About

Michael G. S. Shashaty, MD, MSCE, FCCM, is an Associate Professor of Medicine in the Department of Pulmonary, Allergy and Critical Care at the Hospital of the University of Pennsylvania. He is also an Associate Scholar at the Center for Clinical Epidemiology and Biostatistics. His career is focused on epidemiologic and translational research studies of the risks for and mechanisms of acute organ dysfunction, primarily acute kidney injury (AKI), in critical illness and populations. Dr. Shashaty has formal training in the clinical practice of pulmonary and critical care medicine, biostatistical and epidemiologic methods, and protein, gene expression, and genomic analyses of human biospecimens. He is the principal investigator for the Lung Transplant Outcomes Group–Acute Kidney Injury (LTOG-AKI) study, a multicenter prospective cohort of lung transplant recipients designed to study the clinical and molecular epidemiology of post-lung transplant AKI, with a focus on identifying clinical characteristics and novel biomarkers for AKI prediction and understanding molecular mechanisms. Additionally, he leads the Penn Trauma Organ Dysfunction Study (PETROS) cohort of critically ill trauma patients and is a co-investigator in the Molecular Epidemiology of Severe Sepsis in the ICU (MESSI) cohort, where he studies AKI and related conditions. His research includes exploring circulating cell-free DNA as a mechanistic contributor to AKI and ARDS, as well as identifying novel phenotypes of AKI. Clinically, Dr. Shashaty is trained in internal medicine, pulmonary diseases, and critical care medicine. He spends most of his clinical time in the medical intensive care unit at the Hospital of the University of Pennsylvania and leads the Critical Care Outreach and Procedure Service (CCOPS). From 2017 to 2024, he served as the Rapid Response Medical Director at HUP, overseeing clinical emergencies, training, and quality improvement initiatives, including adaptations during the COVID-19 pandemic. He actively engages in teaching fellows, house officers, medical students, and advanced practice providers through clinical services, courses at the Perelman School of Medicine, and training programs at the Penn School of Nursing.

Research topics

• Internal medicine
• Medicine
• Emergency medicine
• Virology
• Demography
• Nursing
• Intensive care medicine

Selected publications

• CT-adipose measures identify severe SARS-CoV-2 risk beyond traditional obesity metrics: a C4R cohort study

  BMC Pulmonary Medicine · 2026-05-25

  articleOpen access
  PublisherDOI

• Considerations for Endpoints in Lung Transplant Clinical Trials: Perspective on the ISHLT Consensus Statement

  The Journal of Heart and Lung Transplantation · 2026-01-16

  article
  PublisherDOI

• Genetic Pathway Dysregulation is Both Shared and Distinct in Sepsis-Associated and Trauma-Associated ARDS

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract Rationale: Acute respiratory distress syndrome (ARDS) is a complex trait influenced by both environmental insults and underlying genetic susceptibility. Sepsis and trauma are two environmental exposures that precede ARDS development, yet the genetic pathways implicated in ARDS following these insults remain unknown. We sought to determine which genetic signaling pathways were shared in sepsis-associated and trauma-associated ARDS by using pathway enrichment analysis to understand the underlying pathophysiology and to identify future therapeutic targets. Methods: We enrolled critically ill subjects with sepsis (n=2,048) or trauma (n=1,222) in separate prospective cohort studies. All sepsis subjects fulfilled Sepsis-3 consensus criteria. All trauma subjects presented within 24-hours of severe trauma with an injury severity score >15 and survived for at least 24 hours. We extracted DNA from whole blood and ascertained genotype via Affymetrix Axiom TxArrayv1. Subjects were phenotyped for ARDS via Berlin criteria while invasively ventilated within 6 days of ICU admission. We applied multivariable logistic regression to test the association of single nucleotide polymorphism (SNP) genotype with ARDS risk adjusting for age, sex, and principal component-determined genetic ancestry in an additive model. We conducted a functional pathway enrichment analysis using SNPs that demonstrated association with ARDS (p=0.01) using QIAGEN Ingenuity Pathway Analysis for genes only. A p-value less than 0.05 as calculated by the Benjamini-Hochberg method was used to determine the statistical significance for each pathway. Results: ARDS occurred in 880 (43%) genotyped sepsis subjects and 279 (23%) genotyped trauma subjects. In the sepsis cohort, the protein citrullination (p=1.40x10-3), IL-27 signaling (p=9.30x10-3), and STAT3 signaling (p=9.30x10-3) pathways demonstrated the strongest enrichment (Table). The IL-6 signaling (p=4.19x10-2) and the potassium channel signaling (p=4.11x10-2) pathways were also enriched in sepsis. In the trauma cohort, the synaptogenesis signaling (p=9.94x10-7), glutaminergic receptor signaling (p=9.94x10-7), protein kinase A signaling (p=2.70x10-4), and Rho-GTPase signaling (p=8.89x10-4) pathways demonstrated significant enrichment. The potassium channel signaling (p=7.10x10-3) pathway was also enriched in trauma-associated ARDS. Conclusion: Sepsis-associated and trauma-associated ARDS demonstrated enrichment of both shared and distinct genetic pathways. The STAT3 pathway, which was enriched in the sepsis population, is therapeutically targeted by baricitinib in SARS-CoV-2 ARDS. In both populations, there was genetic dysregulation of the potassium channel signaling pathways. Prior work has implicated voltage-gated potassium channels in pulmonary vascular tone and pulmonary hypoxic vasoconstriction. These findings warrant further investigation to identify novel drug targets from the canonical pathways across all environmental causes of ARDS.

  PublisherDOI

• Static Compliance of the Respiratory System is a Genetically Regulated Quantitative Trait in Sepsis-Associated Acute Hypoxemic Respiratory Failure

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract Rationale: Static compliance of the respiratory system (Crs) is an objective measurement of lung and chest wall stiffness and a relevant quantitative trait in acute hypoxemic respiratory failure (AHRF). Genetic polymorphisms associated with Crs in AHRF may elucidate pathophysiology and identify important targets for treatment and prevention. We aimed to identify single-nucleotide polymorphisms (SNPs) associated with Crs in a cohort of patients with sepsis and AHRF requiring mechanical ventilation (MV), and to determine their relationship with 30-day mortality. Methods: We conducted a genome-wide association study of Crs on the day of MV initiation in a prospective cohort of patients admitted to the intensive care unit with sepsis from 2011-19. We included cohort participants newly requiring MV within 48 hours after ICU admission. We determined genotype using the Affymetrix Axiom TxArrayv1 with DNA extracted from whole blood. The outcome was average Crs on the first day of MV, collected every 8 hours by clinical respiratory therapists. We used multivariable linear regression to test the association of genotype with Crs, adjusted for genetic ancestry by principal components, age, and sex, assuming additive genetic effects. We considered p<5x10-8 to have genome-wide significance and p<1x10-6 to be suggestive. We excluded SNPs with a minor allele frequency of less than 5%. We examined the relationship between compliance-associated variants and 30-day mortality with logistic regression adjusted for principal components. Results: Of 691 participants, the median (interquartile range) Crs was 32.3 mL/cmH2O (23.3-40.0). 30-day mortality was high at 60%. One intergenic SNP (rs41409444) between LINC02484 and ARAP2 met genome-wide significance for association with higher compliance (p = 5.40 x 10-9); this SNP was also associated with decreased mortality (odds ratio 0.65, 95% CI 0.46 – 0.93). Several other SNPs that met suggestive criteria for Crs were also associated with decreased mortality (Table), including an intronic SNP on the SLC40A1 gene, an intergenic SNP near LINC01310, and five additional SNPs between LINC02484 and ARAP2. Conclusion: We report several polymorphisms associated with increased Crs and decreased mortality in AHRF. ARAP2, LINC02484, and LINC01310 have been implicated in the genetic regulation of obesity and the metabolic syndrome, and their association with compliance and mortality may reflect biologic pathways by which adiposity confers a protective effect in critical illness. Additionally, SCL40A1 encodes ferroportin, an iron transport protein important in mitigating pulmonary fibrosis via regulation of fibroblast iron accumulation. These genes warrant further investigation as potential mechanisms and targets in AHRF pathophysiology.

  PublisherDOI

• Venous Thromboembolism Complicates Covid Sepsis More Frequently Than During Non-Covid Sepsis

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract RATIONALE: Venous thromboembolism (VTE) frequently complicates sepsis, which incites inflammation and vascular activation. VTE was reported to be highly prevalent in patients critically ill with sepsis due to SARS-CoV-2 (COVID-19). We conducted this study to determine the risk factors for VTE during sepsis and to test whether the incidence was higher in sepsis patients with COVID-19 compared to their non-COVID counterparts. METHODS: We analyzed a single-center cohort of critically ill patients with sepsis prospectively enrolled between April 2015 and January 2024. Eligibility required strongly suspected or confirmed infection and acute organ failure consistent with sepsis-3 criteria. To determine VTE, we searched all clinically-obtained vascular ultrasound and chest computed tomography angiography studies occurring from 5 days before until 14 days after ICU admission for key terms including ‘thromb’, ‘embol’, ‘clot’ and pattern-matched results for VTE diagnosis or lack thereof. COVID-19 was classified by positive polymerase chain reaction or rapid COVID test. We used multivariable logistic regression to test the association between COVID and VTE accounting for covariates previously associated with VTE: early receipt of invasive ventilation or vasopressors, presence of a central venous catheter, history of solid malignancy, and thrombocytopenia. RESULTS: Of the 3,243 enrolled patients, 235 (7.2%) were diagnosed with VTE: 120 (3.7%) with deep vein thrombosis (DVT), 125 (3.9%) with pulmonary embolus (PE), and 10 (<1%) with both. Approximately 10% of the population (306 participants) had sepsis due to COVID-19, with a VTE rate of 10% (31/306). In multivariable adjusted analysis, COVID-19 was an independent risk factor for VTE (OR 1.54, 95% CI 1.02 – 2.33), p=0.042. Other factors associated with higher severity of illness, including receipt of vasopressors, invasive ventilation, and a central catheter were more common in the VTE group though these associations did not independent association in adjusted analysis (Table). CONCLUSION: In critically ill patients with sepsis, VTE was diagnosed more frequently in COVID-19 sepsis than non-COVID sepsis. Our study was conducted at a single health system, and our COVID population sample size was modest. We did not screen for VTE and relied on clinical detection. We acknowledge death as a competing risk that might influence results. COVID sepsis may pose a higher risk for VTE development compared to other sepsis etiologies although clinical trials have not demonstrated a benefit of therapeutic anticoagulation in this population.

  PublisherDOI

• Two Physiologic Latent Classes of Acute Hypoxemic Respiratory Failure in Sepsis Are Distinguished by Lung Mechanics and Gas Exchange

  Critical Care Explorations · 2025-09-22 · 1 citations

  articleOpen access

  OBJECTIVES: Physiologic subtypes of acute hypoxemic respiratory failure (AHRF) may confer a differential response to treatments, particularly therapeutic strategies that are specific to pulmonary organ failure. We sought to identify physiologic latent classes of sepsis-associated AHRF defined by respiratory mechanics, oxygenation, ventilation, and radiographic patterns of lung injury, and to determine the association between class membership and 30-day mortality. DESIGN: We performed latent class analysis of patients with AHRF newly requiring mechanical ventilation enrolled in a prospective cohort of patients with sepsis from 2011 to 2020. We used logistic regression adjusted for Acute Physiology and Chronic Health Evaluation to determine the association between class membership and 30-day mortality and examined the distribution of patients classified as "hyperinflammatory" by previously described biomarker-based subphenotyping paradigms. SETTING: Philadelphia, Pennsylvania, United States. PATIENTS: Eight hundred eighty-two patients. MEASUREMENTS AND MAIN RESULTS: We identified two physiologic latent classes. Class 1 (n = 390) was characterized by low static compliance and impaired ventilation when compared with class 2 (n = 432). Mortality at 30 days was higher in the more physiologically severe class 1 when compared with class 2 (adjusted risk difference 0.12, p < 0.001) despite a similar severity of sepsis. Class 1 also contained a higher proportion of female patients and patients with obesity. CONCLUSIONS: We identified two physiologic latent classes of sepsis-associated AHRF. Relative to class 2, class 1 was distinguished by low compliance, impaired ventilation, and higher 30-day mortality independent of the severity of sepsis. The higher percentage of female patients and patients with obesity in class 1 suggests a potential role for body composition in class determination. Physiologic classes were not primarily determined by qualification for acute respiratory distress syndrome or previously described biomarker-based subphenotypes, suggesting a distinct physiologic "axis" of heterogeneity.

  PublisherDOI

• Parsimonious Subphenotyping Algorithms Perform Differently in Patients With Sepsis and Hematologic Malignancy

  Critical Care Medicine · 2025-07-10

  articleOpen access

  OBJECTIVES: Latent class assignment-derived subphenotyping algorithms may identify treatment-responsive subgroups of critically ill patients with sepsis and acute respiratory distress syndrome. It is unclear if these algorithms are generalizable to patients with comorbid malignancy, a state which may perturb influential inflammatory biomarkers. This study aimed to test whether malignancy or neutropenia modified the effect of subphenotype assignment by two algorithms as applied to a prospective cohort enriched for ICU patients with active malignancy. DESIGN: Prospective cohort study at a single U.S. quaternary referral center. SETTING/PATIENTS: ICU patients older than 18 admitted to an ICU with a primary admission indication of sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied two published subphenotyping algorithms utilizing either interleukin (IL)-6 or IL-8 (in addition to soluble tumor necrosis factor receptor 1 and bicarbonate) to our cohort of 930 patients with sepsis, 396 (42%) of whom had active malignancy. A greater proportion of hematologic malignancy patients were assigned the "hyperinflammatory" subphenotype by the IL-8-utilizing algorithm than the IL-6 algorithm (58% vs. 32%). Patients with leukemia and neutropenia were overrepresented among those classified as hyperinflammatory by IL-8 algorithm. We constructed Cox proportional hazards models to assess for interaction between the presence of solid malignancy, hematologic malignancy, and severe neutropenia and the subphenotype/mortality association. Hematologic malignancy uniquely appeared to attenuate the associated mortality of the IL-6-assigned hyperinflammatory subphenotype (interaction; p = 0.037), but not the IL-8-assigned hyperinflammatory subphenotype (interaction; p = 0.260), which retained an independent association with mortality in hematologic malignancy subjects (hazard ratio, 1.50; 95% CI, 1.08-2.07; p = 0.014). CONCLUSIONS: As subphenotyping algorithms are being tested as point-of-care prognostic tools, it is important to understand their generalizability to patients with comorbid malignancy, which constitute an increasing proportion of ICU patients. The differential behavior of these algorithms in patients with hematologic malignancy suggests a need for independent derivation and validation in this specific population.

  PublisherDOI

• Rapidly Improving Acute Respiratory Distress Syndrome (ARDS) is Common and Unique in Sepsis-related ARDS

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract RATIONALE: Rapidly improving acute respiratory distress syndrome (RIARDS) is a subgroup of ARDS in which hypoxemia significantly improves within 24 hours after initiation of mechanical ventilation. RIARDS has been described in up to 20% of all-cause ARDS cases in an observational cohort, and has been associated with the hypoinflammatory ARDS phenotype. The purpose of this study was to define the clinical characteristics and outcomes of RIARDS among patients with sepsis-associated ARDS, and to validate its association with inflammatory subphenotypes within this cohort. METHODS: We analyzed data from 787 endotracheally intubated patients who met Berlin criteria for ARDS within three days of ICU admission and were enrolled in a prospective observational cohort of critically ill patients with sepsis. RIARDS was defined according to previous studies as improvement of hypoxemia determined by either (i) PaO2:FIO2 &amp;gt; 300 or SpO2:FIO2 &amp;gt; 315 on the day following diagnosis of ARDS (day 2); or (ii) unassisted breathing by day 2 and for the next 48 hours (defined as absence of endotracheal intubation on day 2 through day 4). Participants who did not meet RIARDS criteria were categorized as persistent ARDS. Plasma biomarkers were measured on samples collected on the day of ICU admission, and ARDS subphenotypes were determined using a published parsimonious algorithm using IL-8, sTNFR1, and serum bicarbonate. Two-group comparisons between RIARDS and persistent ARDS were done using the Mann-Whitney U test or Fisher's exact test. RESULTS: Of the 787 enrolled patients, 70 (9%) met criteria for RIARDS. Participants with RIARDS had a lower prevalence of vasopressors use (17% vs 36%, p=0.003), less severe ARDS (p=0.004), and lower 28-day mortality (50% vs 64%; p=0.028). Compared to persistent ARDS, patients with RIARDS less commonly had sepsis from pneumonia (57% vs 70%, p=0.042) and had lower plateau pressures on the day of ARDS diagnosis (21cmH2O vs 23 cmH2O, p=0.005). Plasma levels of inflammatory biomarkers did not differ between RIARDS and persistent disease, and the hyperinflammatory ARDS phenotype was present in over two-thirds of both groups (86% and 71%, p=0.009, respectively). CONCLUSION: In patients with sepsis-associated ARDS, we detected a lower prevalence of RIARDS than previously reported in all-cause ARDS. Consistent with previous studies, RIARDS was associated with less severe clinical disease and lower mortality. The hyperinflammatory phenotype was equally highly enriched in both RIARDS and persistent ARDS, suggesting that the degree of systematic inflammation may not explain clinical differences between these groups among sepsis-associated ARDS.

  PublisherDOI

• Culture Negative Sepsis is Associated With Increased 30-day Mortality Despite Lower Severity of Illness and Plasma Levels of Inflammatory Markers

  American Journal of Respiratory and Critical Care Medicine · 2025-05-01

  article

  Abstract Culture negative sepsis (CNS), in which no pathogen is identified, has highly variable prevalence and associated mortality in published studies. CNS may adversely affect clinical outcomes due to under-recognition of sepsis, inappropriate antimicrobial coverage, or biologically distinct host response. We sought to determine CNS prevalence in a cohort of patients critically ill with sepsis, assess the relationship between CNS and 30-day mortality, and compare the inflammatory and endothelial biomarker profile of CNS and culture positive sepsis. We conducted a prospective cohort study of critically ill adults admitted to the ICU between 2008 and 2022 with presumed sepsis as defined by sepsis-3 criteria. Trained staff reviewed all clinically obtained microbiologic data within a 14-day window centered on ICU admission and recorded positive or negative results. Body site of infection was determined by physician investigators reviewing clinical notes and physiologic, microbiologic, and radiographic data; if no site was suggested, site of infection was classified ‘unknown.’ Culture negative cases could be adjudicated to a body site if signs and symptoms suggested a source. We tracked survival through 30 days. We tested the association of CNS with 30-day mortality using logistic regression adjusted for age, year of cohort entry, and severity of illness as measured by the APACHE III score. Additionally, inflammatory and vascular plasma biomarkers were measured in a subset of participants using electrochemiluminescence. We tested for differences in plasma biomarker levels between CNS and culture positive sepsis using the Wilcoxon rank-sum test. Of 3,213 patients enrolled, 1,827 (57%) were male, the median age was 63 and APACHE III was 86. The prevalence of CNS was 36%, and overall 30-day mortality was 45%. Patients with CNS were more likely to have an underlying malignancy, and to have a lower severity of illness as defined by APACHE III. Patients with CNS had a higher mortality at 30-days in adjusted models (OR 1.29, 95% CI 1.10-1.52, p = 0.002). Testing over 1000 participants, participants with CNS had lower levels of inflammatory biomarkers but similar concentrations of endothelial biomarkers (Table). In our cohort, participants with CNS manifested a higher adjusted mortality compared to those with a confirmed culture, despite lower APACHE III scores and lower inflammatory plasma markers. Vascular injury markers were comparable by culture positivity. CNS may be a distinct biological subtype of sepsis with unique risk factors and host response, which should be investigated for therapeutic heterogeneity.

  PublisherDOI

• Identifying a unique signature of sepsis in patients with pre-existing cirrhosis

  Critical Care · 2025-05-19 · 4 citations

  articleOpen access

  BACKGROUND: The pre-existing diagnosis of cirrhosis is a complicating factor in the progression and prognosis of sepsis; however, the unique epidemiology, sepsis characteristics, and underlying mechanisms of immune dysregulation in sepsis among patients with cirrhosis remain incompletely understood. Our primary objective was to identify clinical outcomes and biological characteristics that differ between patients with and without cirrhosis among critically ill patients with sepsis. METHODS: We analyzed data from a prospective cohort of critically ill patients presenting to single center with sepsis. Subjects were followed for 6 days for the development of acute respiratory distress syndrome (ARDS) and acute kidney injury (AKI), and 30 days for mortality. Inflammatory, endothelial, and coagulopathic proteins were measured in plasma collected at ICU admission in a subset of patients. We determined associations of cirrhosis with outcomes using multivariable logistic regression adjusting for pre-specified confounders. We tested differences in plasma protein levels by cirrhosis diagnosis using the Wilcoxon Rank-sum test. RESULTS: We enrolled 2962 subjects, 371 (13%) of whom had a pre-existing diagnosis of cirrhosis. Patients with cirrhosis had higher severity of illness scores, were more likely to have an abdominal source of sepsis, and had more significant clinically measured coagulation abnormalities relative to patients without cirrhosis. In multivariate analysis, cirrhosis was associated with higher AKI risk (adjusted OR 1.65; 95% CI 1.21 to 2.26; P = 0.002), and 30-day mortality (adjusted OR 1.38; 95% CI 1.05 to 1.82; P = 0.022). There was no significant difference in risk for ARDS (adjusted OR 1.02; 95% CI 0.69 to 1.50; P = 0.92). Cirrhosis was associated with higher plasma levels of angiopoietin-2 (P < 0.001), von Willebrand factor (P < 0.001), and soluble thrombomodulin (P < 0.001), as well as lower levels of interleukin (IL)-10 (P < 0.001), IL-1β (P = 0.008), and IL-1RA (P = 0.036). There were no significant differences in levels of IL-6 (P = 0.30). CONCLUSIONS: We identified associations between pre-existing cirrhosis and endothelial injury, AKI, and mortality in sepsis. Patients with pre-existing cirrhosis who develop sepsis may display a unique phenotype of endothelial dysfunction that requires unique targeted approaches.

  PublisherOA PDFDOI

Recent grants

• Defining optimal tacrolimus dosing and concentrations in the early post-lung transplant period based on short- and long-term clinical impacts

  NIH · $756k · 2022–2025

• NIH Grant K23DK097307

  NIH · $626k · 2017

• Clinical and molecular epidemiology of acute kidney injury after lung transplant

  NIH · $3.4M · 2017–2024

Frequent coauthors

• Jason D. Christie

  University of Pennsylvania

  118 shared

• Nuala J. Meyer

  University of Pennsylvania

  101 shared

• John P. Reilly

  100 shared

• Brian J. Anderson

  University of Pennsylvania

  59 shared

• C.A.G. Ittner

  University of Pennsylvania

  57 shared

• Todd A. Miano

  University of Pennsylvania

  52 shared

• Tiffanie K. Jones

  University of Pennsylvania

  43 shared

• Thomas Dunn

  Mayo Clinic Hospital

  43 shared

Labs

• Shashaty LabPI