Kenneth S Knox

Interests

Teaching

Valley Fever, Interstitial Lung Disease, Sarcoidosis, careers in academic medicine, and mentoring

Research

HIV Lung Disease, Microbiome, ILD, Host Immunity, Fugal Diagnostics, BAL, and Fibrosis

Courses

No activities entered.

Scholarly Contributions

Chapters

• Knox, K. S., & Martinez, G. F. (2021). Principles of academic life-appointments, promotion and tenure. In AAMC Group on Faculty Affairs: New Members Tool Kit.

Journals/Publications

• Liu, B., Yi, D., Li, S., Ramirez, K., Xia, X., Cao, Y., Zhao, H., Tripathi, A., Qiu, S., Kala, M., Rafikov, R., Gu, H., De Jesus Perez, V., Lemay, S. E., Glembotski, C. C., Knox, K. S., Bonnet, S., Kalinichenko, V. V., Zhao, Y. Y., , Fallon, M. B., et al. (2025). Single-Cell and Spatial Transcriptomics Identified Fatty Acid-Binding Proteins Controlling Endothelial Glycolytic and Arterial Programming in Pulmonary Hypertension. Arteriosclerosis, Thrombosis, and Vascular Biology, 45(Issue 7). doi:10.1161/atvbaha.124.321173
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  BACKGROUND: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for patients with PAH. Recent studies showed that FABP (fatty acid-binding protein) 4 and FABP5 are expressed in endothelial cells (ECs) across multiple tissues, and circulating FABP4 level is elevated in patients with PAH. However, the role of endothelial FABP4/5 in the pathogenesis of PAH remains undetermined. METHODS: FABP4/5 expression was examined in pulmonary arterial ECs and lung tissues from patients with idiopathic PAH and pulmonary hypertension (PH) rat models. Plasma proteome analysis was performed in human PAH samples. Echocardiography, hemodynamics, histology, and immunostaining were performed to evaluate the lung and heart PH phenotypes in Egln1Tie2Cre (CKO) mice and Egln1Tie2Cre/Fabp4/5-/- (TKO) mice. Bulk RNA sequencing (RNA-seq), single-cell RNA sequencing analysis, and spatial transcriptomic analysis were performed to understand the cellular and molecular mechanisms of endothelial FABP4/5-mediated PAH pathogenesis. RESULTS: Both FABP4 and FABP5 were highly induced in ECs of CKO mice and pulmonary arterial ECs from patients with idiopathic PAH (IPAH) and in whole lungs of PH rats. Plasma levels of FABP4/5 were upregulated in patients with IPAH and directly correlated with severity of hemodynamics and biochemical parameters. Genetic deletion of both Fabp4 and Fabp5 in CKO mice caused a reduction of right ventricular systolic pressure and right ventricular hypertrophy, attenuated pulmonary vascular remodeling, and prevented the right heart failure secondary to PH. FABP4/5 deletion also normalized EC glycolysis and distal arterial programming, reduced reactive oxygen species and HIF (hypoxia-inducible factor)-2α expression, and decreased aberrant EC proliferation in CKO lungs. CONCLUSIONS: PH causes aberrant expression of FABP4/5 in pulmonary ECs, which leads to enhanced EC glycolysis and distal arterial programming, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.
• Anidi, I., Sakai, S., Brooks, K., Fling, S., Wagner, M., Lurain, K., Lindestam Arlehamn, C., Sette, A., Knox, K., Brenchley, J., Uldrick, T., Sharon, E., & Barber, D. (2024). Exacerbation of CMV and Nontuberculous Mycobacterial Infections Following PD-1 Blockade for HIV-Associated Kaposi Sarcoma. Open Forum Infectious Diseases, 11(5). doi:10.1093/ofid/ofae183
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  Blockade of the co-inhibitory receptor PD-1 enhances antitumor responses by boosting the function of antigen-specific T cells. Although rare, PD-1 blockade in patients with cancer can lead to exacerbation of infection-associated pathology. Here, we detail the case of a 38-year-old man who was enrolled in a clinical trial for assessment of the safety and activity of anti–PD-1 therapy for Kaposi sarcoma in people with HIV well-controlled on antiretroviral therapy. Less than a week after receiving the first dose of anti–PD-1 antibody (pembrolizumab), he presented with severe abdominal pain associated with sudden exacerbations of preexisting cytomegalovirus (CMV) enteritis and nontuberculous mycobacterial mesenteric lymphadenitis. Plasma biomarkers of gastrointestinal tract damage were highly elevated compared with healthy controls, consistent with HIV-associated loss of gut epithelial barrier integrity. Moreover, CMV-specific CD8 T cells expressed high levels of PD-1, and 7 days following PD-1 blockade, there was an increase in the frequency of activated CD38+ Ki67+ CMV-specific CD8 T cells. This case highlights the potential for PD-1 blockade to drive rapid exacerbations of inflammatory symptoms when administered to individuals harboring multiple unresolved infections.
• Bixby, B., Vrba, L., Lenka, J., Oshiro, M. M., Watts, G. S., Hughes, T., Erickson, H., Chopra, M., Knepler, J. L., Knox, K. S., Jarnagin, L., Alalawi, R., Kala, M., Bernert, R., Routh, J., Roe, D. J., Garland, L. L., Futscher, B. W., & Nelson, M. A. (2024). Cell-free DNA methylation analysis as a marker of malignancy in pleural fluid. Scientific Reports, 14(Issue 1). doi:10.1038/s41598-024-53132-x
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  Diagnosis of malignant pleural effusion (MPE) is made by cytological examination of pleural fluid or histological examination of pleural tissue from biopsy. Unfortunately, detection of malignancy using cytology has an overall sensitivity of 50%, and is dependent upon tumor load, volume of fluid assessed, and cytopathologist experience. The diagnostic yield of pleural fluid cytology is also compromised by low abundance of tumor cells or when morphology is obscured by inflammation or reactive mesothelial cells. A reliable molecular marker that may complement fluid cytology for the diagnosis of malignant pleural effusion is needed. The purpose of this study was to establish a molecular diagnostic approach based on pleural effusion cell-free DNA methylation analysis for the differential diagnosis of malignant pleural effusion and benign pleural effusion. This was a blind, prospective case–control biomarker study. We recruited 104 patients with pleural effusion for the study. We collected pleural fluid from patients with: MPE (n = 48), indeterminate pleural effusion in subjects with known malignancy or IPE (n = 28), and benign PE (n = 28), and performed the Sentinel-MPE liquid biopsy assay. The methylation level of Sentinel-MPE was markedly higher in the MPE samples compared to BPE control samples (p < 0.0001) and the same tendency was observed relative to IPE (p = 0.004). We also noted that the methylation signal was significantly higher in IPE relative to BPE (p < 0.001). We also assessed the diagnostic efficiency of the Sentinel-MPE test by performing receiver operating characteristic analysis (ROC). For the ROC analysis we combined the malignant and indeterminate pleural effusion groups (n = 76) and compared against the benign group (n = 28). The detection sensitivity and specificity of the Sentinel-MPE test was high (AUC = 0.912). The Sentinel-MPE appears to have better performance characteristics than cytology analysis. However, combining Sentinel-MPE with cytology analysis could be an even more effective approach for the diagnosis of MPE. The Sentinel-MPE test can discriminate between BPE and MPE. The Sentinel-MPE liquid biopsy test can detect aberrant DNA in several different tumor types. The Sentinel-MPE test can be a complementary tool to cytology in the diagnosis of MPE.
• Watanabe, M., Davidson, L., Smith, P., Castellucio, P., Jergovic, M., Uhrlaub, J., Smithey, M., Fantry, L., Dechambre, B., Wilson, R., Knox, K., Ren, J., Stowe, R., Weinstock, G., Twigg, H., & Nikolich, J. (2024). Anti-cytomegalovirus antibody levels stratify human immune profiles across the lifespan. GeroScience, 46(5). doi:10.1007/s11357-024-01124-0
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  Human cytomegalovirus (hCMV) is a ubiquitous latent persistent herpesvirus infecting 60–90% of the population worldwide. hCMV carriage in immunocompetent people is asymptomatic; thus, hCMV can be considered a component of normative aging. However, hCMV powerfully modulates many features of the immune, and likely other, systems and organs. Questions remain as to how hCMV carriage affects the human host. We used anti-CMV antibody titers as a stratifying criterion to examine the impact of “intensity” of hCMV infection as a potential biomarker of aging, inflammation, and immune homeostasis in a cohort of 247 participants stratified into younger (21–40 years) and older (> 65 years of age) groups. We showed that anti-CMV antibody titers increased with age and directly correlated to increased levels of soluble tumor necrosis factor (sTNFR) I in younger but not older participants. CD8 + cell numbers were reduced in the older group due to the loss in CD8 + T naïve (Tn) cells. In CMV carriers and, in particular, in anti-CMV Ab-high participants, this loss was mitigated or reversed by an increase in the numbers of CD8 + T effector memory (Tem) and T effector memory reexpressing CD45RA (Temra) cells. Analysis of CD38, HLA-DR, and CD57 expression revealed subset (CD4 or CD8)-specific changes that correlated with anti-CMV Ab levels. In addition, anti-CMV Ab levels predicted anti-CMV CD8 T cell responsiveness to different CMV open reading frames (ORFs) selectively in older participants, which correlated to the transcriptional order of expression of specific CMV ORFs. Implications of these results for the potential predictive value of anti-CMV Ab titers during aging are discussed.
• Zhai, J., Choi, Y., Yang, X., Chen, Y., Knox, K., Twigg, H., Won, J., Zhou, H., & Zhou, J. (2024). DeepBiome: A Phylogenetic Tree Informed Deep Neural Network for Microbiome Data Analysis. Statistics in Biosciences, 17(Issue 1). doi:10.1007/s12561-024-09434-9
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  Evidence linking the microbiome to human health is rapidly growing. The microbiome profile has the potential as a novel predictive biomarker for many diseases. However, tables of bacterial counts are typically sparse, and bacteria are classified within a hierarchy of taxonomic levels, ranging from species to phylum. Existing tools focus on identifying microbiome associations at either the community level or a specific, pre-defined taxonomic level. Incorporating the evolutionary relationship between bacteria can enhance data interpretation. This approach allows for aggregating microbiome contributions, leading to more accurate and interpretable results. We present DeepBiome, a phylogeny-informed neural network architecture, to predict phenotypes from microbiome counts and uncover the microbiome–phenotype association network. It utilizes microbiome abundance as input and employs phylogenetic taxonomy to guide the neural network’s architecture. Leveraging phylogenetic information, DeepBiome reduces the need for extensive tuning of the deep learning architecture, minimizes overfitting, and, crucially, enables the visualization of the path from microbiome counts to disease. It is applicable to both regression and classification problems. Simulation studies and real-life data analysis have shown that DeepBiome is both highly accurate and efficient. It offers deep insights into complex microbiome–phenotype associations, even with small to moderate training sample sizes. In practice, the specific taxonomic level at which microbiome clusters tag the association remains unknown. Therefore, the main advantage of the presented method over other analytical methods is that it offers an ecological and evolutionary understanding of host–microbe interactions, which is important for microbiome-based medicine. DeepBiome is implemented using Python packages Keras and TensorFlow. It is an open-source tool available at https://github.com/Young-won/DeepBiome.
• , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , ., , , ., et al. (2023). Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA, 329(22), 1934. doi:10.1001/jama.2023.8823
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  Importance: SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals. Objective: To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections. Design, Setting, and Participants: Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: PASC and 44 participant-reported symptoms (with severity thresholds). Results: A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months. Conclusions and Relevance: A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.
• Feng, A., Caro, Y., Gardner, C., Grischo, G., Liang, Y., Wickremasinghe, P., Polmann, M., Kala, M., Marlowe, T., Black, S., Knox, K., & Wang, T. (2023). PTK2-associated gene signature could predict the prognosis of IPF. Respiratory Research, 24(1). doi:10.1186/s12931-023-02582-4
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  Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease with a poor prognosis. Current/available clinical prediction tools have limited sensitivity and accuracy when evaluating clinical outcomes of IPF. Research has shown that focal adhesion kinase (FAK), produced by the protein tyrosine kinase 2 (PTK2) gene, is crucial in IPF development. FAK activation is a characteristic of lesional fibroblasts; Thus, FAK may be a valuable therapeutic target or prognostic biomarker for IPF. This study aimed to create a gene signature based on PTK2-associated genes and microarray data from blood cells to predict disease prognosis in patients with IPF. PTK2 levels were found to be higher in lung tissues of IPF patients compared to healthy controls, and PTK2 inhibitor Defactinib was found to reduce TGFβ-induced FAK activation and increase α-smooth muscle actin. Although the blood PTK2 levels were higher in IPF patients, blood PTK level alone could not predict IPF prognosis. From 196 PTK2-associated genes, 11 genes were prioritized to create a gene signature (PTK2 molecular signature) and a risk score system using univariate and multivariate Cox regression analysis. Patients were divided into high-risk and low-risk groups using PTK2 molecular signature. Patients in the high-risk group experienced decreased survival rates compared to patients in the low-risk group across all discovery and validation cohorts. Further functional enrichment and immune cell proportion analyses revealed that the PTK2 molecular signature strongly reflected the activation levels of immune pathways and immune cells. These findings suggested that PTK2 is a molecular target of IPF and the PTK2 molecular signature is an effective IPF prognostic biomarker.
• Horwitz, L., Thaweethai, T., Brosnahan, S., Cicek, M., Fitzgerald, M., Goldman, J., Hess, R., Hodder, S., Jacoby, V., Jordan, M., Krishnan, J., Laiyemo, A., Metz, T., Nichols, L., Patzer, R., Sekar, A., Singer, N., Stiles, L., Taylor, B., , Ahmed, S., et al. (2023). Researching COVID to Enhance Recovery (RECOVER) adult study protocol: Rationale, objectives, and design. PLoS ONE, 18(6). doi:10.1371/journal.pone.0286297
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  Importance SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis. Methods RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged 18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms. Discussion RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options. Registration NCT05172024.
• Jasbi, P., Patterson, J., Knox, K., Jin, Y., Weinstock, G., Smith, P., Twigg, H., Gu, H., & Nikolich-Žugich, J. (2023). Targeted metabolomics reveals plasma biomarkers and metabolic alterations of the aging process in healthy young and older adults. GeroScience, 45(6). doi:10.1007/s11357-023-00823-4
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  With the exponential growth in the older population in the coming years, many studies have aimed to further investigate potential biomarkers associated with the aging process and its incumbent morbidities. Age is the largest risk factor for chronic disease, likely due to younger individuals possessing more competent adaptive metabolic networks that result in overall health and homeostasis. With aging, physiological alterations occur throughout the metabolic system that contribute to functional decline. In this cross-sectional analysis, a targeted metabolomic approach was applied to investigate the plasma metabolome of young (21–40y; n = 75) and older adults (65y + ; n = 76). A corrected general linear model (GLM) was generated, with covariates of gender, BMI, and chronic condition score (CCS), to compare the metabolome of the two populations. Among the 109 targeted metabolites, those associated with impaired fatty acid metabolism in the older population were found to be most significant: palmitic acid (p < 0.001), 3-hexenedioic acid (p < 0.001), stearic acid (p = 0.005), and decanoylcarnitine (p = 0.036). Derivatives of amino acid metabolism, 1-methlyhistidine (p = 0.035) and methylhistamine (p = 0.027), were found to be increased in the younger population and several novel metabolites were identified, such as cadaverine (p = 0.034) and 4-ethylbenzoic acid (p = 0.029). Principal component analysis was conducted and highlighted a shift in the metabolome for both groups. Receiver operating characteristic analyses of partial least squares-discriminant analysis models showed the candidate markers to be more powerful indicators of age than chronic disease. Pathway and enrichment analyses uncovered several pathways and enzymes predicted to underlie the aging process, and an integrated hypothesis describing functional characteristics of the aging process was synthesized. Compared to older participants, the young group displayed greater abundance of metabolites related to lipid and nucleotide synthesis; older participants displayed decreased fatty acid oxidation and reduced tryptophan metabolism, relative to the young group. As a result, we offer a better understanding of the aging metabolome and potentially reveal new biomarkers and predicted mechanisms for future study. Graphical Abstract: [Figure not available: see fulltext.].
• Jergović, M., Watanabe, M., Bhat, R., Coplen, C. P., Sonar, S. A., Wong, R., Castaneda, Y., Davidson, L., Kala, M., Wilson, R. C., Twigg, H. L., Knox, K., Erickson, H. E., Weinkauf, C. C., Bime, C., Bixby, B. A., Parthasarathy, S., Mosier, J. M., LaFleur, B. J., , Bhattacharya, D., et al. (2023). T-cell cellular stress and reticulocyte signatures, but not loss of naïve T lymphocytes, characterize severe COVID-19 in older adults. GeroScience, 45(Issue 3). doi:10.1007/s11357-022-00724-y
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  In children and younger adults up to 39 years of age, SARS-CoV-2 usually elicits mild symptoms that resemble the common cold. Disease severity increases with age starting at 30 and reaches astounding mortality rates that are ~330 fold higher in persons above 85 years of age compared to those 18–39 years old. To understand age-specific immune pathobiology of COVID-19, we have analyzed soluble mediators, cellular phenotypes, and transcriptome from over 80 COVID-19 patients of varying ages and disease severity, carefully controlling for age as a variable. We found that reticulocyte numbers and peripheral blood transcriptional signatures robustly correlated with disease severity. By contrast, decreased numbers and proportion of naïve T-cells, reported previously as a COVID-19 severity risk factor, were found to be general features of aging and not of COVID-19 severity, as they readily occurred in older participants experiencing only mild or no disease at all. Single-cell transcriptional signatures across age and severity groups showed that severe but not moderate/mild COVID-19 causes cell stress response in different T-cell populations, and some of that stress was unique to old severe participants, suggesting that in severe disease of older adults, these defenders of the organism may be disabled from performing immune protection. These findings shed new light on interactions between age and disease severity in COVID-19.
• Lowery, M. M., Lowery, M., Hill, N., Wang, L., Rosenzweig, E., Bhat, A., Erzurum, S., Erzurum, S. C., Finet, J. E., Finet, J., Jellis, C., Jellis, C., Kaur, S., Kwon, D., Kwon, D., Nawabit, R., Nawabit, R., Radeva, M., Radeva, M., , Beck, G., et al. (2023). Sleep-Related Hypoxia, Right Ventricular Dysfunction, and Survival in Patients With Group 1 Pulmonary Arterial Hypertension. Journal of the American College of Cardiology, 82(21). doi:10.1016/j.jacc.2023.09.806
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  Background: Group 1 pulmonary arterial hypertension (PAH) is a progressive fatal condition characterized by right ventricular (RV) failure with worse outcomes in connective tissue disease (CTD). Obstructive sleep apnea and sleep-related hypoxia may contribute to RV dysfunction, though the relationship remains unclear. Objectives: The aim of this study was to prospectively evaluate the association of the apnea-hypopnea index (AHI) and sleep-related hypoxia with RV function and survival. Methods: Pulmonary Vascular Disease Phenomics (National Heart, Lung, and Blood Institute) cohort participants (patients with group 1 PAH, comparators, and healthy control participants) with sleep studies were included. Multimodal RV functional measures were examined in association with AHI and percentage of recording time with oxygen saturation
• Yi, D., Liu, B., Ding, H., Li, S., Li, R., Pan, J., Ramirez, K., Xia, X., Kala, M., Ye, Q., Lee, W., Frye, R., Wang, T., Zhao, Y., Knox, K., Glembotski, C., Fallon, M., & Dai, Z. (2023). E2F1 Mediates SOX17 Deficiency-Induced Pulmonary Hypertension. Hypertension, 80(11). doi:10.1161/HYPERTENSIONAHA.123.21241
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  BACKGROUND: Rare genetic variants and genetic variation at loci in an enhancer in SOX17 (SRY-box transcription factor 17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutations in SOX17 in PAH pathogenesis has not been reported. METHODS: SOX17 expression was evaluated in the lungs and pulmonary endothelial cells (ECs) of patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion were generated to determine the role of SOX17 deficiency in the pathogenesis of PAH. Human pulmonary ECs were cultured to understand the role of SOX17 deficiency. Single-cell RNA sequencing, RNA-sequencing analysis, and luciferase assay were performed to understand the underlying molecular mechanisms of SOX17 deficiency-induced PAH. E2F1 (E2F transcription factor 1) inhibitor HLM006474 was used in EC-specific Sox17 mice. RESULTS: SOX17 expression was downregulated in the lung and pulmonary ECs from patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion induced spontaneously mild pulmonary hypertension. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced pulmonary hypertension in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and antiapoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP (bone morphogenetic protein) signaling. E2F1 signaling was shown to mediate the SOX17 deficiency-induced EC dysfunction. Pharmacological inhibition of E2F1 in Sox17 EC-deficient mice attenuated pulmonary hypertension development. CONCLUSIONS: Our study demonstrated that endothelial SOX17 deficiency induces pulmonary hypertension through E2F1. Thus, targeting E2F1 signaling represents a promising approach in patients with PAH.
• Bowers, E. C., Motta, A., Knox, K., McKay, B. S., & Ramos, K. S. (2022). LINE-1 Cargo and Reverse Transcriptase Activity Profiles in Extracellular Vesicles from Lung Cancer Cells and Human Plasma. International journal of molecular sciences, 23(7).
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  Long Interspersed Element-1 (LINE-1) is an oncogenic human retrotransposon that 'copies and pastes' DNA into new locations via reverse transcription. Given that enzymatically active LINE-1 can be exported in extracellular vesicles (EVs), and that LINE-1 mRNA and its two encoded proteins, ORF1p and ORF2p, are required for retrotransposition, the present study examined LINE-1 EV loading patterns relative to reverse transcriptase (RT) activity in vivo and in vitro. Density gradient ultracentrifugation identified conserved patterns of LINE-1 mRNA and protein distribution in EVs, with RT activity readily detected in EV fractions containing both LINE-1 mRNA and protein. Unlike whole cell and tissue lysates, the ORF1p in EVs was detected as a dimer. EVs from ostensibly healthy plasma donors showed variable but consistent ORF1p profiles, with residual levels of LINE-1 mRNA measured in some but not all samples. EVs from cancer cell lines had elevated mean LINE-1 levels and 5-85 times greater RT activity than EVs from normal cells or healthy plasma. EV RT activity was associated with EV LINE-1 mRNA content and was highest in cell lines that also expressed an elevated expression of ORF1p and ORF2p. Given that LINE-1 activation is a hallmark of many cancer types, our findings suggest that an EV LINE-1 'liquid biopsy' may be developed to monitor LINE-1 activity during the course of malignant progression.
• Chaudhary, S., Knox, K. S., Malo, J., & Natt, B. (2022). Prophylaxis in Lung Transplant Recipients. Clinical Infectious Diseases, 76(2), 368-369. doi:10.1093/cid/ciac706
• Gu, H., Jasbi, P., Jin, Y., Knox, K., Nikolich‐Zugich, J., Patterson, J., Smith, P., Twigg, H., & Weinstock, G. (2022). Targeted Metabolomics Reveals Plasma Biomarkers and Metabolic Alterations of the Aging Process in Healthy Young and Older Adults. The FASEB Journal, 36(S1). doi:10.1096/fasebj.2022.36.s1.r2302
• Khassawneh, B., Zhu, C., Barkes, B., Vestal, B., Shrock, S., Gillespie, M., Pacheco, K., Deane, K. D., Maier, L. A., Li, Q. Z., Hamzeh, N., Senior, R. M., Berry, C., Casanova, N., Garcia, J., Knepler, J., Knox, K., Navarrete, J., Oliva, I., , Breslin, L., et al. (2022). Autoantibody profile in sarcoidosis, analysis from the GRADS sarcoidosis cohort. PLoS ONE, 17(Issue 10). doi:10.1371/journal.pone.0274381
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  Background Sarcoidosis, a multi-systemic granulomatous disease, is a predominantly T-cell disease but evidence for a role for humoral immunity in disease pathogenesis is growing. Utilizing samples from the Genomic Research in Alpha-1 anti-trypsin Deficiency and Sarcoidosis (GRADS) study, we examined the prevalence of autoantibodies in sarcoidosis patients with pulmonary-only and extra-pulmonary organ involvement compared to normal controls. Study design and methods We analyzed serum samples from sarcoidosis patients who participated in the GRADS study utilizing an autoantigen microarray platform for both IgM and IgG antibodies. The cohort included sarcoidosis patients with pulmonary-only disease (POS, n = 106), sarcoidosis patients with extra-pulmonary disease (EPS, n = 120) and a normal control cohort (NC, n = 101). Organ involvement was assessed following a standardized format across all GRADS participating centers. Results Sarcoidosis patients overall had increased levels of IgM and IgG autoantibodies compared to normal controls. In addition, several autoantibodies were elevated in the POS and EPS cohorts compared to the NC cohort. Differences in autoantibody levels were also noted between the POS and the EPS cohorts. When comparing organ involvement with sarcoidosis, bone, spleen and ear, nose and throat involvement had higher IgM expression than other organs. Conclusion Sarcoidosis patients have elevated IgM and IgG autoantibody levels compared to normal controls. In addition, individuals with pulmonary as well as additional organ involvement had higher IgM expression. Further research is needed focusing on specific organ-autoantibody pairs and role of autoantibodies in disease pathogenesis.
• Knox, K. S., & Martinez, G. F. (2022). Precepting medical students in the clinical setting: Its time, not money. Medical Education, 56(7), 698-700. doi:10.1111/medu.14815
• Bime, C., Camp, S. M., Casanova, N. G., Garcia, J. G., Knox, K. S., & Nikolich-zugich, J. (2021). Strategies to DAMPen COVID-19-mediated lung and systemic inflammation and vascular injury.. Translational research : the journal of laboratory and clinical medicine, 232, 37-48. doi:10.1016/j.trsl.2020.12.008
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  Approximately 15%-20% of patients infected with SARS-CoV-2 coronavirus (COVID-19) progress beyond mild and self-limited disease to require supplemental oxygen for severe pneumonia; 5% of COVID-19-infected patients further develop acute respiratory distress syndrome (ARDS) and multiorgan failure. Despite mortality rates surpassing 40%, key insights into COVID-19-induced ARDS pathology have not been fully elucidated and multiple unmet needs remain. This review focuses on the unmet need for effective therapies that target unchecked innate immunity-driven inflammation which drives unchecked vascular permeability, multiorgan dysfunction and ARDS mortality. Additional unmet needs including the lack of insights into factors predicting pathogenic hyperinflammatory viral host responses, limited approaches to address the vast disease heterogeneity in ARDS, and the absence of clinically-useful ARDS biomarkers. We review unmet needs persisting in COVID-19-induced ARDS in the context of the potential role for damage-associated molecular pattern proteins in lung and systemic hyperinflammatory host responses to SARS-CoV-2 infection that ultimately drive multiorgan dysfunction and ARDS mortality. Insights into promising stratification-enhancing, biomarker-based strategies in COVID-19 and non-COVID ARDS may enable the design of successful clinical trials of promising therapies.
• Carmona, E. M., Epelbaum, O., Evans, S. E., Hage, C. A., Jarrett, B., Knox, K. S., Limper, A. H., & Pennington, K. M. (2021). Antifungal Prophylaxis for Adult Recipients of Veno-Venous Extracorporeal Membrane Oxygenation: A Cautionary Stance During the COVID-19 Pandemic.. ASAIO journal (American Society for Artificial Internal Organs : 1992), 67(6), 611-613. doi:10.1097/mat.0000000000001456
• Casanova, N. G., Garcia, J. G., Gonzalez-garay, M. L., Knox, K. S., Lussier, Y. A., Ma, S. F., Ma, S., Noth, I., Sweiss, N. J., & Zhou, T. (2021). MicroRNA and protein-coding gene expression analysis in idiopathic pulmonary fibrosis yields novel biomarker signatures associated to survival.. Translational research : the journal of laboratory and clinical medicine, 228, 1-12. doi:10.1016/j.trsl.2020.07.009
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  Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown etiology that poses significant challenges in early diagnosis and prediction of progression. Analyses of microRNA and gene expression in IPF have yielded potentially predictive information. However, the relationship between microRNA/gene expression and quantitative phenotypic value in IPF remains controversial, as is the added value of this approach to current molecular signatures in IPF. To identify biomarkers predictive of survival in IPF via a microRNA-driven strategy. We profiled microRNA and protein-coding gene expression in peripheral blood mononuclear cells from 70 IPF subjects in a discovery cohort. We linked the microRNA/gene expression level with the quantitative phenotypic variation in IPF, including diffusing capacity of the lung for carbon monoxide and the forced vital capacity percent predicted. In silico analyses of expression profiles and quantitative phenotypic data allowed the generation of 2 sets of IPF molecular signatures (unique for microRNAs and protein-coding genes) that predict IPF survival. Each signature performed well in a validation cohort comprised of IPF patients aggregated from distinct patient populations recruited from different sites. Resampling test suggests that the protein-coding gene based signature is comparable and potentially superior to published IPF prognostic gene signatures. In conclusion, these results highlight the utility of microRNA-driven peripheral blood molecular signatures as valuable and novel biomarkers associated to individuals at high survival risk and for potentially facilitating individualized therapies in this enigmatic disorder.
• Christie, I., Knox, K. S., Lifshitz, J., Nakaji, P., Rice, A. D., Roberts, R. G., Rowe, R. K., Saber, M., & Wang, T. (2021). Remote Ischemic Conditioning Reduced Acute Lung Injury After Traumatic Brain Injury in the Mouse.. Shock (Augusta, Ga.), 55(2), 256-267. doi:10.1097/shk.0000000000001618
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  Traumatic brain injury (TBI) can induce acute lung injury (ALI). The exact pathomechanism of TBI-induced ALI is poorly understood, limiting treatment options. Remote ischemic conditioning (RIC) can mitigate detrimental outcomes following transplants, cardiac arrests, and neurological injuries. In this study, we hypothesized that RIC would reduce TBI-induced ALI by regulating the sphingosine-1-phosphate (S1P)-dependent pathway, a central regulator of endothelial barrier integrity, lymphocyte, and myokine trafficking. Male mice were subjected to either diffuse TBI by midline fluid percussion or control sham injury and randomly assigned among four groups: sham, TBI, sham RIC, or TBI RIC; RIC was performed 1 h prior to TBI. Mice were euthanized at 1-h postinjury or 7 days post-injury (DPI) and lung tissue, bronchoalveolar lavage (BAL) fluid, and blood were collected. Lung tissue was analyzed for histopathology, irisin myokine levels, and S1P receptor levels. BAL fluid and blood were analyzed for cellularity and myokine/S1P levels, respectively. One-hour postinjury, TBI damaged lung alveoli and increased neutrophil infiltration; RIC preserved alveoli. BAL from TBI mice had more neutrophils and higher neutrophil/monocyte ratios compared with sham, where TBI RIC mice showed no injury-induced change. Further, S1P receptor 3 and irisin-associated protein levels were significantly increased in the lungs of TBI mice compared with sham, which was prevented by RIC. However, there was no RIC-associated change in plasma irisin or S1P. At 7 DPI, ALI in TBI mice was largely resolved, with evidence for residual lung pathology. Thus, RIC may be a viable intervention for TBI-induced ALI to preserve lung function and facilitate clinical management.
• Epelbaum, O., Carmona, E., Evans, S., Hage, C., Jarrett, B., Knox, K., Limper, A., & Pennington, K. (2021). Antifungal Prophylaxis for Adult Recipients of Veno-Venous Extracorporeal Membrane Oxygenation: A Cautionary Stance During the COVID-19 Pandemic. ASAIO Journal, 67(6). doi:10.1097/MAT.0000000000001456
• Harris, D. T., Badowski, M., Jernigan, B., Sprissler, R., Edwards, T., Cohen, R., Paul, S., Merchant, N., Weinkauf, C. C., Bime, C., Erickson, H. E., Bixby, B., Parthasarathy, S., Chaudhary, S., Natt, B., Cristan, E., El Aini, T., Rischard, F., Campion, J., , Chopra, M., et al. (2021). SARS-CoV-2 rapid antigen testing of symptomatic and asymptomatic individuals on the University of Arizona campus. Biomedicines, 9(Issue 5). doi:10.3390/biomedicines9050539
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  SARS-CoV-2, the cause of COVID19, has caused a pandemic that has infected more than 80 M and killed more than 1.6 M persons worldwide. In the US as of December 2020, it has infected more than 32 M people while causing more than 570,000 deaths. As the pandemic persists, there has been a public demand to reopen schools and university campuses. To consider these demands, it is necessary to rapidly identify those individuals infected with the virus and isolate them so that disease transmission can be stopped. In the present study, we examined the sensitivity of the Quidel Rapid Antigen test for use in screening both symptomatic and asymptomatic individuals at the University of Arizona from June to August 2020. A total of 885 symptomatic and 1551 asymptomatic subjects were assessed by antigen testing and real-time PCR testing. The sensitivity of the test for both symptomatic and asymptomatic persons was between 82 and 90%, with some caveats.
• Saber, M., Rice, A., Christie, I., Roberts, R., Knox, K., Nakaji, P., Rowe, R., Wang, T., & Lifshitz, J. (2021). Remote ischemic conditioning reduced acute lung injury after traumatic brain injury in the mouse. Shock, 55(2). doi:10.1097/SHK.0000000000001618
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  Traumatic brain injury (TBI) can induce acute lung injury (ALI). The exact pathomechanism of TBI-induced ALI is poorly understood, limiting treatment options. Remote ischemic conditioning (RIC) can mitigate detrimental outcomes following transplants, cardiac arrests, and neurological injuries. In this study, we hypothesized that RIC would reduce TBIinduced ALI by regulating the sphingosine-1-phosphate (S1P)-dependent pathway, a central regulator of endothelial barrier integrity, lymphocyte, and myokine trafficking. Male mice were subjected to either diffuse TBI by midline fluid percussion or control sham injury and randomly assigned among four groups: sham, TBI, sham RIC, or TBI RIC; RIC was performed 1 h prior to TBI. Mice were euthanized at 1-h postinjury or 7 days post-injury (DPI) and lung tissue, bronchoalveolar lavage (BAL) fluid, and blood were collected. Lung tissue was analyzed for histopathology, irisin myokine levels, and S1P receptor levels. BAL fluid and blood were analyzed for cellularity and myokine/S1P levels, respectively. One-hour postinjury, TBI damaged lung alveoli and increased neutrophil infiltration; RIC preserved alveoli. BAL from TBI mice had more neutrophils and higher neutrophil/monocyte ratios compared with sham, where TBI RIC mice showed no injury-induced change. Further, S1P receptor 3 and irisin-associated protein levels were significantly increased in the lungs of TBI mice compared with sham, which was prevented by RIC. However, there was no RIC-associated change in plasma irisin or S1P. At 7 DPI, ALI in TBI mice was largely resolved, with evidence for residual lung pathology. Thus, RIC may be a viable intervention for TBI-induced ALI to preserve lung function and facilitate clinical management.
• Zhou, J., Zhai, J., Zhou, H., Chen, Y., Guerra, S., Robey, I., Weinstock, G., Weinstock, E., Dong, Q., Knox, K., & Twigg, H. (2021). Supraglottic Lung Microbiome Taxa Are Associated with Pulmonary Abnormalities in an HIV longitudinal cohort. American Journal of Respiratory and Critical Care Medicine, 202(12). doi:10.1164/rccm.202004-1086LE
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  Rationale: CC16 (club cell secretory protein) is a pneumoprotein produced predominantly by pulmonary club cells. Circulating CC16 is associated with protection from the inception and progression of the two most common obstructive lung diseases (asthma and chronic obstructive pulmonary disease). Objectives: Although exact mechanisms remain elusive, studies consistently suggest a causal role of CC16 in mediating antiinflammatory and antioxidant functions in the lung. We sought to determine any novel receptor systems that could participate in CC16's role in obstructive lung diseases. Methods: Protein alignment of CC16 across species led to the discovery of a highly conserved sequence of amino acids, leucine-valine-aspartic acid (LVD), a known integrin-binding motif. Recombinant CC16 was generated with and without the putative integrin-binding site. A Mycoplasma pneumoniae mouse model and a fluorescent cellular adhesion assay were used to determine the impact of the LVD site regarding CC16 function during live infection and on cellular adhesion during inflammatory conditions. Measurements and Main Results: CC16 bound to integrin a4b1), also known as the adhesion molecule VLA-4 (very late antigen 4), dependent on the presence of the LVD integrin-binding motif. During infection, recombinant CC16 rescued lung function parameters both when administered to the lung and intravenously but only when the LVD integrin-binding site was intact; likewise, neutrophil recruitment during infection and leukocyte adhesion were both impacted by the loss of the LVD site. Conclusions: We discovered a novel receptor for CC16, VLA-4, which has important mechanistic implications for the role of CC16 in circulation as well as in the lung compartment.
• Aini, T. E., Bhattacharya, D., Bime, C., Bixby, B., Bradshaw, C., Campion, J., Capaldi, A. P., Castaneda, Y., Chaudhary, S., Chopra, M., Cristan, E., Dake, M. D., Edwards, T., Erickson, H. L., Harris, D. T., Hypes, C., Insel, M., Kaplan, M. E., Knepler, J. L., , Knox, K. S., et al. (2020). Orthogonal SARS-CoV-2 Serological Assays Enable Surveillance of Low-Prevalence Communities and Reveal Durable Humoral Immunity.. Immunity, 53(5), 925-933.e4. doi:10.1016/j.immuni.2020.10.004
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  We conducted a serological study to define correlates of immunity against SARS-CoV-2. Compared to those with mild coronavirus disease 2019 (COVID-19) cases, individuals with severe disease exhibited elevated virus-neutralizing titers and antibodies against the nucleocapsid (N) and the receptor binding domain (RBD) of the spike protein. Age and sex played lesser roles. All cases, including asymptomatic individuals, seroconverted by 2 weeks after PCR confirmation. Spike RBD and S2 and neutralizing antibodies remained detectable through 5-7 months after onset, whereas α-N titers diminished. Testing 5,882 members of the local community revealed only 1 sample with seroreactivity to both RBD and S2 that lacked neutralizing antibodies. This fidelity could not be achieved with either RBD or S2 alone. Thus, inclusion of multiple independent assays improved the accuracy of antibody tests in low-seroprevalence communities and revealed differences in antibody kinetics depending on the antigen. We conclude that neutralizing antibodies are stably produced for at least 5-7 months after SARS-CoV-2 infection.
• Ampel, N. M., Carranza-chahal, R., Durkin, M., Erickson, H., Holbrook, E. D., Hoover, S. E., Knox, K. S., Malo, J., Oren, E., Robey, I. F., Strawter, C., Thompson, C., Wheat, L. J., & Zangeneh, T. T. (2020). Comparison of three anti-coccidioides antibody enzyme immunoassay kits for the diagnosis of coccidioidomycosis.. Medical mycology, 58(6), 774-778. doi:10.1093/mmy/myz125
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  Coccidioidomycosis is a common cause of community-acquired pneumonia in endemic areas of the southwestern United States. Clinical presentations range from self-limited disease to severe, disseminated disease. As such, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic testing has variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from patients with coccidioidomycosis and controls were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies using the MVista Coccidioides antibody detection EIA and two commonly used commercial enzyme immunoassay (EIA) kits: the IMMY Omega EIA and the Meridian Premier EIA. The sensitivity of the IgG antibody detection was 87.4% using the MVista test compared to 46.6% for IMMY and 70.9% for Meridian. The sensitivity for IgM antibody detection was 61.2% for the MVista test, 22.3% for IMMY and 29.1% for Meridian. For IgG antibody detection, specificity was 90% for the MVista EIA, 94.6% for IMMY, 96.4% for Meridian. For IgM antibody detection, specificity was 95.3% for the MVista test 98.2% for IMMY and 99.1% for Meridian. The MVista Coccidioides antibody EIA offers improved sensitivity, including among high-risk patient populations, for the detection of IgG and IgM antibodies in comparison to other currently available EIAs.
• Bhattacharya, D. T., Bhattacharya, D. S., Bhattacharya, D. J., Bhattacharya, D., Fain, M. J., Knox, K. S., Natt, B., Nikolich-zugich, J., & Tafich Rios, C. T. (2020). Correction to: SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes.. GeroScience, 42(3), 1013-1013. doi:10.1007/s11357-020-00193-1
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  The affiliation of the second author (Kenneth S. Knox) should have been Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, AZ 85004, USA instead of Department of Medicine, University of Arizona-Phoenix, Phoenix, AZ 85004, USA.
• Bhattacharya, D., Fain, M. J., Knox, K. S., Natt, B., Nikolich-zugich, J., Rios, C. T., & Tafich Rios, C. T. (2020). SARS-CoV-2 and COVID-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes.. GeroScience, 42(2), 505-514. doi:10.1007/s11357-020-00186-0
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  SARS-CoV-2 virus, the causative agent of the coronavirus infectious disease-19 (COVID-19), is taking the globe by storm, approaching 500,000 confirmed cases and over 21,000 deaths as of March 25, 2020. While under control in some affected Asian countries (Taiwan, Singapore, Vietnam), the virus demonstrated an exponential phase of infectivity in several large countries (China in late January and February and many European countries and the USA in March), with cases exploding by 30–50,000/day in the third and fourth weeks of March, 2020. SARS-CoV-2 has proven to be particularly deadly to older adults and those with certain underlying medical conditions, many of whom are of advanced age. Here, we briefly review the virus, its structure and evolution, epidemiology and pathogenesis, immunogenicity and immune, and clinical response in older adults, using available knowledge on SARS-CoV-2 and its highly pathogenic relatives MERS-CoV and SARS-CoV-1. We conclude by discussing clinical and basic science approaches to protect older adults against this disease.
• Bime, C., Casanova, N. G., Chaudhary, S., Crouser, E. D., Garcia, J. G., Gonzales, T., Gonzalez-garay, M. L., Knox, K. S., Lussier, Y. A., Natt, B., Sammani, N., Sun, X., & Sun, B. (2020). Differential transcriptomics in sarcoidosis lung and lymph node granulomas with comparisons to pathogen-specific granulomas.. Respiratory research, 21(1), 321. doi:10.1186/s12931-020-01537-3
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  Despite the availability of multi-"omics" strategies, insights into the etiology and pathogenesis of sarcoidosis have been elusive. This is partly due to the lack of reliable preclinical models and a paucity of validated biomarkers. As granulomas are a key feature of sarcoidosis, we speculate that direct genomic interrogation of sarcoid tissues, may lead to identification of dysregulated gene pathways or biomarker signatures..To facilitate the development sarcoidosis genomic biomarkers by gene expression profiling of sarcoidosis granulomas in lung and lymph node tissues (most commonly affected organs) and comparison to infectious granulomas (coccidiodomycosis and tuberculosis)..Transcriptomic profiles of immune-related gene from micro-dissected sarcoidosis granulomas within lung and mediastinal lymph node tissues and compared to infectious granulomas from paraffin-embedded blocks. Differentially-expressed genes (DEGs) were profiled, compared among the three granulomatous diseases and analyzed for functional enrichment pathways..Despite histologic similarities, DEGs and pathway enrichment markedly differed in sarcoidosis granulomas from lymph nodes and lung. Lymph nodes showed a clear immunological response, whereas a structural regenerative response was observed in lung. Sarcoidosis granuloma gene expression data corroborated previously reported genomic biomarkers (STAB1, HBEGF, and NOTCH4), excluded others and identified new genomic markers present in lung and lymph nodes, ADAMTS1, NPR1 and CXCL2. Comparisons between sarcoidosis and pathogen granulomas identified pathway divergences and commonalities at gene expression level..These findings suggest the importance of tissue and disease-specificity evaluation when exploring sarcoidosis genomic markers. This relevant translational information in sarcoidosis and other two histopathological similar infections provides meaningful specific genomic-derived biomarkers for sarcoidosis diagnosis and prognosis.
• Bime, C., Chaudhary, S., Glassberg, M. K., Knox, K. S., & Natt, B. (2020). Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused.. Frontiers in medicine, 7, 539. doi:10.3389/fmed.2020.00539
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  After decades of research, two therapies for chronic fibrotic lung disease are now approved by the FDA, with dozens more anti-fibrotic therapies in the pipeline. A great deal of enthusiasm has been generated for the use of these drugs, which are by no means curative but clearly have a favorable impact on lung function decline over time. Amidst a flurry of newly developed and repurposed drugs to treat the coronavirus disease 2019 (COVID-19) and its accompanying acute respiratory distress syndrome (ARDS), few have emerged as effective. Historically, survivors of severe viral pneumonia and related acute lung injury with ARDS often have near full recovery of lung function. While the pathological findings of the lungs of patients with COVID-19 can be diverse, current reports have shown significant lung fibrosis predominantly in autopsy studies. There is growing enthusiasm to study anti-fibrotic therapy for inevitable lung fibrosis, and clinical trials are underway using currently FDA-approved anti-fibrotic therapies. Given the relatively favorable outcomes of survivors of virus-mediated ARDS and the low prevalence of clinically meaningful lung fibrosis in survivors, this perspective examines if there is a rationale for testing these repurposed antifibrotic agents in COVID-19-associated lung disease.
• Bime, C., Chaudhary, S., Glassberg, M. K., Knox, K. S., & Natt, B. (2020). Corrigendum: Antifibrotics in COVID-19 Lung Disease: Let Us Stay Focused.. Frontiers in medicine, 7, 604640. doi:10.3389/fmed.2020.604640
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  [This corrects the article DOI: 10.3389/fmed.2020.00539.].
• Brenchley, J. M., Flynn, J. K., Knox, K. S., Lai, S. H., Ortiz, A. M., Sereti, I., Sortino, O., Starke, C. E., & Vinton, C. L. (2020). Biomarkers of Cellular Stress Do Not Associate with sCD14 in Progressive HIV and SIV Infections in Vivo.. Pathogens & immunity, 5(1), 68-88. doi:10.20411/pai.v5i1.363
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  Background: Microbial translocation occurs after damage to the structural and/or immunological barrier of the gastrointestinal (GI) tract into circulation. Microbial components that trans-locate from the lumen of the GI tract directly stimulate the immune system and contribute to inflammation. When microbial translocation becomes chronic, the inflammation has detrimental consequences. Given that microbial translocation is an important phenomenon in many diseases, defining biomarkers that reliably reflect microbial translocation is critical. Measurement of systemic microbial products is difficult since: 1) robust assays to measure microbial antigens simultaneously are lacking; 2) confounding factors influence assays used to detect microbial products; and 3) biological clearance mechanisms limit their detection in circulation. Thus, host proteins produced in response to microbial stimulation are used as surrogates for microbial translocation; however, many of these proteins are also produced in response to host proteins expressed by dying cells. Methods: We measured plasma levels of biomarkers associated with GI tract damage, immune responses to microbial products, and cell-death in people living with HIV before and after antiretroviral administration, and in macaque nonhuman primates before and after SIV infection. Results: Proteins secreted during cellular stress (receptor for advanced glycation endproducts-RAGE and high motility group box 1-HMGB1), which can induce sCD14 production in vitro and in vivo, do not associate with elevated levels of biomarkers associated with microbial translocation in progressively HIV-infected individuals and SIV-infected NHPs. Conclusions: Bystander cell death and generalized inflammation do not contribute to elevated levels of sCD14 observed in HIV/SIV-infected individuals.
• Chen, Q., Gu, W., Knox, K. S., Li, W., Li, R., Li, M., Liu, H., Lv, J., Qi, T., Qian, Z., Shi, J., Wang, Z., Wang, X., Wang, T., Wen, G., Zhang, X., Zhou, T., Zhou, J. J., Zhou, D., , Zhou, C., et al. (2020). Peripheral blood non-canonical small non-coding RNAs as novel biomarkers in lung cancer.. Molecular cancer, 19(1), 159. doi:10.1186/s12943-020-01280-9
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  One unmet challenge in lung cancer diagnosis is to accurately differentiate lung cancer from other lung diseases with similar clinical symptoms and radiological features, such as pulmonary tuberculosis (TB). To identify reliable biomarkers for lung cancer screening, we leverage the recently discovered non-canonical small non-coding RNAs (i.e., tRNA-derived small RNAs [tsRNAs], rRNA-derived small RNAs [rsRNAs], and YRNA-derived small RNAs [ysRNAs]) in human peripheral blood mononuclear cells and develop a molecular signature composed of distinct ts/rs/ysRNAs (TRY-RNA). Our TRY-RNA signature precisely discriminates between control, lung cancer, and pulmonary TB subjects in both the discovery and validation cohorts and outperforms microRNA-based biomarkers, which bears the diagnostic potential for lung cancer screening.
• Chen, Y., Dong, Q., Guerra, S., Knox, K. S., Robey, I. F., Twigg, H. L., Weinstock, G. M., Weinstock, E. S., Zhai, J., Zhou, J. J., & Zhou, H. (2020). Supraglottic Lung Microbiome Taxa Are Associated with Pulmonary Abnormalities in an HIV Longitudinal Cohort.. American journal of respiratory and critical care medicine, 202(12), 1727-1731. doi:10.1164/rccm.202004-1086le
• Garcia, J. G., Gonzalez-Garay, M. L., Knox, K. S., Wang, T., Lussier, Y. A., Casanova, N., & Zhou, T. (2020). MicroRNA and Protein-Coding Gene Expression Analysis in Idiopathic Pulmonary Fibrosis Yields Novel Biomarker Signatures Predicting Survival. Translational Research.
• Malo, J., Holbrook, E., Zangeneh, T., Strawter, C., Oren, E., Robey, I., Erickson, H., Carranza-Chahal, R., Durkin, M., Thompson, C., Hoover, S., Ampel, N., Joseph Wheat, L., & Knox, K. (2020). Comparison of three anti-coccidioides antibody enzyme immunoassay kits for the diagnosis of coccidioidomycosis. Medical Mycology, 58(6). doi:10.1093/MMY/MYZ125
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  Coccidioidomycosis is a common cause of community-acquired pneumonia in endemic areas of the southwestern United States. Clinical presentations range from self-limited disease to severe, disseminated disease. As such, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic testing has variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from patients with coccidioidomycosis and controls were tested for immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies using the MVista Coccidioides antibody detection EIA and two commonly used commercial enzyme immunoassay (EIA) kits: the IMMY Omega EIA and the Meridian Premier EIA. The sensitivity of the IgG antibody detection was 87.4% using the MVista test compared to 46.6% for IMMY and 70.9% for Meridian. The sensitivity for IgM antibody detection was 61.2% for the MVista test, 22.3% for IMMY and 29.1% for Meridian. For IgG antibody detection, specificity was 90% for the MVista EIA, 94.6% for IMMY, 96.4% for Meridian. For IgM antibody detection, specificity was 95.3% for the MVista test 98.2% for IMMY and 99.1% for Meridian. The MVista Coccidioides antibody EIA offers improved sensitivity, including among high-risk patient populations, for the detection of IgG and IgM antibodies in comparison to other currently available EIAs.
• Carmona, E. M., Epelbaum, O., Evans, S. E., Gabe, L. M., Hage, C. A., Haydour, Q., Knox, K. S., Kolls, J. K., Limper, A. H., Murad, M. H., & Wengenack, N. L. (2019). Microbiological Laboratory Testing in the Diagnosis of Fungal Infections in Pulmonary and Critical Care Practice. An Official American Thoracic Society Clinical Practice Guideline.. American journal of respiratory and critical care medicine, 200(5), 535-550. doi:10.1164/rccm.201906-1185st
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  Background: Fungal infections are of increasing incidence and importance in immunocompromised and immunocompetent patients. Timely diagnosis relies on appropriate use of laboratory testing in susceptible patients.Methods: The relevant literature related to diagnosis of invasive pulmonary aspergillosis, invasive candidiasis, and the common endemic mycoses was systematically reviewed. Meta-analysis was performed when appropriate. Recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation approach.Results: This guideline includes specific recommendations on the use of galactomannan testing in serum and BAL and for the diagnosis of invasive pulmonary aspergillosis, the role of PCR in the diagnosis of invasive pulmonary aspergillosis, the role of β-d-glucan assays in the diagnosis of invasive candidiasis, and the application of serology and antigen testing in the diagnosis of the endemic mycoses.Conclusions: Rapid, accurate diagnosis of fungal infections relies on appropriate application of laboratory testing, including antigen testing, serological testing, and PCR-based assays.
• Carmona, E. M., Epelbaum, O., Evans, S. E., Gabe, L. M., Hage, C. A., Haydour, Q., Knox, K. S., Kolls, J. K., Limper, A. H., Murad, M. H., Prokop, L. J., & Wengenack, N. L. (2019). Diagnosis of Fungal Infections. A Systematic Review and Meta-Analysis Supporting American Thoracic Society Practice Guideline.. Annals of the American Thoracic Society, 16(9), 1179-1188. doi:10.1513/annalsats.201811-766oc
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  Rationale: Prompt diagnosis of invasive fungal infections is important because of the associated morbidity and mortality; however, diagnosis is challenging because of the nonspecific symptoms and radiographic findings.Objectives: To conduct a systematic review and meta-analysis of studies that evaluated the diagnostic accuracy of serum and bronchoalveolar lavage (BAL) galactomannan (GM) and serum or BAL polymerase chain reaction (PCR) in patients with suspected invasive aspergillosis (IA), β-d-glucan in critically ill patients at risk for candidiasis or candidemia, and serology testing and antigen detection in patients with endemic mycoses (histoplasmosis, blastomycosis, and coccidioidomycosis).Methods: Studies were selected and appraised by pairs of reviewers. Bivariate random effects meta-analysis was used to generate pooled sensitivity, specificity, and diagnostic likelihood ratios.Results: Serum GM in patients with impaired immunity suspected of having IA had sensitivity of 0.71 (95% confidence interval [CI], 0.64-0.78) and specificity of 0.89 (95% CI, 0.84-0.92). A cutoff of 1 optical density index yielded optimal sensitivity and specificity. BAL GM in patients with impaired immunity suspected of having IA had sensitivity of 0.84 (95% CI, 0.73-0.91) and specificity of 0.88 (95% CI, 0.81-0.91). Serum or whole-blood PCR in immunocompromised patients with suspected IA had sensitivity of 0.81 (95% CI, 0.73-0.86) and specificity of 0.79 (95% CI, 0.68-0.86). BAL PCR in patients at high risk for IA had high sensitivity of 0.90 (95% CI, 0.77-0.96) and specificity of 0.96 (95% CI, 0.93-0.98) for diagnosing IA. β-d-glucan assay in patients in the intensive care unit at risk for invasive candidiasis or candidemia had sensitivity of 0.81 (95% CI, 0.74-0.86) and specificity of 0.60 (95% CI, 0.49-0.71). Data on diagnostic accuracy of antigen detection and serology testing for endemic mycoses were limited and heterogeneous (varied according to test, patient immunity, and suspected endemic disease).Conclusions: The diagnosis of invasive fungal infections remains a challenge. Various serum and BAL markers can aid in diagnosis. This evidence supports the development of clinical practice recommendations by the American Thoracic Society.
• Zhou, H., Knox, K. S., Twigg, H. L., Zhai, J., & Zhou, J. J. (2019). Exact variance component tests for longitudinal microbiome studies.. Genetic epidemiology, 43(3), 250-262. doi:10.1002/gepi.22185
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  In metagenomic studies, testing the association between microbiome composition and clinical outcomes translates to testing the nullity of variance components. Motivated by a lung human immunodeficiency virus (HIV) microbiome project, we study longitudinal microbiome data by using variance component models with more than two variance components. Current testing strategies only apply to models with exactly two variance components and when sample sizes are large. Therefore, they are not applicable to longitudinal microbiome studies. In this paper, we propose exact tests (score test, likelihood ratio test, and restricted likelihood ratio test) to (a) test the association of the overall microbiome composition in a longitudinal design and (b) detect the association of one specific microbiome cluster while adjusting for the effects from related clusters. Our approach combines the exact tests for null hypothesis with a single variance component with a strategy of reducing multiple variance components to a single one. Simulation studies demonstrate that our method has a correct type I error rate and superior power compared to existing methods at small sample sizes and weak signals. Finally, we apply our method to a longitudinal pulmonary microbiome study of HIV-infected patients and reveal two interesting genera Prevotella and Veillonella associated with forced vital capacity. Our findings shed light on the impact of the lung microbiome on HIV complexities. The method is implemented in the open-source, high-performance computing language Julia and is freely available at https://github.com/JingZhai63/VCmicrobiome.
• Zhai, J., Kim, J., Knox, K. S., Twigg, H. L., Zhou, H., & Zhou, J. J. (2018). Variance Component Selection With Applications to Microbiome Taxonomic Data. Frontiers in microbiology, 9, 509.
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  High-throughput sequencing technology has enabled population-based studies of the role of the human microbiome in disease etiology and exposure response. Microbiome data are summarized as counts or composition of the bacterial taxa at different taxonomic levels. An important problem is to identify the bacterial taxa that are associated with a response. One method is to test the association of specific taxon with phenotypes in a linear mixed effect model, which incorporates phylogenetic information among bacterial communities. Another type of approaches consider all taxa in a joint model and achieves selection via penalization method, which ignores phylogenetic information. In this paper, we consider regression analysis by treating bacterial taxa at different level as multiple random effects. For each taxon, a kernel matrix is calculated based on distance measures in the phylogenetic tree and acts as one variance component in the joint model. Then taxonomic selection is achieved by the lasso (least absolute shrinkage and selection operator) penalty on variance components. Our method integrates biological information into the variable selection problem and greatly improves selection accuracies. Simulation studies demonstrate the superiority of our methods versus existing methods, for example, group-lasso. Finally, we apply our method to a longitudinal microbiome study of Human Immunodeficiency Virus (HIV) infected patients. We implement our method using the high performance computing language Julia. Software and detailed documentation are freely available at https://github.com/JingZhai63/VCselection.
• Zhou, T., Xie, X., Li, M., Shi, J., Zhou, J. J., Knox, K. S., Wang, T., Chen, Q., & Gu, W. (2018). Rat BodyMap transcriptomes reveal unique circular RNA features across tissue types and developmental stages. RNA (New York, N.Y.), 24(11), 1443-1456.
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  Circular RNAs (circRNAs) are a novel class of regulatory RNAs. Here, we present a comprehensive investigation of circRNA expression profiles across 11 tissues and four developmental stages in rats, along with cross-species analyses in humans and mice. Although the expression of circRNAs is positively correlated with that of cognate mRNAs, highly expressed genes tend to splice a larger fraction of circular transcripts. Moreover, circRNAs exhibit higher tissue specificity than cognate mRNAs. Intriguingly, while we observed a monotonic increase of circRNA abundance with age in the rat brain, we further discovered a dynamic, age-dependent pattern of circRNA expression in the testes that is characterized by a dramatic increase with advancing stages of sexual maturity and a decrease with aging. The age-sensitive testicular circRNAs are highly associated with spermatogenesis, independent of cognate mRNA expression. The tissue/age implications of circRNAs suggest that they present unique physiological functions rather than simply occurring as occasional by-products of gene transcription.
• Arteaga, V., & Knox, K. S. (2017). Medical image of the week: fibrosing mediastinitis. Southwest Journal of Pulmonary and Critical Care, 14(2), 85-85. doi:10.13175/swjpcc015-17
• Block, K. E., Bradley, C. P., Felix, K. M., Huang, H., Knox, K. S., Littman, D. R., Naskar, D., Sano, T., Teng, F., & Wu, H. J. (2017). Segmented Filamentous Bacteria Provoke Lung Autoimmunity by Inducing Gut-Lung Axis Th17 Cells Expressing Dual TCRs.. Cell host & microbe, 22(5), 697-704.e4. doi:10.1016/j.chom.2017.10.007
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  Lung complications are a major cause of rheumatoid arthritis-related mortality. Involvement of gut microbiota in lung diseases by the gut-lung axis has been widely observed, but the underlying mechanism remains mostly unknown. Using an autoimmune arthritis model, we show that a constituent of the gut microbiota, segmented filamentous bacteria (SFB), distantly provoke lung pathology. SFB induce autoantibodies in lung during the pre-arthritic phase, and SFB-dependent lung pathology requires the T helper 17 (Th17) responses. SFB-induced gut Th17 cells are preferentially recruited to lung over spleen due to robust expression in the lung of the Th17 chemoattractant, CCL20. Additionally, we found that in peripheral tissues, SFB selectively expand dual T cell receptor (TCR)-expressing Th17 cells recognizing both an SFB epitope and self-antigen, thus augmenting autoimmunity. This study reveals mechanisms for commensal-mediated gut-lung crosstalk and dual TCR-based autoimmunity.
• Chaudhary, S., Meinke, L., Ateeli, H., Knox, K. S., Raz, Y., & Ampel, N. M. (2017). Coccidioidomycosis among persons undergoing lung transplantation in the coccidioidal endemic region. Transplant infectious disease : an official journal of the Transplantation Society, 19(4).
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  Coccidioidomycosis, an endemic fungal infection, is more likely to be symptomatic and severe among those receiving allogeneic transplants. While several case series have been published for various transplanted organs, none has described the incidence and outcomes in those receiving lung transplants within the coccidioidal endemic region.
• DiNapoli, S. R., Ortiz, A. M., Wu, F., Matsuda, K., Twigg, H. L., Hirsch, V. M., Knox, K., & Brenchley, J. M. (2017). Tissue-resident macrophages can contain replication-competent virus in antiretroviral-naive, SIV-infected Asian macaques. JCI insight, 2(4), e91214.
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  SIV DNA can be detected in lymphoid tissue-resident macrophages of chronically SIV-infected Asian macaques. These macrophages also contain evidence of recently phagocytosed SIV-infected CD4 T cells. Here, we examine whether these macrophages contain replication-competent virus, whether viral DNA can be detected in tissue-resident macrophages from antiretroviral (ARV) therapy-treated animals and humans, and how the viral sequences amplified from macrophages and contemporaneous CD4 T cells compare. In ARV-naive animals, we find that lymphoid tissue-resident macrophages contain replication-competent virus if they also contain viral DNA in ARV-naive Asian macaques. The genetic sequence of the virus within these macrophages is similar to those within CD4 T cells from the same anatomic sites. In ARV-treated animals, we find that viral DNA can be amplified from lymphoid tissue-resident macrophages of SIV-infected Asian macaques that were treated with ARVs for at least 5 months, but we could not detect replication-competent virus from macrophages of animals treated with ARVs. Finally, we could not detect viral DNA in alveolar macrophages from HIV-infected individuals who received ARVs for 3 years and had undetectable viral loads. These data demonstrate that macrophages can contain replication-competent virus, but may not represent a significant reservoir for HIV in vivo.
• Gabe, L. M., Malo, J., & Knox, K. S. (2017). Diagnosis and Management of Coccidioidomycosis. Clinics in chest medicine, 38(3), 417-433.
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  Coccidioidomycosis is a leading cause of community-acquired pneumonia within its traditional endemic zone in the Southwestern United States and portions of Mexico and Central and South America. Its incidence has increased dramatically within the endemic region; its presence outside of the region, facilitated by a mobile society, is also now substantial. Although only a fraction of the incident disease progresses beyond subclinical illness, this proportion is large in absolute terms and causes substantial disease burden. Diagnosis often depends on serologic interpretation. Treatment has been revolutionized by azole therapy. Controversy remains regarding the decision to treat in less severe disease.
• Kato, K., Hanss, A. D., Zemskova, M. A., Morgan, N. E., Kim, M., Knox, K. S., Lin, Y., Lillehoj, E. P., & Kim, K. C. (2017). Pseudomonas aeruginosa increases MUC1 expression in macrophages through the TLR4-p38 pathway. Biochemical and biophysical research communications, 492(2), 231-235.
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  Alveolar macrophages (AMs) play a critical role in the clearance of Pseudomonas aeruginosa (Pa) from the airways. However, hyper-activation of macrophages can impair bacterial clearance and contribute to morbidity and mortality. MUC1 mucin is a membrane-tethered, high molecular mass glycoprotein expressed on the apical surface of mucosal epithelial cells and some hematopoietic cells, including macrophages, where it counter-regulates inflammation. We recently reported that Pa up-regulates the expression of MUC1 in primary human AMs and THP-1 macrophages, and that increased MUC1 expression in these cells prevents hyper-activation of macrophages that appears to be important for host defense against severe pathology of Pa lung infection. The aims of this study were to elucidate the mechanism by which Pa increases MUC1 expression in macrophages. The results showed that: (a) Pa stimulation of THP-1 macrophages increased MUC1 expression both at transcriptional and protein levels in a dose-dependent manner; (b) Both Pa- and LPS-induced MUC1 expression in THP-1 cells were significantly diminished by an inhibitory peptide of TLR4; and (c) LPS-stimulated MUC1 expression was diminished at both the mRNA and protein levels by an inhibitor of the p38 mitogen-activated protein kinase, but not by inhibitors of ERK1/2, JNK, or IKK. We conclude that Pa-stimulated MUC1 expression in THP-1 macrophages is regulated mainly through the TLR4-p38 signaling pathway.
• Knox, K. S. (2017). Known unknowns: how might the persistent herpesvirome shape immunity and aging?. Current Opinion in Immunology.
• Knox, K. S., Ross, E., & Martinez, G. F. (2017). Academic medicine: Vice Chairs’ for Education perceptions of departmental culture. Journal of Higher Education Theory and Practice.
• Knox, K. S., Wheat, L. J., Ampel, N., Hoover, S. E., Thompson, C., Durkin, M., Chahal, R., Erickson, H., Robey, I., Oren, E., Strawter, C., Zangeneh, T. T., Holbrook, E., & Malo, J. (2017). Enhanced Antibody Detection and Diagnosis of Coccidioidomycosis with the MiraVista IgG and IgM Detection Enzyme. Journal of Clinical Microbiology, 55, 1-9.
• Malo, J., Holbrook, E., Zangeneh, T., Strawter, C., Oren, E., Robey, I., Erickson, H., Chahal, R., Durkin, M., Thompson, C., Hoover, S. E., Ampel, N. M., Wheat, L. J., & Knox, K. S. (2017). Enhanced Antibody Detection and Diagnosis of Coccidioidomycosis with the MiraVista IgG and IgM Detection Enzyme Immunoassay. Journal of clinical microbiology, 55(3), 893-901.
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  Coccidioidomycosis is a common cause of community-acquired pneumonia in areas of the southwestern United States in which the disease is endemic. Clinical presentations range from self-limited disease to severe disseminated disease. Therefore, early and accurate diagnosis is essential to ensure appropriate treatment and monitoring. Currently available diagnostic tests have variable accuracy, particularly in certain patient populations, and new tests may offer improved accuracy for the diagnosis of coccidioidomycosis. Serum samples from 103 cases of coccidioidomycosis and 373 controls were tested for IgG and IgM antibodies using the MVista anti- antibody enzyme immunoassay. Serum specimens from 170 controls from areas in which the disease is endemic and 44 cases were tested by immunodiffusion at MiraVista Diagnostics. The sensitivity of the MVista antibody assay was 88.3%, and the specificity was 90%. The sensitivity was maintained in the presence of immunocompromising conditions or immunosuppressive therapies. The sensitivity of immunodiffusion was 60.2%, and the specificity was 98.8%. The sensitivity of complement fixation (62 cases) was 66.1%, but the specificity could not be determined. The MVista anti- antibody enzyme immunoassay offers improved sensitivity, compared with immunodiffusion and complement fixation, is not impaired in immunocompromised patients, and permits highly reproducible semiquantification.
• Nikolich-Zugich, J., Goodrum, F., Knox, K., & Smithey, M. J. (2017). Known unknowns: how might the persistent herpesvirome shape immunity and aging?. Current opinion in immunology, 48, 23-30.
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  The microbial community that colonizes all living organisms is gaining appreciation for its contributions to both physiologic and pathogenic processes. The virome, a subset of the overall microbiome, large and diverse, including viruses that persistently inhabit host cells, endogenous viral elements genomically or epigenomically integrated into cells, and viruses that infect the other (bacterial, protozoan, fungal, and archaeal) microbiome phylla. These viruses live in the organism for its life, and therefore are to be considered part of the aging process experienced by the organism. This review considers the impact of the persistent latent virome on immune aging. Specific attention will be devoted to the role of herpesviruses, and within them, the cytomegalovirus, as the key modulators of immune aging.
• Zhou, T., Casanova, N., Pouladi, N., Wang, T., Lussier, Y., Knox, K. S., & Garcia, J. G. (2017). Identification of Jak-STAT signaling involvement in sarcoidosis severity via a novel microRNA-regulated peripheral blood mononuclear cell gene signature. Scientific reports, 7(1), 4237.
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  Sarcoidosis is a granulomatous lung disorder of unknown cause. The majority of individuals with sarcoidosis spontaneously achieve full remission (uncomplicated sarcoidosis), however, ~20% of sarcoidosis-affected individuals experience progressive lung disease or cardiac and nervous system involvement (complicated sarcoidosis). We investigated peripheral blood mononuclear cell (PBMC) microRNA and protein-coding gene expression data from healthy controls and patients with uncomplicated or complicated sarcoidosis. We identified 46 microRNAs and 1,559 genes that were differentially expressed across a continuum of sarcoidosis severity (healthy control → uncomplicated sarcoidosis → complicated sarcoidosis). A total of 19 microRNA-mRNA regulatory pairs were identified within these deregulated microRNAs and mRNAs, which consisted of 17 unique protein-coding genes yielding a 17-gene signature. Pathway analysis of the 17-gene signature revealed Jak-STAT signaling pathway as the most significantly represented pathway. A severity score was assigned to each patient based on the expression of the 17-gene signature and a significant increasing trend in the severity score was observed from healthy control, to uncomplicated sarcoidosis, and finally to complicated sarcoidosis. In addition, this microRNA-regulated gene signature differentiates sarcoidosis patients from healthy controls in independent validation cohorts. Our study suggests that PBMC gene expression is useful in diagnosis of sarcoidosis.
• Ampel, N. M., Chahal, R., Durkin, M., Erickson, H., Holbrook, E. D., Hoover, S. E., Knox, K. S., Malo, J., Oren, E., Robey, I. F., Strawter, C., Thompson, C., Wheat, L. J., & Zangeneh, T. T. (2016). Development of an Improved Antibody Detection EIA for Use in Diagnosis of Coccidioidomycosis.. Open Forum Infectious Diseases, 3(suppl_1). doi:10.1093/ofid/ofw172.1254
• Cordery, A. G., Desai, A. A., Garcia, J. G., Gupta, A., Knox, K. S., Larson, B. T., Lynn, H., Nair, V., Sprissler, R., & Yuan, J. X. (2016). Abstract 17494: Exome Sequencing Reveals a Novel SNP in TRPC6 in Pulmonary Arterial Hypertension. Circulation.
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  Introduction: The Ca2+ sensing receptor TRPC6 has been reported to promote pulmonary vascular disease. A functional promoter SNP (-254(C/G) has also been previously reported to be over-represented in patients with PAH. We hypothesized that there may be other novel SNPs associated with PAH in TRPC6. Methods: Whole-exome sequencing (WES) was performed on lung tissue DNA collected at the time of transplant or autopsy from 12 patients with PAH (WHO Group I). Standard BWA, SAMTOOLS, and GATK protocols were used to analyze WES data. Filtered SNPs on were compared against 1000 genomes and dbSNP databases for case-control analysis. In a separate PAH cohort (n=47, WHO Group I) with available clinical data, genotyping of a top candidate SNP, rs191383391, was performed via PCR. Association between genotype [wild-type (GG), homozygous recessive (TT)] and clinical phenotypes including right heart catheterization-defined pulmonary vascular resistance (PVRi), cardiac index (CI), cardiac MRI-defined right ventricular eje...
• Dherange, P., Black, S. M., Desai, A. A., Garcia, J. G., Khalpey, Z., Knox, K. S., Nair, V., Natarajan, B., Patel, K., Riaz, I. B., Rischard, F., Shewale, A., Suryanarayana, P., Whitaker, M., Yarlagadda, V., & Yuan, J. X. (2016). Abstract 18384: Hispanic Disparities in PAH: Multi-Modality Validation of Increased Susceptibility to Right Ventricular Dysfunction. Circulation, 134.
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  Introduction: Hispanics are known to have increased baseline right ventricular (RV) wall thickness and cardiovascular risk factors compared to non-Hispanics. We, therefore, hypothesized that Hispanics have reduced RV function in response to increased pulmonary afterload compared to non-Hispanics. Methods: A total of 127 WHO Groups I and IV pulmonary arterial hypertension (PAH) patients were prospectively enrolled and underwent echocardiography and right heart catheterization (RHC) within 4 months, with a subset also performing six-minute walk test (6MWT, n=86). After comparing baseline characteristics between self-reported Hispanics (n=28) and non-Hispanics (n=99), ethnicity effects were assessed using hierarchical linear regression models adjusted for age, gender, indexed pulmonary vascular resistance (PVRi), PAH medication use, and days from echo to RHC. Results: Baseline characteristics between the two groups were not significantly different except for age, which was higher in non-Hispanics (60.9+13.7 yrs) compared to Hispanics (51.9+12.2 yrs, P Conclusions: Hispanics with PAH exhibit increased pathological RV remodeling and systolic dysfunction validated by both echo and RHC with decreased trends in functional capacity (6MWT) compared to non-Hispanics. This susceptibility may be influenced, in part, by increased pulmonary artery elastance and relatively higher but “normal” wedge pressures.
• Kato, K., Uchino, R., Lillehoj, E. P., Knox, K., Lin, Y., & Kim, K. C. (2016). Membrane-Tethered MUC1 Mucin Counter-Regulates the Phagocytic Activity of Macrophages. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 54(4), 515-523.
• Kato, K., Uchino, R., Lillehoj, E. P., Knox, K., Lin, Y., & Kim, K. C. (2016). Membrane-tethered MUC1 mucin counter-regulates the phagocytic activity of macrophages. American Journal of Respiratory Cell and Molecular Biology, 54(Issue 4). doi:10.1165/rcmb.2015-0177oc
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  MUC1 (MUC in human; Muc in animals) is a transmembrane mucin glycoprotein expressed in mucosal epithelial cells and hematopoietic cells. MUC1 is involved in the resolution of inflammation during airway Pseudomonas aeruginosa (Pa) infection by suppressing Toll-like receptor signaling in airway epithelial cells. Although alveolar macrophages are recognized as critical mediators of cell-mediated immunity against microorganisms inhaled into the airways, the role of MUC1 in regulating their response is unknown. The aims of this study were to determine whether macrophages express MUC1, and, if so, whetherMUC1 expression might be associated with macrophage M0/M1/M2 differentiation or phagocytic activity. Human and mouse MUC1/Muc1 expression was drastically up-regulated in classically activated (M1) macrophages compared with nonactivated (M0) and alternatively activated (M2) macrophages. M1 polarization and Pa stimulation each increased MUC1 ectodomain shedding from the macrophage surface in a TNF-a-converting enzyme-dependent manner. MUC1/Muc1 deficiency in M0 macrophages increased adhesion and phagocytosis of Pa and Escherichia coli compared with MUC1/Muc1-expressing cells, and attenuation of phagocytosis by MUC1 was augmented after polarization into M1 macrophages compared with M0 macrophages. Finally, MUC1/Muc1 deficiency in macrophages increased reactive oxygen species production and TNF-a release in response to Pa compared with MUC1/Muc1-sufficient cells. These results indicate that MUC1/Muc1 expression by macrophages is predominantly in the M1 subtype, and that MUC1/Muc1 expression in these cells decreases their phagocytic activity in an antiinflammatory manner.
• Knox, K. S., & Martinez, G. F. (2016). A qualitative systematic review of the professionalization of the vice chair for education. Southwest Journal of Pulmonary and Critical Care, 12(6), 240-252. doi:10.13175/swjpcc044-16
• Pulko, V., Davies, J. S., Martinez, C., Lanteri, M. C., Busch, M. P., Diamond, M. S., Knox, K., Bush, E. C., Sims, P. A., Sinari, S., Billheimer, D., Haddad, E. K., Murray, K. O., Wertheimer, A. M., & Nikolich-Zugich, J. (2016). Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. NATURE IMMUNOLOGY, 17(8), 966-+.
• Pulko, V., Davies, J. S., Martinez, C., Lanteri, M. C., Busch, M. P., Diamond, M. S., Knox, K., Bush, E. C., Sims, P. A., Sinari, S., Billheimer, D., Haddad, E. K., Murray, K. O., Wertheimer, A. M., & Nikolich-Žugich, J. (2016). Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nature Immunology, 17(Issue 8). doi:10.1038/ni.3483
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  The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8+ T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8+ T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8+ T MNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens.
• Pulko, V., Davies, J. S., Martinez, C., Lanteri, M. C., Busch, M. P., Diamond, M. S., Knox, K., Bush, E. C., Sims, P. A., Sinari, S., Billheimer, D., Haddad, E. K., Murray, K. O., Wertheimer, A. M., & Nikolich-Žugich, J. (2016). Human memory T cells with a naive phenotype accumulate with aging and respond to persistent viruses. Nature immunology, 17(8), 966-75.
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  The number of naive T cells decreases and susceptibility to new microbial infections increases with age. Here we describe a previously unknown subset of phenotypically naive human CD8(+) T cells that rapidly secreted multiple cytokines in response to persistent viral antigens but differed transcriptionally from memory and effector T cells. The frequency of these CD8(+) T cells, called 'memory T cells with a naive phenotype' (TMNP cells), increased with age and after severe acute infection and inversely correlated with the residual capacity of the immune system to respond to new infections with age. CD8(+) TMNP cells represent a potential new target for the immunotherapy of persistent infections and should be accounted for and subtracted from the naive pool if truly naive T cells are needed to respond to antigens.
• Twigg Iii, H. L., Knox, K. S., Zhou, J., Crothers, K. A., Nelson, D. E., Toh, E., Day, R. B., Lin, H., Gao, X., Dong, Q., Mi, D., Katz, B. P., Sodergren, E., & Weinstock, G. M. (2016). Effect of Advanced HIV Infection on the Respiratory Microbiome. American journal of respiratory and critical care medicine.
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  Previous work found the lung microbiome in healthy HIV-infected subjects was similar to uninfected subjects. We hypothesized lung microbiome from HIV-infected subjects with more advanced disease would differ from an uninfected control population.
• Abdeljalil, A., Adler, A., Allen, S., Amend-libercci, D., Anthonisen, N. R., Antoine, A., Arana, J., Archer, N., Atik, M. A., Bacharier, L. B., Bailey, W. C., Banquet, A., Berry, C. E., Bertrand, L., Bhat, A., Bime, C., Blake, K., Boyer, J., Brees, A., , Brown, E. D., et al. (2015). Effect of a soy isoflavone supplement on lung function and clinical outcomes in patients with poorly controlled asthma: a randomized clinical trial.. JAMA, 313(20), 2033-43. doi:10.1001/jama.2015.5024
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  Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control..To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease..Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24..Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks..The primary outcome measure was change in forced expiratory volume in the first second (FEV1) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation..Mean changes in prebronchodilator FEV1 over 24 weeks were 0.03 L (95% CI, -0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, -0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different (P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, -3.48 ppb [95% CI, -5.99 to -0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, -1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL (P < .001) in participants receiving the supplement..Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma..clinicaltrials.gov Identifier: NCT01052116.
• Ampel, M., Nesbit, M., Nguyen, M., Chavez, M., Knox, M., Johnson, M., & Pappagianis, M. (2015). Cytokine Profiles from Antigen-Stimulated Whole-Blood Samples among Patients with Pulmonary or Nonmeningeal Disseminated Coccidioidomycosis. Clinical and vaccine immunology : CVI, 22(8), 917-22.
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  The outcome of coccidioidomycosis depends on a robust specific cellular immune response. A T-helper type 1 (Th1) cellular immune response has been previously associated with resolution of clinical illness. However, the precise elements of this response and whether cytokines not involved with the Th1 response play a role in coccidioidomycosis are not known. Whole-blood samples were obtained from subjects with active coccidioidomycosis and controls and incubated for 18 h with T27K, a coccidioidal antigen preparation. The supernatant was then assayed for gamma interferon (IFN-γ), interleukin-2 (IL-2), tumor necrosis factor alpha (TNF-α), IL-4, IL-6, IL-10, and IL-17A. A total of 43 subjects, 16 with acute pneumonia, 9 with pulmonary sequelae of nodules and cavities, and 18 with nonmeningeal disseminated coccidioidomycosis, were studied. Compared to concentrations in healthy immune and nonimmune donors, the median concentration of IL-17A was significantly higher in those with active coccidioidomycosis (for both, P < 0.01). In addition, IL-6 concentrations were higher while IL-2 and IFN-γ concentrations were significantly lower in those with nonmeningeal disseminated disease diagnosed within 12 months than in those with acute pneumonia (for all, P < 0.05). The cytokine profile among patients with active coccidioidomycosis is distinct in that IL-17A is persistently present. In addition, those with nonmeningeal disseminated disease have an increased inflammatory cytokine response and diminished Th1 responses that modulate over time.
• Ampel, N. M., Chahal, R., Erickson, H., Holbrook, E. D., Knox, K. S., Malo, J., Oren, E., Robey, I. F., Strawter, C., Thompson, C., Wheat, L. J., & Zangeneh, T. T. (2015). Development of an Improved Antibody Detection Enzyme Immunoassay for Use in Detection of Coccidioidomycosis. Open Forum Infectious Diseases, 2(suppl_1). doi:10.1093/ofid/ofv133.128
• Casanova, N., Zhou, T., Knox, K. S., & Garcia, J. G. (2015). Identifying Novel Biomarkers in Sarcoidosis Using Genome-Based Approaches. Clinics in chest medicine, 36(4), 621-30.
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  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.
• Martinez, G., & Knox, K. (2015). Mentor Match for physician-faculty: the search for 'Dr Right'. Medical education, 49(5), 533-4.
• Martinez, G., & Knox, K. S. (2015). Mentor Match for physician-faculty: the search for 'Dr Right'. Medical Education, 533-534.
• Mosier, J. M., Malo, J., Sakles, J. C., Hypes, C. D., Natt, B., Snyder, L., Knepler, J., Bloom, J. W., Joshi, R., & Knox, K. (2015). The impact of a comprehensive airway management training program for pulmonary and critical care medicine fellows. A three-year experience. Annals of the American Thoracic Society, 12(4), 539-48.
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  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.
• Mosier, J. M., Malo, J., Sakles, J. C., Hypes, C. D., Natt, B., Snyder, L., Knepler, J., Bloom, J. W., Joshi, R., & Knox, K. (2015). The impact of a comprehensive airway management training program for pulmonary and critical care medicine fellows: A three-year experience. Annals of the American Thoracic Society, 12(Issue 4). doi:10.1513/annalsats.201501-023oc
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  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. Methods: Training is provided in small group sessions twice monthly using a high-fidelity simulation program under the guidance of a core group of two to three 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, preoxygenation, optimization of hemodynamics, choice of induction agents, selection of appropriate devices for the scenario, anticipation of difficulties, back-up plans, and immediate postintubation management. Clinical performance is monitored through a continuous quality improvement program. Measurements and Main Results: Sixteen 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), first-attempt success has improved from 74% (358/487) to 82%(305/374) compared with the 18 months before 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%). First-attempt success in a 6-month period after implementation (July 1, 2014-December 31, 2014) was significantly higher (82.1 compared with 70.9%, P = 0.03) than during a similar 6-month period before 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.
• Mosier, J., Malo, J., Sakles, J., Hypes, C., Natt, B., Snyder, L., Knepler, J., Bloom, J., Joshi, R., & Knox, K. S. (2015). The impact of a comprehensive airway management training program for pulmonary and critical care medicine fellows. A three-year experience. Annals of the American Thoracic Society, 539-548.
• Shetty, S., & Knox, K. S. (2015). Medical image of the week: DBS polysomnogram artifact. Southwest Journal Of pulmonary and Critical care. doi:http://dx.doi.org/10.13175/swjpcc096-15 PDF
• Shetty, S., Knox, K. S., & Bartell, J. (2015). Medical image of the week: REM without atonia. Southwest Journal of Pulmonary and Critical care.
• Zangeneh, M., Malo, M., Luraschi-Monjagatta, M., Hage, M., Wheat, M., Strawter, M., Klotz, M., & Knox, M. (2015). Positive (1-3) B-d-glucan and cross reactivity of fungal assays in coccidioidomycosis. Medical mycology, 53(2), 171-3.
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  Fungal antigen testing in immunosuppressed patients has emerged as a powerful diagnostic tool. Some assays are relatively nonspecific, and misinterpretation can have severe clinical consequences. Additionally, when new assays become commercially available it is important to evaluate the potential for cross reactivity. We recently observed several immunosuppressed patients with positive (1→3)-β-D-glucan (BG) who were eventually diagnosed with coccidioidomycosis in the endemic area of Tucson, Arizona. Although the BG assay is known to detect glucans of many fungal pathogens, reports of cross-reactivity with Coccidioides remain sparsely reported. To test the cross-reactivity of fungal antigens in detection assays, serum samples from patients with coccidioidomycosis testing positive for Coccidioides antigen were evaluated for BG. Of 12 samples positive for Coccidioides antigen (≥0.07 ng/ml), 11 (92%) were positive by BG (>80 pg/ml), and of 11 positive for Aspergillus galactomannan, 10 (91%) were positive by BG (>80 pg/ml). We conclude that the BG assay is nonspecific, detecting glucans from many fungal pathogens, including Coccidioides. In the endemic area, a positive BG warrants further specific testing.
• Zhou, T., Casanova, N., Sweiss, N., Wang, T., Knox, K. S., & Garcia, J. (2015). A Novel Microrna-Regulated Peripheral Blood Gene Signature Differentiates Sarcoidosis. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 191.
• Arteaga, V., & Knox, K. S. (2014). Medical image of the week: PE with infarct and pulmonary cavitation. Southwest Journal of Pulmonary and Critical Care, 9(6), 333-334. doi:10.13175/swjpcc158-14
• Azar, M. M., Hage, C. A., Knox, K. S., & Malo, J. (2014). Pulmonary fungal infections- recent updates. Current Respiratory Care Reports, 3(4), 150-160. doi:10.1007/s13665-014-0089-x
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  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.
• Crothers, K., Day, R. B., Dong, Q., Gregory, R. L., Knox, K. S., Nelson, D. E., Rong, R., Sodergren, E., Twigg, H. L., & Weinstock, G. M. (2014). Comparison of Whole and Acellular Bronchoalveolar Lavage to Oral Wash Microbiomes. Should Acellular Bronchoalveolar Lavage Be the Standard. Annals of the American Thoracic Society, 11(Supplement 1), S72-S73. doi:10.1513/annalsats.201306-162mg
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  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 1. Dendogram showing clustering using bray-curtis dissimilarity at the genus level. Blue = acellular bronchoalveolar lavage (BAL); red = whole BAL; green = oral wash. 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.
• Goodrum, F., Knox, K. S., Ricciotti, R. W., Sam, A., & Sobonya, R. E. (2014). Medical image of the week: CMV cytopathic effect. Southwest Journal of Pulmonary and Critical Care, 9(6), 341-342. doi:10.13175/swjpcc161-14
• Hage, C. A., Knox, K. S., & Wheat, L. J. (2014). Approach to the Diagnosis of Histoplasmosis, Blastomycosis and Coccidioidomycosis. Current Treatment Options in Infectious Diseases, 6(3), 337-351. doi:10.1007/s40506-014-0020-6
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  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.
• Knox, K. S. (2014). Perspective on Coccidioidomycosis and Histoplasmosis. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 189(6), 752-753.
• Knox, K. S. (2014). Perspective on coccidioidomycosis and histoplasmosis. American journal of respiratory and critical care medicine, 189(6), 752-3.
• Knox, K. S., & Malo, J. (2014). Medical image of the week: fat embolism syndrome. Southwest Journal of Pulmonary and Critical Care, 8(4), 246-246. doi:10.13175/swjpcc041-14
• Knox, K. S., & Nahapetian, R. (2014). Medical image of the week: REM sleep behavior disorder in Parkinson disease. Southwest Journal of Pulmonary and Critical Care, 8(6), 347-348. doi:10.13175/swjpcc062-14
• Malo, J., Luraschi-Monjagatta, C., Wolk, D. M., Thompson, R., Hage, C. A., & Knox, K. S. (2014). Update on the diagnosis of pulmonary coccidioidomycosis. Annals of the American Thoracic Society, 11(2), 243-53.
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  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.
• Martinez, G. F., Fain, M. J., Knox, K. S., Lisse, J., Spear-ellinwood, K., Szerlip, H., & Vemulapalli, T. (2014). Finding a mentor: the complete examination of an online academic matchmaking tool for physician-faculty. Southwest Journal of Pulmonary and Critical Care, 9(6), 320-332. doi:10.13175/swjpcc138-14
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  Background: To have a successful career in academic medicine, finding a mentor is critical for physician-faculty. However, finding the most appropriate mentor can be challenging for junior faculty. As identifying a mentor pool and improving the search process are paramount to both a mentoring program’s success, and the academic medical community, innovative methods that optimize mentees’ searches are needed. This cross-sectional study examines the search and match process for just over 60 junior physician-faculty mentees participating in a department-based junior faculty mentoring program. To extend beyond traditional approaches to connect new faculty with mentors, we implement and examine an online matchmaking technology that aids their search and match process. Methods: We describe the software used and events leading to implementation. A concurrent mixed method design was applied wherein quantitative and qualitative data, collected via e-surveys, provide a comprehensive analysis of primary usage patterns, decision making, and participants’ satisfaction with the approach. Results: Mentees reported using the software to primarily search for potential mentors in and out of their department, followed by negotiating their primary mentor selection with their division chief’s recommendations with those of the software, and finally, using online recommendations for self-matching as appropriate. Mentees found the online service to be user-friendly while allowing for a non-threatening introduction to busy senior mentors. Conclusions: Our approach is a step toward examining the use of technology in the search and match process for junior physician-faculty. Findings underscore the complexity of the search and match process.
• Natt, B. S., Campion, J. M., & Knox, K. S. (2014). Acute eosinophilic pneumonia associated with ingestion of Ulomoides dermestoides larvae ("Chinese beetles"). Annals of the American Thoracic Society, 11(10), 1667-8.
• Reyes, N., Onadeko, O. O., Luraschi-Monjagatta, M. d., Knox, M., Rennels, M., Walsh, M., & Ampel, M. (2014). Positron emission tomography in the evaluation of pulmonary nodules among patients living in a coccidioidal endemic region. Lung, 192(4), 589-93.
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  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.
• Hage, C. A., Horan, D. J., Durkin, M., Connolly, P., Desta, Z., Skaar, T. C., Knox, K. S., & Wheat, L. J. (2013). Histoplasma capsulatum preferentially induces IDO in the lung. Medical mycology, 51(3), 270-9.
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  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.
• Knox, K. S., & Sobonya, R. E. (2013). Medical image of the week: lepidic growth. Southwest Journal of Pulmonary and Critical Care, 7(2), 109-109. doi:10.13175/swjpcc111-13
• Lozupone, C., Cota-Gomez, A., Palmer, B. E., Linderman, D. J., Charlson, E. S., Sodergren, E., Mitreva, M., Abubucker, S., Martin, J., Yao, G., Campbell, T. B., Flores, S. C., Ackerman, G., Stombaugh, J., Ursell, L., Beck, J. M., Curtis, J. L., Young, V. B., Lynch, S. V., , Huang, L., et al. (2013). Widespread colonization of the lung by Tropheryma whipplei in HIV infection. American journal of respiratory and critical care medicine, 187(10), 1110-7.
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  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 individuals infected with HIV.
• Nesbit, L. A., Knox, K. S., Nguyen, C. T., Roesch, J., Wheat, L. J., Johnson, S. M., Pappagianis, D., Chavez, S., & Ampel, N. M. (2013). Immunological Characterization of Bronchoalveolar Lavage Fluid in Patients With Acute Pulmonary Coccidioidomycosis. JOURNAL OF INFECTIOUS DISEASES, 208(5), 857-863.
• Twigg, H. L., & Knox, K. S. (2013). Impact of antiretroviral therapy on lung immunology and inflammation. Clinics in chest medicine, 34(2), 155-64.
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  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.
• Twigg, H. L., Morris, A., Ghedin, E., Curtis, J. L., Huffnagle, G. B., Crothers, K., Campbell, T. B., Flores, S. C., Fontenot, A. P., Beck, J. M., Huang, L., Lynch, S., Knox, K. S., Weinstock, G., & , L. H. (2013). Use of bronchoalveolar lavage to assess the respiratory microbiome: signal in the noise. The Lancet. Respiratory medicine, 1(5), 354-6.
• Hage, C. A., Knox, K. S., & Wheat, L. J. (2012). Endemic mycoses: overlooked causes of community acquired pneumonia. Respiratory medicine, 106(6), 769-76.
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  The endemic mycoses are important but often overlooked causes for community acquired pneumonia. Delays in recognition, diagnosis and proper treatment often lead to disastrous outcomes. This topic is not usually discussed in reviews and guidelines addressing the subject of community acquired pneumonia. In this review we discuss the three major endemic mycoses in North America that present as community acquired pneumonias; Coccidioidomycosis, Histoplasmosis and Blastomycosis. We discuss their epidemiology, clinical presentations, methods of diagnosis and current treatment strategies.
• Tao, S., Zhu, L., Lee, P., Lee, W., Knox, K., Chen, J., Di, Y. P., & Chen, Y. (2012). Negative Control of TLR3 Signaling by TICAM1 Down-Regulation. AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, 46(5), 660-667.
• Zhou, T., Zhang, W., Sweiss, N. J., Chen, E. S., Moller, D. R., Knox, K. S., Ma, S., Wade, M. S., Noth, I., Machado, R. F., & Garcia, J. (2012). Peripheral Blood Gene Expression as a Novel Genomic Biomarker in Complicated Sarcoidosis. PLOS ONE, 7(9).
• Hage, C. A., Knox, K. S., Davis, T. E., & Wheat, L. J. (2011). Antigen detection in bronchoalveolar lavage fluid for diagnosis of fungal pneumonia. Current opinion in pulmonary medicine, 17(3), 167-71.
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  The purpose of this review is to describe important findings published during the past 18 months using bronchoalveolar lavage (BAL) for diagnosis of pulmonary mycoses.
• Hage, C. A., Teague, S., Twigg, H. L., Gebregziabher, N., Daggy, J., Waltz, J., Zwickl, B., Goldman, M., Douek, D., Brenchley, J., & Knox, K. S. (2011). Cytometric Analysis Of Blood And Lung CD4 Lymphocyte Subsets Correlates With CT Scan Abnormalities After 1 Month Of Highly Active Antiretroviral Therapy. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 183.
• Hershcovici, T., Jha, L. K., Johnson, T., Gerson, L., Stave, C., Malo, J., Knox, K. S., Quan, S., & Fass, R. (2011). Systematic review: the relationship between interstitial lung diseases and gastro-oesophageal reflux disease. ALIMENTARY PHARMACOLOGY & THERAPEUTICS, 34(11-12), 1295-1305.
• Limper, A. H., Knox, K. S., Sarosi, G. A., Ampel, N. M., Bennett, J. E., Catanzaro, A., Davies, S. F., Dismukes, W. E., Hage, C. A., Marr, K. A., Mody, C. H., Perfect, J. R., Stevens, D. A., & , A. T. (2011). An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. American journal of respiratory and critical care medicine, 183(1), 96-128.
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  With increasing numbers of immune-compromised patients with malignancy, hematologic disease, and HIV, as well as those receiving immunosupressive drug regimens for the management of organ transplantation or autoimmune inflammatory conditions, the incidence of fungal infections has dramatically increased over recent years. Definitive diagnosis of pulmonary fungal infections has also been substantially assisted by the development of newer diagnostic methods and techniques, including the use of antigen detection, polymerase chain reaction, serologies, computed tomography and positron emission tomography scans, bronchoscopy, mediastinoscopy, and video-assisted thorascopic biopsy. At the same time, the introduction of new treatment modalities has significantly broadened options available to physicians who treat these conditions. While traditionally antifungal therapy was limited to the use of amphotericin B, flucytosine, and a handful of clinically available azole agents, current pharmacologic treatment options include potent new azole compounds with extended antifungal activity, lipid forms of amphotericin B, and newer antifungal drugs, including the echinocandins. In view of the changing treatment of pulmonary fungal infections, the American Thoracic Society convened a working group of experts in fungal infections to develop a concise clinical statement of current therapeutic options for those fungal infections of particular relevance to pulmonary and critical care practice. This document focuses on three primary areas of concern: the endemic mycoses, including histoplasmosis, sporotrichosis, blastomycosis, and coccidioidomycosis; fungal infections of special concern for immune-compromised and critically ill patients, including cryptococcosis, aspergillosis, candidiasis, and Pneumocystis pneumonia; and rare and emerging fungal infections.
• Twigg, H. L., Nelson, D., Dong, Q., Revanna, K., Gao, X., Day, R., Knox, K. S., Sodergren, E., & Weinstock, G. (2011). Analysis Of The Respiratory Microbiome Using Bronchoalveolar Lavage From HIV-Infected And Uninfected Subjects. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 183.
• Walsh, T., Ampel, N. M., Knox, K. S., Onadeko, O. O., Rennels, M. A., & Walsh, T. K. (2011). Positron Emission Tomography in the Evaluation of Solitary Pulmonary Nodules Due to Coccidioidomycosis. Chest, 140(4), 647A. doi:10.1378/chest.1112072
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  PURPOSE: In endemic areas, up to 40% of solitary pulmonary nodules (SPN) are due to coccidioidomycosis and are difficult to distinguish from malignancy by imaging. The objective of this study was to determine if additional diagnostic information could be obtained from positron emission tomography (PET) in the evaluation of SPN due to coccidioidomycosis.
• Ampel, N. M., Chavez, S., Goldman, M., Knox, K. S., Nesbit, L. A., & Onadeko, O. O. (2010). Coccidioides Antigen Detection in Bronchoalveolar Lavage. Chest, 138(4), 686A. doi:10.1378/chest.10822
• Carlos, W. G., Rose, A. S., Wheat, L. J., Norris, S., Sarosi, G. A., Knox, K. S., & Hage, C. A. (2010). Blastomycosis in indiana: digging up more cases. Chest, 138(6), 1377-82.
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  The endemic region of blastomycosis historically has included the state of Indiana. However, few published reports of blastomycosis exist to substantiate this distinction. A surge of patients with blastomycosis in central Indiana (Indianapolis and surrounding counties) beginning in 2005 prompted us to review our local experience. We propose that this surge was related to major highway construction around Indianapolis.
• Chaudhary, S., Knox, K. S., Raz, Y., & Meinke, L. E. (2010). Coccidioidomycosis in Lung Transplant Recipients in an Endemic Area. American College of Clinical Pharmacy.
• Hage, C. A., Davis, T. E., Fuller, D., Egan, L., Witt, J. R., Wheat, L. J., & Knox, K. S. (2010). Diagnosis of histoplasmosis by antigen detection in BAL fluid. Chest, 137(3), 623-8.
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  Detection of antigen in BAL is useful for diagnosis of histoplasmosis. The MVista Histoplasma antigen enzyme immunoassay has been modified to permit quantification. The purpose of this study is to compare the sensitivity of the quantitative antigen detection assay with cytopathology and culture of BAL specimens.
• Knox, K. S., & Hage, C. A. (2010). Histoplasmosis. Proceedings of the American Thoracic Society, 7(3), 169-72.
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  Histoplasmosis is the most prevalent endemic fungal infection in North America. The clinical spectrum ranges from asymptomatic, self-limited illness to a life-threatening progressive disseminated disease. Chronic manifestations of healed infection can also be problematic. Clinical presentation depends on the infectious load, underlying immune status, and lung function. The preferred diagnostic methods and treatment options vary with clinical scenario and severity of illness. New diagnostic tools and treatment options are now available in clinical practice. We present an overview of this important endemic mycosis with emphasis on diagnosis and treatment recommendations for the different clinical syndromes of histoplasmosis.
• Knox, K. S., & Onadeko, O. O. (2010). The early riser. Reassurance.. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine, 6(3), 297-8.
• Knox, K. S., Vinton, C., Hage, C. A., Kohli, L. M., Twigg, H. L., Klatt, N. R., Zwickl, B., Waltz, J., Goldman, M., Douek, D. C., & Brenchley, J. M. (2010). Reconstitution of CD4 T cells in bronchoalveolar lavage fluid after initiation of highly active antiretroviral therapy. Journal of virology, 84(18), 9010-8.
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  The massive depletion of gastrointestinal-tract CD4 T cells is a hallmark of the acute phase of HIV infection. In contrast, the depletion of the lower-respiratory-tract mucosal CD4 T cells as measured in bronchoalveolar lavage (BAL) fluid is more moderate and similar to the depletion of CD4 T cells observed in peripheral blood (PB). To understand better the dynamics of disease pathogenesis and the potential for the reconstitution of CD4 T cells in the lung and PB following the administration of effective antiretroviral therapy, we studied cell-associated viral loads, CD4 T-cell frequencies, and phenotypic and functional profiles of antigen-specific CD4 T cells from BAL fluid and blood before and after the initiation of highly active antiretroviral therapy (HAART). The major findings to emerge were the following: (i) BAL CD4 T cells are not massively depleted or preferentially infected by HIV compared to levels for PB; (ii) BAL CD4 T cells reconstitute after the initiation of HAART, and their infection frequencies decrease; (iii) BAL CD4 T-cell reconstitution appears to occur via the local proliferation of resident BAL CD4 T cells rather than redistribution; and (iv) BAL CD4 T cells are more polyfunctional than CD4 T cells in blood, and their functional profile is relatively unchanged after the initiation of HAART. Taken together, these data suggest mechanisms for mucosal CD4 T-cell depletion and interventions that might aid in the reconstitution of mucosal CD4 T cells.
• Onadeko, O., & Knox, K. S. (2010). The Early Riser. JOURNAL OF CLINICAL SLEEP MEDICINE, 6(3), 297-298.
• Onadeko, O., Sam, A., Bloom, J., & Knox, K. (2010). AN UNUSUAL CASE OF SEVERE RESPIRATORY FAILURE IN A PREVIOUSLY HEALTHY YOUNG MAN. CRITICAL CARE MEDICINE, 38(12), U282-U282.
• Crouser, E. D., Culver, D. A., Knox, K. S., Julian, M. W., Shao, G., Abraham, S., Liyanarachchi, S., Macre, J. E., Wewers, M. D., Gavrilin, M. A., Ross, P., Abbas, A., & Eng, C. (2009). Gene Expression Profiling Identifies MMP-12 and ADAMDEC1 as Potential Pathogenic Mediators of Pulmonary Sarcoidosis. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179(10), 929-938.
• Crouser, E. D., Culver, D. A., Knox, K. S., Julian, M. W., Shao, G., Abraham, S., Liyanarachchi, S., Macre, J. E., Wewers, M. D., Gavrilin, M. A., Ross, P., Abbas, A., & Eng, C. (2009). Gene expression profiling identifies MMP-12 and ADAMDEC1 as potential pathogenic mediators of pulmonary sarcoidosis. American Journal of Respiratory and Critical Care Medicine, 179(Issue 10). doi:10.1164/rccm.200803-490oc
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  Rationale: Little is known about the genetic regulation of granulomatous inflammation in sarcoidosis. Objectives: To determine if tissue gene array analysis would identify novel genes engaged in inflammation and lung remodeling in patients with sarcoidosis. Methods: Gene expression analysis was performed on tissues obtained from patients with sarcoidosis at the time of diagnosis (untreated) (n = 6) compared with normal lung tissue (n = 6). Expression of select genes was further confirmed in lung tissue from a second series of patients with sarcoidosis and disease-free control subjects (n = 11 per group) by semi-quantitative RT-PCR. Interactive gene networks were identified in patients with sarcoidosis using Ingenuity Pathway Analysis (Ingenuity Systems, Inc., Redwood, CA) software. The expression of proteins corresponding to selected overexpressed genes was determined using fluorokine multiplex analysis, and immunohistochemistry. Selected genes and proteins were then analyzed in bronchoalveolar lavage fluid in an independent series of patients with sarcoidosis (n = 36) and control subjects (n = 12). Measurements and Main Results: A gene network engaged in Th1-type responses was most significantly overexpressed in the sarcoidosis lung tissues, including genes not previously reported in the context of sarcoidosis (e.g., IL-7). MMP-12 and ADAMDEC1 transcripts were most highly expressed (> 25-fold) in sarcoidosis lung tissues, corresponding with increased protein expression by immunohistochemistry. MMP-12 and ADAMDEC1 gene and protein expression were increased in bronchoalveolar lavage samples from patients with sarcoidosis, correlating with disease severity. Conclusions: Tissue gene expression analyses provide novel insights into the pathogenesis of pulmonary sarcoidosis. MMP-12 and ADAMDEC1 emerge as likely mediators of lung damage and/or remodeling and may serve as markers of disease activity.
• Hage, C. A., Baddley, J., Connolly, P., Knox, K. S., & Wheat, K. J. (2009). Histoplasma Antigen Clearance during Treatment of Histoplasmosis Using the MVista (R) Quantitative Immunoassay.. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179.
• Hage, C. A., Hatoum, H. H., Knox, K. S., & Sarosi, G. A. (2009). Acute respiratory failure and diffuse pulmonary infiltrates four weeks after rituximab therapy. Respiratory Medicine Cme, 2(3), 134-136. doi:10.1016/j.rmedc.2008.12.004
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  Summary We report a 51-year-old woman with known SLE on low dose prednisone, recently started on rituximab, who presents with acute respiratory failure and bilateral air space disease. After an initial treatment with broad spectrum antibiotics for healthcare-associated pneumonia and negative serologic studies, a diagnosis of pneumocystis pneumonia was established using bronchoalveolar lavage. We suggest that rituximab can be an aggravating cause of pneumocystis in patients treated with prednisone.
• Hage, C. A., Hosein, M., Knox, K. S., Melendez, A. G., & Sheski, F. D. (2009). Broncholithiasis causing acute respiratory failure: Successfully treated by flexible bronchoscopy. Respiratory Medicine Cme, 2(1), 27-30. doi:10.1016/j.rmedc.2008.10.015
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  A 65-year-old male with history of COPD presented to our institution with a two-month history of worsening dyspnea, cough, and wheezing and with occasional blood-tinged sputum. He had been recently evaluated in the emergency room for these symptoms, at which time chest radiograph revealed a right lung density (Fig. 1A). A chest CT scan demonstrated a large calcified lymph node involving the bronchus intermedius, resulting in collapse of the right middle and lower lobes (Fig. 1B). Bronchoscopy showed broncholithiasis that subtotally occluded the bronchus intermedius. The broncholith was firmly imbedded in the bronchial wall. He was treated for acute exacerbation of COPD with azithromycin and a tapering course of
• Hage, C. A., Rose, A. S., Miller, M., Xhani, D., Sarosi, G., & Knox, K. S. (2009). Blastomycosis in Indianapolis-12 Year Experience.. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 179.
• Hammoud, Z. T., Rose, A. S., Hage, C. A., Knox, K. S., Rieger, K., & Kesler, K. A. (2009). Surgical management of pulmonary and mediastinal sequelae of histoplasmosis: a challenging spectrum. The Annals of thoracic surgery, 88(2), 399-403.
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  Histoplasmosis may result in a spectrum of complications that require thoracic surgical intervention. We reviewed our 17-year experience in the management of histoplasmosis to determine outcomes as well as gain insight into the distribution of complications requiring surgical intervention.
• Knox, K. S., & Meinke, L. (2009). Role of Bronchoalveolar Lavage Diagnostics in Fungal Infections. CLINICS IN CHEST MEDICINE, 30(2), 355-+.
• Knox, K. S., & Sarosi, G. A. (2009). Fungal disease - Preface. CLINICS IN CHEST MEDICINE, 30(2).
• Bosslet, G. T., Knox, K. S., & Noor, A. (2008). Severe idiopathic hypereosinophilic syndrome. Respiratory Medicine Cme, 1(2), 100-102. doi:10.1016/j.rmedc.2007.12.005
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  Summary Hypereosinophilic syndrome (HES) is a systemic illness that usually presents with nonspecific symptoms. However, HES can be fatal, particularly when eosinophils infiltrate vital organs. We report a patient with HES who presented with a perforated viscus and sepsis-like syndrome and rapidly improved with drotrecogin-alfa and steroid therapy.
• Brenchley, J. M., Knox, K. S., Asher, A. I., Price, D. A., Kohli, L. M., Gostick, E., Hill, B. J., Hage, C. A., Brahmi, Z., Khoruts, A., Twigg, H., Schacker, T. W., & Douek, D. C. (2008). High frequencies of polyfunctional HIV-specific T cells are associated with preservation of mucosal CD4 T cells in bronchoalveolar lavage. MUCOSAL IMMUNOLOGY, 1(1), 49-58.
• Brenchley, J. M., Paiardini, M., Knox, K. S., Asher, A. I., Cervasi, B., Asher, T. E., Scheinberg, P., Price, D. A., Hage, C. A., Kholi, L. M., Khoruts, A., Frank, I., Else, J., Schacker, T., Silvestri, G., & Douek, D. C. (2008). Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood, 112(7), 2826-35.
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  Acute HIV infection is characterized by massive loss of CD4 T cells from the gastrointestinal (GI) tract. Th17 cells are critical in the defense against microbes, particularly at mucosal surfaces. Here we analyzed Th17 cells in the blood, GI tract, and broncheoalveolar lavage of HIV-infected and uninfected humans, and SIV-infected and uninfected sooty mangabeys. We found that (1) human Th17 cells are specific for extracellular bacterial and fungal antigens, but not common viral antigens; (2) Th17 cells are infected by HIV in vivo, but not preferentially so; (3) CD4 T cells in blood of HIV-infected patients are skewed away from a Th17 phenotype toward a Th1 phenotype with cellular maturation; (4) there is significant loss of Th17 cells in the GI tract of HIV-infected patients; (5) Th17 cells are not preferentially lost from the broncheoalveolar lavage of HIV-infected patients; and (6) SIV-infected sooty mangabeys maintain healthy frequencies of Th17 cells in the blood and GI tract. These observations further elucidate the immunodeficiency of HIV disease and may provide a mechanistic basis for the mucosal barrier breakdown that characterizes HIV infection. Finally, these data may help account for the nonprogressive nature of nonpathogenic SIV infection in sooty mangabeys.
• Brenchley, J. M., Paiardini, M., Knox, K. S., Asher, A. I., Cervasi, B., Asher, T. E., Scheinberg, P., Price, D. A., Hage, C. A., Kholi, L. M., Khoruts, A., Frank, I., Else, J., Schacker, T., Silvestri, G., & Douek, D. C. (2008). Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood, 112(Issue 7). doi:10.1182/blood-2008-05-159301
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  Acute HIV infection is characterized by massive loss of CD4 T cells from the gastrointestinal (GI) tract. Th17 cells are critical in the defense against microbes, particularly at mucosal surfaces. Here we analyzed Th17 cells in the blood, Gl tract, and broncheoalveolar lavage of HIV-infected and uninfected humans, and SIV-infected and uninfected sooty mangabeys. We found that (1) human Th17 cells are specific for extracellular bacterial and fungal antigens, but not common viral antigens; (2)Th17 cells are infected by HIV in vivo, but not preferentially so; (3) CD4 T cells in blood of HIV-infected patients are skewed away from a Th17 phenotype toward a Th1 phenotype with cellular maturation; (4) there is significant loss of Th17 cells in the Gl tract of HIV-infected patients; (5) Th17 cells are not preferentially lost from the broncheoalveolar lavage of HIV-infected patients; and (6) SIV-infected sooty mangabeys maintain healthy frequencies of Th17 cells in the blood and Gl tract. These observations further elucidate the immunodeficiency of HIV disease and may provide a mechanistic basis for the mucosal barrier breakdown that characterizes HIV infection. Finally, these data may help account for the nonprogressive nature of nonpathogenic SIV infection in sooty mangabeys. Copyright 2007 by The American Society of Hematology.
• Diab, K., Knox, K. S., & Hage, C. A. (2008). An 81-year-old man with lactic acidosis, refractory hypoglycemia, and lymphocytosis. Chest, 133(1), 306-10.
• Egan, L., Connolly, P. A., Fuller, D., Davis, T. E., Witt, J., Knox, K. S., Hage, C. A., & Wheat, L. J. (2008). Detection of Histoplasma capsulatum antigenuria by ultrafiltration of samples with false-negative results. Clinical and vaccine immunology : CVI, 15(4), 726-8.
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  Patients with histoplasmosis may test falsely negative for Histoplasma capsulatum antigenuria. In some cases antigen is present at levels below the assay's detection limit, and ultrafiltration could improve sensitivity. Antigen was detected following ultrafiltration in 73.8% of falsely negative specimens versus 2% of controls. Ultrafiltration improved sensitivity with a small reduction in specificity.
• Egan, L., Connolly, P., Wheat, L. J., Fuller, D., Dais, T. E., Knox, K. S., & Hage, C. A. (2008). Histoplasmosis as a cause for a positive Fungitell (1 --> 3)-beta-D-glucan test. Medical mycology, 46(1), 93-5.
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  We evaluated the Fungitell beta-glucan (BG) test with specimens from patients with presumed histoplasmosis. The sensitivity of the test was 87% in histoplasmosis cases and had a specificity of 68% with controls. Histoplasmosis should be considered as a possible cause for a positive BG test, but such results may be found with many other conditions that are clinically similar to this fungal disease. Therefore, there is a need to conduct confirmatory tests for histoplasmosis in the appropriate clinical setting.
• Hage, C. A., Wheat, L. J., Loyd, J., Allen, S. D., Blue, D., & Knox, K. S. (2008). Pulmonary histoplasmosis. Seminars in respiratory and critical care medicine, 29(2), 151-65.
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  Pulmonary manifestations of histoplasmosis were last reviewed in Seminars in 2004. This review highlights the management of the most common clinical syndromes, emphasizing recognition, diagnosis, and treatment. The reader is referred to the earlier review for subjects not fully addressed herein. Knowledge of the utility of serological testing is essential, particularly when antigen tests and cultures are negative. Antigen testing is most useful in patients with more diffuse pulmonary involvement and those with progressive disseminated disease due to the high fungal burden. Detection of antigen in bronchoalveolar lavage fluid may be particularly helpful in certain circumstances. Guidelines for antifungal therapy have been updated and will be discussed for pulmonary syndromes.
• Husain, S., Clancy, C. J., Nguyen, M. H., Swartzentruber, S., Leather, H., LeMonte, A. M., Durkin, M. M., Knox, K. S., Hage, C. A., Bentsen, C., Singh, N., Wingard, J. R., & Wheat, L. J. (2008). Performance Characteristics of the Platelia Aspergillus Enzyme Immunoassay for Detection of Aspergillus Galactomannan Antigen in Bronchoalveolar Lavage Fluid. CLINICAL AND VACCINE IMMUNOLOGY, 15(12), 1760-1763.
• Husain, S., Clancy, C. J., Nguyen, M. H., Swartzentruber, S., Leather, H., LeMonte, A. M., Durkin, M. M., Knox, K. S., Hage, C. A., Bentsen, C., Singh, N., Wingard, J. R., & Wheat, L. J. (2008). Performance characteristics of the platelia Aspergillus enzyme immunoassay for detection of Aspergillus galactomannan antigen in bronchoalveolar lavage fluid. Clinical and Vaccine Immunology, 15(Issue 12). doi:10.1128/cvi.00226-08
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  We have evaluated the Platelia Aspergillus enzyme immunoassay for detection of galactomannan in bronchoalveolar lavage (BAL) specimens in solid organ transplant patients with aspergillosis. The precision and reproducibility in serum or BAL to which galactomannan was added were similar. Sensitivity was 81.8% in patients with aspergillosis, and specificity was 95.8% in lung transplant patients who underwent BAL for surveillance for infection or rejection. Among transplant controls, positive results were more common in patients (i) who underwent diagnostic BAL performed for evaluation of symptoms or chest computed tomographic abnormalities, (ii) who had undergone lung transplantation, or (iii) who were colonized with Aspergillus. Galactomannan testing in BAL is useful for diagnosis of aspergillosis in transplant patients. The significance of positive results in patients without confirmed aspergillosis requires further evaluation. Copyright © 2008, American Society for Microbiology. All Rights Reserved.
• Petrache, I., Diab, K., Knox, K. S., Twigg, H., Stephens, R. S., Flores, S., & Tuder, R. M. (2008). HIV associated pulmonary emphysema: a review of the literature and inquiry into its mechanism. THORAX, 63(5), 463-469.
• Rose, A. S., Knox, K. S., & Hage, C. A. (2008). A 24-year-old man with mediastinal mass, dyspnea, and a pleural effusions. CHEST, 134(1), 200-203.
• Rose, A. S., Tielker, M. A., & Knox, K. S. (2008). Hepatic, ocular, and cutaneous sarcoidosis. CLINICS IN CHEST MEDICINE, 29(3), 509-+.
• Hage, C. A., Davis, T. E., Egan, L., Parker, M., Fuller, D., Lemonte, A. M., Durkin, M., Connelly, P., Joseph Wheat, L., Blue-Hnidy, D., & Knox, K. S. (2007). Diagnosis of pulmonary histoplasmosis and blastomycosis by detection of antigen in bronchoalveolar lavage fluid using an improved second-generation enzyme-linked immunoassay. Respiratory medicine, 101(1), 43-7.
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  Antigen detection is a useful adjunct for the diagnosis of histoplasmosis. The purpose of this study was to evaluate antigen detection in bronchoalveolar lavage (BAL) fluid using an improved second-generation Histoplasma antigen assay. Antigen was detected in 16 of 19 (84%) cases of histoplasmosis and 5 of 6 (83.3%) blastomycosis cases using the second-generation assay vs. 13 of 19 (68%) and 4 of 6 (66.7%), respectively, in the original assay. Ten-fold concentration permitted detection of antigen in an additional case of histoplasmosis and another with blastomycosis, for an overall sensitivity of 23 of 25 (92.0%). Specificity was 98.2% in both assays in controls with other pulmonary infections. These findings support the diagnostic utility of the second-generation assay in patients with pulmonary histoplasmosis and blastomycosis.
• Hage, C. A., Reynolds, J. M., Durkin, M., Wheat, L. J., & Knox, K. S. (2007). Plasmalyte as a cause of false-positive results for Aspergillus galactomannan in bronchoalveolar lavage fluid. Journal of clinical microbiology, 45(2), 676-7.
• Noor, A., & Knox, K. S. (2007). Immunopathogenesis of sarcoidosis. CLINICS IN DERMATOLOGY, 25(3), 250-258.
• Rose, A. S., & Knox, K. S. (2007). Bronchoalveolar lavage as a research tool. SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE, 28(5), 561-573.
• Thornburg, A., Abonour, R., Smith, P., Knox, K., & Twigg, H. L. (2007). Hypersensitivity pneumonitis-like syndrome associated with the use of lenalidomide. Chest, 131(5), 1572-4.
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  Lenalidomide is an immunomodulatory agent approved for use in patients with myelodysplastic syndrome, and in combination with dexamethasone for refractory or relapsed multiple myeloma. Pulmonary toxicity is believed to be uncommon. In this report, we describe a patient receiving lenalidomide in whom dyspnea, fever, hypoxia, and diffuse pulmonary infiltrates developed. BAL demonstrated a significant lymphocytic alveolitis typical for hypersensitivity pneumonitis. Extensive workup for other causes, including infections, was negative. Finally, the patient had improvement in symptoms and oxygenation after withdrawing lenalidomide and recurrence of symptoms when the drug was restarted. Thus, the patient's clinical course and workup strongly support a diagnosis of lenalidomide-induced hypersensitivity pneumonitis-like syndrome. Physicians should be cognizant of this potential complication in patients receiving thalidomide or thalidomide-like drugs who present with fever and pulmonary infiltrates and fail to improve despite treatment with broad-spectrum antibiotics.
• Twigg, H. L., & Knox, K. S. (2007). HIV-Related Lung Disorders. Drug discovery today. Disease mechanisms, 4(2), 95-101.
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  Highly active antiretroviral therapy (HAART) has dramatically altered the spectrum of morbidity and mortality in HIV-infected patients. This has been attributed to improvements in the lung microenvironment leading to enhanced pulmonary immunity, either by preventing the progressive loss of immune function or by actually promoting immune restoration. However, these changes have been accompanied by the recognition of new pulmonary complications in HIV-infected subjects, especially those associated with immune reconstitution. In this review we will describe how HIV infection alters the normal pulmonary environment, highlight the effect of HAART on these perturbations, and discuss potential complications of HAART in the lung, focusing on the pulmonary immune reconstitution inflammatory syndrome.
• Wheat, L. J., Hackett, E., Durkin, M., Connolly, P., Petraitiene, R., Walsh, T. J., Knox, K., & Hage, C. (2007). Histoplasmosis-associated cross-reactivity in the BioRad Platelia Aspergillus enzyme immunoassay. Clinical and vaccine immunology : CVI, 14(5), 638-40.
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  We observed false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA) for specimens from patients with histoplasmosis and mice with experimental infection. Platelia Aspergillus EIA-positive specimens were negative in the second-generation Histoplasma antigen EIA. Care must be taken to exclude histoplasmosis for patients with positive Platelia Aspergillus EIA results.
• Wheat, L. J., Hackett, E., Durkin, M., Connolly, P., Petraitiene, R., Walsh, T. J., Knox, K., & Hage, C. (2007). Histoplasmosis-associated cross-reactivity in the biorad platelia Aspergillus enzyme immunoassay. Clinical and Vaccine Immunology, 14(Issue 5). doi:10.1128/cvi.00479-06
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  We observed false-positive results in the Platelia Aspergillus enzyme-linked immunoassay (EIA) for specimens from patients with histoplasmosis and mice with experimental infection. Platelia Aspergillus EIA-positive specimens were negative in the second-generation Histoplasma antigen EIA. Care must be taken to exclude histoplasmosis for patients with positive Platelia Aspergillus EIA results. Copyright © 2007, American Society for Microbiology. All Rights Reserved.
• Xhani, D., Hage, C. A., & Knox, K. S. (2007). A 30-year-old man with HIV infection and fever with cough 2 months after starting antiretroviral therapy. Chest, 132(1), 354-7.
• Xhani, D., Hage, C. A., & Knox, K. S. (2007). A 30-year-old man with HIV infection and fever with cough 2 months after starting antiretroviral therapy. Chest, 132(Issue 1). doi:10.1378/chest.06-2871
• Bhatt, J. M., Diab, K. J., Hage, C. A., Knox, K. S., & Wilkes, D. S. (2006). CLINICAL MANIFESTATIONS, DIAGNOSIS, AND TREATMENT OF NEUROSARCOIDOSIS: A REVIEW OF 39 PATIENTS. Chest, 130(4), 128S. doi:10.1378/chest.130.4_meetingabstracts.128s-c
• Diab, K. J., Bhatt, J., Wilkes, D. S., Hage, C. A., & Knox, K. S. (2006). Clinical manifestations, diagnosis, and treatment of neurosarcoidosis: A review of 39 patients. CHEST, 130(4), 128S-128S.
• Kahi, C. J., Saxena, R., Temkit, M., Canlas, K., Roberts, S., Knox, K., Wilkes, D., & Kwo, P. Y. (2006). Hepatobiliary disease in sarcoidosis. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES, 23(2), 117-123.
• Knox, K. S., Day, R. B., Kohli, L. M., Hage, C. A., & Twigg, H. L. (2006). Functional impairment of CD4 T cells despite normalization of T cell number in HIV. Cellular immunology, 242(1), 46-51.
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  Using an in vitro model, we demonstrate that when CD4 T cells from HIV infected subjects are enriched from total blood lymphocytes the immune response to antigen is augmented. However, augmentation of this response is confined to HIV infected subjects with relatively preserved CD4 T cell counts. Enriching for CD4 T cells had no effect on antigen responses in patients with low CD4 lymphocyte counts. These findings support the concept that CD4 T cells in late stage HIV have inherent qualitative defects.
• Roberts, S. D., Farber, M. O., Knox, K. S., Phillips, G. S., Bhatt, N. Y., Mastronarde, J. G., & Wood, K. L. (2006). FEV1/FVC ratio of 70% misclassifies patients with obstruction at the extremes of age. CHEST, 130(1), 200-206.
• Smith, P. A., Kohli, L. M., Wood, K. L., Hage, C. A., Twigg, H. L., & Knox, K. S. (2006). Cytometric analysis of BAL T cells labeled with a standardized antibody cocktail correlates with immunohistochemical staining. Cytometry. Part B, Clinical cytometry, 70(3), 170-8.
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  Determining T-cell phenotypes of lung cells obtained by bronchoalveolar lavage (BAL) is frequently clinically useful, particularly for evaluating causes of interstitial lung disease. The current standard of determining CD4/CD8 T-cell subsets by immunohistochemical (IHC) staining of cytocentrifuge slides is labor-intensive and subject to interpreter variation. Flow cytometry (FCM) is a precise and rapid method commonly used in research to characterize cells in the lung. However, few studies address the methodology of analysis of BAL lymphocytes by FCM.
• Blue-hnidy, D., Davis, T. E., Hage, C. A., Knox, K. S., Monte, A. M., & Wheat, L. J. (2005). DETECTION OF HISTOPLASMA CAPSULATUM ANTIGEN IN BRONCHIAL ALVEOLAR LAVAGE SPECIMENS BY IMPROVED ANTIGEN DETECTION ENZYME-LINKED IMMUNOASSAY. Chest, 128(4), 374S. doi:10.1378/chest.128.4_meetingabstracts.374s-a
• Cho, S., Knox, K. S., Kohli, L. M., He, J. J., Exley, M. A., Wilson, S. B., & Brutkiewicz, R. R. (2005). Impaired cell surface expression of human CD1d by the formation of an HIV-1 Nef/CD1d complex. VIROLOGY, 337(2), 242-252.
• Hage, C. A., Kohli, L. L., Cho, S., Brutkiewicz, R. R., Twigg, H. L., & Knox, K. S. (2005). Human immunodeficiency virus gp120 downregulates CD1d cell surface expression. Immunology letters, 98(1), 131-5.
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  CD1d is an MHC class I-like surface molecule that presents endogenous glycoplipid antigens. The effect of HIV infection on CD1d surface expression has not yet been reported. FACS analysis revealed significantly lower levels of CD1d on CD14(+) monocytes from HIV-infected subjects compared to HIV-infected subjects on HAART and healthy controls. CD1d expression correlated inversely with viral load in infected individuals. CD1d surface expression on human cell lines was downregulated after infection with M-tropic HIV, T-tropic HIV, or after exposure to HIV gp120 in vitro. These data suggest that CD1d-mediated responses are altered during HIV infection and may thus contribute to the global immunodeficiency seen in these patients.
• Hage, C. A., Wheat, L. J., Twigg, H. L., & Knox, K. S. (2005). Infliximab does not affect dendritic cells' mediated lymphoproliferative response to Histoplasma capsulatum. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 41(11), 1685-7; author reply 1687.
• Knox, K. S., Miller, D. E., Noor, A., & Smith, P. A. (2005). HYPEREOSINOPHILIC SYNDROME MIMICKING SEPSIS AND LUNG INJURY: DRAMATIC IMPROVEMENT AFTER ACTIVATED PROTEIN C THERAPY. Chest, 128(4), 421S. doi:10.1378/chest.128.4_meetingabstracts.421s-a
• Noor, A., Miller, D. E., Smith, P. A., & Knox, K. S. (2005). Hypereosinophilic syndrome mimicking sepsis and lung injury: Dramatic improvement after activated protein C therapy. CHEST, 128(4), 421S-422S.
• Roberts, S. D., Kohli, L. L., Wood, K. L., Wilkes, D. S., & Knox, K. S. (2005). CD4+CD28 - T cells are expanded in sarcoidosis. SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES, 22(1), 13-19.
• Snyder, M. J., Jacobs, M. R., Grau, R. G., Wilkes, D. S., & Knox, K. S. (2005). Resolution of severe digital ulceration during a course of bosentan therapy. ANNALS OF INTERNAL MEDICINE, 142(9), 802-803.
• Weyar, P., Cummings, O. W., & Knox, K. S. (2005). A 49-year-old woman with hepatitis, confusion, and abnormal chest radiograph findings. CHEST, 128(4), 3076-3079.
• Wheat, L. J., Le Monte, A. M., Hage, C., Knox, K. S., Blue-Hnidy, D., & Davis, T. E. (2005). Detection of histoplasma capsulatum antigen in bronchial alveolar lavage specimens by improved antigen detection enzyme-linked immunoassay. CHEST, 128(4), 374S-374S.
• Wood, K. L., Knox, K. S., Wang, Y., Day, R. B., Schnizlein-Bick, C., & Twigg, H. L. (2005). Apoptosis of CD57+ and CD57- lymphocytes in the lung and blood of HIV-infected subjects. Clinical immunology (Orlando, Fla.), 117(3), 294-301.
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  Patients infected with HIV frequently have a CD8+ lymphocytic alveolitis consisting of HIV-specific CD8+CD57- cytotoxic T lymphocytes. However, in late stage disease, there is expansion of a CD8+CD57+ population with suppressive properties. We examined role of lymphocyte apoptosis in the expansion of the CD8+CD57+ lymphocytes in late stage HIV in the lung and blood compartment in human subjects. Fas was expressed on virtually all lung lymphocytes from HIV-infected and normal subjects. Fas ligand expression was increased in HIV infection in both CD8+CD57+ and CD8+CD57- lymphocytes, though a significantly greater percentage of CD8+CD57+ cells expressed this marker. CD8+CD57+ lymphocytes in normal and HIV-infected subjects underwent more apoptosis than CD8+CD57- cells. However, in late stage HIV infection, the percentage of CD8+CD57+ cells undergoing apoptosis declined. These data demonstrate that under normal conditions CD8+CD57+ cells appear destined to undergo programmed cell death. Expansion of suppressive CD8+CD57+ cells in the lungs of HIV-infected subjects with advanced disease may be due to the failure of this normal regulatory process.
• Day, R. B., Wang, Y., Knox, K. S., Pasula, R., Martin, W. J., & Twigg, H. L. (2004). Alveolar macrophages from HIV-infected subjects are resistant to Mycobacterium tuberculosis in vitro. American journal of respiratory cell and molecular biology, 30(3), 403-10.
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  HIV-infected individuals frequently develop Mycobacterium tuberculosis (MTB) infection. Alveolar macrophages (AM) are the initial host defense against this organism. We measured MTB growth in AM from normal and HIV-infected subjects after in vitro exposure. Intracellular growth of MTB was reduced in AM from HIV-infected subjects compared with normal macrophages. This was confined to subjects with CD4 counts greater than 200/microl. Growth of avirulent mycobacteria in HIV macrophages was significantly less than virulent MTB. Because avirulent MTB is more sensitive to tumor necrosis factor-alpha (TNF-alpha), we examined the relationship between cytokine secretion and mycobacterial growth. Higher AM spontaneous TNF-alpha secretion was associated with reduced MTB growth in normal AM. This relationship was not seen in HIV-infected subjects, suggesting that other factors contributed to mycobacteria resistance. Mycobacteria-induced TNF-alpha secretion was inversely associated with growth in normal AM but not in HIV-infected subjects. Finally, binding and internalization of MTB was augmented in HIV macrophages compared with normal, demonstrating that reduced intracellular MTB growth was not due to impaired phagocytosis. In conclusion, the increased incidence of MTB infection in HIV-infected subjects does not appear to be due to a defect in macrophage innate immunity.
• Knox, K. S., Day, R. B., Wood, K. L., Kohli, L. L., Hage, C. A., Foresman, B. H., Schnizlein-Bick, C. T., & Twigg, H. L. (2004). Macrophages exposed to lymphotropic and monocytotropic HIV induce similar CTL responses despite differences in productive infection. Cellular immunology, 229(2), 130-8.
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  Macrophages are accessory cells that are vulnerable to infection by HIV-1. HTLV-IIIB, a lymphotropic strain of HIV, infects macrophages poorly resulting in either no or low levels of virus expression compared to high levels of productive infection after exposure of macrophages to the monocytotropic HIV strain Ada-M. Whether this results in an impaired ability of HTLV-IIIB-exposed macrophages to initiate protective cytotoxic T lymphocyte (CTL) immune responses against these strains is not well defined. We investigated the ability of monocyte-derived macrophages (MDM) exposed to lymphotropic and monocytotropic HIV strains to initiate primary CTL responses in vitro. MDM exposed to HTLV-IIIB induced a specific primary CTL response that was comparable to MDM exposed to the monocytotropic strain Ada-M despite marked differences in productive HIV infection in MDM between the two strains. CTL generated in this model were MHC-restricted, strain-specific, and CD8+. These data demonstrate that high levels of productive HIV infection in accessory cells are not a prerequisite for the generation of a primary CTL response, suggesting a novel immunologic interaction between MDM and lymphotropic HIV strains.
• Roberts, S. D., Mirowski, G. W., Wilkes, D., Kwo, P. Y., & Knox, K. S. (2004). Sarcoidosis. Part II: Extrapulmonary and systemic manifestations. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 51(4), 628-630.
• Roberts, S. D., Mirowski, G. W., Wilkes, D., Teague, S. D., & Knox, K. S. (2004). Sarcoidosis. Part I: Pulmonary manifestations. JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY, 51(3), 448-451.
• Sriram, P. S., Knox, K. S., Busk, M. F., Sarosi, G. A., & Mastronarde, J. G. (2004). A 19-Year-Old Man with Nonresolving Pneumonia. Chest, 125(Issue 1). doi:10.1378/chest.125.1.330
• Sriram, P. S., Knox, K. S., Busk, M. F., Sarosi, G. A., & Mastronarde, J. G. (2004). A 19-year-old man with nonresolving pneumonia - Pulmonary blastomycosis. CHEST, 125(1), 330-333.
• Canlas, K., Kahi, C. J., Knox, K. S., Kwo, P. Y., Roberts, S. D., Roberts, S. C., Temkit, M., & Wilkes, D. S. (2003). Hepatobiliary disease in sarcoidosis. Gastroenterology, 124(4), A718. doi:10.1016/s0016-5085(03)83624-7
• Hage, C. A., Wood, K. L., Sarosi, G., & Knox, K. S. (2003). Pulmonary cryptococcosis after initiation of anti-Tumor Necrosis Factor-alpha therapy. CHEST, 124(4), 254S-255S.
• Hage, C. A., Wood, K. L., Winer-Muram, H. T., Wilson, S. J., Sarosi, G., & Knox, K. S. (2003). Pulmonary Cryptococcosis after Initiation of Anti-Tumor Necrosis Factor-α Therapy. Chest, 124(Issue 6). doi:10.1378/chest.124.6.2395
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  Many patients with rheumatoid arthritis are being treated with immunosuppressive regimens that include an agent directed at blocking tumor necrosis factor (TNF)-α. Although reportedly safe, tuberculous and fungal infections have emerged as significant complications of therapy. We report a case of pulmonary cryptococcosis soon after the initiation of therapy with the anti-TNF-α antibody, infliximab. A diagnosis was made early in the disease course, and the patient responded quickly to antifungal therapy. This case should alert clinicians to the increased incidence of pulmonary mycoses in patients receiving anti-TNF-α therapy.
• Roberts, S. D., Wilkes, D. S., Burgett, R. A., & Knox, K. S. (2003). Refractory sarcoidosis responding to infliximab. CHEST, 124(5), 2028-2031.
• Wood, K. L., Hage, C. A., Knox, K. S., Kleiman, M. B., Sannuti, A., Day, R. B., Wheat, L. J., & Twigg, H. L. (2003). Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. American journal of respiratory and critical care medicine, 167(9), 1279-82.
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  Anti-tumor necrosis factor-alpha (TNF-alpha) antibodies are frequently used to treat inflammatory diseases. However, these drugs also have immunosuppressive effects. We report on three patients who developed disseminated histoplasmosis on therapy with TNF-alpha inhibitors. In vitro assays were used to characterize the role of these agents in host defense against Histoplasma capsulatum. Intracellular proliferation of H. capsulatum was measured in alveolar macrophages and peripheral monocytes of normal volunteers in the presence and absence of the TNF-alpha antibody, infliximab. Both infliximab and control antibody enhanced fungal growth in monocytes and alveolar macrophages, suggesting this was a nonspecific antibody response. Despite similar intracellular fungal loads in the presence of both antibodies, lymphocyte proliferation in response to blood monocytes and alveolar macrophages infected with H. capsulatum was inhibited by the addition of physiologic doses of infliximab, whereas control antibody had no effect. The production of H. capsulatum-induced interferon-gamma and TNF-alpha was assessed in 5-day cultures containing lymphocytes and alveolar macrophages or monocytes. Interferon-gamma secretion was significantly reduced in the presence of infliximab. In summary, patients receiving anti-TNF-alpha therapy are at risk for developing disseminated histoplasmosis. This may be due to a defect in the TH1 arm of cellular immunity.
• Knox, K. S., Behnia, M., Smith, L. R., Vance, G. H., Busk, M., Cummings, O. W., Kwo, P. Y., & Wilkes, D. S. (2002). Acute graft-versus-host disease of the lung after liver transplantation. LIVER TRANSPLANTATION, 8(10), 968-971.
• Foresman, B. H., & Knox, K. S. (2000). Workup and indications for polysomnography in patients with sleep-related complaints.. The Journal of the American Osteopathic Association, 100(8 Suppl), S22-7.
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  A significant proportion of the population has chronic sleep problems necessitating an increasing involvement by the primary care physician. Also, the general patient population is becoming more familiar with these disorders and is seeking assistance. Because sleep studies are expensive and time consuming, adhering to the recognized indications for testing reduces the number of inappropriate studies. Under most circumstances, individuals with excessive daytime sleepiness and symptoms suggestive of obstructive sleep apnea are candidates for polysomnography. Other individuals with parasomnias or difficult-to-treat insomnia are also candidates for testing. In some circumstances, procedures designed to assess sleepiness may also need to be used to ascertain the impact of the disorder on daytime functioning and may be part of evaluations involving the transportation industry. Only after taking a thorough history and doing a physical examination can the physician make an accurate determination of the appropriate study type.
• Day, R. B., Knox, K. S., Wang, Y., & Twigg, H. L. (1999). Alveolar macrophages from HIV infected subjects are intrinsically resistant to Mycobacterium tuberculosis infection in vitro.. JOURNAL OF INVESTIGATIVE MEDICINE, 47(7), 234A-234A.
• Knox, K. S., Day, R. B., & Twigg, H. L. (1999). Lymphotropic HIV strains attach to macrophages and remain viable in the absence of productive infection.. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 159(3), A21-A21.
• Twigg, H. L., Soliman, D. M., Day, R. B., Knox, K. S., Anderson, R. J., Wilkes, D. S., & Schnizlein-Bick, C. (1999). Lymphocytic alveolitis bronchoalveolar lavage viral load, and outcome in human immunodeficiency virus infection. AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, 159(5), 1439-1444.
• Twigg, H. L., Spain, B. A., Soliman, D. M., Knox, K., Sidner, R. A., Schnizlein-Bick, C., Wilkes, D. S., & Iwamoto, G. K. (1999). Production of interferon-gamma by lung lymphocytes in HIV-infected individuals. AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY, 276(2), L256-L262.
• Knox, K. S., Day, R. B., & Twigg, H. L. (1998). Macrophages exposed to a lymphotropic HIV strain can induce a cytotoxic T cell response in the absence of productive infections.. JOURNAL OF INVESTIGATIVE MEDICINE, 46(7), 285A-285A.

Proceedings Publications

• Bailey, M., Chaudhary, S., Kato, K., Knox, K. S., & Natt, B. (2019). CA 15-3: A Novel Biomarker for the Diagnosis and Progression of Interstitial Lung Disease. In A38. IDIOPATHIC INTERSTITIAL PNEUMONIA: DIAGNOSIS AND NATURAL HISTORY.
• Ampel, N. M., Knox, K. S., & Nesbit, L. A. (2012). Cytokine Patterns From Bronchalveolar Lavage And Peripheral Blood In Acute Pulmonary Coccidioidomycosis. In B56. PATHOGENESIS AND HOST RESPONSE TO FUNGAL LUNG INFECTIONS.
• Hansen, L., Knox, K. S., Rischard, F., & Vo, T. (2012). Treprpstinil Induced Platelets Dysfunction And Massive Hemoptysis In Pulmonary Hypertension Patient. In D68. PULMONARY VASCULAR DISEASES: CLINICAL CASES.
• Hage, C. A., Iii, H. L., Knox, K. S., Muzoora, M., & Twigg, H. L. (2011). HIV Induced CD1D Down Regulation Is Not Recovered After One Year Of Haart. In A35. LESSONS IN LUNG INFECTIONS.
• Day, R. B., Dong, Q., Gao, X., Iii, H. L., Knox, K. S., Nelson, D. E., Revanna, K. V., Sodergren, E., Twigg, H. L., & Weinstock, G. M. (2010). Analysis Of The Respiratory Microbiome Using Bronchoalveolar Lavage From HIV-Infected And Uninfected Subjects. In D33. AIRWAY INFECTION: MICROBIOME AND MECHANISMS.

Presentations

• Knox, K. S., Martinez, G. F., Giblin, C. R., Hendricks, A., & Meraz, C. (2020, October). Empowering Clinical Faculty in the Promotion Process by Adapting Criteria, Expanding Outreach and Engaging Technology.. AAMC GFA National Professional Development Conference. Portland, OR: AAMC.
• Martinez, G. F., Knox, K. S., Giblin, C. R., Schermer, B., & Christofolo, R. (2020, November). A call to action: Incorporating sustainability into faculty leadership development programming.. AAMC GFA National Professional Development Conference. Portland, OR: AAMC.
• Martinez, G. F., Knox, K. S., Spear-Ellinwood, K. C., Moynahan, K. F., & Clemens, C. J. (2017, February). The GME program conundrum: A grounded theory of valued characteristics.. AAMC-WGEA Conference 2017AAMC.
• Knox, K. S. (2015, June). Update on “Region-ella”: The Endemic Mycoses. Medicine Grand Rounds. Indiana: Indiana University Medical Center.
• Chaudhary, S., Knox, K. S., Raz, Y., & Meinke, L. E. (2010, October/Fall). Coccidioidomycosis in Thoracic Transplants. Infectious Disease Conference at the University of Arizona. Tucson, AZ.

Poster Presentations

• Knox, K. S., Giblin, C. R., Spear-Ellinwood, K. S., Clemens, C., Moynahan, K., & Martinez, G. F. (2018, April). The GME Program Quality Conundrum Across the Continuum: A Discovery of GME Leaders, Residents, Fellows and Medical Student Perceptions. AAMC-Continuum Connections Joint Meeting. Orlando, FL: AAMC.
• Martinez, G. F., Clemens, C., & Knox, K. S. (2018, April). Sufficient Protected Time: A Retrospective Review of Survey Data at One Sponsoring Institution. AAMC-Continuum Connections Joint Meeting. Orlando, FL: AAMC.
• Casanova, N., Casanova, N., Gonzalez-Garay, M. L., Gonzalez-Garay, M. L., Pouladi, N., Pouladi, N., Knox, K. S., Knox, K. S., Garcia, J. G., Garcia, J. G., Navarrete, J., Navarrete, J., Lussier, Y. A., Lussier, Y. A., Berghout, J., & Berghout, J. (2017, May). TNF-α specific PBMC responses in complicated and uncomplicated sarcoidosis by RNA-Seq. American Thoracic Society International Conference. Washington DC: ATS.
• Desai, A., Yuan, J., Garcia, J. G., Larson, B. F., Knox, K. S., Sprissler, R., Cordery, A., Gupta, A., Nair, V., & Lynn, H. D. (2016, November). Exome sequencing reveals a novel SNP in TRPC6 in pulmonary arterial hypertension. American Heart Association Scientific Sessions. New Orleans, LA: American Heart Association.
• Desai, A., Yuan, J., Rischard, F., Garcia, J. G., Black, S., Suryanarayana, P., Khalpey, Z. I., Knox, K. S., Patel, K., Yarlagadda, V., Shewale, A., Riaz, I., Whitaker, M., Dherange, P., Nair, V., & Natarajan, B. (2016, November). Hispanic disparities in PAH: Multi-modality validation of increased susceptibility to right ventricular dysfunction.. American Heart Association Scientific Sessions;. New Orleans, L: American Heart Association.
• Garcia, J. G., Knox, K. S., Zhou, T., & Casanova, N. (2016, May). Peripheral Blood MicroRNA Signature Differentiates Sarcoidosis. American Thoracic Society International Conference. San Francisco: ATS.
• Holbrook, E. D., Malo, J., Zangeneh, T. T., Strawter, C., Oren, E., Robey, I., Erickson, H., Chahal, R., Durkin, M., Thompson, C., Hoover, S. E., Ampel, N., Wheat, L. J., & Knox, K. S. (2016, Fall). Development of an Improved Antibody Detection EIA for use in Diagnosis of Coccidioidomycosis. ID Week. New Orleans, LA.
• Natt, B., Rodriguez, ., Knox, K. S., & Carr, G. E. (2016, May/Spring). Concurrent Myasthenia Gravis and autoimmune featured interstitial lung disease: a case report. ATS International Conference. San Francisco, CA.
• Desai, A., Garcia, J. G., Yuan, J., Hansen, L., Rischard, F., Suryanarayana, P., Khalpey, Z. I., Knox, K. S., Chinthammit, C., Yarlagadda, V., Whitaker, M. E., Shewale, A., Irbaz Bin Riaz, F., Nair, V., & Dherange, P. (2015, August). Disparities in pulmonary arterial hypertension: Effects of Hispanic ethnicity on susceptibility to right ventricular dysfunction. 2015 American College of Physicians Meeting (ACP). Phoenix, AZ: American College of Physicians.
• Holbrook, E. D., Zangeneh, T. T., Malo, J., Strawter, C., Oren, E., Robey, I., Erickson, H., Chahal, R., Thompson, C., Ampel, N., Wheat, L. J., & Knox, K. S. (2015, October). Development of an improved antibody detection EIA for use in detection of coccidioidomycosis. ID Week 2015.
• Natt, B., Malo, J., Snyder, L. S., Knepler, J. L., Knox, K. S., & Mosier, J. M. (2015, May/Spring). Advanced Airway Management in Critical Care Fellowship Training. ATS International Conference. Denver, CO.

Reviews

• Martinez, G. F., & Knox, K. S. (2016. A qualitative systematic review of the professionalization of the vice chair for education.
• Twigg, H. L., Weinstock, G. M., & Knox, K. S. (2017. Lung microbiome in human immunodeficiency virus infection(pp 97-107).
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  The lung microbiome plays a significant role in normal lung function and disease. Because microbial colonization is likely influenced by immunodeficiency, one would speculate that infection with human immunodeficiency virus (HIV) alters the lung microbiome. Furthermore, how this alteration might impact pulmonary complications now seen in HIV-infected patients on antiretroviral therapy (ART), which has shifted from opportunistic infections to diseases associated with chronic inflammation, is not known. There have been limited publications on the lung microbiome in HIV infection, many of them emanating from the Lung HIV Microbiome Project. Current evidence suggests that the lung microbiome in healthy HIV-infected individuals with preserved CD4 counts is similar to uninfected individuals. However, in individuals with more advanced disease, there is an altered alveolar microbiome characterized by a loss of richness and evenness (alpha diversity) within individuals. Furthermore, as a group the taxa making up the HIV-infected and uninfected lung microbiome are different (differences in beta diversity), and the HIV-infected population is more spread out (greater dispersion) than the uninfected population. These differences decline with ART, but even after effective therapy the alveolar microbiome in HIV-infected individuals contains increased amounts of signature bacteria, some of which have previously been associated with chronic lung inflammation. Furthermore, more recent investigations into the lung virome in HIV infection suggest that perturbations in lung viral communities also exist in HIV infection, and that these too are associated with evidence of lung inflammation. Thus, it is likely both microbiome and virome alterations in HIV infection contribute to lung inflammation in these individuals, which has important implications on the changing spectrum of pulmonary complications in patients living with HIV.

Other Teaching Materials

• Knox, K. S., & Martinez, G. F. (2023. MD, PhD Career Planning: Exploring Private and Academic Career Options. University of Arizona College of MEdicine-Phoenix.
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  Educational presentation for COM-P MD-PhD Students
• Knox, K. S., Giblin, C. R., & Martinez, G. F. (2020. Exploring Physician Career Options in Academic Medicine. Association of American Medical Colleges (AAMC) iCollaborative Educational Innovation, Policy and Best Practices Shared Resources.

Others

• Knox, K. S., & Martinez, G. F. (2018, February). A fourth year credit bearing course on a career in academic medicine: Institutional commitment towards early awareness for future physician-faculty. National Pre-Faculty Career Development Conference.
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  BNGAP and Florida International University Herbert Wertheim College of Medicine hosts