**5. Drug induced hypersensitivity syndrome**

#### **5.1. Nosology**

The term hypersensitivity syndrome has been used for decades to describe a cutaneous drug reaction accompanied by involvement of internal organs. In 1938, Merritt and Putnam described a toxic reaction to phenytoin characterized by exfoliative dermatitis, fever and eosinophilia [178]. This was distinguished from those patients who developed a mild, morbilliform rash. Chaiken et al coined the term Dilantin hypersensitivity in 1950 to further characterize the systemic reaction described by Merritt and Putnam to also include lympha‐ denopathy and multivisceral involvement [179]. Saltzein in 1959 described a drug-induced lymphoma characterized by lymphadenopathy and diffuse skin nodules and plaques without internal organ involvement. [180]. The anticonvulsant hypersensitivity syndrome was named in 1988 by Shear and Spielberg to refer the similar cutaneous and systemic manifestations of idiosyncratic reactions to a range of anticonvulsant medications including phenytoin, pheno‐ barbitol and carbamazepine [181]. In 1996, Bocquet et al introduced the term drug reaction with eosinophilia and systemic symptoms (DRESS) to distinguish it from drug-induced pseudolymphoma and other drug reactions that are not associated with eosinophilia [182]. Finally, Shiohara et al proposed the term drug induced hypersensitivity syndrome (DIHS) to include patients who may not have marked eosinophilia but have other evidence of leukocyte abnormalities, internal organ involvement and evidence of HHV-6 reactivation [183],[184].

#### **5.2. Epidemiology**

The incidence of DIHS is estimated to be between 1 in 1000 and 1 in 10000 to phenytoin [185]. The true incidence remains to be determined because of the variable presentations and the lack of universally accepted criteria. The JSCAR and RegiSCAR studies will provide more accurate reporting on the basis of stringent criteria. Preliminary data from the RegiSCAR study suggests that it affects males and females equally with a mean age of 47.4 years (range 3-84 years) [186].

#### **5.3. Etiology and clinical features**

Various diagnostic criteria have been proposed. Bocquet et al stipulated the presence of (1) cutaneous drug eruption; (2) hematologic abnormalities including eosinophilia greater than 1.5 x109 /L or the presence of atypical lymphocytes; and (3) systemic involvement including adenopathy greater than 2 cm in diameter, hepatitis (liver transaminase values >2 normal), interstitial nephritis, interstitial pneumonia, or carditis.

Kardaun et al developed a scoring system to validate the diagnosis [187].

The potential role of HHV-6 in the pathogenesis of DIHS was incorporated into the criteria for DIHS by the JSCAR group [188]: (1) maculopapular rash developing more than 3 weeks after starting a limited number of drugs; (2) prolonged clinical symptoms 2 weeks after discontin‐ uation of the causative drug; (3) fever greater than 38 C; (4) liver abnormalities (eg, ALT levels >100 U/L); (5) leukocyte abnormalities such as leukocytosis (>11 x 109 /L), atypical lymphocy‐ tosis (>5%), and/or eosinophilia (>1.5 109/L); (6) lymphadenopathy; and (7) HHV-6 reactiva‐ tion. Diagnosis of typical DIHS requires the presence of all 7 criteria. If criteria 1-5 are present only, then a diagnosis of atypical DIHS is made.

The syndrome typically begins 3 weeks to 3months after commencing therapy with a limited number of drugs of which the most prominent ones are listed below.

High-grade fever (38-40°C) is usually the first symptom followed by the development of facial oedema (Fig. 8), often with pinhead-sized pustules, and an erythroderma with edematous, follicular and purpuric lesions (Fig. 9). An exfoliative dermatitis often eventuates especially if

Assessment/Score -1 0 1 2 min max Fever ≥38.5oC n y -1 0 Enlarged lymph nodes n/u y 0 1

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 71

*Eosinophilia* n/u 700-1499/μL "/>1500/μL 0 2

Atyical lymphocytes n/u y 0 1

*Skin rash suggestive of DRESS* n u y -2 2

Lung n/u "/>1 y ≥2 y 0 2

Resolution ≥15 days n y -1 0

*If non +ve and* ≥3 -ve n 0 1 Total -4 9

\*After exclusion of other causes: 0, no organ involvement; 1, 1 organ involved; 2, ≥ 2 organs involved.

Final score: <2, excluded; 2-3, possible; 4-5, probable; >5, definite.

**Table 3.** Diagnostic validation score for DRESS

Eosinophilia if WCC<4000/μL 10-19.9% ≥20%

*Skin rash extent (%TBSA)* n/u "/>50%

*Histology suggestive of DRESS* n y/u

Eosinophilia

Skin involvement

Organ involvement \*

Liver *Kidney*

*Heart Pancreas Other organ*

ANA Blood culture

y, yes; n, no.

Serology/PCR Hepatitis A,B,C EBV,CMV

Mycoplasma,Chlamydia


\*After exclusion of other causes: 0, no organ involvement; 1, 1 organ involved; 2, ≥ 2 organs involved.

Final score: <2, excluded; 2-3, possible; 4-5, probable; >5, definite.

**Table 3.** Diagnostic validation score for DRESS

eosinophilia [178]. This was distinguished from those patients who developed a mild, morbilliform rash. Chaiken et al coined the term Dilantin hypersensitivity in 1950 to further characterize the systemic reaction described by Merritt and Putnam to also include lympha‐ denopathy and multivisceral involvement [179]. Saltzein in 1959 described a drug-induced lymphoma characterized by lymphadenopathy and diffuse skin nodules and plaques without internal organ involvement. [180]. The anticonvulsant hypersensitivity syndrome was named in 1988 by Shear and Spielberg to refer the similar cutaneous and systemic manifestations of idiosyncratic reactions to a range of anticonvulsant medications including phenytoin, pheno‐ barbitol and carbamazepine [181]. In 1996, Bocquet et al introduced the term drug reaction with eosinophilia and systemic symptoms (DRESS) to distinguish it from drug-induced pseudolymphoma and other drug reactions that are not associated with eosinophilia [182]. Finally, Shiohara et al proposed the term drug induced hypersensitivity syndrome (DIHS) to include patients who may not have marked eosinophilia but have other evidence of leukocyte abnormalities, internal organ involvement and evidence of HHV-6 reactivation [183],[184].

The incidence of DIHS is estimated to be between 1 in 1000 and 1 in 10000 to phenytoin [185]. The true incidence remains to be determined because of the variable presentations and the lack of universally accepted criteria. The JSCAR and RegiSCAR studies will provide more accurate reporting on the basis of stringent criteria. Preliminary data from the RegiSCAR study suggests that it affects males and females equally with a mean age of 47.4 years (range 3-84 years) [186].

Various diagnostic criteria have been proposed. Bocquet et al stipulated the presence of (1) cutaneous drug eruption; (2) hematologic abnormalities including eosinophilia greater than

adenopathy greater than 2 cm in diameter, hepatitis (liver transaminase values >2 normal),

The potential role of HHV-6 in the pathogenesis of DIHS was incorporated into the criteria for DIHS by the JSCAR group [188]: (1) maculopapular rash developing more than 3 weeks after starting a limited number of drugs; (2) prolonged clinical symptoms 2 weeks after discontin‐ uation of the causative drug; (3) fever greater than 38 C; (4) liver abnormalities (eg, ALT levels

tosis (>5%), and/or eosinophilia (>1.5 109/L); (6) lymphadenopathy; and (7) HHV-6 reactiva‐ tion. Diagnosis of typical DIHS requires the presence of all 7 criteria. If criteria 1-5 are present

The syndrome typically begins 3 weeks to 3months after commencing therapy with a limited

/L or the presence of atypical lymphocytes; and (3) systemic involvement including

/L), atypical lymphocy‐

**5.2. Epidemiology**

70 Skin Biopsy - Diagnosis and Treatment

1.5 x109

**5.3. Etiology and clinical features**

interstitial nephritis, interstitial pneumonia, or carditis.

only, then a diagnosis of atypical DIHS is made.

Kardaun et al developed a scoring system to validate the diagnosis [187].

>100 U/L); (5) leukocyte abnormalities such as leukocytosis (>11 x 109

number of drugs of which the most prominent ones are listed below.

High-grade fever (38-40°C) is usually the first symptom followed by the development of facial oedema (Fig. 8), often with pinhead-sized pustules, and an erythroderma with edematous, follicular and purpuric lesions (Fig. 9). An exfoliative dermatitis often eventuates especially if


the causative drug is not withdrawn (Fig. 10). Cheilitis (Fig. 8), pharyngeal erythema and oral ulceration may occur but severe stomatitis is not present. Tender lymphadenopathy in more than two sites and bilateral swelling of salivary glands with xerostomia is evident early in the course of disease. Hepatosplenomegaly is a common finding. Leukocytosis with atypical lymphocytes and eosinophilia (60-70% of cases) is a prominent feature of this syndrome although the eosinophilia may not be observed for 1-2 weeks. Thrombocytopenia and anemia may also be present. Hypogammaglobulinema is noted at the onset of disease with the nadir occurring several days after the withdrawal of the causative drug [189]. An overshoot in the IgG level occurs 1-2 weeks after the nadir before returning to normal on full recovery. Internal

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 73

organ involvement is listed in table 5.

**Figure 9.** Maculopapular eruption and erythroderma of the trunk in DIHS.

The onset of symptoms is variable with patients developing 2-3 symptomatic features followed by stepwise development of other manifestations. In most cases, withdrawal of the drug is not followed by rapid resolution of symptoms. Many patients may continue to deteriorate and

Several reports have described the occurrence of autoantibody formation and autoimmune diseases up to 4 years after the acute resolution of DIHS/DRESS [201] and these include type 1 diabetes mellitus [202], autoimmune thyroid disease [203], scleroderma GVHD [204], SLE [205], and bullous pemphigoid [206]. One of the likely explanations for the occurrence of

show periodic relapses for weeks after the withdrawal of the causative drug.

autoimmune disease is the depletion of regulatory T cells upon recovery of disease.

**Table 4.** The main causative drugs of DIHS

**Figure 8.** Facial erythema and edema with labial ulceration in a young woman with DIHS/DRESS.

the causative drug is not withdrawn (Fig. 10). Cheilitis (Fig. 8), pharyngeal erythema and oral ulceration may occur but severe stomatitis is not present. Tender lymphadenopathy in more than two sites and bilateral swelling of salivary glands with xerostomia is evident early in the course of disease. Hepatosplenomegaly is a common finding. Leukocytosis with atypical lymphocytes and eosinophilia (60-70% of cases) is a prominent feature of this syndrome although the eosinophilia may not be observed for 1-2 weeks. Thrombocytopenia and anemia may also be present. Hypogammaglobulinema is noted at the onset of disease with the nadir occurring several days after the withdrawal of the causative drug [189]. An overshoot in the IgG level occurs 1-2 weeks after the nadir before returning to normal on full recovery. Internal organ involvement is listed in table 5.

**Figure 9.** Maculopapular eruption and erythroderma of the trunk in DIHS.

Carbamazepine

Phenobarbitol

Zonisamide

Lamotrigine

Allopurinol

Dapsone

Mexiletine

Minocycline

Abacavir

**Table 4.** The main causative drugs of DIHS

72 Skin Biopsy - Diagnosis and Treatment

Strontium ranelate

**Figure 8.** Facial erythema and edema with labial ulceration in a young woman with DIHS/DRESS.

Sulphasalazine

Phenytoin

The onset of symptoms is variable with patients developing 2-3 symptomatic features followed by stepwise development of other manifestations. In most cases, withdrawal of the drug is not followed by rapid resolution of symptoms. Many patients may continue to deteriorate and show periodic relapses for weeks after the withdrawal of the causative drug.

Several reports have described the occurrence of autoantibody formation and autoimmune diseases up to 4 years after the acute resolution of DIHS/DRESS [201] and these include type 1 diabetes mellitus [202], autoimmune thyroid disease [203], scleroderma GVHD [204], SLE [205], and bullous pemphigoid [206]. One of the likely explanations for the occurrence of autoimmune disease is the depletion of regulatory T cells upon recovery of disease.

breath. Headache, myalgia and/or arthralgia may also be present. Eosinophilia is present in < 10% of cases and liver function test abnormalities are detected in < 20% of cases [209]. Also, the manifestations resolve within 72 hours rather than having a protracted relapsing course

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 75

Viral infections such as EBV, CMV, and measles can be distinguished by the absence of eosinophilia, hypogammaglobulinemia, and supportive serology. In children, DIHS/DRESS is differentiated from Kawasaki's disease by the absence of a bulbar conjunctivitis, strawberry tongue, coronary aneurysms, hypoalbuminemia and thrombocytosis. Serum sickness is characterized by urticarial lesions and the absence of internal organ involvement. Atopic erythroderma with bacterial infection does not usually involve hepatitis or nephritis. Druginduced pseudolymphoma from carbamazepine or phenytoin is distinguished from DIHS/ DRESS by the absence of internal organ involvement and the prompt resolution of symptoms when the drug is withdrawn. Cutaneous B and T cell lymphomas have an indolent course and

The histopathology of DIHS/DRESS is relatively non-specific and consists of a lymphocytic infiltrate that is superficial, perivascular, dense and diffuse. Eosinophils may be present but is often absent. The presence of loose rather than discrete granulomatous aggregates of histio‐ cytes have been recently reported (Figs. 11, 12) [210]. This may be due to continued exposure to the culprit drug after the onset of DIHS/DRESS. Granuloma formation occurs as a conse‐ quence of a delayed-type hypersensitivity (type IV) reaction, the classic example of which is the tuberculin reaction where a cutaneous granuloma is induced after injection of purified protein derivative in a previously sensitized individual. The expansion of CD4 cells and the secretion of IFN-γ and other Th-1 cytokines result in the recruitment of macrophages. Sus‐ tained drug exposure and the persistence of cytokine release promote differentiation of macrophages into epithelioid cells, which secrete TNF promoting their fusion to form multi‐ nucleate giant cells and granulomas. HHV-6 and DNA from other herpes viruses may be

Santiago et al recently studied the utility of patch testing in DIHS/DRESS and found a positive reaction in 32% of the 56 patients. Patch testing was performed between 6 weeks and 6 months after healing of the lesion and at least one month after corticosteroids were ceased. They found that 76% of the 17 patients with carbamazepine-induced DIHS/DRESS were patch test positive but none of the 19 allopurinol-sensitive patients were positive to allopurinol and its metabolite, oxypurinol. No systemic reactions occurred during or after testing [211]. Hence patch testing may prove useful once the reagent and timing of such testing is optimized. Patch testing has,

and the role of herpetic viruses in this condition is unknown.

detected in skin lesions by PCR or in situ hybridization [183].

**5.4. Differential diagnosis**

characteristic histopathology.

**5.6. Drug allergy testing**

*5.6.1. Patch tests*

**5.5. Pathology**

**Figure 10.** Exfoliative dermatitis involving the hand in a young woman with DIHS/DRESS who had continued to ingest the culprit drug for 4 weeks when this image was taken.


**Table 5.** Internal organ involvement in DIHS

Abacavir, an HIV nucleoside analogue reverse transcriptase inhibitor causes a potentially lifethreatening hypersensitivity syndrome in approximately 5-8% of recipients within 6 weeks of therapy [207],[208]. The clinical and laboratory features of this syndrome differs from typical cases of DIHS/DRESS in that there is a predilection for the gastrointestinal system with nausea, abdominal pain, diarrhoea, and the respiratory tract with cough, pharyngitis and shortness of breath. Headache, myalgia and/or arthralgia may also be present. Eosinophilia is present in < 10% of cases and liver function test abnormalities are detected in < 20% of cases [209]. Also, the manifestations resolve within 72 hours rather than having a protracted relapsing course and the role of herpetic viruses in this condition is unknown.

## **5.4. Differential diagnosis**

Viral infections such as EBV, CMV, and measles can be distinguished by the absence of eosinophilia, hypogammaglobulinemia, and supportive serology. In children, DIHS/DRESS is differentiated from Kawasaki's disease by the absence of a bulbar conjunctivitis, strawberry tongue, coronary aneurysms, hypoalbuminemia and thrombocytosis. Serum sickness is characterized by urticarial lesions and the absence of internal organ involvement. Atopic erythroderma with bacterial infection does not usually involve hepatitis or nephritis. Druginduced pseudolymphoma from carbamazepine or phenytoin is distinguished from DIHS/ DRESS by the absence of internal organ involvement and the prompt resolution of symptoms when the drug is withdrawn. Cutaneous B and T cell lymphomas have an indolent course and characteristic histopathology.

#### **5.5. Pathology**

The histopathology of DIHS/DRESS is relatively non-specific and consists of a lymphocytic infiltrate that is superficial, perivascular, dense and diffuse. Eosinophils may be present but is often absent. The presence of loose rather than discrete granulomatous aggregates of histio‐ cytes have been recently reported (Figs. 11, 12) [210]. This may be due to continued exposure to the culprit drug after the onset of DIHS/DRESS. Granuloma formation occurs as a conse‐ quence of a delayed-type hypersensitivity (type IV) reaction, the classic example of which is the tuberculin reaction where a cutaneous granuloma is induced after injection of purified protein derivative in a previously sensitized individual. The expansion of CD4 cells and the secretion of IFN-γ and other Th-1 cytokines result in the recruitment of macrophages. Sus‐ tained drug exposure and the persistence of cytokine release promote differentiation of macrophages into epithelioid cells, which secrete TNF promoting their fusion to form multi‐ nucleate giant cells and granulomas. HHV-6 and DNA from other herpes viruses may be detected in skin lesions by PCR or in situ hybridization [183].

#### **5.6. Drug allergy testing**

#### *5.6.1. Patch tests*

Abacavir, an HIV nucleoside analogue reverse transcriptase inhibitor causes a potentially lifethreatening hypersensitivity syndrome in approximately 5-8% of recipients within 6 weeks of therapy [207],[208]. The clinical and laboratory features of this syndrome differs from typical cases of DIHS/DRESS in that there is a predilection for the gastrointestinal system with nausea, abdominal pain, diarrhoea, and the respiratory tract with cough, pharyngitis and shortness of

Haemaophagocytic syndrome Rare, occurs 2 weeks after onset of disease[198]

**Figure 10.** Exfoliative dermatitis involving the hand in a young woman with DIHS/DRESS who had continued to ingest

Interstitial nephritis 11%, frequent with Allopurinol-induced

Myocarditis Occurs at onset or 40 days after onset of

Limbic encephalitis 2-4 weeks after onset of DIHS, HHV-6

CMV Gastrointestinal ulceration with bleeding 4-5 weeks after onset of DIHS[197]

Pneumonitis/pleuritis Common in minocycline[192] and abacavir[193]

DIHS[191]

DIHS[194]

induced DIHS

reactivation in CSF[195]

May be assoiciated with SiADH[196]

the culprit drug for 4 weeks when this image was taken.

74 Skin Biopsy - Diagnosis and Treatment

**Manifestation Comments** Hepatitis (mixed hepatocellular and cholestatic) 71%[190]

Parotid gland enlargement Rare[199] Pancreatitis Rare[200]

**Table 5.** Internal organ involvement in DIHS

Santiago et al recently studied the utility of patch testing in DIHS/DRESS and found a positive reaction in 32% of the 56 patients. Patch testing was performed between 6 weeks and 6 months after healing of the lesion and at least one month after corticosteroids were ceased. They found that 76% of the 17 patients with carbamazepine-induced DIHS/DRESS were patch test positive but none of the 19 allopurinol-sensitive patients were positive to allopurinol and its metabolite, oxypurinol. No systemic reactions occurred during or after testing [211]. Hence patch testing may prove useful once the reagent and timing of such testing is optimized. Patch testing has,

however, proven to be very useful in confirming suspected cases for abacavir hypersensitivity

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 77

LTTs are usually negative up to 3 weeks after the onset of DIHS/DRESS but most patients are positive at 5-7 weeks and have persistent responses even at 1 year. Treatment with corticoste‐ roids did not affect the results [97]. One possible explanation for the negative LTT result during the acute phase of DIHS is the expansion T regulatory cells with a naïve phenotype (CD4CD25FoxP3), which then are depleted by apoptosis during the recovery phase. These regulatory T cells are capable of suppressing proliferation of memory T cells in LTTs [55].

The pathogenesis of DIHS/DRESS is still to be fully elucidated. The precise role of HHV-6 in DIHS is unclear. The initiating event may be the reactivation of one or more herpetic viruses, which is clinically unapparent. Virus-stimulated T cells may then cross react with drug-derived hapten-protein conjugates that are presented by dendritic cells to naïve antigen-specific CD4 T-cells with the subsequent differentiation into effector/memory CD4 cells. These dendritic cells may also activate CD8 T-cells by cross-presentation. The expansion of effector CD4 T-cells with their production of IFN-γ and other cytokines results in recruitment and activation of macrophages. Failure to eradicate the antigenic stimulus, in this instance due to the continued ingestion of the drug, causes persistent cytokine release and promotes differentiation of macrophages into epithelioid cells, which secrete large amounts of TNF promoting their fusion to form multinucleate giant cells [210]. Analogous to that observed in GVHD, longitudinal real-time PCR analyses of viral loads in blood samples drawn from patients with DIHS show that various herpetic viruses are sequentially activated as a result of massive T cell stimulation, B cell loss and hypogammaglobulinemia [213]; Activation of Epstein-Barr virus or HHV-6 extends to the sequential activation of HHV-7, cytomegalovirus and varicella-zoster virus [189]. The frequent deterioration or several exacerbations that occur despite continuation of the drug may at least be partly explained by sequential reactivation of herpetic viruses and the immune response to viral replication. An alternative explanation is that drug specific T cells are activated resulting in reactivation of the viral genome and sequential reactivation of

Genetic susceptibility may also play a role as all patients with allopurinol-induced DIHS in a Han Chinese population harboured the *HLA-B\*5801* allele compared with 15% of control subjects [67]. Recently, an association was described between *HLA-A\*3101* and DIHS in Northern Europeans; OR 12.41 [1.27-121.03] [64] and in the Japanese; OR 9.5 [4.6–19.5] [65]. In a Western Australian HIV Cohort Study, *HLA-B\*5701* was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients; OR 117 [29-481] [193]. There is a discrepancy in the association of *HLA-B\*5701* and abacavir hyper‐ sensitivity across various racial groups The association was confirmed in a separate cohort of HIV-infected white Americans and was also found to confer susceptibility in Hispanics but not in blacks [214]. No association was found in a cohort of Korean patients [215]. Hence

with a higher degree of specificity than can be confirmed clinically [212].

*5.6.2. Lymphocyte transformation tests(LTTs)*

**5.7. Pathogenesis**

herpes viruses.

**Figure 11.** Low power view of a skin biopsy from a patient with DIHS demonstrating the superficial dermal nature and perivascular distribution of the inflammatory infiltrate with acanthosis and hyperkeratosis of the epidermis (Hematox‐ ylin-eosin, original magnification x40).

**Figure 12.** High power view of a skin biopsy from a patient with DIHS demonstrates granulomatous inflammation with prominent, but relatively loosely aggregated histiocytes, mixed with lymphocytes. Eosinophils are absent (Hema‐ toxylin-eosin, original magnification x200).

however, proven to be very useful in confirming suspected cases for abacavir hypersensitivity with a higher degree of specificity than can be confirmed clinically [212].

#### *5.6.2. Lymphocyte transformation tests(LTTs)*

LTTs are usually negative up to 3 weeks after the onset of DIHS/DRESS but most patients are positive at 5-7 weeks and have persistent responses even at 1 year. Treatment with corticoste‐ roids did not affect the results [97]. One possible explanation for the negative LTT result during the acute phase of DIHS is the expansion T regulatory cells with a naïve phenotype (CD4CD25FoxP3), which then are depleted by apoptosis during the recovery phase. These regulatory T cells are capable of suppressing proliferation of memory T cells in LTTs [55].

#### **5.7. Pathogenesis**

**Figure 11.** Low power view of a skin biopsy from a patient with DIHS demonstrating the superficial dermal nature and perivascular distribution of the inflammatory infiltrate with acanthosis and hyperkeratosis of the epidermis (Hematox‐

**Figure 12.** High power view of a skin biopsy from a patient with DIHS demonstrates granulomatous inflammation with prominent, but relatively loosely aggregated histiocytes, mixed with lymphocytes. Eosinophils are absent (Hema‐

ylin-eosin, original magnification x40).

76 Skin Biopsy - Diagnosis and Treatment

toxylin-eosin, original magnification x200).

The pathogenesis of DIHS/DRESS is still to be fully elucidated. The precise role of HHV-6 in DIHS is unclear. The initiating event may be the reactivation of one or more herpetic viruses, which is clinically unapparent. Virus-stimulated T cells may then cross react with drug-derived hapten-protein conjugates that are presented by dendritic cells to naïve antigen-specific CD4 T-cells with the subsequent differentiation into effector/memory CD4 cells. These dendritic cells may also activate CD8 T-cells by cross-presentation. The expansion of effector CD4 T-cells with their production of IFN-γ and other cytokines results in recruitment and activation of macrophages. Failure to eradicate the antigenic stimulus, in this instance due to the continued ingestion of the drug, causes persistent cytokine release and promotes differentiation of macrophages into epithelioid cells, which secrete large amounts of TNF promoting their fusion to form multinucleate giant cells [210]. Analogous to that observed in GVHD, longitudinal real-time PCR analyses of viral loads in blood samples drawn from patients with DIHS show that various herpetic viruses are sequentially activated as a result of massive T cell stimulation, B cell loss and hypogammaglobulinemia [213]; Activation of Epstein-Barr virus or HHV-6 extends to the sequential activation of HHV-7, cytomegalovirus and varicella-zoster virus [189]. The frequent deterioration or several exacerbations that occur despite continuation of the drug may at least be partly explained by sequential reactivation of herpetic viruses and the immune response to viral replication. An alternative explanation is that drug specific T cells are activated resulting in reactivation of the viral genome and sequential reactivation of herpes viruses.

Genetic susceptibility may also play a role as all patients with allopurinol-induced DIHS in a Han Chinese population harboured the *HLA-B\*5801* allele compared with 15% of control subjects [67]. Recently, an association was described between *HLA-A\*3101* and DIHS in Northern Europeans; OR 12.41 [1.27-121.03] [64] and in the Japanese; OR 9.5 [4.6–19.5] [65]. In a Western Australian HIV Cohort Study, *HLA-B\*5701* was present in 14 (78%) of the 18 patients with abacavir hypersensitivity, and in four (2%) of the 167 abacavir tolerant patients; OR 117 [29-481] [193]. There is a discrepancy in the association of *HLA-B\*5701* and abacavir hyper‐ sensitivity across various racial groups The association was confirmed in a separate cohort of HIV-infected white Americans and was also found to confer susceptibility in Hispanics but not in blacks [214]. No association was found in a cohort of Korean patients [215]. Hence screening for *HLA-B\*5701* is not useful in predicting sensitivity in all patients. The racial variation may be partly explained by the differences in MHC haplotypes across different racial groups. The Caucasian 57.1 ancestral haplotype, which confers susceptibility to abacavir hypersensitivity possibly as a result of strong linkage disequilibrium with other candidate genetic factors such as cellular chaperones (e.g. heat shock proteins), inflammatory cytokines (e.g. TNF), and proteins involved in the stress response (e.g. MHC class I chain-related genes, MIC-A and MIC-B). African populations do not demonstrate this haplotype [216]. However, in a recent study by Saag et al, all 42 white patients with immunologically confirmed (i.e. positive patch tests) hypersensitivity reactions were *HLA-B\*5701* positive (sensitivity 100%, OR 1945 [110-34,352]) but in addition all 5 black patients with immunologically confirmed hypersensitivity reactions were *HLA-B\*5701* positive (sensitivity 100%, OR 900 [ 38-21,045]. Screening for the *HLA-B\*5701* has eliminated immunologically confirmed cases of abacavir hypersensitivity [217].

**6.2. Epidemiology**

**6.3. Clinical features**

[226].

[227],[228].

**6.4. Etiology**

it was 11 days [18].

AGEP is rare with an incidence of 1-5 cases per million per year [223]. The EuroSCAR study comprising 97 validated cases of AGEP recruited from Austria, France, Israel, Italy and the Netherlands, revealed a mean age (±SD) of 56 (±21) years and a female preponderance with a male/female ratio of 0.8 [18]. The predominance in women was shown to be even greater in case series reports from Taiwan (68.7% of 16 cases) [224], and Israel (76.9% of 13 cases) [225]. AGEP has been reported in children, with the largest pediatric series of 20 cases from China

The clinical manifestations are characterized by fever and a pruritic or burning edematous erythema (Figs. 13 A&B) followed by the rapid appearance of dozens of small (< 5 mm) nonfollicular sterile pustules (Fig. 14). The skin lesions are often accentuated in the intertriginous

third of cases, a mild eosinophilia. A mild non-erosive mucous membrane involvement occurs in 20% of cases. Internal organ involvement is uncommon and usually is confined to a slight

The clinical course is characterized by spontaneous resolution of skin and systemic manifes‐ tations over a period of up to 15 days once the offending agent is withdrawn [223]. AGEP has a favourable prognosis; the reported mortality rate is up to 5% and poor outcomes usually result from secondary infection in the elderly or those patients with significant comorbidities

AGEP is caused by drugs in at least 90% of cases. According to the EuroSCAR study, the agents conferring the highest risk are pristinamycin, aminopenicillins, hydroxychloroquine, antibac‐ terial sulphonamides, terbinafine and diltiazem [18]. The latent period is short (usually 1-5 days) with the EuroScar study demonstrating that it may vary for different drugs. For antibiotics, including sulphonamides, the median latent period was 1 day, and for other drugs

Contact sensitivity has been implicated in a few case reports. Causative agents include mercury[229], and bufexemac, a potent topical NSAID[230]. Neither of these agents was implicated in the 97 cases of AGEP in the EuroScar. The role of infectious agents in AGEP has been suggested in various case reports due to the absence of an inciting drug [231]. The organisms include coxsackie B4 [232], cytomegalovirus [233], parvovirus B19 [234], *Chlamydia pneumoniae* [235], and *Escherichia coli* [236]. No significant risk for infection was found in the EuroScar study although the study was not designed to identify potential causative organisms. Spider bites were suggested as a cause AGEP in a series of three cases from Israel, presumably as a result of the venom's ability to induce IL-8 and GM-CSF [237]. Finally, as illustrated in

two recent cases, AGEP may develop without preceding medication or disease [238].

/L) and in a

Severe Cutaneous Adverse Reactions http://dx.doi.org/10.5772/54820 79

areas (Fig. 13 C). There is usually an accompanying marked neutrophilia (7 x 109

reduction in creatinine clearance and mild elevation of aminotransferases.

#### **5.8. Treatment**

Early recognition of the syndrome with cessation of the causative drug is essential in improving patient outcomes. No randomized controlled trials have been conducted to determine the appropriate adjunctive therapy for DIHS/DRESS. Oral corticosteroids at 1 mg/kg/daily is commenced and tapered over at least 6-8 weeks to prevent relapse of various cutaneous and visceral manifestations of the syndrome. If symptoms deteriorate despite corticosteroid therapy then IVIg [218],[219], plasma exchange [220], rituximab, gangciclovir or a combination of these modalities [221] can be considered.

Recently, the French Society of Dermatology formulated guidelines on the management of DIHS/DRESS [133]:

