is there an association between stevens-johnson …...stevens-johnson syndrome is a rare, severe,...

Ann Ig 2020; 32(1): 81-96 doi:10.7416/ai.2020.2333

1 Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy2 Faculty of Pharmacy, University of Lisbon, Portugal

Is there an association between Stevens-Johnson Syndrome and vaccination? A systematic review

I. Grazina1,2, A. Mannocci1, A. Meggiolaro1, G. La Torre1

Key words: Stevens-Johnson Syndrome, vaccination, systematic reviewParole chiave: Sindrome di Stevens-Johnson, vaccinazione, revisione sistematica

Abstract

Aims and background. It is essential to make sure that vaccines are safe, effective, and of good quality. In the past years, there have been some reports of adverse effects regarding vaccination. One of these adverse effects is the development of Stevens-Johnson syndrome. Stevens-Johnson syndrome is a rare, severe, skin disorder, that usually occurs after medication. In Europe, its estimated incidence is of 2-3 cases/million population/year. Therefore, the aim of this study was to investigate, through a systematic review, the association between vaccination and the development of Stevens-Johnson syndrome. Materials and methods. We performed a systematic review using PubMed, Scopus and Web of Science databases. We included studies dated between January 2000 and February 2018. The main selection criterion was the reporting of the disease, following vaccination. Results. Ten studies were selected, from a total of 391 studies. Of these, 5 were case reports, 3 were cohort studies and 2 were case-control. All the studies were regarding cases of Stevens-Johnson syndrome after vaccination. The selected studies reported cases following vaccines such as influenza vaccine, smallpox, anthrax and tetanus vaccine, MMR vaccine, varicella vaccine, DTaP-IPV vaccine or rabies vaccine. None of the cohort studies reported statistically significant associations between vaccination and the syndrome. In the case-control studies, it was not observed significant increased risk for the Stevens-Johnson syndrome following the administration of vaccines. Regarding the case reports, there was not sufficient evidence to form a positive association between these two factors, and more studies are needed. Conclusions. In this review it was not possible to establish a positive relation between vaccination and the development of Stevens-Johnson syndrome.

Introduction

Over 100 million children worldwide are being immunized, and vaccines prevent more than 2.5 million child deaths per year. Nowadays, there’s a constant concern regarding vaccination and more vaccines are being made available to protect adolescents and adults, such as vaccines against

influenza, meningitis and cancers that occur in adulthood.

It is essential to make sure that vaccines are safe, effective, and of good quality. Over the past few years, there have been some reports of adverse events related to vaccination. Nonetheless, vaccination is still one of the most cost-effective health interventions. Giving the fact that fear of

82 I. Grazina et al.

vaccines and immunization is usually related to lack of information, it is crucial to keep the population informed about the safety of vaccines and how they can reduce disease and deaths (1).

There is evidence that Stevens-Johnson syndrome (SJS) may, in very rare occasions, be caused by vaccination (2).

SJS is a rare, severe skin disorder, characterized by an immune-mediated cutaneous reaction, usually secondary to a hypersensitivity reaction to medication. Lesions consist of widespread flat atypical targets or purpuric macules. Patients are febrile and prostrated by disease. The distribution of skin lesions is predominantly central with involvement of at least two mucosal sites (3).

SJS is an unpredictable reaction that involves drug specific CD8+ cytotoxic lymphocytes, the Fas-Fas ligand (FasL) pathway of apoptosis, and granule-mediated exocytosis and tumour necrosis factor-α (TNF-α)/death receptor pathway (4). In Europe, its incidence is estimated at 2-3 cases/million population/year. Most patients are aged 10-30 years old, but the disease can also affect children as young as 3 months old. SJS is more common in females than in males (5), it can affect people of any age, gender, or race (4). SJS is a life-threatening disease. The average reported lethality rate is 1-5% (6).

In the acute phase, initial symptoms can be not specific, such as fever, stinging eyes and discomfort upon swallowing. These symptoms precede cutaneous manifestations by a few days. Early sites of cutaneous involvement include the presternal region of the trunk and the face, the palms and soles. Involvement of the buccal, genital and/or ocular mucosa is very usual and the respiratory and gastrointestinal tracts may also be affected. In a second phase, epidermal detachment of large areas may occur (6).

The diagnosis is based upon clinical symptoms and histological features. The

clinical signs include areas of erythematous and livid macules on the skin, with a positive Nikolsky sign. The Nikolsky sign, even though is not specific for this syndrome, can be assessed by applying mechanical pressure on the skin. If the pressure is followed by epidermal detachment characterized by the development of blisters, the sign is positive. The mucosal involvement follows the skin signs or can occur simultaneously with these. SJS is distinguished from other diseases, such as Toxic Epidermal Necrolysis (TEN), through the surface area of epidermal detachment (6). In SJS, there is a detachment of less than 10% of all body surface area, while in TEN there is a detachment of more than 30%. If there is a detachment between 10% and 30%, it is considered to be a case of SJS-TEN overlap (7).

In the light of clarifying some safety issues concerning vaccinations, the objective of the present study was to perform a systematic review about the association between vaccination and development of SJS.

Materials and methods

Identification of relevant studiesThis systematic review was performed

according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (8). Search was made using the electronic databases PubMed, Scopus and Web of Science, applying the following algorithm: (Stevens-Johnson AND syndrome) AND (vaccine OR vaccines OR immunization OR vaccination OR vaccinations). The studied population was the world population, the intervention was vaccination and the comparator group was non-vaccinated people. The outcome was the development of SJS. The search was undertaken in February 2018, concerning papers published from 1 January 2000 to February 2018. Eligible studies

83Association between Stevens-Johnson Syndrome and vaccination?

were selected according to a multi-step approach (title reading, abstract and full-text assessment) by two researchers, working independently. We registered the protocol in the PROSPERO database (registration number CRD42018089119).

Furthermore, the references to review, letters, comments, editorials, and case reports, identified by the search strategy, were evaluated for retrieving further relevant literature.

Study selection and eligibility criteriaThe first selection was performed filtering

duplicates by JabRef 2.10 program and ZOTERO 4.0.

The articles identified by search strategy were selected initially, through the analysis of the title and the abstract, independently by two researchers, and then the inclusion criteria were evaluated by the analysis of full-text by each investigator. Disagreements between the two researchers were resolved by a third one.

Inclusion criteria- Patients with SJS; - Article including vaccination as a

factor; - Primary studies as descriptive studies

(case-reports), observational studies (such as cohort, case-control, cross-sectional studies) and experimental studies (randomized and non-randomized);

- Secondary studies as narrative studies or systematic reviews.

Exclusion criteria- Patients without SJS, since this is the

only disease we wanted to study; - Article not including vaccination as

a factor, because vaccination is the main intervention we were studying;

- Publication in language other than English, French, German, Italian, Portuguese and Spanish, considering these are the languages spoken by the researchers.

Data extraction and quality assessmentData extraction was carried out following

the same strategy as the studies, by two researchers.

A quality assessment was performed, according to the Newcastle-Ottawa Scale (NOS) for observational studies (9), and a conceptual scheme for evaluating the quality of a case report (10). To assess risk of bias of our systematic review, the ROBIS tool was used, which is in annex (11).

The following characteristics were collected: authors, study design (cross-sectional, cohort, case control, narrative review, case report, systematic review and/or meta-analysis), year of publication, country, results, funding.

The main outcome was the development of SJS.

Results

Study selectionThe search results for the selection

of articles are shown in the flowchart in Fig. 1. The PRISMA checklist is attached (Annex “PRISMA Statement Checklist”). Grey literature was not included in the review.

Overall, 444 papers were found. Of those, 72 articles were found on PubMed, 43 through Web of Science and 329 on Scopus. Using the software JabRef 2.10, 53 duplicates were excluded. Through the analysis of the abstract and title, we excluded 177 articles. Then, 38 articles were excluded after the analysis of full text, 94 articles were not available and 72 were from before the year 2000. The list of articles excluded after the analysis of full text is in annex.

Finally, 10 articles were included for analysis: 5 case reports, 5 observational (3 cohort studies and 2 case-control). The characteristics of the studies are summarized in the table 1.


Fig. 1


Figure 2 - Flowchart


Tabl

e 1

- C

hara

cter

istic

s of

the

stud

ies

Firs

tau

thor

Yea

rSt

udy

Type

Vac

cine

Typ

eC

ases

Res

ults

Qua

lity

Bal

l R20

01C

ase

Rep

ort

and

Rev

iew

Var

icel

la v

acci

ne1

repo

rted

cas

e, 5

pro

babl

e ca

ses.

A c

ausa

l lin

k be

twee

n va

ccin

atio

n an

d SJ

S ca

n’t b

e es

tabl

ishe

d by

this

stu

dy.

3*

Cho

pra

A20

04C

ase

Rep

ort

Tri

ad o

f sm

allp

ox (

vacc

inia

vi

rus)

, an

thra

x an

d te

tanu

s va

ccin

e1

The

pat

ient

dev

elop

ed a

cas

e of

SJS

aft

er

vacc

inat

ion

with

sm

allp

ox, a

nthr

ax a

nd

teta

nus

vacc

ines

. 9*

Flem

ing

D20

11C

ase

Rep

ort

Influ

enza

vac

cine

1T

here

is n

ot a

n es

tabl

ishe

d lin

k be

twee

n th

e de

velo

pmen

t of

SJS

and

infl

uenz

a va

ccin

e.

10*

Rau

cci U

2013

Cas

e-co

ntro

lH

exav

alen

t va

ccin

e; H

aem

o-ph

ilus

influ

enza

vac

cine

; MM

R

vacc

ine;

Flu

vac

cine

4 ca

ses,

137

con

trol

s.It

was

not

obs

erve

d an

inc

reas

ed r

isk

betw

een

vacc

ines

and

the

dev

elop

men

t of

the

dise

ase.

6**

Dal

ey M

F20

14C

ohor

tD

TaP-

IPV

vac

cine

0T

here

wer

e no

cas

es o

f SJ

S fo

llow

ing

201,

116

child

ren.

8**

Oda

T20

17C

ase

Rep

ort

Influ

enza

vac

cine

1T

his

was

the

firs

t re

port

ed c

ase

of S

JS

afte

r in

fluen

za v

acci

ne m

onot

hera

py.

9*

Ma

L20

18C

ase

Rep

ort

Rab

ies

vacc

ine

1It

was

des

crib

ed th

e fir

st c

ase

of S

JS th

at

seem

ed to

be

caus

ed b

y ra

bies

vac

cine

. 10

*

Dal

ey M

F20

18C

ohor

tL

ive

Att

enu

ated

In

flu

enza

va

ccin

e8

case

s in

ris

k w

indo

w;

14 c

ases

in

cont

rol p

erio

d; 0

con

firm

ed c

ases

.T

here

wer

e no

con

firm

ed c

ases

of

SJS

caus

ed b

y th

e va

ccin

e.7*

*

Lev

i N20

09C

ase-

cont

rol

80 c

ases

, 21

6 co

ntro

ls.

Of

thes

e, 3

ca

ses

whe

re fo

llow

ing

vacc

inat

ion

in

the

last

mon

th (

4 co

ntro

ls).

Thi

s st

udy

did

not c

onfir

m a

sig

nific

ant

incr

ease

d ri

sk f

or S

JS i

n ch

ildre

n, f

ol-

low

ing

the

adm

inis

trat

ion

of v

acci

nes.

6**

Pers

son

I20

14C

ohor

tIn

fluen

za A

(H

1N1)

vac

cine

52 c

ases

in

the

who

le c

ohor

t, i

n w

hich

als

o ot

her

med

icat

ions

wer

e co

nsid

ered

.

The

re i

s no

t a

posi

tive

asso

ciat

ion

re-

gard

ing

SJS

and

H1N

1 va

ccin

e.8*

*

*- a

ccor

ding

to th

e ca

se-r

epor

t con

cept

ual s

chem

e **

- a

ccor

ding

to N

ewca

stle

Otta

wa

scal

e


Analysis of the studiesBall R. reported, in his 2001 study, one

case of SJS following the administration of varicella vaccine, in a 27-month old baby. In the same study, Ball et al. reviewed the data from the vaccine adverse event reporting system (VAERS), where one definite case of SJS/TEN and 5 probable cases were diagnosed, after vaccination (2).

In 2004, Chopra et al. reported the case of a 19-year old male patient who developed SJS after vaccination with smallpox, anthrax and tetanus vaccines (12).

Fleming D. reported, in 2011, one case of SJS following influenza immunization (13).

Raucci U. et al. did a case-control study regarding the potential association between drugs and vaccines and a hypothetical development of SJS. In this study, there were 4 cases of SJS following vaccination, with 137 controls, having an odds-ratio of 0,9 (95%CI: 0,3-2,8) (14).

In a 2014 study, by Daley MF et al., the safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine was evaluated. Following 201,116 children from January 2009 through September 2012, no cases of SJS were reported (15).

Oda T. et al. reported, in 2017, the first case of Stevens-Johnson syndrome after influenza vaccine monotherapy, in a 75-year old Japanese man (16). In 2018, Ma L et al. reported, in China, the first case of SJS after rabies vaccination, in a 22-year old woman (17).

In 2018, Daley et al. studied the safety of live attenuated influenza vaccine (LAIV) in children and adolescents, having no confirmed cases (N=0) of SJS following immunization. Although it was observed a single case of SJS following LAIV, the patient was also exposed to acetaminophen, which may have caused the development of the disease (18).

On an analysis of medications (vaccines

in the last month included) as risk-factors of SJS in children, Levi et al. made a pooled analysis of two case-control studies, found there were 3 vaccinated among cases of SJS, and 4 vaccinated among controls. The odds-ratio was of 2.0 (95%CI: 0.5-9.4) (19).

Regarding a Swedish cohort study of influenza A (H1N1) vaccine, the association with SJS gave a non-significant HR of 1.59 (95% CI: 0.95-2.65) (20).

Discussion

This systematic review investigated a hypothetical link between vaccination and the development of Stevens-Johnson syndrome.

In cohort studies, the authors concluded that there was not a positive association between the development of SJS and the administration of a vaccine (20). In a different cohort study, it was concluded that, regarding the information of that study, it was not possible to establish a direct association between vaccination and development of the syndrome. However, they considered that it was not possible to exclude the vaccine as a potential cause to the development of the disease and more information was needed (18). In the third cohort study included in this review, there was no increased risk of developing the disease following the administration of the vaccine (15).

In a case-control study developed by Raucci et al., it was concluded that, regarding the studied population, there was no increased risk between the development of the disease and vaccination (14).

Regarding the work published by Levi et al. (19), the study did not confirm an increasing risk for the development of SJS in vaccinated children.

As far as concerns the case-reports, the study conducted by Fleming concluded that there was not an established relation


Strengths and limitationsOur review has both strengths and

limitations. The number of included studies in the final analysis was limited and it was not possible to conduct a meta-analysis, because of the heterogeneity observed in the study design. The lack of a meta-analysis makes it more difficult to draw conclusions. Also, most of the studies were case reports, which can rarely prove a causal link between two factors and are subjected to biases, such as reporting bias.

When it comes to strengths, this is, to our knowledge, the first systematic review investigating the association between vaccination and Stevens-Johnson syndrome. We believe that our review has special importance in alerting the medical community to the need of more studies concerning this hypothetical association. Another strength is that through ROBIS Tool, we assessed the risk of bias within our study. We concluded that there was low risk of bias.

Conclusions

Through the analysis of the studies, we can conclude that it is not possible to establish a positive relation between these two factors, since most of the studies were inconclusive or presented statistically non-significant results. In this systematic review, convincing evidence of an association between vaccines and SJS does not exist. SJS and TEN are very rare indeed in the absence of vaccination. They remain so also after vaccination.

There is few evidence from the studies on the development of the disease being related to vaccines. Plus, most of the studies reported cases following different kinds of vaccines. Therefore, it is difficult to compare the outcomes and establish an association between the two factors in study.

between the vaccine and the development of the disease. Nonetheless, clinicians should be aware of a potential link between immunization and the concomitant use of penicillin, that could develop the syndrome (13). Ball R. et al. mentioned that they could not establish a causal link between the two factors in study (vaccination and SJS). In their opinion, more studies regarding the recurrence of SJS with revaccination are needed. They also concluded that if vaccination really causes SJS, it happens very rarely and the benefits of the vaccine itself are bigger than the risk (2). Chopra et al. reported a case of a patient who developed a case of Stevens-Johnson syndrome after been immunized with smallpox, anthrax, and tetanus vaccines. It is stated that based on his previous tolerance to tetanus vaccines and the rarity of severe skin eruptions after the administration of anthrax vaccine, the most likely cause of the reaction was smallpox vaccine (12).

Oda T. et al. reported a case of a man who developed SJS after influenza vaccine. They performed a test to investigate if a possible cause of the development of the syndrome could be the additives in the vaccine (thiomersal and formalin). Since these results came back negative, they concluded that the most likely cause was the influenza vaccine itself. The adverse effects following the administration of this vaccine are quite rare, so more studies are required in order to clarify this hypothetical link (16). Finally, Ma L. et al. described a case of SJS following the administration of the first dose of a series of three doses rabies vaccine. Giving the absence of any other concurrent disease or risk factor, including drugs consumption or exposure to chemicals, and due to a plausible time relationship, the most likely cause of the development of the disease was attributed to rabies vaccine. According to this study, clinicians should be vigilant on the possibility of SJS occurrence after the administration of the vaccine (17).


Funding: This work was not supported by other orga-nizations.Declarations of interest: NoneConflict of interest: The authors declare that they have no conflict of interest. Annex: ROBIS Tool, PRISMA statement checklist, List of excluded articles by full-text assessment

Riassunto

Esiste un’associazione tra la sindrome di Stevens-Johnson e la vaccinazione? Una revisione siste-matica

Obiettivi. È essenziale assicurarsi che i vaccini siano sicuri, efficaci e di buona qualità. Negli ultimi anni, ci sono state alcune segnalazioni di effetti avversi riguar-danti la vaccinazione. Uno di questi effetti avversi è lo sviluppo della sindrome di Stevens-Johnson. La sindro-me di Stevens-Johnson è una malattia rara, grave, che di solito si verifica dopo la medicazione. In Europa, la sua incidenza stimata è di 2-3 casi / milione di abitanti / anno. Pertanto, lo scopo di questo studio è di indagare, attraverso una revisione sistematica, l’associazione tra la vaccinazione e lo sviluppo della sindrome di Stevens-Johnson.

Materiali e metodi. Abbiamo eseguito una revisio-ne sistematica utilizzando PubMed, Scopus e Web of Science. Abbiamo incluso studi datati tra gennaio 2000 e febbraio 2018. Il principale criterio di selezione era la segnalazione della malattia, dopo la vaccinazione.

Risultati. Sono stati selezionati dieci studi, su un totale di 391. Di questi, 5 erano case report, 3 erano studi di coorte e 2 caso-controllo. Tutti gli studi ri-guardavano casi di sindrome di Stevens-Johnson dopo la vaccinazione.

Gli studi selezionati hanno riguardato casi in seguito a vaccini quali vaccino dell’influenza, vaiolo, antrace e vaccino antitetanico, vaccino MMR, vaccino contro la varicella, vaccino DTaP-IPV o vaccino antirabbico. Nessuno degli studi di coorte ha riportato associazioni statisticamente significative tra la vaccinazione e la sin-drome. Negli studi caso-controllo, non è stato osservato un aumento significativo del rischio di SJS in seguito alla somministrazione di vaccini. Per quanto riguarda i casi clinici, non c’erano prove sufficienti per formare un’associazione positiva tra questi due fattori e sono necessari ulteriori studi.

Conclusioni. In questa revisione non è stato possible stabilire una relazione positiva tra la vaccinazione e lo sviluppo della sindrome di Stevens-Johnson.

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List of excluded articles after full-text assessment

1. Fernando SL, Broadfoot AJ. Prevention of severe cutaneous adverse drug reactions: The emerging value of pharmacogenetic screening. CMAJ 2010; 182(5): 476–80.

2. Morales-Olivas FJ, Martínez-Mir I, Ferrer JM, Rubio E, Palop V. Adverse drug reactions in children reported by means of the yellow card in Spain. J Clin Epidemiol 2000; 53(10): 1076–80.

3. Rosenthal SR, Merchlinsky M, Kleppinger C, Goldenthal KL. Developing new smallpox vaccines. Emerg Infect Dis 2001; 7(6): 920–6.

4. Breathnach SM. Adverse cutaneous reactions to drugs. Clin Med 2002; 2(1): 15–9.

5. Fulginiti VA, Papier A, Lane JM, Neff JM, Hen-derson DA. Smallpox vaccination: a review, part II. Adverse events. Clin Infect Dis 2003; 37(2): 251–71.

6. Garin D, Crance JM, Fuchs F, Autran B, Drillien R. Actualités sur la vaccination antivariolique. Med Mal Infect 2004; 34(1): 20–7.

7. Tom WL, Kenner JR, Friedlander SF. Smallpox: Vaccine reactions and contraindications. Derma-tol Clin 2004; 22(3): 275–89.

8. Wollenberg A, Engler R. Smallpox, vaccina-tion and adverse reactions to smallpox vaccine. Curr Opin Allergy Clin Immunol 2004; 4(4): 271–5.

9. Leissner KB, Holzman RS, McCann ME. Bio-terrorism and children: Unique concerns with infection control and vaccination. Anesthesiol Clin North America 2004; 22(3): 563–77.

10. Wise RP. Postlicensure Safety Surveillance for 7-Valent Pneumococcal Conjugate Vaccine. JAMA [Internet]. 2004; 292(14): 1702. Avail-able from: http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.292.14.1702

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Corresponding author: Dr. Ines Grazina, Faculty of Pharmacy, University of Lisbon, Avenida Professor Gama Pinto, S/N, 1649-003, Lisbon, Portugale-mail: [email protected]

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