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.

Pathogenesis to management of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer whose incidence continues to rise in many parts of the world due to a concomitant rise in many associated risk factors, such as alcohol use and obesity. Although early-stage HCC can be potentially curable through liver resection, liver-directed therapies, or transplantation, patients usually present with intermediate to advanced disease, which continues to be associated with a poor prognosis. This is because HCC is a cancer with significant complexities, including substantial clinical, histopathologic, and genomic heterogeneity. However, the scientific community has made a major effort to better characterize HCC in those aspects via utilizing tissue sampling and histological classification, whole genome sequencing, and developing viable animal models. These efforts ultimately aim to develop clinically relevant biomarkers and discover molecular targets for new therapies. For example, until recently, there was only one approved systemic therapy for advanced or metastatic HCC in the form of sorafenib. Through these efforts, several additional targeted therapies have gained approval in the United States, although much progress remains to be desired. This review will focus on the link between characterizing the pathogenesis of HCC with current and future HCC management.

Whole slide image data utilization informed by digital diagnosis patterns.

Context: Despite the benefits of digital pathology, data storage and management of digital whole slide images introduces new logistical and infrastructure challenges to traditionally analog pathology labs. Aims: Our goal was to analyze pathologist slide diagnosis patterns to determine the minimum number of pixels required during the diagnosis. Methods: We developed a method of using pathologist viewing patterns to vary digital image resolution across virtual slides, which we call variable resolution images. An additional pathologist reviewed the variable resolution images to determine if diagnoses could still be rendered. Results: Across all slides, the pathologists rarely zoomed in to the full resolution level. As a result, the variable resolution images are significantly smaller than the original whole slide images. Despite the reduction in image sizes, the final pathologist reviewer could still proide diagnoses on the variable resolution slide images. Conclusions: Future studies will be conducted to understand variability in resolution requirements between and within pathologists. These findings have the potential to dramatically reduce the data storage requirements of high-resolution whole slide images.

Pancreatic Cancer Patient-derived Organoids Can Predict Response to Neoadjuvant Chemotherapy.

OBJECTIVE: To evaluate if patient-derived organoids (PDOs) may predict response to neoadjuvant (NAT) chemotherapy in patients with pancreatic adenocarcinoma. BACKGROUND: PDOs have been explored as a biomarker of therapy response and for personalized therapeutics in patients with pancreatic cancer. METHODS: During 2017-2021, patients were enrolled into an IRB-approved protocol and PDO cultures were established. PDOs of interest were analyzed through a translational pipeline incorporating molecular profiling and drug sensitivity testing. RESULTS: One hundred thirty-six samples, including both surgical resections and fine needle aspiration/biopsy from 117 patients with pancreatic cancer were collected. This biobank included diversity in stage, sex, age, and race, with minority populations representing 1/3 of collected cases (16% Black, 9% Asian, 7% Hispanic/Latino). Among surgical specimens, PDO generation was successful in 71% (15 of 21) of patients who had received NAT prior to sample collection and in 76% (39 of 51) of patients who were untreated with chemotherapy or radiation at the time of collection. Pathological response to NAT correlated with PDO chemotherapy response, particularly oxaliplatin. We demonstrated the feasibility of a rapid PDO drug screen and generated data within 7 days of tissue resection. CONCLUSION: Herein we report a large single-institution organoid biobank, including ethnic minority samples. The ability to establish PDOs from chemotherapy-naive and post-NAT tissue enables longitudinal PDO generation to assess dynamic chemotherapy sensitivity profiling. PDOs can be rapidly screened and further development of rapid screening may aid in the initial stratification of patients to the most active NAT regimen.

Oral famotidine versus placebo in non-hospitalised patients with COVID-19: a randomised, double-blind, data-intense, phase 2 clinical trial.

OBJECTIVE: We assessed whether famotidine improved inflammation and symptomatic recovery in outpatients with mild to moderate COVID-19. DESIGN: Randomised, double-blind, placebo-controlled, fully remote, phase 2 clinical trial (NCT04724720) enrolling symptomatic unvaccinated adult outpatients with confirmed COVID-19 between January 2021 and April 2021 from two US centres. Patients self-administered 80 mg famotidine (n=28) or placebo (n=27) orally three times a day for 14 consecutive days. Endpoints were time to (primary) or rate of (secondary) symptom resolution, and resolution of inflammation (exploratory). RESULTS: Of 55 patients in the intention-to-treat group (median age 35 years (IQR: 20); 35 women (64%); 18 African American (33%); 14 Hispanic (26%)), 52 (95%) completed the trial, submitting 1358 electronic symptom surveys. Time to symptom resolution was not statistically improved (p=0.4). Rate of symptom resolution was improved for patients taking famotidine (p<0.0001). Estimated 50% reduction of overall baseline symptom scores were achieved at 8.2 days (95% CI: 7 to 9.8 days) for famotidine and 11.4 days (95% CI: 10.3 to 12.6 days) for placebo treated patients. Differences were independent of patient sex, race or ethnicity. Five self-limiting adverse events occurred (famotidine, n=2 (40%); placebo, n=3 (60%)). On day 7, fewer patients on famotidine had detectable interferon alpha plasma levels (p=0.04). Plasma immunoglobulin type G levels to SARS-CoV-2 nucleocapsid core protein were similar between both arms. CONCLUSIONS: Famotidine was safe and well tolerated in outpatients with mild to moderate COVID-19. Famotidine led to earlier resolution of symptoms and inflammation without reducing anti-SARS-CoV-2 immunity. Additional randomised trials are required.

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.

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.

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.

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. .

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.

Tissue dynamics spectroscopic imaging: functional imaging of heterogeneous cancer tissue.

SIGNIFICANCE: Tumor heterogeneity poses a challenge for the chemotherapeutic treatment of cancer. Tissue dynamics spectroscopy captures dynamic contrast and can capture the response of living tissue to applied therapeutics, but the current analysis averages over the complicated spatial response of living biopsy samples. AIM: To develop tissue dynamics spectroscopic imaging (TDSI) to map the heterogeneous spatial response of tumor tissue to anticancer drugs. APPROACH: TDSI is applied to tumor spheroids grown from cell lines and to ex vivo living esophageal biopsy samples. Doppler fluctuation spectroscopy is performed on a voxel basis to extract spatial maps of biodynamic biomarkers. Functional images and bivariate spatial maps are produced using a bivariate color merge to represent the spatial distribution of pairs of signed drug-response biodynamic biomarkers. RESULTS: We have mapped the spatial variability of drug responses within biopsies and have tracked sample-to-sample variability. Sample heterogeneity observed in the biodynamic maps is associated with histological heterogeneity observed using inverted selective-plane illumination microscopy. CONCLUSION: We have demonstrated the utility of TDSI as a functional imaging method to measure tumor heterogeneity and its potential for use in drug-response profiling.

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.

Bone marrow fibrosis in chronic myelomonocytic leukemia is associated with increased megakaryopoiesis, splenomegaly and with a shorter median time to disease progression.

Bone marrow (BM) fibrosis is an adverse prognostic marker in several myeloid neoplasms, particularly in myelodysplastic syndrome (MDS) with fibrosis; however, its significance in chronic myelomonoctyic leukemia (CMML) has not been evaluated. We performed a retrospective analysis to investigate the prognostic and clinicopathological features of CMML with and without BM fibrosis. The study included specimens from a total of 83 untreated CMML patients from 2 large institutions. Patients with any amount of BM fibrosis (MF-1 or higher; MF1+) had significantly shorter progression-free survival (MF1+, 28.3 months vs MF0, not reached; p = 0.001, log rank test), splenomegaly (p = 0.016), and increased BM megakaryocytes (p = 0.04) compared to patients without BM fibrosis (MF-0). No association was observed between fibrosis and peripheral blood parameters, presence of JAK2 V617F mutation, BM blasts, or overall survival. Our study demonstrates the importance of assessing BM fibrosis in CMML. Similar to MDS, the presence of BM fibrosis may identify a distinct subgroup of CMML patients (CMML-F) with a more aggressive clinical course.

Increased Osteoid Formation in BMP-2-Loaded Silk-Based Screws.

BACKGROUND: Resorbable osteosynthesis systems are used to treat craniofacial fractures. However, conventional synthetic polyester materials are potentially associated with inflammatory reaction and negative host response and may result in incomplete bone remodeling. The authors have developed a resorbable silk fibroin-based osteosynthesis system and propose that silk screws loaded with bone morphogenetic protein-2 (BMP-2) may exhibit biocompatibility and promote bone remodeling. METHODS: Resorbable silk screws were prepared and loaded with BMP-2. The BMP-2-loaded and nonloaded silk screws were inserted into the distal femora in 15 Sprague-Dawley rats by self-tapping, similar to conventional metal systems. Animals were euthanized after 1, 3, and 6 months. The femora were explanted at the designated time points, dissected for histologic evaluation, and compared regarding osteoid formation and inflammatory response. RESULTS: Increasing organization of newly formed bone tissue was observed over time in both groups. No appreciable difference in inflammation was noted between the BMP-2-loaded and nonloaded silk screws. Notably, mineralized collagen around the periphery of the screw appears to be greatest and more organized in the BMP-2-loaded samples. There was greater recruitment of osteoclasts and osteoblasts around the perimeter of the BMP-2-loaded screws at 3 and 6 months. CONCLUSIONS: The BMP-2-loaded silk-based fixation device in this study exhibited characteristics comparable to the current nonloaded silk screws with regard to integration and biocompatibility. However, functionalization of silk screws with BMP-2 appeared to allow for more organized collagen and osteoid deposition after 3 and 6 months and may increase the potential of successful remodeling.

Nuclear factor-erythroid 2, nerve growth factor receptor, and CD34-microvessel density are differentially expressed in primary myelofibrosis, polycythemia vera, and essential thrombocythemia.

Because of the presence of various overlapping findings, the discrimination of polycythemia vera (PV) from prefibrotic/fibrotic primary myelofibrosis (PF/F-PMF) and essential thrombocythemia (ET) may be challenging, particularly in suboptimal bone marrow biopsy specimens. In this study, we assessed whether differences in the expression of nuclear factor-erythroid 2 (NF-E2), nerve growth factor receptor (NGFR; CD271), CD34, CD68, p53, CD3, CD20, and CD138 by immunohistochemistry could be useful in separating among them. Higher frequencies of nuclear positive erythroblasts with NF-E2 were observed in ET and PV cases (50% ± 13.3% and 41.5% ± 9.4%, respectively) when compared with both PF-PMF (21% ± 11.7%) and F-PMF (28.5% ± 10.8%). We found that with a cutoff level of at least 30% nuclear staining for NF-E2 in erythroblasts, we could reliably exclude the possibility of PMF. Conversely, NGFR+ stromal cells per high-power field (HPF) was significantly increased in F-PMF (53.5 ± 19.1/HPF) and PF-PMF (13.5 ± 3.8/HPF) compared with ET (4.4 ± 2.2/HPF) and PV (6.6 ± 3.3/HPF). Similarly, differences in CD34-microvessel density was remarkable in F-PMF and PF-PMF cases in comparison with PV and ET (49.9 ± 12.1/HPF, 29.3 ± 12.4/HPF, 13.7 ± 4.6/HPF, and 11.9 ± 5.1/HPF, respectively). Thus, the assessment of NF-E2 and NGFR expression and the evaluation of CD34-microvessel density may provide additional support in reaching a correct diagnosis in these cases of myeloproliferative neoplasms.

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.