A challenging case of eosinophilic myocarditis leading to heart failure and transplantation.

The large spectrum of etiologies, severities, and histologic appearances of eosinophilic myocarditis (EoM) poses challenges to its diagnosis and management. Endomyocardial biopsy is the current gold standard for diagnosis. However, cardiovascular magnetic resonance imaging is becoming more frequently used to diagnose acute myocarditis because of enhanced sensitivity when compared to histopathologic examination, and its less invasive nature. We report a complicated case of EoM in a male in his mid-thirties that led to fulminant cardiogenic shock that required immunosuppressive therapy on day 5 of admission and implantation of a left ventricular assist device (LVAD) on day 30. EoM was diagnosed on histopathologic examination of the resected fragment of the left ventricular myocardium. Nine months after the initial presentation, the patient ultimately required heart transplantation. The explanted heart showed minimal residual interstitial inflammation with evidence of mildly active intimal arteritis and patchy areas of interstitial fibrosis. In this report, we describe our patient's clinical features and correlate them with imaging and histopathologic findings to illustrate the difficulty in diagnosing EoM, particularly in this complicated patient that ultimately required heart transplantation. The diagnosis can be challenging due to the variable histopathologic features, clinical presentation, and utilization of therapeutic medications and devices.

Pulmonary Endobronchial Hamartoma Presenting With Post-obstructive Pneumonia.

Pulmonary hamartomas (PH) are rare but are the most common benign tumors found in the lungs. They are slow-growing and are usually found incidentally on chest imaging during the sixth decade of life. Approximately 10% of pulmonary hamartomas are endobronchial. Rarely, pulmonary hamartomas can cause a spectrum of pulmonary symptoms depending on their size and location. We present a case of endobronchial hamartoma causing airway obstruction and recurrent post-obstructive pneumonia.

Computed Tomography Tissue Characterization of Pediatric Cardiac Tumor.

Little is known about tissue characterization of cardiac tumors by dedicated cardiac computed tomography (CT) protocols in pediatric patients. We report using arterial and delayed CT acquisitions to characterize a large left ventricular free wall tumor in a 12-year-old female with congenital mitral insufficiency and an automatic implantable cardioverter defibrillator. (Level of Difficulty: Intermediate.).

Fulminant lung fibrosis in non-resolvable COVID-19 requiring transplantation.

BACKGROUND: Coronavirus Disease 2019 (COVID-19) can lead to the development of acute respiratory distress syndrome (ARDS). In some patients with non-resolvable (NR) COVID-19, lung injury can progress rapidly to the point that lung transplantation is the only viable option for survival. This fatal progression of lung injury involves a rapid fibroproliferative response and takes on average 15 weeks from initial symptom presentation. Little is known about the mechanisms that lead to this fulminant lung fibrosis (FLF) in NR-COVID-19. METHODS: Using a pre-designed unbiased PCR array for fibrotic markers, we analyzed the fibrotic signature in a subset of NR-COVID-19 lungs. We compared the expression profile against control lungs (donor lungs discarded for transplantation), and explanted tissue from patients with idiopathic pulmonary fibrosis (IPF). Subsequently, RT-qPCR, Western blots and immunohistochemistry were conducted to validate and localize selected pro-fibrotic targets. A total of 23 NR-COVID-19 lungs were used for RT-qPCR validation. FINDINGS: We revealed a unique fibrotic gene signature in NR-COVID-19 that is dominated by a hyper-expression of pro-fibrotic genes, including collagens and periostin. Our results also show a significantly increased expression of Collagen Triple Helix Repeat Containing 1(CTHRC1) which co-localized in areas rich in alpha smooth muscle expression, denoting myofibroblasts. We also show a significant increase in cytokeratin (KRT) 5 and 8 expressing cells adjacent to fibroblastic areas and in areas of apparent epithelial bronchiolization. INTERPRETATION: Our studies may provide insights into potential cellular mechanisms that lead to a fulminant presentation of lung fibrosis in NR-COVID-19. FUNDING: National Institute of Health (NIH) Grants R01HL154720, R01DK122796, R01DK109574, R01HL133900, and Department of Defense (DoD) Grant W81XWH2110032 to H.K.E. NIH Grants: R01HL138510 and R01HL157100, DoD Grant W81XWH-19-1-0007, and American Heart Association Grant: 18IPA34170220 to H.K.-Q. American Heart Association: 19CDA34660279, American Lung Association: CA-622265, Parker B. Francis Fellowship, 1UL1TR003167-01 and The Center for Clinical and Translational Sciences, McGovern Medical School to X.Y.

Clinicopathological correlations in heart transplantation recipients complicated by death or re-transplantation.

Purpose: This study aimed to identify and correlate pathological findings with clinical outcomes in patients after orthotopic heart transplantation (OHT) who either died or underwent a re-transplantation. Methodology and study design: Single-center retrospective analysis of primary OHT patients who died or were re-transplanted between October 2012 and July 2021. Clinical data were matched with corresponding pathological findings from endomyocardial biopsies on antibody-mediated rejection, cellular rejection, and cardiac allograft vasculopathy. Re-assessment of available tissue samples was performed to investigate acute myocardial injury (AMI) as a distinct phenomenon. These were correlated with clinical outcomes, which included severe primary graft dysfunction. Patients were grouped according to the presence of AMI and compared. Results: We identified 47 patients with truncated outcomes after the first OHT. The median age was 59 years, 36 patients (76%) were male, 25 patients (53%) had a prior history of cardiac operation, and 21 patients (45%) were supported with a durable assist device before OHT. Of those, AMI was identified in 22 (47%) patients (AMI group), and 25 patients had no AMI (non-AMI group). Groups were comparable in baseline and perioperative data. Histopathological observations in AMI group included a non-significant higher incidence of antibody-mediated rejection Grade 1 or higher (pAMR ≥ 1) (32% vs. 12%, P = 0.154), and non-significant lower incidence of severe acute cellular rejection (ACR ≥ 2R) (32% vs. 40%, P = 0.762). Clinical observations in the AMI group found a significantly higher occurrence of severe primary graft dysfunction (68% vs. 20%, P = 0.001) and a highly significant shorter duration from transplantation to death or re-transplantation (42 days [IQR 26, 120] vs. 1,133 days [711-1,664], P < 0.0001). Those patients had a significantly higher occurrence of cardiac-related deaths (64% vs. 24%, P = 0.020). No difference was observed in other outcomes. Conclusion: In heart transplant recipients with a truncated postoperative course leading to either death or re-transplantation, AMI in endomyocardial biopsies was a common pathological phenomenon, which correlated with the clinical occurrence of severe primary graft dysfunction. Those patients had significantly shorter survival times and higher cardiac-related deaths. The presence of AMI suggests a truncated course after OHT.

Biochemical, biophysical, and immunological characterization of respiratory secretions in severe SARS-CoV-2 infections.

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.

Biochemical, Biophysical, and Immunological Characterization of Respiratory Secretions in Severe SARS-CoV-2 (COVID-19) Infections.

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 factorâ€"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.

The value of SOX2 in the differential diagnosis of SMARCA4 (BRG1)-deficient uterine neoplasms.

SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1)-deficient undifferentiated uterine sarcoma (SDUS) is a recently described uterine sarcoma. It is characterized by predominantly rhabdoid or large epithelioid cells with abundant cytoplasm and varying components of small and spindle cells, resembling the 'large cell variant' of small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). In addition, SMARCA4-inactivating mutations have been described as the driver mutations in SDUS. However, undifferentiated endometrial carcinoma (UDEC) and dedifferentiated endometrial carcinoma (DDEC) may show some clinical and morphological overlaps with SDUS, and about 20% of reported UDEC/DDEC cases also have loss expression of SMARCA4. SDUS is a very aggressive disease and universally lethal in all reported cases. Differentiating SDUS from UDEC/DDEC is relevant for the prognosis, pathogenesis, and possible targeted therapies for the disease. In this study, we compared the clinical, morphological, immunohistochemical, and molecular characteristics of 10 tumors including 2 SDUS, 2 SCCOHT, 1 uterine carcinoma with neuroendocrine differentiation (UDEC?), and 5 UDEC/DDEC. All 5 UDEC/DDEC cases showed strong and diffuse nuclear positivity for SOX2, while all SCCOHT and SDUS cases were completely negative. We concluded that SOX2 could be a useful marker for the differential diagnosis between SDUS and UDEC/DDEC.

Double Delayed Enhancement: Concomitant Cardiac Amyloidosis and Acute Coronary Embolism.

Hereditary cardiac amyloidosis (CA) is a relatively rare cause of nonischemic cardiomyopathy. The risk of intracardiac thrombi increases significantly in patients with CA. We report a case of a patient presenting with chest pain and acute myocardial infarction who was subsequently diagnosed with concomitant CA and acute coronary embolism.

Granulomatous fungal and non-tuberculous mycobacterial infestation complicating chronic lung disease: Outcomes in patients undergoing lung transplantation.

INTRODUCTION: Granulomatous infections are common in patients with chronic lung disease. We aim to study the incidence and clinicopathological features of granulomatous infections in a cohort of patients undergoing lung transplantation for end-stage chronic lung disease. METHODS: Pathology reports of 50 explanted native lungs of patients who underwent lung transplantation since 2015 at our institution were reviewed. Four cases with granulomatous lesions were identified. Correlation was made with clinical findings in the 4 cases. RESULTS: The granulomatous infections include non-necrotizing cryptococcal pneumonitis (case 1), necrotizing pneumonia due to Scedosporium sp. and Mycobacterium avium Complex (MAC) (Cases 2 and 3), and invasive Aspergillus pneumonia (Case 4). One patient received pre-transplant fungal prophylaxis (Case 4). Post-transplant infectious complications included invasive (Cases 2 and 4) and non-invasive (Case 1) fungal infections and bacterial pneumonia (Cases 1 and 2). Two patients (Cases 3 and 4) developed acute cellular rejection (ACR) in the first 30 days. The third patient (Case 1) was identified with ACR in the 9 months post-transplant and chronic lung allograft dysfunction at 29 months. In terms of mortality, 1 patient (Case 1) died at 30 months post-transplant from pseudomonal sepsis and chronic graft failure. Two patients with invasive fungal infections (Cases 2 and 4) are on secondary prophylaxis and doing well. One patient (Case 3) remains infection-free and on MAC prophylaxis. CONCLUSIONS: In our case series, patients with chronic lung diseases with superimposed granulomatous infestations frequently experienced post-transplant complications. These include invasive infections and repeat ACRs that predispose patients to chronic graft dysfunction. Pre- and post-transplant antifungal prophylaxis reduces fungal load and complication risk post-transplant.

Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy.

AIMS: Although immune checkpoint inhibitor (ICI) myocarditis carries a high reported mortality, increasing reports of smoldering myocarditis suggest a clinical spectrum of disease. Endomyocardial biopsy (EMB) remains the gold standard for diagnosis of ICI myocarditis, but different pathologic diagnostic criteria exist. The objective of this study was to classify the spectrum of ICI myocarditis and myocardial inflammation by pathology findings on EMB and correlate this with clinical outcomes. METHODS AND RESULTS: All patients who had EMB at MD Anderson Cancer Center between January 2018 and August 2019 for suspected ICI myocarditis were retrospectively reviewed. A grading system (Grades 0-2) based on the degree of inflammatory infiltrate was developed by pathologists. Cardiovascular outcomes and treatment were compared between grades of pathology. We identified 28 patients who had EMB for suspected ICI myocarditis, of which 18 were positive for myocarditis/inflammation. There were four deaths (two in Grade 2 and two in Grade 1), but only one was attributable to myocarditis. Grade 2 patients had no myocarditis-associated deaths despite having the highest troponin T values (median 2063 pg/mL). Four patients with Grade 1 myocardial inflammation continued ICI without any immunomodulation, and all were alive without adverse cardiovascular events at follow-up. CONCLUSION: We defined an EMB grading system for ICI myocarditis encompassing a spectrum of histologic findings of inflammatory infiltrates. A subset of low-grade myocardial inflammation patients were able to continue ICI without immunosuppressive therapy. Further studies are needed to identify low-risk patients who can be safely treated with ICI.

The Terrible Triad of Checkpoint Inhibition: A Case Report of Myasthenia Gravis, Myocarditis, and Myositis Induced by Cemiplimab in a Patient with Metastatic Cutaneous Squamous Cell Carcinoma.

BACKGROUND: We report a case of a patient with squamous cell carcinoma (SCC) who developed myasthenia gravis (MG), myositis, and myocarditis after receiving cemiplimab, an anti-PD-1 immune checkpoint inhibitor (ICI). Case Presentation. An 86-year-old man with metastatic periocular SCC presented with decreased vision in the left eye, severe fatigue, and lower back and bilateral hip pain 3 weeks after receiving cemiplimab. Within hours, he developed dysphonia, pharyngeal secretions, and dysphagia, necessitating intubation. Endomyocardial biopsy revealed active lymphocyte-mediated necrosis consistent with ICI-induced myocarditis. Anti-striated muscle and anti-acetylcholine receptor antibodies were elevated, consistent with myositis and myasthenia gravis. Despite plasma exchange therapy, steroids, and intravenous immunoglobulin, he died from cardiac arrest. CONCLUSIONS: The presence of myasthenia gravis, myocarditis, or myositis should prompt evaluation for all three toxicities as they may represent an overlap syndrome. The severity of these immunotoxicities highlights the need for clinicians to suspect multiple simultaneous adverse effects of ICIs.

Deadly combination of Vaping-lnduced lung injury and Influenza: case report.

BACKGROUND: E-cigarette and vaping use-associated acute lung injury (EVALI) has been recently recognized as a complication in individuals who use vaping devices. Another consideration is that EVALI may have an adverse influence on the outcome of intercurrent respiratory infections. We document this deadly combination in the case of a young man who had EVALI and simultaneous 41 Influenza-A infection leading to severe Acute Respiratory Distress Syndrome (ARDS). CASE PRESENTATION: A 27-year-old male with a history of tobacco and vaping use was admitted to hospital after two weeks of flu-like symptoms, diarrhea and vomiting. A chest x-ray was consistent with multifocal pneumonia, and microbiological tests were positive for Influenza-A and methicillin-sensitive Staphalacoccus aureus (MSSA). Bronchoscopy provided evidence of acute inhalational injury. After admission, he acutely decompensated with severe hypoxia and hypotension; he required intubation, sedation and vasopressors. He developed sepsis with acute kidney failure, liver failure, biventricular systolic dysfunction and severe rhabdomyolysis. He was placed on veno-venous (VV) extracorporeal membrane oxygenation (ECMO) initially and later changed to Veno-Arterial (VA) ECMO. Nevertheless, the patient continued to deteriorate, and he expired two weeks after admission. CONCLUSION: This case documents that EVALI can act as a major factor leading a respiratory infection to progress into severe ARDS with a fatal outcome.

Clinicopathological manifestations of myocarditis in a heart failure population.

Myocarditis continues to present challenges in diagnosis and management. The goal of this study is to determine the occurrence and manifestations of myocarditis in a heart failure (HF) population. The analyzed patients had acute or persistent HF and were referred over a 6-year period to a quaternary HF center for advanced HF therapies including mechanical circulatory support, left ventricular assist device (LVAD) implantation, and/or heart transplantation. The histopathological diagnosis of myocarditis was made based on the presence of an inflammatory infiltrate of the myocardium, typically with associated cardiomyocyte (CMC) damage, combined as indicated with immunohistochemical and molecular biology characterization. The pathological findings were correlated with a panel of clinical parameters and clinical course of the patients. Myocarditis was identified in 36 patients, with initial diagnoses made in 10 (40%) of 25 by endomyocardial biopsy (EMB), 1 by atrial biopsy (maze procedure), 7 (2.1%) of 331 at LVAD implantation, and 18 (7.8%) of 229 in the explanted heart. There were 20 cases of lymphocytic myocarditis, 4 cases of giant cell myocarditis, 3 cases of eosinophilic myocarditis, and 9 cases of lymphohistocytic with granulomas myocarditis - cardiac sarcoidosis. EMB was performed in 25 patients and was positive in 10 (40%) of cases. Myocarditis was found in 23 explanted hearts including 18 cases de novo and 5 cases with a previously positive specimen. Of the 23 explanted hearts, 21 were nonischemic cardiomyopathy and 2 were ischemic cardiomyopathy. Our findings show that, in patients presenting to a quaternary medical center, myocarditis can be manifest as acute HF as well as a complicating factor in chronic HF.

Poorly Differentiated Biliary Adenocarcinoma Leading to Boerhaave syndrome: A Case Report and Review of the Literature.

Boerhaave syndrome is a transmural disruption of the esophagus, due to an increase in esophageal pressure and is associated with high morbidity and mortality. There are cases reported secondary to bowel obstructions such as incarcerated hernias and gallstone ileus. Here, we describe an unusual autopsy case of Boerhaave syndrome, due to bowel obstruction secondary to biliary adenocarcinoma, which has never been reported in the literature. The patient was an 87-year old male presenting with severe chest and epigastric pain. Computed tomography showed fluid-filled esophagus, gastric distention and an ill-defined mass within the liver. Patient underwent esophagogastroduodenoscopy, which revealed esophageal rupture. Patient expired within 20 hours of admission. On autopsy, the decedent was found to have an esophageal perforation and an inferior hepatic mass, which morphologically and immunohistochemically was consistent with a biliary adenocarcinoma.

Eosinophilic granulomatosis with polyangiitis in a continuous flow left ventricular assist device patient: a case report and review of literature.

Eosinophilic granulomatosis with polyangiitis (EGPA), also known as Churg-Strauss syndrome (CSS), is a rare autoimmune disease with an estimated incidence of approximately 0.11 to 2.66 new cases per 1 million people per year and an overall prevalence of 10.7 to 14 per 1 million adults [1]. No gender predominance or ethnic predisposition has clearly been demonstrated in CSS [1]. Most of the patients are misdiagnosed over a period of time prior to being correctly classified with the disease. Here, we report the complex case of a 64-year-old African American man with advanced heart failure who received a left ventricular assist device (LVAD) and was subsequently diagnosed with EGPA. EGPA is a clinical syndrome that is associated with sequelae that can negatively add to the morbidity associated with LVAD placement.

Mammary Analogue Secretory Carcinoma of Minor Salivary Glands: A Rare Case Series and Review of the Literature.

Mammary analogue secretory carcinoma (MASC) is a rare salivary gland tumor that recapitulates the cytomorphology, immunophenotype, and genetics of an equally rare malignancy of the breast, secretory carcinoma (SC). Here we present two cases of MASC of minor salivary glands from a single institutional experience.

Cardiac sarcoidosis presenting as arrhythmogenic right ventricular cardiomyopathy/dysplasia with ventricular aneurysms: a case report.

A 70-year old Caucasian man with recurrent ventricular tachycardia and progressive biventricular failure attributed to arrhythmogenic right ventricular cardiomyopathy/dysplasia was evaluated for heart transplantation. Cardiac ventriculography revealed an abnormal left ventricle with five saccular aneurysms. Heart transplantation was performed. Pathology of the explanted heart showed multifocal sarcoid granulomas. Replacement fibrosis was widespread in both ventricles and associated with saccular aneurysms. No genetic basis was identified. Thus, the evidence suggested progressive cardiac sarcoidosis caused this patient's unusual condition.

Myeloid Sarcoma in a Patient with Myelodysplastic Syndrome Associated with del(5q-): Case Report and Literature Review.

OBJECTIVE: Myeloid sarcoma (MS) is defined in the World Health Organization classification as a tumor mass consisting of myeloblasts with or without maturation and involving any anatomic site other than the bone marrow. We present a case of MS developing in a patient with 5q- myelodysplastic syndrome (MDS) and review the relevant literature. METHODS: A 77-year-old woman with recent diagnosis of MDS associated with del(5q) presented with symptoms and signs attributable to a mass involving the T8 vertebra. Biopsy of the spinal mass was performed and the specimen was analyzed using routine hematoxylin-eosin stain, immunohistochemical methods, and fluorescence in situ hybridization (FISH). RESULTS: Microscopic examination revealed an infiltrate of intermediate-large cells with basophilic cytoplasm and nuclei containing occasional prominent nucleoli. Immunohistochemical analysis showed that the neoplastic cells were positive for CD4, CD43, CD45, CD68, and CD117, and negative for B- and T-cell antigens supporting the diagnosis of MS. Fluorescence in situ hybridization of the spinal mass showed del(5q) in the neoplastic cells. CONCLUSION: Although the 5q- syndrome is a clinically indolent form of MDS, a small subset of patients may develop MS as illustrated in this patient. The relevant literature is also reviewed.