Australasian Journal of DermatologyVolume 63, Issue 1 p. 128-130 Letter to the EditorsFree Access An unusual presentation of pemphigus foliaceus following COVID-19 vaccination Angelyn Chen Yin Lua, Corresponding Author Angelyn Chen Yin Lua angelyn.lua@mohh.com.sg orcid.org/0000-0001-8065-4642 Department of Dermatology, Singapore General Hospital, Singapore City, SingaporeSearch for more papers by this authorFelicia Li Ling Ong, Felicia Li Ling Ong Department of Dermatology, Singapore General Hospital, Singapore City, SingaporeSearch for more papers by this authorKaren Jui Lin Choo, Karen Jui Lin Choo Department of Dermatology, Singapore General Hospital, Singapore City, Singapore Duke-NUS Medical School, Singapore City, SingaporeSearch for more papers by this authorYi Wei Yeo, Yi Wei Yeo Department of Dermatology, Singapore General Hospital, Singapore City, Singapore Duke-NUS Medical School, Singapore City, SingaporeSearch for more papers by this authorChoon Chiat Oh, Choon Chiat Oh orcid.org/0000-0002-4769-8595 Department of Dermatology, Singapore General Hospital, Singapore City, Singapore Duke-NUS Medical School, Singapore City, SingaporeSearch for more papers by this author Angelyn Chen Yin Lua, Corresponding Author Angelyn Chen Yin Lua angelyn.lua@mohh.com.sg orcid.org/0000-0001-8065-4642 Department of Dermatology, Singapore General Hospital, Singapore City, SingaporeSearch for more papers by this authorFelicia Li Ling Ong, Felicia Li Ling Ong Department of Dermatology, Singapore General Hospital, Singapore City, SingaporeSearch for more papers by this authorKaren Jui Lin Choo, Karen Jui Lin Choo Department of Dermatology, Singapore General Hospital, Singapore City, Singapore Duke-NUS Medical School, Singapore City, SingaporeSearch for more papers by this authorYi Wei Yeo, Yi Wei Yeo Department of Dermatology, Singapore General Hospital, Singapore City, Singapore Duke-NUS Medical School, Singapore City, SingaporeSearch for more papers by this authorChoon Chiat Oh, Choon Chiat Oh orcid.org/0000-0002-4769-8595 Department of Dermatology, Singapore General Hospital, Singapore City, Singapore Duke-NUS Medical School, Singapore City, SingaporeSearch for more papers by this author First published: 24 November 2021 https://doi.org/10.1111/ajd.13755Citations: 4 Conflict of interest: The authors have no conflicts of interest to declare. Funding: There is no financial interest to report. Informed consent: Written informed consent was obtained from the patient for the publication of this case report. Ethics approval: Ethics approval was not required for this case report with the patient’s informed consent. We certify that the submission is original work and is not under review at any other publication. AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Dear Editor, Pemphigus foliaceus (PF) is a rare immunobullous disease which develops as a result of binding of autoantibodies to desmoglein-1, causing separation of surface keratinocytes with blister formation.1 Following the recent introduction of vaccination against the novel coronavirus SARS-CoV-2 virus in the COVID-19 pandemic, there have been reported cases of other immunobullous disorders, namely pemphigus vulgaris and bullous pemphigoid, post-vaccination.2-5 Here, we present a case of PF presenting with near-generalised exfoliative dermatitis following COVID-19 vaccination. An 83-year-old male with a history of asthma, hypertension and hyperlipidaemia presented with an extensive pruritic rash over his face, scalp, trunk and limbs of 3 weeks' of duration. This had developed 2 days after he received the second dose of Pfizer-BioNTech COVID-19 vaccine. Physical examination revealed extensive scaly erosive plaques over his entire upper trunk with annular scaly pink plaques and erosions on all four limbs (Fig. 1). There was facial desquamation and thick adherent crust over the scalp. Oral and genital mucosa was unaffected. Figure 1Open in figure viewerPowerPoint Clinical image of extensive annular erosive plaques on the back. Histopathological examination of his abdominal skin showed subacute spongiotic dermatitis with dermal eosinophils and plasma cells from the abdomen (Fig. 2). Direct immunofluorescence showed C3 staining at the dermal–epidermal junction and intercellular bridges within the epidermis. Figure 2Open in figure viewerPowerPoint Punch biopsy from the abdomen shows moderate spongiosis (Hematoxylin and eosin, ×10). Indirect immunofluorescence was positive with an intercellular pattern. Anti-desmoglein 1 antibody level was >200 RU/mL, and anti-desmoglein 3 antibody level was <2 RU/mL. This was consistent with pemphigus foliaceus. Oral prednisolone 20 mg daily was started for him with good clinical response. The classical presentation of pemphigus foliaceus is fragile flaccid bullae, distributed in seborrhoeic areas such as the face, scalp and upper trunk. Mucous membranes are spared. In most instances, only superficial erosions may be seen on examination as blisters rupture easily. We wish to highlight that PF can thus present with non-specific clinical features, such as exfoliative dermatitis with scaling in our patient, mimicking other exfoliative dermatoses and resulting in diagnostic delay.6 Classic features of PF on histopathological examination are pre-acantholytic vacuole formation in intercellular spaces and subcorneal blisters. However, in most cases, only non-specific or chronic inflammatory features may be seen, as the blister roof is usually absent in samples taken from lesional skin. This can also result in direct immunofluorescence being falsely negative.6 In such situations, anti-desmoglein and indirect immunofluorescence serologies are key in clinching the diagnosis, as was the case for our patient. A pertinent question raised was the possibility of COVID-19 vaccination triggering the onset of PF in our patient. To date, several cases of vaccine-related flares in autoimmune blistering disease, and newly diagnosed cases post-vaccination, have been reported.2-5 These cases are summarised in Table 1. A possible mechanism for vaccine-related autoimmune disease is molecular mimicry, in which an immune reaction directed against foreign pathogenic elements, bearing similarity to human proteins, evolves into an autoimmune process targeting self-proteins.7 Other possible mechanisms are inflammatory dysregulation in genetically susceptible persons, epitope spreading or bystander activation.3 Table 1. Summary table of immunobullous disease cases reported after COVID-19 vaccination Reference Age Sex COVID-19 Vaccine Dose of Vaccine Autoimmune Blistering Dermatosis New onset versus flare Latency after vaccination (days) Solimani et al3 40 Female Pfizer/BioNTech 1 Pemphigus vulgaris New onset 5 Thongprasom et al4 38 Female AstraZeneca 1 Pemphigus vulgaris New onset 7 Damiani et al2 40 Male Moderna 1 Pemphigus vulgaris Flare 3 80 Male Pfizer/BioNTech 1 Pemphigus vulgaris Flare 3 63 Female Moderna 1 Bullous pemphigoid Flare 1 84 Male Moderna 1 Bullous pemphigoid Flare 14 82 Female Pfizer/BioNTech 1 Bullous pemphigoid Flare 3 Tomayko et al5 97 Female Pfizer/BioNTech 2 Bullous pemphigoid New onset 2 75 Male Pfizer/BioNTech 2 Bullous pemphigoid New onset 10 64 Male Pfizer/BioNTech 2 Bullous pemphigoid New onset 14 82 Male Pfizer/BioNTech 2 Bullous pemphigoid New onset 1 95 Female Pfizer/BioNTech 1 Bullous pemphigoid New onset 5 87 Male Moderna 2 Bullous pemphigoid New onset 21 42 Female Moderna 2 Bullous pemphigoid New onset 3 85 Male Pfizer/BioNTech 1 Bullous pemphigoid New onset 5 83 Female Moderna 1 Bullous pemphigoid New onset 8 66 Female Pfizer/BioNTech 1 Bullous pemphigoid New onset 7 70 Female Moderna 1 Bullous pemphigoid New onset 9 83 Female Pfizer/BioNTech 2 Bullous pemphigoid New onset 7 83 Male Pfizer/BioNTech 1 Bullous pemphigoid Flare 7 Given the novelty of COVID-19 vaccinations, limited data exist to draw definite associations between PF onset and COVID-19 vaccination. It is still possible that the temporal relationship between vaccination and PF onset in our patient was coincidental. One possible way to overcome this uncertainty would be to use an algorithm or scoring system to predict the likelihood of vaccine-associated reaction, as opposed to pure coincidence. To date, various methods have been proposed to assess causality in adverse drug reactions, including expert judgement, probabilistic approaches and algorithms.8, 9 An example of a commonly used method would be the Naranjo Adverse Drug Reaction Probability Scale,10 on which our patient scored 4, indicating possible adverse drug reaction. However, efforts to identify a universal method for assessing adverse drug reactions have proven unsuccessful thus far, largely due to issues with reproducibility and validity between methods. In the current climate, vaccination has proven to be of paramount importance in our ongoing battle against the novel coronavirus. Larger studies and longer-term data are needed to provide better understanding on COVID-19 vaccination and its effects. We believe this will refine decision-making for clinicians and patients alike, with regard to vaccination choice, type of vaccine and administration of booster doses down the road. In the meantime, we propose that expert judgement is used to determine causality of autoimmune bullous disorders with COVID-19 vaccination. REFERENCES 1Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet 2019 Sep 07; 394: 882– 94. CrossrefCASPubMedWeb of Science®Google Scholar 2Damiani G, Pacifico A, Pelloni F et al. The first dose of COVID-19 vaccine may trigger pemphigus and bullous pemphigoid flares: is the second dose therefore contraindicated? J. Eur. Acad. Dermatol. Venereol. 2021 Oct; 35: e645. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 3Solimani F, Mansour Y, Didona D et al. Development of severe pemphigus vulgaris following SARS-CoV-2 vaccination with BNT162b2. J. Eur. Acad. Dermatol. Venereol. 2021 Oct; 35: e649. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar 4Thongprasom K, Pengpis N, Phattarataratip E et al. Oral pemphigus after COVID-19 vaccination. Oral. Dis. 2021 Sep 21. Early view. Wiley Online LibraryPubMedWeb of Science®Google Scholar 5Tomayko MM, Damsky W, Fathy R et al. Subepidermal blistering eruptions, including bullous pemphigoid, following COVID-19 vaccination. J. Allergy. Clin. Immunol. 2021 Sep 1; 148: 750– 1. CrossrefCASPubMedWeb of Science®Google Scholar 6James KA, Culton DA, Diaz LA. Diagnosis and clinical features of pemphigus foliaceus. Dermatol. Clin. 2011 Jul; 29: 405– 12. CrossrefCASPubMedWeb of Science®Google Scholar 7Segal Y, Shoenfeld Y. Vaccine-induced autoimmunity: the role of molecular mimicry and immune crossreaction. Cell. Mol. Immunol. 2018 Jun; 15: 586– 94. CrossrefCASPubMedWeb of Science®Google Scholar 8Théophile H, Arimone Y, Miremont-Salamé G et al. Comparison of three methods (Consensual Expert Judgement, Algorithmic and Probabilistic Approaches) of causality assessment of adverse drug reactions: an assessment using reports made to a French pharmacovigilance centre. Drug. Saf. 2010 Nov; 33: 1045– 54. CrossrefPubMedWeb of Science®Google Scholar 9Agbabiaka TB, Savović J, Ernst E. Methods for causality assessment of adverse drug reactions: a systematic review. Drug. Saf. 2008; 31: 21– 37. CrossrefPubMedWeb of Science®Google Scholar 10Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin. Pharmacol. Ther. 1981; 30: 239– 45. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Citing Literature Volume63, Issue1February 2022Pages 128-130 FiguresReferencesRelatedInformation