The persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses in patients on immunosuppressive therapy compared to healthy controls—a prospective cohort study

The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline.publishedVersio

Ejection Time-Corrected Systolic Velocity Improves Accuracy in the Evaluation of Myocardial Dysfunction: A Study in Piglets

This study aimed to assess the effect of correcting for the impact of heart rate (HR) or ejection time (ET) on myocardial velocities in the long axis in piglets undergoing hypoxia. The ability to eject a higher volume at a fixed ET is a characteristic of contractility in the heart. Systolic velocity of the atrioventricular annulus displacement is directly related to volume changes of the ventricle. Both ET and systolic velocity may be measured in a single heartbeat. In 29 neonatal pigs, systolic velocity and ET were measured with tissue Doppler techniques in the mitral valve annulus, the tricuspid valve annulus, and the septum. All ejection time corrected velocities (S(ET), mean ± SEM, cm/s) decreased significantly during hypoxia (Smva(ET) 15.5 ± 0.2 to 13.2 ± 0.3 (p < 0.001), Sseptal(ET) 9.9 ± 0.1 to 7.8 ± 0.2 (p < 0.001), Stva(ET) 12.1 ± 0.2 to 9.8 ± 0.3 (p < 0.001)). The magnitude of change from baseline to hypoxia was greater for ejection time corrected systolic velocities than for RR-interval corrected velocities (mean ± SEM, cm/s); ΔSmva(ET) 2.3 ± 2.0 vs. ΔSmva(RR) 1.6 ± 1.1 (p = 0.02), ΔSseptal(ET) 2.1 ± 1.0 vs. ΔSseptal(RR) 1.6 ± 1.0 (p < 0.01), ΔStva(ET) 2.3 ± 1.1 vs. ΔStva(RR) 1.8 ± 1.3 (p = 0.04). The receiver operator characteristic (ROC) showed superior performance of S(ET) compared with uncorrected velocities. The decrease in S(ET) during hypoxia was not influenced by important hemodynamic determinants. ET-corrected systolic velocity improves accuracy and decreases variability in the evaluation of systolic longitudinal function and contractility during global hypoxia in neonatal pigs compared with systolic velocity alone. It is robust toward hemodynamic changes. This novel method has the potential of becoming a useful tool in clinical practice

Usage of Antivirals and the Occurrence of Antiviral Resistance in Norway 2021. RAVN

The usage of antivirals According to The Norwegian Drug Wholesales Statistics Database, the sales of antiviral drugs measured in defined daily doses (DDDs) were reduced in 2021, after several years of increase. This reduction was primarily due to a small decrease in sales of antivirals against HIV, which make up a large proportion of the antiviral drugs sold in Norway. There was no decrease in the number of people being treated with HIV drugs compared to previous years, but as a growing proportion of patients is treated with single tablet regimens, the number of drugs sold is reduced. When looking at the number of persons treated with antiviral drugs, the antiviral treatment received by the highest number of patients are drugs used against herpes viruses. In 2021, the sale of antivirals against herpes virus, especially valaciclovir, increased even further. There was a decrease in the sales of agents against hepatitis C and influenza, while treatments for hepatitis B were unchanged. Influenza virus Similar to the previous influenza season, the season of 2021/2022 was also unusual, mainly due to the infection control measures implemented in response to the pandemic. There was a very low incidence of influenza at the beginning of the season, followed by a short period with significant spread of infection during the spring of 2021. No drug resistance against neuraminidase inhibitors was detected, but a mutation conferring resistance to the new drug baloxavir marboxil was found in one sample. Human immunodeficiency virus-1 The decreasing trend in the number of new HIV-infections has continued in 2021, which is also reflected in a reduction in the number of samples received for surveillance of primary drug resistance. A total of 64 samples were analysed as part of the surveillance in 2021, and only 13 of these were from patients infected in Norway. For the first time, we have been able to classify cases according to site of residence at the time of infection. Among those living in Norway at the time of infection, as much as 88% of the cases reported to MSIS were also reported to RAVN. This indicates that national routines for follow-up of newly diagnosed patients with regard to antiviral resistance are good. Resistance mutations were detected in 11% of the examined samples, which is comparable to previous years. In 2021, only mutations affecting reverse transcriptase inhibitors and none affecting protease inhibitors were found. Hepatitis B virus In 2021, a total of 134 samples with hepatitis B virus (HBV) were analysed for resistance mutations. Most of these samples (n=117) had been submitted to the reference laboratory for genotyping prior to treatment. These samples constitute the Norwegian surveillance of primary resistance. The remaining 17 samples were from patients with ongoing antiviral treatment and were submitted for investigation of resistance as a possible cause of treatment failure. Relevant resistance mutations were found in five of the 17 samples from patients with treatment failure. No resistance mutations were found in any of the surveillance samples. Human herpes viruses: Cytomegalovirus In 2021, 19 samples were submitted for resistance testing at the reference laboratory for cytomegalovirus (CMV). Relevant resistance mutations were detected in five of these samples. Low or moderate resistance to ganciclovir was found in four of these samples, while moderate resistance to the new drug maribavir was found in one sample. There is no systematic surveillance of resistance in CMV, and the true incidence of drug resistance cannot be determined. Human herpes viruses: Herpes simplex virus In 2021, only five samples with herpes simplex virus (HSV) were analysed for resistance. Two of the samples had mutations conferring resistance to aciclovir. Despite an increase in the use of aciclovir both as treatment and prophylaxis, samples are rarely submitted for resistance testing. Like CMV, there is no systematic surveillance of HSV drug resistance. Hepatitis C virus A systematic surveillance system for newly diagnosed HCV infections was launched in May 2022. In 2021, resistance testing was performed on a limited number of samples submitted for resistance testing. Drug resistance data is cross-referenced with epidemiological data from MSIS to enable comparisons of different subgroups. Resistance associated substitutions were detected in seven out of eight samples analysed for resistance, two of which were from treatment experienced patients, one sample was from a patient with no previous treatment exposure and the remaining four were from patients where treatment exposure was not known. SARS-CoV-2 Surveillance of antiviral resistance in SARS-CoV-2 has not been collected to RAVN in 2021. Oral drugs for the treatment of COVID-19 will be available in Norway from the autumn of 2022, and a system for surveillance of antiviral resistance will probably be implemented from the beginning of 2023. This surveillance will be based on the same sequence data that is part of the national monitoring of variants

Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study

Background In rituximab-treated patients with rheumatoid arthritis, humoral and cellular immune responses after two or three doses of SARS-CoV-2 vaccines are not well characterised. We aimed to address this knowledge gap. Methods This prospective, cohort study (Nor-vaC) was done at two hospitals in Norway. For this sub-study, we enrolled patients with rheumatoid arthritis on rituximab treatment and healthy controls who received SARS-CoV-2 vaccines according to the Norwegian national vaccination programme. Patients with insufficient serological responses to two doses (antibody to the receptor-binding domain [RBD] of the SARS-CoV-2 spike protein concentration <100 arbitrary units [AU]/mL) were allotted a third vaccine dose. Antibodies to the RBD of the SARS-CoV-2 spike protein were measured in serum 2–4 weeks after the second and third doses. Vaccine-elicited T-cell responses were assessed in vitro using blood samples taken before and 7–10 days after the second dose and 3 weeks after the third dose from a subset of patients by stimulating cryopreserved peripheral blood mononuclear cells with spike protein peptides. The main outcomes were the proportions of participants with serological responses (anti-RBD antibody concentrations of ≥70 AU/mL) and T-cell responses to spike peptides following two and three doses of SARS-CoV-2 vaccines. The study is registered at ClinicalTrials.gov, NCT04798625, and is ongoing. Findings Between Feb 9, 2021, and May 27, 2021, 90 patients were enrolled, 87 of whom donated serum and were included in our analyses (69 [79·3%] women and 18 [20·7%] men). 1114 healthy controls were included (854 [76·7%] women and 260 [23·3%] men). 49 patients were allotted a third vaccine dose. 19 (21·8%) of 87 patients, compared with 1096 (98·4%) of 1114 healthy controls, had a serological response after two doses (p<0·0001). Time since last rituximab infusion (median 267 days [IQR 222–324] in responders vs 107 days [80–152] in non-responders) and vaccine type (mRNA-1273 vs BNT162b2) were significantly associated with serological response (adjusting for age and sex). After two doses, 10 (53%) of 19 patients had CD4+ T-cell responses and 14 (74%) had CD8+ T-cell responses. A third vaccine dose induced serological responses in eight (16·3%) of 49 patients, but induced CD4+ and CD8+ T-cell responses in all patients assessed (n=12), including responses to the SARS-CoV-2 delta variant (B.1.617.2). Adverse events were reported in 32 (48%) of 67 patients and in 191 (78%) of 244 healthy controls after two doses, with the frequency not increasing after the third dose. There were no serious adverse events or deaths. Interpretation This study provides important insight into the divergent humoral and cellular responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis. A third vaccine dose given 6–9 months after a rituximab infusion might not induce a serological response, but could be considered to boost the cellular immune response

Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency

Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With written parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in IL2RG, RAG2, and RMRP were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the IL2RG-SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky RAG2-SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with RMRP-SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in DCLRE1C, JAK3, NBN, and IL2RG were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal cytomegalovirus (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID