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F1000Research 2020Stevens-Johnson syndrome and toxic epidermal necrolysis are rare severe blistering skin reactions triggered by medications or infections. Over the last 5 to 10 years, a... (Review)
Review
Stevens-Johnson syndrome and toxic epidermal necrolysis are rare severe blistering skin reactions triggered by medications or infections. Over the last 5 to 10 years, a number of important publications have advanced understanding of these diseases and their response to treatment. Importantly, a subset of patients with disease triggered by infection has been identified as having Mycoplasma pneumoniae-induced rash and mucositis, suggesting a reconsideration of the diagnostic paradigm. We present an update on pediatric Stevens-Johnson syndrome and toxic epidermal necrolysis in the broader context of cutaneous adverse drug reactions and focus on challenges and recent advances in diagnosis, management, and prevention.
Topics: Child; Humans; Stevens-Johnson Syndrome
PubMed: 32850118
DOI: 10.12688/f1000research.20419.1 -
The Journal of Allergy and Clinical... May 2022Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is one example of a severe delayed T-cell-mediated adverse drug...
Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) is one example of a severe delayed T-cell-mediated adverse drug reaction. DIHS/DRESS presents with fever, widespread rash and facial edema, organ involvement, and hematological abnormalities, including eosinophilia and atypical lymphocytosis. DIHS/DRESS is associated with relapse 2 to 4 weeks after acute symptoms, often coinciding with reactivation of prevalent chronic persistent human herpesviruses such as human herpesvirus 6, EBV, and cytomegalovirus. The mortality of DIHS/DRESS is up to 10% and often related to unrecognized myocarditis and cytomegalovirus complications, with longer-term consequences that contribute to morbidity including autoimmune diseases such as thyroiditis. It is essential that all potential drug causes, including all new drugs introduced within the 8 weeks preceding onset of DIHS/DRESS symptoms, are identified. All potential drug culprits, as well as drugs that are closely related structurally to the culprit drug, should be avoided in the future. Systemic corticosteroids have remained the mainstay for the treatment of DIHS/DRESS with internal organ involvement. Steroid-sparing agents, such as cyclosporine, mycophenolate mofetil, and monthly intravenous immune globulin, have been successfully used for treatment, and careful follow-up for cytomegalovirus reactivation is recommended. Strong associations between HLA class I alleles and DIHS/DRESS predisposition include HLA-B∗13:01 and dapsone, HLA-B∗58:01 and allopurinol, and HLA-B∗32:01 and vancomycin. These have opened a pathway for prevention, risk stratification, and earlier diagnosis. Single-cell sequencing and other studies of immunopathogenesis promise to identify targeted treatment approaches.
Topics: Cytomegalovirus; Drug Hypersensitivity Syndrome; Eosinophilia; Exanthema; Herpesvirus 6, Human; Humans
PubMed: 35176506
DOI: 10.1016/j.jaip.2022.02.004 -
Journal of the American Academy of... Nov 2020Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related... (Review)
Review
Immune checkpoint inhibitors have emerged as a pillar in the management of advanced malignancies. However, nonspecific immune activation may lead to immune-related adverse events, wherein the skin and its appendages are the most frequent targets. Cutaneous immune-related adverse events include a diverse group of inflammatory reactions, with maculopapular rash, pruritus, psoriasiform and lichenoid eruptions being the most prevalent subtypes. Cutaneous immune-related adverse events occur early, with maculopapular rash presenting within the first 6 weeks after the initial immune checkpoint inhibitor dose. Management involves the use of topical corticosteroids for mild to moderate (grades 1-2) rash, addition of systemic corticosteroids for severe (grade 3) rash, and discontinuation of immunotherapy with grade 4 rash. Bullous pemphigoid eruptions, vitiligo-like skin hypopigmentation/depigmentation, and psoriasiform rash are more often attributed to programmed cell death-1/programmed cell death ligand-1 inhibitors. The treatment of bullous pemphigoid eruptions is similar to the treatment of maculopapular rash and lichenoid eruptions, with the addition of rituximab in grade 3-4 rash. Skin hypopigmentation/depigmentation does not require specific dermatologic treatment aside from photoprotective measures. In addition to topical corticosteroids, psoriasiform rash may be managed with vitamin D analogues, narrowband ultraviolet B light phototherapy, retinoids, or immunomodulatory biologic agents. Stevens-Johnson syndrome and other severe cutaneous immune-related adverse events, although rare, have also been associated with checkpoint blockade and require inpatient care as well as urgent dermatology consultation.
Topics: Drug Eruptions; Humans; Immune Checkpoint Inhibitors; Neoplasms
PubMed: 32454097
DOI: 10.1016/j.jaad.2020.03.132 -
American Journal of Clinical Dermatology May 2021Erythema nodosum is the most common form of panniculitis and is characterized by tender erythematous nodules mainly in the lower limbs on the pretibial area. The exact... (Review)
Review
Erythema nodosum is the most common form of panniculitis and is characterized by tender erythematous nodules mainly in the lower limbs on the pretibial area. The exact cause of erythema nodosum is unknown, although it appears to be a hypersensitivity response to a variety of antigenic stimuli. Although the etiology is mostly idiopathic, ruling out an underlying disease is imperative before diagnosing primary erythema nodosum. Erythema nodosum can be the first sign of a systemic disease that is triggered by a large group of processes, such as infections, inflammatory diseases, neoplasia, and/or drugs. The most common identifiable causes are streptococcal infections, primary tuberculosis, sarcoidosis, Behçet disease, inflammatory bowel disease, drugs, and pregnancy. We propose a diagnostic algorithm to optimize the initial work-up, hence initiating prompt and accurate management of the underlying disease. The algorithm includes an initial assessment of core symptoms, diagnostic work-up, differential diagnosis, and recommended therapies. Several treatment options for the erythema nodosum lesions have been previously reported; nevertheless, these options treat the symptoms, but not the triggering cause. Making an accurate diagnosis will allow the physician to treat the underlying cause and determine an optimal therapeutic strategy.
Topics: Anti-Inflammatory Agents; Diagnosis, Differential; Drug Therapy, Combination; Erythema Nodosum; Humans; Incidence; Skin; Treatment Outcome
PubMed: 33683567
DOI: 10.1007/s40257-021-00592-w -
Clinical Reviews in Allergy & Immunology Jun 2022Hypersensitivity reactions including IgE-mediated and delayed cell-mediated reactions to aminoglycosides, clindamycin, linezolid, and metronidazole are rare. For... (Review)
Review
Hypersensitivity reactions including IgE-mediated and delayed cell-mediated reactions to aminoglycosides, clindamycin, linezolid, and metronidazole are rare. For aminoglycosides, allergic contact dermatitis is the most frequent reaction for which patch testing can be a useful step in evaluation. For clindamycin, delayed maculopapular exanthems are the most common reactions. There are case reports of clindamycin associated with drug rash with eosinophilia and systemic symptoms (DRESS), acute generalized exanthematous pustulosis (AGEP), acute febrile neutrophilic dermatosis, and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). For linezolid, cases of hypersensitivity were exceedingly rare and included urticaria, angioedema, anaphylaxis, delayed rashes, and DRESS. For metronidazole, only rare cases were found across a broad spectrum of reactions including allergic contact dermatitis, fixed drug eruption, angioedema, anaphylaxis, serum sickness-like reaction, SJS/TEN, AGEP, SDRIFE, and a possible case of DRESS. IgE-mediated reactions and anaphylaxis to these types of antibiotics are uncommon, and reports of skin testing concentrations and desensitization protocols are largely limited to case reports and series. Non-irritating skin testing concentrations have been reported for gentamycin, tobramycin, and clindamycin. Published desensitization protocols for intravenous and inhaled tobramycin, oral clindamycin, intravenous linezolid, and oral and intravenous metronidazole have also been reported and are reviewed.
Topics: Aminoglycosides; Anaphylaxis; Angioedema; Anti-Bacterial Agents; Clindamycin; Dermatitis, Allergic Contact; Drug Eruptions; Drug Hypersensitivity; Eosinophilia; Humans; Hypersensitivity, Delayed; Immunoglobulin E; Linezolid; Metronidazole; Tobramycin
PubMed: 34910281
DOI: 10.1007/s12016-021-08878-x -
Clinical Reviews in Allergy & Immunology Dec 2021Adverse drug reactions involving the skin are commonly known as drug eruptions. Severe drug eruption may cause severe cutaneous adverse drug reactions (SCARs), which are... (Review)
Review
Adverse drug reactions involving the skin are commonly known as drug eruptions. Severe drug eruption may cause severe cutaneous adverse drug reactions (SCARs), which are considered to be fatal and life-threatening, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Although cases are relatively rare, approximately 2% of hospitalized patients are affected by SCARs. There is an incidence of 2 to 7 cases/million per year of SJS/TEN and 1/1000 to 1/10,000 exposures to offending agents result in DRESS. However, the mortality rate of severe drug eruptions can reach up to 50%. SCARs represent a real medical emergency, and early identification and proper management are critical to survival. The common pathogenesis of severe drug eruptions includes genetic linkage with HLA- and non-HLA-genes, drug-specific T cell-mediated cytotoxicity, T cell receptor restriction, and cytotoxicity mechanisms. A multidisciplinary approach is required for acute management. Immediate withdrawal of potentially causative drugs and specific supportive treatment is of great importance. Immunoglobulins, systemic corticosteroids, and cyclosporine A are the most frequently used treatments for SCARs; additionally, new biologics and plasma exchange are reasonable strategies to reduce mortality. Although there are many treatment methods for severe drug eruption, controversies remain regarding the timing and dosage of drug eruption. Types, dosages, and indications of new biological agents, such as tumor necrosis factor antagonists, mepolizumab, and omalizumab, are still under exploration. This review summarizes the clinical characteristics, risk factors, pathogenesis, and treatment strategies of severe drug eruption to guide clinical management.
Topics: Drug Eruptions; Humans; Risk Factors; Severity of Illness Index
PubMed: 34273058
DOI: 10.1007/s12016-021-08859-0 -
Allergology International : Official... Jul 2019The aim of this review was to provide an updated overview of drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS).... (Review)
Review
The aim of this review was to provide an updated overview of drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS). Several new insights have been made, particularly with regards to the diagnosis, pathogenesis and care of some important complications and sequelae. The indication of herpesvirus reactivations in diagnosis in the assessment of disease severity is now better specified. Nevertheless, because fatal complications and autoimmune sequelae have been under-recognized, there is a clear need to identify effective parameters for assessing disease severity and predicting prognosis of the disease in the early phase. In this regard, we have established a scoring system that can be used to monitor severity, predict prognosis and stratify the risk of developing severe complications including fatal cytomegalovirus (CMV) disease. Regulatory T cells are likely to be central to the mechanism and would represent potential targets for therapeutic approaches that can ameliorate inflammatory responses occurring at the acute phase while preventing the subsequent development of harmful outcomes, such as CMV disease and autoimmune diseases.
Topics: Adrenal Cortex Hormones; Autoimmune Diseases; Drug Hypersensitivity Syndrome; Herpesviridae; Humans; Prognosis; Severity of Illness Index; T-Lymphocytes, Regulatory; Virus Activation
PubMed: 31000444
DOI: 10.1016/j.alit.2019.03.006 -
F1000Research 2020Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane.... (Review)
Review
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by detachment of the epidermis and mucous membrane. SJS/TEN are considered to be on the same spectrum of diseases with different severities. They are classified by the percentage of skin detachment area. SJS/TEN can also cause several complications in the liver, kidneys, and respiratory tract. The pathogenesis of SJS/TEN is still unclear. Although it is difficult to diagnose early stage SJS/TEN, biomarkers for diagnosis or severity prediction have not been well established. Furthermore, optimal therapeutic options for SJS/TEN are still controversial. Several drugs, such as carbamazepine and allopurinol, are reported to have a strong relationship with a specific human leukocyte antigen (HLA) type. This relationship differs between different ethnicities. Recently, the usefulness of HLA screening before administering specific drugs to decrease the incidence of SJS/TEN has been investigated. Skin detachment in SJS/TEN skin lesions is caused by extensive epidermal cell death, which has been considered to be apoptosis via the Fas-FasL pathway or perforin/granzyme pathway. We reported that necroptosis, i.e. programmed necrosis, also contributes to epidermal cell death. Annexin A1, released from monocytes, and its interaction with the formyl peptide receptor 1 induce necroptosis. Several diagnostic or prognostic biomarkers for SJS/TEN have been reported, such as CCL-27, IL-15, galectin-7, and RIP3. Supportive care is recommended for the treatment of SJS/TEN. However, optimal therapeutic options such as systemic corticosteroids, intravenous immunoglobulin, cyclosporine, and TNF-α antagonists are still controversial. Recently, the beneficial effects of cyclosporine and TNF-α antagonists have been explored. In this review, we discuss recent advances in the pathophysiology and management of SJS/TEN.
Topics: Apoptosis; Epidermis; Humans; Necrosis; Stevens-Johnson Syndrome
PubMed: 32595945
DOI: 10.12688/f1000research.24748.1 -
Pediatric Blood & Cancer Nov 2019Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a... (Review)
Review
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology.
Topics: Adult; Age of Onset; Child; Clinical Trials as Topic; Diagnosis, Differential; Disease Management; Drug Eruptions; Fetal Diseases; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Infant; Infant, Newborn; Liver Failure; Lymphohistiocytosis, Hemophagocytic; Macrophage Activation; Metabolism, Inborn Errors; Neoplasms; Phenotype; Sepsis
PubMed: 31339233
DOI: 10.1002/pbc.27929 -
Medicina (Kaunas, Lithuania) Sep 2021The similarity between pustular psoriasis (PP) and acute generalized exanthematous pustulosis (AGEP) poses problems in the diagnosis and treatment of these two... (Review)
Review
The similarity between pustular psoriasis (PP) and acute generalized exanthematous pustulosis (AGEP) poses problems in the diagnosis and treatment of these two conditions. Significant clinical and histopathologic overlap exists between PP and AGEP. PP is an inflammatory disorder that has numerous clinical subtypes, but all with sterile pustules composed of neutrophils. AGEP is a severe cutaneous adverse reaction that is also characterized by non-follicular sterile pustules. Clinical features that suggest a diagnosis of PP over AGEP include a history of psoriasis and the presence of scaling plaques. Histologically, eosinophilic spongiosis, vacuolar interface dermatitis, and dermal eosinophilia favor a diagnosis of AGEP over PP. Importantly, PP and AGEP vary in clinical course and treatment. PP treatment involves topical steroids, oral retinoids, and systemic immunosuppressants. Newer therapies targeting IL-36, IL-23, IL-1, and PDE-4 have been investigated. The removal of the offending agent is a crucial part of the treatment of AGEP.
Topics: Acute Generalized Exanthematous Pustulosis; Humans; Psoriasis; Skin
PubMed: 34684041
DOI: 10.3390/medicina57101004