New aspects of drug-induced hypersensitivity syndrome

Authors


Mikiko Tohyama, M.D., Ph.D., Department of Dermatology, Ehime University Graduate School of Medicine, Shitsukawa, Toon City, Ehime 791-0205, Japan. Email: tohm@m.ehime-u.ac.jp

Abstract

Drug-induced hypersensitivity syndrome (DIHS) is caused by a limited number of specific drugs and is characterized by late onset, infectious mononucleosis-like symptoms, and herpesvirus 6 (HHV-6) reactivation. Recently, the involvement of herpes viruses other than HHV-6, such as Epstein–Barr virus and cytomegalovirus, has been reported. Many approaches have been used to analyze the pathological mechanism, and have revealed new aspects of DIHS. Here, we focused on three key recent findings regarding DIHS: (i) overlap between DIHS and Stevens–Johnson syndrome/toxic epidermal necrolysis; (ii) the relevance of Epstein–Barr virus in the development of infectious mononucleosis-like symptoms of DIHS; and (iii) roles of monomyeloid precursors increased in the blood and plasmacytoid dendritic cells increased in the lesion skin in HHV-6 reactivation.

Introduction

Drug-induced hypersensitivity syndrome (DIHS) has been established as a clinical entity in severe cutaneous drug adverse reactions (Table 1).1,2 DIHS is characterized by a limited number of causative drugs, late onset, clinical similarity to infectious mononucleosis-like syndrome and prolonged clinical course due to relapse.1,2

Table 1.   Diagnostic criteria for drug-induced hypersensitivity syndrome (DIHS) established by a Japanese consensus group
  1. The diagnosis is confirmed by the presence of the seven criteria above (typical DIHS) or of the five (1–5) (atypical DIHS). *This can be replaced by other organ involvement, such as renal involvement.

1. Maculopapular rash developing >3 weeks after starting with a limited number of drugs
2. Prolonged clinical symptoms 2 weeks after discontinuation of the causative drug
3. Fever (>38°C)
4. Liver abnormalities* (alanine aminotransferase >100 U/L)
5. Leukocyte abnormalities (at least one present)
 a. Leukocytosis (>11 × 109/L)
 b. Atypical lymphocytosis (>5%)
 c. Eosinophilia (>1.5 × 109/L)
6. Lymphadenopathy
7. Human herpesvirus 6 reactivation

Anticonvulsants, such as carbamazepine, phenytoin, phenobarbital and zonisamide, are major culprit drugs of DIHS, and lamotrigine has been reported to be a new causative drug of DIHS in Japan.1,2 In addition to anticonvulsants, allopurinol, diaphenylsulfone (DDS), salazosulfapyridine and mexiletine can also cause DIHS.1,2 Although minocycline-induced DIHS is rare in Japan, it has been reported frequently in other countries.

Drug-induced hypersensitivity syndrome typically develops 2–6 weeks after the initiation of drug administration, and the initial symptoms are fever and maculopapular eruptions that may progress to erythroderma. Lymphadenopathy, hepatitis, renal dysfunction and hematological abnormalities, such as leukocytosis, eosinophilia and atypical lymphocytosis, are observed to varying degrees. Flare-ups involving clinical signs, such as fever, eruption or hepatitis, often occur several weeks after withdrawal of the causative drug.2,3

In DIHS, human herpesvirus (HHV)-6 is commonly reactivated 2–3 weeks after onset, sometimes resulting in relapse of fever and hepatitis.3 The reactivation of herpesviruses other than HHV-6, including cytomegalovirus (CMV), Epstein–Barr virus (EBV) and HHV-7, has also been reported.4–6 In general, the cascade of virus reactivation initiated by HHV-6 and HHV-7 extends to EBV and CMV. EBV and HHV-7 reactivation are thought to have no clinical relevance. In contrast, when CMV reactivation is observed, recurring transient fever, skin rash, or severe complications, such as myocarditis, pneumonia or gastrointestinal bleeding, may occur.7,8

The clinical features of DIHS have been established over the past 10 years, and the pathological mechanism has been analyzed. This review discusses recent insights into three topics: (i) overlap between DIHS and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN); (ii) relevance of EBV in the development of infectious mononucleosis-like symptoms of DIHS; and (iii) the roles of monomyeloid precursors increased in the blood and plasmacytoid dendritic cells increased in the lesion skin in HHV-6 reactivation.

Overlap between dihs and sjs/ten

Drug-induced hypersensitivity syndrome is distinct from other severe cutaneous drug reactions, such as SJS and TEN. However, DIHS cases associated with skin manifestations similar to SJS/TEN have been reported.9,10 They fulfilled all or most of the criteria of DIHS, and coincidently revealed mucosal involvement and epidermal detachment (Fig. 1). It seems likely that these findings caused confusion in the definition of DIHS.

Figure 1.

 Drug-induced hypersensitivity syndrome (DIHS) due to zonisamide associated with Stevens–Johnson syndrome. DIHS developed after administration of zonisamide for 3 months. High fever, leukocytosis, appearance of atypical lymphocytes, hepatitis and lymphadenopathy were observed. Human herpesvirus 6 and cytomegalovirus reactivation were confirmed. Atypical target lesions appeared over the whole body (a), and oral and genital mucosae were involved (b). The area of epidermal detachment was approximately 1%. Histopathologically, numerous apoptotic cells were observed in the epidermis (c) (hematoxylin–eosin, original magnification ×100).

However, specific types of skin rash are not essential for diagnosis of DIHS, because DIHS is diagnosed based on its characteristic clinical course, multiple organ involvement and detection of herpesvirus reactivation. The skin manifestations of DIHS include maculopapular rash, erythema multiforme, exfoliative dermatitis, acute generalized exanthematous pustular dermatosis-like eruption or erythroderma. Mucosal involvement may also be observed in some cases to a lesser extent. On the other hand, SJS/TEN is diagnosed by characteristic skin and mucosal manifestations, but not by organ involvement. Therefore, a case diagnosed as SJS or TEN based on epidermal detachment may also be diagnosed as DIHS based on the clinical course, laboratory findings and viral reactivation.

Late onset is a characteristic feature of DIHS. In contrast, SJS/TEN most often begins in the early stages, after the initiation of causative drugs.11 We compared the day of onset between SJS/TEN, DIHS and SJS/TEN–DIHS overlapping cases. Data from 46 cases of SJS/TEN, 167 of DIHS and seven overlapping cases due to anticonvulsants (carbamazepine, phenobarbital, phenytoin, and zonisamide) were collected. These cases were published as articles or meeting abstracts in medical journals between 2000 and 2009 in Japan, and the available data included the time between the start of drug administration and onset of symptoms. The onset of SJS/TEN was within 3 weeks after the start of drug administration in 67% of cases (Fig. 2). In contrast, DIHS developed at 2–6 weeks in 80% of cases, and occurred most frequently at 4–5 weeks. Thus, the day of onset was clearly different between anticonvulsant-induced DIHS and SJS/TEN. Moreover, six of seven overlapping cases developed symptoms at 4–5 weeks after commencement of drug administration. These findings indicated that overlapping SJS/TEN–DIHS is a subtype of DIHS.

Figure 2.

 Duration of drug administration until the appearance of drug adverse reaction. Japanese cases of carbamazepine-induced Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), drug-induced hypersensitivity syndrome (DIHS), and SJS/TEN–DIHS overlapping were analyzed.

Infectious mononucleosis-like symptoms and viral infection

Infectious mononucleosis-like symptoms, including lymphadenopathy, hepatitis, renal dysfunction, atypical lymphocytosis and mononucleosis, are observed during the early phase of DIHS. Interestingly, HHV-6 reactivation is observed 2–3 weeks after onset, but not concomitant with infectious mononucleosis-like symptoms. HHV-6 DNA can be detected after the appearance of infectious mononucleosis-like symptoms, followed by an increase in anti-HHV-6 antibody titer (Fig. 3). These findings suggest that HHV-6 reactivation may not participate directly in production of the infectious mononucleosis-like symptoms.

Figure 3.

 Relationship between infectious mononucleosis-like symptoms and viral reactivation in drug-induced hypersensitivity syndrome (DIHS). Infectious mononucleosis-like symptoms precede human herpesvirus (HHV)-6 reactivation, followed by Epstein–Barr virus (EBV) and cytomegalovirus reactivation.

Recently, Picard et al.12 suggested that EBV participates in the development of multi-organ involvement with drug rash and eosinophilia with systemic symptoms (DRESS). Although DRESS and DIHS are often mistakenly taken to be synonymous, they are not identical,1,13 and DIHS patients probably represent severe cases of DRESS. That is, DRESS consists of DIHS and other mild drug rashes. Therefore, HHV-6 reactivation is detected in the majority of DIHS patients but in only a limited number of DRESS patients. Picard et al.12 analyzed HHV-6, HHV-7, CMV and EBV reactivation by polymerase chain reaction (PCR) in peripheral blood mononuclear cells (PBMC) and serum from 40 DRESS patients, and detected HHV-6 reactivation in 17 of 38 cases (45%). EBV DNA was detected in the PBMC from all of these patients, and EBV reactivation occurred in 16 of 38 cases (42%). The authors demonstrated that expanded CD8 T cells during the course of DRESS responded to EBV antigen, regardless of whether EBV reactivation was detected. No healthy controls showed the reactivity. Moreover, culprit drugs induced EBV reactivation in EBV-transformed blood B cells from patients in a dose-dependent manner. From these results, they proposed that culprit drugs induce EBV reactivation and antigenic presentation may trigger a multi-organ immune response through activation of CD8 T cells.

It has been suggested that reactivation of EBV usually occurs after HHV-6 reactivation (Fig. 3).4,5 We examined viral DNA in whole blood from 32 DIHS patients in whom HHV-6 reactivation was confirmed during the clinical course. EBV DNA was detected in 24 of these 32 patients (75%) (Mikiko Tohyama, unpubl. data, 2009). High viral loads were detected in approximately half of these patients, but associated symptoms were not confirmed. EBV DNA could not be detected up to day 12 of the disease, and was detected for the first time on day 13. The highest copy number of EBV DNA was observed with or after HHV-6 reactivation in 22 of 24 patients positive for EBV DNA. In infectious mononucleosis caused by primary EBV infection, the viral DNA is abundant in the early phase of the disease and decreases in association with recovery from the acute phase.14,15 During reactivation, the antiviral immune response differs from that of primary infection. Therefore, the viral load may also be different from that of primary infection. EBV that is disseminated to multiple organs before onset of DIHS may be cleared rapidly by cytotoxic T cells. The virus may then proliferate again, following a decline of immune activation. Therefore, it will be necessary to investigate EBV in the very early phase of DIHS. However, we were unable to examine EBV DNA in whole blood collected within 3 days after onset in the present study. Picard et al.12 observed HHV-6 or EBV reactivation on day 0 in 14 patients. However, day 0 was the day on which patients were included in the study and not the day of onset.

Although CMV was not detected by PCR in the study of Picard et al.,12 we detected CMV DNA in blood samples from 10 of 32 patients (31%) (Mikiko Tohyama, unpubl. data, 2009). CMV reactivation is a common feature in severe DIHS in Japan, and the viral DNA was detected in the late phase.4–6,8 As the viral load of CMV in DIHS is similar to that of EBV, CMV may also play an important role in DIHS, similar to EBV. In fact, Hashizume et al.16 reported that CD8 T cells bearing T-cell receptor (TCR)-Vβ recognizing CMV-derived antigenic peptides were expanded during the infectious mononucleosis-like clinical course in a Japanese DIHS patient.

Viral infection is an attractive hypothesis to explain the infectious mononucleosis-like symptoms of DIHS. Further studies are required to determine viral involvement in the very early phase of DIHS and to characterize expanded CD8 T cells in these patients. It is not sufficient to examine EBV alone, and future studies should include other viruses, such as CMV.

Involvement of skin inflammation in hhv-6 reactivation

As mentioned above, HHV-6 viremia is detected after the occurrence of infectious mononucleosis-like symptoms in DIHS. It remains unclear how HHV-6 is reactivated in DIHS. As HHV-6 is often detected in the saliva, it is possible that HHV-6 reactivation always occurs in salivary glands.17,18 In addition, under conditions of immunosuppression, HHV-6 may be reactivated from latently infected monocytes.

Recently, Hashizume et al.19 reported that the numbers of monomyeloid precursors were increased in the peripheral blood of DIHS patients. These cells were not observed in control subjects. The population of monomyeloid precursors increased within 10 days after onset of disease and then decreased gradually thereafter. It is of interest that HHV-6 viral antigen was detected in the cells from 8–30 days, but not in a patient in whom HHV-6 reactivation was not detected. These observations suggest that the monomyeloid precursors appearing early in the peripheral blood may participate in HHV-6 reactivation of DIHS.

Human herpesvirus 6 viremia is detected in graft-versus-host disease (GVHD), measles and dengue fever, as well as DIHS.20–24 HHV-6 reactivation in GVHD is frequently associated with skin rash.21,22 Measles and dengue fever show clinical features similar to DIHS, such as skin rash, liver dysfunction, lymphadenopathy and the appearance of atypical lymphocytes. It seems likely that the presence of cutaneous inflammation is essential for HHV-6 reactivation. Immune reaction accompanied with skin inflammation may cause an increase in the number of monomyeloid precursors and facilitate HHV-6 reactivation. Alternatively, monomyeloid precursors may be recruited into the lesion skin, where HHV-6 reactivation and proliferation may occur. As monomyeloid precursors express cutaneous lymphocyte-associated antigen, it is possible that these cells infiltrate into the skin.19

Human herpesvirus 6 reactivation is considered to require immunosuppression. Shiohara’s group has reported several immune defects, such as a marked decrease in serum immunoglobulin (Ig)G levels and circulating B-cell number at the onset stage, as well as dysfunction of regulatory T cells.25,26 Skin inflammation may be involved in the induction of immunosuppressive conditions. More recently, Sugita et al.27 demonstrated a reduction in the number of plasmacytoid dendritic cells (pDC) in the peripheral blood of DIHS patients, but an increase in these cells in the lesion skin (Fig. 4). Human pDC are a subset of leukocytes capable of producing large amounts of interferon (IFN)-α, which induces maturation of B cells to produce IgG and thus plays a crucial role in antiviral responses.28,29 Therefore, they proposed that pDC in the circulation may accumulate in the skin and thus reduce the number of pDC in the circulation. Therefore, antiviral responses may be reduced, facilitating viral reactivation in peripheral blood and tissues other than the skin. However, further studies are required to determine whether the lack of pDC in the circulation reduces the antiviral defense activity, thus leading to viral reactivation.

Figure 4.

 Infiltration of plasmacytoid dendritic cells (pDC) in normal skin (left) and lesion skin of drug-induced hypersensitivity syndrome (DIHS) (right). The lesion skin was obtained from DIHS due to carbamazepine on day 8 of the disease. In this patient, human herpesvirus 6 reactivation was observed 5 days later. Numerous CD123-positive cells (labeled green), indicating pDC, were found to have infiltrated into the dermis (original magnification ×200).

Conclusion

Drug-induced hypersensitivity syndrome has been established as a clinical entity in severe cutaneous drug adverse reaction in which HHV-6 reactivation is a hallmark. Many approaches, such as epidemiology, virology and immunology, have been used to analyze the pathological mechanism of DIHS. However, various questions still remain unsolved. Further studies are required to investigate the roles of herpesvirus, including HHV-6, EBV and cytomegalovirus in this disease entity.

Acknowledgment

This work was partly supported by Health and Labor Sciences Research Grants (Research on Intractable Diseases) from the Ministry of Health, Labor and Welfare of Japan.

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