Absolute CD4 Research Articles

RADT-49. IMPACT OF SHORT COURSE RADIOTHERAPY IN REDUCING LYMPHOPENIA IN PATIENTS WITH GLIOBLASTOMA (SAGA STUDY)

Abstract INTRODUCTION Lymphopenia attributed to postoperative chemoradiotherapy (CRT) can accelerate tumor recurrence and contribute to poor prognosis in GBM. We hypothesize that short course (1-2 weeks) CRT can mitigate lymphopenia compared to standard course and may provide immune benefits for future combination therapy. METHODS GBM patients were randomized on a multi-site phase II study comparing short course (35Gy/5Fx or 40Gy/10Fx depending on target volume) (Arm A) versus standard dose fractionation (60Gy/30Fx or 40Gy/15Fx, Arm B). All patients received concurrent and adjuvant temozolomide (TMZ). This unplanned interim analysis evaluates changes of absolute lymphocyte count (ALC), CD4 and CD8 prospectively at 3-timepoints: baseline (prior to CRT), end of CRT, and 1-month post-CRT. RESULTS To date, 72 patients enrolled (34 Arm A, 38 Arm B). Median age 66 (35-86), ECOG 0-2. Patients characteristics as followed in Arm A vs. Arm B, respectively: female 47% vs. 42%, MGMT promotor methylated 31% vs. 34%, steroid use 46% vs. 45%, ALC 1310 cells/mm3 (330 –9730) vs. 1480 (750 –7750), CD4 531 cells/mm3 (86 –1368) vs. 662 (318 –1671), and CD8 151 cells/mm3 (56 –940) vs. 272 (68 –875). Lymphocytes data were collected in 49 patients (21 Arm A, 28 Arm B). There were signficantly fewer reductions of ALC, CD4 and CD8 in Arm A. Median ALC changes were 95% and 99% of baseline (Arm A) vs 52% and 61% of baseline (Arm B) at the end of CRT and 1-month post-CRT, respectively (p<0.01). Median CD4 changes 93% and 96% of baseline (Arm A) vs 51% and 49% (Arm B), and median CD8 changes 97% and 98% of baseline (Arm A) vs 57% and 71% (Arm B) at the end of CRT and 1-month post-CRT, respectively (p<0.05). CONCLUSIONS This interim analysis suggests that short course RT could reduce treatment-related lymphopenia and immune suppression compared to standard RT, thus could be potentially beneficial to combine with immunotherapy.

Population-Specific Predictors of Immunologic Reconstitution Following Initiation of Combined Antiretroviral Therapy in Children: A Retrospective Observational Study from a 15-Year Cohort of HIV-Positive Children and Adolescents in Eritrea.

In the landscape of HIV treatment, combined antiretroviral therapy (cART) is a cornerstone in managing viral loads and boosting CD4+ T-cell counts. Nevertheless, disparities in treatment outcomes remain persistent, and a subset of children fail to achieve adequate immunologic reconstitution (IR). This study aims to investigate the demographic and clinical factors associated with inadequate IR in HIV-infected children in Eritrea. A retrospective observational study was conducted on 822 children followed at Orotta National Pediatric Referral Hospital between 2005 and 2020. Two distinct analyses were performed, with univariate and multivariate logistic regression models employed to investigate risk factors contributing to inadequate immunologic reconstitution (IR) at the study endpoints of 6- and 12-months post-cART initiation. From the initial cohort of 822 patients [53.4% were males, cohort median age at cART initiation was 78 (IQR: 48-101) months and median absolute CD4 count 270 (151-441) cells/µL]. Two separate analyses were conducted on two cohort subsets with complete data, including 456 children at the 6-month mark and 495 children at 12 months of follow-up. Following 6 months on cART, Immunologic reconstitution was achieved in 87.8% (95% CI: 84.3-91.2) and increased to 90.4% (95% CI: 87.3-93.5) after 12 months of treatment. Independent predictors of inadequate IR after 6 months of cART were higher baseline absolute CD4 counts (aOR = 1.003, (95% CI: 1.002-1.005); p-value <0.001) and NNRTI (EFV: aOR = 3.9, (95% CI: 1.3-11.9); p-value = 0.01). Meanwhile, gender (females: aOR = 0.3, (95% CI: 0.1-0.9, p-value = 0.03) and higher baseline absolute CD4 counts (aOR = 1.003, (95% CI: 1.002-1.005); p-value < 0.001) were independent risk factors of inadequate IR after 12 months of treatment. The study underscores the interplay of baseline CD4 count, gender, and regimen choice in shaping the effectiveness of cART in children. Lower baseline absolute CD4 count was associated with IR after starting cART. Notably, children on EFV had a higher likelihood of inadequate IR after 6 months, and male children were more prone to insufficient IR at 12 months. Targeting these population-specific factors may be pivotal in advancing gender-responsive therapeutic strategies and improving health outcomes for HIV-infected children in sub-optimal clinical settings and resource-constrained environments.

Evaluation of CMV T-cell Mediated Immunity in Children with CMV DNAemia After Allogeneic Hematopoietic Cell Transplantation

Abstract Background Cytomegalovirus (CMV) is among the most common infectious complications following allogeneic hematopoietic cell transplantation (allo-HCT). A commercially available CMV T-cell immune panel (CMV-TCIP, Viracor®), reported as percentages of CMV-specific interferon gamma releasing CD4 and CD8 cells (%CMV-CD4 or %CMV-CD8 IFN-γ), may be used to assess CMV cell-mediated immunity (CMV-CMI). However, the utility of this assay among pediatric allo-HCT recipients remains unknown. Methods A retrospective analysis among pediatric allo-HCT recipients (age ≤18 years) from 1/2020 to 11/2023 who developed CMV DNAemia and had CMV-TCIP testing was performed. Per institutional protocol, weekly quantitative plasma CMV PCR was performed until day +100. Clinically significant CMV infection (csCMVi) was defined as CMV viral load (VL) ≥500IU/ml and pre-emptive therapy (PET) was provided for csCMVi. The most frequent indications for CMV-TCIP testing were to evaluate CMV-CMI to inform the need of CMV virus-specific T-cell therapy (CMV-VST) in the setting of resistant/refractory CMV, to monitor CMV-CMI as a proxy of VST expansion post CMV-VST, or to evaluate the need of ongoing secondary antiviral prophylaxis. A %CMV-CD4 or %CMV-CD8 IFN-γ ≤0.2% was categorized as a poor response, whereas a result &amp;gt;0.2% was classified as an adequate response. Specimens with insufficient quality, high background, or discrepant results from %CMV-CD4 or %CMV-CD8 were classified as a discordant response. Demographics, underlying condition, HCT type, conditioning regimen, antiviral agents and use of VST, VL, and CMV-TCIP results were recorded. Descriptive and nonparametric statistics (median, interquartile range [IQR]) were used for analysis. Results Twenty-seven CMV-TCIP results from 10 unique allo-HCT recipients were analyzed. The median age at transplant was 8.5 years (IQR 2.75-14.3), predominantly for hematologic malignancy (70%). CMV donor/recipient (D/R) serostatus were D+/R+ (60%), D-/R+ (30%) and D+/R- (10%). CMV DNAemia developed post-HCT in 80% (8/10) with median onset of 4 days post-HCT (IQR 3-40) and 2 subjects had known DNAemia prior to HCT. Nine (90%) subjects were started on PET for csCMVi, whereas 1 (10%) received antiviral therapy when VL was &amp;lt;500IU/ml. The first CMV-TCIP was obtained at median of 112 days (IQR 42-130) post-HCT. Despite appropriate antiviral therapy, patients with a peak VL ≥500 IU/mL (obtained within 1 week before and after CMV-TCIP testing) demonstrated significantly lower absolute CD4 (median 12 vs. 198 cells/uL, p=0.02) and CD8 (median 79 vs. 443 cells/uL, p=0.04) counts and %CMV-CD4 IFN-γ (0.04% vs. 0.36%, p=0.02) compared to those with a peak VL &amp;lt;500 IU/mL. Conclusion Our results suggest that CMV-CMI, particularly %CMV-CD4 IFN-γ &amp;gt;0.2%, was observed concurrently with downward trending VL, and may serve as a proxy of VST expansion in patients receiving CMV-VSTs. Figure 1A. The distribution of peak VLs over time based on %CMV-CD4 and %CMV-CD8 IFN-γ are demonstrated in Figure 1B. CMV peak VLs were lower with TCIP testing results reported as adequate combined responses compared to those with poor combined responses. In five subjects (50%) who received CMV-VSTs as part of CMV therapy, increased %CMV-CD4 and %CMV-CD8 IFN-γ were observed post-infusion with an observed downward trend in VL.

Enhanced metabolic health and immune response with bictegravir/emtricitabine/TAF: Insights from a 96‑week retrospective study.

Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF), as a fixed dosed combination, is effective in people living with human immunodeficiency virus (PLWH) previously treated with other therapeutic regimens. The aim of the present retrospective observational real-life study was to analyze virological suppression and immunological, metabolic and safety profile of B/F/TAF. Data were collected from 127 PLHW who switched from any regimen to B/F/TAF. Viral load and virological suppression (viral load <50 copies/ml) were assessed by using real-time PCR methodologies; CD4 and CD8 T cell count as well as CD4/CD8 ratio were determined by cytofluorimetric analyses; other metabolic parameters such as total cholesterol, triglycerides, High- and Low-Density Lipoproteins were assessed by using immunoenzymatic assay. All of the aforementioned parameters were assessed at different timepoints (Baseline, 48 and 96 weeks) for the patients switching to B/F/TAF. Of 127 PLHW [96 (75.6%) male and 31 (24.4%) female, with a mean age of 46.8±10.7 years], 107 PLHW were included in the analysis. The percentage of virologically suppressed PLWH increased from 66.4 to 74.8% at 96 weeks. A statistically significant increase in absolute CD4 (P<0.0001) and CD8 T cell count (P=0.002) was observed. Of importance, there was a significant increase in CD4/CD8 ratio from 0.95 (0.52-1.31) to 1.16 (0.75-1.39) (P=0.003) after 96 weeks. There was a significant decrease in the median values of triglycerides (P<0.0001) and total cholesterol (P<0.0001). Serum creatinine showed a significant increase (P=0.0001). In real life, switching to B/F/T was safe and highly effective both virologically and immunologically. Decrease in cholesterol and triglyceride levels suggested a favorable metabolic profile, which may decrease inflammation, leading to a healthier state and less organ damage.

Management of Stage-4 HIV with Cerebral Toxoplasmosis Coinfection and SIADH Complication

HIV/AIDS stage 4 is the stage where the HIV/AIDS patients have low immunity protection against infections, which can led to coinfections and complications. This case report presented an evaluation of the diagnosis and treatment of an HIV/AIDS stage 4 patient with cerebral toxoplasmosis coinfection and SIADH complications. A man (47 years, 35 kg), married with two children, complaining of weakness, nausea, vomiting, weight loss, and low appetite. Sodium level were measured, showing a 117 mg/dL level that continued to decrease throughout the patient's treatment. Five days later, the patient lost his consciousness with a GCS score of 224, indicating severe brain injury, and was diagnosed with cerebral toxoplasmosis based on the result of head CT-SCAN with contrast. On day 6, the patient was tested positive for HIV and diagnosed with stage 4 with an absolute CD4 count of 4 cells/μl. Therapy was provided by giving pyrimethamine-clindamycin therapy for cerebral toxoplasmosis, followed by Tenofovir, Lamivudine, and Evafirenz as antiretroviral therapy. Treatment for hyponatremia was done by administration of 3% NaCl and tolvaptan. The patient started experiencing an improvement in consciousness after the 10th day of medication, and sodium levels fluctuated throughout the treatments. Patient was discharged after 15 days with clinical improvements.

Effect of highly-active antiretroviral therapy on neuroendocrine regulation of immunogenesis in HIV-infected children

Comparative assay has been made against the parameters of the immune and endocrine systems in 84 HIV-infected children born from HIV-infected mothers. One group of analyzed children (36 patients) did not receive highly-active antiretroviral therapy. Another group (48 patients) received different variants of highly-active antiretroviral therapy. Children aged from 1 to 182 months were examined. Venous blood samples taken from young patients were used to determine leukocyte blood composition considering the relative (%) and absolute number of blood cell counts. Hormone concentration was determined concurrently. CD-molecule expression by mononuclear cells was registered using flow cytofluorimeter. Plasma viral load in HIV-infected children was quantitatively detected with RT-PCR. Statistically significant lowering in the levels of free thyroxin, cortisol and progesterone was observed in children against a background of highly-active antiretroviral therapy as compared to those without HAART use. Correlation assay between the hormone level and the immunological parameters in children not receiving the antiretroviral preparations revealed marked positive correlations among the somatotropic hormone level and CD3+, CD4+ and CD8+ absolute numbers. Similar positive correlation with absolute T-subset number was found against free T4. The progesterone level also positively correlated with relative CD3+ and CD8+ numbers and showed negative correlation with absolute CD4+ amount. There is another positive correlation with relative T-subset number against the dehydroepiandrosterone level in the group of children without antiretroviral preparation therapy. As for HIV-infected group of children, against a background of highly-active antiretroviral therapy, the results of correlation assay between the hormone concentrations and cell parameters were found to significantly vary. There were observed positive correlations between the levels of cortisol and CD3+ (%), cortisol and CD8+ (%), estradiol and CD4/CD8, progesterone and absolute CD8+ number. As with children not receiving the antiretroviral preparations marked positive relation was revealed between the concentration of free thyroxin and absolute values of CD4+. Negative correlations were recorded between the estradiol level and the relative CD3+ numbers. Against a background of applying the antiretroviral preparations the correlation assay conducted between the viral RNA concentration (lg of copy number of mRNA/ml) and analyzed endocrinological parameters was found to have marked positive correlation with HIV concentration demonstrated by estradiol and testosterone. During the antiretroviral therapy, however, the negative correlation between the thyrotropin level and lg concentration of viral RNA was observed. Analytical results of correlation among the viral RNA concentration (lg copy number of mRNA/ml) and analyzed immunological parameters in this group of children evidence for specific ‘normalization’ due to highly-active antiretroviral therapy as the only positive correlation with virus concentration was detected for CD4+T subsets. Therefore, the alteration in endocrine system state in children born from HIV-infected mothers could be of great significance while monitoring the systemic regulation of the immunogenesis.

Sleep actigraphy results and HIV health outcomes in an urban HIV clinic sample

ABSTRACT Sleep disorders are prevalent and interfering conditions that affect people living with HIV (PLWH) at higher rates than the general population. Lower quality sleep has been associated with poorer health-related quality of life and immune function in PWH, though sleep is typically assessed subjectively. The current study aimed to examine the association between objective sleep/wake patterns measured via actigraphy with HIV outcomes. Participants (N = 87) were recruited from a public, urban HIV clinic located in the Southeastern United States. Participants were instructed to wear actigraphy monitors for one week (Range: 5–8 days). Log viral load and absolute CD4 were obtained via medical chart review. Linear regression analyses predicting HIV RNA Viral Load (log transformed) and CD4 Count were employed with three actigraphy sleep variables: sleep efficiency, wake after sleep onset (WASO), and sleep quantity. Backward entry regression with both significant actigraphy predictors, sleep efficiency and WASO, included as predictors resulted in sleep efficiency remaining in the model and WASO being removed. Separate models revealed that each one-unit increase in sleep efficiency was associated with a b = 0.032-point decrease in the log-transformed HIV RNA viral load (p = 0.03) and for each one-unit increase in wake after sleep onset (WASO) was associated with a b = 0.35-point increase in the log-transformed HIV RNA viral load (p = 0.04). Sleep quantity, however, was not, and none were associated with absolute CD4 count. The findings add to the evidence for an association of objectively measured poorer sleep efficiency being associated with higher HIV RNA viral load. Implications for clinical practice include assessing and addressing sleep efficiency as part of comprehensive clinical HIV care.

Empowering adolescents living with perinatally-acquired HIV: tailored CD4+ count assessment for optimized care, the EDCTP READY-study.

The elevated rate of AIDS-related mortality in Sub-Saharan Africa among adolescents living with HIV (ALHIV) is influenced by various factors, notably immunosuppression, within a framework of limited therapeutic alternatives. We aimed to enhance the management of pediatric HIV by assessing the immune response and associated factors in perinatally-infected ALHIV on antiretroviral therapy (ART) in Cameroon. A cohort study was conducted from 2018-2020 among 271 ART-experienced ALHIV in Cameroon. Sociodemographic data, immunological (CD4), and virological (plasma viral load, PVL) responses were measured at enrolment (T0), 6-months (T1), and 12-months (T2) using PIMA CD4 (Abbott/Pantech (Pty) Ltd) and Abbott Applied Biosystem platform (Real-Time PCR m2000RT) respectively. Immunological failure (IF) was defined as absolute CD4 < 250 cells/mm3, and Virological failure (VF) as PVL ≥ 1,000 copies/ml. A linear mixed-effects model with R version 4.4.1 was used to estimate both fixed and random effects, with significance set at p < 0.05. Of the 271 perinatally-infected ALHIV enrolled over three phases, females were predominant (55.7, 55.1, and 56.0%); median age was 14 (IQR: 12-17); majority of the participants were followed-up in urban areas (77.5, 74.5, and 78.6%); and the age distribution favored older adolescents (48.7, 61.2, and 58.5%). Most participants achieved clinical success (93.1, 89.7, 88.9%), predominantly on first-line ART (80.8, 66.2, and 53.0%), with good adherence (64.2, 58.9, and 64.5%). Most participants had secondary education (67.2, 70.1, and 67.5%). Median CD4+ counts fluctuated overtime, with values of 563 (IQR: 249.0-845.0), 502 (IQR: 319.0-783.5), and 628 (IQR: 427.5-817.5), respectively. Of note, being male was linked to a reduction in CD4+ count compared to females, [-200.63 (-379.32 to -21.95), p = 0.028]. Similarly, late adolescence was associated with lower CD4+ counts compared to early adolescence, [-181.08 (-301.08 to -61.09), p = 0.003]. Moreover, participants experiencing VF showed significantly lower CD4+ counts compared to those with undetectable viral loads, [-353.08 (-465.81 to -240.36), p < 0.001]. Additionally, there was a marginally significant interaction between male gender and secondary educational level, [209.78 (-6.94-426.51), p = 0.058]. Among perinatally-infected ALHIV, age, gender, educational level, and virological status are key factors influencing their immune health and treatment outcomes. Prioritizing targeted interventions and close monitoring within these subgroups is crucial for optimal management, employing holistic care strategies that consider not only medical interventions but also psychosocial support and education.

Kikuchi-Fujimoto lymphadenitis in a patient with human immunodeficiency virus infection: The importance of precision pathology.

Kikuchi-Fujimoto lymphadenitis (or histiocytic necrotising lymphadenitis) is a rare disease that is usually benign and self-limiting. A higher prevalence is reported amongst East Asian populations. No clear etiology has been identified although it has been associated with some viruses, rarely the Human Immunodeficiency Virus (HIV) and autoimmune pathologies. To date, there has only been a handful of cases reported globally in association with HIV, and this association is even rarer in the Asian context. A 20-year-old Asian ethnic Malay male, with no past medical history, presented with daily fevers and chills for 2weeks associated with constitutional symptoms and bilateral non-tender cervical, axillary and inguinal lymphadenopathy. Full blood count showed lymphocytosis with large granular lymphocytes. HIV viral load returned positive at >10million copies/mL. His absolute CD4 T helper cell count was 375cells/uL (7%). The rest of the infective and autoimmune workup were negative. Excision biopsy of an enlarged left cervical lymph node revealed Kikuchi lymphadenitis in the proliferative phase, with no evidence of lymphoproliferative disease. He was started on anti-retroviral therapy with resolution of the lymphadenopathy in 3months. We present a case of Kikuchi lymphadenitis associated with HIV. This highlights that Kikuchi lymphadenitis may mimic sinister pathologies (such as tuberculosis and lymphoma) and that it needs to be considered in the differential diagnosis before empirical treatment for tuberculosis or invasive investigations for lymphoma are done.

Posterior Segment Manifestations of Syphilis and Correlation With Serologic Markers of Infection.

Retrospective analysis correlating serologic titers of ocular syphilis with posterior segment manifestations. This study consisted of 40 patients (80 eyes imaged, 68 affected) with positive rapid plasma reagin (RPR) and Treponema Pallidum immunoglobulin G. We collected demographic and presentation data including HIV status, absolute CD4 count, RPR, cerebrospinal fluid-venereal disease research laboratory (CSF-VDRL) test, and retinal zone. We categorized imaging into syphilitic outer retinopathy (SOR), acute syphilitic posterior placoid chorioretinopathy, retinitis/chorioretinitis (RC), and papillitis. Multivariate analysis correlated HIV status, RPR, and VDRL titers with posterior segment findings and zone. Mean age of 42.8 ± 10.7 years, with 70% male patients. Presenting visual acuity (logMAR) 0.66 ± 0.74 did not correlate with RPR, nor was it associated with papillitis, RC, or acute syphilitic posterior placoid chorioretinopathy. Higher RPR (≥ 1:128) positively associated with SOR (P = 0.031) and zone 1 (odds ratio [OR], 1.62; P = 0.02), but negatively associated with zone 2 (OR 0.35; P = 0.005). HIV positivity increased RC odds (OR, 4.45; P = 0.047). Higher RPR correlated with SOR and zone 1, whereas HIV positivity correlated with RC. [Ophthalmic Surg Lasers Imaging Retina 2024;55:511-516.].

Brief Report: Low-Dose Methotrexate Does Not Affect Measures of HIV-1 Persistence in Individuals With Chronically Treated HIV-1 Infection.

People with HIV-1 often have chronic inflammation leading to severe non-AIDS morbidity and mortality. The AIDS Clinical Trials Group Study A5314 sought to lower inflammation with low-dose methotrexate (LDMTX). The primary study outcomes were reported previously but here we present the impact of LDMTX on multiple measures of HIV-1 persistence. A5314 was a phase 2 randomized, double-blind, multicenter trial in 176 adult people with HIV-1 on virally suppressive antiretroviral therapy. LDMTX (5-15 mg/wk) was administered for 24 weeks with an additional 12 weeks of participant follow-up. The current analyses of HIV-1 persistence were restricted to 60 participants (30 LDMTX and 30 placebo) randomly selected from the total population. Plasma HIV-1 RNA, total HIV-1 DNA, and cell-associated HIV-1 RNA (CA HIV-1 RNA) were measured by sensitive quantitative PCR assays. LDMTX treatment had no significant effect on sensitive measures of plasma HIV-1 RNA, HIV-1 DNA, CA HIV-1 RNA, or CA HIV-1 RNA/DNA ratio at any time point or from baseline to week 24. As observed in the main study, absolute peripheral CD4+ and CD8+ T-cell numbers decreased from baseline to week 24 among the 30 participants receiving LDMTX compared with placebo (median decrease of -31.5 CD4+ T cells/µL, -83.5 CD8+ T cells/µL). LDMTX had no significant effect on any measure of HIV-1 persistence in plasma or peripheral blood mononuclear cells. Further studies are needed to determine whether other immunosuppressive and/or immunoreductive interventions are safe and capable of affecting HIV-1 persistence.

Differences in immunological profile in atopic dermatitis patients with and without dupilumab therapy

Our aim is to determine the number of leukocytes, T lymphocytes and B lymphocytes and the expression of activation markers CD200 and CD23 on B lymphocytes in atopic dermatitis (AD) patients (treated and not treated with dupilumab) during the pollen season. We examined 29 patients not treated with dupilumab, 24 patients treated with dupilumab and 40 healthy subjects as a control group. The count of T and B lymphocytes and their subsets were assessed by flow cytometry. The non-parametric Kruskal–Wallis one-factor analysis of variance with post hoc by Dunn’s test with Bonferroni’s modification was used for statistical processing. Although there was a significant improvement in skin findings in patients treated with dupilumab, the changes in immunological profile show a persistent altered immune response characterized by dysregulation and overactivation of B lymphocytes. Dupilumab therapy leads to normalization of relative T regulatory lymphocytes and total memory B lymphocytes and to decreased count of absolute CD8+ T lymphocytes. Why carry out this study?Studies investigating the immunological profile of atopic dermatitis (AD) patients during the pollen season are rare. There are no studies investigating the count of B lymphocytes (CD5+, CD22+ and CD73+ B lymphocytes) and the expression of activation markers CD23 and CD200 on B lymphocytes and on their subsets during pollen season in AD patients treated and non-treated with dupilumab therapy. What was learned from the study?In atopic dermatitis (AD) patients with and without dupilumab therapy, we confirmed the significantly higher count of absolute neutrophils, absolute monocytes, absolute eosinophils, absolute basophils, non-switched B lymphocytes, transitional B lymphocytes, CD23 memory, naive, non-switched, switched and total CD23 B lymphocytes, the relative count of CD200 memory and CD200 switched B lymphocytes. In dupilumab treated patients, we confirmed the significantly higher count of relative eosinophils, relative CD16+ eosinophils, relative CD200 non-switched B lymphocytes and lower count of absolute CD8+ T lymphocytes. Further studies should focus on investigating the effect of dupilumab on CD8+ T lymphocytes and their subpopulations. In patients without dupilumab therapy, we confirmed the significantly higher count of relative neutrophils, relative T regulatory lymphocytes and total memory B lymphocytes. The changes in the count of CD5+, CD22+ and CD73+ B lymphocytes were not observed during pollen season in both groups of AD patients.

Tofacitinib therapy in systemic lupus erythematosus with arthritis: a retrospective study.

To estimate the effectiveness and safety of tofacitinib in treating systemic lupus erythematosus (SLE) patients with arthritis. This research was a retrospective cohort study that focused on SLEpatients who had arthritis and were treated with tofacitinib at the Department of Rheumatology and Immunology from January 2020 to January 2022. Clinical outcomes, disease activity, immunological parameters, and adverse events were systematically evaluated pre- and post-treatment at 4, 12, and 24weeks. Twenty-two patients were analyzed. At the 4-week mark, 5 (22.7%) patients were partially relieved, and 17 (77.3%) unalleviated. By the 12-week assessment, CR off corticosteroids was observed in four patients (18.2%), and CR on corticosteroids was seen in six patients (27.3%), with an additional six (27.3%) maintaining partial remission. At 24weeks after treatment, three patients (13.6%) achieved CR off corticosteroids, ten patients (45.5%) achieved CR on corticosteroids, and all patients received remission. Compared to before treatment, The SLEDAI and PGA scores significantly improved. The level of C3 was increased significantly, and the absolute CD3+ T cell count, the 28-tender and the 28-swollen joint count, and the levels of serum IL-6 were significantly decreased at 24weeks after treatment. Tofacitinib demonstrates significant therapeutic potential in SLE patients with arthritis, with a safety profile, and the therapeutic mechanism of tofacitinib may be related to reducing IL-6 expression and inhibiting T cell activation. Key Points • Tofacitinib demonstrates significant therapeutic potential in SLE patients with arthritis • The therapeutic mechanism of tofacitinib may be related to reducing IL-6 expression and inhibiting T cell activation.

Longitudinal Study of Cognitive Function in People with HIV and Toxoplasmic Encephalitis or Latent toxoplasma Infection.

Neurocognitive impairment (NCI) may occur during and persist even after recovery from HIV-related CNS co-infections such as toxoplasmic encephalitis (TE). The long-term cognitive effects of TE and latent toxoplomasmic infections (LTI) among persons with HIV (PWH) are unknown. We measured longitudinal effects on NC functioning in PWH with TE compared to LTI or no toxoplasmal infection. PWH (n = 345) followed in two longitudinal cohort studies underwent comprehensive neurocognitive assessments and an anti-Toxoplamic IgG assay. Participants were classified into one of three groups: TE+ (n = 39), LTI+ (n = 34), LTI- (n = 272). The primary outcome was change in neurocognitive function between baseline and 7-year visit. The mean age was 48 ± 11 years, mean educational level 13 ± 3 years, and 13% were female. TE+ patients were less likely to have undetectable viral loads (≤50 copies/mL) and had lower absolute CD4 counts. The TE+ group had the highest prevalence of NCI globally and in domains of verbal, executive function, learning, recall, working memory, processing speed and motor at baseline and at 7-year follow-up. Changes in longitudinal NC function over 7 years were small and did not differ significantly among all groups, except that speed of information processing improved more in TE+ compared with LTI- participants. PWH with a history of TE had cognitive impairment over a broad range of severity at both baseline and last follow-up. Changes in cognition from baseline to last examination in all groups were minimal and did not differ significantly among the groups with the exception of speed of information processing.

Immune effect and prognosis of transcatheter arterial chemoembolization and tyrosine kinase inhibitors therapy in patients with hepatocellular carcinoma.

The combination of transcatheter arterial chemoembolization (TACE) and tyrosine kinase inhibitors (TKIs) has shown broad prospects in prolonging the survival of patients with hepatocellular carcinoma (HCC). TACE and TKIs can affect the immune microenvironment in patients with HCC. To determine the overall effects and differences between TACE and different TKIs combinations on the immune microenvironment. Data and immune cell profile test results from 213 HCC patients treated with TACE combined with apatinib, lenvatinib, sorafenib, or donafenib before and after 3 wk of treatment were collected. Monocytes were co-cultured with LM3 liver cancer cells, and their ability to inhibit cancer cell growth was analyzed using the MTT method and a nude mouse subcutaneous tumorigenesis experiment. Simulated combined therapy was done using an in situ liver cancer C57BL/6 male mouse model, and the immune response of tumor tissues was analyzed using immunohistochemistry. Compared to before combination therapy, the proportion of programmed cell death protein 1 (PD-1)+ mononuclear cells and the number of CD4+ T cells decreased in the TACE + apatinib group, while the number of absolute count of CD4+ and CD8+ T cells increased in the TACE + lenvatinib group. Furthermore, the number of regulatory cells decreased in the TACE + donafenib group, whereas the number of CD8+ T and natural killer cells increased. Additionally, monocytes in the TACE combined with donafenib or lenvatinib groups had a stronger ability to inhibit cancer cell growth than those in the other groups. Combining TACE with donafenib or lenvatinib increased CD8+ T cell infiltration into the tumor tissue. In addition, the proportion of PD-1+ in CD8+ cells, absolute CD8+ T lymphocyte count, and regulatory T cells proportion were independent prognostic factors affecting the survival time of patients with HCC. TACE, in combination with different TKIs, produces different immune responses. Specifically, TACE combined with donafenib or lenvatinib may induce strong anti-tumor immune responses.

A phase 1 clinical trial of NKTR-255 with CD19-22 CAR T-cell therapy for refractory B-cell acute lymphoblastic leukemia

AbstractAlthough chimeric antigen receptor (CAR) T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed/refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, 9 of whom successfully received CAR19-22 followed by NKTR-255. There were no dose-limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with 8 of 9 patients (89%) achieving measurable residual disease–negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T cells in the blood and 10-fold increases in cerebrospinal fluid CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible, and associated with high rates of durable responses. This trial was registered at www.clinicaltrials.gov as #NCT03233854.

Neonatal B-Cell Levels and Infant Health in Newborns Potentially Exposed to Anti-CD20 Monoclonal Antibodies During Pregnancy or Lactation.

To report CD19+ B-cell counts and possible adverse effects on infants of mothers exposed to anti-CD20 mAbs ≤6 months before/during pregnancy or lactation. We conducted a retrospective study using data from the German nationwide neuroimmunologic pregnancy registry. Inclusion criteria involved infants whose mothers received anti-CD20 mAbs ≤6 months before/during pregnancy or lactation, with ≥1 postnatal CD19+ B-cell count. Main outcomes were absolute and relative CD19+ B-cell counts. Comparison with reference values was performed conservatively in a subgroup with maternal exposure ≤3 months before/during pregnancy. Additional outcomes included pregnancy results, severe infections, and lymphocyte counts. The cohort comprised 49 infants (F:M 25:24) exposed to anti-CD20 mAbs ≤6 months before/during pregnancy or lactation. CD19+ B-cell and lymphocyte counts in 40 infants with maternal exposure ≤3 months before/during pregnancy were comparable with normative values. Only 2 cases of complete CD19+ B-cell depletion occurred after second-trimester and third-trimester ocrelizumab exposure, with repopulation observed within 2 months. Exclusive lactation exposure had no significant effect on infants' absolute CD19+ B-cell counts. Administering anti-CD20 mAbs before or at the pregnancy onset, or during lactation, seems safe without significant impact on infant B-cell development. However, second-trimester or third-trimester exposure can cause CD19+ B-cell depletion due to placental transfer, necessitating monitoring and postponing live vaccines.

A Case of Disseminated Cryptococcus in an HIV-Positive Patient

A 69-year-old male with a history of untreated Human Immunodeficiency Virus (HIV) was admitted to the emergency department for symptoms such as cough, shortness of breath, lethargy, and weight loss. His physical examination revealed severe wasting, oral thrush, and hypoxia. Chest imaging revealed cavitary lesions and blood work showed an absolute CD4 count of 23 cells/mm3. An IR-guided biopsy revealed abundant necrosis and scattered narrow-based fungal organisms consistent with Cryptococcus neoformans infection. The patient was treated with liposomal amphotericin B and flucytosine. Due to the increased risk of Immune Reconstitution Inflammatory Syndrome (IRIS), HIV treatment was deferred. The patient deteriorated, transitioned to comfort care, and unfortunately expired. INTRODUCTION Cryptococcus neoformans is a ubiquitous environmental yeast and a leading cause of invasive fungal infection in humans with significant morbidity and mortality that affects both immunocompetent and immune-compromised hosts.1,2 Globally, there are approximately 1 million cases of AIDS-related cryptococcosis each year, leading to over 600,000 deaths. This represents a prevalence of 6.0% (95% CI 5.8–6.2) among people with a CD4 cell count of less than 100 cells per uL.2 The transmission mode is by inhalation of microscopic fungus (desiccated yeast or spores). Immunosuppression is the strongest risk factor for disease development, including HIV infection, stem cell and solid organ transplantation, prolonged immunosuppressive therapy, invasive medical procedures, hematological malignancies, advanced age, and prematurity.1,2,3 Treatment usually involves a fungicidal regimen of IV liposomal amphotericin B, plus flucytosine followed by oral fluconazole.4,5 Overall, 90-day all-cause mortality in patients with cryptococcal infection is 19.4%. Mortality rates are significantly higher in HIV/transplant patients at 90 days (41.7% versus 8.3%, p = 0.017) and one year (41.7% versus 12.5%, p = 0.047).6,7 This case describes a 69-year-old HIV-positive patient who presented with multisystemic manifestations and cavitary lung lesions with blood and cerebrospinal fluid (CSF) findings of cryptococcal antigen and positive fungal culture and lung biopsy confirmation of Cryptococcus.

Elevated Inflammation Associated with Markers of Neutrophil Function and Gastrointestinal Disruption in Pilot Study of Plasmodium fragile Co-Infection of ART-Treated SIVmac239+ Rhesus Macaques.

Human immunodeficiency virus (HIV) and malaria, caused by infection with Plasmodium spp., are endemic in similar geographical locations. As a result, there is high potential for HIV/Plasmodium co-infection, which increases the pathology of both diseases. However, the immunological mechanisms underlying the exacerbated disease pathology observed in co-infected individuals are poorly understood. Moreover, there is limited data available on the impact of Plasmodium co-infection on antiretroviral (ART)-treated HIV infection. Here, we used the rhesus macaque (RM) model to conduct a pilot study to establish a model of Plasmodium fragile co-infection during ART-treated simian immunodeficiency virus (SIV) infection, and to begin to characterize the immunopathogenic effect of co-infection in the context of ART. We observed that P. fragile co-infection resulted in parasitemia and anemia, as well as persistently detectable viral loads (VLs) and decreased absolute CD4+ T-cell counts despite daily ART treatment. Notably, P. fragile co-infection was associated with increased levels of inflammatory cytokines, including monocyte chemoattractant protein 1 (MCP-1). P. fragile co-infection was also associated with increased levels of neutrophil elastase, a plasma marker of neutrophil extracellular trap (NET) formation, but significant decreases in markers of neutrophil degranulation, potentially indicating a shift in the neutrophil functionality during co-infection. Finally, we characterized the levels of plasma markers of gastrointestinal (GI) barrier permeability and microbial translocation and observed significant correlations between indicators of GI dysfunction, clinical markers of SIV and Plasmodium infection, and neutrophil frequency and function. Taken together, these pilot data verify the utility of using the RM model to examine ART-treated SIV/P. fragile co-infection, and indicate that neutrophil-driven inflammation and GI dysfunction may underlie heightened SIV/P. fragile co-infection pathogenesis.

Absolute CD4 count and percentage values among Libyan patients with HIV by single-platform flow cytometry.

Single-platform flow cytometry technology together with CD45-gating is becoming the method of choice for absolute CD4 T cell enumeration. Immunological assessment of HIV patients by monitoring CD4 can provide valuable information on antiviral treatment response and disease progression. A total of 97 HIV-positive individuals were recruited from 2 hospitals in Tripoli, Libya, and 14 healthy blood donors. The HIV-infected individuals were classified by CD4+ count into HIV-positive (>200 cells/µL) or AIDS (≤200 cells/µL) groups. CD4+ and CD8+ cell counts were determined and compared among the groups and with similar published data. The mean ± SD CD4+ cell counts were 1106 ± 442.8 cells/µL in healthy individuals, 460 ± 219.7 cells/µL in the HIV-positive group, and 78 ± 64.3 cells/µL in the AIDS group. The mean ± SD CD4+/CD8+ ratio was 1.6 ± 0.58, 0.4 ± 0.22, and 0.1 ± 0.1, respectively. CD4+ counts in Libyan healthy adults might be higher than those reported in several studies in other regions, whereas CD4+ counts in Libyan AIDS patients seem lower. Reference values for T lymphocyte counts in Libyan healthy individuals should be investigated more extensively, and the reasons why Libyan AIDS patients seem to have such lower CD4+ counts should be examined.