Immune Reconstitution Research Articles

Late events after anti-CD19 CAR T-cell therapy for relapsed/refractory B-cell non-Hodgkin lymphoma.

The short-term complications from chimeric antigen receptor T-cell therapy (CART) are well characterized, but the long-term complications still need to be further investigated. Therefore, herein, we will review the currently available literature published on the late adverse events following CART. We reviewed published data available from pivotal trials and real-world experiences with anti-CD19 CART (CART19) for adults with lymphoma. We defined late events as occurring or persisting beyond 1 month after CART infusion. We focused our literature review on the following late-event outcomes post-CART19: cytopenia, immune reconstitution, infections, and subsequent malignancies. Grade 3-4 cytopenia beyond 30 days occurs in 30%-40% of patients and beyond 90 days in 3%-22% of patients and is usually managed with growth-factor and transfusion support, along with neutropenic prophylaxis. B-cell aplasia and hypogammaglobulinemia are expected on-target off-tumor effects of CART19, 44%-53% of patients have IgG < 400 mg/dL, and approximately 27%-38% of patients receive intravenous immunoglobulin (IVIG) replacement. Infections beyond the initial month from CART19 are not frequent and rarely severe, but they are more prevalent and severe when patients receive subsequent therapies post-CART19 for their underlying disease. Late neurotoxicity and neurocognitive impairment are uncommon, and other causes should be considered. T-cell lymphoma (TCL) after CART is an extremely rare event and not necessarily related to CAR transgene. Myeloid neoplasm is not rare post-CART, but unclear causality given heavily pretreated patient population is already at risk for therapy-related myeloid neoplasm. CART19 is associated with clinically significant long-term effects such as prolonged cytopenia, hypogammaglobulinemia, and infections that warrant clinical surveillance, but they are mostly manageable with a low risk of non-relapse mortality. The risk of subsequent malignancies post-CART19 seems low, and the relationship with CART19 and/or prior therapies is unclear; but regardless of the possible causality, this should not impact the current benefit-risk ratio of CART19 for relapsed/refractory B-cell non-Hodgkin lymphoma (NHL).

CD4 nadir and neurocognitive trajectories in people living with HIV.

Human immunodeficiency virus-associated neurocognitive disorders persist in the combination antiretroviral therapy era. CD4 nadir is a well-established predictor of cognition cross-sectionally, but its impact on longitudinal neurocognitive (NC) trajectories is unclear. The few studies on this topic examined trajectories of global cognition, rather than specific NC domains. The current study examined CD4 nadir in relation to domain-specific NC decline. 132 HIV + adults from the Temple/Drexel Comprehensive NeuroHIV Center, Clinical and Translational Research Support Core Cohort were administered comprehensive NC assessments longitudinally, with last visit occurring an average of 12years after CD4 nadir. Linear mixed models were used to examine CD4 nadir in relation to longitudinal NC trajectories in three empirically identified NC domains: speed/executive function (S/EF), visuospatial memory (VM), and verbal fluency (VF). CD4 nadir was associated with change in VF (p = 0.020), but not with S/EF or VM. Specifically, those with CD4 nadir < 200 demonstrated increasing VF over time (p = .002), whereas those with CD4 nadir > 200 demonstrated stable VF (p = .568), though these differing trajectories may partly reflect regression to the mean or differential practice effect. CD4 dynamics over time were analyzed as potential mechanisms for the identified associations, with mixed findings. While low CD4 nadir has been associated with weaker neurocognition among people living with HIV, the results of this study suggest that low CD4 nadir is not associated with ongoing decline a decade later. Nadir-related deficits in VF may be stable or even improve over time, possibly reflecting the beneficial cognitive effects of long-term treatment and immune reconstitution.

Fetal liver CD34+ contain human immune and endothelial progenitors and mediate solid tumor rejection in NOG mice

BackgroundTransplantation of CD34+ hematopoietic stem and progenitor cells (HSPC) into immunodeficient mice is an established method to generate humanized mice harbouring a human immune system. Different sources and methods for CD34+ isolation have been employed by various research groups, resulting in customized models that are difficult to compare. A more detailed characterization of CD34+ isolates is needed for a better understanding of engraftable hematopoietic and potentially non-hematopoietic cells. Here we have performed a direct comparison of CD34+ isolated from cord blood (CB-CD34+) or fetal liver (FL-CD34+ and FL-CD34+CD14−) and their engraftment into immunocompromised NOD/Shi-scid Il2rgnull (NOG) mice.MethodsNOG mice were transplanted with either CB-CD34+, FL-CD34+ or FL-CD34+CD14− to generate CB-NOG, FL-NOG and FL-CD14−-NOG, respectively. After 15–20 weeks, the mice were sacrificed and human immune cell reconstitution was assessed in blood and several organs. Liver sections were pathologically assessed upon Haematoxylin and Eosin staining. To assess the capability of allogenic tumor rejection in CB- vs. FL-reconstituted mice, animals were subcutaneously engrafted with an HLA-mismatched melanoma cell line. Tumor growth was assessed by calliper measurements and a Luminex-based assay was used to compare the cytokine/chemokine profiles.ResultsWe show that CB-CD34+ are a uniform population of HSPC that reconstitute NOG mice more rapidly than FL-CD34+ due to faster B cell development. However, upon long-term engraftment, FL-NOG display increased numbers of neutrophils, dendritic cells and macrophages in multiple tissues. In addition to HSPC, FL-CD34+ isolates contain non-hematopoietic CD14+ endothelial cells that enhance the engraftment of the human immune system in FL-NOG mice. We demonstrate that these CD14+CD34+ cells are capable of reconstituting Factor VIII-producing liver sinusoidal endothelial cells (LSEC) in FL-NOG. However, CD14+CD34+ also contribute to hepatic sinusoidal dilatation and immune cell infiltration, which may culminate in a graft-versus-host disease (GVHD) pathology upon long-term engraftment. Finally, using an HLA-A mismatched CDX melanoma model, we show that FL-NOG, but not CB-NOG, can mount a graft-versus-tumor (GVT) response resulting in tumor rejection.ConclusionOur results highlight important phenotypical and functional differences between CB- and FL-NOG and reveal FL-NOG as a potential model to study hepatic sinusoidal dilatation and mechanisms of GVT.

Graft-versus-tumor effect of post-transplant cyclophosphamide-based allogeneic hematopoietic cell transplantation.

Post-transplant cyclophosphamide (PTCy) is becoming the standard prophylaxis for graft-versus-host disease (GVHD) in HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT) and in HLA-matched allo-HCT. Immune reconstitution in the post-transplant setting may influence the graft-versus-tumor (GVT) effect because PTCy has a profound effect on T cell and natural killer cell functions and their reconstitution after allo-HCT. However, many recent studies have shown that the incidence of relapse after allo-HCT with PTCy is comparable to that after conventional allo-HCT. To further improve the outcomes, it is critical to establish a strategy to maintain or effectively induce the GVT effect when using PTCy as a platform for GVHD prophylaxis. However, there is a paucity of studies focusing on the GVT effect in allo-HCT with PTCy. Therefore, focusing on this issue may lead to the establishment of more appropriate strategies to improve transplantation outcomes without exacerbating GVHD, including novel therapies involving cell modification.

The impact of immunosuppression on the mortality and hospitalization of Monkeypox: a systematic review and meta-analysis of the 2022 outbreak

BackgroundLimited data is available regarding the severity and mortality of Mpox in individuals with immunocompromised conditions. Therefore, we performed this meta-analysis to understand the impact of HIV- or non-HIV-associated immunosuppression on the severity of Mpox requiring hospitalization and mortality.MethodsA thorough literature search was performed from 2022 up to January 2024. The results were presented as odds ratios (ORs). We only included patients who required hospitalization for severity rather than isolation.ResultsA total of 34 studies were included in this analysis. Our analysis did not find a significant difference in the hospitalization risk between HIV-positive individuals and those who were HIV-negative (OR = 1.03; P = 0.85; 7 studies; CD4 count of fewer than 200 cells/µL was less than 0.5% across all studies). Patients with a CD4 count lower than 200 cells/µL or an unsuppressed RNA viral load (> 200 copies/ml) had a significantly higher hospitalization risk (OR = 5.3, P < 0.001) and (OR = 3, P < 0.001), respectively. Most of the reported deaths were reported in patients with HIV with CD4 counts below 200 cells/µL, with some fatal cases occurring in non-HIV immunosuppressed patients, particularly organ transplant recipients. Based on the autopsy findings, Mpox was confirmed in multiple organs, particularly the digestive tract, lung, and testes. Furthermore, some studies documented cases of death that were suspected to be related to hemophagocytic lymphohistiocytosis (HLH) and immune reconstitution inflammatory syndrome (IRIS). Most of the death reports showed concomitant non-Mpox infections at the time of hospitalization and deathConclusionsOur finding shows that Mpox acts as an opportunistic pathogen in immunocompromised individuals. These individuals should be prioritized for early care and closely monitored for signs of deteriorating clinical conditions. Clinical manifestations and autopsy findings strongly suggest Mpox dissemination to multiple organs, particularly the digestive tract, and lungs. However, the presence of concomitant non-Mpox infections complicates the assessment of the attribution of Mpox to death. Caution should be exercised when interpreting data suggesting poorer outcomes in individuals with non-HIV immunosuppression, as current evidence is scarce and further research is needed.

HIV-Induced Thymic Insufficiency and Aging-Related Immunosenescence on Immune Reconstitution in ART-Treated Patients.

The mechanisms underlying unsatisfactory immune reconstitution in HIV-1 positive patients under ART have not been fully elucidated, even after years of investigation. Thus, this study aimed to assess the correlation between age and thymic production profile, and its influence on inadequate immunological recovery. Here, 44 ART-treated patients with undetectable plasma HIV-1 load (<40 copies/mL) were classified as 31 immunological responders (IR) and 13 immunological non-responders (INR), according to their CD4+ T-cell count after 18 months of ART. The thymic function was assessed by identifying recent thymic emigrants (RTEs) CD4+ T cells (CD4+/CD45RA+CD31+) in PBMCs using flow cytometry. Clinical data were also analyzed from medical records. The INR group showed a higher age at ART initiation (41 ± 3.0) compared to the IR (33.7 ± 2.1) group (p = 0.041). Evaluating RTE CD4+ T-cells, we observed a lower percentage in the INR group (19.5 ± 6.3) compared to the IR group (29.9 ± 11.5) (p = 0.012). There was a strong negative correlation between age at ART initiation and RTE CD4+ T-cells in INRs (r = -0.784, p = 0.004). Our study has highlighted the thymic insufficiency and aging-related immunosenescence with unsatisfactory immunological recovery during ART in HIV-1 positive patients.

Circulating GDF-15: a biomarker for metabolic dysregulation and aging in people living with HIV.

Despite effective control of HIV replication by antiretroviral therapy (ART), a significant number of people living with HIV (PLWH) fail to achieve complete immune reconstitution and thus are deemed immune non-responders (INRs). Compared with immune responders (IRs) who have restored their CD4 T cell numbers and functions, CD4 T cells from these INRs exhibit prominent mitochondrial dysfunction and premature aging, which play a major role in increasing the incidence of non-AIDS, non-communicable diseases (NCDs). To date, there are no reliable biomarkers that can be used to typify and manage PLWH, especially INRs with non-AIDS NCDs. Growth differential factor-15 (GDF-15) is a transforming growth factor-β (TGF-β) family member known to regulate several biological processes involved in cell aging and stress responses. Since PLWH exhibit premature aging and metabolic dysregulation, here we measured the plasma levels of GDF-15 by ELISA and metabolic proteins by proteomic array and correlated the results with clinical parameters in ART-controlled PLWH (including INRs and IRs) and healthy subjects (HS). We found that GDF-15 levels were significantly elevated in PLWH compared to HS. GDF-15 levels were positively correlated with age and negatively associated with body mass and LDL cholesterol levels in the study subjects. Also, elevated GDF-15 levels were correlated with differential dysregulation of multiple metabolic proteins in PLWH. These results suggest that GDF-15 protein may serve as a biomarker of metabolic dysregulation and aging, and this biomarker will be useful in clinical trials targeting aging and metabolic disorders in ART-treated PLWH.

The reparative immunologic consequences of stem cell transplantation as a cellular therapy for refractory Crohn's disease.

Treatment strategies for Crohn's disease (CD) suppress diverse inflammatory pathways but many patients remain refractory to treatment. Autologous hematopoietic stem cell transplantation (SCT) has emerged as a therapy for medically refractory CD. SCT was developed to rescue cancer patients from myelosuppressive chemotherapy but its use for CD and other immune diseases necessitates reimagining SCT as a cellular therapy that restores appropriately responsive immune cell populations from hematopoietic progenitors in the stem cell autograft (i.e. immune "reset"). Here we present a paradigm to understand SCT as a cellular therapy for immune diseases and reveal how SCT re-establishes cellular immunity utilizing high-dimensional cellular phenotyping and functional studies of the stem cell grafts. Immunophenotyping using CyTOF, single cell RNA sequencing (scRNA-seq) and T cell receptor (TCR) sequencing was performed on peripheral blood and intestinal tissue samples from refractory CD patients who underwent SCT. The stem cell graft from these patients was analyzed using flow cytometry and functionally interrogated using a murine model for engraftment. Our study revealed a remodeling of intestinal macrophages capable of supporting mucosal healing that was independently validated using multimodal studies of immune reconstitution events including CyTOF and scRNA-seq. Functional interrogation of hematopoietic stem cells (HSCs) using a xenograft model demonstrated that HSCs shape the timing of immune reconstitution, the selected reconstitution of specific cell lineages and potentially the clinical efficacy of SCT. These studies indicate that SCT serves as a myeloid-directed cellular therapy re-establishing homeostatic intestinal macrophages that support intestinal healing and suggest refractory CD evolves from impairment of restorative functions in myeloid cells. Furthermore, we report heterogeneity among HSCs from CD patients which may drive SCT outcomes and suggests an unrecognized impact of CD pathophysiology on HSC in the marrow niche.

Advances in Mechanism of HIV-1 Immune Reconstitution Failure: Understanding Lymphocyte Subpopulations and Interventions for Immunological Nonresponders.

In individuals diagnosed with AIDS, the primary method of sustained suppression of HIV-1 replication is antiretroviral therapy, which systematically increases CD4+ T cell levels and restores immune function. However, there is still a subset of 10-40% of people living with HIV who not only fail to reach normal CD4+ T cell counts but also experience severe immune dysfunction. These individuals are referred to as immunological nonresponders (INRs). INRs have a higher susceptibility to opportunistic infections and non-AIDS-related illnesses, resulting in increased morbidity and mortality rates. Therefore, it is crucial to gain new insights into the primary mechanisms of immune reconstitution failure to enable early and effective treatment for individuals at risk. This review provides an overview of the dynamics of key lymphocyte subpopulations, the main molecular mechanisms of INRs, clinical diagnosis, and intervention strategies during immune reconstitution failure, primarily from a multiomics perspective.

Suspected Case of Histoplasmosis-Related Immune Reconstitution Inflammatory Syndrome Manifesting as Unilateral Pleural Effusion

Background: Histoplasmosis is a prevalent endemic mycosis that frequently causes opportunistic infections among individuals living with HIV (human immunodeficiency virus), and acquired immunodeficiency syndrome (AIDS). The initiation of antiretroviral therapy (ART) can result in a rare histoplasma-associated immune reconstitution inflammatory syndrome (IRIS) that may be difficult to distinguish between active progressive disease and inflammatory reaction to the medication. Case report: A 35-year-old male with newly diagnosed HIV and cervical biopsy-confirmed histoplasmosis was admitted from the emergency department with disseminated histoplasmosis for HIV antiretroviral treatment and antifungal treatment. Discharged after a 2-week inpatient treatment the patient returned 1 week later with a large left pleural effusion. Two liters of serosanguinous fluid were removed and all fluid cultures and cytology were negative. An extensive work-up remained negative, and given the timeline of presentation in relation to the initiation of ART, it was felt that this isolated left-sided pleural effusion was a manifestation of IRIS. Eventually, corticosteroids were given for IRIS and the patient improved and was discharged on long-term treatment. Conclusions: Immunocompromised subjects are at serious risk for a virulent, aggressive, rapidly advancing histoplasma infection and should be counselled accordingly. Any clinical signs or symptoms of organ system deterioration or compromise should be reported to the provider and a workup for histoplasmosis considered. In patients treated with antiretrovirals, IRIS is particularly confounding since it is difficult to differentiate from active disease. Using corticosteroids in already immunocompromised patients with an established fungal infection requires caution. Compliance with treatment is one of the most important components of care, especially considering the months of protocol.

A complex case study: coexistence of multi-drug-resistant pulmonary tuberculosis, HBV-related liver failure, and disseminated cryptococcal infection in an AIDS patient

BackgroundHepatitis B virus (HBV) infection can cause liver failure, while individuals with Acquired Immunodeficiency Virus Disease (AIDS) are highly susceptible to various opportunistic infections, which can occur concurrently. The treatment process is further complicated by the potential occurrence of immune reconstitution inflammatory syndrome (IRIS), which presents significant challenges and contributes to elevated mortality rates.Case presentationThe 50-year-old male with a history of chronic hepatitis B and untreated human immunodeficiency virus (HIV) infection presented to the hospital with a mild cough and expectoration, revealing multi-drug resistant pulmonary tuberculosis (MDR-PTB), which was confirmed by XpertMTB/RIF PCR testing and tuberculosis culture of bronchoalveolar lavage fluid (BALF). The patient was treated with a regimen consisting of linezolid, moxifloxacin, cycloserine, pyrazinamide, and ethambutol for tuberculosis, as well as a combination of bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) for HBV and HIV viral suppression. After three months of treatment, the patient discontinued all medications, leading to hepatitis B virus reactivation and subsequent liver failure. During the subsequent treatment for AIDS, HBV, and drug-resistant tuberculosis, the patient developed disseminated cryptococcal disease. The patient’s condition worsened during treatment with liposomal amphotericin B and fluconazole, which was ultimately attributed to IRIS. Fortunately, the patient achieved successful recovery after appropriate management.ConclusionEnhancing medical compliance is crucial for AIDS patients, particularly those co-infected with HBV, to prevent HBV reactivation and subsequent liver failure. Furthermore, conducting a comprehensive assessment of potential infections in patients before resuming antiviral therapy is essential to prevent the occurrence of IRIS. Early intervention plays a pivotal role in improving survival rates.

Antiretroviral Therapy Switch in HIV-Infected Adults from a Regional HIV/AIDS Center in NE Romania.

Background and Objectives: Antiretroviral therapy (ART) has revolutionized the management of HIV infection, transforming it from a once-debilitating disease to a chronic, manageable condition. However, challenges such as treatment resistance, medication side effects, and long-term tolerability persist, prompting the exploration of novel therapeutic approaches. We aimed to highlight the characteristics and related comorbidities of HIV/AIDS cases in which the antiretroviral therapy was modified. Material and Methods: A cross-sectional clinical investigation was conducted on adults diagnosed with HIV/AIDS who were hospitalized at the "St. Parascheva" Clinical Hospital of Infectious Diseases in Iasi in the Northeastern region of Romania. The timeframe under investigation was 1 January 2023 to 30 June 2023. Results: In the Northeastern part of Romania, from a total of 1692 patients in the active records, there were a total of 148 recorded cases of antiretroviral therapy switch in HIV-infected patients. The main reason for the ART switch was the simplification of the ART regimen (82 cases, 55.40%), viro-immunological failure (16 cases, 10.66%), other disturbances correlated to the ART regimen, dyslipidemia (34 cases 22.97%), depression (3 cases, 2.02%), suicide attempt (1 case, 0.67%), new situations, including the appearance of pregnancy (3 cases 2.02%), and tuberculosis (9 cases, 6.08%). ART before the switch was represented by protease inhibitors that accounted for 84 cases (56.75%) of the ART switch. Following the therapy switch, integrase inhibitor-based ART single-tablet regimens accounted for 43.91% (65 cases) of all changeovers, with non-nucleoside reverse transcriptase inhibitor regimens coming in second, in 63 cases, 42.66%. Conclusions: ART switch as an experimental therapy offers a promising approach to optimizing HIV treatment outcomes. By focusing on viral suppression and immune reconstitution, addressing treatment challenges, and exploring novel ARV agents, ART switch strategies aim to improve the overall health and well-being of individuals living with HIV.

Demographic and clinical factors correlated with clinical outcomes among people with HIV treated by antiretroviral therapy: a retrospective cohort study.

As is known, CD4 cell count is a significant parameter predicting HIV progression, opportunistic infections and death in HIV-infected individuals, as well was an important indicator for initiating antiretroviral therapy (ART). In China's National Free Antiretroviral Treatment Program, people with HIV (PWH) on ART can receive a CD4 count test at least once every six months. Importantly, the baseline CD4 count (before ART initiation) is significantly correlated with ART and even prognosis, but the influence of the peak CD4 cell count on ART and/or clinical outcomes is still unknown. A retrospective study was conducted among 7965 PWH who received ART from October 2003 to September 2022 at Yunnan Infectious Disease Hospital. Clinical features and laboratory data were collected and analyzed by Chi-square test, univariate and multivariate Cox regression analysis. After elimination of confounding variables, multivariate Cox regression analysis was performed to identify survival-related factors. Of a total of 7965 PWH in the ART treatment cohort who met the inclusion and exclusion criteria, 7939 were finally included in the subsequent analyses. First, it was found that the proportion of clinical variables, including sex, age distribution, interval from diagnosis to ART initiation, marital status, and others, was significantly different between the living and dead groups (P < 0.05). Impressively, significantly more PWH had the higher level of baseline, peak and recent CD4 cell counts in the living group compared to those in the dead group. Due to multicollinearity effect, after excluding confounders, the following factors were found to be significantly associated with mortality by multivariate Cox regression analysis: (1) male sex (hazard ratio (HR) = 1.268 [1.032, 1.559]; P = 0.024); (2) time from HIV confirmation to ART initiation ≥ 6 months (HR = 1.962 [1.631, 2.360]; P < 0.001); (3) peak CD4 cell count: Peak CD4 < 100cells/µL group (HR = 16.093 [12.041, 21.508]; P < 0.001), 100cells/µL ≤ x < 200cells/µL group (HR = 7.904 [6.148, 10.160]; P < 0.001), 200cells/µL ≤ x < 350cells/µL group (HR = 3.166 [2.519, 3.980]; P < 0.001), 350cells/µL ≤ x < 500cells/µL group (HR = 1.668 [1.291, 2.155]; P < 0.001). Interestingly, patients in male, time from HIV confirmation to ART initiation ≥ 6 months, or peak CD4 count < 500 cells/µl had inferior clinical outcomes, in other word, a lower peak CD4 cell count significantly increased the risk of death, and peak CD4 cell was independent in predicting the overall survival of PWH. It is important to promote "early diagnosis and treatment of HIV" and regularly monitor CD4 levels in HIV/AIDS to evaluate the efficacy of ART and immune reconstitution, and optimize the ART regimen in time to further reduce the mortality of PWH.

Predictors of Fatal Outcome in Newly Diagnosed Tuberculosis/HIV Co-Infection with Chronic Alcoholism (Clinical Case)

Our own case of tuberculosis/HIV co-infection’s diagnosis in chronic alcoholism and analysis of the fatal outcome predictors are presented. The patient abused alcohol for a long time in the presented case, he was hospitalised with acute psychosis in a psychoneurological dispensary, where pulmonary tuberculosis and HIV infection were diagnosed for the first time during additional examination. The patient was admitted to the department in serious condition after prolonged alcohol intoxication. The patient’s condition stabilized after detoxification therapy. Antimycobacterial therapy according to the scheme of an individual treatment regimen, antiretroviral therapy, treatment of hepatitis B and C, detoxification therapy, prophylaxis with Biseptol and Fluconazole and symptomatic therapy were prescribed. After 20 days immune reconstitution inflammatory syndrome developed. It was manifested with meningitis and cryptococci were detected in the cerebrospinal fluid 17 days later. Prescribed treatment of cryptococcal meningoencephalitis with fluconazole in high doses intravenously had a significant positive effect, which made it possible to reduce the dose of the drug to the maintenance level. The treatment was not stopped, but sterility of the liquor was not achieved. After 98 days the patient entered a coma and after 113 days he died from the progression of multiple organ failure and cryptococcal meningitis. It should be noted that the patient was diagnosed with tuberculosis with multiple drug resistance for the first time, the treatment of which had positive dynamics, despite the progression of multiple organ failure and the presence of cryptococcal meningoencephalitis. Therefore, although tuberculosis was not the direct cause of the patient’s death, the disease itself deepened the severity of the general condition. Considering the presented clinical case, it was established that predictors of the fatal outcome of newly diagnosed tuberculosis/HIV co-infection in chronic alcoholism are: antisocial lifestyle; concomitant diseases (tuberculosis, chronic viral hepatitis B and C); cryptococcal meningoencephalitis; fever, altered mental status, cryptococci in the cerebrospinal fluid; the number of CD4+ lymphocytes is less than 200/μL; lack of early screening for CrAg; early initiation of antiretroviral therapy before the diagnosis of cryptococcal meningoencephalitis, which provokes immune reconstitution inflammatory syndrome, against the background of which cryptococcal infection progresses; monotherapy of cryptococcal meningoencephalitis with Fluconazole. Knowledge and practice gaps among medical practitioners contribute to the high fatality rate of cryptococcal meningoencephalitis in tuberculosis/HIV co-infection in chronic alcoholism.

Model-Based Antithymocyte Globulin in αβhaplo-Hematopoietic Stem Cell Transplantation Facilitates Engraftment, Expedites T Cell Recovery, and Mitigates the Risk of Acute Graft-versus-Host Disease

In αβ T-cell/CD19 B-cell depleted hematopoietic stem cell transplantation (αβhaplo-HSCT) recipients, antithymocyte globulin (ATG; Thymoglobulin) is used for preventing graft rejection and graft-versus-host disease (GVHD). The optimal dosing remains to be established, however. Here we present the first comparative analysis of 3 different ATG dosing strategies and their impact on immune reconstitution and GVHD. Our study aimed to evaluate the effects of 3 distinct dosing strategies of ATG on engraftment success, αβ+ and γδ+ T cell immune reconstitution, and the incidence and severity of acute GVHD in recipients of αβhaplo-HSCT. This comparative analysis included 3 cohorts of pediatric patients with malignant (n = 36) or nonmalignant (n = 8) disease. Cohorts 1 and 2 were given fixed ATG doses, whereas cohort 3 received doses via a new nomogram, based on absolute lymphocyte count (ALC) and body weight (BW). Cohort 3 showed a 0% incidence of day 100 grade II-IV acute GVHD, compared to 48% in cohort 1 and 27% in cohort 2. Furthermore, cohort 3 (the ALC/BW-based cohort) had a significant increase in CD4+ and CD8+ naïve T cells by day 90 (P = .04 and .03, respectively). Additionally, we found that the reconstitution and maturation of γδ+ T cells post-HSCT was not impacted across all 3 cohorts. Cumulative ATG exposure in all cohorts was lower than previously reported in T cell-replete settings, with a lower pre-HSCT exposure (<40 AU*day/mL) correlating with engraftment failure (P = .007). Conversely, a post-HSCT ATG exposure of 10 to 15 AU*day/mL was optimal for improving day 100 CD4+ (P = .058) and CD8+ (P = .03) immune reconstitution without increasing the risk of relapse or nonrelapse mortality. This study represents the first comparative analysis of ATG exposure in αβhaplo-HSCT recipients. Our findings indicate that (1) a 1- to 2-fold ATG to ATLG bioequivalence is more effective than previously established standards, and (2) ATG exposure post-HSCT does not adversely affect γδ+ T cell immune reconstitution. Furthermore, a model-based ATG dosing strategy effectively reduces graft rejection and day 100 acute GVHD while also promoting early CD4+/CD8+ immune reconstitution. These insights suggest that further optimization, including more distal administration of higher ATG doses within an ALC/BW-based strategy, will yield even greater improvements in outcomes.

Immune reconstitution after transplantation of autologous peripheral stem cells in children: a comparison between CD34+ selected and nonmanipulated grafts

Background and aimsHigh-dose chemotherapy (HDC) followed by autologous stem cell transplantation (ASCT) improves the prognosis in pediatric patients with several solid tumors and lymphomas. Little is known about the reconstitution of the immune system after ASCT and the influence of CD34+ cell selection on the reconstitution in pediatric patients. MethodsBetween 1990 and 2001, 94 pediatric patients with solid tumors and lymphomas received autologous CD34+ selected or unmanipulated peripheral stem cells after HDC. CD34+ selection was carried out with magnetic microbeads. The absolute numbers of T cells, B cells and natural killer (NK) cells were measured and compared in both groups at various time points post-transplant. ResultsRecovery of T cells was significantly faster in the unmanipulated group at day 30, with no significant difference later on. Reconstitution of B and NK cells was similar in both groups without significant differences at any time. The CD34+-selected group was divided into patients receiving less or more than 5.385 × 106/kg CD34+ cells. Patients in the CD34+ high-dose group displayed significantly faster reconstitutions of neutrophiles and lymphocyte subsets than the CD34+ low-dose group. ConclusionsEngraftment and reconstitution of leukocytes, B cells and NK cells after transplantation of CD34+ selected stem cells were comparable to that in patients receiving unmanipulated grafts. T-cell recovery was faster in the unmanipulated group only within the first month. However, this delay could be compensated by transplantation of >5.385 × 106 CD34+ cells/kg. Especially for patients receiving immunotherapy after HDC large numbers of immune effector cells such as NK and T cells are necessary to mediate antibody-dependent cellular cytotoxicity. Therefore, in patients receiving autologous CD34+-selected grafts, our data emphasize the need to administer high stem cell counts.

Addition of CD14 improves discrimination of lymphocytes in the TBNK phenotyping panel.

Peripheral blood lymphocyte phenotyping panels typically include CD45 for discrimination of the lymphocyte population, and fluorophore-conjugated monoclonal antibodies to identify T, B, and Natural Killer (NK) cells. While CD45 combined with side scatter is generally sufficient to clearly distinguish lymphocytes from monocytes in the majority of peripheral blood samples, it is challenging to accurately gate lymphocytes in samples from patients with monocytosis or significant lymphopenia, or from very young infants. Addition of a monocyte marker to lymphocyte phenotyping panels for monocyte exclusion has previously been evaluated for improved discrimination of lymphocytes, albeit largely in healthy donor adult samples. Here we evaluate the effect of the addition of CD14 to a standard lymphocyte phenotyping panel on total lymphocyte, T, B, and NK cell percentages in a predominantly pediatric population of patients under evaluation chiefly for immunodeficiency, immune-depletion, or immune reconstitution. Addition of CD14 to the standard lymphocyte phenotyping improved discrimination of lymphocytes from monocytes, resulted in decreased NK cell percentages, likely because CD16+ and/or CD56+ monocytes were included in the CD56+CD16+ NK cell gate with conventional gating, and although less significant, resulted in an increased percentage of B cells, since relatively larger B cells were likely gated out by more restrictive light scatter gating used with the conventional gating approach. The change in NK and B cell percentages were more pronounced in samples from patients below a year of age, and in patients who were relatively lymphopenic. These data suggest that addition of CD14 to conventional lymphocyte phenotyping panels that utilize CD45 versus side scatter gating results in significant improvement in the accuracy of lymphocyte gating, and accurate quantification of NK and B cells particularly in samples from infants and lymphopenic individuals.

B-NHL Cases in a Tertiary Pediatric Hematology-Oncology Department: A 20-Year Retrospective Cohort Study.

Non-Hodgkin lymphoma (NHL) is among the five most common pediatric cancer diagnoses in children and adolescents and consists of a heterogeneous group of lymphoid tissue malignancies -with B-cell-derived NHL accounting for nearly 80% of cases. Novel and high-throughput diagnostic tools have significantly increased our understanding of B-NHL biology and molecular pathogenesis, leading to new NHL classifications and treatment options. This retrospective cohort study investigated 17 cases of both mature B-cell NHL (Burkitt lymphoma or BL; Diffuse large B-cell lymphoma or DLBCL; Primary mediastinal large B-cell lymphoma or PMBCL; Follicular lymphoma or FL) and immature B-cell progenitor NHL (B-lymphoblastic lymphoma or BLL) that were treated in a tertiary Pediatric Hematology-Oncology Department during the last 20 years. Modern NHL protocols for children, adolescents, and young adults, along with the addition of rituximab, are safe and efficient (100% overall survival; one relapse). Elevated ESR was more prevalent than elevated LDH. Analyses have focused on immune reconstitution (grade ≥3 infections, lymphocyte and immunoglobulin levels recovery) and body-mass-index changes post-treatment, late effects (in 53% of patients), and the presence of histology markers BCL2, BCL6, CD30, cMYC, and Ki-67%. One patient was diagnosed with a second malignant neoplasm (papillary thyroid cancer).

Molecular Diagnostics of Cryptococcus spp. and Immunomics of Cryptococcosis-Associated Immune Reconstitution Inflammatory Syndrome.

Cryptococcal infection poses a significant global public health challenge, particularly in regions near the equator. In this review, we offer a succinct exploration of the Cryptococcus spp. genome and various molecular typing methods to assess the burden and genetic diversity of cryptococcal pathogens in the environment and clinical isolates. We delve into a detailed discussion on the molecular pathogenesis and diagnosis of immune reconstitution inflammatory syndrome (IRIS) associated with cryptococcosis, with a specific emphasis on cryptococcal meningitis IRIS (CM-IRIS). Our examination includes the recent literature on CM-IRIS, covering host cellulomics, proteomics, transcriptomics, and genomics.

Immune reconstitution is the trigger of herpes zoster with lymphopenia and high neutrophil-to-lymphocyte ratio in a retrospective cohort study.

Herpes zoster (HZ) rarely results in subsequent death, but predictive biomarkers for mortality necessitate further elucidation. To investigate immune dynamics prior to an HZ event, risk factors for HZ onset and immune status at initial HZ. This retrospective study extracted from patient records the absolute neutrophil and lymphocyte counts (ANC and ALC, respectively) at the initial HZ date of appearance and up to 30 days before HZ. A follow-up survey was completed within 180 days of onset of illness. Patients with HZ showed a higher neutrophil-to-lymphocyte ratio (NLR) and lower ALC than patients in the control group at the initial date and had a poorer prognosis. In the pre-onset examination, the maximum and minimum ALC values were significantly lower in patients with HZ than in the control group, and the maximum ALC value in patients with HZ was lower than the minimum value in the control group. The lowest ALC was observed 7 days before the onset of HZ. An NLR of 4.53 or more and an ALC of 0.64 × 109 cells L-1 or less were predictive markers of HZ development within 30 days. Patients who died after HZ had a lower minimum ALC than those who survived longer. HZ develops in a state of immune reconstitution in patients with immunocompromised conditions, as part of 'unmasking' the immune reconstitution inflammatory syndrome. Lymphopenia prior to HZ onset is one of the most crucial factors in its pathogenesis and vital prognosis. Limitations of the study were small population size, varying age distribution, retrospective nature, and potential overestimation of pre-onset data.