Drug-induced Hypersensitivity Syndrome in a Breast Cancer Patient:

A Case Report

Raditya Bagas Wicaksono

, Wahyu Djatmiko

, Ismiralda Oke Putranti

Department of Bioethics and Humanities, Faculty of Medicine Universitas Jenderal Soedirman, Purwokerto, Indonesia

Department of Internal Medicine, Faculty of Medicine Universitas Jenderal Soedirman

Department of Dermatovenerology, Faculty of Medicine Universitas Jenderal Soedirman

Keywords: Drug Allergy, Drug Eruption, DIHS, Breast Cancer.

Abstract: Drug-induced hypersensitivity syndrome (DIHS) is a life-threatening condition. The diagnosis of DIHS is

quite challenging due to highly variable clinical manifestations. This paper was aimed to describe the

diagnosis criteria, pathogenesis, and relation of DIHS with cancer. We describe a case of DIHS, probably

induced by cefadroxil, in a 50-year-old woman post modified radical mastectomy for her non-specific-type

unilateral breast cancer. After four weeks of cefadroxil therapy, the patient started to develop symptoms of

drug eruption with elevated liver function tests, direct bilirubin, alkaline phosphatase (ALP), and gamma-

glutamyl transferase (GGT). The laboratory tests also showed decreased hemoglobin and albumin. The

patient's clinical manifestations were highly suggestive of DIHS. Discontinuation of drug consumption and

administration of symptomatic therapy did not improve the condition. After four days of postoperative

monitoring in the intensive care unit, the patient did not survive the external and internal bleeding due to

severe thrombocytopenia. Several hypothetical mechanisms involved in this syndrome include defective

detoxifying enzymes, genetic defects related to human leukocyte antigen, viral infections, and concurrent

disease processes, such as a neoplasm.

1 INTRODUCTION

Drug-induced hypersensitivity syndrome (DIHS) is

one of the adverse drug reactions with systemic

manifestation. Approximately 15,1% of adverse drug

reaction happens during hospitalization, and 6,7% of

them are a severe adverse drug reaction (Demoly et

al., 2014). The diagnosis of DIHS is quite challenging

due to highly variable clinical manifestations. The

DIHS is also recently referred to as DRESS (drug

reaction with eosinophilia and systemic symptoms) or

DIDMOHS (drug-induced delayed multi-organ

hypersensitivity syndrome) (Kumari et al., 2011).

A recent report from a tertiary hospital in

Indonesia showed that drug eruption with

maculopapular rash was the most common diagnosis

(29,82%) in drug hypersensitivity reaction patients,

with antibiotics as the most frequent culprit drug

(29,8%). Septic shock was the condition that

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increases the mortality of the patients (Soegiarto and

Putra, 2020).

The diagnosis of DIHS/DRESS is sometimes

difficult due to its similar characteristics with viral

exanthems. Physicians are often more aware of other

severe adverse reactions to drugs such as Stevens-

Johnson Syndrome and Toxic Epidermal Necrolysis

(SJS–TEN) Acute Generalized Exanthematous

Pustulosis (AGEP) than the DIHS. We want to raise

awareness of DIHS, which could happen to any

patient, including cancer patients. A better

understanding of this condition might improve

survival and life expectancy. In this case report, we

want to describe the diagnosis criteria and

pathogenesis of the DIHS.

Wicaksono, R., Djatmiko, W. and Putranti, I.

Drug-induced Hypersensitivity Syndrome in a Breast Cancer Patient: A Case Report.

DOI: 10.5220/0010490702410244

In Proceedings of the 1st Jenderal Soedirman International Medical Conference in conjunction with the 5th Annual Scientiﬁc Meeting (Temilnas) Consortium of Biomedical Science Indonesia

(JIMC 2020), pages 241-244

ISBN: 978-989-758-499-2

241

2 CASE PRESENTATION

We describe a case of DIHS, probably induced by

cefadroxil, in a 50-year-old woman post modified

radical mastectomy for her non-specific-type

unilateral breast cancer. The patient previously

underwent the first operation on August 16th, 2017,

an excisional biopsy for the lump in her right breast.

6 months before the excision, she had felt the tumor

but hesitated to see the doctor. The size of the tumor

was approximately 5x7 cm. Cefadroxil and

mefenamic acid were given two weeks after the

excisional biopsy. Histopathology results showed a

non-specific type of adenocarcinoma with invasion to

local lymph vessels. The patient then underwent the

second operation on September 2nd, 2017, unilateral

modified mastectomy and axillary

lymphadenectomy, thus given another two weeks of

cefadroxil and mefenamic acid. The patient started to

have a fever, jaundice, and maculopapular rash all

around her skin. She also had facial edema, scaling,

anorexia, and nausea. The suspected culprit,

cefadroxil, was directly stopped. The patient did not

have any history of a previous allergic reaction. She

was hospitalized on September 17th, 2017, for the

next five days. Increased levels of liver function tests,

ALP, GGT, and direct bilirubin were observed. The

attending physician administered dexamethasone,

diphenhydramine, cetirizine, Curcuma, and

ursodeoxycholic acid. The patient was hospitalized

for the second time on October 11th, 2017, due to

severe anemia and hypoalbuminemia. We found the

liver function test level was too high, and the rash was

reappeared all around her body, despite the

discontinuation of the culprit drug consumption.

An abdominal CT scan showed a sign of

cholestasis and paraaortic mass. She went to the third

operation on October 27th, 2017, a cholecysto-

jejunostomy shunt with a planned biopsy for the mass

above. During the procedure, we did not found any

intraabdominal mass. The liver surface was clean and

smooth. Hence, there was possibly no sign of liver

metastasis. The patient was monitored thoroughly in

the Intensive Care Unit after the operation was done.

Day by day, she showed marked deterioration of vital

signs. There was also significant bleeding inside her

respiratory tract in which the blood clot disturbed her

airway. Laboratory tests showed a considerable

increase of leukocytes with prolonged hemostasis

profile, hypoglycemia, and hypoalbuminemia. We

had given human albumin, packed red cells, and

thrombocyte concentrate. Endotracheal intubation

was done to support the patient's airway.

Norepinephrine and dopamine were also

administered for her fluid refractory shock.

Unfortunately, the patient passed away on October

31st, 2017, due to cardiorespiratory failure. Skin

manifestation and macroscopic examination of the

breast tumor can be seen in figure 1. The patient's

clinical course is described in table 1, and her

laboratory results are shown in Table 2.

Figure 1: (1) Maculopapular skin rash; (2) The excised

breast tumor.

Table 1: Patient’s clinical course.

Timeline

(

2017

)

Descri

tion

August 16

Excisional biopsy for right breast tumo

Consumption of cefadroxil (two weeks)

September 1

Histopathology: nonspecific type of adenocarcinoma with invasion to local lymph vessel

tember 2

Unilateral modified radical mastectom

Consum

tion of cefadroxil

(

another two weeks

)

tember 17

Fever,

aundice,

eneralized maculo

ular rash, facial edema, scalin

, anorexia and nausea

Discontinuation of cefadroxil consumption and hospitalization (5 days)

October 11

Severe anemia and hypoalbuminemia - rehospitalization

Abdominal CT scan : cholestasis and paraaortic mass

October 27

Cholec

stic-

unostom

shunt with

lanned bio

Posto

erative ICU monitorin

October 31

Patient passed away due to severe hypoalbuminemia, external-internal bleeding, and

cardiores

irator

failure

JIMC 2020 - 1’s t Jenderal Soedirman International Medical Conference (JIMC) in conjunction with the Annual Scientiﬁc Meeting

(Temilnas) Consortium of Biomedical Science Indonesia (KIBI )

242

Table 2: Patient's laboratory results.

Parameter

11/10/17

(hospital

admission)

14/10/17

(post-

transfusion)

28/10/17

(post-

operation)

Hemoglobin (g/dL) 7,1 (L) 11,3

Leukocyte (U/L) 10.870 11.570 (H)

Haematocrit (%) 21 (L) 33

Erhythrocyte

(cells/µL)

2,8x106

(L)

4,18x106

(L)

Thrombocyte

(cells/µL)

296.000 430.000

Eosinophil (%) 0,0% 0,0%

Lymphocyte (%) 14,5% (L) 18,2%

MCV (fL) 72,7 (L) 80,4

MCH (pg/cell) 25,2 (L) 27,4

MCHC (%) 34,6 34

Serum Iron

(µg/dL)

208 (H)

TIBC (ng/dL) 91 (L)

CEA (ng/mL) 2,4

AFP (ng/mL) 1,4

SGOT (U/L) 202 (H) 184 (H) 102 (H)

SGPT (U/L) 279 (H) 286 (H) 121 (H)

ALP (U/L) 371 (H) 249 (H) 102

GGT (U/L) 434 (H) 282 (H) 105 (H)

Albumin (g/dL) 2,47 (L) 3,05 (L) 1,78 (L)

Total Bilirubin

(mg/dL)

8,27 (H) 27,27 (H)

Direct Bilirubin

(mg/dL)

6,41 (H) 18,91 (H)

Indirect Bilirubin

(mg/dL)

1,86 (H) 8,36 (H)

3 DISCUSSION

Incidence of drug-induced hypersensitivity syndrome

ranges from 1:1.000 to 1:10.000 drug exposures. This

syndrome can turn into a fatal condition in 10% of

patients. It can be related to difficulties in diagnosing

the patient. Diagnosis of DIHS is indeed quite

challenging. Delay of diagnosis can happen because

of variable clinical manifestations and late-onset

symptoms (Cacoub et al., 2011). A maculopapular

rash can develop three weeks after starting the culprit

drug. Discontinuation of the drug consumption did

not directly eliminate the symptoms. They may

prolong more than 15 days (Shiohara et al., 2009).

European Registry of Severe Cutaneous Adverse

Reactions to Drugs and Collection of Biological

Samples (RegiSCAR) Group Criteria can be used to

diagnose DIHS by using a scoring system accurately.

Table 3: Diagnostic criteria from the RegiSCAR group

(Kardaun et al., 207)

Clinical Features -1 +1 +2

Fever No or

unknown

≥38,5°C

Lymphadenopathy ≥2 sites,

≥1 c

Atypical

lymphocytes

Present

Eosinophilia 10%-

19,9%

≥20%

Skin rash

- Body surface

area involve

>50%

- Edema,

infiltration,

purpura,

scaling

No Minimum

two

- Biopsy

suggesting

DIHS

Internal organ

involvement

1 organ ≥2

organs

Resolution in more

than 15 days

No or

unknown

Yes

More than 3

biological

investigations

and negative to

exclude alternative

dia

nosis

Yes

From the scoring system, patients are then

classified into definite (>5), probable (4-5), possible

(2-3), or no cases (50% (+1), edema and scaling (+1),

liver and gallbladder involvement (+2), also the

resolution in more than 15 days (+1). Treatment for

DIHS includes discontinuation of the culprit drug

consumption followed by administration of steroid.

Figure 3: The clinical course of DIHS. Symptoms like

maculopapular rash and fever appear three weeks after the

culprit drug was initiated (Shiohara et al., 2009

Drug-induced Hypersensitivity Syndrome in a Breast Cancer Patient: A Case Report

243

Two main hypotheses involved in DIHS

pathogenesis are the (pro) hapten hypothesis and the

pharmacoimmunological (p-i) hypothesis. The drug

can act as a hapten or prohapten, covalently bind with

larger molecules in vivo - such as protein – forming a

brand new antigen. This newly formed antigen will be

presented by antigen-presenting cells (APC). Hence,

it activates the drug-specific T cells, leading to

lymphocyte proliferation. Meanwhile, the p-i

hypothesis is proposing a non-covalent interaction

between drug and APC. The interaction will activate

HLA alleles (probably HLA-B) and T-cell receptors,

subsequently trigger an immune response

(Choudhary et al., 2013; Schrijvers et al., 2015). Viral

infection - such as human herpesvirus 6 (HHV-6),

cytomegalovirus (CMV), Epstein Barr virus (EBV),

and paramyxovirus – can also induce inflammation

and activate the proliferation of drug-specific T cells.

Viral infection may lower the threshold for T cell

activation. There may be a cross-reaction between

activated T cells and the culprit drug. Several

individuals can be more susceptible to DIHS due to

defects in the detoxification mechanism, resulting in

reactive metabolite formation and subsequent

immune reaction (Cacoub et al., 2011; Shiohara et al.,

2009).

4 CONCLUSIONS

Drug-induced hypersensitivity syndrome is a

complicated and fatal condition. The patient

presented in this case report is classified into a

probable case of DIHS by using the RegiSCAR

scoring system. This patient underwent a different

path and eventually passed away, despite

discontinuing the culprit drug consumption and

administration of steroids and other symptomatic

drugs. The culprit drugs may act as a (pro) hapten or

non covalently interact with APC, resulting in severe

immune reaction. The pathogenesis of DIHS may be

related to breast cancer via the activity of T helper-2

cells and eosinophils.

ACKNOWLEDGEMENTS

We want to express our gratitude to the family of the

patient and the hospital staff, who had been very

supportive of this work.

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