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

2333

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 review

Parole 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 influenza, meningitis and cancers that occur

in adulthood.
Over 100 million children worldwide It is essential to make sure that vaccines
are being immunized, and vaccines prevent are safe, effective, and of good quality.
more than 2.5 million child deaths per Over the past few years, there have been
year. Nowadays, there’s a constant concern some reports of adverse events related to
regarding vaccination and more vaccines are vaccination. Nonetheless, vaccination is
being made available to protect adolescents still one of the most cost-effective health
and adults, such as vaccines against interventions. Giving the fact that fear of

1
Department of Public Health and Infectious Diseases, Sapienza University of Rome, Italy
2
Faculty of Pharmacy, University of Lisbon, Portugal
82 I. Grazina et al.

vaccines and immunization is usually related clinical signs include areas of erythematous
to lack of information, it is crucial to keep and livid macules on the skin, with a positive
the population informed about the safety of Nikolsky sign. The Nikolsky sign, even
vaccines and how they can reduce disease though is not specific for this syndrome, can
and deaths (1). be assessed by applying mechanical pressure
There is evidence that Stevens-Johnson on the skin. If the pressure is followed by
syndrome (SJS) may, in very rare occasions, epidermal detachment characterized by the
be caused by vaccination (2). development of blisters, the sign is positive.
SJS is a rare, severe skin disorder, The mucosal involvement follows the skin
characterized by an immune-mediated signs or can occur simultaneously with these.
cutaneous reaction, usually secondary to SJS is distinguished from other diseases,
a hypersensitivity reaction to medication. such as Toxic Epidermal Necrolysis (TEN),
Lesions consist of widespread flat atypical through the surface area of epidermal
targets or purpuric macules. Patients are detachment (6). In SJS, there is a detachment
febrile and prostrated by disease. The of less than 10% of all body surface area,
distribution of skin lesions is predominantly while in TEN there is a detachment of more
central with involvement of at least two than 30%. If there is a detachment between
mucosal sites (3). 10% and 30%, it is considered to be a case
SJS is an unpredictable reaction that of SJS-TEN overlap (7).
involves drug specific CD8+ cytotoxic In the light of clarifying some safety
lymphocytes, the Fas-Fas ligand (FasL) issues concerning vaccinations, the objective
pathway of apoptosis, and granule-mediated of the present study was to perform a
exocytosis and tumour necrosis factor-α systematic review about the association
(TNF-α)/death receptor pathway (4). In between vaccination and development of
Europe, its incidence is estimated at 2-3 SJS.
cases/million population/year. Most patients
are aged 10-30 years old, but the disease can
also affect children as young as 3 months Materials and methods
old. SJS is more common in females than
in males (5), it can affect people of any age, Identification of relevant studies
gender, or race (4). SJS is a life-threatening This systematic review was performed
disease. The average reported lethality rate according to the Preferred Reporting Items
is 1-5% (6). for Systematic Reviews and Meta-Analyses
In the acute phase, initial symptoms can (PRISMA) statement (8). Search was made
be not specific, such as fever, stinging eyes using the electronic databases PubMed,
and discomfort upon swallowing. These Scopus and Web of Science, applying the
symptoms precede cutaneous manifestations following algorithm: (Stevens-Johnson
by a few days. Early sites of cutaneous AND syndrome) AND (vaccine OR vaccines
involvement include the presternal region OR immunization OR vaccination OR
of the trunk and the face, the palms and vaccinations). The studied population was
soles. Involvement of the buccal, genital the world population, the intervention
and/or ocular mucosa is very usual and the was vaccination and the comparator
respiratory and gastrointestinal tracts may group was non-vaccinated people. The
also be affected. In a second phase, epidermal outcome was the development of SJS. The
detachment of large areas may occur (6). search was undertaken in February 2018,
The diagnosis is based upon clinical concerning papers published from 1 January
symptoms and histological features. The 2000 to February 2018. Eligible studies
Association between Stevens-Johnson Syndrome and vaccination? 83

were selected according to a multi-step Data extraction and quality assessment

approach (title reading, abstract and full-text Data extraction was carried out following
assessment) by two researchers, working the same strategy as the studies, by two
independently. We registered the protocol researchers.
in the PROSPERO database (registration A quality assessment was performed,
number CRD42018089119). according to the Newcastle-Ottawa Scale
Furthermore, the references to review, (NOS) for observational studies (9), and a
letters, comments, editorials, and case conceptual scheme for evaluating the quality
reports, identified by the search strategy, of a case report (10). To assess risk of bias of
were evaluated for retrieving further relevant our systematic review, the ROBIS tool was
literature. used, which is in annex (11).
The following characteristics were
Study selection and eligibility criteria collected: authors, study design (cross-
The first selection was performed filtering sectional, cohort, case control, narrative
duplicates by JabRef 2.10 program and review, case report, systematic review and/or
ZOTERO 4.0. meta-analysis), year of publication, country,
The articles identified by search strategy results, funding.
were selected initially, through the analysis The main outcome was the development
of the title and the abstract, independently of SJS.
by two researchers, and then the inclusion
criteria were evaluated by the analysis of
full-text by each investigator. Disagreements Results
between the two researchers were resolved
by a third one. Study selection
The search results for the selection
Inclusion criteria of articles are shown in the flowchart in
- Patients with SJS; Fig. 1. The PRISMA checklist is attached
- Article including vaccination as a (Annex “PRISMA Statement Checklist”).
factor; Grey literature was not included in the
- Primary studies as descriptive studies review.
(case-reports), observational studies (such as Overall, 444 papers were found. Of
cohort, case-control, cross-sectional studies) those, 72 articles were found on PubMed,
and experimental studies (randomized and 43 through Web of Science and 329 on
non-randomized); Scopus. Using the software JabRef 2.10,
- Secondary studies as narrative studies 53 duplicates were excluded. Through
or systematic reviews. the analysis of the abstract and title, we
excluded 177 articles. Then, 38 articles
Exclusion criteria were excluded after the analysis of full
- Patients without SJS, since this is the text, 94 articles were not available and 72
only disease we wanted to study; were from before the year 2000. The list of
- Article not including vaccination as articles excluded after the analysis of full
a factor, because vaccination is the main text is in annex.
intervention we were studying; Finally, 10 articles were included for
- Publication in language other than analysis: 5 case reports, 5 observational
English, French, German, Italian, Portuguese (3 cohort studies and 2 case-control). The
and Spanish, considering these are the characteristics of the studies are summarized
languages spoken by the researchers. in the table 1.
84 I. Grazina et al.

Fig. 1
Association between Stevens-Johnson Syndrome and vaccination? 85
86 I. Grazina et al.
Association between Stevens-Johnson Syndrome and vaccination? 87
88 I. Grazina et al.
Association between Stevens-Johnson Syndrome and vaccination? 89

Figure 2 - Flowchart
 90
Table 1 - Characteristics of the studies

First
Year Study Type Vaccine Type Cases Results Quality
author
Case Report A causal link between vaccination and
Ball R 2001 Varicella vaccine 1 reported case, 5 probable cases. 3*
and Review SJS can’t be established by this study.
Triad of smallpox (vaccinia The patient developed a case of SJS after
Chopra A 2004 Case Report virus), anthrax and tetanus 1 vaccination with smallpox, anthrax and 9*
vaccine tetanus vaccines.
There is not an established link between
Fleming D 2011 Case Report Influenza vaccine 1 the development of SJS and influenza 10*
vaccine.
Hexavalent vaccine; Haemo- It was not observed an increased risk
Raucci U 2013 Case-control philus influenza vaccine; MMR 4 cases, 137 controls. between vaccines and the development 6**
vaccine; Flu vaccine of the disease.
There were no cases of SJS following
Daley MF 2014 Cohort DTaP-IPV vaccine 0 8**
201,116 children.
This was the first reported case of SJS
Oda T 2017 Case Report Influenza vaccine 1 9*
after influenza vaccine monotherapy.
It was described the first case of SJS that
Ma L 2018 Case Report Rabies vaccine 1 10*
seemed to be caused by rabies vaccine.
Live Attenuated Influenza 8 cases in risk window; 14 cases in There were no confirmed cases of SJS
Daley MF 2018 Cohort 7**
vaccine control period; 0 confirmed cases. caused by the vaccine.
80 cases, 216 controls. Of these, 3 This study did not confirm a significant
Levi N 2009 Case-control cases where following vaccination in increased risk for SJS in children, fol- 6**
the last month (4 controls). lowing the administration of vaccines.
52 cases in the whole cohort, in
There is not a positive association re-
Persson I 2014 Cohort Influenza A (H1N1) vaccine which also other medications were 8**
garding SJS and H1N1 vaccine.
considered.
*- according to the case-report conceptual scheme ** - according to Newcastle Ottawa scale
I. Grazina et al.
Association between Stevens-Johnson Syndrome and vaccination? 91

Analysis of the studies in the last month included) as risk-factors of

Ball R. reported, in his 2001 study, one SJS in children, Levi et al. made a pooled
case of SJS following the administration of analysis of two case-control studies, found
varicella vaccine, in a 27-month old baby. In there were 3 vaccinated among cases of SJS,
the same study, Ball et al. reviewed the data and 4 vaccinated among controls. The odds-
from the vaccine adverse event reporting ratio was of 2.0 (95%CI: 0.5-9.4) (19).
system (VAERS), where one definite case Regarding a Swedish cohort study of
of SJS/TEN and 5 probable cases were influenza A (H1N1) vaccine, the association
diagnosed, after vaccination (2). with SJS gave a non-significant HR of 1.59
In 2004, Chopra et al. reported the case (95% CI: 0.95-2.65) (20).
of a 19-year old male patient who developed
SJS after vaccination with smallpox, anthrax
and tetanus vaccines (12). Discussion
Fleming D. reported, in 2011, one case
of SJS following influenza immunization This systematic review investigated
(13). a hypothetical link between vaccination
Raucci U. et al. did a case-control study and the development of Stevens-Johnson
regarding the potential association between syndrome.
drugs and vaccines and a hypothetical In cohort studies, the authors concluded
development of SJS. In this study, there that there was not a positive association
were 4 cases of SJS following vaccination, between the development of SJS and the
with 137 controls, having an odds-ratio of administration of a vaccine (20). In a
0,9 (95%CI: 0,3-2,8) (14). different cohort study, it was concluded
In a 2014 study, by Daley MF et al., that, regarding the information of that
the safety of diphtheria, tetanus, acellular study, it was not possible to establish a
pertussis and inactivated poliovirus (DTaP- direct association between vaccination and
IPV) vaccine was evaluated. Following development of the syndrome. However,
201,116 children from January 2009 through they considered that it was not possible to
September 2012, no cases of SJS were exclude the vaccine as a potential cause to
reported (15). the development of the disease and more
Oda T. et al. reported, in 2017, the first information was needed (18). In the third
case of Stevens-Johnson syndrome after cohort study included in this review, there
influenza vaccine monotherapy, in a 75-year was no increased risk of developing the
old Japanese man (16). In 2018, Ma L et disease following the administration of the
al. reported, in China, the first case of SJS vaccine (15).
after rabies vaccination, in a 22-year old In a case-control study developed
woman (17). by Raucci et al., it was concluded that,
In 2018, Daley et al. studied the safety regarding the studied population, there was
of live attenuated influenza vaccine (LAIV) no increased risk between the development
in children and adolescents, having no of the disease and vaccination (14).
confirmed cases (N=0) of SJS following Regarding the work published by Levi
immunization. Although it was observed et al. (19), the study did not confirm an
a single case of SJS following LAIV, the increasing risk for the development of SJS
patient was also exposed to acetaminophen, in vaccinated children.
which may have caused the development of As far as concerns the case-reports, the
the disease (18). study conducted by Fleming concluded
On an analysis of medications (vaccines that there was not an established relation
92 I. Grazina et al.

between the vaccine and the development Strengths and limitations

of the disease. Nonetheless, clinicians Our review has both strengths and
should be aware of a potential link between limitations. The number of included studies
immunization and the concomitant use of in the final analysis was limited and it was
penicillin, that could develop the syndrome not possible to conduct a meta-analysis,
(13). Ball R. et al. mentioned that they could because of the heterogeneity observed in the
not establish a causal link between the two study design. The lack of a meta-analysis
factors in study (vaccination and SJS). makes it more difficult to draw conclusions.
In their opinion, more studies regarding Also, most of the studies were case reports,
the recurrence of SJS with revaccination which can rarely prove a causal link between
are needed. They also concluded that if two factors and are subjected to biases, such
vaccination really causes SJS, it happens as reporting bias.
very rarely and the benefits of the vaccine When it comes to strengths, this is,
itself are bigger than the risk (2). Chopra et to our knowledge, the first systematic
al. reported a case of a patient who developed review investigating the association
a case of Stevens-Johnson syndrome after between vaccination and Stevens-Johnson
been immunized with smallpox, anthrax, and syndrome. We believe that our review has
tetanus vaccines. It is stated that based on his special importance in alerting the medical
previous tolerance to tetanus vaccines and community to the need of more studies
the rarity of severe skin eruptions after the concerning this hypothetical association.
administration of anthrax vaccine, the most Another strength is that through ROBIS
likely cause of the reaction was smallpox Tool, we assessed the risk of bias within
vaccine (12). our study. We concluded that there was low
Oda T. et al. reported a case of a man who risk of bias.
developed SJS after influenza vaccine. They
performed a test to investigate if a possible
cause of the development of the syndrome Conclusions
could be the additives in the vaccine
(thiomersal and formalin). Since these Through the analysis of the studies,
results came back negative, they concluded we can conclude that it is not possible to
that the most likely cause was the influenza establish a positive relation between these
vaccine itself. The adverse effects following two factors, since most of the studies were
the administration of this vaccine are quite inconclusive or presented statistically non-
rare, so more studies are required in order significant results. In this systematic review,
to clarify this hypothetical link (16). Finally, convincing evidence of an association
Ma L. et al. described a case of SJS following between vaccines and SJS does not exist.
the administration of the first dose of a series SJS and TEN are very rare indeed in the
of three doses rabies vaccine. Giving the absence of vaccination. They remain so also
absence of any other concurrent disease or after vaccination.
risk factor, including drugs consumption There is few evidence from the studies
or exposure to chemicals, and due to a on the development of the disease being
plausible time relationship, the most likely related to vaccines. Plus, most of the
cause of the development of the disease was studies reported cases following different
attributed to rabies vaccine. According to kinds of vaccines. Therefore, it is difficult
this study, clinicians should be vigilant on to compare the outcomes and establish
the possibility of SJS occurrence after the an association between the two factors in
administration of the vaccine (17). study.
Association between Stevens-Johnson Syndrome and vaccination? 93

Funding: This work was not supported by other orga- References

nizations.
Declarations of interest: None 1. World Health Organization (WHO). State of
Conflict of interest: The authors declare that they have the world’s vaccines and immunization. 3rd ed.
no conflict of interest. WHO, 2009.
Annex: ROBIS Tool, PRISMA statement checklist, List
2. Ball R, Ball LK, Wise RP, Braun MM, Beeler JA,
of excluded articles by full-text assessment
Salive ME. Stevens-Johnson syndrome and toxic
epidermal necrolysis after vaccination: reports to
the vaccine adverse event reporting system. Pe-
Riassunto diatr Infect Dis J [Internet]. 2001 Feb [cited 2018
Esiste un’associazione tra la sindrome di Stevens- Apr 16]; 20(2): 219–23. Available from: http://
Johnson e la vaccinazione? Una revisione siste- www.ncbi.nlm.nih.gov/pubmed/11224848
matica 3. Pereira FA, Mudgil AV, Rosmarin DM. Toxic
epidermal necrolysis. J Am Acad Dermatol
Obiettivi. È essenziale assicurarsi che i vaccini siano [Internet]. 2007 Feb [cited 2018 Apr 16]; 56(2):
sicuri, efficaci e di buona qualità. Negli ultimi anni, ci 181–200. Available from: http://www.ncbi.nlm.
sono state alcune segnalazioni di effetti avversi riguar- nih.gov/pubmed/17224365
danti la vaccinazione. Uno di questi effetti avversi è lo 4. Oakley AM, Krishnamurthy K. Stevens John-
sviluppo della sindrome di Stevens-Johnson. La sindro- son Syndrome (Toxic Epidermal Necrolysis)
me di Stevens-Johnson è una malattia rara, grave, che [Internet]. StatPearls. 2018 [cited 2018 Apr 16].
di solito si verifica dopo la medicazione. In Europa, la Available from: http://www.ncbi.nlm.nih.gov/
sua incidenza stimata è di 2-3 casi / milione di abitanti / pubmed/29083827
anno. Pertanto, lo scopo di questo studio è di indagare, 5. Fritsch P. European Dermatology Forum: skin
attraverso una revisione sistematica, l’associazione tra diseases in Europe. Skin diseases with a high
la vaccinazione e lo sviluppo della sindrome di Stevens- public health impact: toxic epidermal necrolysis
Johnson. and Stevens-Johnson syndrome. Eur J Dermatol
Materiali e metodi. Abbiamo eseguito una revisio- [Internet]. [cited 2018 Apr 16];18(2): 216–7.
ne sistematica utilizzando PubMed, Scopus e Web of Available from: http://www.ncbi.nlm.nih.gov/
Science. Abbiamo incluso studi datati tra gennaio 2000
pubmed/18424404
e febbraio 2018. Il principale criterio di selezione era la
6. Harr T, French LE. Toxic epidermal necrolysis
segnalazione della malattia, dopo la vaccinazione.
and Stevens-Johnson syndrome. Orphanet J Rare
Risultati. Sono stati selezionati dieci studi, su un
totale di 391. Di questi, 5 erano case report, 3 erano Dis [Internet]. 2010 Dec 16 [cited 2018 Apr 16];
studi di coorte e 2 caso-controllo. Tutti gli studi ri- 5(1): 39. Available from: http://www.ncbi.nlm.
guardavano casi di sindrome di Stevens-Johnson dopo nih.gov/pubmed/21162721
la vaccinazione. 7. Bastuji-Garin S, Rzany B, Stern RS, Shear NH,
Gli studi selezionati hanno riguardato casi in seguito Naldi L, Roujeau JC. Clinical classification of
a vaccini quali vaccino dell’influenza, vaiolo, antrace cases of toxic epidermal necrolysis, Stevens-
e vaccino antitetanico, vaccino MMR, vaccino contro Johnson syndrome, and erythema multiforme.
la varicella, vaccino DTaP-IPV o vaccino antirabbico. Arch Dermatol [Internet]. 1993 Jan [cited 2018
Nessuno degli studi di coorte ha riportato associazioni Apr 16];129(1): 92–6. Available from: http://
statisticamente significative tra la vaccinazione e la sin- www.ncbi.nlm.nih.gov/pubmed/8420497
drome. Negli studi caso-controllo, non è stato osservato 8. Moher D, Liberati A, Tetzlaff J, Altman DG,
un aumento significativo del rischio di SJS in seguito PRISMA Group. Preferred Reporting Items
alla somministrazione di vaccini. Per quanto riguarda for Systematic Reviews and Meta-Analyses:
i casi clinici, non c’erano prove sufficienti per formare The PRISMA Statement. PLoS Med [Internet].
un’associazione positiva tra questi due fattori e sono 2009 Jul 21 [cited 2018 Apr 16]; 6(7):e1000097.
necessari ulteriori studi.
Available from: http://www.ncbi.nlm.nih.gov/
Conclusioni. In questa revisione non è stato possible
pubmed/19621072
stabilire una relazione positiva tra la vaccinazione e lo
9. Wells G, Shea B, O’Connell D, Peterson J, Welch
sviluppo della sindrome di Stevens-Johnson.
V, Losos M, et al. The Newcastle-Ottawa Scale
(NOS) for Assessing the Quality of Nonrando-
94 I. Grazina et al.

mised Studies in Meta-analyses. The Ottawa of neurological and immune-related diseases,

Hospital Research Institute, 2000. including narcolepsy, after vaccination with
10. Pierson DJ. How to Read a Case Report (or Teaching Pandemrix: a population- and registry-based
Case of the Month). [cited 2018 Apr 16]. Available cohort study with over 2 years of follow-up (J
from: https://pdfs.semanticscholar.org/03af/23f7f6 Intern Med 2014; 275(2): 172-190). J Intern Med
d04fd1170361904c6266c6c8739dfd.pdf 2017; 281(1): 102–4.
11. Whiting P, Savović J, Higgins JPT, et al. ROBIS:
A new tool to assess risk of bias in systematic List of excluded articles after full-text
reviews was developed. J Clin Epidemiol 2016; assessment
69: 225–34.
12. Chopra A, Drage LA, Hanson EM, Touchet NL. 1. Fernando SL, Broadfoot AJ. Prevention of severe
Stevens-Johnson syndrome after immunization cutaneous adverse drug reactions: The emerging
with smallpox, anthrax, and tetanus vaccines. value of pharmacogenetic screening. CMAJ
Mayo Clin Proc 2004; 79(9): 1193–6. 2010; 182(5): 476–80.
13. Fleming JD, Fogo AJ, Creamer DJ. Stevens- 2. Morales-Olivas FJ, Martínez-Mir I, Ferrer
Johnson syndrome triggered by seasonal influen- JM, Rubio E, Palop V. Adverse drug reactions
za vaccination and flucloxacillin: a pathogenic in children reported by means of the yellow
hypothesis. Eur J Dermatol [Internet]. 2011; card in Spain. J Clin Epidemiol 2000; 53(10):
21(3): 434-5. Available from: http://www.ncbi. 1076–80.
nlm.nih.gov/pubmed/21515437 3. Rosenthal SR, Merchlinsky M, Kleppinger
14. Raucci U, Rossi R, Da Cas R, Rafaniello C, C, Goldenthal KL. Developing new smallpox
Mores N, Bersani G, et al. Stevens-johnson vaccines. Emerg Infect Dis 2001; 7(6): 920–6.
syndrome associated with drugs and vaccines in 4. Breathnach SM. Adverse cutaneous reactions to
children: a case-control study. PLoS One 2013; drugs. Clin Med 2002; 2(1): 15–9.
8(7): e68231. 5. Fulginiti VA, Papier A, Lane JM, Neff JM, Hen-
15. Daley MF, Yih WK, Glanz JM, et al. Safety of derson DA. Smallpox vaccination: a review, part
diphtheria, tetanus, acellular pertussis and inac- II. Adverse events. Clin Infect Dis 2003; 37(2):
tivated poliovirus (DTaP-IPV) vaccine. Vaccine 251–71.
2014; 32(25): 3019-24. 6. Garin D, Crance JM, Fuchs F, Autran B, Drillien
16. Oda T, Sawasa Y, Okada E, et al. Stevens-John- R. Actualités sur la vaccination antivariolique.
son Syndrome After Influenza Vaccine Injection. Med Mal Infect 2004; 34(1): 20–7.
J Investig Allergol Clin Immunol 2017; 27(4): 7. Tom WL, Kenner JR, Friedlander SF. Smallpox:
274-5. Vaccine reactions and contraindications. Derma-
17. Ma L, Du X, Dong Y, et al. First case of Stevens- tol Clin 2004; 22(3): 275–89.
Johnson syndrome after rabies vaccination. Br J 8. Wollenberg A, Engler R. Smallpox, vaccina-
Clin Pharmacol [Internet]. 2018; 84(4): 803–5. tion and adverse reactions to smallpox vaccine.
Available from: http://doi.wiley.com/10.1111/ Curr Opin Allergy Clin Immunol 2004; 4(4):
bcp.13512 271–5.
18. Daley MF, Clarke CL, Glanz JM, et al. The safety 9. Leissner KB, Holzman RS, McCann ME. Bio-
of live attenuated influenza vaccine in children terrorism and children: Unique concerns with
and adolescents 2 through 17 years of age: A infection control and vaccination. Anesthesiol
Vaccine Safety Datalink study. Pharmacoepi- Clin North America 2004; 22(3): 563–77.
demiol Drug Saf 2018; 27(1): 59-68. 10. Wise RP. Postlicensure Safety Surveillance for
19. Levi N, Bastuji-Garin S, Mockenhaupt M, et al. 7-Valent Pneumococcal Conjugate Vaccine.
Medications as Risk Factors of Stevens-Johnson JAMA [Internet]. 2004; 292(14): 1702. Avail-
Syndrome and Toxic Epidermal Necrolysis able from: http://jama.jamanetwork.com/article.
in Children: A Pooled Analysis. Pediatrics aspx?doi=10.1001/jama.292.14.1702
[Internet]. 2009; 123(2): e297–304. Available 11. Snape MD, Pollard AJ. Meningococcal poly-
from: http://pediatrics.aappublications.org/cgi/ saccharide-protein conjugate vaccines. Lancet
doi/10.1542/peds.2008-1923 Infect Dis 2005; 5(1): 21–30.
20. Persson I, Granath F, Askling J, Ludvigsson JF, 12. Casey CG, Iskander JK, Roper MH, et al. Ad-
Olsson T, Feltelius N. Corrigendum to: Risks verse events associated with smallpox vaccina-
Association between Stevens-Johnson Syndrome and vaccination? 95

tion in the United States, January-October 2003. Apr 26]; 182(5): 476–80. Available from: http://
J Am Med Assoc 2005; 294(21): 2734–43. www.ncbi.nlm.nih.gov/pubmed/19933789
13. Wittek R. Vaccinia immune globulin: current 21. Harr T, French LE. Severe Cutaneous Adverse
policies, preparedness, and product safety and Reactions: Acute Generalized Exanthematous
efficacy. Int J Infect Dis 2006; 10(3): 193–201. Pustulosis, Toxic Epidermal Necrolysis and
14. Payne DC, Franzke LH, Stehr-Green PA, Stevens-Johnson Syndrome. Med Clin North Am
Schwartz B, McNeil MM. Development of the [Internet]. 2010 Jul [cited 2018 Apr 26]; 94(4):
Vaccine Analytic Unit’s research agenda for 727–42. Available from: http://www.ncbi.nlm.
investigating potential adverse events associated nih.gov/pubmed/20609860
with anthrax vaccine adsorbed. Pharmacoepide- 22. Milstien J, Cárdenas V, Cheyne J, Brooks A.
miol Drug Saf [Internet] 2007 Jan [cited 2018 WHO policy development processes for a new
Apr 26]; 16(1): 46–54. Available from: http:// vaccine: case study of malaria vaccines. Malar
www.ncbi.nlm.nih.gov/pubmed/16444796 J [Internet]. 2010 Jun 24 [cited 2018 Apr 26];
15. Nayak S, Acharjya B. Adverse cutaneous 9(1): 182. Available from: http://malariajournal.
drug reaction. Indian J Dermatol [Internet]. biomedcentral.com/articles/10.1186/1475-2875
2008 Jan [cited 2018 Apr 26]; 53(1): 2–8. -9-182
Available from: http://www.ncbi.nlm.nih.gov/ 23. Traynor K. Newer smallpox vaccines require
pubmed/19967009 new test methods. Am J Heal Pharm [Internet].
16. Thomas TN, Reef S, Neff L, Sniadack MM, 2011 Nov 1 [cited 2018 Apr 26]; 68(21): 2012–4.
Mootrey GT. A Review of the Smallpox Vaccine Available from: http://www.ncbi.nlm.nih.gov/
Adverse Events Active Surveillance System. Clin pubmed/22011978
Infect Dis [Internet]. 2008 Mar 15 [cited 2018 24. Smyth RMD, Gargon E, Kirkham J, et al. Ad-
Apr 26]; 46(s3): S212–20. Available from: http:// verse drug reactions in children--a systematic
www.ncbi.nlm.nih.gov/pubmed/18284361 review. PLoS One [Internet]. 2012 [cited 2018
17. Neff J, Modlin J, Birkhead GS, et al. Moni- Apr 26]; 7(3): e24061. Available from: http://
toring the Safety of a Smallpox Vaccination www.ncbi.nlm.nih.gov/pubmed/22403604
Program in the United States: Report of the 25. MacFadden DR, Gold WL. A 69-year-old man
Joint Smallpox Vaccine Safety Working Group with a painful vesicular rash. CMAJ [Internet].
of the Advisory Committee on Immunization 2012 Sep 18 [cited 2018 Apr 26]; 184(13):
Practices and the Armed Forces Epidemio- 1489–91. Available from: http://www.ncbi.nlm.
logical Board. Clin Infect Dis [Internet]. 2008 nih.gov/pubmed/22777993
Mar 15 [cited 2018 Apr 26]; 46(s3): S258–70. 26. Sicherer SH, Leung DYM. Advances in al-
Available from: http://www.ncbi.nlm.nih.gov/ lergic skin disease, anaphylaxis, and hypersen-
pubmed/18284367 sitivity reactions to foods, drugs, and insects
18. Verstraeten T, Descamps D, David M-P, et al. in 2012. J Allergy Clin Immunol [Internet].
Analysis of adverse events of potential auto- 2013 Jan [cited 2018 Apr 26]; 131(1): 55–66.
immune aetiology in a large integrated safety Available from: http://www.ncbi.nlm.nih.gov/
database of AS04 adjuvanted vaccines. Vaccine pubmed/23199604
[Internet]. 2008 Dec 2 [cited 2018 Apr 26]; 27. Angelo M-G, David M-P, Zima J, et al. Pooled
26(51): 6630–8. Available from: http://www. analysis of large and long-term safety data
ncbi.nlm.nih.gov/pubmed/18845199 from the human papillomavirus-16/18-AS04-
19. Vellozzi C, Burwen DR, Dobardzic A, Ball R, adjuvanted vaccine clinical trial programme.
Walton K, Haber P. Safety of trivalent inactivated Pharmacoepidemiol Drug Saf [Internet]. 2014
influenza vaccines in adults: Background for May [cited 2018 Apr 26]; 23(5): 466–79.
pandemic influenza vaccine safety monitoring. Available from: http://www.ncbi.nlm.nih.gov/
Vaccine [Internet]. 2009 Mar 26 [cited 2018 Apr pubmed/24644063
26]; 27(15): 2114–20. Available from: http:// 28. Weber SK, Schlagenhauf P. Childhood vaccina-
www.ncbi.nlm.nih.gov/pubmed/19356614 tion associated adverse events by sex: A litera-
20. Fernando SL, Broadfoot AJ. Prevention of severe ture review. Travel Med Infect Dis [Internet].
cutaneous adverse drug reactions: the emerging 2014 Sep [cited 2018 Apr 26]; 12(5): 459–80.
value of pharmacogenetic screening. Can Med Available from: http://www.ncbi.nlm.nih.gov/
Assoc J [Internet]. 2010 Mar 23 [cited 2018 pubmed/24680600
96 I. Grazina et al.

29. Haber P, Moro PL, Cano M, Lewis P, Stewart 2016 Oct 14 [cited 2018 Apr 26]; 36(4): 300–4.
B, Shimabukuro TT. Post-licensure surveillance Available from: http://www.ncbi.nlm.nih.gov/
of quadrivalent live attenuated influenza vaccine pubmed/26384567
United States, Vaccine Adverse Event Reporting 34. Hon KLE, Choi CLP. Steven Johnson Syndrome:
System (VAERS), July 2013–June 2014. Vaccine Drug or Bug? Indian J Pediatr [Internet]. 2016
[Internet]. 2015 Apr 15 [cited 2018 Apr 26]; Dec 27 [cited 2018 Apr 26]; 83(12–13): 1508–9.
33(16): 1987–92. Available from: http://www. Available from: http://www.ncbi.nlm.nih.gov/
ncbi.nlm.nih.gov/pubmed/25678241 pubmed/27460489
30. Lalosevic J, Nikolic M, Gajic-Veljic M, Skiljevic 35. Carnovale C, Gentili M, Matacena M, et al. A
D, Medenica L. Stevens-Johnson syndrome and retrospective review of paediatric adverse drug
toxic epidermal necrolysis: a 20-year single- reactions reported in Lombardy and Croatia from
center experience. Int J Dermatol [Internet]. 2005 to 2013. Expert Opin Drug Saf [Internet].
2015 Aug [cited 2018 Apr 26]; 54(8): 978–84. 2016 Dec 22 [cited 2018 Apr 26]; 15(Suppl. 2):
Available from: http://www.ncbi.nlm.nih.gov/ 35–43. Available from: http://www.ncbi.nlm.nih.
pubmed/25385069 gov/pubmed/27875921
31. Gorse GJ, Falsey AR, Ozol-Godfrey A, Landolfi 36. Myers TR, McNeil MM, Ng CS, Li R, Lewis
V, Tsang PH. Safety and immunogenicity of a PW, Cano M V. Adverse events following quadri-
quadrivalent intradermal influenza vaccine in valent meningococcal CRM-conjugate vaccine
adults. Vaccine [Internet]. 2015 Feb 25 [cited (Menveo®) reported to the Vaccine Adverse
2018 Apr 26]; 33(9): 1151–9. Available from: Event Reporting system (VAERS), 2010–2015.
https://www.sciencedirect.com/science/article/ Vaccine [Internet]. 2017 Mar 27 [cited 2018 Apr
pii/S0264410X15000444 26]; 35(14): 1758–63. Available from: http://
32. Cliff-Eribo KO, Choonara I, Dodoo A, Darko www.ncbi.nlm.nih.gov/pubmed/28262331
DM, Sammons H. Adverse drug reactions in 37. Durrieu G, Maupiler M, Rousseau V, et al. Fre-
Ghanaian children: review of reports from 2000 quency and Nature of Adverse Drug Reactions
to 2012 in VigiBase. Expert Opin Drug Saf [In- Due to Non-Prescription Drugs in Children: A
ternet]. 2015 Dec 2 [cited 2018 Apr 26]; 14(12): Retrospective Analysis from the French Pharma-
1827–33. Available from: http://www.ncbi.nlm. covigilance Database. Pediatr Drugs [Internet].
nih.gov/pubmed/26436964 2018 Feb 1 [cited 2018 Apr 26]; 20(1): 81–7.
33. Obebi Cliff-Eribo K, Sammons H, Star K, Available from: http://www.ncbi.nlm.nih.gov/
Ralph Edwards I, Osakwe A, Choonara I. pubmed/28766184
Adverse drug reactions in Nigerian children: a 38. Wetter DA, Camilleri MJ. Clinical, etiologic, and
retrospective review of reports submitted to the histopathologic features of Stevens-Johnson syn-
Nigerian Pharmacovigilance Centre from 2005 drome during an 8-year period at Mayo Clinic.
to 2012. Paediatr Int Child Health [Internet]. Mayo Clin Proc 2010; 85(2): 131–8.

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