allergic reactions to drugs - j-stage

80 歯薬療法 Vol.25 No.3 2006

Allergic reactions to drugs

•` Investigation with our therapeutic experience cases•`

DAISUKE M0HRI1, KAORU SHIMAZU1 and KIYOSHI OHURA2

Abstract: Rashes due to drugs may be relatively mild such as erosions like canker sores, erythema papula, urticarial rashes, and fixed drug eruption, or they may be quite severe as with Stevens-Johnson syndrome or toxic epidermal necrolysis (Lyell syndrome).

Since severe drug eruptions and rashes can affect internal organs in addition to skin and mucosa

and can result in permanent disabilities, they must be diagnosed and treated as soon as possible.

The vital elements of effective diagnosis are to clearly grasp which types of reactions are the most

severe and to quickly identify the reactions which may become serious or threatening. We have

found in our own practice that the most serious types of drug erosions and rashes are those that

affect the whole body. There is a possibility that a very serious case may develop if an erosion

of the oral mucosa spreads out beyond the region of the lip where the mucosa changes to skin or

if erythema of the epidermis quickly spreads and red spots grow together over a relatively large area. The treatment is to immediately stop taking all suspect drugs and begin a rigorous course

of steroids.

Key words: adverse drug reaction, drug eruption, Stevens-Johnson syndrome, toxic epidermal necrolysis

Introduction

Drugs commonly have a variety of side effects

which are roughly categorized as those produced by

the drug itself and those which are allergic reactions

to the drug.

Pharmacological side effects are predictable, and

these can be minimized by appropriate dosage and

administration. Allergic reactions are essentially dif-

ferent because they are caused by a response of the

immune system to specific antibodies or lymphocytes

acting against the drug itself or a related metabolic

product1). These reactions damage various organs

and tissues but most commonly the skin and mucous

membranes which typically present various symptoms

such as skin rashes or erosions and rashes of mucous

membranes.

In the field of otolaryngology (ENT) and odontol-

ogy, many drugs which may cause an allergic reaction

are frequently prescribed including various kinds of

antibiotics, non-steroid anti-inflammatory analgesics,

antihistamines, anti-inflammatory enzymes, hemostatic

agents, and anti-depressants.

Since it is inevitable that ENT and odontology spe-

cialists will have cases of allergic reactions to drugs,

it is critical that they know what kind of symptom is

important and what symptoms may lead to serious ill-

ness. In this paper, we examine the clinical features of

allergic reactions to drugs based on cases we have ex-

perienced and discuss how we normally handle these

cases.

Materials and Methods

The subjects were outpatients who'requested treat-

ment for erosions or rashes of the lips or oral mucosa

and hospitalized patients who contracted diseases with

rashes of the skin or mucous membranes.

Diagnosis began with close questioning of the

1 Department of Otolaryngology, Osaka Dental University (Chief: Associate Prof. TOURU MINATOGAWA)

1大阪歯科大学耳鼻咽喉科学講座(主任:湊川徹助教授)

2 Department of Pharmacology , Osaka Dental University (Chief: Prof. KIYOSHI OHURA)2大阪歯科大学薬理学講座(主任:大浦清教授)

〔2006年5月15日受付〕

Vol.25 No.3 2006 Allergic reactions to drugs 81

Table 1 Clinical types of drug eruption (modified from Mohri2))

patient's history of allergic reactions to drugs, what

medication the patient had been taking, and how long

the patient had been taking the medication before the

skin or mucous membrane rash first appeared. Then

we examined the oral mucosa, pharynx, larynx, skin,

eyes and external genitals.

Results

We classified clinical pathologies in five categories

according to the region where the drug-induced reac-

tion appeared (Table 1)2). Three of the categories

are for reactions that only appear in a single region,

the skin, oral mucosa, or genitals. Another category is

for reactions that appear on the skin and the mucous

membrane simultaneously such as a fixed drug erup-

tion. The fifth category is for the most severe form of

allergic reactions to drugs. mucocutaneo-occular syn-

drome.

Most cases appear from 3 or 4 days to about a week

after the patient begins taking a drug. Fixed drug

eruptions occurred in only a few hours after starting

to take the drug. We also found that severe drug

reactions are preceded by symptoms similar to those

for the common cold such as fever, joint pain, poor ap-

petite, general tiredness, etc.

Representative usual exhibition of allergic reaction

to drugs.

Subject 1: Female, Age: 35yrs.

The subject contracted a disease with an irregularly

shaped erosion accompanied by tongue fur on her lip

Fig. 1 Erosion. (Subject 1: Female, 35 years old)

mucosa, and it had spread beyond the region where

the mucosa changes into epidermis (Fig. 1). WBC

was 9200/mmz, mature granulocyte 78%, lymphocyte

13% in the clinical laboratory, and the viral disease

was negative. In this case. signs of erosive stomati-

tis and stomatitis pseudo membrosa appeared three

days after the subject began taking a non-steroid anti-

inflammatory analgesic (diclofenac sodium). It was

diagnosed as erosion of mucosal lesions. The potency

which shifted to seriously ill conformer was suggested

by erosion having spread to the mucosa cutis migra-

tion region. We immediately stopped internal use of

the causing agent and started whole body administra-

tion of steroid. Prednisolone of 40mg/day was admin-

istered as an initial dose and reduced slowly for 14

1. Mucosal lesions

1) Erosion2) Pigmentation

2. Cutaneous lesions

1) Maculo-papular

2) Uruticaria

3) Pigmentation

4) Erythema exsudativum multiform

3. Genital lesions

4. Fixed drug eruption

5. Mucocutaneo-ocular syndrome

1) Erythema exsudativum multiform syndrome (Stevens-Johnson syndrome)

2) Toxic epidermal necrolysis (Lyell syndrome)

82 歯薬療法 Vol.25 No.3 2006

Fig.2 Pigmentation. (Subject 2: Female, 42 years old)

Fig.3 Maculopapular. (Subject 3: Female, 38 years old)

days: 30mg on the second and third day, 20mg on the

fourth and fifth day, 15mg on the sixth and seventh

day, 10mg on the eighth day and ninth day, and 5mg

from the tenth day (total dose: 215mg).


Pigmentation built up around the lips while the

subject was taking a general common cold medicine

(Pavulon'5) (Fig. 2A). The composition of Pavulon is

bromhexine hydrochloric, dl- methylephedrine hydro-

chloride, dihydrocodeine phosphate, carbinoxamine ma-

leate, acetaminophen, lysozyme hydrochloride, caffeine,

vitamin B, and vitamin B2. Clearly defined, circular

pigmentation also appeared on the subject's abdomen

but it was not particularly conspicuous (Fig. 2B).

This case could be diagnosed as a fixed drug eruption,

but mucosal pigmentation became quite prominent

due to taking the cold medication. We diagnosed it as

pigmentation of mucosal lesions. We stopped internal

use of the general common cold medicine at the first

treatment and did a follow-up survey. Drug eruption

left chromatosis, the border of which blurred in about

3 weeks. and was cured.


This woman developed small red spots like those

associated with measles and rubella and papular erup-

tions all over her body four days after the subject be-

gan taking an antimicrobial drug (penicillin) (Fig. 3). WBC was 7500/mm, mature granulocyte 84%, lym-

phocyte 8% in the clinical laboratory, and the viral dis-

ease was negative. These rashes quickly disappeared

when the woman stopped taking the drug which was

causing the allergic reactions. It was diagnosed as

maculopapular type drug eruption of cutaneous le-

sions. The rashes healed upon withdrawal of internal

medicine and the efflorescence disappeared rapidly by

administering betamethasone sodium phosphate 3mg/

day internally.

Subject 4: Male, Age: 62yrs.

Pigmentation appeared on the torso and palms

of the hands wherever there were signs of habitual

scratching one week after the subject began taking

bleomycin, an anticarcinogenic drug (Fig. 4). This

type of pigmentation is called •gscratch dermatitis.•h We


Fig. 4 Pigmentation (scratch dermatitis). (Subject 4: Male, 62 years old)

Fig. 5 Erythema exsudativum multiform. (Subject 5: Male, 32 years old)

Fig. 6 Fixed drug eruption. (Subject 6: Female, 20 years old)

were able to distinguish it from fixed drug eruption

by its association with regions subjected to habitual

scratching. This case was diagnosed as pigmentation

of cutaneous lesions. The treatment was application

of betamethasone valerate ointment to the scratched

region, but the chromatosis remained.

Subject 5: Male, Age: 32yrs.

After lancing of a peritonsillar abscess, the subject

was taking several drugs including an antibiotic, non-

steroid anti-inflammatory analgesic, and an anti-inflam-

matory enzyme. After five days, red spots of various

sizes and shapes appeared from the neck to the chest.

The spots tended to fuse together, but there was no

conspicuous blistering (Fig. 5). Since the subject

was taking a number of drugs, it was quite difficult to

identify the one that had induced the spots. After ter-

minating the administration of all the drugs and begin-

ning treatment with steroids, the red spots gradually

faded away. The drug induced reaction appeared at

about the time when pharyngalgia and trismus re-

duced following abscess incision. We began treatment

with prednisolone of 40mg/day and reducing the dos-

age slowly for ten days (total dose: 135mg). Erythema

and blister of cutaneous skin disappeared after seven

days of treatment. It was diagnosed as erythema ex-

sudativum multiform of cutaneous lesions.

84 Vol.25 No.3 2006

Fig. 7 Mucocutaneo-ocular syndrome. (Subject 7: Female, 58 years old)


Clearly defined red spots appeared on the subject's

fingers (Fig. 6B) and the region of the lips (Fig. 6A)

where the mucosa changes to skin two hours after

taking Saridon, a medication used to relieve menstrual

pain. The spots disappeared about 10 days after the

subject stopped taking the medication and started re-

ceiving prednisolone of 15mg on the first day, 10mg on

the second day, and 5 mg on the third, fourth and fifth

day, leaving light-gray pigmentation. We diagnosed it

as typical fixed drug eruption, because she commented

that the same area had shown eruption of erythema

when taking Saridon previously.


The subject was taking a commonly available cold

medicine (combination of fumaric acid clemastine, ly-

sozyme chloride, acetaminophen, narcotine, phosphoric

acid dihydrocodeine. anhydrous caffeine, benfotiamine,

potassium guaiacolsulfonate and dl-hydrochloric acid

methyl ephedrine) for two days, but symptoms such

as fever and joint pain were not relieved. Pain of the

oral cavity interfered with eating, and the subject

experienced considerable exhaustion. A rash then ap-

peared on the cutis of her face and thorax. Simultane-ously, erosions appeared on her buccal and lip mucosa.

The erosion on her lip mucosa was especially promi-

nent and was spreading out beyond the region where

the mucosa and skin meet. Conjunctive membranes

of the eyes were bloodshot, and an examination by

an ophthalmologist returned a diagnosis of catarrhic

conjunctivitis (Fig. 7A). The red spots on her chest

were multiform, multi-size and exudative, but blister-

ing was not especially prominent (Fig. 7B). Later the

red spots rapidly fused, and blistering became quite

noticeable (Fig. 7C).

Although the external genitalia were not affected,

we diagnosed her condition as mucocutaneo-ocular

syndrome based on the condition of the oral mucosa,

skin and eyes, which were typical of that disease. We

referred this subject to an ophthalmologist because of

the risk of development of extremely serious eye pa-

thologies.

Discussion

An adverse drug reaction should always be consid-

ered whenever unexplained rashes of the skin or mu-

cosa appear. In many cases, adverse reactions appear

one or two weeks after the patient begins taking the

drug, but if a patient has been sensitized to a condition

such as fixed drug eruption, the symptoms can appear


within a few hours. The time that elapses from taking

a drug to the appearance of the symptoms is a critical

factor in diagnosis and treatment.

A quick diagnosis is the most important, and this

depends on close questioning of the patient's history

of allergic reactions to drugs, what medication the

patient has been taking, and how long the patient had

been taking the medication before the pathology first

appeared.

One of the best ways to identify the offending drug

is to conduct an inducement test. However, induce-

ment tests must be carried out with great care and

prudence and with a readiness to respond to any ad-

verse reaction and prevent it from developing into a

severe condition. Naturally, the patient must be fully

informed of the nature and details of the test. We do

not enforce the inducement test in clinical treatment.

Many adverse drug reactions such as erosion, pig-

mentation, maculopapulas, erythema exsudativum mul-

tiform, etc. are not particularly difficult to diagnose, but

it is vital to clearly distinguish them from other mala-

dies. For example, maculopapular type rashes must

be distinguished from rashes caused by viral infection.

Erythema exsudativum multiform can have a number

of causes other than adverse drug reaction including

infectious diseases, malignant tumors, food, exposure

to cold temperatures, etc. Erosions of the oral mucosa

must be distinguished from pemphigus vulgaris.

According to the World Health Organization, one

or more of the following three criteria indicate a seri-

ous drug-induced rash: 1. Life-threatening, 2. Requires

hospitalization, 3. Results in some type of disability 3).

Serious drug-induced rashes are classified into three

types: Steven-Johnson syndrome (SJS), toxic epider-

mal necrolysis (Lyell syndrome)4), and drug-induced

hypersensitivity (DIHS).

Nanko5,6) has collected records of critical adverse

drug reactions including those that resulted in death

and permanent disability in Japan over the last 23

years. According to these records, the most common

types of adverse drug reactions are those that affect

the skin, mucosa, and related organs (968 cases, 20.7%

of all adverse reactions). About half of these were ei-

ther Steven-Johnson syndrome (SJS) or toxic epider-

mal necrolysis (TEN). Many cases of TEN develop

into SJS resulting in a rather high fatality rate of 32%.

The second largest category was diseases affecting the

entire biological system such as shock, anaphylactic

shock, and dangerously high fever (790 cases). Third

(789 cases) was disorders of the nervous system such

as hypoxia, aseptic meningitis, etc., followd by hepato-

biliary function disorder (631 cases). Ocular disorders

including loss of sight were fifth; many of these were

the result of SJS or TEN. The first four of the above

categories accounted for 80% of all adverse drug reac-

tions.

In our practice, serious outbreaks of allergic reac-

tions were preceded by symptoms similar to those

for the common cold such as fever, joint pain, poor

appetite, general tiredness, etc. followed by the appear-

ance of erosions, erythema exsudativum multiform, or

conjunctivitis. We judged a malady to be serious if

an erosion on the lip spread beyond the boundary be-

tween the mucosa and skin, if erythema quickly spread

and fused, or if a pathology of the eye occurred. We

found it rather difficult to distinguish between SJS and

TEN. In the field of dermatology, there are three cri-

teria used to determine if there is a reason to suspect

a serious disease: 1. High fever, 2. Mucosal pathologies

such as erosion on the lip, bloodshot eyes, sore throat,

and 3. A rash resembling multiform erythema. For

multiform erythema, the possibility of an outbreak of

a serious disease is considered to be especially high if

red spots are clearly defined with notably dark centers

and if erosion or blistering occurs in the center of the

spots (fiat atypical targets). For an early diagnosis,

we recommend a biopsy which can detect necrolysis

of the epidermis and separation of the epidermis and

the dermis that results in peeling7).

The reason for the difficulty in distinguishing SJS

and TEN is that both conditions develop on a single

continuum. According to diagnostic standards set by

the Ministry of Health and Welfare in Japan8), SJS is

determined if less than 10% of the body's surface area

is affected by blistering accompanied by necrolysis of

the epidermis and erosions (peeling epidermis). More

than 10% is diagnosed as TEN, and more than 30% is

diagnosed as SJS-derived TEN, so there is an overlap

from 10% to 30%9). This is the standard we use to

diagnose TEN.

86 Vol.25 No.3 2006

Treatment consists of immediately stopping the use

of all suspect drugs. Light cases of mucosal and skin

rashes are treated mainly with a topical steroid, and

the administration of anti-histamines and anti-inflam-

matory analgesics should be avoided. If a light to mild

rash is accompanied by considerable intra-oral pain or

itchy skin, oral administration of steroids may be called

for. In serious cases, a rigorous course of steroid treat-

ment should be instituted (60 to 80mg of Predonin).

An appropriate and timely response to eye and skin

pathologies is vital. Seventy to eighty per cent of SJS cases have some effect on the eyes, and in about half

of the cases, this consists of corneal disorder and catar-

rhic conjunctivitis accompanied by discharge and pseu-

domembrane. If this condition is not treated properly,

it can result in severe damage to the patients eyesight

due to kerato conjunctivitis with scarification10' If

patients complain of eyelid swelling, eye soreness, tear-

ing, foreign debris lodged in the eye etc., they should

be referred to an ophthalmologist to be examined for

inflammatory eye disease. For skin pathologies, the

affected areas should be bandaged similar to a burn to

prevent blood poisoning due to endermatic infection or

dryness11,12)

To avoid severe permanent disability or injury,

treatment must be given as soon as possible under the

guidance of the appropriate specialists.

References

1) Tadokoro, K.: Medicine. 6th ed 1186-1190

Asakura-syobou Tokyo 1995.

2) Mohri, M.: Allergic stomatitis. Stomato-pharyngol

1999 11: 175•`184.

3) Roujeau, J.C.: Treatment of severe drug eruptions.

J Dermatol 1999 26: 718•`722.

4) Lyell, A.: Toxic epidermal necrolysis. An eruption

resembling scalding of the skin. Brit J Dermatol

1956 68: 355•`361.

5) Nanko, H.: Risk management Adverse reaction of

drug. Seriously ill harmful drug response in Japan.

J Otolaryngol Jpn 2005 108: 108•`115.

6) Nanko, H.: Adverse Drug Reactions (ADR) and

Severe Drug Eruptions in Japan. Jpn J Dermatol

2005 115: 1155•`1162.

7) Hashimoto, K., et al.: Diagnosis and treatment of

seriously ill conformer drug ereption. Jpn J Aller-

gol 2003 52: 251•`254.

8) Hashimoto, K.: 2001 public welfare scientific re-

search. Diagnosis basis and guide to medical care

of Stevens-Johnson syndrome, Toxic epidermal

necrolysis (TEN) and hypersensitivity syndrome.

MB Derma 2004 86: 8•`12.

9) Roujeau, J.C.: The spectrum of Stevens-Johnson

syndrome and toxic epidermal necrolysis. A clini-

cal classification. J Invest Dermatol 1944 102

(suppL): 28•`30.

10) Power, W.J., et al.: Analysis of the acute ophthal-

mic manifestations of the erythema multiform/

Stevens Johnson syndrome/ toxic epidermal ne-

crosis disease spectrum. Ophthalmology 1995

102: 1669•`1676.

11) Ishiguro, H., et al.: Toxic epidermal necrolysis

which merged esophagus and gastric mucosa le

sion. Jpn J din Dermatol 2005 47: 396•`400.

12) Ugami, T., et al.: A case report of toxic epidermal

necrolysis (TEN). Jpn J din Dermatol 2005

47: 951•`955.


薬物アレルギー

～われわれの治療経験症例における検討～

毛利大介1,島津薫1,大浦清2

薬疹はびらん,色素沈着,紅斑丘疹,毒麻疹,固定薬疹などの軽症なものから,Stevens-Johnson

syndromeや中毒性表皮壊死融解症(Lyellsyndrome)のような重症型まで種々である.

重症型薬疹は口腔粘膜,皮膚以外の臓器に重篤な後遺症を残すことがあるため,早期診断早期治療が必

要である.診断で最も重要なことは重症型の薬疹はどれであるかを明確に把握すること,どのような薬疹が

重症型に移行するかを見逃さないことである.自験例から,全身症状を伴う薬疹,口腔粘膜のびらんが口唇

の粘膜皮膚移行部を越えて拡大する場合,皮膚の紅斑が急速に癒合拡大する場合には重症型に移行する可能

性が高いと考えられた.治療は疑わしい薬剤を含め原因薬剤の投与を直ちに中止し,ステロイドの大量療法

を行う.

キーワード:薬物有害反応,薬物アレルギー,スティーブ・ジョンソン症候群,中毒性表皮壊死融解症

allergic reactions to drugs - j-stage

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