Histopathological and Clinical Analysis of Skin Rashes in Children With Multisystem Inflammatory Syndrome Associated With COVID-19.

INTRODUCTION: A new entity, which occurs a few weeks after SARS-CoV-2 infection and resembling incomplete Kawasaki disease or toxic shock syndrome, has been defined and named multisystem inflammatory syndrome (MIS-C) associated with COVID-19 in children. The aim of our study was to describe histopathological characteristics of skin lesions of MIS-C patients to reveal whether there is a relationship between histopathological features and clinical manifestations. MATERIALS AND METHODS: Seventeen who had skin involvement of 57 patients who were diagnosed with MIS-C between December 2020 and February 2021 were included in this prospective study. Demographic information, laboratory findings, and patients' managements were recorded. Skin biopsies were taken simultaneously of each patient. Formalin-fixed, paraffin-embedded skin samples were examined microscopically. RESULTS: The rate of skin rash was 30% in patients with MIS-C and was predominantly the maculopapular type. The anatomical distribution of the rash was evaluated as localized in 10 and generalized in 7 patients. In patients with myocarditis, C-reactive protein and fibrinogen were found to be significantly higher, and lymphocyte and albumin values were found to be low. Herpes-like inclusions were found in the microscopic examination of 2 patients with a history of zona zoster in themselves or in their mother. There was a significant difference between keratinocyte necrosis and some clinical parameters. DISCUSSION: Localized skin lesions appear to be associated with a more severe inflammatory.

Lessons from dermatology about inflammatory responses in Covid-19.

The SARS-Cov-2 is a single-stranded RNA virus composed of 16 non-structural proteins (NSP 1-16) with specific roles in the replication of coronaviruses. NSP3 has the property to block host innate immune response and to promote cytokine expression. NSP5 can inhibit interferon (IFN) signalling and NSP16 prevents MAD5 recognition, depressing the innate immunity. Dendritic cells, monocytes, and macrophages are the first cell lineage against viruses' infections. The IFN type I is the danger signal for the human body during this clinical setting. Protective immune responses to viral infection are initiated by innate immune sensors that survey extracellular and intracellular space for foreign nucleic acids. In Covid-19 the pathogenesis is not yet fully understood, but viral and host factors seem to play a key role. Important points in severe Covid-19 are characterized by an upregulated innate immune response, hypercoagulopathy state, pulmonary tissue damage, neurological and/or gastrointestinal tract involvement, and fatal outcome in severe cases of macrophage activation syndrome, which produce a 'cytokine storm'. These systemic conditions share polymorphous cutaneous lesions where innate immune system is involved in the histopathological findings with acute respiratory distress syndrome, hypercoagulability, hyperferritinemia, increased serum levels of D-dimer, lactic dehydrogenase, reactive-C-protein and serum A amyloid. It is described that several polymorphous cutaneous lesions similar to erythema pernio, urticarial rashes, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicles lesions, and purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema. This review describes the complexity of Covid-19, its pathophysiological and clinical aspects.

Histopathological Spectrum and Immunophenotypic Characterization of Symmetrical Drug-Related Intertriginous and Flexural Exanthema.

INTRODUCTION: Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) is a clinically very well-defined drug eruption, but the histopathological findings are still considered to be nonspecific. OBJECTIVES: To characterize the histopathological and immunophenotypical features of SDRIFE. MATERIAL AND METHODS: We performed a retrospective study that identified 11 biopsies from 9 patients with SDRIFE. The histopathological features were analyzed in conjunction with the immunohistochemical findings. RESULTS: The most common histopathological feature was basal cell vacuolization, which was often associated with necrotic keratinocytes and focal spongiosis. TIA1+ T cells and neutrophils were frequently detected in the epidermis and at the dermoepidermal junction. The dermal inflammatory infiltrate was mixed, consisting of CD3+ T cells, macrophages, granulocytes, low numbers of CD20+ B cells, and plasma cells. A combination of histopathological patterns was observed in 5 cases. The most frequent combined histopathological patterns were interface dermatitis, spongiotic dermatitis, and psoriasiform dermatitis. Other histopathological patterns found in different combinations were pustular dermatitis, perivascular and interstitial neutrophilic dermatitis, and interstitial granulomatous dermatitis. In the other 4 cases, a single histopathological pattern predominated, such as psoriasiform dermatitis, vacuolar interface dermatitis of erythema multiforme-like type, or superficial and deep perivascular and interstitial dermatitis with eosinophils and neutrophils. CONCLUSIONS: SDRIFE is characterized histologically by a vacuolar interface dermatitis induced by cytotoxic T lymphocytes and neutrophilic granulocytes. This pattern may be obscured by accompanying spongiotic, psoriasiform, or pustular features combined with a mixed superficial and sometimes deep dermal infiltrate.

Review of adverse cutaneous reactions of pharmacologic interventions for COVID-19: A guide for the dermatologist.

The new coronavirus, severe acute respiratory syndrome coronavirus 2, is associated with a wide variety of cutaneous manifestations. Although new skin manifestations caused by COVID-19 are continuously being described, other cutaneous entities should also be considered in the differential diagnosis, including adverse cutaneous reactions to drugs used in the treatment of COVID-19 infections. The aim of this review is to provide dermatologists with an overview of the cutaneous adverse effects associated with the most frequently prescribed drugs in patients with COVID-19. The skin reactions of antimalarials (chloroquine and hydroxychloroquine), antivirals (lopinavir/ritonavir, ribavirin with or without interferon, oseltamivir, remdesivir, favipiravir, and darunavir), and treatments for complications (imatinib, tocilizumab, anakinra, immunoglobulins, corticosteroids, colchicine and low molecular weight heparins) are analyzed. Information regarding possible skin reactions, their frequency, management, and key points for differential diagnosis are presented.

Follicular Eruption With Folliculotropic Lymphocytic Infiltrates Associated With Iatrogenic Immunosuppression: Report and Study of 3 Cases, and Review of the Literature.

BACKGROUND: Several cases of folliculotropic mycosis fungoides, associated with immunosuppressive therapy, including calcineurin inhibitors, have been reported in solid organ transplant patients. We have encountered 3 patients on immunosuppressive therapy who developed follicular eruptions with folliculocentric infiltrates of nonatypical lymphocytes. OBJECTIVE: To characterize these follicular eruptions and review the literature. METHODS: Three patients, aged 7-15 years, who were treated with systemic immunosuppressive therapy developed follicular eruptions characterized histopathologically by folliculocentric lymphocytic infiltrates. These were studied clinically, histopathologically, immunophenotypically, and molecularly for T-cell receptor (TCR) gene rearrangement. RESULTS: All 3 cases were characterized histopathologically by folliculocentric infiltrates of nonatypical CD3 T lymphocytes with variable follicular exocytosis. Two cases also showed follicular mucinosis. Marked reduction in CD7 staining, and marked predominance of CD4 cells over CD8 cells was observed in all 3 cases. The TCR gene rearrangement studies were monoclonal in 2 cases. Oral calcineurin inhibitors (2 cyclosporine A and 1 tacrolimus) were part of the therapeutic regimen in all 3 patients. Their cessation along with local corticosteroid creams in 2 patients, and phototherapy with oral acitretin in one patient, was associated with complete clinical remission. CONCLUSIONS: Patients undergoing systemic immunosuppressive therapy that includes calcineurin inhibitors might develop follicular eruption with some immunophenotypical variations and a monoclonal TCR gene rearrangement but lack sufficient cytomorphological features of folliculotropic mycosis fungoides. Altering the immunosuppressive agent including calcineurin inhibitors may result in regression of the eruptions.

T-Cell Lymphoblastic Lymphoma/Leukemia Presenting as a Diffuse Viral Exanthem-like Reaction: A Clinical and Histopathological Challenge.

Cutaneous involvement by leukemia, or leukemia cutis, is a rare manifestation of leukemic disorders, most frequently occurring in children. The skin findings, which usually include multiple violaceous or erythematous nodules on the face, most often follow the classic presenting signs and symptoms of leukemia and occur in patients with an established primary diagnosis. Patients with T-cell acute lymphoblastic leukemia and associated leukemia cutis typically present with a solitary firm red to bluish nodule, often with an accompanying mediastinal mass, that can produce respiratory symptoms. In this article, we report a case of a patient with primary T-cell acute lymphoblastic leukemia/lymphoma presenting with a diffuse exanthem mimicking a viral illness with an associated SET-NUP214 translocation.

PD-1+CXCR5-CD4+T cells are correlated with the severity of systemic lupus erythematosus.

OBJECTIVES: PD-1+CXCR5-CD4+T peripheral helper (Tph) cells, a recently identified T cell subset, are proven to promote B cell responses and antibody production in rheumatoid arthritis, but their role in the pathogenesis of SLE is unknown. We explored the role of Tph in lupus disease development. METHODS: This cohort study included 68 patients with SLE and 41 age- and sex-matched healthy individuals. The frequency of PD-1+CXCR5-CD4+T cells was analysed in peripheral blood by flow cytometry. Inducible T-cell costimulator, CD38, MHC-II, IL-21, CXCR3 and CCR6 expression were measured in Tph cells. Comparisons between the two groups were performed, and correlations between Tph cells and other parameters were investigated. RESULTS: We revealed a markedly expanded population of Tph cells (8.31 ± 5.45 vs 2.86 ± 1.31%, P < 0.0001) in the circulation of patients with SLE (n = 68), compared with healthy controls (n = 41). Tph cells were much higher in the active group than in the inactive group (14.21 ± 5.21 vs 5.49 ± 2.52%, P < 0.0001). Tph cells were significantly associated with SLEDAI score (r = 0.802), ESR (r = 0.415), IgG (r = 0.434), C3 (r = -0.543), C4 (r = -0.518) and IL-21 level (r = 0.628), and ANA titre (r = 0.272). Furthermore, Tph cells were much higher in lupus patients with arthritis, nephritis, rash, alopecia, pleuritis, pericarditis and haematological involvement. Tph cells were associated with CD138+/CD19+ plasma cells (r = 0.518). Furthermore, MHC-II, inducible T-cell costimulator, CD38, and IL-21 expression were all higher in Tph cells from SLE patients compared with healthy controls. CXCR3+CCR6-Tph (Tph1) cells were expanded in the SLE patients. CONCLUSION: Our data show that relative number of Tph cells is correlated with disease measures in patients with SLE, suggesting an important role in lupus disease development.

Abdominal pain, unconsciousness, and skin rash after lung transplantation.

Long-term success of lung transplantation is limited by allograft dysfunction and frequent infections. Varicella zoster virus infection (VZV) is one of the most common opportunistic infections among solid organ transplantation recipients. However the occurrence of visceral involvement or disseminated disease, as seen after bone marrow transplantation, is rare. We report a case of a 59-year-old woman who underwent double-lung transplantation with a fatal visceral and disseminated varicella zoster virus infection.

An Unusual Cause of Fever and Rash in a Child With Severe Aplastic Anemia.

A 4-year-old girl with severe aplastic anemia and 2 previous failed T-depleted haploidentical peripheral blood stem cell transplants developed persistent neutropenic fever and multiple erythematous maculopapular rashes 2 days after her third T-replete haploidentical bone marrow transplant. Skin biopsy confirmed the diagnosis of Trichosporon asahii infection. She was on caspofungin prophylaxis which is not effective against Trichosporon. A high index of suspicion, prompt investigation, and appropriate treatment with voriconazole for 4 months was instrumental in controlling the infection and she remains well presently 9 months posttransplant with full donor chimerism and free from infection.

Immunohistochemical Demonstration of Parvovirus B19 Viral Protein 2 in Periflexural Exanthema in an Adult, Supporting Antibody-Dependent Enhancement as Means of Endothelial Uptake of the Virus.

Human parvovirus B19 (B19V) causes a number of skin exanthemas and has been related to both cutaneous and systemic diseases. Tropism of the virus for the rapidly proliferating erythroid progenitor cells in the bone marrow and fetal liver explains the pathogenesis of anemia and fetal hydrops. The cutaneous lesions of erythema infectiosum and other B19V-related exanthemas have been attributed to the deposition of immune complexes in the skin. We report on the immunohistochemical detection of B19V protein in the cytoplasm of dermal endothelial cells in a case of periflexural exanthema in a 28-year-old woman. An antibody-dependent enhancement mechanism of entry has been suggested for B19V in myocardial endothelial cells and could also be involved in B19V-related exanthemas.

T-Lymphoblastic Leukemia/Lymphoma With Annular Skin Rash and Epidermotropism.

Leukemia cutis is uncommon in patients with acute lymphoblastic leukemia. It typically presents with dermal papules or subcutaneous nodules, with no epidermal or upper papillary dermal involvement on histopathology. We present an unusual clinical presentation of leukemia cutis, with annular plaques and epidermotropism.

Drug-specific CD4+ T-cell immune responses are responsible for antituberculosis drug-induced maculopapular exanthema and drug reaction with eosinophilia and systemic symptoms syndrome.

BACKGROUND: A multidrug regimen including isoniazid, rifampicin, pyrazinamide and ethambutol is commonly used as first-line treatment for tuberculosis. However, this regimen can occasionally result in severe adverse drug reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome and drug-induced liver injury. The culprit drug and mechanistic basis for the hypersensitive reaction are unknown. OBJECTIVES: To investigate drug-specific T-cell responses in patients with antituberculosis drug (ATD)-induced cutaneous hypersensitivity and its underlying mechanism. METHODS: We enrolled eight patients with ATD-induced maculopapular exanthema and DRESS and performed a lymphocyte transformation test. Subsequently, drug-specific T-cell clones were generated from four of the patients who showed proliferation in response to ATDs. We measured the drug-specific proliferative responses and counted the drug-specific interferon (IFN)-γ/granzyme B-producing cells after drug stimulation. Antihuman leukocyte antigen (HLA) class I and class II blocking antibodies were used to analyse human leukocyte antigen-restricted T-cell responses. RESULTS: Positive proliferative responses to ATDs were mostly found in patients with cutaneous hypersensitivity. Furthermore, we isolated isoniazid/rifampicin-specific T cells from patients, which consisted primarily of CD4+ T cells. Drug-specific CD4+ T cells proliferated and secreted IFN-γ/granzyme B when stimulated with isoniazid or rifampicin, respectively. Isoniazid-responsive T-cell clones did not proliferate in the presence of rifampicin and vice versa. Drug-specific T-cell responses were blocked in the presence of anti-HLA class II antibodies. CONCLUSIONS: This study identifies the presence of isoniazid/rifampicin-specific T cells in patients with ATD-induced maculopapular exanthema and DRESS. Furthermore, it highlights the important role of drug-specific T-cell immune responses in the pathogenesis of these reactions.

Annular Eruptive Pseudoangiomatosis and Adenovirus Infection: A Novel Clinical Variant of Paraviral Exanthems and a Novel Virus Association.

Eruptive pseudoangiomatosis is a distinct exanthem thought to be caused by viruses. The usual rash configu-ration is erythematous papules and macules. An association with echovirus infection has been reported. We present here one adult and one child with this exanthem, supported by clinical, histopathological, and immunohistochemical findings. Both patients presented with prodromal symptoms, widespread angioma-like macules in annular configuration, blanchable telangiectasia, followed by spontaneous remission in 6-8 weeks. Lesional histopathology of the adult patient revealed dilated dermal blood vessels and lymphohistiocytic infiltrates predominated by CD4+ lymphocytes with a 5:1 ratio of CD4:CD8 lymphocytes. No B cells or CD56+ natural killer cells were found. Serology of both patients revealed evidence of active infections by adenoviruses, and a range of other viruses were excluded. We believe that these 2 patients manifested annular eruptive pseudoangio-matosis, a novel variant of the rash with a probable adenovirus association that has not yet been reported.

Lichenoid drug eruption induced by colchicine: case report.

Lichenoid drug eruption (LDE) is a common cutaneous side effect of drugs including antimalarials, antihypertensives, nonsteroids, anti-inflammatory drugs and diuretics. The physiopathologic relationship between colchicine treatment and LDE is unclear. There is very little documentation of LDE induced by colchicine in the literature. In this report, we present a case that developed LDE on the abdomen and the legs during the colchicine treatment.

Prognostic implications of active discoid lupus erythematosus and malar rash at the time of diagnosis of systemic lupus erythematosus: Results from a prospective cohort study.

OBJECTIVE: Cutaneous lupus erythematosus (CLE) may have prognostic implications for systemic lupus erythematosus (SLE). We aimed to determine the impact of discoid lupus erythematosus (DLE) and malar rash on SLE disease activity. METHODS: Data were analyzed from the Toronto Lupus Clinic prospective cohort study. We compared SLE patients with active DLE or malar rash at SLE diagnosis to SLE patients who never developed CLE. Outcomes were assessed at one and five years, including Adjusted Mean Systemic Lupus Erythematosus Disease Activity Index 2000 (AMS). RESULTS: A total of 524 SLE patients (284 without CLE, 65 with DLE, and 175 with malar rash) were included. Mean AMS scores in patients without CLE at one and five years were 5.96 ± 5.06 and 4.00 ± 3.52, which did not differ significantly from scores at one (6.93 ± 5.31, p = 0.17) and five years (4.29 ± 2.62, p = 0.63) in the DLE group. In patients with malar rash, AMS scores at one (8.30 ± 6.80, p < 0.001) and five years (5.23 ± 3.06, p = 0.004) were higher than controls without CLE. CONCLUSIONS: Malar rash may be a marker of more severe systemic disease over time, while DLE has no significant impact on general SLE disease activity.

Evaluation of engraftment syndrome in children following full-matched related donor hematopoietic stem cell transplantations.

The term "ES" has been widely used for describing a clinical condition consisting of skin rash, fever, and weight gain that occur during neutrophil recovery period following HSCT. In this study, the incidence, clinical features, risk factors, and outcomes of ES were evaluated in 169 children following allogeneic HSCT from full-matched related donor according to the Spitzer criteria. Seventeen patients (10.1%) presented with clinical conditions suggesting ES. In both univariate and multivariate analysis underlying malignant disease and early release of monocytes to the PB, and in univariate analysis using only CsA for GVHD prophylaxis were found to be the significant risk factors for the development of ES. Patients with ES experienced significantly higher incidence of acute and chronic GVHD and propensity toward a higher rate of TRM. OS did not differ between the patient groups. Thirteen of 17 patients received steroid therapy, and all but one patient responded to therapy. Monitoring for early detection of ES and early intervention with steroid therapy is the key for recovery. The most crucial approach for this purpose mainly is to find out and use the most useful and feasible diagnostic criteria for routine medical practice.

Engraftment Syndrome after Autologous Stem Cell Transplantation: An Update Unifying the Definition and Management Approach.

Engraftment syndrome (ES) encompasses a continuum of periengraftment complications after autologous hematopoietic stem cell transplantation. ES may include noninfectious fever, skin rash, diarrhea, hepatic dysfunction, renal dysfunction, transient encephalopathy, and capillary leak features, such as noncardiogenic pulmonary infiltrates, hypoxia, and weight gain with no alternative etiologic basis other than engraftment. Given its pleiotropic clinical presentation, the transplant field has struggled to clearly define ES and related syndromes. Here, we present a comprehensive review of ES in all documented disease settings. Furthermore, we discuss the proposed risk factors, etiology, and clinical relevance of ES. Finally, our current approach to ES is included along with a proposed treatment algorithm for the management of this complication.