Toxic epidermal necrolysis after first dose of Pfizer-BioNTech (BNT162b2) vaccination with pharmacogenomic testing

Abstract

Toxic epidermal necrolysis (TEN) is a rare and acute life-threatening condition and one of the severe cutaneous adverse drug reactions. There are limited data on TEN from the COVID-19 vaccine regarding its pathogenesis, treatment, and prognosis, particularly in children. We report a case of COVID-19 vaccine-induced TEN and the patient’s human leukocyte antigen pharmacogenomic profile.

1 INTRODUCTION

Toxic epidermal necrolysis (TEN) is a rare, acute, life-threatening, drug-related disease, which has an estimated mortality rate of 14.8%–48%^1, 2 and an annual incidence of 0.4–1.2 cases per million from various culprit drugs.³

There have been a small number of case reports of patients who have developed Stevens-Johnson syndrome (SJS)/TEN following COVID-19 vaccine. Here we present the case of a 12-year-old girl with TEN after her first dose of Pfizer-BioNTech (BNT162b2) vaccine.

1.1 Case presentation

A healthy 12-year-old girl with no previous medical history presented 6 days after her first dose of Pfizer-BioNTech (BNT162b2) vaccine. Two days after vaccination, she developed a low-grade fever with a mild sore throat. The patient did not take any oral prescribed or over-the-counter medications or herbal remedies during the past 8 weeks. On the 6th day after the vaccine, there were erythematous, painful patches and plaques on the chest wall and trunk, which subsequently spread to the face, palms, and soles. Mucocutaneous erosions were observed in the ocular, oral, and genital regions. She was diagnosed with TEN and immediately admitted to the pediatric intensive care unit.

During the first day of admission, the rash rapidly coalesced and she developed tense bullae, prominently seen on both cheeks and left arm. (Figure 1) Multiple, tiny bullae, dusky patches, and macules were observed. Her lips and oral mucosa were covered with painful hemorrhagic crusts and genital mucosal lesions appeared. She had conjunctival and mucopurulent discharge from both eyes. Asboe-Hansen sign was noted all over the body. She was estimated to have epidermal detachment over 40% of the body surface area. (Figure 2).

FIGURE 1Open in figure viewerPowerPointSecond day of admission, rapid progressive necrosis and denuded area at face and oral mucosa with worsening ophthalmologic symptoms.

FIGURE 2Open in figure viewerPowerPointA wide-spread area of necrotic skin at the back with Nikolsky sign.

Complete blood count, standard chemistry panels, transaminases, and urine analysis were all within normal limits. Chest radiography was normal with negative serology for Mycoplasma pneumoniae, Epstein–Barr virus, and human immunodeficiency virus (HIV). Pediatric SCORTEN was 2 on the first day of admission, reflecting a heart rate over 120 beats per minute and epidermal detachment area involving BSA >30%. Histopathology showed subepidermal bullae, full thickness epidermal necrosis, patchy areas of basal cell degeneration and necrotic keratinocytes and interface dermatitis with perivascular inflammatory cell infiltration (Figure 3). Human leukocyte antigen (HLA) class I and II alleles were determined using PCR sequence-specific oligonucleotide probes. The HLA genotyping in the patient showed HLA-A*02:03/31:01, HLA-B*13:01/15:27, HLA-C*04:01/04:06, HLA-DRB1*04:06/15:02, HLA-DQB1* 03:02/05:01, HLA-DQA1* 01:01/03:01.

FIGURE 3Open in figure viewerPowerPointBiopsy of full thickness epidermal necrosis with keratinocytes necrosis.

Intravenous immunoglobulin (IVIG) (2 g/kg) was given within 24 h after diagnosis, in conjunction with nonpharmacologic treatments, such as fluid, electrolyte and nutritional support, and wound management. No prophylactic antibiotics were prescribed.

Clinical improvement occurred on the second day after IVIG administration, with defervescence of fever and no new skin lesions. Reepithelialization of the skin was noticed on the 7 day after admission. The patient had complete skin reepithelialization on the 12 day after admission, with a total hospitalization of 18 days. She had a full recovery without sequelae.

2 DISCUSSION

SJS/TEN is an extremely rare adverse event from basic vaccination. In addition, cases of SJS/TEN associated with the COVID-19 vaccine have been rarely reported and are summarized in Table 1.^4–12TABLE 1. Reported cases of COVID-19 vaccine induced SJS/TEN

Author’s name, Reference	Age (years)	Gender	Underlying diseases, drug	Vaccine	Dose	Onset duration after vaccination (days)	Diagnosis	Skin biopsy	SCORTEN	Laboratory	Treatment	Recovery time (days)	Prognosis
Bakir M, et al.4	49	F	No	Pfizer-BioNTech(BNT 162b1)	First dose	7 days	TEN	Confirmed	2 (1 day)	AST 178 U/LALT 90 U/LCXR-normal	Etanercept × 2 doses	22 days	Good
Elboraey MO, et al.5	“Middle-age”	F	N/R	Pfizer-BioNTech(BNT 162b1)	Second dose	5 days	SJS	Not done	N/R	N/R	Oral prednisolone(30 mg/day)	N/R	Good
Dash S, et al.6	60	M	DM-metformin, teneligliptinHT- amlodipine	Astra Zeneca(ChAdOx1 nCoV-19)	First dose	3 days	SJS	Confirmed	1 (1 day)	N/R	Cyclosporine 300 mg	7 days	Good
Mansouri P, et al.7	49	F	Breast cancer(tamoxifen, sodium valproate, alprazolam)	Sinopharm, (China National Biotec Group)	Second dose	3 days	SJS(mild symptoms)	Confirmed	N/R	N/R	Oral prednisolone(30 mg/day)	14 days	Good
Mardani M, et al.8	76	M	Hyperlipidemia (atrovastatin)	China National Biotec Group)	First dose	1 day	TEN	Confirmed	N/R	AST 90 U/LALT 82 U/LCXR-normal	Oral prednisolone	14 days	Good
Aimo C, et al.9	65	M	No	Vaxvetria (AZD1222)	Second dose	10 days	SJS	Confirmed	N/R	-Thrombocytopenia-Elevated CRP, LDH, fibrinogen, D-dimer-Sagittal sinus thrombosis	Oral prednisolone(1 mg/kg/day)	Within 8 weeks	Good
Kherlopian A, et al.10	48	F	N/R	Astra Zeneca(ChAdOx1 nCoV-19)	First dose	14 days	TEN	Confirmed	2 (day-not reported)	-Serology: M. pneunoniae, herpes simplex virus, adenovirus, HIV, hepatitis B, C- negative	Etanercept × 3 doses	35 days	Good
Mansouri P, et al.11	63	F	Psoriasis,DM- Sitagliptin, metformin	Sinopharm, (China National Biotec Group)	First dose	1 day	SJS	Confirmed	N/R	-CBC, BUN, Cr- normal-HbA1C 6.4% (normal 4%–5.6%)	Oral prednisolone(40 mg/day)	3 weeks	Good
Padniewski JJ, et al.12	46	F	Hyperlipidemia- atorvastatinObesityDM- metformin	Moderna(Moderna Inc., MRNA 1273)	First dose	3 days	SJS	Confirmed	N/R	-Serology: M. pneunoniae, herpes simplex virus, varicella, tuberculosis, hepatitis B, C- negative-CXR-normal	Oral prednisolone(80 mg/day)	6 days	Good
Our case	12	F	No	Pfizer-BioNTech(BNT 162b2)	First dose	6 days	TEN	Confirmed	2 (1 day):Pediatric SCORTEN	Normal	IVIG 2 g/kg/day	12 days	Good

• Abbreviations: F, female; M, Male; N/R, not reported.

There have been only nine reported cases of SJS/TEN after COVID-19 vaccine. Five of these patients had underlying diseases, such as hyperlipidemia, diabetes mellitus and breast cancer with a history of medication use.^{6–8, 11, 12} Most cases of SJS/TEN occurred following the first dose of COVID-19 vaccine. The onset of SJS/TEN after vaccination was about 1–2 weeks (1–14 days). However, underlying diseases, vaccine type, concomitant factors (medication type and duration of treatment, and probably infection) could be additional predisposing factors for SJS/TEN. From the literature review, treatments included anti-tumor necrosis factor-alpha (anti TNF-α), prednisolone, cyclosporine, and IVIG. All patients had a good prognosis, with a complete time of resolution ranging from 7 days to 35 days. The hospitalization time of drug-induced SJS/TEN in a previous study was 11.8 ± 10.6 days.¹³ However, long-term sequelae should be monitored.

Our case was treated with IVIG due to concern regarding the side-effects of other treatments, including systemic corticosteroids and cyclosporine. Being in a resource-limited setting, we were unable to use anti-TNF-alpha agents in Thailand. Despite clinical data from a systematic review and meta-analysis in 2017¹⁴ regarding the nonusefulness of IVIG, other systematic reviews and meta-analyses in 2012 and 2015 suggested that IVIG was beneficial in reducing mortality in children when compared to studies in adults.¹⁵ Dosages of ≥2 g/kg appeared to significantly decrease mortality in patients with SJS or TEN.¹⁶ Thus, IVIG use in pediatric patients is another option in a country with limited resources.

The COVID-19 vaccine is comprised of virotopes and excipients (L-histidine, L-histidine hydrochloride, sucrose, sodium chloride, polysorbate 80, ethanol, water, polyethylene glycol [PEG-2000] and others). The most likely causative vaccine component in one case report was thought to be the virotopes.⁶ The presumptive hypothesis of SJS/TEN from routine vaccination was proposed by Chahal et al.¹⁷The expression of virotopes on the surface of keratinocytes is similar to drug antigens on keratinocytes that can potentially activate a CD8+ T-cell lymphocyte response. This activation induces the release of chemokines, cytolytic molecules, cytotoxic agents, and enzymes, such as granulysin, granzyme B, and perforin, leading to keratinocyte apoptosis and detachment of epidermis.^17,18

mRNA vaccines initially activate toll-like receptor-7/8 (TLR7/8) and retinoic acid-inducible gene-1-like (RIG-I-like) receptors (RLRs), inducing a cellular immune response embraced by CD8+ T cells and macrophages with a T-helper 1 cell profile (Th1). Key cytokines include interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin(IL)-2 and IL-6.¹⁹

The implementation of pharmacogenomics in clinical practice represents a feasible and likely useful enhancement to the therapeutic management of medication-induced adverse events. Pharmacogenomics may have a role in personalized vaccination plans and potentially could reduce adverse events. HLA encoded by the HLA gene are an important modulator of the immune response and drug hypersensitivity reactions. HLA variants can be a risk factor for developing potentially fatal drug and vaccine-induced hypersensitivity reactions. Interestingly, specific HLA genotypes that confer genetic susceptibility to SCARs have been found in this patient (HLA-A* 31:01-carbamazepine, HLA-B*13:01-cotrimoxazole and dapsone, HLA-DRB1*15:02-allopurinol).²⁰ We hope that the HLA-pattern of this patient might be beneficial for future research on drug susceptibility, particularly of vaccines.

3 CONCLUSION

The impact of COVID-19 infection is well-recognized all over the world. To date, 3.15 billion doses of vaccines have been provided with only 10 cases (including our reported case) of SJS/TEN. The occurrence of SJS/TEN is extremely rare and the benefits of vaccination clearly outweigh the risks.

In our case, we describe how early IVIG administration was as an effective and safe treatment for TEN induced Pfizer (BNT162b2) vaccination. We also report the HLA pharmacogenetic biomarkers of this patient: HLA-A* 02:03/31:01, HLA-B* 13:01/15:27, HLA-C* 04:01/04:06, HLA-DRB1* 04:06/15:02, HLA-DQB1* 03:02/05:01, HLA-DQA1* 01:01/03:01.

FUNDING STATEMENT

None declared.

CONFLICT OF INTEREST

None declared.

https://onlinelibrary.wiley.com/doi/10.1111/pde.15074

Bullous pemphigoid after SARS-CoV-2 vaccination: spike-protein-directed immunofluorescence confocal microscopy and T-cell-receptor studies

Dear Editor, Growing evidence suggests that SARS-CoV-2 vaccination is associated with a variety of cutaneous reactions. These include autoimmune-mediated conditions such as autoimmune blistering diseases (AIBDs), one of which is bullous pemphigoid (BP).^1, 2 We report new-onset BP in two patients following their first SARS-CoV-2 vaccination.

The first patient was an 80-year-old man who noticed reddish itchy macules with small blisters on his lower legs 1 week after vaccination with BTN162b2.² Two weeks later, after he had received his second shot, these erythematous/bullous lesions spread over his trunk (Figure 1a). The second patient was an 89-year-old man who noticed 2 days after the first BTN162b2 vaccination itchy erythematous/bullous lesions on his entire integument. Neither of the patients reported intake of any new medications or other newly diagnosed conditions prior to the AIBDs.

Figure 1Open in figure viewerPowerPoint(a) Clinical presentation of COVID-19 vaccine-induced bullous pemphigoid in the first patient. (b) On haematoxylin–eosin histology, both patients displayed slight spongiosis and subepidermal blisters with lymphocytic and eosinophilic infiltrates. (c, d) Representative immunofluorescence confocal microscopy images of normal skin of a control patient (c) and lesional skin of patient 1 (d) showing spike protein immunoreactivity. However, there was only a very likely unspecific immunoreactivity in the horny layer of the patient and control skin. (e) T-cell receptor (TCR) analysis of patient 1. Classical TCR repertoire metrics: richness gives the number of unique TCR rearrangements within a sample; iChao1 is an estimator of the lower bound of the true richness of a sample; Simpsons’ diversity reflects the probability that two randomly picked sequences from a sample are the same; clonality reflects the abundance of clonally expanded T-cell clonotypes within a sample. PBMC, peripheral blood mononuclear cell. (f) Frequency of the top six expanded T-cell clonotypes within the whole TCR repertoire including blood and tissue of a patient. TCRMatch was used to infer the antigen specificity of the respective clonotype. (g) Clonotypes were annotated with the antigen specificity with the highest score according to TCRMatch. Depiction of the results from application of the GLIPH algorithm. Global similarities are marked in orange and local similarities in blue. Additional TCR sequences that recognize the SARS-CoV-2 spike protein (VDJdb) were subjoined to infer antigen specificity.

In both cases, subepidermal clefts were demonstrated on routine histology (Figure 1b). In both patients, direct immunofluorescence on frozen sections revealed linear deposits of IgG and C3 at the basement membrane zone. Indirect immunofluorescence showed bandlike IgG deposits on the epidermal side in both patients. In both cases, enzyme-linked immunosorbent assay revealed highly elevated autoantibody levels against BP-180 (365 U mL⁻¹ and 115 U mL⁻¹, normal range < 20) and BP-230 (223 U mL⁻¹ and 41 U mL⁻¹, normal range < 20). Hence, both patients were diagnosed with BP. Both were successfully treated with a tapered systemic prednisolone regimen.

For immunofluorescence confocal laser scanning microscopy imaging, we used the antibody SARS-CoV/SARS-CoV-2 Spike Protein S2 [mouse/IgG1, monoclonal antibody (clone 1A9), catalogue no. MA5-35946 (Thermo Fisher Scientific, Waltham, MA, USA)]. We did not observe immunoreactivity for SARS-CoV-2 spike protein in the subepidermal compartment. There was only a very likely unspecific immunoreactivity in the horny layer of the patient and control skin specimens (Figure 1c, d). High-throughput sequencing of the T-cell receptor (TCR)Vβ CDR3 and TCR repertoire was investigated in lesional skin tissue and isolated peripheral blood mononuclear cells. Within the lesions of both patients, we observed a high clonality of T cells, with the top expanded T-cell clone contributing almost 20% of all TCR transcripts (Figure 1e).

Using TCRMatch³ to estimate the antigen specificity of the expanded T-cell clonotype we found that several of the expanded T-cell clones were indeed reactive to SARS-CoV-2 (Figure 1f). Using the GLIPH algorithm,⁴ we identified several TCR clusters derived from T cells in both lesional tissue and peripheral blood that co-clustered with the added spike-protein-reactive TCRs (Figure 1g). Importantly, by contrast, in control tissues obtained prior to the COVID-19 pandemic or SARS-CoV-2 vaccinations, SARS-CoV-2 spike-protein-reactive T cells were not observed (data not shown).

The similarities with respect to both timing and the clinical and molecular features in the cases presented here point to a causal relationship between the vaccination and BP. There are several published cases of vaccine-induced BP, the majority involving influenza but more recently also COVID-19.^1, 5, 6 For SARS-CoV-2 vaccines, the target antigen is the surface spike protein, which is used by the virus to bind and fuse with host cells. When speculating on autoimmune mechanisms following SARS-CoV-2 infection one may particularly consider molecular mimicry.^7, 8 We hypothesized that molecular mimicry may exist between basement-membrane-specific proteins (e.g. BP-180, BP-230) and the SARS-CoV-2 spike protein. However, using an antibody against the spike protein we could not confirm this hypothesis.

With respect to the TCR repertoire in lesional skin, we observed a marked clonal expansion of T cells in both patients with BP, indicating an ongoing adaptive immune response. However, we cannot exclude that this T-cell expansion was an epiphenomenon due to the vaccination per se. The two bioinformatic approaches further suggested that these T-cell responses were reactive to SARS-CoV-2-derived epitopes.^3, 4 Our TCRMatch results suggested that some of the expanded T-cell clones detected in the patients might be reactive to other SARS-CoV-2-derived epitopes including nucleocapsid proteins. However, whether these T-cell clones might hint at an undocumented previous infection with SARS-CoV2 or some other mechanism, whereby a spike protein vaccine may induce such T cells, remains unclear at this point.

Author Contribution

Thilo Gambichler: Investigation (equal); Visualization (equal); Writing-review & editing (equal). Nazha Hamdani: Formal analysis (equal); Investigation (equal); Methodology (equal); Supervision (equal); Writing-review & editing (equal). Heidi Budde: Investigation (equal); Methodology (equal); Writing-review & editing (equal). Marcel Sieme: Investigation (equal); Methodology (equal); Visualization (equal); Writing-review & editing (equal). Marina Skrygan: Investigation (equal); Methodology (equal); Supervision (equal); Writing-review & editing (equal). Lisa Scholl: Investigation (equal); Visualization (equal); Writing-review & editing (equal). Heinrich Dickel: Data curation (equal); Supervision (equal); Writing-review & editing (equal). Bertold Behle: Data curation (equal); Investigation (equal); Writing-review & editing (equal). Nomun Ganjuur: Data curation (equal); Investigation (equal); Writing-review & editing (equal). Christina Scheel: Validation (equal); Writing-review & editing (equal). Nessr Abu Rached: Data curation (equal); Investigation (equal); Writing-review & editing (equal). Lennart Ocker: Formal analysis (equal); Investigation (equal); Writing-review & editing (equal). Rene Stranzenbach: Investigation (equal); Supervision (equal); Writing-review & editing (equal). Martin Doerler: Investigation (equal); Writing-review & editing (equal). Lukas Pfeiffer: Investigation (equal); Methodology (equal); Software (equal); Visualization (equal); Writing-review & editing (equal). Juergen Becker: Conceptualization (equal); Formal analysis (equal); Investigation (equal); Methodology (equal); Validation (equal); Visualization (equal); Writing-review & editing (equal).

https://onlinelibrary.wiley.com/doi/10.1111/bjd.20890

Autoimmune mucocutaneous blistering diseases after SARS-Cov-2 vaccination: A Case report of Pemphigus Vulgaris and a literature review

Abstract

Background: Cases of severe autoimmune blistering diseases (AIBDs) have recently been reported in association with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination.

Aims: To describe a report of oropharyngeal Pemphigus Vulgaris (OPV) triggered by the mRNABNT162b2 vaccine (Comirnaty®/ Pfizer/ BioNTech) and to analyze the clinical and immunological characteristics of the AIBDs cases reported following the SARS-CoV-2 vaccination.

Methods: The clinical and immunological features of our case of OPV were documented. A review of the literature was conducted and only cases of AIBDs arising after the SARS-CoV-2 vaccination were included.

Case report: A 60-year old female patients developed oropharyngeal and nasal bullous lesions seven days after the administration of a second dose of the mRNABNT162b2 vaccine (Comirnaty®/ Pfizer/BioNtech). According to the histology and direct immunofluorescence findings showing the presence of supra-basal blister and intercellular staining of IgG antibodies and the presence of a high level of anti-Dsg-3 antibodies (80 U/ml; normal < 7 U/ml) in the serum of the patients, a diagnosis of oropharyngeal Pemphigus Vulgaris was made.

Review: A total of 35 AIBDs cases triggered by the SARS-CoV-2 vaccination were found (including our report). 26 (74.3%) were diagnosed as Bullous Pemphigoid, 2 (5.7%) as Linear IgA Bullous Dermatosis, 6 (17.1%) as Pemphigus Vulgaris and 1 (2.9%) as Pemphigus Foliaceus. The mean age of the sample was 72.8 years and there was a predominance of males over females (F:M=1:1.7). In 22 (62.9%) cases, the disease developed after Pfizer vaccine administration, 6 (17.1%) after Moderna, 3 (8.6%) after AstraZeneca, 3 (8.6%) after CoronaVac (one was not specified). All patients were treated with topical and/or systemic corticosteroids, with or without the addition of immunosuppressive drugs, with a good clinical response in every case.

Conclusion: Clinicians should be aware of the potential, though rare, occurrence of AIBDs as a possible adverse event after the SARS-CoV-2 vaccination. However, notwithstanding, they should encourage their patients to obtain the vaccination in order to assist the public health systems to overcome the COVID-19 pandemic.

Keywords: Bullous Pemphigoid; Covid-19 vaccine; Pemphigus; SARS-Cov-2.

https://pubmed.ncbi.nlm.nih.gov/35278817/

AMERICAN GOSPEL | Christ Alone

AMERICAN GOSPEL | Christ Alone – Is Christianity Christ + the American dream? American Gospel examines how the prosperity gospel (the Word of Faith movement) has dangerously distorted the gospel message, and how this theology is being exported abroad.

Russophobia: History of Hate | RT Documentary

Russia has been portrayed as a ‘savage and barbaric’ nation, from Ivan the Terrible to Vladimir Putin. But where does the image come from? The documentary explores the creation of the anti-Russian narrative in the West and how it spread to the media and popular culture.

Researchers, historians and writers in the documentary claim Russia became a convenient target after the Great Schism. Throughout history, European rulers and philosophers constructed the image of an uncivilised nation, unfit for talks. For example, French philosophers Diderot, Voltaire and Rousseau argued if Russia could become a civilised country or if it was destined to remain barbarian.

The mythical ferocious Russian bear and the tale of bad Russia still feature in the media and contribute to modern russophobia. The documentary traces the origins of the anti-Russian narrative in the West and explores who benefits from it.

Bio Terrorist China threatens Canada with “forceful measures” over proposed Taiwan trip

The Chinese government said it was willing to resort to “forceful measures” should Canada interfere in Taiwan.

China’s warning comes at a time when the federal government mulls sending a delegation of officials to the island nation. 

“We urge the Canadian side to abide by the one-China principle and respect China’s sovereignty and territorial integrity,” wrote the Chinese embassy in Canada.

“China will take resolute and forceful measures against any country that attempts to interfere with or infringe upon China’s sovereignty and territorial integrity.”

A trade diplomatic visit has been planned by Ottawa for October. According to Liberal MP Judy Sgro, Canada has no intention to further disrupt relations with China.

China threatens Canada with “forceful measures” over proposed Taiwan trip

Should Fauci Be in Prison? | Ep. 189

First, we get rid of Liz Cheney. Then, Brian Stelter is ousted. Now, Fauci announces his retirement. But why the sudden recalculation on his part? Why so soon? Liz examines whether, given his corruption and consistent mismanagement of the pandemic, Fauci should be in prison. And most importantly, THIS is how we prevent another partisan, tyrannical hack from infiltrating the highest levels of government. This is The Liz Wheeler Show.

Disney’s Pedo, Vaxxed Cult Exposed: Vax-Obsessed, Trans, And Gays Finally Face The Consequences

The war for personal freedom is FAR from OVER! Disney is finally facing the consequences of their own actions! Leslie Manookian is backing the fight for freedom of Disney employees.