Heterogeneous immunological recovery trajectories revealed in post-acute COVID-19

The immunological picture of how different patients recover from COVID-19, and how those recovery trajectories are influenced by infection severity, remain unclear. We investigated 140 COVID-19 patients from diagnosis to convalescence using clinical data, viral load assessments, and multi-omic analyses of blood plasma and circulating immune cells. Immune-phenotype dynamics resolved four recovery trajectories. One trajectory signals a return to pre-infection healthy baseline, while the other three are characterized by differing fractions of persistent cytotoxic and proliferative T cells, distinct B cell maturation processes, and memory-like innate immunity. We resolve a small panel of plasma proteins that, when measured at diagnosis, can predict patient survival and recovery-trajectory commitment. Our study offers novel insights into post-acute immunological outcomes of COVID-19 that likely influence long-term adverse sequelae.

Determinants of immunological recovery following HAART among severely immunosuppressed patients at enrolment to care in Northern Ethiopia: a retrospective study

ObjectiveThis study aimed to identify determinants of immunological recovery following highly active antiretroviral therapy (HAART) among severely immunosuppressed patients at enrolment to care in Northern Ethiopia.MethodsA retrospective study.SettingThe study was done in Tigray Region, Northern Ethiopia.ParticipantsThe study was done among severely immunosuppressed (<200 CD4 cells/mm3) individuals at initial enrolment to care and whose samples were sent for viral load determination from April 2015 to March 2019 in Tigray Health Research Institute.Main outcomesThe main outcome variable was immunological recovery, modelled using binary logistic regression.ResultsAmong the 9687 patients with severe immunosuppression at enrolment, 2746 (28.35%, 95% CI 27.45% to 29.26%) had immunological recovery following HAART for at least 6 months. Male gender (adjusted OR (AOR)=0.50, p<0.001), age 20–34 years old (AOR=0.33, p<0.001), age ≥50 years old (AOR=0.26, p<0.001), WHO clinical stage III (OR=0.68, p=0.036) and viral non-suppression (AOR=0.38, p<0.001) were strong predictors of immunological failure.ConclusionsImmunological recovery following HAART was low among severely immunosuppressed individuals at enrolment to care. Gender, age, WHO stage III and viral non-suppression were determinants of immunological recovery. Male patients, adolescents and virally non-suppressed patients should be identified as groups at higher risk for immunological failure. Therefore, greater support and intensive counselling should be prioritised among adolescents, men and virally non-suppressed patients for better immunological recovery.

Enhanced Immunological Recovery With Early Start of Antiretroviral Therapy During Acute or Early HIV Infection–Results of Italian Network of ACuTe HIV InfectiON (INACTION) Retrospective Study

Background: Viral load peak and immune activation occur shortly after exposure during acute or early HIV infection (AEHI). We aimed to define the benefit of early start of antiretroviral treatment (ART) during AEHI in terms of immunological recovery, virological suppression, and treatment discontinuation.Setting: Patients diagnosed with AEHI (Fiebig stages I-V) during 2008-2014 from an analysis of 20 Italian centers.Methods: This was an observational, retrospective, and multicenter study. We investigated the effect of early ART (defined as initiation within 3 months from AEHI diagnosis) on time to virological suppression, optimal immunological recovery (defined as CD4 count ≥ 500/µL, CD4 ≥ 30%, and CD4/CD8 ≥ 1), and first-line ART regimen discontinuation by Cox regression analysis. Results: There were 321 patients with AEHI included in the study (82.9% in Fiebig stage III-V). At diagnosis, the median viral load was 5.67 log10copies/mL and the median CD4 count was 456 cells/µL. Overall, 70.6% of patients started early ART (median time from HIV diagnosis to ART initiation 12 days, IQR 6-27). Higher baseline viral load and AEHI diagnosis during 2012-2014 were independently associated with early ART. HBV co-infection, baseline CD4/CD8 ≥ 1, lower baseline HIV-RNA, and AEHI diagnosis in recent years (2012-2014) were independently associated with a shorter time to virological suppression. Early ART emerged as an independent predictor of optimal immunological recovery after adjustment for baseline CD4 (absolute and percentage count) and CD4/CD8 ratio. The only independent predictor of first-line ART discontinuation was an initial ART regimen including > 3 drugs.Conclusions: In a large cohort of well-characterized patients with AEHI, we confirmed the beneficial role of early ART on CD4+ T-cell recovery and on rates of CD4/CD8 ratio normalization. Moreover, we recognized baseline CD4/CD8 ratio as an independent factor influencing time to virological response in the setting of AEHI, thus giving new insights into research of immunological markers associated with virological control.

Long Term Responses to Venetoclax and Ibrutinib in Mantle Cell Lymphoma Are Associated with Immunological Recovery and Prognostic Changes in Inflammatory Biomarkers

Combination Ibrutinib (IB) plus Venetoclax (Ven) for the treatment of Mantle Cell Lymphoma (MCL) has demonstrated efficacy in the relapsed/refractory setting. The AIM trial treated 24 patients with IB monotherapy for 4 weeks (560mg/day) with Ven added (stepwise to 400mg/day) thereafter resulting in an overall response rate of 71% at 16 weeks (Tam et al, NEJM 2018). 5 patients discontinued treatment within 6 months due to resistant disease and 3 patients relapsed. 16 patients remained on treatment for more than 1 year. In this study we examined the longitudinal changes in peripheral blood (PB) immunology in patients treated in the AIM trial in order to identify immunological and inflammatory biomarkers associated with response and to examine if stable control of MCL without further chemotherapy exposure was associated with immunological recovery. Multiparameter flow cytometry of cryopreserved PBMCs collected at enrolment (baseline), and weeks 4, 16, 56 and 110 of treatment was used to assess the proportions of immune subsets (CD4 and CD8 memory subsets, γδ T cells and CD16+ NK cells) in AIM patients and compared to 13 age matched healthy donor (HD) samples. At baseline samples from MCL patients exhibited alterations in multiple immune subsets - most notably skewing in CD8+ memory subsets (Figure 1). Despite reduction of circulating B cell numbers consistent with clinical responses, there were no significant changes to PB immune subset distributions between baseline and 16 weeks. However at the later time points of 56 and 110 weeks there was evidence in responding patients of PB immunology normalisation to HD levels in T cell subsets including a shift in CD8 T cells from Naïve and Central Memory (CM) to Effector Memory (EM) and Terminally differentiated EM (TEMRA) phenotype and a shift in CD4 T cells from Naïve and CM to EM phenotype (Figure 2). Increased proportions of γδ T cells (Baseline 2.8 ± 3.0% week 56 4.4 ± 3.4% P<0.05) and CD16+ NK cells (Baseline 40.1 ± 28.0% week 56 79.1 ± 21.0% P<0.01) were also observed. T cell function assessed by intracellular IFNγ, TNFα and IL-2 in CD4 and CD8 T cells in response to T cell stimulation beads showed no change in IFNγ or TNFα production by CD4 or CD8 cells following therapy. In patients with elevated IL2+ CD4 and CD8 populations at early time points, these normalised by week 56 to HD levels. To further examine changes in immune function pathways, targeted multiplex gene expression profiling using 770 gene NanoString nCounter® PanCancer Immune Profiling Panel was performed on PBMCs at baseline and weeks 4, 16 and 56 and analyzed using nSolver advanced analysis module. Consistent with the flow cytometric findings there were minimal changes in gene expression at week 16 compared to baseline. The greatest changes were observed at week 56 with alterations in multiple pathways including increased signalling through complement, adhesion, TNF superfamily and transporter pathways in responding patients. The top upregulated genes at week 56 were CTSS (Cathepsin S), FCER1G (Fc fragment of IgE), S100A8 (S100 calcium binding protein A8) and CD14 while the top downregulated gene was CD22 (reflecting the change in B cell burden). Increased expression of C1QA and C1QB at week 16 was significantly associated with disease non-response or relapse on IB + Ven and warrants further investigation in an independent cohort to assess its applicability as a predicative biomarker for patient response. Our findings show that long term treatment with combination IB and Ven in MCL is associated with immune recovery and changes in the expression of inflammatory biomarkers. This study demonstrates that while short term assessments can be used to examine clinical disease responses, long term assessments are required to determine the immunological consequences of small molecule inhibitors. Restoration of immune system function in these patients may allow responses to subsequent immunotherapies and suggests that, in contrast to conventional chemotherapy-based regimens, this combination targeted therapy may result in beneficial impacts on immunological recovery. Disclosures Handunnetti: Gilead: Honoraria. Anderson:Walter and Eliza Hall Institute: Employment, Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.. Roberts:AbbVie: Other: Unremunerated speaker for AbbVie, Research Funding; BeiGene: Research Funding; Janssen: Research Funding; Walter and Eliza Hall Institute: Patents & Royalties: Institute receives royalties for venetoclax, and I receive a fraction of these.; Australasian Leukaemia and Lymphoma Group: Membership on an entity's Board of Directors or advisory committees. Seymour:AbbVie: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Acerta: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Takeda: Consultancy. Tam:Janssen: Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie company: Honoraria; Roche: Honoraria; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria; Novartis: Honoraria. Ritchie:Sanofi: Honoraria; Novartis: Honoraria; Imago: Research Funding; Beigene: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding. Koldej:NanoString Technologies: Other: Travel grant.