Drug-Induced Hypersensitivity Syndrome/Drug Reaction With Eosinophilia and Systemic Symptoms: Predictive Score and Outcomes.

BACKGROUND: We previously developed a drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) severity (DDS) score that may predict DIHS/DRESS-associated complications (DACs), including myocarditis, gastrointestinal bleeding, and autoimmune diseases. OBJECTIVE: To externally confirm the predictive accuracy of the DDS score, clarify its ability to identify patients at high risk of DACs and fatal outcome, and determine which treatments might reduce or increase the risk. METHODS: We conducted a nationwide multicenter retrospective study in which we followed 48 patients with DIHS/DRESS at 5 university hospitals in Japan for 1 year after onset. Patients were divided into mild, moderate, and severe DIHS/DRESS groups depending on their early DDS score. RESULTS: Eight cases had DACs in the severe group (n = 17); no DACs were observed in the mild group (n = 12). Receiver-operating characteristic curve analysis showed that a cutoff DDS score of ≥4.0 and ≤2.0 could differentiate patients who would and would not develop DACs, respectively. In the moderate-to-severe disease groups, DACs occurred only in patients who received corticosteroids and not in those who received supportive care. None of the patients who received early treatment for cytomegalovirus developed DACs. Autoimmune DACs were significantly more common in patients who received pulse corticosteroid therapy. Four deaths occurred within the 1-year follow-up; all were in patients with infectious DACs who received systemic corticosteroids. CONCLUSION: Our scoring system allows early identification of patients at increased risk for DACs. Risk factors for DACs include systemic or pulse corticosteroid therapy.

Pathological role of regulatory T cells in the initiation and maintenance of eczema herpeticum lesions.

It remains unknown why the occurrence of eczema herpeticum (EH) caused by an extensive disseminated cutaneous infection with HSV-1 or HSV-2 is associated with the exacerbation of atopic dermatitis lesions after withdrawal of treatment. Although regulatory T cells (Tregs) limit the magnitude of HSV-specific T cell responses in mice, their role in the induction and resolution of EH has not been defined. We initially investigated the frequencies, phenotype, and function of Tregs in the peripheral blood of atopic dermatitis with EH (ADEH) patients at onset and after clinical resolution, atopic dermatitis patients without EH, and healthy controls. Tregs with the skin-homing phenotype and the activated/induced phenotype were expanded at onset and contracted upon resolution. Treg-suppressive capacity was retained in ADEH patients and, the expanded Tregs suppressed IFN-γ production from HSV-1-specific CD8(+) and CD4(+) T cells. The increased frequency of CD14(dim)CD16(+) proinflammatory monocytes (pMOs) was also observed in the blood and EH skin lesions. Thus, pMOs detected in ADEH patients at onset were characterized by an increased ability to produce IL-10 and a decreased ability to produce proinflammatory cytokines, unlike their normal counterparts. Our coculture study using Tregs and pMOs showed that the pMOs can promote the expansion of inducible Tregs. Tregs were detected frequently in the vicinity of HSV-expressing and varicella zoster virus-expressing CD16(+) monocytes in the EH lesions. Expansions of functional Tregs, together with pMOs, initially required for ameliorating excessive inflammation occurring after withdrawal of topical corticosteroids could, in turn, contribute to the initiation and progression of HSV reactivation, resulting in the onset of EH.

A syringotropic variant of cutaneous sarcoidosis: presentation of 3 cases exhibiting defective sweating responses.

BACKGROUND: Although nodular collections of epithelioid histiocytes and multinuclear cells can be present at all levels of the dermis in cutaneous sarcoidosis, sarcoidal granulomas characterized by marked syringotropism of epithelioid histiocytes have not been previously reported to our knowledge. OBJECTIVE: We sought to determine whether syringotropic sarcoidosis bears characteristic clinical and histologic features and exhibits defective sweating responses. METHODS: We investigated the clinical, histologic, and immunohistochemical features of syringotropic sarcoidosis, and sweating responses to thermal stress in 3 patients. RESULTS: Multiple erythematous patches/plaques predominantly affected the extensor aspect of the lower legs and thighs. Immunohistochemical analyses of the sweat glands surrounded by syringotropic granulomas exhibited profoundly decreased expression of dermcidin and aquaporin 5, both of which are constitutively expressed in sweat glands of control subjects, suggesting functional defects. Indeed, sweating responses to thermal stress were markedly decreased in the involved area, as compared with those in the uninvolved area and in healthy control subjects. LIMITATIONS: There were a limited number of cases in our study. CONCLUSION: A syringotropic variant of cutaneous sarcoidosis might be a distinct entity clinically and histologically or represent an abortive variant.

Increased susceptibility to cutaneous viral infections in atopic dermatitis: the roles of regulatory T cells and innate immune defects.

Much attention has been focused on the elucidation of mechanisms whereby atopic dermatitis (AD) skin lesions are especially susceptible to certain viral infections, such as herpes simplex virus (HSV). Although one of the most likely hypotheses is that the primary defect is in an impaired epidermal barrier function, alternative hypotheses include an imbalance between antiviral immune responses and regulatory T (T(reg)) cells, and the defects in the innate immune system. Eczema herpeticum (EH) occurs almost exclusively in patients with AD, particularly in those who fail to control skin inflammation. According to our scenario, expansions of T(reg) cells would be initially required for preventing such excessive inflammation resulting from the failure, and the expansions could in turn contribute to HSV reactivation, resulting in the initiation and progression of EH. A selective impairment of Toll-like-receptor-2-mediated proinflammatory cytokine production by monocytes could be the additional mechanism responsible for the increased susceptibility of AD subjects to curtain viral infections. Here we provide several potential explanations for why AD patients are at greater risk for eczema molluscatum.

Relationship between cytomegalovirus reactivation and dermatomyositis.

Dermatomyositis (DM) is an autoimmune disease manifested by muscle weakness and characteristic cutaneous eruptions. Cytomegalovirus (CMV) belongs to the ß-herpesvirinae subfamily of herpesviridae that cause morbidity and mortality in immunocompromised patients. With respect to the relationship between CMV and DM, it remains unknown whether CMV plays a pathogenetic role or whether CMV disease is an opportunistic infection due to immunosuppressive treatment. We report two patients with DM who developed cutaneous CMV ulcers within one month after the initiation of systemic corticosteroid treatment. In this context, we retrospectively studied the clinical characteristics of six DM patients with CMV reactivation and the effect of corticosteroid treatment on CMV reactivation in these patients. We also examined possible predictive parameters of CMV reactivation during the course of DM. Our results suggest that CMV reactivation occurs more frequently in DM patients than previously recognized; CMV reactivation occurs regardless of the dosage and duration of corticosteroid administration or the presence of underlying disease. Furthermore, our study shows that a reduction in platelets, serum globulin and IgG levels during the course of DM may be useful predictive parameters for CMV reactivation in patients with DM.

Recognition of immune reconstitution syndrome necessary for better management of patients with severe drug eruptions and those under immunosuppressive therapy.

The immune reconstitution syndrome (IRS) is an increasingly recognized disease concept and is observed with a broad-spectrum of immunosuppressive therapy-related opportunistic infectious diseases and severe drug eruptions complicated by viral reactivations. Clinical illness consistent with IRS includes tuberculosis, herpes zoster, herpes simples, cytomegalovirus infections and sarcoidosis: thus, the manifestations of this syndrome and diverse and depend on the tissue burden of the preexisting infectious agents during the immunosuppressive state, the nature of the immune system being restored, and underlying diseases of the hosts. Although IRS has originally been reported to occur in the setting of HIV infection, it has become clear that the development of IRS can also be in HIV-negative hosts receiving immunosuppressive agents, such as prednisolone and tumor necrosis factor α inhibitors, upon their reduction and withdrawal. Drug-induced hypersensitivity syndrome, a life-threatening multiorgan system reaction, is another manifestation of the newly observed IRS. Clinical recognition of the IRS is especially important in improving the outcome for diseases with an otherwise life-threatening progenosis. Clinicians should be aware of the implications of IRS and recognize that relieving the symptoms and signs of immune recovery by anti-inflammatory therapies needs to be balanced with anti-microbial therapies aiming at reducing the amplitude and duration of tissue burden of preexisting microbes.