Higher plasma levels of thymosin-α1 are associated with a lower waning of humoral response after COVID-19 vaccination: an eight months follow-up study in a nursing home.

BACKGROUND: Older people achieve lower levels of antibody titers than younger populations after Covid-19 vaccination and show a marked waning humoral immunity over time, likely due to the senescence of the immune system. Nevertheless, age-related predictive factors of the waning humoral immune response to the vaccine have been scarcely explored. In a cohort of residents and healthcare workers from a nursing home that had received two doses of the BNT162b2 vaccine, we measured specific anti-S antibodies one (T1), four (T4), and eight (T8) months after receiving the second dose. Thymic-related functional markers, including thymic output, relative telomere length, and plasma thymosin-α1 levels, as well as immune cellular subsets, and biochemical and inflammatory biomarkers, were determined at T1, and tested for their associations with the magnitude of the vaccine response (T1) and the durability of such response both, at the short- (T1-T4) and the long-term (T1-T8). We aimed to identify age-related factors potentially associated with the magnitude and persistence of specific anti-S immunoglobulin G (IgG)-antibodies after COVID-19 vaccination in older people. RESULTS: Participants (100% men, n = 98), were subdivided into three groups: young (< 50 years-old), middle-age (50-65 years-old), and older (≥65 years-old). Older participants achieved lower antibody titers at T1 and experienced higher decreases in both the short- and long-term. In the entire cohort, while the magnitude of the initial response was mainly associated with the levels of homocysteine [ß (95% CI); - 0.155 (- 0.241 to - 0.068); p = 0.001], the durability of such response at both, the short-term and the long-term were predicted by the levels of thymosin-α1 [- 0.168 (- 0.305 to - 0.031); p = 0.017, and - 0.123 (- 0.212 to - 0.034); p = 0.008, respectively]. CONCLUSIONS: Higher plasma levels of thymosin-α1 were associated with a lower waning of anti-S IgG antibodies along the time. Our results suggest that plasma levels of thymosin-α1 could be used as a biomarker for predicting the durability of the responses after COVID-19 vaccination, possibly allowing to personalize the administration of vaccine boosters.

The persistence of low CD4/CD8 ratio in chronic HIV-infection, despite ART suppression and normal CD4 levels, is associated with pre-therapy values of inflammation and thymic function.

BACKGROUND: Persistence of a low CD4/CD8 ratio is associated with an increased morbimortality in people living with HIV (PLWH) under effective antiretroviral therapy. We aimed to explore the immunological significance of a persistently low CD4/CD8 ratio, even despite normal CD4 levels, and assess whether these features vary from those associated to a low nadir-CD4, another well-established predictor of disease progression. METHODS: CD4-recovered PLWH were classified by CD4/CD8 ratio after three-years of ART (viral suppression, CD4≥500; R < 0.8, n = 24 and R > 1.2, n = 28). sj/ß-TRECs ratio and inflammatory-related markers were quantified. PBMCs were immunophenotyped by CyTOF and functionally characterized by ELISPOT. Subjects were also reclassified depending on nadir-CD4 (N ≤ 350/N > 350). RESULTS: R < 0.8 showed a differential inflammatory profile compared to R > 1.2 (increased ß2-microglobulin, D-dimers and IP-10 before ART). R < 0.8 presented lower baseline thymic function, being inversely correlated with post-ART inflammation. R < 0.8 at follow-up showed most alterations in CD8 subsets (increasing frequency and exhibiting a senescent phenotype [e.g., CD57+, CD95+]) and enhanced T-cell IFNγ/IL-2 secretion. However, comparing N ≤ 350 to N > 350, the main features were altered functional markers in CD4 T-cells, despite no differences in maturational subsets, together with a restricted T-cell cytokine secretion pattern. CONCLUSION: Persistence of low CD4/CD8 ratio in successfully-treated PLWH, with normal CD4 counts, is associated with baseline inflammation and low thymic function, and it features post-therapy alterations specific to CD8 T-cells. Differently, subjects recovered from low nadir-CD4 in this setting feature post-therapy alterations on CD4 T-cells. Hence, different mechanisms of disease progression could underlie these biomarkers, potentially requiring different clinical approaches.

Dysregulation of iron metabolism modulators in virologically suppressed HIV-infected patients.

Background: Iron metabolism plays an essential role in cellular functions. Since virologically suppressed chronic HIV-infected subjects under effective antiretroviral treatment (ART) exhibit a persistent immune dysfunction that leads to comorbidities, iron homeostasis may be relevant in this context. We aimed to explore iron metabolism in virologically suppressed chronic HIV infected subjects under a successful ART. Methods: In this retrospective study, traditional iron metabolism biomarkers (total iron, ferritin, transferrin, and transferrin saturation index), as well as soluble transferrin receptor (sTfR), hepcidin, and inflammatory markers were determined in virologically suppressed chronic HIV-infected subjects under at least 2 years of ART (HIV) who also had >350 CD4-T-cells/mm3 (N=92) from Spain. As controls, we collected non-HIV age-matched healthy donors (Young, N=25) and elderly subjects (>65 years old; Elderly; N=25). Additionally, an external group of non-HIV patients with ferritin<50 ng/mL diagnosed with absolute iron deficiency (Ferropenic group; N=84) was included. Comparisons between groups were performed using Kruskal-Wallis or Mann-Whitney U-tests, while associations between variables were explored by Spearman's rho correlation coefficient. Results: We selected samples from HIV-infected subjects (aged 42[34-47], 95% males), young age-matched (aged 40[30-58], 60% males), and elderly controls (aged 82[78-88], 100% males). Compared to both healthy (Young and Elderly) groups, HIV exhibited decreased iron, transferrin saturation, and sTfR, and increased ferritin, but similar hepcidin levels. Notably, associations between sTfR and iron (Young, r=-0.587, p=0.002; Elderly, r=-0.496, p=0.012) or transferrin saturation index (Young, r=-0.581, p=0.002; Elderly, r=-0.489, p=0.013) were negative in both controls while positive in HIV (r=0.464, p<0.0001 and r=0.421, p<0.0001, respectively). Moreover, the expected negative correlation between hepcidin and sTfR, observed in controls (Young, r=-0.533, p=0.006; Elderly, r=-0.473, p=0.017), was absent in HIV (r=0.082; p=0.438). Interestingly, the HIV inflammatory profile differed from the Elderly one, who despite their inflammaging-related profile, succeed in maintaining these associations. Furthermore, subjects from the ferropenic group (aged 42[32-51], 5% males), showing significantly lower levels of hepcidin and higher sTfR, as expected, reflected similar correlations as those Young and Elderly, in contrast to HIV. Conclusions: Virologically suppressed chronic HIV-infected patients under successful ART exhibit altered levels of iron metabolism modulators suggesting a complex functional iron deficiency.

CD4(+)CD25(+/hi)CD127(lo) phenotype does not accurately identify regulatory T cells in all populations of HIV-infected persons.

The most commonly used regulatory T cell (Treg) phenotypes, CD4(+)CD25(hi)CD127(lo) and CD4(+)CD25(hi)FoxP3(+), were simultaneously used to determine the Treg frequency in 2 different groups of human immunodeficiency virus (HIV)-infected persons, one viremic and other aviremic. As expected, a strong correlation between both Treg phenotypes was observed in the aviremic group (r = 0.913; P < .001), but surprisingly, this correlation was completely absent in the viremic group (r = 0.143; P = .572). Data on T cell activation levels of both HIV groups suggest that the CD4(+)CD25(hi)CD127(lo) phenotype could just be mirroring the elevated numbers of activated non-regulatory T cells in the viremic HIV group.

Increased regulatory T cell counts in HIV-infected nonresponders to hepatitis B virus vaccine.

Hepatitis B virus (HBV) coinfection is a main cause of liver-related mortality in human immunodeficiency virus (HIV)-infected subjects. Unfortunately, HIV-infected subjects show a low rate of response to standard HBV vaccination (23%-56%), in contrast to rates >90% found in the general population, and the underlying causes (particularly cellular and molecular causes) are still unknown. We hypothesized that an increased frequency of regulatory T (T(reg)) cells could be involved in the low rate of seroconversion in HIV-infected subjects. Forty HIV-infected subjects were enrolled in the Assistance Vaccination Program against HBV of the Infectious Diseases Service from the Virgen del Rocío University Hospital, Seville, Spain. Freshly isolated peripheral blood mononuclear cells from baseline were immunophenotyped for T(reg) cells, CD4, and CD8 T cells in both naive and memory subpopulations and activation degree, as well as recent thymic emigrants. Baseline T(reg) cell frequency was found independently associated with the final nonresponse to HBV vaccine in HIV-infected subjects. Furthermore, a negative correlation between baseline frequency of T(reg) cells and antibody titers in the final response was found. These findings suggest an active role played by T(reg) cells on the immunization antigen-specific T and/or B cell responses with the final consequence of a B cell anti-HBs lower production.

Mejoría de la función cardio-respiratoria en paciente con circulación de fontán tras la intervención quirúrgica de su escoliosis / Improvement of the cardio-respiratory function in fontan patients after surgery of scoliosis

La escoliosis puede tener un impacto negativo sobre la función cardio-respiratoria en pacientes con cirugía de Fontán. Cuando las consecuencias de la progresión de la deformidad sobre la calidad de vida y la supervivencia potencial a largo plazo del paciente superan los riesgos de la intervención se aconseja el tratamiento quirúrgico de la curva. Desafortunadamente, este grupo de pacientes presenta un elevado riesgo anestésico y un difícil manejo durante el procedimiento quirúrgico, debido a la necesidad de mantener una presión venosa central elevada que garantice un adecuado flujo pulmonar, circunstancia que dificulta la consecución de una hipotensión controlada, habitual en estos procedimientos para el control del sangrado. Presentamos el caso de una paciente de 13 años con enfermedad congénita cardiaca (ECC) y fisiología de Fontán sometida a corrección quirúrgica de su escoliosis tóraco-lumbar, su manejo y mejora de la función cardiaca tras la cirugía raquídea mediante fusión raquídea posterior

Scoliosis can negatively impact the cardio respiratory function in patients with Fontan anatomy. Surgical treatment of the spinal curvature is advised when the consequences of the progression of the deformity on the survival and quality of life at the long term overcome the risks of the intervention. Unfortunately, this group of patients presents a high anesthetic risk and a difficult management during the surgical procedure, because they need to support a high central venous pressure to ensure an adequate pulmonary flow, circumstance which makes difficult to achieve a controlled hypotension, usual in these procedures for control of bleeding. We report here about a 13 years old patient with congenital heart disease (CHD) and Fontan physiology presented for posterior spinal fusion for the treatment of thoracolumbar scoliosis, her management and later progress of her cardiac function after the spinal fusion surgery