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SARS-CoV-2 infection triggers pro-atherogenic inflammatory responses in human coronary vessels

Eberhardt, Natalia; Noval, Maria Gabriela; Kaur, Ravneet; Amadori, Letizia; Gildea, Michael; Sajja, Swathy; Das, Dayasagar; Cilhoroz, Burak; Stewart, O'Jay; Fernandez, Dawn M; Shamailova, Roza; Guillen, Andrea Vasquez; Jangra, Sonia; Schotsaert, Michael; Newman, Jonathan D; Faries, Peter; Maldonado, Thomas; Rockman, Caron; Rapkiewicz, Amy; Stapleford, Kenneth A; Narula, Navneet; Moore, Kathryn J; Giannarelli, Chiara
Patients with coronavirus disease 2019 (COVID-19) present increased risk for ischemic cardiovascular complications up to 1 year after infection. Although the systemic inflammatory response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection likely contributes to this increased cardiovascular risk, whether SARS-CoV-2 directly infects the coronary vasculature and attendant atherosclerotic plaques remains unknown. Here we report that SARS-CoV-2 viral RNA is detectable and replicates in coronary lesions taken at autopsy from severe COVID-19 cases. SARS-CoV-2 targeted plaque macrophages and exhibited a stronger tropism for arterial lesions than adjacent perivascular fat, correlating with macrophage infiltration levels. SARS-CoV-2 entry was increased in cholesterol-loaded primary macrophages and dependent, in part, on neuropilin-1. SARS-CoV-2 induced a robust inflammatory response in cultured macrophages and human atherosclerotic vascular explants with secretion of cytokines known to trigger cardiovascular events. Our data establish that SARS-CoV-2 infects coronary vessels, inducing plaque inflammation that could trigger acute cardiovascular complications and increase the long-term cardiovascular risk.
PMID: 38076343
ISSN: 2731-0590
CID: 5589542

Estimating the Irreducible Uncertainty in Visual Diagnosis: Statistical Modeling of Skill Using Response Models

Pusic, Martin V; Rapkiewicz, Amy; Raykov, Tenko; Melamed, Jonathan
BACKGROUND:For the representative problem of prostate cancer grading, we sought to simultaneously model both the continuous nature of the case spectrum and the decision thresholds of individual pathologists, allowing quantitative comparison of how they handle cases at the borderline between diagnostic categories. METHODS:Experts and pathology residents each rated a standardized set of prostate cancer histopathological images on the International Society of Urological Pathologists (ISUP) scale used in clinical practice. They diagnosed 50 histologic cases with a range of malignancy, including intermediate cases in which clear distinction was difficult. We report a statistical model showing the degree to which each individual participant can separate the cases along the latent decision spectrum. RESULTS:The slides were rated by 36 physicians in total: 23 ISUP pathologists and 13 residents. As anticipated, the cases showed a full continuous range of diagnostic severity. Cases ranged along a logit scale consistent with the consensus rating (Consensus ISUP 1: mean -0.93 [95% confidence interval {CI} -1.10 to -0.78], ISUP 2: -0.19 logits [-0.27 to -0.12]; ISUP 3: 0.56 logits [0.06-1.06]; ISUP 4 1.24 logits [1.10-1.38]; ISUP 5: 1.92 [1.80-2.04]). The best raters were able to meaningfully discriminate between all 5 ISUP categories, showing intercategory thresholds that were quantifiably precise and meaningful. CONCLUSIONS:We present a method that allows simultaneous quantification of both the confusability of a particular case and the skill with which raters can distinguish the cases. IMPLICATIONS/CONCLUSIONS:The technique generalizes beyond the current example to other clinical situations in which a diagnostician must impose an ordinal rating on a biological spectrum. HIGHLIGHTS/CONCLUSIONS:
PMID: 37401184
ISSN: 1552-681x
CID: 5539092

α2,6-Sialylation Is Upregulated in Severe COVID-19, Implicating the Complement Cascade

Qin, Rui; Kurz, Emma; Chen, Shuhui; Zeck, Briana; Chiribogas, Luis; Jackson, Dana; Herchen, Alex; Attia, Tyson; Carlock, Michael; Rapkiewicz, Amy; Bar-Sagi, Dafna; Ritchie, Bruce; Ross, Ted M; Mahal, Lara K
Better understanding of the molecular mechanisms underlying COVID-19 severity is desperately needed in current times. Although hyper-inflammation drives severe COVID-19, precise mechanisms triggering this cascade and what role glycosylation might play therein are unknown. Here we report the first high-throughput glycomic analysis of COVID-19 plasma samples and autopsy tissues. We find that α2,6-sialylation is upregulated in the plasma of patients with severe COVID-19 and in autopsied lung tissue. This glycan motif is enriched on members of the complement cascade (e.g., C5, C9), which show higher levels of sialylation in severe COVID-19. In the lung tissue, we observe increased complement deposition, associated with elevated α2,6-sialylation levels, corresponding to elevated markers of poor prognosis (IL-6) and fibrotic response. We also observe upregulation of the α2,6-sialylation enzyme ST6GAL1 in patients who succumbed to COVID-19. Our work identifies a heretofore undescribed relationship between sialylation and complement in severe COVID-19, potentially informing future therapeutic development.
PMID: 36219583
ISSN: 2373-8227
CID: 5352012

COVID-19-Associated cardiac pathology at the postmortem evaluation: a collaborative systematic review

Almamlouk, Raghed; Kashour, Tarek; Obeidat, Sawsan; Bois, Melanie C; Maleszewski, Joseph J; Omrani, Osama A; Tleyjeh, Rana; Berbari, Elie; Chakhachiro, Zaher; Zein-Sabatto, Bassel; Gerberi, Dana; Tleyjeh, Imad M; Paniz Mondolfi, Alberto E; Finn, Aloke V; Duarte-Neto, Amaro Nunes; Rapkiewicz, Amy V; Frustaci, Andrea; Keresztesi, Arthur-Atilla; Hanley, Brian; Märkl, Bruno; Lardi, Christelle; Bryce, Clare; Lindner, Diana; Aguiar, Diego; Westermann, Dirk; Stroberg, Edana; Duval, Eric J; Youd, Esther; Bulfamante, Gaetano Pietro; Salmon, Isabelle; Auer, Johann; Maleszewski, Joseph J; Hirschbühl, Klaus; Absil, Lara; Barton, Lisa M; Ferraz da Silva, Luiz Fernando; Moore, Luiza; Dolhnikoff, Marisa; Lammens, Martin; Bois, Melanie C; Osborn, Michael; Remmelink, Myriam; Nascimento Saldiva, Paulo Hilario; Jorens, Philippe G; Craver, Randall; Aparecida de Almeida Monteiro, Renata; Scendoni, Roberto; Mukhopadhyay, Sanjay; Suzuki, Tadaki; Mauad, Thais; Fracasso, Tony; Grimes, Zachary
BACKGROUND:Many postmortem studies address the cardiovascular effects of COVID-19 and provide valuable information, but are limited by their small sample size. OBJECTIVES/OBJECTIVE:The aim of this systematic review is to better understand the various aspects of the cardiovascular complications of COVID-19 by pooling data from a large number of autopsy studies. DATA SOURCES/METHODS:We searched the online databases Ovid EBM Reviews, Ovid Embase, Ovid Medline, Scopus, and Web of Science for concepts of autopsy or histopathology combined with COVID-19, published between database inception and February 2021. We also searched for unpublished manuscripts using the medRxiv services operated by Cold Spring Harbor Laboratory. STUDY ELIGIBILITY CRITERIA/METHODS:Articles were considered eligible for inclusion if they reported human postmortem cardiovascular findings among individuals with a confirmed SARS coronavirus type 2 (CoV-2) infection. PARTICIPANTS/METHODS:Confirmed COVID-19 patients with post-mortem cardiovascular findings. INTERVENTIONS/METHODS:None. METHODS:Studies were individually assessed for risk of selection, detection, and reporting biases. The median prevalence of different autopsy findings with associated interquartile ranges (IQRs). RESULTS:This review cohort contained 50 studies including 548 hearts. The median age of the deceased was 69 years. The most prevalent acute cardiovascular findings were myocardial necrosis (median: 100.0%; IQR, 20%-100%; number of studies = 9; number of patients = 64) and myocardial oedema (median: 55.5%; IQR, 19.5%-92.5%; number of studies = 4; number of patients = 46). The median reported prevalence of extensive, focal active, and multifocal myocarditis were all 0.0%. The most prevalent chronic changes were myocyte hypertrophy (median: 69.0%; IQR, 46.8%-92.1%) and fibrosis (median: 35.0%; IQR, 35.0%-90.5%). SARS-CoV-2 was detected in the myocardium with median prevalence of 60.8% (IQR 40.4-95.6%). CONCLUSIONS:Our systematic review confirmed the high prevalence of acute and chronic cardiac pathologies in COVID-19 and SARS-CoV-2 cardiac tropism, as well as the low prevalence of myocarditis in COVID-19.
PMCID:8941843
PMID: 35339672
ISSN: 1469-0691
CID: 5253122

COVID-19-Associated Large- and Medium-Sized-Vessel Pathology: A Case Series

Chen, Stacey; Malas, Jad; Latson, Larry A; Narula, Navneet; Rapkiewicz, Amy V; Williams, David M; Pass, Harvey I; Galloway, Aubrey C; Smith, Deane E
BACKGROUND: Coronavirus disease-19 (COVID-19) remains a public health crisis. The epidemiology of COVID-19-associated large- and medium-sized-vessel pathology is not well characterized. The aim of this study is to identify patients with possible COVID-19-associated large- and medium-sized-vessel pathology based on computed tomography (CT) imaging to provide insight into this rare, but potentially devastating, cardiovascular manifestation. METHODS: This is a single-center retrospective review of patients with CT chest, abdomen, and/or pelvis concerning for large- and medium-vessel pathology and confirmed COVID-19 infection from March 1, 2020 to October 31, 2020. RESULTS: During the study period, 6,553 CT reports were reviewed and pertinent imaging was identified in 139 patients. Of these, 8 patients (median age: 59 years, range 51-82) were COVID-19 positive. All patients had preexisting cardiovascular risk factors and three (37.5%) had an autoimmune disease. Four patients were never hospitalized for COVID-19. Among these, two presented to the hospital at a median of 39 days (range: 27-50) after their initial COVID-19 test with chest and back pain where imaging revealed extensive aortic pathology. One patient required surgical management for aortic pathology. All other patients were treated with expectant management and outpatient follow-up. CONCLUSION/CONCLUSIONS: The clinical and radiological presentations of COVID-19-associated large- and medium-vessel pathology are heterogeneous and can be a late finding after COVID-19 recovery. Close clinical follow-up and surveillance imaging for large- and medium-sized-vessel pathology may be warranted in COVID-19 patients.
PMCID:9626037
PMID: 36318931
ISSN: 2325-4637
CID: 5358562

Fatal Excipients: An Autopsy Case Series of Excipient Lung Disease [Case Report]

Hossein-Zadeh, Zarrin; Shuman, Mark J; Rapkiewicz, Amy
ABSTRACT/UNASSIGNED:Crushed oral tablets, when injected intravenously, may induce a foreign body granulomatous reaction in and around pulmonary arterioles, because of the presence of filler materials (excipients). This typically presents as shortness of breath in the context of pulmonary hypertension with arteriolar dilation and centrilobular nodules on imaging modalities. The constellation of findings may be overlooked or misdiagnosed by clinicians and pathologists, ultimately affecting patient care and postmortem assessment. We describe 5 patients with excipient lung disease that had antemortem chronic medical conditions that required a peripherally inserted catheter or port. All 5 patients had intravascular and perivascular deposition of polarizable foreign material within the pulmonary arteries. Foreign body granulomatosis as a result of intravenous drug use was not clinically suspected in any patient, and 2 of the 5 patients were misdiagnosed with mycobacterium infections. Pulmonary congestion, dyspnea, and symptoms of heart failure were noted in 3 patients and 2 had a history of upper arm deep vein thrombosis. We conclude that excipient lung disease may be underdiagnosed cause of dyspnea, pulmonary hypertension, and death in patients with a known history of intravenous drug use.
PMID: 34510050
ISSN: 1533-404x
CID: 5156492

Platelets contribute to disease severity in COVID-19

Barrett, Tessa J; Bilaloglu, Seda; Cornwell, Macintosh; Burgess, Hannah M; Virginio, Vitor W; Drenkova, Kamelia; Ibrahim, Homam; Yuriditsky, Eugene; Aphinyanaphongs, Yin; Lifshitz, Mark; Xia Liang, Feng; Alejo, Julie; Smith, Grace; Pittaluga, Stefania; Rapkiewicz, Amy V; Wang, Jun; Iancu-Rubin, Camelia; Mohr, Ian; Ruggles, Kelly; Stapleford, Kenneth A; Hochman, Judith; Berger, Jeffrey S
OBJECTIVE:Heightened inflammation, dysregulated immunity, and thrombotic events are characteristic of hospitalized COVID-19 patients. Given that platelets are key regulators of thrombosis, inflammation, and immunity they represent prime candidates as mediators of COVID-19-associated pathogenesis. The objective of this study was to understand the contribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the platelet phenotype via phenotypic (activation, aggregation) and transcriptomic characterization. APPROACH AND RESULTS/UNASSIGNED:In a cohort of 3915 hospitalized COVID-19 patients, we analyzed blood platelet indices collected at hospital admission. Following adjustment for demographics, clinical risk factors, medication, and biomarkers of inflammation and thrombosis, we find platelet count, size, and immaturity are associated with increased critical illness and all-cause mortality. Bone marrow, lung tissue, and blood from COVID-19 patients revealed the presence of SARS-CoV-2 virions in megakaryocytes and platelets. Characterization of COVID-19 platelets found them to be hyperreactive (increased aggregation, and expression of P-selectin and CD40) and to have a distinct transcriptomic profile characteristic of prothrombotic large and immature platelets. In vitro mechanistic studies highlight that the interaction of SARS-CoV-2 with megakaryocytes alters the platelet transcriptome, and its effects are distinct from the coronavirus responsible for the common cold (CoV-OC43). CONCLUSIONS:Platelet count, size, and maturity associate with increased critical illness and all-cause mortality among hospitalized COVID-19 patients. Profiling tissues and blood from COVID-19 patients revealed that SARS-CoV-2 virions enter megakaryocytes and platelets and associate with alterations to the platelet transcriptome and activation profile.
PMID: 34538015
ISSN: 1538-7836
CID: 5018172

Platelets amplify endotheliopathy in COVID-19

Barrett, Tessa J; Cornwell, MacIntosh; Myndzar, Khrystyna; Rolling, Christina C; Xia, Yuhe; Drenkova, Kamelia; Biebuyck, Antoine; Fields, Alexander T; Tawil, Michael; Luttrell-Williams, Elliot; Yuriditsky, Eugene; Smith, Grace; Cotzia, Paolo; Neal, Matthew D; Kornblith, Lucy Z; Pittaluga, Stefania; Rapkiewicz, Amy V; Burgess, Hannah M; Mohr, Ian; Stapleford, Kenneth A; Voora, Deepak; Ruggles, Kelly; Hochman, Judith; Berger, Jeffrey S
[Figure: see text].
PMCID:8442885
PMID: 34516880
ISSN: 2375-2548
CID: 5012252

Association of anti-phospholipid antibodies (APL) with poor clinical outcomes in hospitalized patients with COVID-19 [Meeting Abstract]

Yaich, D; Ptak, B; Roellke, E; Miller, E; Kim, J; Gaztanaga, J; Drewes, W; Ciancarelli, J; Divers, J; Winner, M; Rapkiewicz, A; Carsons, S
Background/Purpose: Critically ill patients with COVID-19 infection have a profound hypercoagulable state and can often develop thromboses in many different vascular beds. Given the presence of anti-phospholipid antibodies among COVID-19 patients reported previously, we hypothesized that poor outcomes and thrombosis could also be promoted by autoimmunity. In this retrospective case control analysis, we aimed to evaluate associations between aPL titers, clinical outcomes and mortality in hospitalized patients admitted with COVID-19 infection.
Method(s): We analyzed 138 electronic medical records of patients who were admitted to NYU Langone Hospital -Long Island between the months of March-April 2020 with findings of COVID-19 positivity via PCR and who had aPL titers determined. Patients with elevated titers of beta-2-Glycoprotein IgG, IgM, IgA and/or cardiolipin IgG, IgM, IgA were compared to those who were not elevated. Patients with positive lupus anticoagulant titers only were excluded due to prevalent use of anti-coagulation during this time. COVID-19 positive patients with aPL titers were assessed for clinical events (including DVT, PE, MI, CVA, extremity ischemia, skin ulcerations, visceral thrombosis and ocular and line occlusions) and mortality. The control group included patients that were negative for aPL antibody titers. Associations between Anti-Phospholipid (aPL) titer positivity and clinical events was assessed by Chi-square analysis using Fisher's exact test.
Result(s): The predominant aPL species that was noted in COVID-19 patients was anti-cardiolipin IgM. Of those patients with elevated antibody titers, cardiolipin IgM, IgG, IgA, and beta2GPI antibodies were prevalent at rates of 98.9%, 26.7%, 19.2%, and 16.5%, respectively. Multiple aPL isotypes were detected in several patients. There was a positive association between aPL positivity and elevations in IL-6, CRP, D-dimer, and LDH (P< 0.05). There was an increased incidence of clinical events in patients with COVID-19 and positive aPL titers (52/83 or 62%) compared to those who were aPL negative (32/55 or 58% ), however this association was not statistically significant. No significant association was detected between positive aPL titers and gender, age, or self-identified ethnicity. An increased incidence of ARDS and a rising serum creatinine was noted in the aPL positive group (P = 0.03 and P= 0.05 respectively). A significant increase in mortality was identified for the aPL positive group (P=0.01).
Conclusion(s): These findings suggest that aPL titers may provide insight into disease prognosis and outcome in hospitalized patients with COVID-19. Despite lack of significant association with discrete thrombotic events, association of aPL positivity with rising serum creatinine and ARDS suggest that aPL may contribute to end organ dysfunction through enhanced microthrombosis, resulting in increased mortality. (Figure Presented)
PMCID:
EMBASE:637274568
ISSN: 2326-5205
CID: 5164742

A Postmortem Portrait of the Coronavirus Disease 2019 (COVID-19) Pandemic: A Large Multiinstitutional Autopsy Survey Study

Hooper, Jody E; Padera, Robert F; Dolhnikoff, Marisa; da Silva, Luiz Fernando Ferraz; Duarte-Neto, Amaro Nunes; Kapp, Meghan E; Lacy, J Matthew; Mauad, Thais; Nascimento Saldiva, Paulo Hilario; Rapkiewicz, Amy V; Wolf, Dwayne A; Felix, Juan C; Benson, Paul; de Almeida Monteiro, Renata Aparecida; Shanes, Elisheva; Gawelek, Kara L; Marshall, Desiree A; McDonald, Michelle M; Muller, William; Priemer, David S; Solomon, Isaac H; Zak, Taylor; Bhattacharjee, Meenakshi B; Fu, Lucy; Gilbert, Andrea R; Harper, Holly L; Litovsky, Silvio; Lomasney, Jon; Mount, Sharon L; Reilly, Stephanie; Sekulic, Miroslav; Steffensen, Thora S; Threlkeld, Kirsten J; Zhao, Bihong; Williamson, Alex K
CONTEXT/BACKGROUND:This study represents the largest compilation to date of clinical and postmortem data from decedents with coronavirus disease 2019 (COVID-19). It will augment previously published small series of autopsy case reports, refine clinicopathologic considerations, and improve the accuracy of future vital statistical reporting. OBJECTIVE:To accurately reflect the pre-existing diseases and pathologic conditions of decedents with Sars-CoV-2 infection through autopsy. DESIGN/METHODS:Comprehensive data from 135 autopsy evaluations of COVID-19-positive decedents is presented, including histologic assessment. Postmortem examinations were performed by 36 pathologists at 19 medical centers or forensic institutions in the United States and Brazil. Data from each autopsy were collected through the online submission of multiple choice and openended survey responses. RESULTS:Patients dying of or with COVID-19 had an average of 8.89 pathologic conditions documented at autopsy, spanning a combination of prior chronic disease and acute conditions acquired during hospitalization. Virtually all decedents were cited as having more than one preexisting condition, encompassing an average of 2.88 such diseases each. Clinical conditions during terminal hospitalization were cited 395 times for the 135 autopsied decedents and predominantly encompassed acute failure of multiple organ systems and/or impaired coagulation. Myocarditis was rarely cited. CONCLUSIONS:Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of co-morbid conditions in those dying of or with COVID-19. If supported by additional research, this finding may have implications for public health decisions and reporting moving forward through the pandemic.
PMID: 33449998
ISSN: 1543-2165
CID: 4747362