Rubella virus infected macrophages and neutrophils define patterns of granulomatous inflammation in inborn and acquired errors of immunity

Rubella virus (RuV) has recently been found in association with granulomatous inflammation of the skin and several internal organs in patients with inborn errors of immunity (IEI). The cellular tropism and molecular mechanisms of RuV persistence and pathogenesis in select immunocompromised hosts are not clear. We provide clinical, immunological, virological, and histological data on a cohort of 28 patients with a broad spectrum of IEI and RuV-associated granulomas in skin and nine extracutaneous tissues to further delineate this relationship. Combined immunodeficiency was the most frequent diagnosis (67.8%) among patients. Patients with previously undocumented conditions, i.e., humoral immunodeficiencies, a secondary immunodeficiency, and a defect of innate immunity were identified as being susceptible to RuV-associated granulomas. Hematopoietic cell transplantation was the most successful treatment in this case series resulting in granuloma resolution; steroids, and TNF-α and IL-1R inhibitors were moderately effective. In addition to M2 macrophages, neutrophils were identified by immunohistochemical analysis as a novel cell type infected with RuV. Four patterns of RuV-associated granulomatous inflammation were classified based on the structural organization of granulomas and identity and location of cell types harboring RuV antigen. Identification of conditions that increase susceptibility to RuV-associated granulomas combined with structural characterization of the granulomas may lead to a better understanding of the pathogenesis of RuV-associated granulomas and discover new targets for therapeutic interventions

Dermatologic events associated with the anti-CCR4 antibody mogamulizumab: Characterization and management

The CCR4-directed monoclonal antibody mogamulizumab has been shown to significantly improve progression-free survival and overall response rate compared with vorinostat in adults with relapsed/refractory mycosis fungoides (MF) and Sézary syndrome (SS). One of the most common adverse events seen with mogamulizumab in MF/SS patients is rash. Because of the protean nature of MF/SS and the variable clinical and histopathological features of mogamulizumab-associated rash, healthcare providers may have difficulty distinguishing rash from disease, and may not be aware of appropriate treatment strategies for this generally manageable adverse event. The objective of this report was to combine results from published literature with experiences and recommendations from multiple investigators and institutions into clinical best practice recommendations to assist healthcare providers in identifying and managing mogamulizumab-associated rash. Optimal management, which includes biopsy confirmation and steroid treatment, requires a multidisciplinary approach among oncology, dermatology, and pathology practitioners. INFOGRAPHIC

Novel cell adhesion/migration pathways are predictive markers of HDAC inhibitor resistance in cutaneous T cell lymphoma

BACKGROUND: Treatment for Cutaneous T Cell Lymphoma (CTCL) is generally not curative. Therefore, selecting therapy that is effective and tolerable is critical to clinical decision-making. Histone deacetylase inhibitors (HDACi), epigenetic modifier drugs, are commonly used but effective in only ~30% of patients. There are no predictive markers of HDACi response and the CTCL histone acetylation landscape remains unmapped. We sought to identify pre-treatment molecular markers of resistance in CTCL that progressed on HDACi therapy. METHODS: Purified T cells from 39 pre/post-treatment peripheral blood samples and skin biopsies from 20 patients were subjected to RNA-seq and ChIP-seq for histone acetylation marks (H3K14/9 ac, H3K27ac). We correlated significant differences in histone acetylation with gene expression in HDACi-resistant/sensitive CTCL. We extended these findings in additional CTCL patient cohorts (RNA-seq, microarray) and using ELISA in matched CTCL patient plasma. FINDINGS: Resistant CTCL exhibited high levels of histone acetylation, which correlated with increased expression of 338 genes (FDR \u3c 0·05), including some novel to CTCL: BIRC5 (anti-apoptotic); RRM2 (cell cycle); TXNDC5, GSTM1 (redox); and CXCR4, LAIR2 (cell adhesion/migration). Several of these, including LAIR2, were elevated pre-treatment in HDACi-resistant CTCL. In CTCL patient plasma (n = 6), LAIR2 protein was also elevated (p \u3c 0·01) compared to controls. INTERPRETATION: This study is the first to connect genome-wide differences in chromatin acetylation and gene expression to HDACi-resistance in primary CTCL. Our results identify novel markers with high pre-treatment expression, such as LAIR2, as potential prognostic and/or predictors of HDACi-resistance in CTCL. FUNDING: NIH:CA156690, CA188286; NCATS: WU-ICTS UL1 TR000448; Siteman Cancer Center: CA091842

Diagnostic concordance of clinical diagnosis, tissue culture, and histopathology testing for skin and soft tissue infections: A single-center retrospective study

BACKGROUND: Tissue culture and histopathology are the conventional diagnostic modalities for skin and soft tissue infections (SSTIs), but few studies have investigated their concordance. OBJECTIVE: Determine concordance between histopathology and tissue culture in the diagnosis of suspected SSTIs. METHODS: Single-center retrospective study of 355 cases with suspected SSTIs identified from the dermatology inpatient consultation log January 2014-July 2017. RESULTS: Overall concordance between histopathology testing and tissue culture results was high (76.1%). Concordance was high for cases defined as no evidence of infection, fungal infection and mycobacterial infection by histopathology (77.8%, 74.2%, and 80.0%) and tissue culture (92.1%, 67.7%, and 83.3%). Concordance was lower for suspected SSTIs with bacterial infection by histopathology (61.9%) and tissue culture (28.4%). Concordance rates were not significantly affected by age, sex, race, antimicrobial agent use, immunologic status, or biopsy size. LIMITATIONS: Retrospective and single-institution nature of the study. CONCLUSION: This study demonstrated a high concordance between histopathology and tissue culture in SSTIs with no clinical evidence of infection and suspected fungal and mycobacterial SSTIs, though concordance was lower for suspected SSTIs with evidence of bacterial infection. Clinicians should not be deterred from relying on initial histopathological results based on patients\u27 immunosuppressed status, antimicrobial agent use, age, or biopsy tissue size

Rapid and sustained response to immune checkpoint inhibition in cutaneous squamous cell carcinoma after allogenic hematopoietic cell transplant for Sézary syndrome

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is not uncommon in association with indolent malignancies that were treated with prior radiotherapy and after allogenic bone marrow transplantation. On the other hand, cutaneous T-cell lymphoma (CTCL) is a subtype of non-Hodgkin\u27s lymphoma which is characterized by an indolent course, with relative refractoriness to conventional chemotherapies and radiotherapy, and occasionally referred for allogeneic hematopoietic cell transplantation (allo-HCT). Recently, the use of immune checkpoint inhibitors has gained attention in the treatment of both cutaneous squamous cell carcinoma and hematological malignancies. However, many patients with hematological malignancies eventually undergo allo-HCT, raising the concern of potential adverse events (graft versus host disease) due to manipulation of the immune system with use of checkpoint inhibitors. CASE PRESENTATION: We describe a patient with relapsed refractory CTCL (Sézary Syndrome) who underwent allo-HCT with persistence of disease post-transplant. The patient additionally developed a progressively worsening lesion on the right shoulder which was biopsied and showed poorly differentiated carcinoma (cSCC). Pembrolizumab was started for the treatment of cSCC. After second cycle of treatment, the cSCC lesion responded dramatically to the use of immune checkpoint inhibitor. Also, the patient experienced significant resolution of pruritus and generalized erythema. During 24 months of follow up after initial treatment with checkpoint inhibition immunotherapy, the patient showed durable response of both cSCC and CTCL, as well as restoration of full donor chimerism, without obvious worsening of graft versus host disease (GVHD). CONCLUSION: This is the first case to our knowledge of rapid and durable response of both cSCC and CTCL to immune checkpoint inhibition after allo-HCT. Although this report highlights the potential for significant response to this class of medication, further studies are required to confirm the efficacy and safety of this approach in patients with CTCL after allo-HCT given the potential concern of GVHD