The role of lymphocyte transformation tests (LTT) in suspected severe delayed hypersensitivity reactions following COVID-19 vaccination.

Coronavirus (COVID-19) vaccines have proved to be effective in the pandemic response but can cause adverse events such as delayed hypersensitivity reactions (DHRs). Delayed-reading intradermal tests (IDT) to vaccines are limited by false-positive results and may reflect a cell-mediated rather than IgE-mediated immune response. Lymphocyte transformation test (LTT), which has been utilized in the diagnosis of drug allergy, may be helpful in suspected COVID-19 vaccine and/or its excipient-related DHRs. To investigate the use of LTT in two suspected cases of COVID-19 vaccine-induced DHRs, two patients with suspected DHRs to COVID-19 vaccination were tested by delayed-reading IDT and LTT against vaccines and their excipients. A 47-year-old man developed acute mixed-pattern hepatitis after the second dose of ChAdOx1 vaccine. LTT performed at 2 months post-vaccination revealed reactivity to the ChAdOx1 vaccine, polysorbate 80 and mildly to PEG 2050 but not BNT162b2 vaccine. Delayed-reading IDT returned negative to both vaccines and excipients. He tolerated BNT162b2 vaccination with no adverse events. A 36-year-old woman presented with subacute morbilliform eruption and hepatitis after the first dose of BNT162b2 vaccine. LTT performed 3 months later revealed reactivity to the BNT162b2 but not PEG 2050. Repeat LTT following subsequent natural Severe Acute Respiratory Coronavirus-2 (SARS-CoV-2) infection revealed reactivity to ChAdOx1 and NVX-CoV2373 vaccines but not polysorbate 80. Delayed-reading IDT remained negative. She proceeded with NVX-CoV2373 vaccination with no symptom recurrence. LTT may be a useful tool in suspected COVID-19 vaccine-related DHRs. Further evaluation with a larger patient cohort is required.

[Multiform exudative erythema caused by hydroxychloroquine, diagnosed by epicutaneous tests: A case report]. / Eritema exudativo multiforme provocado por hidroxicloroquina, diagnosticado mediante pruebas epicutáneas: reporte de un caso.

INTRODUCTION: Multiform exudative erythema is a rare delayed hypersensitivity reaction associated with medications. The manifestations caused by hydroxychloroquine are exceptional; however, due to the increase in its prescription due to the recent SARS-CoV-2 pandemic, adverse reactions have been exacerbated. CASE REPORT: A 60-year-old female patient, who attended the Emergency Department for a picture of erythematous rash of one week of evolution, with involvement of the trunk, face and palms of the hands. Laboratory studies reported: leukocytosis with neutrophilia and lymphopenia, without eosinophilia or abnormal liver enzymes. The lesions continued to descend towards her extremities, with subsequent desquamation. She was prescribed prednisone 15 mg/24 h for three days, tapering to 10 mg/24 h, until her new assessment, in addition to antihistamines. Two days later, new macular lesions appeared in the presternal area and on the oral mucosa. Control laboratory studies did not show alterations. Skin biopsy reported: vacuolar interface dermatitis with spongiosis and parakeratosis, compatible with erythema multiforme. Epicutaneous tests were carried out with meloxicam and 30% hydroxychloroquine in water and vaseline, occluded for two days and interpreted at 48 and 96 hours, with a positive result for the latter. The diagnosis of multiform exudative erythema due to hydroxychloroquine was established. CONCLUSIONS: This study confirms the efficacy of patch tests in patients with delayed hypersensitivity reactions to hydroxychloroquine.

INTRODUCCIÓN: El eritema exudativo multiforme es una reacción de hipersensibilidad retardada poco frecuente asociada con medicamentos. Las manifestaciones provocadas por hidroxicloroquina son excepcionales; sin embargo, debido al incremento de su prescripción, por la reciente pandemia de SARS-CoV-2, las reacciones adversas se han exacerbado. REPORTE DE CASO: Paciente femenina de 60 años, que acudió al servicio de Urgencias por un cuadro de exantema eritematoso de una semana de evolución, con afectación hacia el tronco, la cara y las palmas de las manos. Los estudios de laboratorio informaron: leucocitosis con neutrofilia y linfopenia, sin eosinofilia ni alteración de las enzimas hepáticas. Las lesiones continuaron descendiendo hacia las extremidades, con posterior descamación. Se le indicó prednisona 15 mg/24 h durante tres días, con disminución a 10 mg/24 h, hasta su nueva valoración, además de antihistamínicos. Dos días posteriores aparecieron nuevas lesiones maculares en la zona preesternal y en la mucosa oral. Los estudios de laboratorio de control no mostraron alteraciones. La biopsia cutánea informó: dermatitis de interfase vacuolar con espongiosis y paraqueratosis, compatible con eritema multiforme. Se llevaron a cabo pruebas epicutáneas con meloxicam e hidroxicloroquina al 30% en agua y vaselina, ocluidos dos días e interpretados a las 48 y 96 horas, con resultado positivo para esta última. Se estableció el diagnóstico de eritema exudativo multiforme por hidroxicloroquina. CONCLUSIONES: Este estudio confirma la eficacia de las pruebas epicutáneas en pacientes con reacciones de hipersensibilidad retardada a hidroxicloroquina.

COVID arm as a common cutaneous manifestation after mRNA-1273 vaccination: a systematic review.

BACKGROUND: By August 2022, CoronaVirus Disease-2019 (COVID-19) had caused 600 million illnesses and 6.5 million fatalities globally. A massive vaccination program is being implemented worldwide to suppress this condition. Several works of literature stated that mRNA COVID-19 vaccination, specifically with the mRNA-1273 vaccine, is followed by clear evidence of the COVID arm effects associated with this vaccine. OBJECTIVE: To analyze the latest evidence of COVID arm as a common effect of mRNA-1273 vaccination with the ultimate goal of improving vaccine counseling to help healthcare professionals and reassure patients. METHODS: A comprehensive search was performed on topics that assess the COVID arm as a cutaneous manifestation following mRNA-1273 vaccination from inception up until July 2022. RESULTS: Eighteen studies with a total of 1129 participants after the first and second dose of mRNA-1273 vaccination reported that most participants had COVID arm following the first dose administration. The characteristics of the patients were a mean age of 43.8 years old, and females represented ≥ 50% in most studies, with a mean onset of 6.9 days after the first dose administration. Symptoms resolved within seven days following the treatment and were harmless. CONCLUSIONS: This study found that the COVID arm condition is most common following the first mRNA-1273 vaccination in the female and middle-aged group. The correlation between demographic variables and COVID arm risk elucidates that the reaction is a type IV allergic skin reaction.

A Histologic Timeline of a Delayed Hypersensitivity Reaction after the COVID-19 Pfizer Booster.

A 54-year-old man presented with worsening bilateral rashes on legs and arms 7 days after receiving his BNT162b2 mRNA COVID-19 (Pfizer) vaccine booster. He developed burning on his palms about 5 days after receiving the booster. On day 6, he observed significant edema on his fingers and palms in addition to thin erythematous papules on his forearms. On day 7, he developed edema on his bilateral dorsal feet, and thin erythematous plaques on his shins. He stated that the rashes were pruritic. He had no rashes following the first two doses of the Pfizer vaccine. He denied having any history of skin disease, autoimmune disease, or allergies. Physical examination revealed multiple thin erythematous papules coalescing into thin plaques on his flexor forearms, and thin erythematous plaques on his dorsal feet (Figure 1). Three 4-mm punch biopsies were performed on his left flexor forearm. The biopsies were carried out at papules present for different lengths of time. Papules at biopsy sites "A," "B," and "C" were present for approximately 24-36 hours, 12-18 hours, and 3-6 hours, respectively (Figure 1).

Delayed allergic skin reactions to vaccines.

Background: Recent advances in vaccination against the severe acute respiratory syndrome coronavirus 2 pandemic have brought allergists and dermatologists to the forefront because both immediate and delayed hypersensitivity reactions have been reported. Objective: This literature review focused on delayed reactions to vaccines, including possible causative agents and practical information on how to diagnose, evaluate with patch testing, and manage subsequent dose administration. Methods: Currently published reviews and case reports in PubMed, along with data on vaccines from the Centers for Disease Control and Prevention web site. Relevant case reports and reviews that focused on delayed reactions to vaccines were selected. Results: Most delayed hypersensitivity reactions to vaccines include cutaneous manifestations, which vary from local persistent pruritic nodules to systemic rashes. The onset is usually within a few days but can be delayed by weeks. Multiple excipients have been identified that have been implicated in delayed vaccine reactions, including thimerosal, formaldehyde, aluminum, antibiotics, and gelatin. Treatment with antihistamines, topical corticosteroids, or systemic corticosteroids alleviates symptoms in most patients. Such reactions are generally not contraindications to future vaccination. However, for more-severe reactions, patch testing for causative agents can be used to aid in diagnosis and approach further vaccination. Conclusion: Delayed-type hypersensitivity reactions to vaccines are not uncommon. If needed, patch testing can be used to confirm agents, including antibiotics, formaldehyde, thimerosal, and aluminum. In most cases, delayed cutaneous reactions are not contraindications to further vaccine administration.

SARS-Cov 2 infection and anti-tuberculosis immunity: temporal association or real protective role? (preprint)

Introduction: According to the literature consulted to date, there is epidemiological heterogeneity of covid 19 between countries depending on their vaccination policy, in particular BCG vaccination. These findings have led to several hypotheses, including the protective role of immunity induced by the BCG tuberculosis vaccine against Covid-19 infection. The immunity induced by the BCG vaccine significantly increases the secretion of pro-inflammatory cytokines, in particular IL-1B, which has been shown to play an essential role in antiviral immunity. This cross-immunity, although not specific, if highlighted, is a real providence that must be taken advantage of in the face of this pandemic. The main objective of this study is to rule out or confirm that anti-tuberculosis immunity protects against SARS-COV 2 in our context. Materiel and methods Two groups will be compared: cases infected with the virus and controls who have never been infected with the virus. Both case and control groups will undergo a tuberculin skin test: the intra dermal tuberculin reaction (IDR). Results: We found that our control group had a high IDR immunity value, with an IDR tuberculin positive percentage of 67.2%. This suggests that immunity to IDR is a protective factor against coronavirus disease. Conclusion: The hypothesis of nonspecific anti-tuberculosis protection deserves further verification studies; it would have large positive repercussions for developing countries.

A Possible Type IV Hypersensitivity Reaction to Older Antiepileptic Drugs During and After Recovery from COVID-19 Infection.

Nearly two years after the onset of the coronavirus disease 2019 (COVID-19) pandemic, healthcare workers face new and unexpected complications. Although accelerating the vaccination process in recent months has reduced the incidence and mortality of the COVID-19 infection, the general population (particularly vulnerable groups) remains at risk of new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Over the last two months, Iran has encountered the fifth wave of the COVID-19 pandemic, i. e., the B.1.617.2 (Delta) variant of the SARS-CoV-2, with faster infectiousness and higher severity and mortality among hospitalized patients 1. Although fever, cough, and expectoration are the most common clinical features of COVID-19, recent studies have indicated an increasing number of skin manifestation reports in the disease. Besides, there is growing evidence that underlying SARS-CoV-2 infection may increase the risk of adverse drug reactions 2. However, the enduring concern in our medical centers in recent days is a raised incidence of Stevens-Johnson syndrome (SJS) in recovered COVID-19 patients following monotherapy with older antiepileptic drugs (0.004 vs. 0.0008% - i. e., 5 times higher than the pre-COVID-19 period) 3. It is worth noting that these patients did not have any history of SJS/toxic epidermal necrolysis (TEN) or additional etiopathogenic factors, including infections, genetic factors (particularly HLA-B*1502 allele), and malignancy. Furthermore, for many years before developing the COVID-19 and recovering from it, they had been treated with the above drugs without showing any cutaneous hypersensitivity reactions. These observational findings raise two important questions: (i) Could a history of the COVID-19 infection be a potential risk factor for type IV hypersensitivity reactions to older antiepileptic drugs? (ii) If so, what are its mechanisms of action?

Delayed localized hypersensitivity reactions to COVID-19 mRNA vaccines: a 6-month retrospective study.

Several individuals have developed delayed localized cutaneous vaccine reactions to the two novel mRNA Covid-19 vaccines. Clinical and histopathologic results of this case series study confirm that the localized injection-site reactions to the mRNA COVID-19 vaccines are delayed hypersensitivity reactions that, unlike immediate hypersensitivity reactions, are not a contraindication to vaccination.

Clinical and histopathological spectrum of delayed adverse cutaneous reactions following COVID-19 vaccination.

BACKGROUND: As more people become vaccinated against the SARS-CoV-2 virus, reports of delayed cutaneous hypersensitivity reactions are beginning to emerge. METHODS: In this IRB-approved retrospective case series, biopsy specimens of potential cutaneous adverse reactions from the Pfizer-BioNTech or Moderna mRNA vaccine were identified and reviewed. Clinical information was obtained through the requisition form, referring clinician, or medical chart review. RESULTS: Twelve cases were included. Histopathological features from two injection-site reactions showed a mixed-cell infiltrate with eosinophils and a spongiotic dermatitis with eosinophils. Three biopsy specimens came from generalized eruptions that showed interface changes consistent with an exanthematous drug reaction. Three biopsy specimens revealed a predominantly spongiotic pattern, consistent with eczematous dermatitis. Small-vessel vascular injury was seen in two specimens, which were diagnosed as urticarial vasculitis and leukocytoclastic vasculitis, respectively. There were two cases of new-onset bullous pemphigoid supported by histopathological examination and direct immunofluorescence studies. Eosinophils were seen in 10 cases. CONCLUSIONS: Dermatopathologists should be aware of potential cutaneous adverse reactions to mRNA-based COVID-19 vaccines. Histopathological patterns include mixed-cell infiltrates, epidermal spongiosis, and interface changes. Eosinophils are a common finding but are not always present. Direct immunofluorescence studies may be helpful for immune-mediated cutaneous presentations such as vasculitis or bullous pemphigoid.

COVID Arm: Delayed Hypersensitivity Reactions to SARS-CoV-2 Vaccines Misdiagnosed as Cellulitis.

The term "COVID arm" has been coined to describe a harmless delayed hypersensitivity reaction occurring approximately a week after administration of the novel SARS-CoV-2 mRNA vaccine. It appears as a red, warm, pruritic, indurated, or swollen area in the vicinity of the vaccine site. These reactions, especially if accompanied by systemic symptoms, have been mistaken for cellulitis. We report 3 cases of COVID arm, 2 of which were mistaken for cellulitis. Distinguishing features of COVID arm from cellulitis include pruritus as a common finding, occurrence approximately a week after vaccination, a lack of progression of symptoms, rapid response to topical steroids, and/or spontaneous resolution usually over 4 to 5 days.Practice Points:• Patients receiving SARS-CoV-2 vaccines may experience delayed hypersensitivity reactions characterized by erythema, swelling, and itching occurring near the vaccination site (COVID arm), approximately a week after vaccination.• Clinicians can distinguish SARS-CoV-2 vaccine reactions from cellulitis by the time of onset (approximately a week vs 5 days), by the lack of progression of symptoms, and resolution over 4 to 5 days.• Severe cases of COVID arm may be treated with topical steroids.

A novel application of delayed-type hipersensitivity reaction to measure cellular immune response in SARS-CoV-2 exposed individuals.

OBJECTIVE: To understand the anti-virus adaptive immune response occurring during SARS-Cov-2 infection is necessary to have methods to investigate cellular and humoral components. The goal of this study has been to investigate the utility of a specific spike-DTH test using a coronavirus recombinant protein in COVID-19 patients. METHODS: DTH studies were performed by intradermal injection of a commercial recombinant spike protein from SARS-CoV-2 along with conventional serology studies. RESULTS: Fifty-one COVID-19 patients were studied showing 84,3% of concordance with spike-DTH and anti-RBD-IgG. Spike-DTH was superior to identify seven more COVID-19 individuals. A high specificity was found with no positive spike DTH reactions in the non-sick individuals. The skin test also showed more stable results over time while specific anti-RBD-IgG decreased gradually. Clinical severity groups also showed a progressive gradient of larger positive spike-DTH. CONCLUSION: Specific spike DTH test seems to be an easy method to study cell immune response.

COVID-19: Is there a role for Western blots and skin testing for determining immunity and development of a vaccine?

Infection with the virus, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) stimulates an immune response which can serve as a marker for current or past exposure to this pathogen, and possibly for resistance to re-infection. This response to COVID-19 can be monitored based on the production of antibodies, and thus, serologic tests have become available for diagnostic purposes. Despite progress in this area, concerns have been raised that too many of the commercially available serologic detection systems are not completely reliable. To address this issue, Western blots should be considered for confirming a positive or borderline-positive result from a screening test, such as an ELISA. An additional benefit of Western blots would be to identify antigens that could form the basis for developing a vaccine. Little is known about the cell-mediated immune response against COVID-19. One way to address this would be to use skin testing to measure the delayed-type hypersensitivity response in patients recovering from COVID-19.