Evaluation of breakthrough infections in solid organ transplant recipients: the prospective CONTRAST cohort

Background. Solid organ transplant (SOT) recipients are at higher risk than general population for complicated COVID-19 course. Moreover COVID-19 vaccination in this setting is associated with a suboptimal immune response. However, the impact of this finding on the risk of breakthrough infection (BI) in SOT recipients has to be yet determined. Methods. Single-center prospective longitudinal cohort of adult SOT recipients who received three doses of mRNA COVID-19 vaccine between February and December 2021 and were followed up to March 30 2022. Patients were tested for antibody response at several timepoints (1 st dose, 2 nd dose, 3+/-1 month after 1 st dose, and 1 month after 3 rd dose). Main endpoints were: i) BI defined as laboratory confirmed SARS-CoV2 infection diagnosed >=14 day after 2 nd dose;ii) positive antibody response (AbR) defined as anti-rapid binding domain titer >=5 U/ml determined by Elecsys Anti-SARS-CoV-2 ECLIA assay (Roche Diagnostics, CH), the last available determination before BI was considered. Results. Study cohort consists of 642 SOT (277 kidney, 191 liver, 144 heart, 37 lung) recipients: 63.9% males, median age 54 +/- 14.5 years. Of them, 111 (17.8%) developed BI, BI rates were 19.9%, 18.1%, 15.2% and 10.8% among liver, heart, kidney and lung transplant recipients, respectively. Positive-AbR was observed in 60% of all patients, but rates varied from 8.7% to 91.3% among patients with BI and without BI, respectively. Predictors of BI infection at multivariable analysis were liver (vs. other grafts) transplant (OR 2.98, 95%CI 1.47-6.03), mycophenolate (1.63, 0.92-2.88) and steroids (1.8, 1.05- 3.33), while positive-AbR (0.61, 0.35-1.04) and age (0.97, 0.95-0.99) were protective. On the other hand, liver transplant (1.94, 1.02-3.69), time from transplant (1.09, 1.05-1.21), and Moderna vaccine (2.32, 1.46-3.70) were associated with positive-AbR, while age (0.97, 0.95-0.98), heart transplant (0.56, 0.33-0.96), mycophenolate (0.65, 0.39-1.06) and steroids (0.39, 0.23-0.65) with lower probability of positive-AbR. Conclusion. Although associated with positive-AbR, liver transplant and younger age were also BI predictors, suggesting the importance of social factors and the controversial role of immune monitoring.

Neonates born to mothers with SARS-CoV-2 infection in pregnancy: a follow-up and serological study

Background. To evaluate the early and late clinical outcomes of neonates born to mothers with SARS-CoV-2 infection in pregnancy, the dynamics of maternal IgG trans placental transfer and its persistence during the first month of life. Methods. Prospective study enrolling neonates born to mothers with SARS-CoV-2 infection in pregnancy at IRCCS Azienda Ospedaliero Universitaria di Bologna, Italy, between April 2020 and September 2021. Neonates born to women with infection onset before 2 weeks prior to delivery were enrolled in a 12-month follow-up, including clinical and laboratory evaluations, cranial ultrasound, fundoscopy evaluation. Quantitative IgG to S1/S2 subunits of spike protein were assessed in mother-neonate dyads within 48 hours post-delivery and during follow-up until negative. Transplacental IgG transfer ratio was assessed in relation to the type and trimester of maternal infection. Results. One hundred and forty-five neonates were included. the rate of preterm delivery was similar between women with and without SARS-CoV-2 infection (6.2% versus 8.7%, P=0.53). No clinical, laboratory, cerebral and fundoscopy abnormalities were detected at birth or during follow-up, through 11 months (range 8-12). MedianIgG level at birth was not different between neonates born to asymptomatic or symptomatic mothers (18.5 AU/mL, IQR 12-49, versus 31.5 AU/mL, IQR 15- 71, P=0.07) nor in relation to the trimester of maternal infection (Table 1), even though mothers with third trimester infections had higher IgG level at birth. Transplacental transfer ratio was higher following second trimester maternal infections and was the lowest following third trimester infections (Table 1). Maternally derived IgG were rapidly weaned, with most infants (115/140, 82%) seronegative by 4 months of age. Conclusion. Early and later outcomes of infants born to SARS-CoV-2 infected mothers were favorable. IgG trans placental transfer was higher following second trimester maternal infections, which could be relevant to inform studies on appropriate vaccination strategies aimed at neonatal protection. Maternally derived IgG are rapidly weaned in the first months of life. (Table Presented).

High Humoral Response after Anti-Sars-Cov-2 mRNA-Based Vaccines in Patients with Active Multiple Myeloma (MM) and Relationship with Disease Status/Line of Therapy

mRNA vaccines BNT162b2 and mRNA1273 are highly effective in preventing SARS-CoV-2 infection and mortality in healthy adults. However, their immunogenicity in immunocompromised Multiple Myeloma (MM) patients is less clear. We performed an observational prospective study of 96 MM patients (pts) treated at our centre, aimed at assessing the humoral and cell-mediated immune (CMI) response following the full immunization schedule. To this aim, we measured serum levels of neutralizing IgG anti Spike-protein (IgG anti S-RBD) at 1, 3, 6, 9 and 12 months after the 2 nd dose of vaccination, using the electrochemiluminescence (ECLIA) platform (Elecsys® Anti-sars-Cov-2 ECLIA assay) and evaluated CMI response in terms of pts with a SARS-CoV-2 specific IFNγ T cell response by IGRA (Interferon-Gamma Release Assays) test at 3 and 12 months after 2 nd dose. A concentration level of IgG anti S-RBD ≥0.80 U/ml was considered a seropositive result. Herein, we report preliminary data on the development of humoral response in 96 MM pts who reached the first study timepoint (1 month after 2 nd dose), compared to 54 health-care workers as controls. At vaccination, the median age of the 96 patients (51 males/45 females) was 66.5 (range 47-83) years. The median number of previous lines of therapy was 1 (range 1-11) and only 7 (7.3%) pts were not receiving active treatment. 44.8% (n=43) pts had relapse/refractory MM. Among 72 (75%) transplant-eligible pts, 63 patients had previously received autologous stem-cell transplantation (ASCT) with a median time between ASCT and vaccine of 31 (range 3-274) months. 70 (72.9%) pts had received immunomodulatory drugs (IMIDs) containing regimens, 30 (31.3%) proteasome inhibitors (PIs), 11 (11.5%) IMIDs + PIs, 32 (33.3%) anti-CD38 monoclonal antibodies (anti-CD38 moAbs). 33 (34.4%) pts were in lenalidomide (R) maintenance therapy. At vaccination, 67 (68.8%) pts were in VGPR or higher, 18 (18.7%) in PR and 11 (11.3%) in SD or PD. Immunoparesis (≥1 uninvolved Ig below lower level limit) was observed in 78 (88.6%) pts, of whom 59 (67.1%) showed a reduction of two Ig classes. All pts had completed the 2 planned doses of BNT162b2 (40.6%) or mRNA1273 (59.4%) vaccine 3 or 4 weeks apart, respectively. Control cohort (n=54;median age of 51 [range 40-66] years) received mRNA vaccine during the same period. People with previous SARS-CoV-2 infection (positive IgG anti S-RBD or anti-nucleocapsid N antibody titer before vaccines) were excluded from the analysis. At 1 month post 2 nd dose, (median 30 days, IQR 28-32) seropositive response rate to vaccination was 91.7% (n=88) for MM pts vs 100% for controls, p=0.05;the median IgG anti S-RBD titer was 435 (range 0.4-2500) vs 1040.5 U/ml (range 160-2500), respectively;p=0.008. No difference in the rate of seropositive response between those who received the 2 type of vaccines was found (p=0.09). Pts with response level ≥ CR had a median antibody (Ab) titer (1242 U/ml, range 0.4-2500) significantly higher than those with ≤CR (221.5 U/ml, range 0.4- 2500), p<0.001. Pts receiving PI (median Ab titer 156;range 0.4- 2500) and anti-CD38 MoAbs (median titer 265 U/ml;0.4- 2500) containing regimens had a lower Ab titer than all the other pts (p=0.003 and p<0.001, respectively). Median Ab titer was higher in pts who received ASCT vs others (1042, range 0.4- 2500 vs 160 U/ml, range 228-2500, p<0.001) and in pts receiving R maintenance (1681.2, range 0.4-2500 vs 529.5 U/ml, range 0.4-2500, p<0.001). In pts with 2-Ig immunoparesis, the median Ab titer was 272 (range 0.4-2500) vs 2500 U/ml (range 228-2500) for no immunoparesis (p= 0.0037). A distribution analysis of the Ab titer revealed a significant correlation between better humoral response and hematological response ≥ CR (p<0.001), being in first-line treatment (p=0.039), having received ASCT (p=0.001) and receiving R maintenance (p=0.001). Multivariate analysis confirmed ≥ CR [OR 2.54, 95% CI 93-756], being in first line treatment [OR 2.10, CI 22-722] and R maintenance therapy [OR 4.53, CI 484-1233] as independen predictors of better humoral response at 1 month after 2 nd vaccine dose. In conclusion, mRNA vaccines provided a high seropositivity rate in pts in active MM treatment, with a better humoral response in pts achieving CR, those who received ASCT and receiving R maintenance. Immunoparesis was confirmed to be an unfavourable factor for the development of humoral response, as well as treatment with anti-CD-38 moAbs. Disclosures: Mancuso: Celgene: Honoraria;Takeda: Honoraria;Sanofi: Honoraria;Amgen: Honoraria;Janssen: Honoraria. Zamagni: Takeda: Honoraria;Amgen: Honoraria;Bristol-Myers-Squibb: Honoraria;Janssen: Honoraria. Pantani: Amgen: Honoraria;Janssen: Honoraria. Rocchi: Amgen: Honoraria;GalxoSmithKline: Honoraria;Janssen: Honoraria. Rizzello: Amgen: Honoraria;GlaxoSmithKline: Honoraria;Sanofi: Honoraria. Tacchetti: Amgen: Honoraria;BMS/Celgene: Honoraria;Janssen: Honoraria;Takeda: Honoraria;AbbVie: Honoraria;Sanofi: Honoraria;GlaxoSmithKline: Honoraria;Oncopeptides: Honoraria. Zinzani: JANSSEN-CILAG: Other: Advisory board, Speakers Bureau;MSD: Consultancy, Other: Advisory board, Speakers Bureau;SANDOZ: Other: Advisory board;TG Therapeutics: Other: Advisory board, Speakers Bureau;GILEAD: Other: Advisory board, Speakers Bureau;SERVIER: Other: Advisory board, Speakers Bureau;BMS: Other: Advisory board, Speakers Bureau;CELLTRION: Other: Advisory board, Speakers Bureau;TAKEDA: Other: Advisory board, Speakers Bureau;ROCHE: Other, Speakers Bureau;EUSAPHARMA: Consultancy, Other, Speakers Bureau;KYOWA KIRIN: Other, Speakers Bureau;Incyte: Other, Speakers Bureau;NOVARTIS: Consultancy, Other, Speakers Bureau;ADC Therap.: Other;Beigene: Other, Speakers Bureau;VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau;AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees;Adaptive Biotechnologies: Consultancy, Honoraria;Novartis: Honoraria;Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau;Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;GlaxoSmithKline: Consultancy, Honoraria;Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Major cluster of paediatric 'true' primary chilblains during the COVID-19 pandemic: a consequence of lifestyle changes due to lockdown.

BACKGROUND: Over the last months, during the COVID-19 pandemic, a growing number of chilblain-like lesions were reported mainly in children and rarely in young adults. The relationship with SARS-CoV-2 infection was postulated, often without any laboratory, instrumental or clinical confirmation. The disclosure of information about chilblain-like lesions as a COVID-19 manifestation in social media has created concern in children's families and paediatricians. OBJECTIVES: To verify whether the chilblain-like lesions were caused by SARS-CoV-2 infection. METHODS: Prospective study on a case series including children who presented with acral lesions at the Pediatric Dermatology Outpatient and Pediatric Emergency Unit of the University of Bologna, from 1 April to 30 April 2020. We reported demographical, laboratory and clinical features, history of close contact with COVID-19 patients, presence of similar skin lesions in other family members, precipitating and risk factors for chilblain onset. RESULTS: We evaluated eight patients (five females, three males) aged between 11 and 15 years. We excluded acute or previous SARS-CoV-2 infection with RT-PCR nasopharyngeal swab, serum antibody levels using chemiluminescent immunoassays. Other acute infections causing purpuric lesions at the extremities were negative in all patients. Skin lesion biopsy for histological and immunohistochemical evaluation was made in two cases and was consistent with chilblain. PCR assay on skin lesion biopsy for parvovirus B19, Mycoplasma pneumoniae and SARS-CoV-2 was performed in a patient and resulted negative. We identified common precipitating and risk factors: physical (cold and wet extremities, low BMI), cold and wet indoor and outdoor environment, behaviours, habits and lifestyle. We therefore reached a diagnosis of primary chilblains. CONCLUSIONS: During the COVID-19 pandemic, a 'cluster' of primary chilblains developed in predisposed subjects, mainly teenagers, due to cold exposure in the lockdown period. Laboratory findings support our hypothesis, although it is also possible that an unknown infectious trigger may have contributed to the pathogenesis.