Long term follow-up of humoral and cellular response to mRNA-based vaccines for SARS-CoV-2 in patients with active multiple myeloma.

Long-term kinetics of antibody (Ab) and cell-mediated immune (CMI) response to full anti-SARS-CoV-2 vaccine schedule and booster doses in Multiple Myeloma (MM) patients remain unclear. We prospectively evaluated Ab and CMI response to mRNA vaccines in 103 SARS-CoV-2-naïve MM patients (median age 66, 1 median prior line of therapy) and 63 health-workers. Anti-S-RBD IgG (Elecsys®assay) were measured before vaccination and after 1 (T1), 3 (T3), 6 (T6), 9 (T9) and 12 (T12) months from second dose (D2) and 1 month after the introduction of the booster dose (T1D3). CMI response (IGRA test) was evaluated at T3 and T12. Fully vaccinated MM patients displayed high seropositivity rate (88.2%), but low CMI response (36.2%). At T6 the median serological titer was halved (p=0.0391) in MM patients and 35% reduced (p=0.0026) in controls. D3 (94 patients) increased the seroconversion rate to 99% in MM patients and the median IgG titer in both groups (up to 2500 U/mL), maintained at T12. 47% of MM patients displayed a positive CMI at T12 and double-negativity for humoral and CMI (9.6% at T3) decreased to 1%. Anti-S-RBD IgG level ≥346 U/mL showed 20-times higher probability of positive CMI response (OR 20.6, p<0.0001). Hematological response ≥CR and ongoing lenalidomide maintenance enhanced response to vaccination, hindered by proteasome inhibitors/anti-CD38 monoclonal antibodies. In conclusion, MM elicited excellent humoral, but insufficient cellular responses to anti-SARS-CoV-2 mRNA vaccines. Third dose improved immunogenicity renewal, even when undetectable after D2. Hematological response and ongoing treatment at vaccination were the main predictive factors of vaccine immunogenicity, emphasizing the role of vaccine response assessment to identify patients requiring salvage approaches.

Virological and histological evaluation of intestinal samples in COVID-19 patients.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the pathogen responsible for pandemic coronavirus disease 2019 (COVID-19). It is a highly contagious virus which primarily affects the respiratory tract, nevertheless, the lungs are not the only target organs of the virus. The intestinal tract could represent an additional tropism site for SARS-CoV-2. Several observations have collectively suggested that enteric infections can occur in COVID-19 patients. However, the detection of viral RNA in gastrointestinal (GI) tissue samples has not been adequately investigated and results are conflicting. AIM: To detect the presence of SARS-CoV-2 RNA in intestinal mucosa samples and to evaluate histological features. METHODS: The COVID-19 patients hospitalized at an Italian tertiary hospital from April 2020 to March 2021 were evaluated for enrollment in an observational, monocentric trial. The study population was composed of two groups of adult patients. In the first group (biopsy group, 30 patients), patients were eligible for inclusion if they had mild to moderate disease and if they agreed to have a rectal biopsy; in the second group (surgical specimen group, 6 patients), patients were eligible for inclusion if they underwent intestinal resection during index hospitalization. Fifty-nine intestinal mucosal samples were analyzed. RESULTS: Viral RNA was not detectable in any of the rectal biopsies performed (0/53). Histological examination showed no enterocyte damage, but slight edema of the lamina propria with mild inflammatory lymphoplasmacytic infiltration. There was no difference in inflammatory infiltrates in patients with and without GI symptoms. SARS-CoV-2 RNA was detected in fecal samples in 6 cases out of 14 cases examined (42.9%). In the surgical specimen group, all patients underwent emergency intestinal resection. Viral RNA was detected in 2 surgical specimens of the 6 examined, both of which were from patients with active neoplastic disease. Histological examination also pointed out abundant macrophages, granulocytes and plasma cells infiltrating the muscular layer and adipose tissue, and focal vasculitis. CONCLUSION: Mild-moderate COVID-19 may not be associated with rectal infection by the virus. More comprehensive autopsies or surgical specimens are needed to provide histological evidence of intestinal infection.

Infants Born Following SARS-CoV-2 Infection in Pregnancy.

OBJECTIVES: To evaluate outcomes of neonates born to mothers with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy, the dynamics of placental transfer of maternal antibodies, and its persistence during infancy. METHODS: Cohort study enrolling neonates born to mothers with SARS-CoV-2 infection in pregnancy. All infants were evaluated at birth. Those born to women with infection onset within 2 weeks before delivery were excluded from further analyses. Remaining infants underwent cerebral and abdominal ultrasound, fundoscopy evaluation, and were enrolled in a 12 month follow-up. Qualitative immunoglobulin G (IgG)/immunoglobulin M and quantitative IgG to S1/S2 subunits of spike protein were assessed in mother-neonate dyads within 48 hours postdelivery and during follow-up. RESULTS: Between April 2020 and April 2021, 130 of 2745 (4.7%) neonates were born to mothers with SARS-CoV-2 infection in pregnancy, with 106 of 130 infections diagnosed before 2 weeks before delivery. Rates of preterm and cesarean delivery were comparable between women with and without infection (6% vs 8%, P = .57; 22% vs 32%, P = .06). No clinical or instrumental abnormalities were detected at birth or during follow-up. There was a positive correlation between maternal and neonatal SARS-CoV-2 IgG levels (r = 0.81, P < .001). Transplacental transfer ratio was higher after second-trimester maternal infections as compared with first and third trimester (P = .03). SARS-CoV-2 IgG level progressively decreased in all infants, with 89 of 92 (97%) infants seronegative at 6 months of age. CONCLUSIONS: Clinical outcomes were favorable in all infants. Matching peak IgG level after infection and higher IgG transplacental transfer might result in the most durable neonatal passive immunity.

Unexpected Vertical Transmission of SARS-CoV-2: Discordant Clinical Course and Transmission from Mother to Newborn.

Mother-to-newborn COVID-19 transmission is mainly postnatal, but single-case reports and small case series have also described SARS-CoV-2 transplacental transmission. Unfortunately, studies regarding vertical transmission of SARS-CoV-2 lack systematic approaches to diagnosis and classification. So far, scientific evidence seems to suggest that the severity of maternal infection increases the risk of vertical transmission. We report two neonates born from COVID-19-positive mothers, of which one of the newborns had a vertical infection. The placental involvement, and consequent intrauterine transmission of SARS-CoV-2, were inversely related to the severity of the maternal disease. The description of cases divergent from current evidence on this topic could provide new insights to better understand SARS-CoV-2 vertical transmission.

COVID-19 and the Brain: The Neuropathological Italian Experience on 33 Adult Autopsies.

Neurological symptoms are increasingly recognized in SARS-CoV-2 infected individuals. However, the neuropathogenesis remains unclear and it is not possible to define a specific damage pattern due to brain virus infection. In the present study, 33 cases of brain autopsies performed during the first (February-April 2020) and the second/third (November 2020-April 2021) pandemic waves are described. In all the cases, SARS-CoV-2 RNA was searched. Pathological findings are described and compared with those presently published.

Multisystem Inflammatory Syndrome Following SARS-CoV-2 Infection in Children: One Year after the Onset of the Pandemic in a High-Incidence Area.

SARS-CoV-2 infection in children can trigger cardiovascular manifestations potentially requiring an intensive treatment and defining a new entity named Multisystem Inflammatory Syndrome in Children (MIS-C), whose features partially overlap with Kawasaki Disease (KD). A cross-sectional study including all diagnoses of MIS-C and KD from April 2020 to May 2021 in our metropolitan area was conducted evaluating clinical, laboratory (including immunological response, cytokines, and markers of myocardial damage), and cardiac (coronary and non-coronary) features at onset of the diseases. Evolution of ventricular dysfunction, valve regurgitations, and coronary lesions was documented. The severity of the disease was also considered based on the need for inotropic support and ICU admission. Twenty-four MIS-C were diagnosed (14 boys, median age 82 months): 13/24 cases (54.17%) presented left ventricular dysfunction, 12/24 (50%) required inotropic support, and 10/24 (41.67%) developed coronary anomalies (CALs). All patients received steroids and IVIG at a median time of 5 days (IQR1:4, IQR3:6.5) from onset of fever and heart function normalized 6 days (IQR1: 5, IQR3: 7) after therapy, while CALs persisted in one. One patient (12.5%) required infliximab because of refractory disease and still presented CALs 18 days after therapy. During the same study period, 15 KD were diagnosed: none had ventricular dysfunction, while 7/15 (46.67%) developed CALs. Three out of 15 patients (20%) still presented CALs 46 days from onset. Compared to KD, MIS-C pts have significantly higher IL8 and similar lymphocytes subpopulations. Despite a more severe presentation and initial cardiac findings compared to KD, the myocardial injury in MIS-C has a rapid response to immunomodulatory treatment (median time 6 days), in terms of ventricular function, valve regurgitations, and troponin. Incidence of CALs is similar at onset, but it tends to regress in most of the cases of MIS-C differently than in KD where CALs persist in up to 40% in the subacute stage after treatment.

Spectrum of Cardiovascular Diseases in Children During High Peak Coronavirus Disease 2019 Period Infection in Northern Italy: Is There a Link?

BACKGROUND: Children with coronavirus disease-2019 (COVID-19) have a milder clinical course than adults. We describe the spectrum of cardiovascular manifestations during a COVID-19 outbreak in Emilia-Romagna, Italy. METHODS: A cross-sectional multicenter study was performed, including all patients diagnosed with Kawasaki disease (KD), myocarditis, and multisystem inflammatory syndrome in children (MIS-C) from February to April 2020. KD patients were compared with those diagnosed before the epidemic. RESULTS: KD: 8 patients (6/8 boys, all negative for severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]): complete presentation in 5/8, 7/8 immunoglobulin (IVIG) responders, and 3/8 showed transient coronary lesions (CALs). Myocarditis: one 5-year-old girl negative for SARS-CoV-2 and positive for parvovirus B19. She responded to IVIG. MIS-C: 4 SARS-CoV-2-positive boys (3 patients with positive swab and serology and 1 patient with negative swab and positive serology): 3 presented myocardial dysfunction and pericardial effusion, and 1 developed multicoronary aneurysms and hyperinflammation; all responded to treatment. The fourth boy had mitral and aortic regurgitation that rapidly regressed after steroids. CONCLUSIONS: KD, myocarditis, and MIS-C were distinguishable cardiovascular manifestations. KD did not show a more aggressive form compared with previous years: coronary involvement was frequent but always transient. MIS-C and myocarditis rapidly responded to treatment without cardiac sequelae despite high markers of myocardial injury at the onset, suggesting a myocardial depression due to systemic inflammation rather than focal necrosis. Evidence of actual or previous SARS-CoV-2 infection was documented only in patients with MIS-C.

Recent Advances in the Evaluation of Serological Assays for the Diagnosis of SARS-CoV-2 Infection and COVID-19.

Introduction: Few data on the diagnostic performance of serological tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are currently available. We evaluated sensitivity and specificity of five different widely used commercial serological assays for the detection of SARS-CoV-2-specific IgG, IgM, and IgA antibodies using reverse transcriptase-PCR assay in nasopharyngeal swab as reference standard test. Methods: A total of 337 plasma samples collected in the period April-June 2020 from SARS-CoV-2 RT-PCR positive (n = 207) and negative (n = 130) subjects were investigated by one point-of-care lateral flow immunochromatographic assay (LFIA IgG and IgM, Technogenetics) and four fully automated assays: two chemiluminescence immunoassays (CLIA-iFlash IgG and IgM, Shenzhen YHLO Biotech and CLIA-LIAISON® XL IgG, DiaSorin), one electrochemiluminescence immunoassay (ECLIA-Elecsys® total predominant IgG, Roche), and one enzyme-linked immunosorbent assay (ELISA IgA, Euroimmune). Results: The overall sensitivity of all IgG serological assays was >80% and the specificity was >97%. The sensitivity of IgG assays was lower within 2 weeks from the onset of symptoms ranging from 70.8 to 80%. The LFIA and CLIA-iFlash IgM showed an overall low sensitivity of 47.6 and 54.6%, while the specificity was 98.5 and 96.2%, respectively. The ELISA IgA yielded a sensitivity of 84.3% and specificity of 81.7%. However, the ELISA IgA result was indeterminate in 11.7% of cases. Conclusions: IgG serological assays seem to be a reliable tool for the retrospective diagnosis of SARS-CoV-2 infection. IgM assays seem to have a low sensitivity and IgA assay is limited by a substantial rate of indeterminate results.

Pathological post-mortem findings in lungs infected with SARS-CoV-2.

Italy was the first European nation to be massively infected by SARS-CoV-2. Up to the end of May 2020, more than 33,000 deaths had been recorded in Italy, with a large prevalence among males, those over 75 years of age, and in association with co-morbidities. We describe the lung pathological and immunohistochemical post-mortem findings at the autopsy of nine patients who died of SARS-CoV-2-associated disease. We found in the lung tissues of all patients histological changes consistent with diffuse alveolar damage in various evolution phases ranging from acute exudative to acute proliferative to fibrotic phase. Alveolar damage was associated with prominent involvement of the vascular component in both the interstitial capillaries and the mid-size vessels, with capillary fibrin micro-thrombi, as well as organized thrombi even in medium-sized arteries, in most cases not related to sources of embolism. Eosinophilic infiltrate was also seen, probably reactive to pharmacological treatment. Viral RNA of SARS-CoV-2 was detected from the lung tissues of all the nine patients. Immunohistochemistry for the receptor of the SARS-CoV-2, ACE2, and its priming activator TMPRSS2 revealed that both proteins co-localize in airway cells. In particular, the ACE2 protein was expressed in both endothelial cells and alveolar type I and II pneumocytes in the areas of histological diffuse alveolar damage (DAD). Pneumocytes, but not endothelial cells, also expressed TMPRSS2. There are no distinctive histological features of SARS-CoV-2 infection with respect to SARS-CoV-1 and other DAD with different aetiology. The identification of the cause of death in the course of SARS-CoV-2 infection is more likely multi-factorial. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.