Changes in T and B cell subsets in end stage renal disease patients before and after kidney transplantation

BACKGROUND: The incidence of kidney transplantation performed in elderly patients has increased steadily recently. Higher risk of infection and mortality, but lower rate of rejection, are reported in older kidney transplant patients. This study aims to analyze the effect of transplantation on aging of T and B cells in kidney transplant patients, with the emphasis on age and Cytomegalovirus (CMV) latency. RESULTS: We included 36 patients before and after (median 2.7 years) kidney transplantation and 27 age- and sex-matched healthy controls (HC). T and B cell subsets were measured by flow cytometry, with a focus on aged T cells (CD28-), and age associated B cells (ABCs, CD19 + CD21-CD11c+). Three years after transplantation a significant increase of total T cells among the lymphocytes was found compared to pre-transplantation and HC. Among the T cells CD4+ cells were decreased, especially naïve CD4+ cells and regulatory T cells. Total CD8+ cell proportions were increased, and proportions of naïve CD8+ cells were significantly decreased after transplantation, while CD8+ effector memory T cells re-expressing CD45RA were increased. CD28− T cells were significantly higher compared to HC after transplantation, especially in CMV seropositive patients. B cells were significantly decreased, while among B cells memory B cells and especially ABCs were increased after transplantation. CONCLUSIONS: After transplantation T and B cell subsets change towards more terminally differentiated memory cells compared to age-matched HC. Proportions of aged T cells and ABCs were associated with CMV serostatus. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12979-021-00254-9

Prophylactic vaccination with a live-attenuated herpes zoster vaccine in lung transplant candidates

BACKGROUND: Herpes zoster (HZ) is caused by the reactivation of varicella–zoster virus (VZV). Patients with lung transplants are at high risk for HZ owing to their immunocompromised status and the need for lifelong immunosuppression. In this study, patients on the waiting list for lung transplantation were vaccinated by a live-attenuated HZ vaccine (Zostavax, Merck Sharp & Dohme), and the safety and immunogenicity of this vaccine were studied. METHODS: In total, 105 patients with end-stage pulmonary disease (ESPD) were enrolled (68 participants received 1 dose of Zostavax and 37 participants were enrolled as unvaccinated controls). Among them, 43 patients underwent lung transplantation and were followed up for further analysis. VZV immunoglobulin G antibody titers and VZV-specific cell-mediated immunity (CMI) on multiple time points before and after vaccination and before and after transplantation were measured. RESULTS: Immune response to Zostavax was higher in younger patients, highest within 3 months after vaccination, and not influenced by gender or type of ESPD. Age, cytomegalovirus serostatus, and immunity to VZV at baseline impacted the subsequent immune response to the vaccine. Short-term immunosuppressant treatment had strong effects on VZV CMI levels, which returned to a high level at 6 months after transplantation in vaccinated patients. Zostavax did not impact infection or rejection rate after transplantation. CONCLUSIONS: Zostavax was safe and induced a robust humoral and cellular response for patients awaiting lung transplantation regardless of the type of ESPD. Patients younger than the recommended vaccination age of over 50 years showed a strong response and could also benefit from pre-transplant immunization

Ageing of Immune System and Response to a Live-Attenuated Herpes Zoster Vaccine in Lung Transplant Candidates

The mean age of lung transplant recipients has significantly increased in recent decades. Elderly recipients have a higher risk of developing herpes zoster (HZ), and they have in general a worse response to vaccination than younger persons do. We investigated the relationship between the humoral and cellular immune response to a live-attenuated HZ vaccine (Zostavax(R), Merck Sharp and Dohme) and the frequencies of T and B cell subsets, especially aged cell subsets (CD28-T cells and age associated B cells, ABCs). In total, 37 patients awaiting lung transplantation received one dose of Zostavax(R), and peripheral blood was collected before and within 6 months after vaccination. We observed a robust immune response after vaccination. The frequencies of CD28-T cells before vaccination had no impact on the subsequent immune response to HZ vaccination. However, a higher frequency of ABCs before vaccination correlated with a lower immune response especially regarding the cellular immune response. Cytomegalovirus seropositivity was associated with increased frequencies of CD28-T cells but not with frequencies of ABCs in the patients. In conclusion, increased levels of ABCs might disturb the cellular immune response to HZ vaccination, which could lower the efficacy of such vaccination in elderly transplant recipients

Immune response to varicella-zoster virus before and after renal transplantation

Background: Herpes zoster (HZ) risk is high in renal transplant recipients. Vaccination prior to transplantation may provide a useful strategy for the prevention of HZ in the posttranplantation period. However, it is not known whether immunity to varicella-zoster virus (VZV) is affected due to treatment surrounding transplantation. Methods: Both humoral and cellular immunity to VZV were determined prior to and 2-3 years after renal transplantation in 60 adult patients, and 62 matched healthy controls. VZV-specific cellular immunity was measured by an interferon gamma (IFN gamma) enzyme-linked immunospot (ELISpot) assay and by analyzing T-cell functionality using flowcytometry. VZV-IgG levels were measured using an in-house glycoprotein enzyme-linked immunosorbent assay (gpELISA). Results: Using paired analysis, it was determined that numbers of IFN gamma-producing cells did not change after transplantation, but were significantly lower in transplant recipients after transplantation than in controls (p = 0.028). Patients in whom the post-transplant period was complicated by rejection or any acute infection (excluding HZ) had a lower number of IFN gamma-producing cells than patients who did not. VZV IgG levels did not differ from controls, but a significant decrease was observed after transplantation (p <0.0001). Conclusions: VZV-specific cellular immunity, which is essential in the prevention of HZ, did not markedly change in patients following renal transplantation. This suggests that preventive vaccination before transplantation may be beneficial. Our results extend knowledge on VZV immunity after transplantation, vital when considering strategies for the prevention of HZ in these patients

Immunity to varicella-zoster virus in immunocompromised patients

Na een eerste infectie met het varicella-zoster virus (VZV), bekend als varicella of waterpokken, blijft het virus voor de rest van het leven latent aanwezig. Reactivatie veroorzaakt gordelroos (herpes zoster). Personen met een verminderde afweer hebben een verhoogd risico op gordelroos en complicaties daarvan, vergeleken met de algemene bevolking. Het onderzoek dat beschreven wordt in het eerste deel van het proefschrift, richt zich op vergroten van de kennis van de afweer tegen VZV in groepen patiënten met een verminderde afweer. Met deze informatie hopen we te kunnen bijdragen aan betere preventie van gordelroos bij deze patiënten. Meerdere groepen patiënten komen aan bod: patiënten met verschillende auto-immuunziekten, patiënten die langdurig worden behandeld met nierdialyse en transplantatiepatiënten. Bij de meeste van de onderzochte groepen vonden we een verminderde cellulaire afweer tegen VZV, vergeleken met gezonde controlepersonen, terwijl de humorale afweer tegen VZV gelijk was. Bij patiënten die langdurig behandeld worden met nierdialyse bleek een hogere leeftijd en een transplantatie in de voorgeschiedenis geassocieerd met een lagere cellulaire afweer tegen VZV. Opmerkelijk was de vondst van een hogere humorale afweer tegen VZV (antilichamen van de IgG-klasse) bij patiënten met systemische lupus erythematosus (SLE) dan bij controlepersonen. Wij vonden in een longitudinale studie bij patiënten met SLE echter geen aanwijzingen voor (subklinische) reactivaties van VZV die dit fenomeen zouden kunnen verklaren. Het tweede deel van het proefschrift gaat over vaccinatie bij patiënten met een auto-immuun inflammatoire reumatische aandoening. Een overzicht van de literatuur en een voorstel voor richtlijnen worden in dit deel gepresenteerd

COVID or no COVID: Interpreting inconclusive SARS-CoV-2 qPCR results in different populations and platforms

INTRODUCTION: High cycle threshold values (Ct) value) results for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may be true infections or false-positive results. Misinterpretation of results has negative consequences. Goal of this study was to evaluate quantitative real-time polymerase chain reaction (qPCR) results with high Ct-values, to reach a point where a correct interpretation can be given. METHODS: High Ct-value results of SARS-CoV-2 in respiratory samples taken between April 2020 and January 2021 were analysed. Three different SARS-CoV-2 qPCR assays (in-house, Alinity M and Xpert Xpress) were used for screening patients and healthcare workers (HCW). High Ct-value results were defined as "inconclusive". The Ct-value cut-off for the interpretation of the test as "positive" and "inconclusive" were based on quality assurance panel results and manufacturers' instructions. RESULTS: Out of totally 50.295 samples tested for SARS-CoV-2, the in-house and Alinity M qPCR together yielded 379 inconclusive results. A second sample existed for 217 samples, allowing dynamics of the PCR in time. Of these, 187 were negative (86%), 11 again inconclusive (5%) and 19 positive (9%). Sixteen out of 19 persons with a positive result were HCW, 14 (74%) had a link to a SARS-CoV-2 infected person. The majority of inconclusive results detected with the Xpert Xpress (n=45 of 3603), were related to individuals with a known history of SARS-CoV-2 infection (n=28, 62%). CONCLUSION: This study shows the importance of re-testing inconclusive SARS-CoV-2 qPCR results. Only then, the correct (true or false) interpretation can be given, leading to the right measures

Increased incidence of herpes zoster in patients on renal replacement therapy cannot be explained by intrinsic defects of cellular or humoral immunity to varicella-zoster virus

BACKGROUND: Patients in need of long-term renal replacement therapy (RRT) are known to be at increased risk of herpes zoster, occurring when the latently present varicella-zoster virus (VZV) reactivates. In this study we investigated immunity to VZV in patients receiving RRT, with the aim of better understanding the mechanism behind the increased risk. METHODS: Patients treated for at least three months with hemodialysis or peritoneal dialysis, and matched healthy controls (HC) were included. Cellular immunity to varicella-zoster virus (VZV) was studied using an interferon-γ (IFNγ) enzyme-linked immunospot (ELISpot) assay, flow-cytometric analysis of cytokine production and a proliferation assay. Humoral immunity was determined by measuring immunoglobulin (Ig)G antibody levels to VZV using an in-house glycoprotein enzyme-linked immunosorbent assay (ELISA). Multiple regression was used to assess variables of influence on measures of cellular and humoral immunity to VZV in patients receiving RRT. RESULTS: Similar numbers of IFNγ spot-forming cells and levels of VZV-IgG were found in 97 patients and 89 HC. Age and transplantation history were negatively associated with cellular immunity (p = 0.001 and p = 0.012, respectively) while treatment modality, gender and urea levels were not. No variables were found to be associated with VZV-IgG levels. CONCLUSIONS: Increased incidence of herpes zoster in patients receiving RRT cannot be explained by intrinsic defects of cellular or humoral immunity to VZV as measured by the methods used in this study, although older age and previous transplantation were associated with decreased cellular immunity to VZV. Herpes zoster susceptibility might be caused by a diminished function of otherwise capable T cells in a uremic environment

Decreased Immunity to Varicella Zoster Virus in Giant Cell Arteritis

Introduction: Herpes zoster, which can have a major impact on quality of life, results from reactivation of a latent varicella zoster virus (VZV) infection. We hypothesized that giant cell arteritis (GCA) patients are at increased risk of herpes zoster because of treatment with high-dose glucocorticoids and advanced age. Aim of the study, therefore, was to determine cell-mediated and humoral immunity to VZV in patients with GCA, patients with closely related disease polymyalgia rheumatica (PMR; treated with lower doses of glucocorticoids) and healthy controls (HCs). Methods: Cell-mediated immunity to VZV was determined by performing interferon-gamma (IFN gamma) enzyme-linked immunospot and intracellular cytokine flow cytometry measurements in 11 GCA and 15 PMR patients and in 26 age/sex-matched HCs. Immunoglobulin G antibodies to VZV glycoprotein (VZV-IgG) were measured in serum samples of 35 GCA and 26 PMR patients at different times of follow-up and in 58 age and sex-matched HCs by an enzyme-linked immunosorbent assay. Results: The number of VZV-specific IFN gamma spot-forming cells was significantly lower in GCA patients on treatment, than in age-matched HCs (p = 0.029), but was not different in PMR patients on treatment. Similar levels of VZV-IgG were found in GCA and PMR patients at baseline, compared to HCs. Conclusion: The finding of a decreased cell-mediated immunity to VZV, known to be of great importance in defense to the virus, indicates an increased herpes zoster risk in GCA patients compared to an already at-risk elderly population. Herpes zoster vaccination is, therefore, of special importance in GCA patients, and would ideally be administered at time of diagnosis. Interestingly, as VZV was suggested to be the trigger in GCA pathogenesis, similar levels of VZV-IgG were found in GCA patients at time of diagnosis and age-matched HCs, indicating that GCA patients did not experience herpes zoster substantially more often in the months preceding diagnosis than controls