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J Exp Med ; 216(9): 2038-2056, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31217193


Autosomal recessive IRF7 and IRF9 deficiencies impair type I and III IFN immunity and underlie severe influenza pneumonitis. We report three unrelated children with influenza A virus (IAV) infection manifesting as acute respiratory distress syndrome (IAV-ARDS), heterozygous for rare TLR3 variants (P554S in two patients and P680L in the third) causing autosomal dominant (AD) TLR3 deficiency. AD TLR3 deficiency can underlie herpes simplex virus-1 (HSV-1) encephalitis (HSE) by impairing cortical neuron-intrinsic type I IFN immunity to HSV-1. TLR3-mutated leukocytes produce normal levels of IFNs in response to IAV. In contrast, TLR3-mutated fibroblasts produce lower levels of IFN-ß and -λ, and display enhanced viral susceptibility, upon IAV infection. Moreover, the patients' iPSC-derived pulmonary epithelial cells (PECs) are susceptible to IAV. Treatment with IFN-α2b or IFN-λ1 rescues this phenotype. AD TLR3 deficiency may thus underlie IAV-ARDS by impairing TLR3-dependent, type I and/or III IFN-mediated, PEC-intrinsic immunity. Its clinical penetrance is incomplete for both IAV-ARDS and HSE, consistent with their typically sporadic nature.

Eur J Pediatr ; 178(8): 1275-1281, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230197


Immunoglobulin A (IgA) vasculitis (Henoch-Schonlein purpura (HSP)) is the most common vasculitis in children. It is characterized by purpuric rash, arthritis, gastrointestinal, and/or renal involvement. Spontaneous resolution is the typical outcome. In chronic cutaneous manifestations of IgA vasculitis, dapsone seems to show a good effectiveness. Multiple case reports and case series about dapsone in chronic IgA vasculitis are available. However, no clear evaluation of its indications, its effectiveness, or its usage guidelines (optimal dosage or duration of treatment) is available. We reviewed the published cases of IgA vasculitis treated by dapsone and compared them with 2 similar cases that we encountered. Seventeen patients (ranging from 22 months old to 16 years old) with severe or persistent clinical signs of IgA vasculitis were included. Dapsone showed good results on the resolution of cutaneous lesions but not on renal manifestations. Complications (methemoglobinemia) were observed on 1 patient. Half of the patients relapsed after treatment discontinuation. The difference between the time lapse before initiation and the duration of the treatment was not significant.Conclusion: We suggest that dapsone can have a positive effect in chronic IgA vasculitis when cutaneous manifestations last more than 6 weeks at the dosage of 1-2 mg/kg once per day during 1 week. What is Known: • IgA vasculitis or Henoch-Schonlein purpura is the most common vasculitis in children and affects mostly small vessels of the skin, kidney, and gastrointestinal tract. It resolves spontaneously in most of the cases. Exceptionally, cutaneous lesions can last several weeks. • Dapsone is a bacteriostatic antibacterial sulfonamide drug found to be effective in the treatment of some inflammatory dermatological diseases like IgA vasculitis. What is New: • Dapsone is effective against chronic purpuric lesion (> 6 weeks) at the minimal dose of 1 mg/kg/day. • Relapse occurs frequently after discontinuation but responds after a second course of treatment. A longer duration of treatment or a delay in treatment by dapsone does not seem to influence the relapse rate.