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 Table of Contents  
Year : 2020  |  Volume : 64  |  Issue : 3  |  Page : 308-310  

Erythema multiforme induced by tetanus toxoid vaccine

1 Patient Safety Pharmacovigilance Associate, ADR Monitoring Center, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
2 Assistant Professor, Department of Pharmacology and Toxicology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
3 Additional Professor, Department of Pharmacology and Toxicology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India
4 Senior Resident, Department of Dermatology, All India Institute of Medical Sciences, Bhopal, Madhya Pradesh, India

Date of Submission10-Jul-2019
Date of Decision11-Dec-2019
Date of Acceptance17-May-2020
Date of Web Publication22-Sep-2020

Correspondence Address:
Deepa Chaudhary
Department of Pharmacovigilance, All India Institute of Medical Sciences, Bhopal - 462 020, Madhya Pradesh
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijph.IJPH_335_19

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Erythema multiforme (EM) is an immunomediated mucocutaneous disorder of usually unknown etiology which has been known to occur following an infection like herpes virus or exposure to drugs. It primarily affects adolescents, young adults, but can occur at any age. Vaccines are also documented as precipitating factors for EM. In the year 2017, the case of a 25-year-old male patient with lesions of EM which appeared after 30 min of administration of tetanus toxoid vaccine is reported here.

Keywords: Erythema multiforme, mucocutaneous, tetanus toxoid vaccine, vaccine

How to cite this article:
Chaudhary D, Atal S, Jhaj R, Rupla R. Erythema multiforme induced by tetanus toxoid vaccine. Indian J Public Health 2020;64:308-10

How to cite this URL:
Chaudhary D, Atal S, Jhaj R, Rupla R. Erythema multiforme induced by tetanus toxoid vaccine. Indian J Public Health [serial online] 2020 [cited 2022 Jan 21];64:308-10. Available from:

   Introduction Top

Tetanus is an acute, often fatal, disease caused by a neurotoxic exotoxin tetanospasmin produced by the anaerobic bacterium Clostridium tetani. Spores enter body through puncture wounds coming in contact with soil, fecal matter, or rusty metal. Tetanospasmin blocks the release of neurotransmitters glycine and gamma aminobutyric acid (GABA) at motor nerve endings, causing severe muscle spasms.[1] Active immunization with intramuscular tetanus toxoid (TT) is prophylactically used either alone or with diphtheria toxoid and pertussis vaccine.[2]

Erythema multiforme (EM) is an idiopathic acute, self-limiting skin condition related to certain infections (herpes simplex, mycoplasma), drugs, vaccines, and other triggers. Reports of EM caused by a variety of vaccines are described with single and combined vaccines.[3]

   Case Report Top

In the year 2017, a 25-year-old male visited a private practitioner for acquired active immunization against tetanus after suffering an accidental injury. He was administered vaccine 0.5 ml Dano TT (manufactured by: Dano Vaccines and Biologicals Private Limited, Hyderabad, India), 1 stat, by IM route (on the right buttock – gluteal muscle) for the prevention of tetanus. Each dose of 0.5 ml Dano TT contains ≥5 to ≤25 Lf TT + 1.5 mg aluminum phosphate (mineral carrier) +0.01% w/v thiomersal IP (preservative). The patient developed well-defined generalized hyperpigmented target lesions all over the body, especially the face and genital region after 30 min of administration of the vaccine. Maculopapular lesions developed inside the oral mucosa. Due to increase in the severity of this adverse event following immunization (AEFI), the patient was admitted in the dermatology unit of male medical ward of the hospital. He was seen by a consultant dermatologist who made the diagnosis of EM [Figure 1] and [Figure 2].
Figure 1: Lesions over the face: Hyperpigmented target lesions on skin characteristic of erythema multiforme.

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Figure 2: Oral lesions: Maculopapular lesions on the lips.

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The patient was not receiving any other concomitant medications at the time when the AEFI occurred. He did not have any relevant medical history. Relevant laboratory investigations such as serum Immunoglobulin (IgM) herpes simplex virus (HSV) and Tzanck smear cytology showed no positive findings. Complete blood count (white blood cell count, hemoglobin, and platelet count), renal function tests (serum creatinine and urea), liver function tests (alanine aminotransferase, and aspartate aminotransferase), and serum electrolytes (sodium, potassium, and chloride) were all within the normal range. He recovered from the event after 20 days of treatment. Injection dexamethasone (1 ml BD), tablet acyclovir (400 mg TDS), povidone iodine (2% gargles), mucopain gel (benzocaine), and tablet pantoprazole (40 mg OD) were prescribed to the patient for the treatment of the AEFI.

Worldwide, unique identity number of the reported AEFI is 2017-65426. Using the World Health Organization causality assessment criteria, causality was determined as “probable” with TT Vaccine by the causality assessment committee of the adverse drug reaction (ADR) monitoring center.

   Discussion Top

Reactions due to TT vaccine are generally mild and local. However, in some cases, edema, tenderness, anaphylactoid response, and fever have been described with TT antigen, aluminum phosphate, and thiomersal preservative considered as main precipitants for such allergic reactions. The mechanism possibly involves a delayed hypersensitivity response and inhibition of leukocyte migration.[2]

EM is an acute immune disorder mainly affecting the skin and mucous membrane of the oral cavity characterized by the presence of symmetrical lesions over the extremities.[4] Little is known about molecular and cellular mechanisms triggering EM, but antigens induced by exposure to microbes or drugs are known triggers. Among microbes, herpes simplex is implicated up to 70% of recurrent cases. EM is known to be related to cytotoxic T-lymphocytes and specific CD8 + cells activated in response to antigens. Activation of the Fas membrane receptor by its ligand FasL induces keratinocyte apoptosis through the activation of caspases.[5] Hence, it can be hypothesized that TT vaccine may act as an antigen and activate the pathway involved in the pathogenesis of EM.

Instances of EM have been reported with combination vaccines globally – one containing tetanus and diphtheria, two containing diphtheria, tetanus, acellular pertussis, and another containing diphtheria, tetanus, acellular pertussis (DaPT), inactivated polio and hemophilus type B.[6],[7] In India, only one such case has been reported and published till date to our knowledge, with combination vaccines containingdiphtheria, tetanus, acellular pertussis (DaPT), hepatitis B, and influenza.[8] Hepatitis-B vaccine and meningitis, rabies, and smallpox vaccination have also been accounted as a cause for EM. TT and diphtheria were the common agents in all combination vaccines, seen as potential precipitating factors. TT vaccine alone has not yet been reported to have caused EM.

In this case, the patient received vaccine containing TT and the lesions of EM appeared after 30 min, so a temporal relation existed. The patient had no other illness and was not on any other concomitant medications. HSV is the most common organism involved in the etiopathogenesis of EM, but the patient showed nonreactivity of HSV 1 + 2 IgM in serum; further strengthening the probability of causality due to the vaccine received. The Dano TT vaccine thus was probably responsible for causing EM in the patient.

Public health importance

Vaccination is an important public health activity. The goal of national immunization programme is to protect the public from vaccine preventable diseases. Although vaccines used in the national immunization programme are considered safe and effective, no vaccine is entirely free from adverse reactions like any other drugs. To deal effectively with the concerns associated with risks of immunization, both health-care providers and the general public should be educated about AEFI, and health providers should be encouraged to report AEFI. This would further establish immunization safety and increase public confidence. AEFI reporting is necessary to generate new signals about vaccine reactions that are specific to the population of the country/region. TT is one of the most commonly used vaccines in healthy population including children and adults for pre- and postexposure prophylaxis. Hence, it is imperative to make health-care professionals aware about the possibility of coming across and mitigating rare serious dermatological AEFI like erythrema multiforme which can occur with this vaccine. Publication of this report would definitely contribute to create that necessary awareness.


In this case report, the mechanistic association of EM to TT is not well-documented. Literature also does not provide clear evidence for the same. However, causation has been hypothesized and supported by exclusion of other likely causes. Furthermore, the exact causative agent in the vaccine was also proposed to be explored using patch test with thiomersal (used as preservative in Dano-TT vaccine), but the patient denied the test.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.


We are grateful to Dr. Dinesh Asati, MD, Department of Dermatology, AIIMS, Bhopal, for his contribution by helping in management of this adverse drug reaction.

Financial support and sponsorship

This study was financially supported by Pharmacovigilance program of India.

Conflicts of interest

There are no conflicts of interest.

   References Top

Hamborsky J, Kroger A, Wolfe C, editors. Tetanus. In: The Pink Book-Epidemiology and Prevention of Vaccine-Preventable Diseases. 13rd ed., U.S. Centers for Disease Control and Prevention; 2015. Available from: [Last retrieved on 2018 Jun 24].  Back to cited text no. 1
Das S, Mondal S. Tetanus toxoid induced anaphylaxis. J Vaccines Vaccin 2012;3:126.  Back to cited text no. 2
Verma P. Erythema multiforme possibly triggered by rabies vaccine in a 10-year-old boy. Pediatr Dermatol 2013;30:e297-8.  Back to cited text no. 3
Samim F, Auluck A, Zed C, Williams PM. Erythema multiforme: A review of epidemiology, pathogenesis, clinical features, and treatment. Dent Clin North Am 2013;57:583-96.  Back to cited text no. 4
de Arruda JA, Silva P, Amaral MB, Cotta F, Avendanho R, Mesquita R. Erythema multiforme induced by alendronate sodium in a geriatric patient: A case report and review of the literature. J Clin Exp Dent 2017;9:e929-33.  Back to cited text no. 5
Frederiksen MS, Brenøe E, Trier J. Erythema multiforme minor following vaccination with paediatric vaccines. Scand J Infect Dis 2004;36:154-5.  Back to cited text no. 6
Leung AK. Erythema multiforme following DPT vaccination. J R Soc Med 1984;77:1066-7.  Back to cited text no. 7
Kaur S, Handa S. Erythema multiforme following vaccination in an infant. Indian J Dermatol Venereol Leprol 2008;74:251-3.  Back to cited text no. 8
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1 Tetanus-vaccine
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