Immunogenicity of Intradermal Versus Intramuscular BNT162b2 COVID-19 Booster Vaccine in Patients with Immune-Mediated Dermatologic Diseases: A Non-Inferiority Randomized Controlled Trial.

The intradermal route has emerged as a dose-sparing alternative during the coronavirus disease 2019 (COVID-19) pandemic. Despite its efficacy in healthy populations, its immunogenicity has not been tested in immune-mediated dermatologic disease (IMDD) patients. This assessor-blinded, randomized-controlled, non-inferiority trial recruited patients with two representative IMDDs (i.e., psoriasis and autoimmune bullous diseases) to vaccinate with fractionated-dose intradermal (fID) or standard intramuscular (sIM) BNT162b2 vaccines as a fourth booster dose under block randomization stratified by age, sex, and their skin diseases. Post-vaccination SARS-CoV-2-specific IgG and interferon-γ responses measured 4 and 12 weeks post-intervention were serological surrogates used for demonstrating treatment effects. Mean differences in log-normalized outcome estimates were calculated with multivariable linear regression adjusting for their baseline values, systemic immunosuppressants used, and prior COVID-19 vaccination history. The non-inferiority margin was set for fID to retain >80% immunogenicity of sIM. With 109 participants included, 53 received fID (all entered an intention-to-treat analysis). The fID demonstrated non-inferiority to sIM in humoral (mean outcome estimates of sIM: 3.3, ΔfID-sIM [mean, 95%CI]: -0.1, -0.3 to 0.0) and cellular (mean outcome estimates of sIM: 3.2, ΔfID-sIM [mean, 95%CI]: 0.1, -0.2 to 0.3) immunogenicity outcomes. Two psoriasis patients from the fID arm (3.8%) developed injection-site Koebner's phenomenon. Fewer fID recipients experienced post-vaccination fever (fID vs. sIM: 1.9% vs. 12.5%, p = 0.027). The overall incidence of disease flare-ups was low without a statistically significant difference between groups. The intradermal BNT162b2 vaccine is a viable booster option for IMDD patients troubled by post-vaccination fever; its role in mitigating the risk of flare-ups remains unclear.

Refractory Bullous Systemic Lupus Erythematosus Successfully Treated with Rituximab: A Case Report and Literature Review.

Bullous systemic lupus erythematosus (BSLE) is a rare blistering skin manifestation of systemic lupus erythematosus (SLE). Dapsone is reported to be helpful in mild-to-moderate BSLE cases; however, its use may be limited or prohibited due to particular complications such as drug hypersensitivity, dose-dependent hemolytic anemia, and other significant hematologic abnormalities. Rituximab, an anti-CD20 monoclonal antibody, has been reported with off-label use in BSLE patients, but data are still limited. Hence, our objective is to explore the efficacy of rituximab among these patients. Herein, we report a 21-year-old Thai woman presented with blistering eruption on the oral cavity, scalp, trunk, and extremities for 1 month. The investigations revealed a positive direct Coomb's test, an elevated erythrocyte sedimentation rate (ESR), and a positive antinuclear antibody (ANA). Skin biopsy showed focal interface dermatitis. Direct immunofluorescence (DIF) illustrated mixed linear and granular deposition of immunoglobulin (Ig)G, IgM, IgA, and C3 along the dermo-epidermal junction (DEJ). Enzyme-linked immunosorbent assay (ELISA) showed circulating antibodies to type VII collagen. She was diagnosed with severe BSLE and autoimmune hemolytic anemia (AIHA) refractory to several oral immunosuppressants but was successfully treated with rituximab. The authors also performed a review of the literature on prior BSLE cases managed with rituximab.

Optimal time for COVID-19 vaccination in rituximab-treated dermatologic patients.

Background: By depleting circulating B lymphocytes, rituximab time-dependently suppresses coronavirus disease 2019 (COVID-19) vaccines' humoral immunogenicity for a prolonged period. The optimal time to vaccinate rituximab-exposed immune-mediated dermatologic disease (IMDD) patients is currently unclear. Objective: To estimate the vaccination timeframe that equalized the occurrence of humoral immunogenicity outcomes between rituximab-exposed and rituximab-naïve IMDD patients. Methods: This retrospective cohort study recruited rituximab-exposed and age-matched rituximab-naïve subjects tested for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunity post-vaccination. Baseline clinical and immunological data (i.e., immunoglobulin levels, lymphocyte immunophenotyping) and SARS-CoV-2-specific immunity levels were extracted. The outcomes compared were the percentages of subjects who produced neutralizing antibodies (seroconversion rates, SR) and SARS-CoV-2-specific IgG levels among seroconverters. The outcomes were first analyzed using multiple regressions adjusted for the effects of corticosteroid use, steroid-spearing agents, and pre-vaccination immunological status (i.e., IgM levels, the percentages of the total, naïve, and memory B lymphocytes) to identify rituximab-related immunogenicity outcomes. The rituximab-related outcome differences with a 95% confidence interval (CI) between groups were calculated, starting by including every subject and then narrowing down to those with longer rituximab-to-vaccination intervals (≥3, ≥6, ≥9, ≥12 months). The desirable cut-off performances were <25% outcome inferiority observed among rituximab-exposed subgroups compared to rituximab-naïve subjects, and the positive likelihood ratio (LR+) for the corresponding outcomes ≥2. Findings: Forty-five rituximab-exposed and 90 rituximab-naive subjects were included. The regression analysis demonstrated a negative association between rituximab exposure status and SR but not with SARS-CoV-2-specific IgG levels. Nine-month rituximab-to-vaccination cut-off fulfilled our prespecified diagnostic performance (SR difference between rituximab-exposed and rituximab-naïve group [95%CI]: -2.6 [-23.3, 18.1], LR+: 2.6) and coincided with the repopulation of naïve B lymphocytes in these patients. Conclusions: Nine months of rituximab-to-vaccination interval maximize the immunological benefits of COVID-19 vaccines while avoiding unnecessary delay in vaccination and rituximab treatment for IMDD patients.

A real-world prospective cohort study of immunogenicity and reactogenicity of ChAdOx1-S[recombinant] among patients with immune-mediated dermatological diseases.

BACKGROUND: Immunogenicity and reactogenicity of COVID-19 vaccines have been established in various groups of immunosuppressed patients; however, studies involving patients with immune-mediated dermatological diseases (IMDDs) are scarce. OBJECTIVES: To investigate the influence of IMDDs on the development of SARS-CoV-2-specific immunity and side-effects following ChAdOx1-S[recombinant] vaccination. METHODS: This prospective cohort study included 127 patients with IMDDs and 97 participants without immune-mediated diseases who received ChAdOx1-S[recombinant]. SARS-CoV-2-specific immunity and side-effect profiles were assessed at 1 month postvaccination and compared between groups. Immunological (primary) outcomes were the percentages of participants who tested positive for neutralizing antibodies [seroconversion rate (SR)] and those who developed T-cell-mediated immunity demonstrated by an interferon-γ-releasing assay (IGRA) [positive IGRA rate (+IGRA)]. Reactogenicity-related (secondary) outcomes were the unsolicited adverse reactions and worsening of IMDD activity reflected by the uptitration of immunosuppressants during and within 1 month of vaccination. RESULTS: Overall, the SR for the IMDD group was similar to that of participants without immune-mediated conditions (75·6 vs. 84·5, P = 0·101), whereas + IGRA was lower (72·4 vs. 88·7, P = 0·003). Reactogenicity was similar between groups. No severe adverse reaction was reported. By stratifying the participants in the IMDD group according to individual disease, the immunogenicity of the vaccine was lowest in patients with autoimmune bullous diseases (AIBD) (SR 64·5%, +IGRA 62·9%) and highest in patients with psoriasis (SR 87·7%, +IGRA 80·7%). The reverse trend was found for vaccine-related reactions. Immunosuppressants were uptitrated in 15·8% of cases; 75% of these were patients with AIBD. CONCLUSIONS: Among participants with IMDDs, ChAdOx1-S[recombinant] showed good immunogenicity among patients with psoriasis, but demonstrated lower levels of immunogenicity for patients with AIBD. Some patients, especially patients with AIBD, should be closely monitored as they may require treatment escalation within 1 month postvaccination.

Coexistence of Discoid Lupus Erythematosus and Paraneoplastic Pemphigus: A Case Report and Literature Review.

Pemphigus and lupus erythematosus are both B-cell-mediated autoimmune diseases, dependent on autoreactive CD4+ T lymphocytes to modulate autoimmune B-cell response. Many forms of pemphigus have been reported to occur in association with systemic lupus erythematosus (SLE) as well as other autoimmune diseases. However, it remains unclear whether this association occurs because of a shared immunopathogenesis or the coexistence may be coincidental. We hereby present a case report of discoid lupus erythematosus and paraneoplastic pemphigus associated with marginal zone lymphoma in a 54-year-old Thai man who had persistent oral erosions for 1 year together with generalized polymorphic cutaneous eruptions for 2 months. Simultaneous occurrence of paraneoplastic pemphigus and discoid lupus erythematosus without SLE has never been reported in the same individual. Hydroxychloroquine, immunosuppressive agents including prednisolone and azathioprine together with chemotherapy were given to treat these conditions.

Inactivated COVID-19 Vaccine Induces a Low Humoral Immune Response in a Subset of Dermatological Patients Receiving Immunosuppressants.

Inactivated Sinovac-CoronaVac vaccine (Sinovac Life Sciences, Beijing) for coronavirus disease 2019 (COVID-19) has been used in many countries. However, its immunogenicity profile in immunosuppressed dermatological patients is lacking. This prospective observational case-control study compared the humoral immune response between adult dermatological patients receiving systemic immunosuppressive therapies (n = 14) and those who did not (n = 18); excluding patients with HIV infection, cancer, non-dermatological autoimmune conditions, previous COVID-19 infection, and positive anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG prior to vaccination. The subjects were advised to withhold methotrexate for 1 week after each vaccine dose while continuing other therapies unadjusted. Anti-SARS-CoV-2 IgG antibody, surrogate neutralizing antibody (sNAb), and seroconversion rates (calculated from the percentages of participants in the group with positive sNAb) were used to assess immunogenicity. We found that participants using azathioprine, cyclosporin, mycophenolate mofetil, or prednisolone ≥ 10 mg/day had a lower level of serum anti-SARS-CoV-2 IgG antibody and sNAb than those received methotrexate ≤ 10 mg/week, prednisolone < 10 mg/day, or biologics (i.e., secukinumab, ixekizumab, omalizumab). Patients who received methotrexate ≤ 10 mg/week, prednisolone < 10 mg/day or the biologics had a similar immunogenicity profile to those without immunosuppressive therapies. Despite the lack of statistical significance, a reduction of humoral immune response was observed among the study participants who used ≥2 immunosuppressants or pemphigus patients. Our findings suggest that a subset of patients with immune-mediated skin conditions respond poorly to the vaccine despite having low-level immunosuppression. These patients could benefit from vaccines that trigger a greater level of immunogenicity or booster doses.

The Concentration of Large Extracellular Vesicles Differentiates Early Septic Shock From Infection.

Septic shock represents a subset of sepsis with severe physiological aberrations and a higher mortality rate than sepsis alone. Currently, the laboratory tools which can be used to identify the state of septic shock are limited. In pre-clinical studies, extracellular vesicles (EVs), especially large EVs (lEVs), have been demonstrated a role as functional inflammatory mediators of sepsis. However, its longitudinal trend during the disease course has not been explored. In this study, the quantities and subtypes of plasma-derived lEVs were longitudinally compared between patients with septic shock (n = 21) and non-sepsis infection (n = 9), who presented within 48 h of their symptom onset. Blood specimens were collected for seven consecutive days after hospital admission. lEVs quantification and subtyping were performed using an imaging flow cytometer. The experiments revealed a higher lEVs concentration in septic shock patients than infected patients at the onset of the disease. In septic shock patients, lEVs concentration decreased over time as opposed to infected patients whose lEVs concentration is relatively static throughout the study period. The major contributors of lEVs in both septic shock and infected patients were of non-leukocyte origins; platelets, erythrocytes, and endothelial cells released approximately 40, 25, and 15% of lEVs, respectively. Among lEVs of leukocyte origins, neutrophils produced the highest number of EVs. Nevertheless, the proportion of each subtype of lEVs among the given amount of lEVs produced was similar between septic shock and infected patients. These findings raise the possibility of employing lEVs enumeration as a septic shock identifying tool, although larger studies with a more diverse group of participants are warranted to extrapolate the findings to a general population.

Prolonged Extracorporeal Membrane Oxygenation Support In a Patient with Drug Reaction with Eosinophilia and Systemic Symptoms Syndrome-associated Fulminant Myocarditis - A Case Report and Literature Review.

Introduction: Myocarditis is a rare presentation of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, traditionally associated with poor clinical outcomes. Prompt recognition and treatment are crucial. Case presentation: A 16-year-old patient presented with acute chest pain, hypotension, and pulmonary oedema 2 months after being diagnosed with trimethoprim/sulfamethoxazole-induced DRESS syndrome. Typical DRESS features were absent at onset of these symptoms. Echocardiography demonstrated biventricular systolic dysfunction, and electrocardiography (ECG) showed complete right bundle branch block and diffuse ST-segment elevation. The patient was admitted for high-dose inotropic support; however, his condition deteriorated. Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and intra-aortic balloon pump were initiated on the third day of admission. Endomyocardial biopsy suggested the diagnosis of DRESS-associated myocarditis and a high-dose corticosteroid was commenced. While he was ECMO-dependent, the patient suffered multiple episodes of ventricular tachycardia on a background of cardioversion-resistant accelerated idioventricular rhythm. After 24 days of ECMO support, the ventricular function improved, and ECG reverted to sinus rhythm. His recovery allowed corticosteroid discontinuation 15 months after hospital discharge. Conclusion: Typical DRESS syndrome features may not accompany the onset of DRESS-associated myocarditis. Mechanical circulatory support and adequate immunosuppression could save patients with malignant arrhythmias and delayed myocardial recovery.

Distinguishing Sepsis From Infection by Neutrophil Dysfunction: A Promising Role of CXCR2 Surface Level.

Sepsis is one of the well-established diseases with specific patterns of neutrophil dysfunctions. Previous studies demonstrated sepsis-related neutrophil dysfunctions in comparison with subjects without infection. Since sepsis and infection are recently recognized as distinctive processes, whether these neutrophil dysfunctions are associated with sepsis or infection are not known. Therefore, we longitudinally compared neutrophil functions, widely-cited as exhibiting sepsis-related changes, between patients with septic shock and infection. The surface level of cluster of differentiation 64 (CD64), C-C motif chemokine receptor 2 (CCR2), C-X-C motif chemokine receptor 2 (CXCR2); apoptosis; and NETosis were measured from peripheral blood neutrophils for seven consecutive days using flow cytometry. The between-group comparisons of neutrophil functions were made both on a day-by-day basis and as linear regression between time and measured neutrophil functions (sepsis status included as model predictors). Our study found that, among neutrophil functions studied, only CXCR2 surface level is associated with sepsis. At disease onset, CXCR2 level decrease, with a dose-response relationship with clinical severity. Its level reverts to resemble infected patients by the end of the week. The relationship between CD64 surface level, CCR2 surface level, NETosis, and sepsis are mediated through the effect of infection. Apoptosis activity between these groups are similar, hence, not sepsis-related.