[Show abstract][Hide abstract] ABSTRACT: This article briefly reviews conventional biomarkers used clinically to (1) support a diagnosis and (2) monitor disease progression in patients with sarcoidosis. Potential new biomarkers identified by genome-wide screening and the approaches to discover these biomarkers are described.
Full-text · Article · Sep 2015 · Clinics in Chest Medicine
[Show abstract][Hide abstract] ABSTRACT: Rationale: Airway management in the intensive care unit (ICU) is challenging as many patients have limited physiologic reserve and are at risk for clinical deterioration if the airway is not quickly secured. In academic medical centers, ICU intubations are often performed by trainees, making airway management education paramount for pulmonary and critical care trainees. Objectives: To improve airway management education for our trainees, we developed a comprehensive training program including an 11-month simulation-based curriculum. The curriculum emphasizes recognition of and preparation for potentially difficult intubations and procedural skills to maximize patient safety and increase the likelihood of first-attempt success (FAS). Methods: Training is provided in small group sessions twice monthly using a high-fidelity simulation program under the guidance of a core group of 2-3 advanced providers. The curriculum is designed with progressively more difficult scenarios requiring critical planning and execution of airway management by the trainees. Trainees consider patient position, pre-oxygenation, optimization of hemodynamics, choice of induction agents, selection of appropriate devices for the scenario, anticipation of difficulties, back-up plans and immediate post intubation management. Clinical performance is monitored through a continuous quality improvement program. Measurements and Main Results: 16 fellows have completed the program since July 1, 2013. In the 18-months since the start of the curriculum (July 1, 2013-December 31, 2014), FAS has improved from 74% (358/487) to 82% (305/374) compared to the 18-months prior to implementation (p=0.006). During that time there were no serious complications related to airway management. Desaturation rates decreased from 26% to 17%, (p=0.002). Other complication rates are low, including aspiration (2.1%), esophageal intubation (2.7%), dental trauma (0.8%), and hypotension (8.3%). FAS in a 6-month period after implementation (July 1, 2014-December 31, 2014) was significantly higher 82.1% compared to 70.9% (p=0.03) during a similar 6-month period prior to implementation (July 1, 2012-December 31, 2012). Conclusions: This comprehensive airway curriculum is associated with improved first-attempt success rate for intensive care unit intubations. Such a curriculum holds the potential to improve patient care.
[Show abstract][Hide abstract] ABSTRACT: The field of pulmonary fungal infections is constantly evolving. The at-risk population continues to increase, and the endemic areas for the dimorphic fungi are expanding with new outbreaks reported across the world. Novel diagnostic methods are being developed and existing methods improved and refined. If started in a timely fashion, currently available antifungal agents are fairly effective. In this review we highlight the recent updates in fungal pneumonias focusing on epidemiology, diagnosis, and treatment.
[Show abstract][Hide abstract] ABSTRACT: The consequences of failing to consider the diagnosis of an endemic fungal infection may be catastrophic. The diagnosis can be made most rapidly by microscopic examination of tissues or by antigen detection in body fluids. These methods are recommended in patients with evidence for acute pulmonary disease, in patients with findings that are concerning for progressive and/or disseminated infection, and in those who are ill enough to require hospitalization. Antibody detection is most sensitive when using enzyme-linked immunoassay methods. However, antibody assays may be falsely negative in immunocompromised patients or within 2 months following acute infection. Conversely, positive results may persist for several years, resulting in an incorrect diagnosis in patients with other conditions. Cross-reactions also occur among the endemic mycoses. Testing for antigen in serum and urine and antibodies in serum are recommended in all acute or severe cases. When a procedure such as bronchoscopy or lumbar puncture is performed, efforts must be made to maximize the yield of the samples obtained. Hence, casting a broad net with antibody testing, antigen testing, and special stains on diverse fluids and tissues is recommended.
[Show abstract][Hide abstract] ABSTRACT: Within a coccidioidal endemic region, pulmonary nodules due to coccidioidomycosis are common. Uptake of (18)fluorodeoxyglucose ((18)FDG) by positron emission tomography with computed axial tomography (PET/CT) has been used to assess whether pulmonary nodules are malignant but inflammatory lesions can be positive. The purpose of this study was to compare by PET/CT the (18)FDG uptake in pulmonary nodules likely due to coccidioidomycosis to that of nodules shown to be malignant among patients living in a coccidioidal endemic region.
We retrospectively reviewed patients who underwent a PET/CT at the Southern Arizona Veterans Affairs Health Care System between January 2008 and March 2012 who were subsequently found on biopsy to have pulmonary nodules that were coccidioidal or granulomatous or were due to malignancy.
Among 245 diagnostic biopsies where the subject had a previous PET/CT, 15 (6.1 %) were either coccidioidal (n = 12) or granulomatous without an identified organism (n = 3). The median maximum standard unit of uptake (SUVmax) on PET/CT of coccidioidal or granulomatous lesions was 2.0 compared to 9.8 for malignant lesions (P < 0.001). The maximum diameter of the coccidioidal or granulomatous nodules was 2.1 cm compared to 3.0 cm for the malignant lesions (P = 0.009). On multivariable analysis, an elevated SUVmax was the only distinguishing feature between the malignant and the granulomatous lesions (OR 1.28, 95 % CI 1.05-1.55; P = 0.013).
Coccidioidal pulmonary nodules take up significantly less (18)FDG than those due to malignancies, but there is considerable overlap between granulomatous and malignant lesions at lower SUVmax.
No preview · Article · May 2014 · Beiträge zur Klinik der Tuberkulose
[Show abstract][Hide abstract] ABSTRACT: Coccidioidomycosis is a common cause of community-acquired pneumonia in the southwest United States, Mexico, and South America. The disease has seen a marked increase in incidence in the western United States in the last decade and can be acquired by individuals who travel even briefly through an endemic area, presenting a diagnostic dilemma for clinicians who are not familiar with the disease. The clinical and radiographic manifestations of pulmonary coccidioidomycosis often mimic those of other causes of pneumonia. However, because treatment recommendations and the potential for chronic sequelae of acute infection differ substantially from those for bacterial community-acquired pneumonia, accurate, timely diagnosis of coccidioidomycosis is paramount. A number of diagnostic tests are available with varying sensitivity and specificity, making the approach complex. Radiographic features, although nonspecific, sometimes demonstrate patterns more suggestive of coccidioidomycosis than bacterial community-acquired pneumonias. A routine blood count may reveal eosinophilia. Serologic testing is used most widely but may be negative early in the course of disease, potentially leading to misdiagnosis with subsequent inappropriate treatment and follow-up. The sensitivity of serologic testing is lower in immunocompromised patients, a population at the highest risk for developing severe disease. When clinically appropriate, other biologic specimens, such as sputum, bronchoalveolar lavage fluid, or lung biopsies, may allow for rapid, definitive diagnosis. In light of the significantly increased incidence and complexities in diagnosis of coccidioidomycosis, we examine the diagnostic approach and provide examples of classic clinical and radiographic presentations, discuss the utility of serologic testing, and suggest algorithms that may aid in the diagnosis.
Full-text · Article · Feb 2014 · Annals of the American Thoracic Society
[Show abstract][Hide abstract] ABSTRACT: Rationale: The ability to determine the respiratory microbiome from bronchoalveolar lavage (BAL) is controversial due to oral contamination during bronchoscopy. To determine if processing BAL improved the ability to distinguish lung from oral wash microbiomes, we compared the oral and lung microbiome from whole and acellular BAL in 34 subjects. Methods: Oral wash samples and bronchoscopy with BAL were performed. After removing an aliquot of whole unprocessed BAL, the remaining was centrifuged at 1,500 rpm for 10 minutes and the supernatant harvested as acellular BAL. DNA was isolated from 2 ml of oral wash and 5 ml of acellular and whole BAL using the Qiagen DNeasy kit (Qiagen, Valencia, CA). DNA encoding 16s ribosomal RNA was amplified using NEB Phusion enzyme (NEB, Ipswich, MA) and degenerate of eubacterial primers that amplify the variable regions 1 through 3. DNA sequencing was performed using 454 sequencing. Results: The amount of genomic DNA isolated from whole BAL was 100-fold higher compared with acellular BAL. Despite this, the number of high-quality genera bacterial reads (RDP classifier > 90%) was identical between the two groups (whole BAL, 4,903 ± 3,209; acellular BAL, 4,245 ± 2,632). Bray-Curtis distances between oral wash and acellular BAL were significantly higher than the distance between whole BAL and oral wash (P = 0.000035), indicating acellular BAL was significantly more different from oral wash compared with whole BAL. Visually, the overlap between oral wash and whole BAL can be seen on the dendogram in Figure 1 (BA = acellular BAL; BW = whole BAL; OR = oral wash). [Figure: see text] Conclusions: The difference between acellular BAL and oral wash is significantly greater than the difference between whole BAL and oral wash. We suggest this represents greater contamination of whole BAL by upper airway organisms. We speculate acellular BAL provides a better representation of the true lower respiratory tract microbiome.
No preview · Article · Jan 2014 · Annals of the American Thoracic Society
[Show abstract][Hide abstract] ABSTRACT: Background:
The specific cellular immunological characteristics of bronchoalveolar lavage (BAL) fluid in acute pulmonary coccidioidomycosis have not been defined.
BAL fluid from patients living in a coccidioidomycosis-endemic region of Arizona who were undergoing bronchoscopy because of pulmonary infiltrates was analyzed. Mononuclear cells from BAL fluid and peripheral blood mononuclear cells (PBMCs) were incubated with the coccidioidal antigen T27K in vitro, and cellular immunological assays were performed.
Forty-six patients were studied. Twelve received a diagnosis of acute pulmonary coccidioidomycosis, 17 received other diagnoses, and 17 had no diagnosis established. There was an increased proportion of polyfunctional CD8(+) T cells after antigen stimulation from subjects with coccidioidomycosis as compared to those with another diagnosis (P = .025). In cells collected from BAL fluid and in PBMCs, the concentrations of interferon γ, tumor necrosis factor α, and interleukin 17 (IL-17) were all significantly increased in samples from those with acute pulmonary coccidioidomycosis, compared with the other 2 groups (for all, P<.05).
When incubated in vitro with a coccidioidal antigen preparation, cells from both BAL fluid and peripheral blood obtained from patients with pulmonary coccidioidomycosis demonstrated specific cellular immune responses, including expression of IL-17.
Preview · Article · Jun 2013 · The Journal of Infectious Diseases
[Show abstract][Hide abstract] ABSTRACT: Human immunodeficiency virus (HIV) infection causes profound changes in the lung compartment characterized by macrophage and lymphocyte activation, secretion of proinflammatory cytokines and chemokines, and accumulation of CD8 T cells in the alveolar space, leading to lymphocytic alveolitis. Because many of the changes seen in the lung can be attributed to the direct effect of HIV on immune cells, therapy to reduce the HIV burden should have significant beneficial effects. Indeed, antiretroviral therapy rapidly reduces the viral burden in the lung, number of CD8 T cells in the alveolar space, and amount of proinflammatory cytokines and chemokines in bronchoalveolar lavage.
No preview · Article · Jun 2013 · Clinics in chest medicine
[Show abstract][Hide abstract] ABSTRACT: RATIONALE: Lung infections caused by opportunistic or virulent pathogens are a principal cause of morbidity and mortality in HIV infection. It is unknown whether HIV infection leads to changes in basal lung microflora, which may contribute to chronic pulmonary complications that increasingly are being recognized in HIV-infected individuals. OBJECTIVES: To determine whether the immunodeficiency associated with HIV infection resulted in alteration of the lung microbiota. METHODS: We used 16S ribosomal RNA targeted pyrosequencing and shotgun metagenomic sequencing to analyze bacterial gene sequences in bronchoalveolar lavage and mouth of 82 HIV-positive and 77 HIV-negative subjects. MEASUREMENTS AND MAIN RESULTS: Sequences representing Tropheryma whipplei, the etiologic agent of Whipple's disease, were significantly more frequent in bronchoalveolar lavage of HIV-positive compared with HIV-negative individuals. T. whipplei dominated the community (>50% of sequence reads) in 11 HIV-positive subjects but only 1 HIV-negative individual (13.4% versus 1.3%; p = 0.0018). In 30 HIV-positive individuals sampled longitudinally, antiretroviral therapy resulted in a significantly reduced relative abundance of T. whipplei in the lung. Shotgun metagenomic sequencing was performed on 8 bronchoalveolar lavage samples dominated by T. whipplei 16S ribosomal RNA. Whole genome assembly of pooled reads showed that uncultured lung-derived T. whipplei had similar gene content to two isolates obtained from subjects with Whipple's disease. CONCLUSIONS: Asymptomatic subjects with HIV infection have unexpected colonization of the lung by T. whipplei, which is reduced by effective antiretroviral therapy and merits further study for a potential pathogenic role in chronic pulmonary complications of HIV infection.
Full-text · Article · Feb 2013 · American Journal of Respiratory and Critical Care Medicine
[Show abstract][Hide abstract] ABSTRACT: Indoleamine 2,3 dioxygenase (IDO) plays an important role in immunoregulation as it is involved in downregulating immune responses
to infections. We sought to characterize IDO activity in histoplasmosis and to do so, C57Bl6 mice were infected intranasally
with Histoplasma capsulatum. After infection, lung and spleen IDO activity was assessed by HPLC and IDO expression by qRT-PCR. The distribution of IDO
was determined by immunohistochemical staining. Cytokine levels were measured in lung and spleen homogenates using cytokine
bead array. Fungal burden was quantified by culture. Subcutaneous pellets containing methyltryptophane (1-MT) were employed
to inhibit IDO in vivo. Histoplasma infection strongly induced functional lung IDO, with activity at its highest at weeks 1 and 2 and then decreased thereafter
as the mice cleared the infection. Lung IDO activity positively correlated with the fungal burden (Rho = 0.845), interferon-γ
(Rho = 0.839) and tumor necrosis factor-α (Rho = 0.791) levels, P < 0.001. In contrast, spleen IDO activity was not induced despite high infection burden and cytokine levels. IDO expressing
cells were predominately located at the ring edge of Histoplasma-induced granulomas. IDO inhibition prior to infection reduced fungal burdens and inflammation in lungs and spleen. Histoplasma preferentially induces lung IDO, as early as one week after infection. IDO appears to modulate the immune response to Histoplasma infection.
Preview · Article · Nov 2012 · Medical mycology: official publication of the International Society for Human and Animal Mycology
[Show abstract][Hide abstract] ABSTRACT: Sarcoidosis, a systemic granulomatous syndrome invariably affecting the lung, typically spontaneously remits but in ∼20% of cases progresses with severe lung dysfunction or cardiac and neurologic involvement (complicated sarcoidosis). Unfortunately, current biomarkers fail to distinguish patients with remitting (uncomplicated) sarcoidosis from other fibrotic lung disorders, and fail to identify individuals at risk for complicated sarcoidosis. We utilized genome-wide peripheral blood gene expression analysis to identify a 20-gene sarcoidosis biomarker signature distinguishing sarcoidosis (n = 39) from healthy controls (n = 35, 86% classification accuracy) and which served as a molecular signature for complicated sarcoidosis (n = 17). As aberrancies in T cell receptor (TCR) signaling, JAK-STAT (JS) signaling, and cytokine-cytokine receptor (CCR) signaling are implicated in sarcoidosis pathogenesis, a 31-gene signature comprised of T cell signaling pathway genes associated with sarcoidosis (TCR/JS/CCR) was compared to the unbiased 20-gene biomarker signature but proved inferior in prediction accuracy in distinguishing complicated from uncomplicated sarcoidosis. Additional validation strategies included significant association of single nucleotide polymorphisms (SNPs) in signature genes with sarcoidosis susceptibility and severity (unbiased signature genes - CX3CR1, FKBP1A, NOG, RBM12B, SENS3, TSHZ2; T cell/JAK-STAT pathway genes such as AKT3, CBLB, DLG1, IFNG, IL2RA, IL7R, ITK, JUN, MALT1, NFATC2, PLCG1, SPRED1). In summary, this validated peripheral blood molecular gene signature appears to be a valuable biomarker in identifying cases with sarcoidoisis and predicting risk for complicated sarcoidosis.