Case Series of Multisystem Inflammatory Syndrome in Adults Associated with SARS-CoV-2 Infection - United Kingdom and United States, March-August 2020.

During the course of the coronavirus disease 2019 (COVID-19) pandemic, reports of a new multisystem inflammatory syndrome in children (MIS-C) have been increasing in Europe and the United States (1-3). Clinical features in children have varied but predominantly include shock, cardiac dysfunction, abdominal pain, and elevated inflammatory markers, including C-reactive protein (CRP), ferritin, D-dimer, and interleukin-6 (1). Since June 2020, several case reports have described a similar syndrome in adults; this review describes in detail nine patients reported to CDC, seven from published case reports, and summarizes the findings in 11 patients described in three case series in peer-reviewed journals (4-6). These 27 patients had cardiovascular, gastrointestinal, dermatologic, and neurologic symptoms without severe respiratory illness and concurrently received positive test results for SARS-CoV-2, the virus that causes COVID-19, by polymerase chain reaction (PCR) or antibody assays indicating recent infection. Reports of these patients highlight the recognition of an illness referred to here as multisystem inflammatory syndrome in adults (MIS-A), the heterogeneity of clinical signs and symptoms, and the role for antibody testing in identifying similar cases among adults. Clinicians and health departments should consider MIS-A in adults with compatible signs and symptoms. These patients might not have positive SARS-CoV-2 PCR or antigen test results, and antibody testing might be needed to confirm previous SARS-CoV-2 infection. Because of the temporal association between MIS-A and SARS-CoV-2 infections, interventions that prevent COVID-19 might prevent MIS-A. Further research is needed to understand the pathogenesis and long-term effects of this newly described condition.

Delayed hypersensitivity reaction to acellular dermal matrix in breast reconstruction: the red breast syndrome?

BACKGROUND: Acellular dermal matrix (ADM) has become a valuable tool in reconstructive breast surgery, in part because it has been considered to be a non-reactive and non-immunogenic entity. However, some patients who undergo breast reconstruction with ADMs develop postoperative erythema overlying their ADM grafts. The etiology of this phenomenon is poorly understood. METHODS: In this article, we summarize clinical cases in which patients developed localized breast erythema following reconstruction with ADMs. We review what is known about postoperative breast erythema after ADM-based breast reconstructions and the possible antigenicity of biologic mesh implants. RESULTS: We report 4 implant-based breast reconstruction patients who developed erythematous reactions overlying the region where ADM was placed: one demonstrated a delayed-type hypersensitivity reaction on punch biopsy of the affected skin, leading to removal of the biologic product; 2 others had a similar clinical presentation that responded to corticosteroids without removal of the biologic material, with 1 patient experiencing recrudescence of erythema that responded fully to a second course of corticosteroids; and a fourth showed erythema that was only moderately responsive to antibiotic therapy but which improved consistently after the patient initiated chemotherapy. CONCLUSION: We propose that the etiology of erythema overlying ADM grafts, and the so-called red breast syndrome, may in some patients be a delayed-type hypersensitivity reaction to the ADM product. Affected patients may benefit from treatment with corticosteroids or similar medications, and that such treatment may, in some cases, enable patients to retain the ADM grafts and enable salvage of the reconstructed breast.

Acute neutrophilic vasculitis (leukocytoclasia) in 36 COVID-19 autopsy brains.

BACKGROUND: Hypercytokinemia, the renin-angiotensin system, hypoxia, immune dysregulation, and vasculopathy with evidence of immune-related damage are implicated in brain morbidity in COVID-19 along with a wide variety of genomic and environmental influences. There is relatively little evidence of direct SARS-CoV-2 brain infection in COVID-19 patients. METHODS: Brain histopathology of 36 consecutive autopsies of patients who were RT-PCR positive for SARS-CoV-2 was studied along with findings from contemporary and pre-pandemic historical control groups. Immunostaining for serum and blood cell proteins and for complement components was employed. Microcirculatory wall complement deposition in the COVID-19 cohort was compared to historical control cases. Comparisons also included other relevant clinicopathological and microcirculatory findings in the COVID-19 cohort and control groups. RESULTS: The COVID-19 cohort and both the contemporary and historical control groups had the same rate of hypertension, diabetes mellitus, and obesity. The COVID-19 cohort had varying amounts of acute neutrophilic vasculitis with leukocytoclasia in the microcirculation of the brain in all cases. Prominent vascular neutrophilic transmural migration was found in several cases and 25 cases had acute perivasculitis. Paravascular microhemorrhages and petechial hemorrhages (small brain parenchymal hemorrhages) had a slight tendency to be more numerous in cohort cases that displayed less acute neutrophilic vasculitis. Tissue burden of acute neutrophilic vasculitis with leukocytoclasia was the same in control cases as a group, while it was significantly higher in COVID-19 cases. Both the tissue burden of acute neutrophilic vasculitis and the activation of complement components, including membrane attack complex, were significantly higher in microcirculatory channels in COVID-19 cohort brains than in historical controls. CONCLUSIONS: Acute neutrophilic vasculitis with leukocytoclasia, acute perivasculitis, and associated paravascular blood extravasation into brain parenchyma constitute the first phase of an immune-related, acute small-vessel inflammatory condition often termed type 3 hypersensitivity vasculitis or leukocytoclastic vasculitis. There is a higher tissue burden of acute neutrophilic vasculitis and an increased level of activated complement components in microcirculatory walls in COVID-19 cases than in pre-pandemic control cases. These findings are consistent with a more extensive small-vessel immune-related vasculitis in COVID-19 cases than in control cases. The pathway(s) and mechanism for these findings are speculative.

Nailfold Videocapillaroscopic Alterations as Markers of Microangiopathy in COVID-19 Patients.

Nailfold videocapillaroscopic alterations have been described in COVID-19, but their correlations with biomarkers of inflammation, coagulation and endothelial perturbation are still unclear, and no information is available on nailfold histopathology. Nailfold videocapillaroscopy was performed on fifteen patients with COVID-19 in Milan, Italy and the signs of microangiopathy were correlated with plasma biomarkers of inflammation (C reactive protein [CRP], ferritin), coagulation (D-dimer, fibrinogen), endothelial perturbation (Von Willebrand factor [VWF]) and angiogenesis (vascular endothelial growth factor [VEGF]) along with genetic drivers of COVID-19 susceptibility. Histopathological analysis of autoptic nailfold excisions was performed on fifteen patients who died for COVID-19 in New Orleans, United States. All COVID-19 patients studied with videocapillaroscopy showed alterations rarely seen in healthy individuals consistent with microangiopathy, such as hemosiderin deposits (sign of microthrombosis and microhemorrhages) and enlarged loops (sign of endotheliopathy). The number of hemosiderin deposits correlated both with ferritin and CRP levels (r = 0.67, p = 0.008 for both) and the number of enlarged loops significantly correlated with the levels of VWF (r = 0.67, p = 0.006). Ferritin levels were higher in non-O groups, determined by the rs657152 C > A cluster, (median 619, min-max 551-3266 mg/dL) than in the O group (373, 44-581 mg/dL, p = 0.006). Nailfold histology revealed microvascular damage, i.e., mild perivascular lymphocyte and macrophage infiltration and microvascular ectasia in the dermal vessels of all cases, and microthrombi within vessels in five cases. Alterations in nailfold videocapillaroscopy and elevated biomarkers of endothelial perturbation that match histopathologic findings open new perspectives in the possibility of non-invasively demonstrating microangiopathy in COVID-19.

Assessment of photoacoustic tomography contrast for breast tissue imaging using 3D correlative virtual histology.

Current breast tumor margin detection methods are destructive, time-consuming, and result in significant reoperative rates. Dual-modality photoacoustic tomography (PAT) and ultrasound has the potential to enhance breast margin characterization by providing clinically relevant compositional information with high sensitivity and tissue penetration. However, quantitative methods that rigorously compare volumetric PAT and ultrasound images with gold-standard histology are lacking, thus limiting clinical validation and translation. Here, we present a quantitative multimodality workflow that uses inverted Selective Plane Illumination Microscopy (iSPIM) to facilitate image co-registration between volumetric PAT-ultrasound datasets with histology in human invasive ductal carcinoma breast tissue samples. Our ultrasound-PAT system consisted of a tunable Nd:YAG laser coupled with a 40 MHz central frequency ultrasound transducer. A linear stepper motor was used to acquire volumetric PAT and ultrasound breast biopsy datasets using 1100 nm light to identify hemoglobin-rich regions and 1210 nm light to identify lipid-rich regions. Our iSPIM system used 488 nm and 647 nm laser excitation combined with Eosin and DRAQ5, a cell-permeant nucleic acid binding dye, to produce high-resolution volumetric datasets comparable to histology. Image thresholding was applied to PAT and iSPIM images to extract, quantify, and topologically visualize breast biopsy lipid, stroma, hemoglobin, and nuclei distribution. Our lipid-weighted PAT and iSPIM images suggest that low lipid regions strongly correlate with malignant breast tissue. Hemoglobin-weighted PAT images, however, correlated poorly with cancerous regions determined by histology and interpreted by a board-certified pathologist. Nuclei-weighted iSPIM images revealed similar cellular content in cancerous and non-cancerous tissues, suggesting malignant cell migration from the breast ducts to the surrounding tissues. We demonstrate the utility of our nondestructive, volumetric, region-based quantitative method for comprehensive validation of 3D tomographic imaging methods suitable for bedside tumor margin detection.

COVID-19: The Heart of the Matter-Pathological Changes and a Proposed Mechanism.

The SARS-CoV-2 virus has resulted in over 88 million cases worldwide of COVID-19 as of January 2021. The heart is one of the most commonly affected organs in COVID-19, but the nature and extent of the cardiac pathology has remained controversial. It has been shown that patients infected with SARS-CoV-2 can sustain type 1 myocardial infarction in the absence of significant atherosclerotic coronary artery disease. However, many patients present with small elevations of troponin enzymes of unclear etiology which correlate with overall COVID-19 disease outcome. Early autopsy reports indicated variable levels of typical lymphocytic myocarditis, while radiology reports have indicated that myocarditis can be a persistent problem after recovery from acute illness, raising concern about participation in college athletics. In this communication, we review the literature to date regarding the gross and microscopic findings of COVID-19 cardiac involvement, present the findings from over 40 cases from our academic medical center, and propose mechanisms by which patients develop small elevations in troponin. .

COVID-19 myocarditis: quantitative analysis of the inflammatory infiltrate and a proposed mechanism.

COVID-19 has a significant effect upon the cardiovascular system. While a number of different cardiovascular histopathologies have been described at post-mortem examination, the incidence of typical viral myocarditis in COVID-19 positive patients appears very low [1-3]. In this study, we further characterize and quantify the inflammatory cell infiltrate in a COVID-19 study cohort and compare the findings to both an age and disease matched control cohort and a cohort of patients diagnosed with typical inflammatory myocarditis. All study and control cohorts had 1 or more of the comorbidities most commonly associated with severe disease (hypertension, type II diabetes, obesity, or known cardiovascular disease). The results demonstrate a skewed distribution of the number of CD68+ cells in COVID-19 hearts, with upper quantiles showing a significant increase as compared to both matched control hearts, and those with myocarditis. In contrast, hearts from typical inflammatory myocarditis contained increased numbers of CD4+, and CD8+ cells compared to both COVID-19 and control cohorts. In conclusion, the presence of an increased number of CD68+ cells suggests that COVID-19 may incite a form of myocarditis different from typical viral myocarditis, and associated with diffusely infiltrative cells of monocytes/macrophage lineage.

The intersection of COVID-19 and autoimmunity.

Acute COVID-19, caused by SARS-CoV-2, is characterized by diverse clinical presentations, ranging from asymptomatic infection to fatal respiratory failure, and often associated with varied longer-term sequelae. Over the past 18 months, it has become apparent that inappropriate immune responses contribute to the pathogenesis of severe COVID-19. Researchers working at the intersection of COVID-19 and autoimmunity recently gathered at an American Autoimmune Related Diseases Association Noel R. Rose Colloquium to address the current state of knowledge regarding two important questions: Does established autoimmunity predispose to severe COVID-19? And, at the same time, can SARS-CoV-2 infection trigger de novo autoimmunity? Indeed, work to date has demonstrated that 10% to 15% of patients with critical COVID-19 pneumonia exhibit autoantibodies against type I interferons, suggesting that preexisting autoimmunity underlies severe disease in some patients. Other studies have identified functional autoantibodies following infection with SARS-CoV-2, such as those that promote thrombosis or antagonize cytokine signaling. These autoantibodies may arise from a predominantly extrafollicular B cell response that is more prone to generating autoantibody-secreting B cells. This Review highlights the current understanding, evolving concepts, and unanswered questions provided by this unique opportunity to determine mechanisms by which a viral infection can be exacerbated by, and even trigger, autoimmunity. The potential role of autoimmunity in post-acute sequelae of COVID-19 is also discussed.

How the timing and quality of early experiences influence the development of brain architecture.

Early life events can exert a powerful influence on both the pattern of brain architecture and behavioral development. In this study a conceptual framework is provided for considering how the structure of early experience gets "under the skin." The study begins with a description of the genetic framework that lays the foundation for brain development, and then proceeds to the ways experience interacts with and modifies the structures and functions of the developing brain. Much of the attention is focused on early experience and sensitive periods, although it is made clear that later experience also plays an important role in maintaining and elaborating this early wiring diagram, which is critical to establishing a solid footing for development beyond the early years.

Pulmonary and cardiac pathology in African American patients with COVID-19: an autopsy series from New Orleans.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread rapidly across the USA, causing extensive morbidity and mortality, particularly in the African American community. Autopsy can considerably contribute to our understanding of many disease processes and could provide crucial information to guide management of patients with coronavirus disease 2019 (COVID-19). We report on the relevant cardiopulmonary findings in, to our knowledge, the first autopsy series of ten African American decedents, with the cause of death attributed to COVID-19. METHODS: Autopsies were performed on ten African American decedents aged 44-78 years with cause of death attributed to COVID-19, reflective of the dominant demographic of deaths following COVID-19 diagnosis in New Orleans. Autopsies were done with consent of the decedents' next of kin. Pulmonary and cardiac features were examined, with relevant immunostains to characterise the inflammatory response, and RNA labelling and electron microscopy on representative sections. FINDINGS: Important findings include the presence of thrombosis and microangiopathy in the small vessels and capillaries of the lungs, with associated haemorrhage, that significantly contributed to death. Features of diffuse alveolar damage, including hyaline membranes, were present, even in patients who had not been ventilated. Cardiac findings included individual cell necrosis without lymphocytic myocarditis. There was no evidence of secondary pulmonary infection by microorganisms. INTERPRETATION: We identify key pathological states, including thrombotic and microangiopathic pathology in the lungs, that contributed to death in patients with severe COVID-19 and decompensation in this demographic. Management of these patients should include treatment to target these pathological mechanisms. FUNDING: None.

Exclusion of PITX2 mutations as a major cause of CHARGE association.

CHARGE is a nonrandom association of ocular coloboma, congenital heart defects, atresia of the choanae, retarded growth and development, genital hypoplasia, and ear anomalies including deafness. The cause of CHARGE remains unknown; however, there is considerable evidence of an underlying genetic basis, as discussed by Tellier et al. [1996: Clin Genet 50:548-550; 1998: Am J Med Genet 76:402-409] and by Martin et al. [2001: Am J Med Genet 99:115-119]. Based on the ocular, cardiac, and craniofacial expression pattern of Pitx2, a homeodomain transcription factor, and the pleiotropic effects of loss of PITX2 function in both mouse and human, we hypothesized that PITX2 mutations may contribute to the multiple phenotypic anomalies present in CHARGE individuals. By direct sequencing of DNA from 29 individuals with CHARGE, we did not identify any mutations in PITX2. We did, however, identify two PITX2 sequence polymorphisms. Large deletions of PITX2 were excluded in most patients by heterozygosity in at least one of several polymorphic markers near the PITX2 locus. Together, these data indicate that PITX2 mutations are unlikely to be a major contributing cause of the multiple anomalies present in individuals with CHARGE.

The use of silk-based devices for fracture fixation.

Metallic fixation systems are currently the gold standard for fracture fixation but have problems including stress shielding, palpability and temperature sensitivity. Recently, resorbable systems have gained interest because they avoid removal and may improve bone remodelling due to the lack of stress shielding. However, their use is limited to paediatric craniofacial procedures mainly due to the laborious implantation requirements. Here we prepare and characterize a new family of resorbable screws prepared from silk fibroin for craniofacial fracture repair. In vivo assessment in rat femurs shows the screws to be self-tapping, remain fixed in the bone for 4 and 8 weeks, exhibit biocompatibility and promote bone remodelling. The silk-based devices compare favourably with current poly-lactic-co-glycolic acid fixation systems, however, silk-based devices offer numerous advantages including ease of implantation, conformal fit to the repair site, sterilization by autoclaving and minimal inflammatory response.

Neural processing of facial identity and emotion in infants at high-risk for autism spectrum disorders.

Deficits in face processing and social impairment are core characteristics of autism spectrum disorder. The present work examined 7-month-old infants at high-risk for developing autism and typically developing controls at low-risk, using a face perception task designed to differentiate between the effects of face identity and facial emotions on neural response using functional Near-Infrared Spectroscopy. In addition, we employed independent component analysis, as well as a novel method of condition-related component selection and classification to identify group differences in hemodynamic waveforms and response distributions associated with face and emotion processing. The results indicate similarities of waveforms, but differences in the magnitude, spatial distribution, and timing of responses between groups. These early differences in local cortical regions and the hemodynamic response may, in turn, contribute to differences in patterns of functional connectivity.

Functional MRI to evaluate "sense of self" following perforator flap breast reconstruction.

BACKGROUND: Breast reconstruction is associated with high levels of patient satisfaction. Previous patient satisfaction studies have been subjective. This study utilizes functional magnetic resonance imaging (fMRI) to objectively evaluate "sense of self" following deep inferior epigastric perforator (DIEP) flap breast reconstruction in an attempt to better understand patient perception. METHODS: Prospective fMRI analysis was performed on four patients before and after delayed unilateral DIEP flap breast reconstruction, and on four patients after immediate unilateral DIEP flap breast reconstruction. Patients were randomly cued to palpate their natural breast, mastectomy site or breast reconstruction, and external silicone models. Three regions of interest (ROIs) associated with self-recognition were examined using a general linear model, and compared using a fixed effects and random effects ANOVA, respectively. RESULTS: In the delayed reconstruction group, activation of the ROIs was significantly lower at the mastectomy site compared to the natural breast (p<0.01). Ten months following reconstruction, activation of the ROIs in the reconstructed breast was not significantly different from that observed with natural breast palpation. In the immediate reconstruction group, palpation of the reconstructed breast was also similar to the natural breast. This activity was greater than that observed during palpation of external artificial models (p<0.01). CONCLUSIONS: Similar activation patterns were observed during palpation of the reconstructed and natural breasts as compared to the non-reconstructed mastectomy site and artificial models. The cognitive process represented by this pattern may be a mechanism by which breast reconstruction improves self-perception, and thus patient satisfaction following mastectomy.

Neural processing of repetition and non-repetition grammars in 7- and 9-month-old infants.

An essential aspect of infant language development involves the extraction of meaningful information from a continuous stream of auditory input. Studies have identified early abilities to differentiate auditory input along various dimensions, including the presence or absence of structural regularities. In newborn infants, frontal and temporal regions were found to respond differentially to these regularities (Gervain et al., 2008), and in order to examine the development of this abstract rule learning we presented 7- and 9-month-old infants with syllables containing an ABB pattern (e.g., "balolo") or an ABC pattern (e.g., "baloti") and measured activity in left and right lateral brain regions using near-infrared spectroscopy (NIRS). While prior newborn work found increases in oxyhemoglobin (oxyHb) activity in response to ABB blocks as compared to ABC blocks in anterior regions, 7- and 9-month-olds showed no differentiation between grammars in oxyHb. However, changes in deoxyhemoglobin (deoxyHb) pointed to a developmental shift, whereby 7-month-olds showed deoxyHb responding significantly different from zero for ABB blocks, but not ABC blocks, and 9-month-olds showed the opposite pattern, with deoxyHb responding significantly different from zero for the ABC blocks but not the ABB blocks. DeoxyHb responses were more pronounced over anterior regions. A grammar by time interaction also illustrated that during the early blocks, deoxyHb was significantly greater to ABC than in later blocks, but there was no change in ABB activation over time. The shift from stronger activation to ABB in newborns (Gervain et al., 2008) and 7-month-olds in the present study to stronger activation to ABC by 9-month-olds here is discussed in terms of changes in stimulus salience and novelty preference over the first year of life. The present discussion also highlights the importance of future work exploring the coupling between oxyHb and deoxyHb activation in infant NIRS studies.

Equestrian-related injuries: implications for treatment in plastic surgery.

BACKGROUND: Equestrian activities have always been popular in the United States. As safety guidelines have become more stringent, horse-related injuries have diminished by 40 percent over the past 20 years. Although perhaps less critical than in the past, injuries to equestrians most frequently involve the face, upper extremity, and lower extremity and are commonly evaluated by the plastic surgeon. The purpose of this study was to determine the characteristics of these equestrian-related injuries. METHODS: The National Electronic Injury Surveillance System database is a stratified probability sample of hospitals in the United States. The database was queried for mechanisms of equestrian-related injuries, and probability estimates were obtained based on 1200 cases reported for the year 2005 in the United States. RESULTS: Based on the National Electronic Injury Surveillance System query, the most commonly injured areas are the upper extremities, lower extremities, and face. Common mechanisms of injury include fall from a horse (60 percent), stepped on by a horse (11 percent), kicks (11 percent), and bites (3 percent). The authors present four illustrative case reports seen in their institution. CONCLUSIONS: Equestrian injuries are commonly seen by plastic surgeons. Proper evaluation of the characteristics and mechanisms of injury can lead to optimal care and outcomes.