Native cardiac valves may undergo calcification in the setting of chronic injury, subsequently impeding normal valve structure and function. In the same setting, there may be evidence of ...metaplasia—specifically osseous metaplasia—with lamellar bone admixed with dystrophic calcification. In this study, the histologic features of 123 native aortic valves (identified from 1094 sequentially reviewed native valves of all types that included a total of 754 aortic valves) with osseous metaplasia are focused upon, as well as correlation with other histopathologic features, and clinical and echocardiographic findings. Osseous metaplasia was identified in aortic and significantly less frequently in mitral valves, and never in tricuspid or pulmonic valves. Notable observations included that osseous metaplasia in aortic valves were seen in patients with greater body mass index, and less commonly identified in patients with a history of autoimmune disease. Aortic valves with osseous metaplasia were more commonly tricuspid (as opposed to bicuspid), and with smaller aortic valve area and greater peak and mean gradients. The rate of osseous metaplasia in aortic valves increased with increasing degree of stenosis and decreasing degree of regurgitation. The rates of the presence of chondromatous metaplasia, smooth muscle, arterial vessels, capillary bed formation, chronic inflammation, and hemosiderin laden macrophages were greater in aortic valves with osseous metaplasia compared to valves without osseous metaplasia. Further investigation is required to determine potential physiologic and/or pathologic consequence of the presence of valvular osseous metaplasia.
Abstract
Objectives
To report methods and findings of 2 autopsies with molecular evaluation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive individuals.
Methods
Postmortem ...examination was completed following Centers for Disease Control and Prevention public guidelines. Numerous formalin-fixed paraffin-embedded (FFPE) tissue types from each case were surveyed for SARS-CoV-2 RNA by quantitative reverse transcription polymerase chain reaction (qRT-PCR). SARS-CoV-2 viral genome was sequenced by next-generation sequencing (NGS) from FFPE lung tissue blocks.
Results
Postmortem examinations revealed diffuse alveolar damage, while no viral-associated hepatic, cardiac, or renal damage was observed. Viral RNA was detected in lungs, bronchi, lymph nodes, and spleen in both cases using qRT-PCR method. RNA sequencing using NGS in case 1 revealed mutations most consistent with Western European Clade A2a with ORF1a L3606F mutation.
Conclusions
SARS-CoV-2 testing and viral sequencing can be performed from FFPE tissue. Detection and sequencing of SARS-CoV-2 in combination with morphological findings from postmortem tissue examination can aid in gaining a better understanding of the virus’s pathophysiologic effects on human health.
Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B ...cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease.
We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence.
In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies.
Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.
Monocytes undergo phenotypic and functional changes in response to inflammatory cues, but the molecular signals that drive different monocyte states remain largely undefined. We show that monocytes ...acquire macrophage markers upon glomerulonephritis and may be derived from CCR2+CX3CR1+ double-positive monocytes, which are preferentially recruited, dwell within glomerular capillaries, and acquire proinflammatory characteristics in the nephritic kidney. Mechanistically, the transition to immature macrophages begins within the vasculature and relies on CCR2 in circulating cells and TNFR2 in parenchymal cells, findings that are recapitulated in vitro with monocytes cocultured with TNF-TNFR2-activated endothelial cells generating CCR2 ligands. Single-cell RNA sequencing of cocultures defines a CCR2-dependent monocyte differentiation path associated with the acquisition of immune effector functions and generation of CCR2 ligands. Immature macrophages are detected in the urine of lupus nephritis patients, and their frequency correlates with clinical disease. In conclusion, CCR2-dependent functional specialization of monocytes into macrophages begins within the TNF-TNFR2-activated vasculature and may establish a CCR2-based autocrine, feed-forward loop that amplifies renal inflammation.
Cardiac amyloidosis is most commonly comprised of either a monoclonal immunoglobulin or transthyretin; however, in practice, detailing of the former beyond light chain restriction is not typically ...performed. We present briefly the case of an 80-year-old man with concern for cardiac amyloidosis and a subsequent endomyocardial biopsy revealing significant deposition of amorphous Congo red-positive material. By immunofluorescence microscopy, the amyloidogenic material showed positive expression for IgG heavy chain and kappa light chain, with negative staining for IgM and IgA heavy chains and lambda light chain supporting a diagnosis of heavy and light chain (AHL)-type amyloidosis. Immunofluorescence staining for the IgG heavy chain subclasses supported and further classified the patient’s AHL-type cardiac amyloidosis as being IgG4/kappa restricted. The presented case is the first to illustrate AHL-type cardiac amyloidosis via sampling of heart tissue.
Allograft rejection is a serious concern in heart transplant medicine. Though endomyocardial biopsy with histological grading is the diagnostic standard for rejection, poor inter-pathologist ...agreement creates significant clinical uncertainty. The aim of this investigation is to demonstrate that cellular rejection grades generated via computational histological analysis are on-par with those provided by expert pathologists.
The study cohort consisted of 2472 endomyocardial biopsy slides originating from three major US transplant centres. The 'Computer-Assisted Cardiac Histologic Evaluation (CACHE)-Grader' pipeline was trained using an interpretable, biologically inspired, 'hand-crafted' feature extraction approach. From a menu of 154 quantitative histological features relating the density and orientation of lymphocytes, myocytes, and stroma, a model was developed to reproduce the 4-grade clinical standard for cellular rejection diagnosis. CACHE-grader interpretations were compared with independent pathologists and the 'grade of record', testing for non-inferiority (δ = 6%). Study pathologists achieved a 60.7% agreement 95% confidence interval (CI): 55.2-66.0% with the grade of record, and pair-wise agreement among all human graders was 61.5% (95% CI: 57.0-65.8%). The CACHE-Grader met the threshold for non-inferiority, achieving a 65.9% agreement (95% CI: 63.4-68.3%) with the grade of record and a 62.6% agreement (95% CI: 60.3-64.8%) with all human graders. The CACHE-Grader demonstrated nearly identical performance in internal and external validation sets (66.1% vs. 65.8%), resilience to inter-centre variations in tissue processing/digitization, and superior sensitivity for high-grade rejection (74.4% vs. 39.5%, P < 0.001).
These results show that the CACHE-grader pipeline, derived using intuitive morphological features, can provide expert-quality rejection grading, performing within the range of inter-grader variability seen among human pathologists.
Cardiac valve inflammation is seen in the setting of autoimmune or infectious processes, and rarely is valvulitis characterized by granulomatous inflammation. We present two patients who underwent ...surgical repair of prolapsing/regurgitating mitral valves. Excised valve tissue in both cases revealed commonly encountered nodular fibrosis and calcification, however each also revealed an isolated focus of non-necrotizing granulomatous inflammation. Typical implicating etiologies for non-necrotizing granulomatous inflammation were not present for either patient based on clinical history, or radiologic and laboratory data. In a review of 1048 cardiac valves excised at our institution, the finding of non-necrotizing granulomatous inflammation was seen in only the two described cases (prevalence of 0.19%). The description of non-necrotizing granulomatous inflammation within cardiac valves is limited in the literature, and the significance of the detailed isolated and incidental finding is unclear and requiring further investigation.
SARS-CoV-2 infection causes severe pulmonary manifestations, with poorly understood mechanisms and limited treatment options. Hyperferritinemia and disrupted lung iron homeostasis in COVID-19 ...patients imply that ferroptosis, an iron-dependent cell death, may occur. Immunostaining and lipidomic analysis in COVID-19 lung autopsies reveal increases in ferroptosis markers, including transferrin receptor 1 and malondialdehyde accumulation in fatal cases. COVID-19 lungs display dysregulation of lipids involved in metabolism and ferroptosis. We find increased ferritin light chain associated with severe COVID-19 lung pathology. Iron overload promotes ferroptosis in both primary cells and cancerous lung epithelial cells. In addition, ferroptosis markers strongly correlate with lung injury severity in a COVID-19 lung disease model using male Syrian hamsters. These results reveal a role for ferroptosis in COVID-19 pulmonary disease; pharmacological ferroptosis inhibition may serve as an adjuvant therapy to prevent lung damage during SARS-CoV-2 infection.
Tubulointerstitial nephritis and uveitis (TINU) is a rare disease of unknown pathogenesis that is characterized by tubulointerstitial nephritis and uveitis. Currently, there are over 250 reported ...cases of TINU syndrome. TINU syndrome typically presents with mild uveitis and nephritis that is self-limited; however, in this case, the symptoms were severe making it different from previous case reports. We present a case of a 29-year-old female with a history of cytomegalovirus (CMV) with a recent diagnosis of bilateral uveitis who was admitted for worsening systemic symptoms. Laboratory testing revealed acute renal insufficiency along with hematuria and proteinuria. A kidney biopsy revealed tubulointerstitial nephritis, and the patient was initiated on corticosteroids for the diagnosis of TINU. The patient's renal function recovered to baseline after a prolonged three-month course of systemic steroids but had a recurrence of her uveitis with steroid taper requiring initiation of steroid-sparing therapies. TINU syndrome should be considered in patients presenting with uveitis and renal dysfunction. Prompt diagnosis is necessary to preserve renal function with corticosteroids. The prognosis for patients with TINU is variable, with a frequently recurring and relapsing course. More research is needed to determine the optimal treatment.
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.
To accurately reflect the preexisting diseases and pathologic conditions of decedents with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection through autopsy.
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 open-ended survey responses.
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 1 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.
Cause-of-death statements in both autopsy reports and death certificates may not encompass the severity or spectrum of comorbid 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.
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