Kenneth S Knox

Interests

Research

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

Teaching

Valley Fever, Interstitial Lung Disease, Sarcoidosis, Careers in Academic Medicine, Mentoring

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

• 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.
• 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.
• 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.
• 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.
• 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.
• 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(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.
• 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.
• 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., 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.
• 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.
• 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.
• 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.
• 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.
• 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., 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.
• 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., 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).
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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 - Pulmonary blastomycosis. CHEST, 125(1), 330-333.
• 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.
• 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.
• 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.

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