Immune Reconstitution Research Articles

Pediatric Transplant and Cellular Therapy Consortium RESILIENT Conference on Pediatric Chronic Graft-versus-Host Disease Survivorship after Hematopoietic Cell Transplantation: Part II. Organ Dysfunction and Immune Reconstitution Considerations for children with chronic GVHD after Hematopoietic Cell Transplantation.

While highly morbid forms of chronic graft versus host disease (cGVHD) and severe late effects of allogeneic hematopoietic cell transplant (HCT) can impact children and adults alike, unique considerations arise in pediatric cases regarding diagnosis, monitoring, treatment, and likelihood of resolution. As children can present with atypical features of cGVHD, and with more significant disease due to inability to communicate symptoms, they may be at increased risk for highly morbid forms of cGVHD and incur greater subsequent late effects, which may be more pronounced in those with underlying chromosomal breakage syndromes, with higher prevalence in pediatric HCT recipients. The long-term effects of cGVHD and its therapies include impaired immune reconstitution, leading to increased risks of infection and secondary malignant neoplasms. However, children also have the greatest potential for full immune reconstitution, due to thymus recovery that could impact the timing of vaccination with respect to tolerance and restoration of optimal immunity. Developing strategies to mitigate the late effects incurred with, and as a result of cGVHD, is of critical importance. The working group recommends surveillance strategies for late effects in patients with cGVHD, increased utilization of emerging diagnostic tools, integration of monitoring for cGVHD treatment response, development of new treatments, and provides aims for future research endeavors.

P0195 Immune reconstitution following autologous hematopoietic stem cell transplantation with cyclophosphamide-free mobilization for refractory Crohn’s disease

Abstract Background Autologous hematopoietic stem cell transplantation (aHSCT) has emerged as an effective therapeutic strategy for patients with severe chronic inflammatory conditions that are refractory to conventional treatment, including Crohn’s disease. The success of aHSCT is thought to be grounded in resetting the break of immunological tolerance, but the exact mechanisms underlying a favourable response remain incompletely understood. Methods We followed the immune reconstitution of 9 patients with severe refractory Crohn’s disease from one month until more than 2 years post-aHSCT. We performed flow cytometry to follow immune cell populations and functional T cells markers over time, in addition to Olink proteomics to study the inflammatory response in serum. Results Transplantation proceeded safely, without major adverse events in any of the 9 patients. aHSCT resulted in considerable improvement of disease status in 6 patients, with 3 patients classified as non-responders. After transplantation, we observed a strong change in the peripheral T-cell subset composition, with a reduction of the CD4/CD8 ratio and a reduction of naïve over effector memory (EM) T cells. Non-responders appeared distinct by a higher CD4/CD8 ratio and higher naïve over T-EM frequencies already before transplantation, and a smaller change in subset composition after transplantation. Remarkably, the local T-cell composition did not mirror the changes in the periphery, with an increased CD4/CD8 ratio in intestinal biopsies post-aHSCT, underscoring that a more detailed study of local versus peripheral responses to aHSCT is essential in aiding our understanding of its efficacy. Functionally, the changes in the peripheral T-cell profile were minimal and not clearly related to response. Although the pro-inflammatory profile was not altered, we did find a small but significant increase in the expression of regulatory markers. Conclusion aHSCT resulted in strong changes in the T-cell subset composition of Crohn’s disease patients, but only small changes in functional markers related to inflammation, regulation and homing. Non-responders could be distinguished at baseline by a different T-cell composition and also experienced less profound changes herein upon transplantation.

Ocular Manifestations of Immune Reconstitution Inflammatory Syndrome in HIV after Highly Active Antiretroviral Therapy: Clinical Use of CD8+ T cell.

To investigate ocular manifestation of immune reconstitution inflammatory syndrome (IRIS) in human immunodeficiency virus (HIV) patients after starting highly active antiretroviral therapy (HAART) and its relationship to T cell immunity. HIV patients with ocular IRIS after HAART were retrospectively reviewed. Clinical presentations with previous opportunistic infection, duration from initiation of HAART to IRIS, blood CD4+, CD8+ T cell count, and HIV RNA copies before HAART and at IRIS were analyzed. Among 19 patients (27 eyes) included, the most common previous opportunistic infection was cytomegalovirus (17 patients, 89.5%) followed by tuberculosis choroiditis (2 patients, 10.5%). The clinical manifestations included vitritis (20 eyes, 74.0%), retinitis (14 eyes, 51.9%), and anterior uveitis (5 eyes, 18.5%). The median duration from initiation of HAART to IRIS was 70 days. CD4+ T cell count before HAART increased at IRIS (p<0.001). CD8+ T cell count before HAART was negatively correlated with duration from HAART to IRIS (p<0.001). Cut-off value of CD8+ T cell count for discerning early or late onset of ocular IRIS was 258/mm3 (p=0.001). When divided into two groups by CD8+ T cell count of 258/mm3, 90% patients with CD8+ T cell count higher than 258/mm3 before HAART developed ocular IRIS within 70 days. There was negative relationship between CD8+ T cell count before HAART and duration from HAART to ocular IRIS. Ocular IRIS with higher CD8+ T cell count before HAART developed earlier after HAART initiation compared to those with lower CD8+ T cell count.

Additive Effects of Glutathione in Improving Antibiotic Efficacy in HIV-M.tb Co-Infection in the Central Nervous System: A Systematic Review.

HIV and tuberculosis (TB) co-infection poses a significant health challenge, particularly when involving the central nervous system (CNS), where it leads to severe morbidity and mortality. Current treatments face challenges such as drug resistance, immune reconstitution inflammatory syndrome (IRIS), and persistent inflammation. Glutathione (GSH) has the therapeutic potential to enhance treatment outcomes by improving antibiotic efficacy, reducing inflammation, and mitigating immune dysfunction. Relevant studies were identified through systematic searches of PubMed, Elsevier, WHO, and related databases. Inclusion criteria focused on preclinical and clinical research examining GSH or its precursors in HIV, TB, or co-infection, with emphasis on microbial control, immune modulation, and CNS-related outcomes. Preclinical studies showed that GSH improves macrophage antimicrobial function, reduces oxidative stress, and limits Mycobacterium tuberculosis (M.tb) growth. Animal models demonstrated reduced bacterial burden in the lungs, liver, and spleen with GSH supplementation, along with enhanced granuloma stability. Clinical studies highlighted increased TH1 cytokine production, reduced inflammatory markers, and improved CD4+ T cell counts in HIV-M.tb co-infected patients. N-acetylcysteine (NAC), a GSH precursor, was shown to significantly enhance the efficacy of first-line TB antibiotics and mitigate treatment-associated toxicity. GSH shows promise as an adjunct therapy for HIV-M.tb co-infection, particularly for cases involving the CNS, where it may improve immune recovery and reduce inflammation. However, evidence is limited by small sample sizes and a lack of randomized trials. Future research should focus on developing CNS-directed GSH formulations and evaluating its integration into current treatment protocols to address the dual burden of HIV and TB, ultimately improving patient outcomes.

Star-Shaped Glatiramer Acetate Mitigates Pulmonary Dysfunction and Brain Neurodegeneration in a Murine Model of Cryptococcus-Associated IRIS.

Cryptococcal-associated immune reconstitution inflammatory syndrome (C-IRIS) is a clinical worsening or new presentation of cryptococcal disease following the initiation of antiretroviral therapy. C-IRIS is primarily driven by an influx of pathological CD4 + T cells, which triggers a hyperinflammatory response. The murine model of C-IRIS is a way to study the disease in mice and understand how the immune system triggers life-threatening outcomes in patients. We previously developed a murine C-IRIS model and demonstrated that C-IRIS is triggered by pathological CD4 + T cells, particularly Th1 cells, in the brain, which triggers neurodegeneration and pulmonary dysfunction. Using this unique mouse model, we tested the therapeutic effect of a star-shaped glatiramer acetate (sGA), which is a more effective isomeric form than linear GA. Here, we observed that sGA suppresses Th1 differentiation in the lung tissues, reducing CD4 + T cell and Th1 cell count. It also reduced microglia populations in the brain. Together, these changes improved respiratory dysfunction caused by C-IRIS, lowered mortality rate, and reduced brain neurodegeneration. These findings suggest that sGA could be an effective therapeutic strategy for managing C-IRIS.

Prognostic significance of immune reconstitution following CD19 CAR T-cell therapy for relapsed/refractory B-cell lymphoma.

Immune deficits after CD19 chimeric antigen receptor (CAR) T-cell therapy can be long-lasting, predisposing patients to infections and non-relapse mortality. In B-cell non-Hodgkin lymphoma (B-NHL), the prognostic impact of immune reconstitution (IR) remains ill-defined, and detailed cross-product comparisons have not been performed to date. In this retrospective observational study, we longitudinally characterized lymphocyte subsets and immunoglobulin levels in 105 B-NHL patients to assess patterns of immune recovery arising after CD19 CAR-T. Three key IR criteria were defined as CD4+ T helper (TH) cells > 200/µL, any detectable B cells, and serum immunoglobulin G (IgG) levels >4 g/L. After a median follow-up of 24.6 months, 38% of patients displayed TH cells, 11% showed any B cells, and 41% had IgG recovery. Notable product-specific differences emerged, including deeper TH cell aplasia with CD28z- versus longer B-cell aplasia with 41BBz-based products. Patients with any IR recovery experienced extended progression-free survival (PFS) (median 20.8 vs. 1.7 months, p < 0.0001) and overall survival (OS) (34.9 vs. 4.0 months, p < 0.0001). While landmark analysis at 90 days confirmed improved PFS in patients with any recovery (34.9 vs. 8.6 months, p = 0.005), no significant OS difference was noted. Notably, 72% of patients with refractory disease never displayed recovery of any IR criteria. Early progressors showed diminished IR at the time of progression/relapse compared to patients with late progression/recurrence (after Day 90). Our results highlight the profound immune deficits observed after CD19 CAR-T and shed light on the intersection of IR and efficacy in B-NHL. Importantly, IR was impaired considerably postprogression, carrying significant implications for subsequent T-cell-engaging therapies and treatment sequencing.

Infection Risks &amp; Immune Reconstitution Challenges in Multiple Myeloma

Infection Risks &amp; Immune Reconstitution Challenges in Multiple Myeloma

Association between poor drug adherence and undernutrition among adult HIV patients in southern Ethiopia: an institution based cross sectional study

ObjectiveUndernutrition is a common issue for HIV and other immune suppressed patients. Approximately 462 million people worldwide living with HIV are experiencing undernutrition, with sub-Saharan Africa having the highest prevalence....

Membrane palmitoylated protein MPP1 inhibits immune escape by regulating the USP12/ CCL5 axis in urothelial carcinoma.

The response rate to immunotherapy in patients with urothelial carcinoma remains limited. Studies have shown that membrane palmitoylated proteins (MPPs) play key roles in tumor progression. However, the mechanisms by which MPP1 regulates immune escape in urothelial carcinoma are not well understood. The TCGA and BEST databases were used to analyze the associations between the expression of members of the MPP family and the prognosis or immunotherapy sensitivity of urothelial carcinoma patients. MPP1 was identified due to its significant association with survival and immunotherapy sensitivity. MPP1 expression in urothelial carcinoma tissues and cell lines was examined. An MPP1 overexpression vector was used to transfect urothelial carcinoma cells. The functional assays included proliferation, migration, urothelial carcinoma cell-CD8+ T-cell coculture, CD8+ T-cell chemotaxis, and tumorigenesis in human immune reconstitution NOG mice (HuNOG). Bioinformatics, coimmunoprecipitation (CO-IP), mass spectrometry, quantitative real-time polymerase chain reaction (RT-qPCR), and western blotting were used to validate the activity of the MPP1/USP12/CCL5 cascade. Analysis of the BEST data revealed that, compared with other MPP family genes, MPP1 was more strongly associated with urothelial carcinoma prognosis and immunotherapy response. Low MPP1 expression was observed in urothelial carcinoma patients and was positively associated with better survival. MPP1 inhibited the proliferation and migration of urothelial carcinoma cells. Bioinformatics, in vitro coculture assays, and in vivo tumorigenesis experiments demonstrated that MPP1 promotes CCL5 production and CD8+ T-cell chemotaxis in the urothelial carcinoma tumor microenvironment (TME). Mechanistically, bioinformatics, mass spectrometry, co-IP, RT-qPCR, and western blot analyses indicated that MPP1 increases CCL5 expression by binding to and promoting USP12. MPP1 significantly inhibits urothelial carcinoma cell proliferation and immune escape via the MPP1/USP12/CCL5 cascade. MPP1 has the potential to serve as a biomarker for guiding immunotherapy in patients with urothelial carcinoma.

Dihydroartemisinin Inhibits T Cell Activation in People Living with HIV with Incomplete Immune Reconstitution In Vitro

Dihydroartemisinin Inhibits T Cell Activation in People Living with HIV with Incomplete Immune Reconstitution <i>In Vitro</i>

New autoimmune disorder development after immune reconstitution therapy for multiple sclerosis

Immune reconstitution therapy (IRT) is a relatively new and highly effective treatment option for multiple sclerosis (MS). Uncertainty regarding the development of autoimmune disorders (ADs) after some therapies remains. The aim of this study was to assess new AD development after IRT in MS patients and to describe the nature of those ADs and the time to onset. A total of 179 patients with relapsing multiple sclerosis (37 after autologous haematopoietic stem cell transplantation (AHSCT), 19 after alemtuzumab (ALE) and 123 after cladribine (CLA) treatment) over a ten year period were included in the study. ADs were observed in 6 patients (16.2%) after AHSCT, 8 patients (42.1%) after ALE and 2 patients (1.6%) after CLA treatment. ADs developed earlier after ALE infusions, but later after AHSCT except for cytopenias. Neurologists should be attentive to the development of secondary ADs after ALE and AHSCT in MS patients.

Combined Sequential Antiretroviral Therapy-Induced Immune Reconstitution Bone Loss and Estrogen Deficiency Bone Loss are Cumulative in Mice Models.

Antiretroviral therapy (ART) causes osteoporosis and bone fractures, increasing morbidity and mortality in people living with HIV (PLH). ART induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent >50% of PLH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study. We used a mouse model of IRBL, applied simultaneously or sequentially with surgical ovariectomy (Ovx), a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed using micro-computed tomography (µCT) and bone turnover quantified by serum markers of bone resorption and formation via ELISA. T cell production of osteoclastogenic cytokines was analyzed by flow cytometry. Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ=-42.6 vs. Control: p<0.01) was significantly reduced by the anti-inflammatory agent Abatacept (Δ=-13.9 vs. Control: p=not significant) and the probiotic Lactobacillus rhamnosus GG (LGG) (Δ=-8.6 vs. Control: p=not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T cell production of the osteoclastogenic cytokines TNF-α and IL-17A. Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women living with HIV (WLH). Probiotic therapy may provide a beneficial alternative to pharmacotherapy.

Thymic and T-cell intrinsic critical roles associated with Severe Combined Immunodeficiency and Omenn syndrome due to a heterozygous variant (G201R) in PSMB10.

Heterozygous immunoproteasome subunit beta-type 10 (PSMB10) mutations can cause severe combined immunodeficiency (SCID) and Omenn syndrome (OS). Hematopoietic stem cell transplantation in these patients is associated with severe complications and poor immune reconstitution, often resulting in death. To perform immunological and molecular characterization of an infant with a PSMB10 heterozygous variant. A heterozygous variant in PSMB10 (p.G201R) was identified in the index but not her parents. Detailed immunophenotyping and functional studies, including flow cytometry, immunoblotting, and T-cell development in artificial thymic organoids (ATO), were performed. The patient presented with severe B-, NK-, as well as T-cell lymphopenia, with a progressive increase in memory CD4+ and loss of CD8+ T-cells, diminished Vbeta family diversity, and abnormal IL-7 signaling. Immunoproteasome protein expression (PSMB10 and 9) was markedly reduced in the patient's cells, including PBMCs, EBV-transformed B cells, and fibroblasts, the mutation likely acting in a dominant negative fashion. Patient CD34+ cells showed a normal early T-cell development but slightly impaired generation of CD3+TCRαβ+ cells in ATO, and human thymus single cell RNA sequencing demonstrated that PSMB10 is expressed in different subsets of cortical and medullary thymic epithelial cells. Collectively, these data indicate that PSMB10 mutations affect positive selection of CD8 T-cells, generation of a diverse T-cell repertoire, and negative selection of autoreactive T-cells. The PSMB10 G201R variant is associated with reduced immunoproteasome expression levels that appear to play vital roles in hematopoietic and extra-hematopoietic immune system development and function. PSMB10-associated thymoproteasome dysfunction leads to impaired thymopoiesis and the development of SCID and OS, suggesting possible benefit from thymus implantation.

Mechanisms of HIV-immunologic non-responses and research trends based on gut microbiota.

With the increasing number of people with HIV (PWH) and the use of antiretroviral treatment (ART) for PWH, HIV has gradually become a chronic infectious disease. However, some infected individuals develop issues with immunologic non-responses (INRs) after receiving ART, which can lead to secondary infections and seriously affect the life expectancy and quality of life of PWH. Disruption of the gut microbiota is an important factor in immune activation and inflammation in HIV/AIDS, thus stabilizing the gut microbiota to reduce immune activation and inflammation and promoting immune reconstitution may become a direction for the treatment of HIV/AIDS. This paper, based on extensive literature review, summarizes the definition, mechanisms, and solutions for INRs, starting from the perspective of gut microbiota.

Dual-Double Stem Cell Ovarian Therapy: A Comprehensive Approach in Regenerative Medicine

Dual-double stem cell therapy, which integrates mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs), represents a cutting-edge approach in regenerative medicine, particularly for conditions such as ovarian decline, premature ovarian insufficiency (POI), and induced ovarian failure. This therapy leverages the unique properties of MSCs and HSCs, enhancing tissue repair, immune modulation, and overall regenerative outcomes. MSCs, known for their ability to differentiate into various cell types, provide a supportive microenvironment and secrete bioactive molecules that promote angiogenesis and reduce inflammation. HSCs, crucial for hematopoiesis and immune function, further enhance this environment by supporting hematopoietic processes and immune regulation. Clinical evidence increasingly supports the effectiveness of stem cell therapy in ovarian regeneration. Studies have demonstrated improved folliculogenesis, normalization of hormone profiles, and successful pregnancies in patients with POI. Furthermore, recent clinical trials in various medical fields underline the superior potential of dual-double therapy compared to monotherapies involving MSCs or HSCs alone, enhancing tissue repair and functional outcomes. However, despite these benefits, the therapy presents risks that require careful consideration. For autologous MSC therapy involving expanded cell populations, risks include tumorigenic potential, with evidence of sarcoma formation in certain cases of cultured MSCs. In contrast, autologous non-expanded MSC and HSC therapies may be limited by low cell yields, potentially compromising therapeutic efficacy. Additionally, non-expanded HSC therapy poses risks of insufficient cell numbers for successful engraftment and delayed immune reconstitution. These considerations underscore the importance of quality control and rigorous screening to optimize safety and efficacy. This article explores the mechanisms of action, clinical applications, and potential complications of dual-double stem cell therapy, underscoring the need for continued research and optimized protocols to enhance safety and outcomes in ovarian insufficiency and related conditions, offering new hope for affected women.

Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide in patients with inborn errors of immunity: Experience in a reference center in Colombia

Inborn errors of immunity is a diverse group of rare diseases caused by over 400 genetic mutations affecting the immune system and increasing infection susceptibility, autoimmunity, and malignancy. Hematopoietic stem cell transplantation offers a curative option for some inborn errors of immunity, with haploidentical donors providing a viable alternative when identical donors are unavailable. To determine survival, usefulness of weekly chimerism monitoring, immune reconstitution, and complications in patients with inborn errors of immunity who underwent haploidentical hematopoietic stem cell transplantation at a reference center in Colombia. We conducted a retrospective and observational study of a case series of pediatric patients who underwent haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide and follow-up with weekly chimerism. Survival analysis was performed using the Kaplan-Meier method. Sixteen patients with haploidentical familial donor transplantation were included. The most frequent diagnosis was severe combined immunodeficiency (n=5). Eleven out of seventeen patients received a non-myeloablative conditioning regimen. Twelve out of sixteen patients developed acute graft-versus-host disease. Out of these, 3 corresponded to grades III-IV. Post-transplant infections affected 14 of the subjects, predominating bacterial agents. Median T-cell chimerism was greater than 80% during the follow-up. Reconstitution of B and T lymphocytes was achieved in more than 80%. Overall survival at five years was 81%. Survival at 100 days was 94%. Haploidentical hematopoietic stem cell transplantation using post-transplant cyclophosphamide is a viable alternative for inborn errors of immunity when an identical donor is unavailable. Serial chimerism monitoring is useful for graft follow-up.

Vaccination After Haematopoietic Stem Cell Transplant: A Review of the Literature and Proposed Vaccination Protocol.

Background/Objectives: Haematopoietic stem cell transplantation (HCT) induces profound immunosuppression, significantly increasing susceptibility to severe infections. This review examines vaccinations' necessity, timing, and efficacy post-HCT to reduce infection-related morbidity and mortality. It aims to provide a structured protocol aligned with international and national recommendations. Methods: A systematic review of current guidelines and studies was conducted to assess vaccination strategies in HCT recipients. The analysis included the timing of vaccine administration, factors influencing efficacy, and contraindications. Recommendations for pre- and post-transplant vaccination schedules were synthesised, specifically for graft-versus-host disease (GVHD), immunosuppressive therapy, and hypogammaglobulinemia. Results: Vaccination is essential as specific immunity is often lost after HCT. Inactivated vaccines are recommended to commence three months post-transplant, including influenza, COVID-19, and pneumococcal vaccines. Live attenuated vaccines remain contraindicated for at least two years post-transplant and in patients with ongoing GVHD or immunosuppressive therapy. Factors such as GVHD and immunosuppressive treatments significantly impact vaccine timing and efficacy. The review also underscores the importance of pre-transplant vaccinations and ensuring that patients' close contacts are adequately immunised to reduce transmission risks. Conclusions: Implementing a structured vaccination protocol post-HCT is critical to improving patient outcomes. Timely and effective vaccination strategies can mitigate infection risks while addressing individual patient factors such as GVHD and immunosuppression. This review highlights the need for tailored vaccination approaches to optimize immune reconstitution in HCT recipients.

Vaccination of children and adolescents treated for acute leukemia, excluding HSCT recipients: Recommendations of the French Society for Childhood and Adolescent Cancer and Leukemia (SFCE)

Children and adolescents who are being treated or have been treated for acute leukemia have a secondary immunodeficiency linked to chemotherapy, resulting in an increased risk of infections. Some of which can be prevented by vaccination but its effectiveness is not optimal during chemotherapy. Upon cessation of chemotherapy, the time required for immune reconstitution varies from three months to more than a year, depending on lymphocyte subpopulations, the patient's age, and the intensity of the treatment received. Although they may have regained their immune functions, studies show that most patients have lost part of their vaccine-induced protection post-chemotherapy and require booster doses of vaccines. Most practitioners agree on the importance of vaccinating or revaccinating these children, but practices are heterogeneous among pediatric hematologist-oncologists in France. Based on a practice study and a recent review of the literature, this work aims to propose new French recommendations for the vaccination strategy to be adopted for children and adolescents treated or recently treated for acute leukemia, excluding allogeneic transplant recipients, in 2024. These recommendations specifically include the vaccination protocols for human papillomavirus and meningococcal infections but do not address the COVID-19 vaccination, as its guidelines are subject to rapid changes.

Evaluation of a commercial Histoplasma antigen detection enzyme immunoassay for the follow-up of histoplasmosis treatment in people living with HIV from Argentina.

Histoplasmosis poses a significant risk to HIV patients, particularly in regions with limited access to antiretroviral therapy. Antigen detection assays are crucial in these settings for timely diagnosis and treatment, which can reduce mortality. While commercial antigen detection kits have performed well in diagnosing histoplasmosis, their effectiveness in monitoring treatment remains unclear. This study aimed to evaluate the correlation between urine antigen levels and clinical response using the clarus Histoplasma Galactomannan (GM) enzyme immunoassays (EIA) kit. The study followed 27 HIV patients diagnosed with histoplasmosis over 24 weeks, measuring urinary Histoplasma antigen (Ag) levels and clinical outcomes. Patients received amphotericin B as induction therapy, followed by maintenance with itraconazole. Results showed a significant decrease in Ag levels over time, with clinical scores improving in correlation with the decline in Ag levels. Four patients exhibited atypical Ag patterns due to immune reconstitution inflammatory syndrome or issues with itraconazole bioavailability. Despite these challenges, all patients showed improvement by week 24. The findings suggest that the clarus Histoplasma GM EIA kit could be a valuable tool for monitoring and evaluating the response to antifungal therapy in histoplasmosis patients.

Impact of Anti-CD4 Autoantibodies on Immune Reconstitution in People With Advanced Human Immunodeficiency Virus.

Despite suppressive antiretroviral therapy (ART), 15%-30% of people with human immunodeficiency virus (HIV) experience a limited recovery of CD4 T cells. Although autoantibodies against the CD4 receptor have previously been identified in people with HIV (PWH), little is known about their longitudinal impact on CD4 T-cell reconstitution. Anti-CD4 autoantibodies were evaluated by the fluid-phase luciferase immunoprecipitation systems immunoassay in ART-naive people with advanced HIV (CD4 count ≤100 cells/µL), PWH with CD4 count >200 cells/µL, long-term nonprogressors, people with idiopathic CD4 lymphopenia, people with autoimmune lymphoproliferative syndrome, and healthy volunteers without HIV. In the participants with advanced HIV, we assessed the association of anti-CD4 autoantibodies at ART initiation with CD4 recovery over a median follow-up of 192 weeks. Anti-CD4 autoantibodies were identified in 29% (61/210) of ART-naive participants with advanced HIV but were absent in people without HIV. Female PWH showed a 4-fold higher prevalence (P < .001) of anti-CD4 autoantibodies compared to males. After ART initiation, people with advanced HIV with anti-CD4 autoantibodies exhibited an overall slower rate of CD4 reconstitution (5.8 vs 6.6 cells/µL/month, P = .007) and lower week 192 CD4 count (268 vs 355 cells/µL, P = .037). Incidental, clinically indicated immunosuppressive therapy in these participants was associated with an improved rate of CD4 reconstitution (P = .0019) and higher week 192 CD4 count (551 vs 268 cells/µL, P = .019). People with advanced HIV harboring anti-CD4 autoantibodies at ART initiation demonstrated a slower rate and extent of CD4 reconstitution after 4 years. Incidental immunosuppressive therapy was associated with increased CD4 counts in these participants.