10.5826/dpc.1301a23
text/xml
2160-9381
2448
en
Paulo Filipe
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
BNT162b2
Localized Vitiligo and Post-Inflammatory Hypopigmentation at the Injection Site of a COVID-19 mRNA Vaccine 
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Research Letter
2023-01-31
2022-03-10
2023-01-31
2023-02-27
e2023023
Dermatol Pract Concept
Paulo Filipe
2023/01/31
10.5826/dpc.1301a23
e2023023
Dermatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte; Dermatology Universitary Clinic, Faculdade de Medicina da Universidade de Lisboa; Dermatology Research Unit, Instituto de Medicina Molecular, Universida de de Lisboa, Lisbon, Portugal
2160-9381
BNT162b2
en
e2023023
Lane Lane C, Leitch J, Tan X, Hadjati J, Bramson JL, Wan Y. Vaccination-induced autoimmune vitiligo is a consequence of secondary trauma to the skin. Cancer Res. 2004;64(4):1509-1514. DOI: 10.1158/0008-5472.can-03-3227. PMID: 14973051.
Localized Vitiligo and Post-Inflammatory Hypopigmentation at the Injection Site of a COVID-19 mRNA Vaccine 
https://dpcj.org/index.php/dpc/article/download/2448/1907
               Localized Vitiligo and Post-Inflammatory
                Hypopigmentation at the Injection Site
                     of a COVID-19 mRNA Vaccine
     Dora Mancha1, Joana Antunes1,2, Luís Soares-de-Almeida1,2,3, João Borges-Costa1,2,3,4,
                                      Paulo Filipe1,2,3


1 Dermatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal
2 Dermatology Universitary Clinic, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
3 Dermatology Research Unit, Instituto de Medicina Molecular, Universidade de Lisboa, Lisbon, Portugal
4 Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisbon, Portugal



Key words: vitiligo, COVID-19, SARS-CoV2, mRNA, vaccine, BNT162b2
Citation: Mancha D, Antunes J, Soares-de-Almeida L, Borges-Costa J, Filipe P. Localized Vitiligo and Post-Inflammatory Hypopigmentation
at the Injection Site of a COVID-19 mRNA vaccine. Dermatol Pract Concept. 2023;13(1):e2023023. DOI: https://doi.org/10.5826/
dpc.1301a23
Accepted: May 2, 2022; Published: January 2023
Copyright: ©2023 Mancha et al. This is an open-access article distributed under the terms of the Creative Commons Attribution-
NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use,
distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Dora Mancha, Dermatology Department, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa
Norte, Av. Prof. Egas Moniz MB, 1649-028 Lisboa, Portugal. Phone: +351 21 780 5243; E-mail: dora.mancha@gmail.com




Introduction                                                             vaccine BNT162b2. After vaccine administration, the pa-
                                                                         tient described an immediate local reaction on the injec-
The COVID-19 pandemic has been a global emergency since                  tion site characterized by an erythematous and edematous
January 2020. One of the most commonly used COVID-19                     plaque. This reaction evolved to a hypopigmented patch
mRNA vaccines is Pfizer- BioNTech vaccine BNT162b2                       with irregular borders measuring 20 mm (Figure 1A). Wood
[1]. In a registry-based study of 414 cutaneous reactions to             lamp examination of the lesion (Figure 1B) revealed nei-
mRNA COVID-19 vaccines, delayed and immediate injec-                     ther fluorescence nor accentuation, which is consistent with
tion site reactions were the most common [2]. Herein, we                 post-inflammatory hypopigmentation. This cutaneous lesion
discuss two similar cutaneous reactions following COVID                  fainted after 2 months without treatment.
mRNA vaccination in order to further characterize derma-                      Case 2. A 30-year-old woman, Fitzpatrick type V, pre-
tologic reactions.                                                       sented to our consultation after the first dose of Pfizer
                                                                         vaccine. Few hours after the vaccine, the patient noted an
Case Presentation                                                        immediate local reaction characterized by an erythema-
                                                                         tous and edematous plaque with a central blister. Over two
Case 1. A 38-year-old woman, Fitzpatrick type III, pre-                  weeks, this reaction evolved to a hypopigmented patch with
sented to our consultation after the second dose of Pfizer               25 mm of diameter and irregular borders, surrounded by



Research Letter | Dermatol Pract Concept. 2023;13(1):e2023023                                                                        1
Figure 1. Skin hypopigmentation. Case 1. (A) Hypopigmented patch with irregular borders on the left arm at three weeks following the
second dose of Pfizer vaccine. (B) Wood lamp examination revealed neither fluorescence nor accentuation. Case 2. (C-E) Site injection reac-
tion on the left arm evolved from an erythematous and edematous plaque with a central blister to a hypopigmented patch over a period of
hours to two weeks following the first dose of Pfizer vaccine. (F) Under Wood lamp examination the hypopigmented patch showed sharply
demarcated bright blue-white fluorescence.



another patch with two shades of brown (Figure 1, C-E).                months of follow-up only the vitiligo lesion remains, the
Wood lamp examination demonstrated a sharply demar-                    brown patch is fading away.
cated bright blue-white fluorescence (Figure 1F), consistent
with vitiligo. Skin biopsy was also compatible with vitiligo
                                                                       Conclusions
(Figure 2) revealing a decrease or absence of melanin pig-
ment in lesional skin with H&E and Masson-Fontana stains,              Post-inflammatory hypopigmentation is an acquired partial
respectively. Autoimmunity laboratory study (ANAs, ANA                 or total loss of skin pigmentation occurring after cutaneous
screening, anti-dsDNA, anti-thyroid antibodies) was nega-              inflammation. There is limited information about the mecha-
tive and SARS-CoV2 anti-spike antibody titers were positive            nism and pathogenesis. Melanogenesis is a complex process.
of (50.8 AU/mL). She was treated with topical tacrolimus               It is controlled by multiple mediators (eg, growth factors,
twice daily with poor response. After the second dose of the           cytokines) acting on melanocytes, keratinocytes and fibro-
vaccine, two months later, she had no skin reaction. At four           blasts. Through the release of these mediators, cutaneous



2                                                                           Research Letter | Dermatol Pract Concept. 2023;13(1):e2023023
Figure 2. Vitiligo, Case 2. Skin biopsy performed on the edge of the hypopigmented patch. (A) Basal epidermal hyperpigmentation explained
by the patient phototype. Scarce inflammatory infiltrate in the superficial dermis (H&E stain, magnification x100). (B) Slight Decrease in
melanin pigment in lesional skin (H&E stain, magnification x400). (C,D) Masson-Fontana stain highlights loss of melanin on the left side of
the biopsy (Fontana-Masson stain, magnification x100 and x400).




inflammation may cause aberration of melanogenesis leading             In the pathogenesis of vitiligo, both IFN-1 and DCs were
to loss of melanocytes [3]. In Case 1, inflammation resulted           demonstrated to play a significant role. The activation of
in hypopigmented patches at the injection site. The hypopig-           DCs and the release of IFN-1 seem to be key events in vitiligo
mentation improved overtime after the inflammation ceased.             following COVID-19 vaccination. Additionally, nonspecific
    Vitiligo is an autoimmune disease. Cytotoxic CD8+ T                activation of autoreactive CD8+/CD4+ T and B cells could
cells are responsible for the destruction of melanocytes. The          stimulate the immune system to produce antibodies against
potential for vaccines to act as triggers of autoimmune reac-          SARS- CoV2 spike protein and incidentally against melano-
tions is well known [4,5]. The pathophysiology underlying              cytes [7-9].
the relationship between SARS- CoV-2 vaccination and vitil-                On the other hand, studies with anti-melanoma vaccines
igo remains unclear.                                                   demonstrated that vitiligo observed around the injection site
    mRNA vaccines encoding the SARS-CoV-2 spike protein                does not occur unless autoreactive T cells are recruited into
encapsulated in lipid nanoparticles gain entry into dendritic          the skin by inflammatory stimuli, suggesting that vitiligo can
cells (DCs) at the injection site. In addition, innate sensors         be initiated by some form of trauma to the skin [10].
are triggered resulting in production of type I interferon                 To date, there are only five reported cases of new-onset
and multiple pro-inflammatory cytokines and chemokines.                vitiligo following COVID-19 mRNA vaccine (Table 1). In
In particular, vaccine-driven production of type I interferon          case 1, the hypopigmented patch was a result of an inflam-
(IFN-1) promotes differentiation of CD4+ and CD8+ effec-               matory response that can occur in any patient and should be
tor T cells producing inflammatory and cytotoxic media-                differentiated from vitiligo. Case 2 is the first report of site
tors, and CD4+ T follicular helper cells, which promote B              injection site vitiligo after an mRNA vaccine. Vaccines gen-
cell differentiation into antibody-secreting plasma cells [6].         erate an immune response which can be a trigger to develop



Research Letter | Dermatol Pract Concept. 2023;13(1):e2023023                                                                            3
Table 1. Literature review: reported cases of new-onset vitiligo following COVID-19 mRNA vaccine.
          Authors/year               Age (years)        Sex          Vaccine                 Local                  Timing
 Aktas H, Ertuğrul G [4]                  58          Male       Pfizer-BioNTech     Face                    1 week after 1st dose
 2021                                                            BNT162b2
 Kaminetsky J, Rudikoff D [7]             61          Female     mRNA-1273           Face, neck, chest,      Several days after 1st
 2021                                                            (Moderna)           abdomen                 dose
 Ciccarese G [9]                          33          Female     Pfizer-BioNTech     Trunk, neck, back       1 week after 1st dose
 2022                                                            BNT162b2
 Militello et al. [5]                     67          Female     mRNA-1273           Hands                   2 weeks after the
 2022                                                            (Moderna)                                   vaccine
 Uğurer E et al. [8]                      47          Male       Pfizer-BioNTech     Axilla, forearms        1 week after 1st dose
 2022                                                            BNT162b2



vitiligo. We can hypothesize that in case 2, autoreactive T           5. Militello M, Ambur AB, Steffes W. Vitiligo Possibly Trig-
cells responses triggered by a local injection site inflamma-            gered by COVID-19 Vaccination. Cureus. 2022;14(1):e20902.
                                                                         doi: 10.7759/cureus.20902. PMID: 35145806. PMCID:
tion along with activation of DCs and the release of IFN-1
                                                                         PMC8809499.
might be responsible for the development of vaccine-induced
                                                                      6. Teijaro JR, Farber DL. COVID-19 vaccines: modes of im-
vitiligo at injection site.                                              mune activation and future challenges. Nat Rev Immunol.
                                                                         2021;21(4):195-197.      DOI:   10.1038/s41577-021-00526-x.
                                                                         PMID: 33674759. PMCID: PMC7934118.
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