Primary Generalized Glucocorticoid Resistance and Hypersensitivity Syndromes: A 2021 Update.

Glucocorticoids are the final products of the neuroendocrine hypothalamic-pituitary-adrenal axis, and play an important role in the stress response to re-establish homeostasis when it is threatened, or perceived as threatened. These steroid hormones have pleiotropic actions through binding to their cognate receptor, the human glucocorticoid receptor, which functions as a ligand-bound transcription factor inducing or repressing the expression of a large number of target genes. To achieve homeostasis, glucocorticoid signaling should have an optimal effect on all tissues. Indeed, any inappropriate glucocorticoid effect in terms of quantity or quality has been associated with pathologic conditions, which are characterized by short-term or long-lasting detrimental effects. Two such conditions, the primary generalized glucocorticoid resistance and hypersensitivity syndromes, are discussed in this review article. Undoubtedly, the tremendous progress of structural, molecular, and cellular biology, in association with the continued progress of biotechnology, has led to a better and more in-depth understanding of these rare endocrinologic conditions, as well as more effective therapeutic management.

Chemokines in Severe Cutaneous Adverse Reactions (SCARs).

Although the incidence of severe cutaneous adverse reactions (SCARs) to medications is very low, SCARs can result in disability or even death if they are not diagnosed and treated properly. As the rapid recognition of SCARs is essential, it is necessary to develop diagnostic markers for them that can also be used to assess severity and predict outcomes in the early phase. In addition, it is important to identify novel therapeutic targets for SCARs. Chemokines are chemotactic cytokines that control the migratory patterns and locations of immune cells and usually exhibit markedly specific associations with certain human diseases. In Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), the Th1-associated chemokines chemokine (C-X-C motif) ligand 9 (CXCL9) and CXCL10 predominate, while in drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS), the levels of the Th2-associated chemokines chemokine (C-C motif) ligand 17 (CCL17) and CCL22 are markedly elevated. We suggest that the distinct chemokine profiles of SJS/TEN and DIHS/DRESS can be used to aid their differential diagnosis. CXCL10 has also been reported to be associated with the development of long-term sequelae in DIHS/DRESS. This review focuses on the chemokines involved in the pathogenesis and adjuvant diagnosis of SCARs, particularly SJS/TEN and DIHS/DRESS, but also provides a brief overview of SCARs and the chemokine superfamily. As it is being increasingly recognized that an association exists between human herpesvirus 6 (HHV-6) and DIHS/DRESS, the possible roles of the chemokine/chemokine receptor homologs encoded by HHV-6 in the pathogenesis of DIHS/DRESS are also discussed.

Diclofenac-induced thrombotic thrombocytopenic purpura with concomitant complement dysregulation: a case report and review of the literature.

BACKGROUND: Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are two forms of thrombotic microangiopathies. They are characterized by severe thrombocytopenia, microangiopathic hemolysis, and thrombosis, leading to a systemic inflammatory response and organ failure. Plasmapheresis is used to treat thrombotic microangiopathies. A different entity known as atypical hemolytic uremic syndrome has garnered more clinical recognition because reported cases have described that it does not respond to standard plasmapheresis. Diclofenac potassium is a non-steroidal anti-inflammatory drug that is used to treat pain. CASE REPORT: A 35-year-old Hispanic man presented to our emergency department with complaints of generalized malaise, fever, and an evanescent skin rash. During admission, he reported the use of diclofenac potassium for back pain on a daily basis for 1 week. He was noted to have peripheral eosinophilia, so he was admitted for suspected drug reaction involving eosinophilia and systemic symptoms. His initial laboratory work-up showed microangiopathic hemolytic anemia and thrombocytopenia. He also experienced a seizure, encephalopathy, and had a PLASMIC score of 7, thus raising concerns for thrombotic thrombocytopenic purpura. He underwent emergent plasmapheresis, which improved his clinical condition. The diagnosis was confirmed by assessing the levels of disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13, which was less than 3%. In addition, his skin biopsy was positive for patchy complement deposition, demonstrating complement dysregulation. CONCLUSION: Thrombotic thrombocytopenic purpura is a rare condition that can be acquired. Our case is rare because it represents the first report of diclofenac potassium-induced thrombotic thrombocytopenic purpura with subjacent complement activation and dysregulation. Early recognition and aggressive management led to a favorable outcome.

Facial pustules due to drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms may histopathologically mimic eosinophilic pustular folliculitis: A case report.

Pustules with facial and/or neck edema is one characteristic feature of drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DIHS/DRESS) at the early stage. Although several retrospective histopathologic studies on DIHS/DRESS have been reported, the detailed histopathologic findings of facial pustules for DIHS/DRESS are unavailable. We herein report a case of DIHS/DRESS with facial pustules that was histopathologically similar to eosinophilic pustular folliculitis (EPF). Eosinophilic infiltration into expanded follicles and sebaceous glands, which is highly characteristic of EPF, was detected in pustules due to DIHS/DRESS in this case. There are numerous pathophysiological similarities between DIHS/DRESS and EPF, which may cause their histopathologic similarity. Our findings suggest that facial pustules of DIHS/DRESS may histopathologically mimic EPF.

Monocytes are involved in the balance between regulatory T cells and Th17 cells in severe drug eruptions.

BACKGROUND: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a distinct phenotype of severe drug eruptions characterized by sequential reactivations of herpesviruses. Although a progressive loss of suppressive function in regulatory T cells (Tregs) occurred during the course of DiHS/DRESS, but not in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), no previous studies investigated the mechanism. Given the recent finding that Treg development could be differentially regulated by CD16+ patrolling monocytes (pMOs) and CD14+ classical monocytes (cMOs), we can hypothesize that a differential fine-tuned interaction between Tregs and monocytes is the driving force behind the possible shift from Tregs to Th17 cells over a prolonged period of time in DiHS/DRESS. OBJECTIVE: To investigate whether the shift from Treg to Th17 could specifically occur during the course of DiHS/DRESS and to elucidate which subsets of monocytes could be involved in the shift. METHODS: We performed a prospective longitudinal study on the frequencies of Tregs, Th17 cells and monocyte subsets after onset of DiHS/DRESS and SJS/TEN, and long after their clinical resolutions. We next examined whether pMOs and cMOs could have a strong impact on the Th17/Treg differentiation and which cytokines could be crucial for the interaction between Th17/Tregs and MO subsets, by in vitro cocultures. RESULTS: Selective depletion of pMOs occurring at the acute stage of DiHS/DRESS was associated with the relative increase in the frequencies of cMOs producing IL-10 and it did drive Treg expansions. After clinical resolution, pMOs producing IL-6 were alternatively recruited and contributed to the eventual shift from a Treg to Th17 responses. CONCLUSIONS AND CLINICAL RELEVANCE: The gradual shift from Treg to Th17 cell development observed during the clinical course of DiHS/DRESS is mediated by the predominance of cMOs at the acute stage and alternatively recruited pMOs at the resolution stage, respectively.

Prevalence, risk factors, and mortality outcome in the drug reaction with eosinophilia and systemic symptoms patients with cardiac involvement.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe cutaneous drug reaction that can affect multiple internal organ systems. Cardiac involvement in DRESS syndrome (CiDs) is uncommon but can be life-threatening. OBJECTIVE: To determine the prevalence, risk factors, and mortality outcome of CiDs. MATERIAL AND METHODS: Forty-one patients who were diagnosed with probable and definite DRESS syndrome according to the RegiSCAR criteria were recruited. Cardiac involvement was evaluated by two independent cardiologists. RESULTS: The cardiac involvement was found in 8/41 (19.5%) patients. Specifically, myocardial involvement was found in five patients, while three patients had pericardial involvement. The majority of culprit drugs were antibiotics followed by anti-epileptic medications. The hemoglobin and albumin levels were significantly lower in the patients with CiDs when compared to the patients without CiDs (P-value = 0.005 for both factors). The mortality rate at 30 and 90 days was significantly higher among CiDs patients, that is, 3/8 (37.5%) versus 2/28 (6.1%); P-value = 0.02 and 4/8 (50.0%) versus 2/33 (6.1%); P-value = 0.002 respectively. CONCLUSION: Our study showed the prevalence of CiDs was as high as 19.5% with high mortality rate. We suggest a thorough cardiac evaluation in all DRESS patients with RegiSCAR score ≥4. The patients with CiDs had significantly lower hemoglobin and albumin levels, which might imply poor health condition, when compared to those without CiDs.

Overexpression of cytotoxic proteins correlates with liver function impairment in patients with drug reaction with eosinophilia and systemic symptoms (DRESS).

Drug reaction with eosinophilia and systemic symptoms (DRESS) is characterised by skin rash and multivisceral involvement. The liver is the organ most frequently affected and the degree of liver function impairment often correlates with the mortality rate of DRESS. We aimed to examine the expression of cytotoxic proteins, including soluble Fas ligand (sFasL), TNF-α, granulysin, perforin, and granzyme B in the sera and skin lesions of patients with DRESS and evaluate their clinical significance. Our cohort consisted of 21 patients with DRESS and control groups including 39 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis, 21 patients with maculopapular eruption, and 29 normal controls. Concentrations of cytotoxic proteins in the sera were measured using enzyme-linked immunosorbent assays. Tissue samples were also obtained from typical skin lesions, and immunohistochemical staining was conducted to assess the local expression of cytotoxic proteins. We found that sFasL and granzyme B were significantly overexpressed in the sera of DRESS patients compared to normal controls. Furthermore, the levels of sFasL, perforin, and granzyme B significantly correlated with the serum level of liver enzymes in DRESS patients. Immunohistochemical examination also showed overexpressed cytotoxic proteins in cutaneous DRESS lesions. Cytotoxic proteins may play a vital role in the pathogenesis of DRESS, and serum sFasL, perforin, and granzyme B may also be involved in liver function impairment in DRESS patients.

The immune response in trichloroethylene hypersensitivity syndrome: A review.

Trichloroethylene (TCE) has been used for a variety of industrial and consumer cleaning purposes because of its ability to dissolve organic substances. The multisystem injuries include those of skin, liver, and kidney, which are defined as TCE hypersensitivity syndrome (THS). THS is a serious occupational health issue. However, the mechanism of immune dysfunction leading to organ injury is poorly understood. Many studies reveal that skin lesions and organ injury caused by TCE are consistent with type IV hypersensitivity, also called delayed hypersensitivity, mediated by T cells. However, many researchers found T cell-mediated type IV hypersensitivity could not account for the pathogenesis of THS fully. Humoral immunity, including immunoglobulins and complement activation, may also play a possible role in THS pathogenesis. This review will describe the history, current understanding, and future research directions of the mechanism of THS.

Probable DRESS syndrome induced by IL-1 inhibitors.

Interleukin (IL)-1 inhibitors have been increasingly used for treating autoinflammatory diseases during the last 10 years, but the spectrum of their possible side effects is not yet fully known. Here, we bring physicians' attention to a new severe complication of IL-1 inhibitors, manifesting as a probable drug reaction with eosinophilia and systemic symptoms (DRESS) in two patients.

Histopathological study of six types of adverse cutaneous drug reactions using granulysin expression.

BACKGROUND: Few studies have been published on the histopathology of cutaneous adverse drug reactions (CADR), and most of these lack information on skin allergological tests. The histopathology of drug reaction with eosinophilia and systemic symptoms (DRESS) is also seldom described. The purpose of our study was to examine six types of well-documented CADR (maculopapular exanthema, DRESS, fixed drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis [TEN], and acute generalized exanthematous pustulosis) using histopathology and immunohistochemistry to evaluate the expression of granulysin, a key molecule in TEN. METHODS: We retrospectively included 106 skin biopsies performed in proven cases of CADR (by chronological investigation, single attributable drug, or/and skin tests). All slides were reviewed, and microscopic changes were analyzed using a standardized form. Granulysin expression was studied by immunohistochemistry. RESULTS: In DRESS, we observed spongiosis, edema, and basal vacuolization, with rare necrotic keratinocytes and constant lymphocytic infiltrate in the superficial dermis. Eosinophils were often present, and pustules were found in 15% of cases. Necrotic keratinocytes are often absent in maculopapular exanthema. Granulysin was expressed in six types of CADR with a trend toward more intense expression in DRESS and TEN. CONCLUSION: We detailed further about the histopathology of DRESS. Granulysin expression was observed in all CADR with a marked overlap of expression pattern between the six types.

Drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome: clinical features of 27 patients.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) [also called drug-induced hypersensitivity syndrome (DIHS)] includes severe reactions to drugs that need to be promptly recognized by physicians. AIM: To explore heterogeneity in the clinical presentation of DRESS/DIHS at a large academic hospital in Latin America, using the criteria defined by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system. METHODS: A retrospective medical record review of 60 patients with diagnostic suspicion of DRESS/DIHS admitted to our hospital between July 2008 and April 2012 was performed, including demographic data, clinical features, laboratory findings and treatment. RESULTS: Of the 60 patients, 27 fulfilled the criteria for DRESS/DIHS. Maculopapular exanthema (85.1%), fever (96.2%) and hepatic involvement (85.1%) were the most common features. Anticonvulsants were the most common causal drugs (77.7%); Phenytoin was the most common individual drug (44.4%), followed by carbamazepine (29.6%). All patients were treated initially with prednisone 1 mg/kg/day. Mortality rate was 4%. CONCLUSION: The major findings of this study (to our knowledge the largest collection of data on DRESS/DIHS in Latin America) include a positive statistical association between presence of atypical lymphocytes and higher levels of alanine aminotransferase (P < 0.001) and reinforce the importance of anticonvulsants in the pathogenesis of this severe reaction.

Monitoring the acute response in severe hypersensitivity reactions to drugs.

PURPOSE OF REVIEW: Severe adverse drug reactions (ADRs) including Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) are acute life-threatening conditions. There is the urgent need for reliable, noninvasive and standardized laboratory tests for identifying patients at higher risk of developing severe ADRs. RECENT FINDINGS: Although previous studies demonstrated the pathogenic role of TNF-α, IFN-γ, IL-10, perforin/granzyme B, Fas L and granulysin in the development of severe ADRs, there have been no biomarkers predicting progression to severe ADRs. We, therefore, measured serum levels of cytokines/chemokines as well as other biological markers in patients who presented with clinical symptoms suggestive of ADRs at their initial presentation. The results show that sFas L represents a useful early biomarker that can predict the subsequent progression to TEN, but not SJS, particularly when combined with the increase in IL-6 and IP-10. The increased levels of IL-6 and IP-10 are reliable biomarkers predictive of the progression to severe ADRs, such as SJS/TEN and DiHS/DRESS. SUMMARY: The use of a combination of several early biomarkers, although not sufficiently sensitive or specific on its own when used alone, could increase the diagnostic and prognostic utility for the prediction of severe ADRs.

Valproic acid derivatives signal for apoptosis and repair in vitro.

PURPOSE: To determine the cytotoxicity of valproic acid (VPA) and its derivatives in human hepatoblastoma (HepG2) cells, and to study the possible toxicity of these compounds in human lymphocytes from patients with known hypersensitivity syndrome reactions (HSRs) to other medication. METHODS: Cells were exposed to physiological doses of VPA, valnoctamide (VCD) and its one carbon homologue sec-Butyl-propyl-acetamide (SPD) for 2h and for 24h. Cell viability was measured using succinate dehydrogenase activity for hepatocytes and lymphocyte toxicity assay (LTA) for lymphocytes. Cytokines and apoptosis [cytokeratine 18 (cCK18-M30)] markers were quantitated by ELISA. RESULTS: VCD and SPD presented lower cytotoxicity compared to VPA in cultured HepG2 cells. SPD led to cytotoxicity in lymphocytes. VPA and its derivatives increased the release of interferon (IFN)-γ and tumor necrosis factor (TNF)-α in media, but had no influence on the release of either interleukin (IL)-1 or IL-6. Significant increases in the release of IFN-γ and TNF-α were observed in lymphocytes exposed to high doses of VPA, and this increased further with exposure time. SIGNIFICANCE: HepG2 cells exposed to VCD and SPD experienced lower direct cytotoxicity than those treated with VPA. Lymphocytes from patients that experienced HSR to other medication have shown cytotoxicity to VPA and its VPA derivatives-induced. High levels of pro-inflammatory cytokines were released in the cell culture media, suggesting that inflammation plays a key role in VPA-derivatives induced lymphocyte toxicity.