We report a case of dapsone hypersensitivity syndrome in a 42-year-old Chinese woman with borderline lepromatous leprosy that included life-threatening hypersensitivity pneumonitis and fulminant hepatitis. Zhang’s1 and Wang’s2 recent studies called our attention to this syndrome’s association with HLA*B13:01 (affecting amino acid residues 94, 95, and 145)1 in Chinese patients undergoing multi-drug treatment for leprosy; our patient was tested after the fact and indeed was HLA*B13:01 positive. In the future, all Chinese patients should be HLA*B13:01 tested prior to receiving dapsone. Furthermore, 13-27% of Australian aborigines, 1-21% of Chinese, 1-12% of Indians, 8-20% of Malaysians, 3-28% of Papuans, and up to 26% of Taiwanese3 are HLA*B13:01 positive. The cost of screening for HLA*B13:01 is only $118 (at Bellevue Hospital New York, NY) and pharmacogenetic testing has been similarly successfully used to reduce the risk of drug-induced hypersensitivity in HLA-B*5701 patients prior to starting abacavir4. HLA*B13:01 testing is clearly indicated in the Chinese population and consideration should be given for the above listed populations as well. We are continuing to study the cost effectiveness in these populations as HLA*B13:01 is in much lower incidence in the European population as is the association of dapsone hypersensitivity syndrome1.
While the mechanism of dapsone hypersensitivity syndrome is still unclear, this striking 21-fold relative risk of HLA*B13:01 for DIHS syndrome in leprosy supports an underlying T-cell mediated process. Two phases of dapsone hypersensitivity syndrome have been reported. In the acute phase, patients have been reported to have a transient decrease of serum total IgG, IgM, and anti-desmoglein1 just before the second phase as noted by reactivation of HHV-6.5 This transient cellular and humoral immunosuppression may trigger viral reactivation, which leads to the development of the second phase of dapsone hypersensitivity syndrome.5
Dapsone may first bind to the MHC class I molecule and then later elicit a strong CD8+ T-cell immune response. While the binding to the MHC-molecule may explain the association of DIHS to HLA*B13:01, a polymorphic CD4+ T-cell response would occur if dapsone interacts primarily with the T-cell receptor. As various MHC-class II molecules adequately provide T-cell stimulation, full stimulation likely occurs via common determinants of the MHC structure6.
Other immune mechanisms have been previously proposed highlighting the dramatic variability in the predominant T-cell population type with respect to time in the disease course7. Treg cells are comprised of different subsets, which limit inflammatory responses and are responsible for immune homeostasis8. One study has found a transient circulating clone T during the acute phase of DIHS9. Significant expansion of functional regulatory T cells has been observed in the acute stages of drug-induced hypersensitivity syndrome, followed by a gradual loss of regulatory T cells after resolution10,11. Additionally, CD8+ cells increased and CD4+ cells dramatically decreased throughout the syndrome course and especially with the HHV-6 reactivation-associated second wave of eruption (with or without hepatic dysfunction); neither express CD6912. CD8+ CLA+ T cells are produced and directed toward the skin.13 Th1 and Tc1 cells both increased and remained during recurrence and after, while Th2 and Tc2 cells decreased.12 CD8+ CCR4+ T cells migrate to the lungs, where CD4+ T cell produce IL-4 and IL-5 and CD4+Th17+ cells produce IL-17; this results in tissue and peripheral eosinophilia.13 Of note, upregulation of Th17 and its hallmark cytokine IL-17A has been associated with type II leprosy reactions14; it is unclear whether dapsone associated hypersensitivity syndrome phenotype may vary by the indication for dapsone use. While Th17 cells can produce IL-9; IL-9 can in turn promote the development of Th17 cells.15 Furthermore, recent reports elucidated the role of Th9 (producer of IL-9 and IL-10) in allergic and autoimmune inflammation, with the potential to modulate Treg function.16 Th9 must be further explored as a potential mediator in the pathogenesis of DIHS.
Dapsone has been thought to undergo bioactivation to create adducts to cellular proteins17. These adducted proteins initiate the immune response that leads to a drug hypersensitivity reaction.17 While keratinocytes may themselves present antigen to hapten-specific cytotoxic T lymphocytes, keratinocytes may also bioactivate dapsone to form drug-protein adducts. These adducts may be acquired by antigen-presenting cells upon keratinocyte cell death, evoking an immune response.18 Dendritic cells may additionally acquire haptenated proteins associated with drugs via uptake of reactive metabolites.19 Although dapsone hydroxylamine demonstrated significantly more potent cytotoxicity than sulfamethoxazole hydroxylamine, only KG-1 cells exposed to dapsone formed significant drug-protein adducts.19,20 Cytochromes P450 and cyclooxygenase do not play important roles in the bioactivation of dapsone, as they did not significantly attenuate protein adduction.17
Low numbers of circulating B cells and plasmacytoid dendritic cells (pDCs), and a decrease in the number of circulating natural killer cells are usually seen in DIHS21-23. pDCs induce B-cell maturation to produce IgG; however, with the reduction of circulating pDCs, antiviral activity in DIHS patients is reduced resulting in low levels of circulating IgG levels.23 Decreased total serum IgG, IgA, and IgM and B lymphocyte count are seen at onset; whereas, memory T cells that cross-react with both drug and virus are increased.21,22 An intrinsic defect in the capacity of NK cells to express CD122 becomes evident only after B cells are significantly reduced.21 Patients with DIHS had low numbers and percentages of circulating CD56dimCD16bright NK cells, which became more pro-