal intestinal fungi on asthma severity and control and underlying mechanisms by which this occurs. METHODS: Wild-type mice were treated with Cefoperazone to deplete gut bacteria and administered Candida albicans or water through gavage. Mice were then sensitized to house dust mite (HDM) and their lungs were analyzed for changes in immune response. Humans with asthma were recruited and stool samples were analyzed for Candida abundance and associations with asthma severity and control. RESULTS: Mice with intestinal Candida dysbiosis had enhanced Th2 response after airway sensitization with HDM, manifesting with greater total white cell and eosinophil counts in the airway, and total IgE concentrations in the serum. Group 2 innate lymphoid cells (ILC2) were more abundant in the lungs of mice with Candida gut dysbiosis, even when not sensitized to HDM, suggesting that ILC2 may be important mediators of the enhanced Th2 response. These effects occurred with no detectable increased Candida in the lung by culture or rtPCR suggesting gut-lung axis interactions were responsible. In humans with asthma, enhanced intestinal Candida burden was associated with the risk of severe asthma exacerbation in the past year, independent of systemic antibiotic and glucocorticoid use. CONCLUSIONS: Candida gut dysbiosis may worsen asthma control and enhance allergic airway inflammation, potentially mediated by ILC2. Further studies are necessary to examine whether microbial dysbiosis can drive difficult-to-control asthma in humans and to better understand the underlying mechanisms.

Emphysematous Lung Lesions Caused by Perivascular and Alveolar-Septal Deposition of Amyloid Light-Chain Amyloidosis.

Pulmonary amyloidosis, whether isolated or seen as part of systemic amyloidosis, has a variety of radiographic manifestations. Known parenchymal lung findings include reticulonodular opacities, diffuse interstitial infiltrates, or cystic lesions. Here, we present a case of systemic amyloid light-chain (AL) amyloidosis presenting with severe exertional dyspnea and emphysematous lung lesions on chest CT, a finding described only once before. Although factors that influence the pattern of pulmonary amyloid deposition remain unclear, CT image findings typically reflect the histopathologic patterns of deposition. In this case, we hypothesize that the emphysematous changes in the lower lung zones are likely a manifestation of severe alveolar-septal involvement. This case suggests that radiographic findings of pulmonary amyloidosis are not limited to the more common findings of reticular opacities or interstitial infiltrates. Emphysematous changes are possible, and clinicians should maintain a broad differential when seen in the setting of dyspnea.

Malassezia Is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Models.

Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn's disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn's disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.

Expansion of commensal fungus Wallemia mellicola in the gastrointestinal mycobiota enhances the severity of allergic airway disease in mice.

The gastrointestinal microbiota influences immune function throughout the body. The gut-lung axis refers to the concept that alterations of gut commensal microorganisms can have a distant effect on immune function in the lung. Overgrowth of intestinal Candida albicans has been previously observed to exacerbate allergic airways disease in mice, but whether subtler changes in intestinal fungal microbiota can affect allergic airways disease is less clear. In this study we have investigated the effects of the population expansion of commensal fungus Wallemia mellicola without overgrowth of the total fungal community. Wallemia spp. are commonly found as a minor component of the commensal gastrointestinal mycobiota in both humans and mice. Mice with an unaltered gut microbiota community resist population expansion when gavaged with W. mellicola; however, transient antibiotic depletion of gut microbiota creates a window of opportunity for expansion of W. mellicola following delivery of live spores to the gastrointestinal tract. This phenomenon is not universal as other commensal fungi (Aspergillus amstelodami, Epicoccum nigrum) do not expand when delivered to mice with antibiotic-depleted microbiota. Mice with Wallemia-expanded gut mycobiota experienced altered pulmonary immune responses to inhaled aeroallergens. Specifically, after induction of allergic airways disease with intratracheal house dust mite (HDM) antigen, mice demonstrated enhanced eosinophilic airway infiltration, airway hyperresponsiveness (AHR) to methacholine challenge, goblet cell hyperplasia, elevated bronchoalveolar lavage IL-5, and enhanced serum HDM IgG1. This phenomenon occurred with no detectable Wallemia in the lung. Targeted amplicon sequencing analysis of the gastrointestinal mycobiota revealed that expansion of W. mellicola in the gut was associated with additional alterations of bacterial and fungal commensal communities. We therefore colonized fungus-free Altered Schaedler Flora (ASF) mice with W. mellicola. ASF mice colonized with W. mellicola experienced enhanced severity of allergic airways disease compared to fungus-free control ASF mice without changes in bacterial community composition.

Commensal Fungi in Health and Disease.

Fungi are increasingly being recognized as common members of the microbiomes found on nearly all mucosal surfaces, and interest is growing in understanding how these organisms may contribute to health and disease. In this review, we investigate recent developments in our understanding of the fungal microbiota or "mycobiota" including challenges faced in characterizing it, where these organisms are found, their diversity, and how they interact with host immunity. Growing evidence indicates that, like the bacterial microbiota, the fungal microbiota is often altered in disease states, and increasingly studies are being designed to probe the functional consequences of such fungal dysbiosis on health and disease.

"Fellow of the Day": A Novel Trainee Role to Improve Fellows' Outpatient Continuity Clinics.

RATIONALE: The implementation of team-based care models in residency programs is one method to improve patient and provider outpatient satisfaction. However, to our knowledge, this has not yet been studied in fellowship programs. OBJECTIVES: We instituted a pilot project to test a team-based model of care in our pulmonary and critical care medicine (PCCM) fellows' clinic by creating a new outpatient role called the "Fellow of the Day," with the goal of reducing clinical disruption for the fellows, providing more educational value for medical students, and improving patient care. METHODS: Data were collected over a 4-month time period from electronic surveys from medical students, fellows, and supervising faculty. We also used timestamp data to determine fellows' response times to patient messages. RESULTS: After implementation of the Fellow of the Day designation, (1) fellows were more engaged in teaching the medical student (P = 0.007); (2) fellows spent less of their personal time (P = 0.04) or time away from critically ill patients to focus on patient care-related messages (P = 0.04) and paperwork (P = 0.02); and (3) medical students had improved experience with more enjoyment (P = 0.03) and active engagement in clinic (P = 0.03). The Fellow of the Day role did not affect faculty workflow. Patients received responses to their postvisit messages in a more timely manner (P = 0.003). CONCLUSIONS: The Fellow of the Day role was successfully implemented at our institution with multiple benefits, not only to fellows but also to patients, medical students, and supervising faculty. Our education committee has recommended continuation of the role in our fellowship program.

Impact of a Preinterview Dinner on Candidate Perception of a Fellowship Training Program.

BACKGROUND: The interview visit is an important component of residency and fellowship recruitment that requires a substantial expenditure of time and resources for both training programs and candidates. OBJECTIVE: Survey aimed to study the impact of a preinterview dinner on fellowship program candidates. METHODS: A single center preintervention and postintervention comparison study was conducted using an electronic survey distributed to all Pulmonary and Critical Care Fellowship candidates over 3 years (2013-2015). The interview visit in 2013 did not include a preinterview dinner (no-dinner group), while the candidates interviewing in 2014 and 2015 were invited to a preinterview dinner with current fellows on the evening before the interview day (dinner group). RESULTS: The survey was distributed to all candidates (N = 70) who interviewed between 2013 and 2015 with a 59% (n = 41) completion rate. Ninety percent of respondents (37 of 41) reported that a preinterview dinner is valuable, primarily to gain more information about the program and to meet current fellows. Among candidates who attended the dinner, 88% (23 of 26) reported the dinner improved their impression of the program. The dinner group was more likely to have a positive view of current fellows in the program as desirable peers compared to candidates in the no-dinner group. CONCLUSIONS: This pilot study suggests that a preinterview dinner may offer benefits for candidates and training programs and may enhance candidates' perceptions of the fellowship program relative to other programs they are considering.

Tunneled Indwelling Pleural Catheters for Refractory Pleural Effusions after Solid Organ Transplant. A Case-Control Study.

RATIONALE: The use of tunneled indwelling pleural catheters for management of refractory pleural effusions continues to increase. Pleural space infections are among the most common and serious complication of the procedure. The risk may be higher in patients receiving immunosuppressive medications. OBJECTIVES: The aim of this study was to assess the risk of infections complicating placement of a tunneled indwelling pleural catheter in patients who have received a solid organ transplant. METHODS: Electronic medical records were retrospectively reviewed to identify patients with prior solid organ transplant who subsequently underwent placement of a tunneled intrapleural catheter. We selected a matched sample of comparison patients without solid organ transplant who underwent the same procedure during the study period. Detailed chart abstraction was performed to compare baseline clinical information with procedure outcomes in both groups. MEASUREMENTS AND MAIN RESULTS: Nineteen study patients underwent kidney, liver, lung, or heart transplant. Another 55 patients were included in the nontransplant comparison group. Transplant patients were taking a mean of 2.4 (range, 1-4) immunosuppressive medications. In transplant patients, the intrapleural catheter remained in place for a median of 95 days (interquartile range, 58-256 d). Two of the 19 transplant patients (16.9% 90-day Kaplan-Meier estimate) and 4 of the 55 control patients (11.0% weighted 90-day Kaplan-Meier estimate) developed a major infectious complication (not significant). There were no deaths attributed to intrapleural catheter placement in either group. CONCLUSIONS: In a series of 19 patients with solid organ transplantation taking daily immunosuppressive medications who underwent placement of a tunneled intrapleural catheter, we report an 11% rate of major infectious complications over the lifetime of the catheter in the transplant group with no significant difference in 90-day estimated risk of complication between transplant and nontransplant comparison group.

Fungal, Viral, and Parasitic Pneumonias Associated with Human Immunodeficiency Virus.

Respiratory illness is an important cause of morbidity and mortality in patients with human immunodeficiency virus (HIV). The spectrum of pulmonary disease that can affect patients with HIV is wide and includes opportunistic infection with many fungal, viral, and parasitic organisms. This article reviews the clinical presentation; approach to diagnosis; and management of fungal, viral, and parasitic pneumonias that can develop in patients with HIV including respiratory disease caused by Aspergillus, Cryptococcus, Histoplasma, Coccidioides, Cytomegalovirus, Toxoplasma, and Strongyloides. Because clinical symptoms and radiographic patterns are often insensitive at distinguishing these pulmonary infections, this review particularly focuses on specific host risk factors and diagnostic testing to consider when approaching HIV patients with respiratory illness.

Pulmonary Abscess as a Complication of Transbronchial Lung Cryobiopsy.

We present the case of a 49-year-old man who developed pulmonary abscess as a complication of transbronchial lung cryobiopsy. He had been receiving prednisone therapy, but otherwise had no specific risk factors for lung abscess. Cryobiopsy is a novel technique for obtaining peripheral lung parenchymal tissue for the evaluation of diffuse parenchymal lung diseases. Cryobiopsy is being increasingly proposed as an alternative to surgical lung biopsy or conventional bronchoscopic transbronchial forceps biopsy, but the safety profile of the procedure has not been fully appreciated. Pulmonary abscess has been rarely reported as a complication of other bronchoscopic procedures such as endobronchial ultrasound-guided needle biopsy, however, to our knowledge this is the first reported case of pulmonary abscess complicating peripheral lung cryobiopsy.

Using Standardized Patients to Teach Point-of-Care Ultrasound-Guided Physical Examination Skills to Internal Medicine Residents.

BACKGROUND: Point-of-care (POC) ultrasound has been shown to improve procedural outcomes and physical examination accuracy in multiple settings. There are limited data regarding the optimal way to train nonradiologists in POC ultrasound. This is a primary barrier to more widespread use of ultrasound in the physical examination. OBJECTIVE: We created a workshop to instruct postgraduate year (PGY)-2 and PGY-3 internal medicine residents in POC ultrasound imaging of the abdominal aorta and kidneys. METHODS: A half-day simulation center workshop was created to review ultrasound operations and teach residents to independently obtain ultrasound images of the abdominal aorta and kidneys on standardized patients with normal anatomy. The workshop incorporated didactic instruction and hands-on ultrasound practice in small groups. Each resident's ability to independently obtain ultrasound images was assessed using a preworkshop and postworkshop skills examination with a standardized patient. Resident knowledge and attitudes toward POC ultrasound were also assessed using a preworkshop and postworkshop test and survey. RESULTS: A total of 58 residents completed the workshop, and 84% were able to independently obtain high-quality images of the abdominal aorta and kidney after workshop completion, compared with 16% on the preworkshop test. Residents demonstrated a statistically significant increase in their self-reported confidence with ultrasound operation and image acquisition. CONCLUSIONS: Training using standardized patients can prepare residents to independently obtain POC ultrasound images of the aorta and kidneys. Training resulted in increased resident confidence with POC ultrasound and self-reported likelihood of future use.

Pathobiology of Pneumocystis pneumonia: life cycle, cell wall and cell signal transduction.

Pneumocystis is a genus of ascomycetous fungi that are highly morbid pathogens in immunosuppressed humans and other mammals. Pneumocystis cannot easily be propagated in culture, which has greatly hindered understanding of its pathobiology. The Pneumocystis life cycle is intimately associated with its mammalian host lung environment, and life cycle progression is dependent on complex interactions with host alveolar epithelial cells and the extracellular matrix. The Pneumocystis cell wall is a varied and dynamic structure containing a dominant major surface glycoprotein, ß-glucans and chitins that are important for evasion of host defenses and stimulation of the host immune system. Understanding of Pneumocystis cell signaling pathways is incomplete, but much has been deduced by comparison of the Pneumocystis genome with homologous genes and proteins in related fungi. In this mini-review, the pathobiology of Pneumocystis is reviewed, with particular focus on the life cycle, cell wall components and cell signal transduction.

The Use of Indwelling Tunneled Pleural Catheters for Recurrent Pleural Effusions in Patients With Hematologic Malignancies: A Multicenter Study.

BACKGROUND: Malignant pleural effusion is a common complication of advanced malignancies. Indwelling tunneled pleural catheter (IPC) placement provides effective palliation but can be associated with complications, including infection. In particular, hematologic malignancy and the associated immunosuppressive treatment regimens may increase infectious complications. This study aimed to review outcomes in patients with hematologic malignancy undergoing IPC placement. METHODS: A retrospective multicenter study of IPCs placed in patients with hematologic malignancy from January 2009 to December 2013 was performed. Inclusion criteria were recurrent, symptomatic pleural effusion and an underlying diagnosis of hematologic malignancy. Records were reviewed for patient demographics, operative reports, and pathology, cytology, and microbiology reports. RESULTS: Ninety-one patients (mean ± SD age, 65.4 ± 15.4 years) were identified from eight institutions. The mean × SD in situ dwell time of all catheters was 89.9 ± 127.1 days (total, 8,160 catheter-days). Seven infectious complications were identified, all of the pleural space. All patients were admitted to the hospital for treatment, with four requiring additional pleural procedures. Two patients died of septic shock related to pleural infection. CONCLUSIONS: We present, to our knowledge, the largest study examining clinical outcomes related to IPC placement in patients with hematologic malignancy. An overall 7.7% infection risk and 2.2% mortality were identified, similar to previously reported studies, despite the significant immunosuppression and pancytopenia often present in this population. IPC placement appears to remain a reasonable clinical option for patients with recurrent pleural effusions related to hematologic malignancy.

Medical thoracoscopy.

The burden of pleural diseases continues to rise and affects an increasingly complex and aging patient population. As such, thoracentesis is one of the most common procedures performed by respiratory physicians, as pleural fluid analysis can establish the diagnosis of pleural effusions in approximately 75% of the cases. When a diagnosis is not reached, options include image-guided biopsies, only possible when focal pleural lesions can be identified by computed tomography or ultrasound; closed pleural biopsies, associated with a relatively low diagnostic yield; and surgical pleural biopsies, which typically require general anesthesia and a hospital stay. Medical thoracoscopy addresses some of the limitations of these techniques, allows a comprehensive pleural examination and targeted pleural biopsies, and offers the possibility of treatment of recurrence in the same setting. As such, medical thoracoscopy is ideally positioned as a valuable tool in the diagnosis of unexplained exudative pleural effusions.