The association of the human herpesvirus family—specifically, human herpesvirus 6—and DHS has been questioned. Descamps et al22 explored the issues regarding viral infection and DHS. Hashimoto et al23 suggested that the prolonged course, slow resolution, and/or relapse of cases of DHS may be attributed to human herpesvirus 6 reactivation. Condat et al24 have shown that reactivation of human herpesvirus 6 coincides with the course of DHS, but the direct causal effect of the virus is yet to be established. Patients with human immunodeficiency virus are at a higher susceptibility to toxic drug metabolites.25 This susceptibility could be explained by the reduced level of glutathione, selenium, and other antioxidants in these patients. Glutathione plays an important role in the antioxidant defense of cells. Immune mechanisms also are thought to contribute to the pathogenesis of DHS in these patients, though the immune mechanism of DHS still is not clear. The changes in DHS suggest both TH1 and TH2 cytokine production. Transient increase in the level of interleukin 5 has been demonstrated early in the disease process in some patients.26 Interleukin 5 released by activated T lymphocytes contributes to the eosinophilia. The differential diagnosis of DHS includes other drug eruptions, viral infection, idiopathic hypereosinophilic syndrome, pseudolymphoma, serum sicknesslike illness, and drug-induced vasculitis. PT is an extended-spectrum synthetic penicillin combined with β-lactamase inhibitor. PT is effective against methicillin-sensitive, coagulase-negative staphylococci; Streptococcus pyogenes; and penicillin-sensitive Streptococcus pneumoniae, Enterobacteriaceae, Haemophilus influenza, Moraxella catarrhalis, Pseudomonus aeruginosa, Enterococcus faecalis, and anaerobes. The main indications of PT include nosocomial pneumonia, intra-abdominal infections, skin and soft tissue infections, pelvic inflammatory disease, septicemia, neutropenic fever, osteomyelitis, and septic arthritis.27 Multiple adverse effects with the administration of PT have been reported, including fever, leucopenia, thrombocytopenia, hemolytic anemia, hypercoagulopathy, and transient bone marrow suppression.28-29 Acute interstitial nephritis,30-31 encephalopathy,32 recurrent paralysis,33 allergic skin eruptions,34 and hemorrhagic cystitis35 have been documented after the administration of PT. There is only one reported case (a letter to the editor36) of hypersensitivity reaction during prolonged use of PT in the treatment of osteomyelitis; the patient developed rash, lymphadenopathy, and hematologic changes. Our patient developed DHS after 2 weeks of initiating therapy with PT for osteomyelitis. The reaction caused severe parenchymal nephritis, leading to anuria that necessitated hemodialysis. Interestingly, our patient complained of numbness and paresthesia of the forearm during intravenous PT infusion 2 days prior to developing DHS; a similar symptom was reported by Behbahani and Kostman36 with numbness of the patient's upper chest during intravenous infusion. Treatment of DHS depends on discontinuation of the offending drug early in the course of the disease. Adding systemic corticosteroids (0.5–1.0 mg/kg/d) to the treatment regimen is essential, especially in life-threatening involvement of the lungs, heart, liver, or kidneys. Systemic corticosteroids should be slowly tapered to avoid a relapse of nephritis and skin eruption. Topical steroids have been used in milder cases of DHS to improve the cutaneous manifestations. Interferon-γ has been used in a few cases of long-standing DHS,37 but studies are not available to establish the role of this drug in treatment.
Conclusion
DHA is an iatrogenic disease that affects multiple organs. The pathogenesis of DHS still is largely unclear. Multiple factors likely are responsible for DHS, such as the offending drug with a drug-drug interaction, susceptible individuals with impaired ability to detoxify toxic drug metabolites, immunologic factors, and viral infection. Identification and discontinuation of the offending drug is crucial, as is a multidisciplinary approach in managing affected patients.