Drug reaction with eosinophila and systemic symptoms

Drug Reaction with
Eosinophilia and Systemic
Symptoms ( DRESS )
Amornrat Prasertcharoensuk , MD.
14 july 2017

Overview
• Historical Background
• Etiology
• Pathogenesis
• Clinical features
• Histopathologic finding
• Diagnosis criteria
• Differential diagnosis
• Clinical testing
• Treatment
• Prognosis

Historical Background
Year Event
1930 phenytoin first became available observed in patients treated
with anticonvulsants .
1950 reported a case of fever, hepatitis, and exfoliative dermatitis
by Chaiken et al .(Dilantin Hypersensitivity )
1959 described this cutaneous drug reaction as pseudolymphoma
by Saltzstein et al .
hypersensitivity syndrome and mononucleosis-like syndrome
1996 Proposed the term DRESS by Bocquet et al .
Zain Husain, MD,a Bobby Y. Reddy, MD,b and Robert A. Schwartz, MD, MPH, FRCP (Edin)c Washington, DC;
Boston, Massachusetts; and Newark, New Jersey J Am Acad Dermatol 2013;68:693.e1-14.

The lymphadenopathy is usually associated with the more common
manifestations of drug reactions, such as esoinophilia, fever, blood
dyscrasias, and skin disorders .
Histologically ,characteristically, there is hyperplasia of the reticulum cells
and infiltration with eosinophils .
Histologically, in the drug reaction there is not the uniform picture of
mature lymphocytes ,ReedSternberg cells are never seen, and the nodes
in the drug reaction are usually discrete rather than matted. There is also
less fibrosis in the drug reaction
CANCER January-February 1959

DRESS
by Bocquet, H., Bagot, M., Roujeau, J.C.
Department of Dermatology, Universite Paris XII, Hopital Henri Mondor,France
two different patterns:
(1) hypersensitivity syndrome which begins acutely in the first 2 months
after the initiation of the drug and associates fever, a severe skin disease
with characteristic infiltrated papules and facial edema or an exfoliative
dermatitis, lymphadenopathy, hematologic abnormalities
(hypereosinophilia, and atypical lymphocytes) and organ involvement
such as hepatitis, carditis, interstitial nephritis, or interstial pneumonitis.
(2) drug-induced pseudolymphoma which has a more insidious beginning
with nodules and infiltrated plaques appearing several weeks after the
beginning of the drug without constitutional symptoms..
Seminars in Cutaneous Medicine and Surgery Volume 15, Issue 4, 1996, Pages 250-257

ETIOLOGY
• severe hypersensitivity to a medication and its reactive drug
metabolites , which may be associated with enzymatic
defects in drug metabolism .
• Immunosuppression especially when accompanied by a
primary or reactivation human herpesvirus-6
(HHV-6) infection
Zain Husain, MD,a Bobby Y. Reddy, MD,b and Robert A. Schwartz, MD , J Am Acad Dermatol
2013;68:693.e1-14.

Zain Husain, MD,a Bobby Y. Reddy, MD,b and Robert A. Schwartz, MD , J Am Acad Dermatol 2013;68:69

British Jourmi of Dcrmatohgij 1997: 1 57: 605-608

Human Herpesvirus 6 Infection as a Risk Factor for the Development of Severe Drug-Induced Hypersensitivity Syndrome, Arch Dermatol. 1998;134(9):1108-1112.
.
Clinical course of a patient with a severe drug-induced
hypersensitivity syndrome in relation to antibody titers against
various viruses

Pathogenesis
• Genetic Factors
• Viral reactivation

Journal of Allergy and Clinical Immunology 2015 136, 219-234DOI: (10.1016/j.jaci.2015.05.050)

Pathogenesis
•Genetic Factors
•Viral reactivation

Journal of Allergy and Clinical Immunology 2015 136, 219-234DOI
Models of T – cell activation by small molecules

Genetic Factors
• Gene encoding metabolizing enzyme for drugs
- cytochrome P (CYP) 450 enzyme
- N-acetyltransferase
- CYP2C9*3
• Gene encoding HLA molecules
Yung-Tsu Cho, Che-Wen Yang and Chia-Yu Chu , Int. J. Mol. Sci. 2017, 18, 1243

Associations between HLA alleles and DRESS
syndrome
Yung-Tsu Cho, Che-Wen Yang and Chia-Yu Chu , Int. J. Mol. Sci. 2017, 18,

Journal of Allergy and Clinical Immunology 2015

Viral Reactivation
-
• Direct effect of drugs or metabolites on viral reactivation
• In vitro
- early stage of DRESS syndrome, or DiHS, the number of Treg cells
expands, even as a reduced number of B cells and hypogammaglobulinemia
- pro-inflammatory cytokines and chemokines, such as
TNF-α, IFN-γ, IL-1, IL-2, IL-6, are seen in lower levels in the early stage of the
disease in patients with HHV-6 reactivation than in those without HHV-6
reactivation,
with the exception of one chemokine, interferon γ-induced protein (IP)-10

Yoko Kano, MD; Miyuki Inaoka, MD; Tetsuo Shiohara, MD ,Arch Dermatol. 2004;140:183-188

Yoko Kano, MD; Miyuki Inaoka, MD; Tetsuo Shiohara, MD ,Arch Dermatol. 2004;140:183

Yoko Kano, MD; Miyuki Inaoka, MD; Tetsuo Shiohara, MD ,Arch Dermatol. 2004;140:183-
188

A decrease in immunoglobulin levels and
B-cell counts can be associated with HHV-6
reactivation and the subsequent onset of AHS.
These immunological alterations might be a
useful predictor of the development of AHS.
Yoko Kano, MD; Miyuki Inaoka, MD; Tetsuo Shiohara, MD ,Arch Dermatol. 2004;140:183

Yung-Tsu Cho, Che-Wen Yang and Chia-Yu Chu , Int. J. Mol. Sci. 2017, 18

Skin lesion
Present in 73-100% .
Facial edema found in
76% of patients, is the
hallmark feature of disease

Skin lesion
J Am Acad Dermatol 2013;68:693.e1-1

Skin lesion
J Am Acad Dermatol
2013;68:693.e1-14.

Internal organ involvement
• Both hematological abnormalities and impairment of solid organs.
• Hematological changes , eosinophilia is the most common (66-95%)
,atypical lymphocyte (27-67%)
• Lymphadenopathy (54%)
• Decreased number of B lymphocytes with hypoglobulinemia.
Yung-Tsu Cho, Che-Wen Yang and Chia-Yu Chu , Int. J. Mol. Sci. 2017, 18, 1

Internal organ involvement
Liver injury found in 75-94% of patients: cholestatic type 44%
, mixed type 33% , hepatocellular type 23%
Renal involvement (12-40%) :allopurinol is the most notorious
one .
Lung involvement : interstitial pneumonitis ,pleuritis,acute
respiratory distress
Cardiac involvement ( 4-27% ) :hypersensitivity myocarditis,
acute necrotizing eosinophilic myocarditis .
Neurologic involvement (menigitis,encephalitis )
1243

Clinical courses
Yung-Tsu Cho, Che-Wen Yang and Chia-Yu Chu , Int. J. Mol. Sci. 2017, 18

Clinical courses
Tetsuo Shiohara1, Miyuki Inaoka1 and Yoko Kano1, Allergology International Vol 55, No1,

Zain Husain, MD,a Bobby Y. Reddy, MD,b and Robert A. Schwartz, MD , J Am Acad Dermatol 2013;68:6

Zain Husain, MD,a Bobby Y. Reddy, MD,b and Robert A. Schwartz, MD , J Am Acad Dermatol 2013;68:693.e1-1

Clinical testing
• patch testing. Its negative predictive values (NPVs) and positive
predictive values (PPVs) are unknown. The PPV of patch testing
under optimal conditions was as high as 80% to 90% for certain drugs,
but only around 10% to 20% for other medications.
Santiago et al reported an overall 32.1% positive patch test result
in patients with DRESS syndrome, with 51.5% reactivity among all
antiepileptics and 72.2% with carbamazepine alone. This contrasts with
the 0% reactivity seen with allopurinol as the causative
agent
As a result, a positive patch test is a highly reliable indicator of an inflammatory
cutaneous hypersensitivity reaction, while a negative test does not exclude it.
J Am Acad Dermatol 2013;68:693.e1-14.

Clinical testing
• LTT technique has a general sensitivity in the range of 60% to
70% and an overall specificity of at least 85%
• it is recommended to perform LTT 5 to 8 weeks after the onset of DRESS
syndrome
• limitations of LTT include its cumbersome nature, the need for significant
experience
with cellular techniques, expensive equipment, and
the reliance upon an interpreter with a strong background in pharmacology
and immunology
because of its limited sensitivity, a negative LTT cannot exclude drug
hypersensitivity

Prognosis and Long-Term Sequelae

Journal of Dermatology 2015; 42: 276–282

Treatment
Tetsuo Shiohara, Yoko Kano, Kazuhisa Hirahara & Yumi Aoyama, Expert Opinion on Drug Metabolism & Toxicology, 13:7, 701-704

- should not be given empiric antibiotics or anti-inflammatory drugs during the
acute stages of DRESS syndrome
- minimum dose of 1.0 mg/kg/day of prednisone or equivalent. Gradual taper over 3 to
6 months after clinical and laboratory stabilization is recommended to avoid relapse
- Can be treated with intravenous methylprednisolone. A course of pulsed
methylprednisolone, 30 mg/kg intravenously for 3 days
- Immunosuppression from steroid therapy may promote the reactivation of viruses,
such as HHV-6 or CMV

Alternative steroid-sparing therapies :
• nevirapine-induced DRESS syndrome successfully treated with IVIG (1 g/kg
for 2 days).
• Did not recommend the use of IVIG monotherapy in the treatment of
DRESS syndrome.
• IVIG is thought to be effective in DRESS syndrome therapy because it
replenishes the low immunoglobulin levels in the patient’s blood, supports
immune protection against HHV-6, and has antiinflammatory properties
• Plasmapharesis and immunosuppressive drugs,
such as cyclophosphamide, cyclosporine, interferons,
muromonab-CD3, mycophenolate mofetil, and rituximab, may also be
potential therapies

A consensus group of the French Society of Dermatology
has published recommendations
1) withdrawal of the culprit drug. Absence of signs of severity
2) systemic corticosteroids equivalent to 1 mg/kg/day of prednisone is
warranted. If life-threatening signs can be treated with steroids
and IVIG at not be administered without associated steroids.
3) In cases with signs of severity with confirmation of major viral
reactivation, antiviral medications such as ganciclovir can be given
in addition to steroids and /or IVIG. a dose of 2 g/kg over 5 days.
The IVIG should

J Am Acad Dermatol 2013;68:693.e1-14

Take Home Message
DRESS syndrome is a potentially fatal cutaneous drug reaction with a
10% mortality rate.
Diagnosis using clinical criteria, laboratory values,histopathology, and
diagnostic testing is imperative.
The offending drug should be immediately discontinued and the
patient given supportive care in an inpatient setting to minimize
complications.
Severe cases of DRESS syndrome require systemic corticosteroids or
other immunotherapeutic treatments

Drug reaction with eosinophila and systemic symptoms

Drug reaction with eosinophila and systemic symptoms

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