tutik kusmiati departemen pulmonology dan kedokteran...

Tutik Kusmiati

Departemen Pulmonology dan Kedokteran Respirasi FK UA Surabaya, 2019

Asia Pac Allergy 2014;4:156-163

Tuberculosis Research and Treatment Volume 2014, Article ID 412893

The World Allergy Organization (WAO) in 2003 defined ‘drug allergy’ as an immunologically mediated drug hypersensitivity reaction.

Severe cutaneous adverse reactions (SCAR):

Stevens Johnson syndrome (SJS),

Toxic epidermal necrolysis ( TEN),

Drug-induced hypersensitivity syndrome (DiHS) or drug rash with eosinophilia and systemic symptoms (DRESS)

Br J Clin Pharmacol / 71:5 / 684–700

Several criteria characterize an allergic reaction:

The reaction is not an expected pharmacologic effect.

The reaction may occur at a dose much lower than that required for a pharmacologic effect.

The clinical symptoms are characteristic of an allergic reaction.

Resolution occurs within an expected interval, usually days, after discontinuation of the offending agent.

Immunol Allergy Clin N Am 24 (2004) 345–356

• Wanita

• Penyakit penyerta (HIV, penyakit ginjal, penyakit liver)

• Etnis

• Polifarmasi

• Pecandu alkohol

• Genetik

• Sifat obat (hapten, pro-hapten, atau kemampuan obat berikatan dengan reseptor imun)

• Cara pemberian obat: topikal, oral, intramuskular, dan intravena lebih sering menyebabkan alergi dibandingkan dengan oral

SAARC J TUBER LUNG DIS HIV/AIDS, 2013;X(2)

A. Peptida termodifikasi oleh hapten menstimulasi sel T mengaktivasi sistem imun

B. Obat berikatan langsung dengan sel T dan HLA sinyal yang diberikan diperkuat sel T terstimulasi

C. Obat berikatan langsung dengan HLA tanpa melalui peptida membentuk suatu ikatan yang dapat menstimulasi sel T

Cit EMJ Allergy Immunol 2016;1(1):92–101

J Dermatol 2015;42(1):42–48.

Ann Allergy, Asthma Immunol 2015;115(1):39–44

Reaksi hipersensitivitas pada OAT >> reaksi hipersensitivitas tipe 1

Tingkat keparahan hipersensitivitas tipe 1 pada OAT: derajat 1 – 3

Kadar total dan spesifik IgE pada pasien TB > tinggi

Infeksi M. Tuberculosis menstimulasi kerja T-helper 2 (Th2) interleukin-4 (IL-4) merangang Sel B untuk memproduksi IgE.

Clin Exp Immunol 2000;122(1):13–15

Ann Allergy, Asthma Immunol 2015;115(1):39–44.

Tipe reaksi kulit Gejala klinis

Erupsi morbiliformis Muncul 7-14 hari setelah paparan sebagai ruam

kemerahan dengan papula. Jarang mengancam nyawa

Sindroma

hipersensitivitas obat

Muncul 3 minggu setelah paparan obat sebagai

demam, edema, dan makula eritematosa yang

progresif disertai eosinofilia dan transaminitis

Stevens-Johnson

Syndrome

Toxic epidermal

necrolisis

Makula eritematosa dengan pengelupasan kulit dan

mukositis, kemerahan yang nyeri pada kulit. SJS <10%

luas kulit, TEN > 30% luas kulit

Fixed drug eruption Muncul sebagai ruam hiperpigmentasi soliter

berbatas jelas dan lokasi muncul tetap sama pada

paparan ulang

Lichenoid drug

eruption

Makula kemerahan dengan permukaan datar dan

poligonal, bersifat gatal

Vaskulitis kutaneus Sering ditemukan pada tungkai bawah sebagai

purpura, bula hemoragis, dan sering disertai ulkus

Expert Rev Anti Infect Ther 2012;10(4):475–486.

Morbilliform Drug Eruption (MDE), also called maculopapular rash, is the most common type of CADR.

The rash usually spreads centrifugally with the lesions becoming progressively confluent.

MDE are usually self-limiting without systemic involvement

It can be difficult to differentiate MDE from early SJS/ TEN and DRESS syndrome

Morbilliform or maculopapular rash showing distinct papules

in a background of erythema

Current Allergy & Clinical Immunology | December 2015 | Vol 28, No 4

The rash in DRESS syndrome has

variable morphology, ranging

from urticarial, maculopapular,

vesicles, pustules, purpura,

targetoid lesions, or

erythroderma

DRESS syndrome showing urticarial papules

coalescing to form plaques


FDE usually presents as solitary or numerous itchy, round well-circumscribed, erythematous macules or indurated plaques on the skin or mucosal surfaces.

They typically resolve with persistent hyperpigmentation of the involved sites


Derajat keparahan reaksi alergi kulit OAT

Derajat 1 Gatal sedang atau ruam kemerahan

Derajat 2 Ruam makulopapular luas dengan atau tanpa gatal

Derajat 3 Ruam papular, vesikuler, atau basah

Purpura

Ulkus pada kulit atau mukosa

Derajat 4 Lesi bulosa (Lyell atau Steven johnson syndrome)

Febril eritroderma

Nekrosis kulit (TEN)

Caminero, José A, 2018

DRESS: a drug eruption associated:

a long latency period (> 3 weeks) and was characterized by:

fever, widespread maculopapular rash, white-cell abnormalities and multiorgan involvement.

SJS and TEN:

a spectrum of the same disease,

epidermal detachment and

mucous membrane erosions.

In SJS, < 10% of the body surface area is affected,

In TEN > 30% of the body surface area is affected.

British Journal of Dermatology (2016)

Allergo J Int 2015;24:94–105

Oral drug provocation tests are still considered the gold standard to identify the offending drug.

The risk of a rechallenge reaction must be balanced against the morbidity and mortality associated with sub-optimal therapy

These include the use of bridging therapy before initiating rechallenge, whether rechallenge should occur at full dose or with incrementally increasing doses and the sequence in which the drugs are rechallenge.


To avoid monotherapy and to minimise the risk of developing mycobacterial resistance during the prolonged rechallenge process with the individual drugs, a bridging therapy of three second-line drugs, to which the patient has not previously been exposed, is advised

The selection of drugs depends on:

local treatment guidelines,

availability,

toxicities and

underlying co-morbidities.

If the rechallenge with first line drugs is initiated too early, the overlapping clinical features of the rechallenge reactions and adverse reactions to the bridge therapy create confusion.

Reactions to the bridge therapy usually develop within two weeks of their initiation.

The most effective drugs, namely rifampicin and isoniazid, should be rechallenged first to minimise the risk of suboptimal therapy during the prolonged rechallenge process

Others suggest that the drugs least likely to cause a reaction should be rechallenged first.

American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) merekomendasikan re-challenging OAT dapat diberikan 2-3 hari setelah gejala membaik.

Drug challenging dimulai dari obat yang paling rendah menimbulkan risiko alergi yaitu isoniazid hingga yang tersering yaitu streptomisin

Prinsip dari re-challenging OAT adalah menemukan OAT penyebab alergi

DRUG CHALLENGING

OAT Hari 1 Hari 2 Hari 3

Isoniazid Penyebab

terjarang

Penyebab

tersering

50 mg 150 mg 300 mg

Rifampisin 75 mg 300 mg Full dose

Pirazinamid 250 mg 1 gram Full dose

Etambutol 100 mg 500 mg Full dose

Streptomisin 125 mg 500 mg Full dose

Drug Challenging Desensitisasi obat

Hipersensitivitas Belum terbukti Sudah terbukti

Tujuan Membuktikan

hipersensitivitas

Membuat toleransi pada obat

Efek pada sistem imun Tidak ada Toleransi

Resiko reaksi alergi Ada Ada

Dosis awal 1/100-1/10 dosis terapi 1/1000000-1/100000 dosis

terapi

Jumlah langkah Biasanya 3-5 Biasanya >10

Waktu interval Tergantung reaksi obat 15 menit sampai 2 jam

Tindakan setelah terjadi

reaksi

Menghentikan tes dan

menatalaksana pasien

Menghentikan sementara

pemberian dan melanjutkan

kembali saat gejala mereda

sesuai protokol Allergy Eur J Allergy Clin Immunol 2010;65(11):1357–1366, Asia Pac Allergy 2011;1(1):2.

Protokol desensitisasi dari obat anti tuberkulosis menurut Philadelphia Guidelines secara umum yaitu:

Mulai OAT dengan dosis hari pertama drug challenging

Jika reaksi (+) setelah pemberian drug challenging, hentikan.

Mulailah desensitisasi dari 1/100-1/1000 dosis hari pertama setelah reaksi mereda

Berikan dosis dua kali lipat setiap jam dan sampai dosis terapi harian tercapai

Bila sudah mencapai dosis terapi pemberian dalam dosis terbagi selama 3 hari rubah ke pemberian dosis tunggal (misal Isoniazid 2x150 mg selama 3 hari, lalu menjadi 300 mg dosis tunggal)

Bila selama terjadi alergi turunkan ke dosis sebelumnya hingga tidak terjadi alergi dan perlahan tingkatkan kembali.

Allergy Eur J Allergy Clin Immunol 2010;65(11):1357–1366.

Waktu Isoniazid

(miligram)

Waktu Rifampisin

(miligram)

07.00 0,1 07.00 0,1

07.15 0,5 07.15 0,5

07.30 1 07.30 1

07.45 2 07.45 2

08.00 4 08.00 4

08.30 8 08.15 8

09.00 16 08.30 16

09.30 32 08.45 32

10.30 50 09.15 50

12.30 100 10.15 75

14.30 150 12.15 100

15.00 150 16.15 150

12.30 Lanjutkan 150 mg

tiap 12 jam

12.15 Lanjutkan 300 mg tiap

12 jam

Chest 1990;98(6):1518–1519.

(1) there was no alternative available for treatment,

(2) an alternative second- line anti-tuberculosis treatment (such as ethionamide, p-aminosalicylic acid, or d-cycloserine) was not generally available and was reserved for multidrug-resistant tuberculosis;

(3) desensitization drugs, such as isoniazid and rifampicin, were superior to alternative second-line drugs.

The risk of desensitization was reduced by close monitoring in the specialized ward for tuberculosis, the desensitization protocol was started at very low drug concentrations, and the increase in drug dosing was quite slow compared to that reported previously (Thong et al., 2014).

International Journal of Infectious Diseases 68 (2018) 61–68

Drug desensitization is generally contraindicated in serious non-IgE-mediated reactions, such as Stevens–Johnson syndrome (SJS).

The results of tuberculosis treatment after drug desensitization are also important, because there has been a case report showing that isoniazid resistance may develop during desensitization

The success rate of desensitization with the use of antihistamines or systemic steroids did not differ from that without antihistamine or systemic steroid use (80.0% vs. 76.9%, respectively, p = 1.000).

Skin tests are carried out in the context of hypersensitivity reactions involving symptoms consistent with allergy in order to determine a sensitization

Skin test reactions occur only in some patients with hypersensitivity reactions

Prick and intradermal test reactions are typically read after 15–20 min, patch tests after 24–48 h and 72 h. In the case of drug eruptions, late readings after24 and 48h (or 48 and 72h) should be performed for prick and intradermal tests

Allergo J Int 2015;24:94–105

The usefulness of drug skin tests (patch tests, prick tests, intradermal tests [IDT]) for the investigation of cutaneous adverse drug reactions (CADR) caused by delayed hypersensitivity to drugs

Many compounds are still not standardized for skin-testing and their use remains experimental.


Khan et al. BMC Research Notes 2014, 7:537

30% dilutions

Freshly prepared before each test by two of the investigators.

The test drugs were mixed in two vehicles, olive oil and sterile water

Liquid vehicles allow for better penetration into the skin.

The first reading was taken at 20 min,

The second and third readings at 24 h and 48 h, respectively.

The participants were instructed not to wet, rub or scratch the test area and to avoid excessive sweating

British Journal of Dermatology (2016)

Patch-testing is a diagnostic procedure that is most commonly used for identifying the possible causes of contact dermatitis, which is a type IV hypersensitivity reaction.

Patch-testing can also be used in the investigation of type I hypersensitivity reactions and in DRESS syndrome (type IVb hypersensitivity reaction)

The procedure involves mixing the allergen to be tested with white petrolatum (i.e. the vehicle) and applied in close proximity with the skin.

The first reading is taken after 30 minutes to look for type 1 hypersensitivity reaction, while a second reading is taken after 48 hours to investigate for type 4 delayed hypersensitivity reaction.


DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a severe form of drug-induced skin reaction because major systemic involvement

DRESS syndrome is characterised by the presence of

a skin condition, erythema and facial oedema, fever, general malaise, haematological disorders, swollen lymph nodes and involvement of one or more internal organs

Fever (≥38◦C) is usually the first manifestation of this syndrome and dermatosis appears approximately 24-48 h later

Rev Med Hosp Gen Mex. 2016;79(2):55-62

Rev Med Hosp Gen Mex. 2016;79(2):55-62

Allergy Asthma Immunol Res. 2019 Jan;11(1):90-103

Alergi obat merupakan suatu respons imunologis terhadap obat

Manifestasi klinis reaksi alergi dapat ringan sampai berat

Penentuan derajat keparahan alergi OAT sangat penting dalam tatalaksana pengobatan TB selanjutnya

Skin tes dapat membantu untuk mengidentifikasi obat penyebab alergi selain cara drug-challenge.

Desensitisasi dapat dilakukan pada kondisi kegagalan melakukan drug challenge

A 17-year old Indian female was diagnosed with HIV infection in January 2011 in a public ART centre.

Her baseline CD4 cell count at the time of diagnosis was 428 cells/ mm

The patient was not initiated on ART at baseline as the national HIV program in India has a threshold of 350 cells/mm3 for ART enrollment in adolescent and adult patients

Cotrimoxazole preventive therapy was initiated when the patient’s CD4 count fell to 340 cells/mm3 in February 2013, nevertheless, ART was not initiated at that time.


The CD4 count at the time of enrollment in the MSF project was 205 cells/mm3 and the HIV viral load result was 29,420 copies/ml. The patient’s weight on admission was 40.3 Kg. There was no history of allergic reactions.


The regimen contained capreomycin, moxifloxacin, para-aminosalicylic acid (PAS), cycloserine, amoxicillin/clavulanic acid (amoxiclav) and clofazimine. ART was to be initiated within 14 to 30 days after anti-TB treatment initiation, after the patient was found to be tolerating the anti-TB treatment.

However, twenty-four hours after TB treatment initiation, the patient developed generalised urticarial and morbilliform rash, fever, angioedema, laryngospasm, and dyspnoea.


To help identify the drug(s) responsible for the hypersensitivity reaction, a careful re-challenge plan was made.

The following 4-step strategy was used to manage the patient’s hypersensitivity reaction related to second-line anti- TB drugs:

Step 1: Skin patch-testing

skin patch-testing one week following the anaphylactic episode and after antihistamine medication had been stopped. The patch-testing included the following drugs: PAS, moxifloxacin, amoxiclav, cycloserine, kanamycin, clofazimine, and cotrimoxazole. The test showed an extremely positive reaction (+3) to clofazimine, strongly positive reaction (+2) to kanamycin and weakly positive reaction (+1) to cycloserine. No reaction was observed to moxifloxacin, amoxiclav, PAS, and cotrimoxazole. We decided to permanently suspend the use of clofazimine and to re-challenge with cycloserine and kanamycin.


Step 2: Introduction of an interim MDR-TB treatment regimen

We initiated the patient on an interim MDR-TB treatment regimen consisting of drugs that were less likely to cause hypersensitivity reactions.

Step 3: Re-challenge with drugs having moderate and mild skin-patch test results

Step 4: Introduction of prophylaxis for opportunistic infections and antiretroviral therapy


tutik kusmiati departemen pulmonology dan kedokteran...

Documents