Bio

Dr. Pacheco-Navarro is a pulmonary and critical care physician with a research interest in long term outcomes after critical illness and the intersection of critical illness and autoimmunity.

Clinical Focus

  • Pulmonary Disease
  • Critical Care

Contact

  • Academic
    apn@stanford.edu
    University - Student Department: Epidemiology and Population Health Position: Graduate
    University - Scholar Department: School of Medicine Position: Medical Fellow

All Publications

  • The Metabolomics of Critical Illness. Handbook of experimental pharmacology Pacheco-Navarro, A. E., Rogers, A. J. 2022

    Abstract

    Critical illness is associated with dramatic changes in metabolism driven by immune, endocrine, and adrenergic mediators. These changes involve early activation of catabolic processes leading to increased energetic substrate availability; later on, they are followed by a hypometabolic phase characterized by deranged mitochondrial function. In sepsis and ARDS, these rapid clinical changes are reflected in metabolomic profiles of plasma and other fluids, suggesting that metabolomics could one day be used to assist in the diagnosis and prognostication of these syndromes. Some metabolites, such as lactate, are already in clinical use and define patients with septic shock, a high-mortality subtype of sepsis. Larger-scale metabolomic profiling may ultimately offer a tool to identify subgroups of critically ill patients who may respond to therapy, but further work is needed before this type of precision medicine is readily employed in the clinical setting.

    View details for DOI 10.1007/164_2022_622

    View details for PubMedID 36376705

  • Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections. JCI insight Kratochvil, M. J., Kaber, G., Demirdjian, S., Cai, P. C., Burgener, E. B., Nagy, N., Barlow, G. L., Popescu, M., Nicolls, M. R., Ozawa, M. G., Regula, D. P., Pacheco-Navarro, A. E., Yang, S., de Jesus Perez, V. A., Karmouty-Quintana, H., Peters, A. M., Zhao, B., Buja, M. L., Johnson, P. Y., Vernon, R. B., Wight, T. N., Stanford COVID-19 Biobank Study Group, Milla, C. E., Rogers, A. J., Spakowitz, A. J., Heilshorn, S. C., Bollyky, P. L. 2022; 7 (12)

    Abstract

    Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e., resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We found the percentages of solids and protein content were greatly elevated in COVID-19 compared with heathy control samples and closely resembled levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) were major components of respiratory secretions in COVID-19 and were likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibited heterogeneous rheological behaviors, with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observed increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factor-stimulated gene-6 staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicated that increases in HA and DNA in COVID-19 respiratory secretion samples correlated with enhanced inflammatory burden and suggested that DNA and HA may be viable therapeutic targets in COVID-19 infection.

    View details for DOI 10.1172/jci.insight.152629

    View details for PubMedID 35730564

  • Oral hymecromone decreases hyaluronan in human study participants. The Journal of clinical investigation Rosser, J. I., Nagy, N., Goel, R., Kaber, G., Demirdjian, S., Saxena, J., Bollyky, J. B., Frymoyer, A. R., Pacheco-Navarro, A. E., Burgener, E. B., Rajadas, J., Wang, Z., Arbach, O., Dunn, C. E., Kalinowski, A., Milla, C. E., Bollyky, P. L. 2022; 132 (9)

    Abstract

    BACKGROUNDHyaluronan (HA), an extracellular matrix glycosaminoglycan, has been implicated in the pathophysiology of COVID-19 infection, pulmonary hypertension, pulmonary fibrosis, and other diseases, but is not targeted by any approved drugs. We asked whether hymecromone (4-methylumbelliferone [4-MU]), an oral drug approved in Europe for biliary spasm treatment that also inhibits HA in vitro and in animal models, could be repurposed as an inhibitor of HA synthesis in humans.METHODSWe conducted an open-label, single-center, dose-response study of hymecromone in healthy adults. Subjects received hymecromone at 1200 (n = 8), 2400 (n = 9), or 3600 (n = 9) mg/d divided into 3 doses daily, administered orally for 4 days. We assessed safety and tolerability of hymecromone and analyzed HA, 4-MU, and 4-methylumbelliferyl glucuronide (4-MUG; the main metabolite of 4-MU) concentrations in sputum and serum.RESULTSHymecromone was well tolerated up to doses of 3600 mg/d. Both sputum and serum drug concentrations increased in a dose-dependent manner, indicating that higher doses lead to greater exposures. Across all dose arms combined, we observed a significant decrease in sputum HA from baseline after 4 days of treatment. We also observed a decrease in serum HA. Additionally, higher baseline sputum HA levels were associated with a greater decrease in sputum HA.CONCLUSIONAfter 4 days of exposure to oral hymecromone, healthy human subjects experienced a significant reduction in sputum HA levels, indicating this oral therapy may have potential in pulmonary diseases where HA is implicated in pathogenesis.TRIAL REGISTRATIONClinicalTrials.gov NCT02780752.FUNDINGStanford Medicine Catalyst, Stanford SPARK, Stanford Innovative Medicines Accelerator program, NIH training grants 5T32AI052073-14 and T32HL129970.

    View details for DOI 10.1172/JCI157983

    View details for PubMedID 35499083

  • Biochemical, Biophysical, and Immunological Characterization of Respiratory Secretions in Severe SARS-CoV-2 (COVID-19) Infections. medRxiv : the preprint server for health sciences Kratochvil, M. J., Kaber, G., Demirdjian, S., Cai, P. C., Burgener, E. B., Nagy, N., Barlow, G. L., Popescu, M., Nicolls, M. R., Ozawa, M. G., Regula, D. P., Pacheco-Navarro, A. E., Yang, S., de Jesus Perez, V. A., Karmouty-Quintana, H., Peters, A. M., Zhao, B., Buja, M. L., Johnson, P. Y., Vernon, R. B., Wight, T. N., Stanford COVID-19 Biobank Study Group, Milla, C. E., Rogers, A. J., Spakowitz, A. J., Heilshorn, S. C., Bollyky, P. L. 2022

    Abstract

    Thick, viscous respiratory secretions are a major pathogenic feature of COVID-19 disease, but the composition and physical properties of these secretions are poorly understood. We characterized the composition and rheological properties (i.e. resistance to flow) of respiratory secretions collected from intubated COVID-19 patients. We find the percent solids and protein content are greatly elevated in COVID-19 compared to heathy control samples and closely resemble levels seen in cystic fibrosis, a genetic disease known for thick, tenacious respiratory secretions. DNA and hyaluronan (HA) are major components of respiratory secretions in COVID-19 and are likewise abundant in cadaveric lung tissues from these patients. COVID-19 secretions exhibit heterogeneous rheological behaviors with thicker samples showing increased sensitivity to DNase and hyaluronidase treatment. In histologic sections from these same patients, we observe increased accumulation of HA and the hyaladherin versican but reduced tumor necrosis factora"stimulated gene-6 (TSG6) staining, consistent with the inflammatory nature of these secretions. Finally, we observed diminished type I interferon and enhanced inflammatory cytokines in these secretions. Overall, our studies indicate that increases in HA and DNA in COVID-19 respiratory secretion samples correlate with enhanced inflammatory burden and suggest that DNA and HA may be viable therapeutic targets in COVID-19 infection.

    View details for DOI 10.1101/2022.03.28.22272848

    View details for PubMedID 35411348