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

Cellular immunity against cytomegalovirus and risk of infection after kidney transplantation

IntroductionCytomegalovirus (CMV) infection remains a challenge following kidney transplantation (KTx). Currently, CMV-IgG serostatus at transplantation is used to individualize CMV preventive strategies. We assessed the clinical utility of CMV-IGRA for predicting CMV infection following KTx.MethodsWe performed a nationwide prospective cohort study from August 2016 until December 2022. Data from all adult KTx recipients in Norway, n=1,546 (R+; n=1,157, D+/R-; n=260, D-/R-; 129), were included with a total of 3,556 CMV-IGRA analyses (1,375 at KTx, 1,188 at eight weeks, 993 one-year after KTx) and 35,782 CMV DNAemia analyses.ResultsIn R+ recipients CMV-IGRA status, measured at any of the time-points, could not identify any differential risk of later CMV infection. D+/R- recipients remaining CMV-IGRA negative 1-year after transplantation (regardless of positive CMV DNAemia and/or CMV IgG status at that time) had increased risk of developing later CMV infection compared to D+/R- recipients who had become CMV-IGRA positive (14% vs. 2%, p=0.01).ConclusionKnowledge of pre-transplant CMV-IGRA status did not provide additional information to CMV-IgG serostatus that could improve current post-transplant CMV treatment algorithms. However, D+/R- recipients with a persisting negative CMV-IGRA one-year after transplantation remained at increased risk of experiencing later CMV infection. Therefore we advocate post-transplant CMV-IGRA monitoring in these patients

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

Early fulminant BK polyomavirus-associated nephropathy in two kidney transplant patients with low neutralizing antibody titers receiving allografts from the same donor

Background - BK Polyomavirus (BKPyV) causes premature graft failure in 1 to 15% of kidney transplant (KT) recipients. High-level BKPyV-viruria and BKPyV-DNAemia precede polyomavirus-associated nephropathy (PyVAN), and guide clinical management decisions. In most cases, BKPyV appears to come from the donor kidney, but data from biopsy-proven PyVAN cases are lacking. Here, we report the early fulminant course of biopsy-proven PyVAN in two male KT recipients in their sixties, receiving kidneys from the same deceased male donor. Case presentations - Both recipients received intravenous basiliximab induction, and maintenance therapy consisting of tacrolimus (trough levels 3–7 ng/mL from time of engraftment), mycophenolate mofetil 750 mg bid, and prednisolone. At 4 weeks post-transplant, renal function was satisfactory with serum creatinine concentrations of 106 and 72 μmol/L in recipient #1 and recipient #2, respectively. Plasma BKPyV-DNAemia was first investigated at 5 and 8 weeks post-transplant being 8.58 × 104 and 1.12 × 106 copies/mL in recipient #1 and recipient #2, respectively. Renal function declined and biopsy-proven PyVAN was diagnosed in both recipients at 12 weeks post-transplant. Mycophenolate mofetil levels were reduced from 750 mg to 250 mg bid while tacrolimus levels were kept below 5 ng/mL. Recipient #2 cleared BKPyV-DNAemia at 5.5 months post-transplant, while recipient #1 had persistent BKPyV-DNAemia of 1.07 × 105 copies/mL at the last follow-up 52 weeks post-transplant. DNA sequencing of viral DNA from early plasma samples revealed apparently identical viruses in both recipients, belonging to genotype Ib-2 with archetype non-coding control region. Retrospective serological work-up, demonstrated that the donor had high BKPyV-IgG-virus-like particle ELISA activity and a high BKPyV-genotype I neutralizing antibody titer, whereas both KT recipients only had low neutralizing antibody titers pre-transplantation. By 20 weeks post-transplant, the neutralizing antibody titer had increased by > 1000-fold in both recipients, but only recipient #2 cleared BKPyV-DNAemia. Conclusions - Low titers of genotype-specific neutralizing antibodies in recipients pre-transplant, may identify patients at high risk for early fulminant donor-derived BKPyV-DNAemia and PyVAN, but development of high neutralizing antibody titers may not be sufficient for clearance

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

Immunogenicity and safety of a three-dose SARS-CoV-2 vaccination strategy in patients with immune-mediated inflammatory diseases on immunosuppressive therapy

Objectives Humoral vaccine responses to SARS-CoV-2 vaccines are impaired and short lasting in patients with immune-mediated inflammatory diseases (IMID) following two vaccine doses. To protect these vulnerable patients against severe COVID-19 disease, a three-dose primary vaccination strategy has been implemented in many countries. The aim of this study was to evaluate humoral response and safety of primary vaccination with three doses in patients with IMID.Methods Patients with IMID on immunosuppressive therapy and healthy controls receiving three-dose and two-dose primary SARS-CoV-2 vaccination, respectively, were included in this prospective observational cohort study. Anti-Spike antibodies were assessed 2–4 weeks, and 12 weeks following each dose. The main outcome was anti-Spike antibody levels 2–4 weeks following three doses in patients with IMID and two doses in controls. Additional outcomes were the antibody decline rate and adverse events.Results 1100 patients and 303 controls were included. Following three-dose vaccination, patients achieved median (IQR) antibody levels of 5720 BAU/mL (2138–8732) compared with 4495 (1591–6639) in controls receiving two doses, p=0.27. Anti-Spike antibody levels increased with median 1932 BAU/mL (IQR 150–4978) after the third dose. The interval between the vaccine doses and vaccination with mRNA-1273 or a combination of vaccines were associated with antibody levels following the third dose. Antibody levels had a slower decline-rate following the third than the second vaccine dose, p&lt;0.001. Adverse events were reported by 464 (47%) patients and by 196 (78%) controls. Disease flares were reported by 70 (7%) patients.Conclusions This study shows that additional vaccine doses to patients with IMID contribute to strong and sustained immune-responses comparable to healthy persons vaccinated twice, and supports repeated vaccination of patients with IMID.Trial registration number NCT04798625