Drug-induced hypersensitivity syndrome associated with a marked increase in anti-paramyxovirus antibody titers in a scleroderma patient.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS) is characterized by a severe multiorgan hypersensitivity reaction that usually appears after prolonged exposure to certain drugs and may be related to reactivation of herpes viruses. There have been few reports regarding the clinical association of DIHS with pathogens other than herpes viruses. CASE SUMMARY: We report a case of scleroderma with DIHS associated with paramyxovirus infection. A 61-year-old man with early diffuse cutaneous scleroderma with myositis and progressive interstitial pneumonia developed generalized erythema with high fever 3 weeks after taking sulfamethoxazole/trimethoprim. The diagnosis of DIHS was made based on the patient's history of using an offending drug, clinical manifestations and laboratory data showing peripheral eosinophilia with the presence of atypical lymphocytes. Virological tests showed significant increases of antibody titers against mumps virus and parainfluenza virus type 2, which strongly suggested that paramyxovirus infection occurred during the clinical course of DIHS. DISCUSSION: These findings suggest that paramyxovirus infection had contributed to the development of DIHS in this patient and that there is a need to seek evidence of other viral infections in some cases of DIHS, especially those without herpes virus reactivation/infection.     

Drug-induced hypersensitivity syndrome associated with reactivation of human herpesvirus 6 presenting with severe hepatic injury

Little is known about the pathophysiology of liver complication seen in drug-induced hypersensitivity syndrome (DIHS). We describe herein a 32-year-old Japanese man with DIHS due to salazosulfapyridine (SASP) associated with reactivation of human herpesvirus 6 (HHV-6) presenting with severe acute hepatic injury. The patient, with a 1-year history of ulcerative colitis (UC), presented with high fever and abnormally elevated liver enzymes. Six weeks prior to his symptoms, prednisolone (PSL) and SASP had been started because of UC aggravation. Besides fever and liver dysfunction, the appearance of atypical lymphocytes together with eosinophils and generalized erythematous maculopapular skin rash developed sequentially, and a diagnosis of DIHS was established. Despite cessation of SASP and increased dose of PSL, his initial abnormalities continued, and biphasic second alanine aminotransferase (ALT) flare with deep jaundice worsened. Based on the significant increase in the titer of HHV-6 IgG antibodies at the second peak of ALT level without HHV-6 IgM antibody elevation, strongly suggesting reactivation of the virus, HHV-6 was first considered to directly contribute to the deterioration of liver function. However, extensive histological analysis of the liver led to the realization that the cause of the DIHS liver injury was essentially drug-related hepatotoxicity induced by SASP, causing wide-ranging damage to both the hepatocytes and cholangiocytes.     

Drug-induced Hypersensitivity Syndrome by EGFR-TKI in a Patient with Lung Cancer

An 83-years-old woman diagnosed with advanced Epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma was administered afatinib as a first-line treatment. On Day 17, the patient presented with grade 3 diarrhea and a blood test analysis showed an increased inflammatory response. Afatinib treatment was discontinued on the same day. On Day 26, the patient displayed blepharedema and multiple irregular erythema covering her entire body. Drug-induced hypersensitivity syndrome (DIHS) was suspected, and the systemic administration of 30 mg/day prednisolone was administered. The symptoms subsided thereafter. A blood test analysis 3 weeks after onset revealed a reactivation of Human herpesvirus 6 (HHV-6) and a diagnosis of DIHS due to afatinib therapy was confirmed.     

An infant with γ-globulin-induced hypersensitivity syndrome who developed Evans' syndrome after a second γ-globulin treatment

One month after treatment with γ-globulin for Kawasaki disease, an 18-month-old girl developed Evans' syndrome in addition to drug-induced hypersensitivity syndrome (DIHS) after a second γ-globulin treatment. She suffered from hyperbilirubinemia, hemolytic anemia, and thrombocytopenia. The findings and her clinical course involved plasma exchange and treatment with prednisolone, with good results. Peripheral lymphocyte stimulation tests indicated that γ-globulin was the likeliest cause of the DIHS. A real-time polymerase chain reaction test showed the human herpes virus (HHV)-6 genome in peripheral blood. We demonstrated that a primary infection or infection reactivation by the HHV-6 virus was involved in the development of γ-globulin-induced hypersensitivity and Evans' syndrome.     

Drug allergy and non-HIV immune reconstitution inflammatory syndrome

Non-HIV immune reconstitution inflammatory syndrome (non-HIV IRIS) is associated with the recovery from an immunocompromised condition. It is defined as inflammatory disorders caused by antigens, including drugs or pathogenic microorganisms present prior to immune recovery, or by the exacerbation of an inflammatory disorder that was already present. Drug-induced hypersensitivity syndrome is a prototype of IRIS, and the pathophysiology of non-HIV IRIS can be recognized in several disorders treated with corticosteroids, immunosuppressants, molecular-targeted drugs, TNF-α antibody drugs, immune checkpoint inhibitors, and dipeptidyl peptidase-4 inhibitors. This review focuses on the relationship between the immune mechanism of non-HIV IRIS and drug allergies, especially severe drug eruption. The antigen recognition mechanism in drug allergy varies depending on the clinical type and the causative drug. The p-i concept is the main mechanism in severe drug eruption such as Stevens-Johnson syndrome/toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Lymphocytes activated by an antigen other than a drug, such as a virus, can also develop drug allergy by the loose binding of drugs with immune receptors of T cells or human leukocyte antigen. Therefore, fluctuations in the immune environment affect the onset of severe drug eruption. Novel agents that cause major changes in immunity have been marketed mainly for autoimmune diseases and malignant tumors; therefore, it is necessary to consider their effects when treating severe drug eruptions. Moreover, although a list of diagnostic criteria for this syndrome has been drafted, predictive and diagnostic biomarkers for this syndrome needs to be urgently developed.     

Immune reconstitution syndrome

Immune reconstitution, or the reversal of HIV-related immune system decline, is one of the primary goals of highly active antiretroviral therapy (HAART). Reconstitution involves an increase in functional CD4 cells to guide the immune response against pathogens such as HIV, resulting in the suppression of viral load and other beneficial outcomes. However, immune reconstitution may trigger an inflammatory reaction in some people soon after they begin anti-HIV therapy and show signs of immunological improvement. Known as immune reconstitution syndrome (IRS) or immune reconstitution inflammatory syndrome (IRIS), this set of symptoms often resembles an AIDS-defining illness or other condition seen in people with HIV. While in most cases the symptoms of IRIS resolve after a few weeks, the syndrome may be severe or mistaken for true disease progression, and should be properly diagnosed and treated.     

A case of hypersensitivity syndrome induced by methimazole for Graves' disease.

Drug-induced hypersensitivity syndrome is one of the most severe forms of drug eruption and is characterized by high fever and multiorgan involvement. Reactivation of human herpesvirus-6 (HHV-6) or cytomegalovirus (CMV) has been suggested to be involved in this syndrome, although the exact role of these viruses remains elusive. We report the case of a 50-year-old Japanese male with Graves' disease who developed hypersensitivity syndrome caused by the antithyroid drug methimazole (MMI). After treatment with MMI 30 mg three times daily for 1(1/2) months, the patient developed generalized exfoliative erythematous eruption and high fever. Cessation of treatment with the drug improved his condition. Readministration of MMI worsened his clinical features. Treatment with high-dose methylprednisolone for 6 days and subsequent administration of prednisolone 20 mg twice daily improved his clinical manifestations. Elevated titers of anti-HHV-6 immunoglobulin G (IgG) and anti-CMV IgG antibodies were observed, and these gradually decreased during the clinical course, indicating reactivation of HHV-6 and CMV. Drug-induced lymphocyte stimulation test for MMI was negative. This is the first reported case of MMI-induced hypersensitivity syndrome associated with the reactivation of HHV-6 and CMV.     

Multiple sclerosis and Kaposi's sarcoma--chronic diseases associated with new human herpesviruses?

Two diseases that for many years have been suspected to be of viral origin are multiple sclerosis (MS) and Kaposi's sarcoma (KS). With the use of a new technique called representational difference analysis both these diseases have recently been associated with new lymphotropic herpesviruses, i.e. human herpesviruses (HHV) 6 and 8. HHV-6 is a ubiquitous virus and the etiological agent of exanthema subitum. Viral neuroinvasion occurs frequently in primary HHV-6 infection, and meningitis, encephalitis and demyelination have been described as rare complications. A relation with MS has been suggested for HHV-6, as the virus has been detected in MS plaques in the brain. Data from different studies are, however, conflicting and a definitive role for HHV-6 in MS pathogenesis has not been established. HHV-8 is believed to be the causative agent of KS, and is also associated with some rare hematological malignancies. The viral genome contains several potential oncogenes that are believed to have been picked up from the human genome during evolution. The role of HHV-8 in healthy, immunocompetent individuals is however uncertain. In conclusion, the full spectrum of human diseases associated with these new viruses is not yet understood, and rapid developments in molecular biology will continue to shed new light on the interactions between herpesviruses and their hosts.     

Drug Hypersensitivity Syndrome to Carbamazepine and Human Herpes Virus 6 Infection: Case Report and Literature Review

We describe a patient with a drug-induced hypersensitivity syndrome to carbamazepine and a concomitant active infection with human herpes virus 6 (HHV-6). The potential role of HHV-6 regarding the drug-induced hypersensitivity syndrome is discussed and the main clinical features of this potentially fatal adverse drug reaction are highlighted.     

Human herpesvirus 6 encephalitis in trimethoprim-sulfamethoxazole-induced hypersensitivity syndrome

INTRODUCTION: Human herpesvirus 6 (HHV-6), the causative agent of the common exanthem subitum, is a known cause of central nervous system infection in immunocompromised patients. It has been suggested that HHV-6 participate in the development of drug-induced hypersensitivity syndrome. CASE REPORT: We reported a case of HHV-6 encephalitis associated with hypersensitivity syndrome induced by trimethoprim-sulfamethoxazole in a 72-year-old HIV-negative woman. DISCUSSION: Our case confirmed that reactivation of HHV-6 infection may contribute to the development of the hypersensitivity syndrome.     

Monitoring of human herpesviruses after allogeneic peripheral blood stem cell transplantation and bone marrow transplantation

Herpesviruses frequently cause serious complications after allogeneic bone marrow transplantation (allo-BMT). Recent studies have shown more rapid immune reconstitution after allogeneic peripheral blood stem cell transplantation (allo-PBSCT) compared with allo-BMT. However, it has not been clarified whether the improved immune reconstitution after allo-PBSCT is associated with a lower incidence of herpesvirus infections. We monitored the emergence of Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus 6 (HHV-6) and HHV-7 DNA by a nested-double polymerase chain reaction in peripheral blood leucocytes from 22 allo-BMT and 16 allo-PBSCT patients. Each virus had an unique temporal profile of detection. HHV-6 DNA was detected most frequently at 3 weeks after transplantation, whereas CMV and EBV DNA were detected later (2-3 months). Detection rates of HHV-6 DNA at 3 and 4 weeks after allo-BMT were significantly higher than those after allo-PBSCT (9/16 v 2/13 at 3 weeks, P < 0.01; 10/21 v 1/15 at 4 weeks, P < 0.01). Detection rates of the other three herpesviruses after the two types of allogeneic transplantation were not significantly different throughout observation period. Furthermore, detection of HHV-6 DNA within the first 4 weeks was associated with delayed platelet engraftment after both allo-BMT and allo-PBSCT (P < 0.01). These results suggest an advantage for allo-PBSCT over allo-BMT in terms of suppression of HHV-6 reactivation and prevention of subsequent complications.     

Herpesvirus Exploitation of Host Immune Inhibitory Pathways

Herpesviruses employ a plethora of mechanisms to circumvent clearance by host immune responses. A key feature of mammalian immune systems is the employment of regulatory pathways that limit immune responsiveness. The primary functions of these mechanisms are to control autoimmunity and limit exuberant responses to harmless antigen in mucosal surfaces. However, such pathways can be exploited by viral pathogens to enable acute infection, persistence and dissemination. Herein, we outline the current understanding of inhibitory pathways in modulating antiviral immunity during herpesvirus infections in vivo and discuss strategies employed by herpesviruses to exploit these pathways to limit host antiviral immunity.     

Illness of immune reconstitution: Recognition and management

Some individuals who initiate highly active antiretroviral therapy (HAART) develop new or worsening opportunistic infections or malignancies despite improvements in surrogate markers of HIV-1 infection. These events of paradoxical clinical worsening, also known as immune reconstitution syndromes (IRS), are increased in individuals with prior opportunistic infections or low CD4+ T-cell nadirs. They are thought to result from reconstitution of the immune system’s ability to recognize pathogens or tumor antigens that were previously present, but clinically asymptomatic. There is no consensus regarding the diagnostic criteria or pathogenesis of IRS. Knowledge of their presentation and treatment is largely based on case reports. With the introduction of HAART into resource-limited settings, it is likely that significantly more and distinct forms of IRS will be observed. Prospective studies of the incidence and treatment of IRS in multiple settings are critical to better understand their pathogenesis and optimal management.     

Prospective monitoring of Epstein–Barr virus and other herpesviruses in patients with juvenile idiopathic arthritis treated with methotrexate and tocilizumab

Methotrexate (MTX) is widely used for the treatment of articular-type juvenile idiopathic arthritis (JIA), but patients receiving MTX for rheumatoid arthritis have been reported to be at increased risk of reactivation of Epstein-Barr virus (EBV) and the development of lymphoproliferative disorder. The association between MTX and reactivation of herpesviruses in pediatric patients is not yet understood. We prospectively monitored the viral load of EBV, cytomegalovirus (CMV), and herpesvirus 6 (HHV-6) in four JIA patients treated with MTX for 12-24?months. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, was added to the therapeutic regimen in three patients during the observation period. Prior to the administration of MTX, EBV and HHV-6 were detected by PCR in two patients. Significant increases in EBV and HHV-6 load were not observed following the administration of MTX or tocilizumab. In one patient, a relatively high EBV load remained detectable during 21?months of observation in the absence of clinical symptoms. CMV was not detected throughout the observation period in any patient. This is the first report monitoring the longitudinal DNA loads of EBV and other herpesviruses in JIA patients. EBV and HHV-6 were often detectable, but treatment with MTX and tocilizumab did not appear to influence the viral load.     

Herpesvirus DNA detection in cerebral spinal fluid: differences in clinical presentation between alpha-, beta-, and gamma-herpesviruses

To evaluate the role of 6 human herpesviruses (cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-6 (HHV-6), herpes simplex virus (HSV) types 1 and 2 and varicella zoster virus (VZV)) in infections of the nervous system, cerebrospinal fluid (CSF) samples from 662 patients with suspected viral aetiology to neurological symptoms were investigated for presence of herpesviral DNA in a PCR-based study. Of the 69 patients (2 patients had 2 herpesvirus DNA detected in CSF) who had herpesvirus DNA detected in the CSF, 60 (87%) were non-immunocompromised (CMV 7; HHV-6 6; EBV 16; HSV-1 18; HSV-2 9 and VZV 6) and 9 (13%) were immunocompromised (CMV 3; HHV-6 0; EBV 5; HSV-1 0; HSV-2 1 and VZV 0). The study was performed in a retrospective/prospective manner. The HSV-1, HSV-2, VZV and CMV DNA-positive patients usually had typical clinical syndromes, such as encephalitis/myelitis and meningitis, but also other neurological conditions were associated with findings of these viruses. HHV-6 and EBV DNA were detected in patients presenting with a variety of neurological symptoms, and in some of the cases, concurrent with diagnosis of other infections of the central nervous system. Despite the overall variability of clinical conditions seen, a pattern associated with each investigated herpesvirus was discernable as regards clinical presentation.     

Herpesvirus infections in solid organ transplant patients at high risk of primary cytomegalovirus disease

The epidemiology of infections with 5 human herpesviruses (HHVs) (HHV-6, HHV-7, HHV-8, varicella zoster virus [VZV], and Epstein-Barr virus [EBV]) was investigated during the first year after solid organ transplantation in 263 patients who received oral ganciclovir or valganciclovir prophylaxis. HHV-6B DNAemia was uncommon, HHV-6A DNAemia was not observed, and HHV-7 DNAemia was prevalent. HHV-6 and HHV-7 DNAemia were not significantly associated with cytomegalovirus (CMV) disease, although a trend toward higher incidence of CMV disease was observed in HHV-6 DNAemic patients. VZV and HHV-8 DNAemia were not detected. EBV infection was common, although incidence of high-level EBV DNAemia was low, especially in patients who received valganciclovir prophylaxis. EBV-related posttransplant lymphoproliferative disease was not observed up to 12 months after transplantation. Compared with historic data, data from the present study suggest that antiviral prophylaxis may lower the incidence, prevalence, or level of DNAemia for infection with HHV-6, HHV-8, VZV, and EBV but not for infection with HHV-7.     

T-cell immune constitution after peripheral blood mononuclear cell transplantation in complete DiGeorge syndrome

Complete DiGeorge syndrome (cDGS) is a congenital disorder characterized by typical facies, thymic aplasia, susceptibility to infections, hypoparathyroidism and conotruncal cardiac defect. Fetal thymus or post-natal thymus tissue transplantations and human leucocyte antigen (HLA)-genoidentical bone marrow transplantations were followed in a few cases by immune reconstitution. More recently, a peripheral blood mononuclear cell transplantation (PBMCT) was performed with an HLA-genoidentical donor and followed by a partial T-cell engraftment and immune reconstitution. We report a boy with cDGS, without cardiac defect, who suffered recurrent severe infections. At the age of 4 years, he underwent PBMCT from his HLA-genoidentical sister. He received no conditioning regimen, but graft-versus-host disease (GVHD) prophylaxis was with oral cyclosporin A and mycophenolate mofetil. Toxicity was mild, with grade I acute GVHD. The patient is currently 2.5 years post-PBMCT with excellent clinical performances. Mixed chimaerism can only be observed on the T-cell population (50% donor T cells). T-lymphocyte count fluctuated (CD3 more than 400 x 10(6)/l at d 84 and CD4 more than 200 x 10(6)/l at d 46). Exclusive memory phenotype T cells and absence of new thymic emigrants suggest expansion of infused T cells. T-cell mitogen and tetanus antigen responses normalized a few months after transplantation. After immunizations, specific antibodies were produced. PBMCT from an HLA identical sibling could be an efficient treatment of immune deficiency in cDGS.     

Prospective monitoring of Epstein–Barr virus and other herpesviruses in patients with juvenile idiopathic arthritis treated with methotrexate and tocilizumab

Abstract

Methotrexate (MTX) is widely used for the treatment of articular-type juvenile idiopathic arthritis (JIA), but patients receiving MTX for rheumatoid arthritis have been reported to be at increased risk of reactivation of Epstein–Barr virus (EBV) and the development of lymphoproliferative disorder. The association between MTX and reactivation of herpesviruses in pediatric patients is not yet understood. We prospectively monitored the viral load of EBV, cytomegalovirus (CMV), and herpesvirus 6 (HHV-6) in four JIA patients treated with MTX for 12–24 months. Tocilizumab, an anti-interleukin 6 receptor monoclonal antibody, was added to the therapeutic regimen in three patients during the observation period. Prior to the administration of MTX, EBV and HHV-6 were detected by PCR in two patients. Significant increases in EBV and HHV-6 load were not observed following the administration of MTX or tocilizumab. In one patient, a relatively high EBV load remained detectable during 21 months of observation in the absence of clinical symptoms. CMV was not detected throughout the observation period in any patient. This is the first report monitoring the longitudinal DNA loads of EBV and other herpesviruses in JIA patients. EBV and HHV-6 were often detectable, but treatment with MTX and tocilizumab did not appear to influence the viral load.     

Two cases of tuberculosis with multiple drug hypersensitivity after drug-induced hypersensitivity syndrome

Here, we report 2 cases of drug-induced hypersensitivity syndrome (DIHS) caused by salazosulfapyridine and allopurinol during tuberculosis treatment. Both patients also developed multiple drug hypersensitivity (MDH) to several antituberculosis drugs that were used at around the period of DIHS onset, and thus, the treatment could not be successfully completed. Our cases show that MDH can easily occur after development of DIHS. Considering that treatment for tuberculosis requires long-term management with several drugs, it is important to refrain from administering drugs that can cause DIHS during tuberculosis treatment.     

Nonmalignant disease associated with human herpesvirus 8 reactivation in patients who have undergone autologous peripheral blood stem cell transplantation

Fever, cutaneous rash, and hepatitis-for which an infectious cause was suspected-developed in an Italian patient with non-Hodgkin lymphoma after autologous peripheral blood stem cell (PBSC) transplantation. Polymerase chain reaction (PCR) with degenerate primers for the highly conserved DNA polymerase gene of herpesviruses detected herpesvirus sequences 100% identical to human herpesvirus-8 (HHV-8) in serial cell-free serum samples, collected immediately before or concomitant with the occurrence of clinical symptoms; no other common infections were documented. The presence of the HHV-8 genome (clade C) was confirmed by PCR with HHV-8-specific primers for orf 26 and orf-K1. HHV-8 viremia was undetectable either before transplantation or when the patient was clinically asymptomatic. Semiquantitative PCR analysis showed variations of the viral load correlating with the clinical status. Anti-HHV-8 antibodies were detected before and after transplantation by an immunofluorescence assay for lytic antigens. Active HHV-8 infection may be associated with nonmalignant illness after PBSC/bone marrow transplantation.