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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].
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)
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

COVID-19 Infection and Placental Histopathology in Women Delivering at Term

Patberg, Elizabeth T; Adams, Tracy; Rekawek, Patricia; Vahanian, Sevan A; Akerman, Meredith; Hernandez, Andrea; Rapkiewicz, Amy V; Ragolia, Louis; Sicuranza, Genevieve; Chavez, Martin R; Vintzileos, Anthony M; Khullar, Poonam
BACKGROUND:- There is a paucity of data describing the effects of COVID-19, especially in asymptomatic patients, on placental pathology. Although the pathophysiology of COVID-19 is not completely understood, there is emerging evidence that it causes a severe systemic inflammatory response and results in a hypercoagulable state with widespread microthrombi. We hypothesized that it is plausible that a similar disease process may occur in the fetal-maternal unit. OBJECTIVE:- The aim of this study was to determine whether COVID-19 in term patients admitted to Labor and Delivery, including women without COVID-19 symptomatology, is associated with increased placental injury compared to a cohort of COVID-19 negative controls. STUDY DESIGN/METHODS:- This was a retrospective cohort study performed at NYU Winthrop Hospital between 3/31/2020 and 6/17/2020. During the study period all women admitted to Labor and Delivery were routinely tested for SARS-CoV-2 regardless of symptomatology. The placental histopathological findings of COVID-19 patients (n=77) who delivered a singleton gestation at term were compared to a control group of term patients without COVID-19 (n=56). Controls were excluded if they had obstetric or medical complications including fetal growth restriction, oligohydramnios, hypertension, diabetes, coagulopathy or thrombophilia. Multivariable logistic regression models were performed for variables that were significant in univariable analyses. A subgroup analysis was also performed comparing asymptomatic COVID-19 cases to negative controls. RESULTS:- In univariable analyses, COVID-19 cases were more likely to have evidence of fetal vascular malperfusion, i.e. presence of avascular villi and/or mural fibrin deposition (32.5% (25/77) vs. 3.6% (2/56), p<0.0001) and villitis of unknown etiology (20.8% (16/77) vs. 7.1% (4/56), p=0.030). These findings persisted in a subgroup analysis of asymptomatic COVID-19 cases compared to COVID-19 negative controls. In a multivariable model adjusting for maternal age, race/ethnicity, mode of delivery, preeclampsia, fetal growth restriction and oligohydramnios, the frequency of fetal vascular malperfusion abnormalities remained significantly higher in the COVID-19 group (OR= 12.63, 95% CI [2.40, 66.40]). While the frequency of villitis of unknown etiology was more than double in COVID-19 cases compared to controls, this did not reach statistical significance in a similar multivariable model (OR=2.11, 95% CI [0.50, 8.97]). All neonates of mothers with COVID-19 tested negative for SARS-CoV-2 by PCR. CONCLUSIONS:- Despite the fact that all neonates born to mothers with COVID-19 were negative for SARS-CoV-2 by PCR, we found that COVID-19 in term patients admitted to Labor and Delivery is associated with increased rates of placental histopathologic abnormalities, particularly fetal vascular malperfusion and villitis of unknown etiology. These findings appear to occur even among asymptomatic term patients.
PMID: 33091406
ISSN: 1097-6868
CID: 4642442

Peripheral blood morphologic and laboratory predictors of death in hospitalized COVID-19 patients [Meeting Abstract]

Karimkhan, A; Hossein-Zadeh, Z; Sekhon, P; Budhathoki, N; Ram, B; Rapkiewicz, A; Donovan, V; Park, C; Braunstein, M
Background: Numerous predictors of poor outcome in COVID-19 patients have been identified, including alterations in the composition of leukocytes in the peripheral blood. There nonetheless remains a need to improve predictions of patient outcomes following hospitalization in order to appropriately triage patients. We addressed this question by evaluating hematologic parameters and peripheral blood smear morphology in patients who either died or recovered following hospitalization.
Design(s): The study groups included 48 patients who died following admission ("cases") and 48 age-matched controls who recovered ("controls"). Laboratory values were collected for PCR-positive COVID-19 hospitalized patients at two time points: T1- the time of admission, and T2 - the time of discharge/death. Peripheral blood smears from two-time points for patients who died were analyzed independently by 4 pathologists.
Result(s): Study patient demographic details are shown in Table 1. Anemia and thrombocytopenia were present at the time of admission in both groups, and there was a significant decline in hemoglobin and RBC count between T1 and T2; PLT counts decreased, but not in a statistically significant manner (Table 2). WBC and absolute neutrophils increased following admission specifically in patients who died of disease (Table 2). No statistically significant differences were observed in all other hematologic parameters evaluated. Blood from patients who died showed pseudo Pelger-Huet changes 60.41% (n=29), toxic granulations 8.3% (n=4), atypical lymphocytes 91% (n=44), and giant platelets 94% (n=45) with immature myeloid forms increasing at T2. In contrast to patients who recovered , patients who died showed increased D-dimer values at admission; D-dimer values did not correlate with the presence of thrombocytopenia.
Conclusion(s): Hospitalized COVID-19 patients who died showed: 1) elevated D-dimer levels at admission; and 2) increasing WBC and neutrophil counts during their hospitalization. While several morphologic changes were observed in the blood in those who subsequently died, the changes observed were not specific to COVID-19; however, the presence of immature myeloid precursors in hospitalized patients was associated with subsequent neutrophilia and death. This finding suggests that in addition to closely monitoring the two laboratory parameters describe above, special care should be taken to asses blood films for the presence of immature myeloid precursors. Additional studies will be required to validate these findings in a larger group of hospitalized patients (Figure Presented)
ISSN: 1530-0307
CID: 4857082


Belovarac, Brendan J; Zabar, Sondra R; Warfield, Dana; Bannan, Michael A; Rapkiewicz, Amy V
OBJECTIVES/OBJECTIVE:Resident assessment tends to consist of multiple-choice examinations, even in nuanced areas, such as quality assurance. Internal medicine and many other specialties use objective structured clinical examinations, or OSCEs, to evaluate residents. We adapted the OSCE for pathology, termed the Objective Structured Pathology Examination (OSPE). METHODS:The OSPE was used to evaluate first- and second-year residents over 2 years. The simulation included an anatomic pathology sign-out session, where the resident could be evaluated on diagnostic skills and knowledge of key information for cancer staging reports, as well as simulated frozen-section analysis, where the resident could be evaluated on communication skills with a "surgeon." The OSPE also included smaller cases with challenging quality issues, such as mismatched slides or gross description irregularities. All cases were scored based on the Pathology Milestones created by the Accreditation Council for Graduate Medical Education. RESULTS:Using this OSPE, we were able to demonstrate that simulated experiences can be an appropriate tool for standardized evaluation of pathology residents. CONCLUSIONS:Yearly evaluation using the OSPE could be used to track the progress of both individual residents and the residency program as a whole, identifying problem areas for which further educational content can be developed.
PMID: 33049036
ISSN: 1943-7722
CID: 4632662

Identification of Immunohistochemical Reagents for In Situ Protein Expression Analysis of Coronavirus-associated Changes in Human Tissues

Szabolcs, Matthias; Sauter, Jennifer L; Frosina, Denise; Geronimo, Jerica A; Hernandez, Enmily; Selbs, Elena; Rapkiewicz, Amy V; Rekhtman, Natasha; Baine, Marina K; Jäger, Elke; Travis, William D; Jungbluth, Achim A
We studied the suitability of commercially available monoclonal antibodies (mAbs) for the immunohistochemical (IHC) detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) in standard archival specimens. Antibodies were screened on HEK293 cells transfected with viral nucleoprotein, S1 subunit and S2 subunit of spike protein and on untransfected cells, as well as a panel of normal tissue. Lung tissue with presence of SARS-CoV2 confirmed by in situ hybridization (ISH) was also used. A total of 7 mAbs were tested: (1) mAb 001 (Sino Biological, 40143-R001), (2) mAb 007 (Sino Biological, 40150-R007), (3) mAb 019 (Sino Biological, 40143-R019), (4) mAb 1A9 (GeneTex, GTX632604), (5) mAb ABM19C9 (Abeomics, 10-10007), (6) FIPV3-70 (Santa Cruz, SC-65653), and (7) mAb 6F10 (BioVision, A2060). Only 2 mAbs, clone 001 to the nucleoprotein and clone 1A9 to the S2 subunit spike protein displayed specific immunoreactivity. Both clones showed strong staining in the acute phase of COVID-19 pneumonia, mostly in areas of acute diffuse alveolar damage, but were not completely congruent. Viral protein was also found in kidney tubules, endothelia of multiple organs and a nasal swab of a patient with persistent SARS-CoV2 infection. The other tested reagents were either poorly reactive or demonstrated nonspecific staining in tissues and lesions not infected by SARS-CoV2. Our study demonstrates that rigid specificity testing is mandatory for the evaluation of mAbs to SARS-CoV2 and that clones 001 to nucleoprotein and 1A9 to S2 subunit spike protein are useful for the in situ detection of SARS-CoV2.
PMID: 33086222
ISSN: 1533-4058
CID: 4642322

Pathological findings in the postmortem liver of patients with coronavirus disease 2019 (COVID-19)

Zhao, Chaohui Lisa; Rapkiewicz, Amy; Maghsoodi-Deerwester, Mona; Gupta, Mala; Cao, Wenqing; Palaia, Thomas; Zhou, Jianhong; Ram, Bebu; Vo, Duc; Rafiee, Behnam; Hossein-Zadeh, Zarrin; Dabiri, Bahram; Hanna, Iman
Although coronavirus disease 2019 (COVID-19) is transmitted via respiratory droplets, there are multiple gastrointestinal and hepatic manifestations of the disease, including abnormal liver-associated enzymes. However, there are not many published articles on the pathological findings in the liver of patients with COVID-19. We collected the clinical data from 17 autopsy cases of patients with COVID-19 including age, sex, Body mass index (BMI), liver function test (alanine aminotransaminase (ALT), aspartate aminotransaminase (AST), alkaline phosphatase (ALP), direct bilirubin, and total bilirubin), D-dimer, and anticoagulation treatment. We examined histopathologic findings in postmortem hepatic tissue, immunohistochemical (IHC) staining with antibody against COVID-19 spike protein, CD68 and CD61, and electron microscopy. We counted the number of megakaryocytes in liver sections from these COVID-19-positive cases. Abnormal liver-associated enzymes were observed in 12 of 17 cases of COVID-19 infection. With the exception of three cases that had not been tested for D-dimer, all 14 patients' D-dimer levels were increased, including the cases that received varied doses of anticoagulation treatment. Microscopically, the major findings were widespread platelet-fibrin microthrombi, steatosis, histiocytic hyperplasia in the portal tract, mild lobular inflammation, ischemic-type hepatic necrosis, and zone 3 hemorrhage. Rare megakaryocytes were found in sinusoids. COVID-19 IHC demonstrates positive staining of the histiocytes in the portal tract. Under electron microscopy, histiocyte proliferation is present in the portal tract containing lipid droplets, lysosomes, dilated ribosomal endoplasmic reticulum, microvesicular bodies, and coronavirus. The characteristic findings in the liver of patients with COVID-19 include numerous amounts of platelet-fibrin microthrombi, as well as various degrees of steatosis and histiocytic hyperplasia in the portal tract. Possible mechanisms are also discussed.
PMID: 33307078
ISSN: 1532-8392
CID: 4770842