Drug Induced Hypersensitivity Syndrome (DIHS) Patient

Characteristics in Dermatology and Venereology Department, Dr.

Cipto Mangunkusumo National General Hospital in the Period 2014

to 2017

Teffy Nuary, Sarah Mahri, Windy Keumala B.

Deparment of Dermatology and Venereology Faculty of Medicine Universitas Indonesia/ Dr. Cipto Mangunkusumo

National General Hospital, Indonesia

Keywords: Drugs induced hypersensitivity, adverse drug reaction, characteristics, eosinofilia, culprit drugs.

Abstract: Drug induced hypersensitivity syndrome (DIHS) is a distinct, severe, idiosyncratic reaction to a drug

characterized by a prolonged latency period with cutaneous presentation and internal organ involvement. In

Asia, DIHS was reported to almost one tenth of adverse drug reaction cases, with a mortality rate ranged 3-

10%. The aim of this study are to describe the sociodemographic and clinical characteristics of patients with

DIHS and causative agents in Dermatology and Venereology Department Dr. Cipto Mangunkusumo National

General Hospital, Jakarta. This study is a descriptive study. Using medical records and electronic health

record of patients with DIHS were retrospectively reviewed. During 2014-2017 we identified 18 female, 14

male patients, with age range 14-87 years. Onset of the disease since exposed by culprit drugs were 14-40

days.The most common underlying disease was accute infection disease (43,7%). The DIHS clinical features

and laboratory finding in this study are fever (93,7%), maculopapular rash (90,6%), target lesions (12,5 %),

facial oedema (21,5%), periorbital oedema (12,5%). lymph nodes enlargement (93,7%), eosinofilia (31,2 %)

, elevating of liver function (100%), and one patients (3,1%) showed kidney involvement .The most common

causative drugs were antibacterials (60 %). all patients, the causative drug was discontinued and treated with

systemic corticosteroids. As the conclusion DIHS is a severe drug hypersensitivity reaction with prominent

cutaneous and systemic manifestations. Dispite the limitations, this study present some variations of DIHS

clinical features and many other drugs that implicated.

1 INTRODUCTION

Drug induced hypersensitivity syndrome (DIHS) is a

distinct, severe, idiosyncratic reaction to a drug

characterized by a prolonged latency period. It is a

life-threatening disease with cutaneous presentation

and internal organ involvement. Mechanisms that

have been implicated in DIHS include drug

detoxification enzyme abnormalities with subsequent

accumulation of reactive drug metabolites, sequential

reactivation of herpesviruses, such as

cytomegalovirus, Epsteine Barr virus, human

herpesvirus-6 and -7, and genetic predisposition

associated with certain human leukocyte antigen

alleles. DIHS clinical manifestations, usually fever,

rash, lymphadenopathy, eosinophilia, and a wide

range of mild-to-severe systemic presentations

(Husain et al, 2013). In Diagnose DIHS, clinicians

must exclude other potentially serious conditions,

including infections, neoplastic processes,

autoimmune disorders, and connective tissue disease.

Clinical testing and biopsy can be helpful, but are not

always specific (Husain et al, 2013) (Avancini et al,

2015). Scoring systems based on diagnostic criteria

have been developed by the European Registry of

Severe Cutaneous Adverse Reaction (RegSCAR):

acute rash, reaction suspected to be drug-related,

hospitalization, fever >38

enlarged lymph nodes

involving >2 sites, Involvement of > 1 internal organ,

blood count abnormalities, lymphocytes above or

below normal limits, platelets under normal limits

(Hiransuthikul et al, 2016).

In Asia, DIHS was reported to almost one tenth of

adverse drug reaction cases, with a mortality rate

ranged 3-10%. Mortality cases were mainly caused

by multiple organ failure and sepsis. Various

Nuary, T., Mahri, S. and B., W.

Drug Induced Hypersensitivity Syndrome (DIHS) Patient Characteristics in Dermatology and Venereology Department, Dr. Cipto Mangunkusumo National General Hospital in the Period

2014 to 2017.

DOI: 10.5220/0008152301270131

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 127-131

ISBN: 978-989-758-494-7

127

medications have been described to be the cause of

DIHS (Hiransuthikul et al, 2016) (Chen et al, 2010).

The aims of this study are to describe the

sociodemographic and clinical characteristics of

patients with DIHS and causative agents in

Dermatology and Venereology Department dr. Cipto

Mangunkusumo Hospital, Jakarta within 2014 - 2017.

2 METHODS

This study is a descriptive retrospective study of

DIHS patients at dr. Cipto Mangunkusumo Hospital

between January 2014 and December 2017. The

medical records and electronic health record of

patients with DIHS were retrospectively reviewed.

The diagnostic criteria used in this study were

purposed by RegiSCAR. Hospitalization and reaction

suspected to be drug related were mandatory for

diagnosis. Also, 3 out of the following 7 criteria were

needed to fulfill the diagnosis: acute skin rash, fever

above 38

C, enlarged lymph node at 2 or more sites,

involved at least 1 internal organ, lymphocyte count

above or below laboratory limits, eosinophil count

above laboratory limits, and platelet count below

laboratory limits. This study has been approved by the

Health Research Ethical Committee of the Faculty of

Medicine, Universitas Indonesia.

3 RESULTS

A total of 32 medical records of DIHS patients in Dr.

Cipto Mangunkusumo Hospital in January 2014 –

December 2017 were reviewed in this study. This

study identified 18 females, 14 male patients, with

age range 14-87 years who fulfill the RegiSCAR

criteria. Onset of the disease since elicited by culprit

drugs 14-40 days. The most common underlying

disease was accute infection disease (43,7%). The

DIHS clinical features and laboratory finding in this

study are fever (93,7%), maculopapular rash (90,6%),

target lesions (12,5 %), facial oedema (21,5%),

periorbital oedema (12,5%). lymph nodes

enlargement (93,7%), eosinofilia (31,2 %), elevating

of liver function (100%) and one patient showed

kidney involvement (3,1%). (Table. 1). The most

common causative drugs were antibacterials (60 %)

(Figure. 1, Table.2). The causative drug was

discontinued in all patients and treated with systemic

corticosteroids. There were four patients in this study

who had done the patch test. One patient had positive

result and relevan to rifampicin, dapsone,

paracetamol, klofazimin, and one patient had positive

result to rifampicin and isoniazid

. Two other

patients showed negative results.

4 DISCUSSION

DIHS is a rare, potentially life-threatening adverse

drug reaction with cutaneous manifestations and

internal organ involvement that occurs in both adults

and children. The latency period of DIHS is longer

than dose Steven - Johnson syndrome (SJS), Toxic

epidermal necrolysis (TEN, acute generelized

exanthematous pustulosis, fixed drug eruptions and

MPE, which all belong to delayed type

hypersensitivity (Shiohara et al, 2017). This study

showed the onset of DIHS were in range 14-40 days

after the start of eliciting drugs. Some study found

that longer period of latency may results in a failure

to properly make the diagnosis (Shiohara et al, 2017)

(Wang et al, 2017).

At the beginning, patients may expirience some

prodormal symptoms before or along with the

development of skin rash. These syptoms include

fever, pruritus, dysphagia, pain (Cho et al, 2017)

(Shiohara et al, 2017). There were 93,7% DIHS

patiens in this study had fever more than 38

C as

prodormal symptom. Although there can be various

cutaneous manifestations, in this study, almost all

patients had maculopapular (90,6%) rash, and some

patients had combination skin rash including,

maculopapular rash, target lesions, facial edema dan

periorbital edema. Akarin et al found. All DIHS

patients presented with rash, almost all were

maculopapular type (94.2%).

RCD 2018 - The 23rd Regional Conference of Dermatology 2018

128

Table 1. DIHS patient characteristics in Department of Dermatology and Venereology, dr. Cipto Mangunkusumo Hospital

between January 2014 and December 2017.

n=32%

Age

43 (14-87) -

Sex

Male

Female

56,3

43.7

Onset (days)

18 (14-40) -

Clinical Symptoms

Skin Rash

Maculopapular Rash

Target Lesion

Facial Oedema

Periorbital Oedema

90,6

12.5

21.8

12.5

Fever >38

C 30 93.7

Enlar

ed l

h nodes involvin

> 2sites 30 93.7

Underlying disease

Accute Infection

Dermatomyositis

Tuberculosis

Convulsion Disorders

Hypothiroid

Leprosy

Cardiovascullar Disease (CVD)

Chronic Kidney Disease

Diabetes Melitus

Hypertension

Poliomiolitis

HIV

43,7

12.5

3.1

15.6

3.1

Internal Organ Involvement

Liver

Elevation of liver function

AST (U/L)

ALT (U/L)

Kidney

165 (42-654)

175 (45-483)

100

3,1

Eosinofil

Eosinophilia

Eosinophil level ove

laboratory limits (µL)

756 (501-6730)

31.2

Therapy

Corticosteroid (methylprednisolon)

1 mg/Kg

Length of Stay (days)

1,5 mg/Kg

Len

th of Sta

(

)

8 (6-15)

(

6-23

)

56.2

43.8

There were 93,7 % patients who showed enlarged

of lymph nodes involving two sites or more in this

study. Akarin et al and Prannee et al, showed

patients may have limited lymph node involvement

or generalized. lymphadenopathy with localized

tenderness involving the cervical, axillary, and

inguinal lymph nodes. In approximately 31,2% of

cases in this study, there is eosinphilia With > 5.0x

eosinophils/L. Eosiophilia can be delayed for 1

to 2 weeks. Hypereosinophilia likely plays a role in

visceral manifestations because eonsinophil granule

proteins are toxic to many tissues (Wang et al,

2017). The liver is the most frequently affected

visceral organ in DIHS, oftennwith varying degrees

of hepatitis (Wongkitisophon et al, 2012). All

patients in this study had elevating of liver function.

Stander et al, found there were Phenytoin,

minocycline, and dapsone are commonly

implicated. The elevated liver enzymes may persist

for several days after withdrawal of culprit drug, but

Drug Induced Hypersensitivity Syndrome (DIHS) Patient Characteristics in Dermatology and Venereology Department, Dr. Cipto

Mangunkusumo National General Hospital in the Period 2014 to 2017

129

may sometimes take months to completely resolve

(Wongkitisophon et al, 2012) (Shiohara et al, 2006).

There were one patients showed kidney

involvement that presented by increasing of urea

and creatinin. There were no lung and heart

alterations. Li Wang et al presented that damage

occurred most commonly to the liver, followed by

the kidneys.

Figure 1. Culprit drugs

Table 2. Culprit drug details of the DIHS in Department of Dermatology and Venereology, dr. Cipto Mangunkusumo

Hospital between January 2014 and December 2017

Drug Categories Drug Names*

Antibacterial Cefadroxil, ceftriaxon, cefixim,

tiamfenicole, ciprofloxacin, ofloxacin,

metronidazole, mero

ene

Antipyretic/ Analgetic Paracetamol, tramadol, ibuprofen,

metampiron, mefinamic aci

Anticonvulsant Carbamaze

in, halo

eridol, Phen

toin

Antituberculosis Rifampicin, isoniazid, ethambutol,

irazinami

Antiretroviral Lamivudine, zidovudine, nevirapine

Antiulcerative Ome

razole, lanso

razole

Sulfonami

sone

Antih

ertensive Amlodi

ine, nifedi

ine

Antiemetic Ondancentron, domperidone

Diuretic Furosemide

Gastric acid suppressant Ranitidine

Others Pet tze huang

*The drug names are arranged respectively

Many drugs have been reported to be a causative

agent of DIHS. However, only a limited number of

drugs are frequently encountered as culprits,

including anti-convulsants, antibacterials

,antivirals, antipyretics, and others (Wang et al,

2017) (Stander et al, 2013). The most peculiar

feature of these culprits is a long latent period,

which ranges from 3 to 8 weeks after

commencement of the drugs (Shiohara et al, 2017).

This study present the most common culprit drugs

were antibacterials (cefadroxil, ceftriaxon, cefixim,

tiamfenicole, ciprofloxacin, ofloxacin,

metronidazole, meropenem, respectively) that

might be associated with the most common patients

underlying disease in this study were accute

infection diseases (43,7%) including acute

respiratory tract, urinary tract infections, and other

secondary infection.

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130

In all patients, the causative drug was

discontinued. All patiens were treated with systemic

corticosteroids, eighteen patients got 1mg/kg body

weight and fourteen patients got 1,5 mg/kg weight

methylprednisolon as initial dose. The state of the

patients was a consideration to determine the initial

dose. This study showed patient who got higher

initial dose had longer length of stay, patient

underlying disease were thought as the factors that

contributing. In this study just four patients who

underwent patch test. Some difficulties were

thought due to DIHS latency and patients

complience.

Study limitations include a retrospective study,

small number of subjects. More epidemiology study

to confirm and provide more useful clinical

information for early detection and improve the

outcome of severe cutaneous adverse reactions

Including DIHS is needed.

5 CONCLUSION

DIHS is a severe drug hypersensitivity reaction with

prominent cutaneous and systemic manifestations.

Dispite the limitations, this study presents some

variations of DIHS clinical features. Although it is

classically caused by anticonvulsants and

sulfonamides, many other drugs have been

implicated, such as antibiotics. More larger

epidemiology study either retrospective or

prospective are needed to provide more useful

clinical informations.

ACKNOWLEDGEMENT

Thanks to medical record staffs helping, for data

collecting.

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Mangunkusumo National General Hospital in the Period 2014 to 2017

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