Lower CD8 Counts Research Articles

SPECTRUM OF PRIMARY IMMUNODEFICIENCY DISORDERS IN CHILDREN IN KASHMIR

Primary immunodeficiency disorders (PIDs) are a genetically heterogeneous group of disorders that affect distinct components of the innate and adaptive immune system. To date, more than 300 different PIDs have been identified, most of these manifesting by 1 year of life. Recognition of these disorders by the clinician is important because appropriate therapy will not only prevent death but also reduce the long-term morbidity from recurrent infections. There is often under diagnosis of these conditions or a delay in the diagnosis of treatable conditions. Delay in the diagnosis of PID disorders is not only evident in undeveloped or developing countries, but is also reported in developed countries. On the other hand, early diagnosis and easy access to care and treatment play key roles in improving the survival, quality of life, and prognosis of patients with these disorders. Evaluation of immune function should be initiated for children with clinical manifestations for a specific immune disorder or with unusual, chronic, or recurrent infections such as systemic bacterial infections, serious respiratory bacterial infections, liver or brain abscesses, infections with unusual pathogens, and infections with common childhood pathogens but of unusual severity. No study regarding the pattern of diseases, clinical profile, complications and outcomes of primary immunodeficiency diseases has been done in Kashmir, which is geographically, socially, culturally, and ethnically a unique population. This study will through some light on the spectrum of primary immunodeficiency Disorders (PID) in this part of the world and help policy makers to set up an ideal platform for the management of these comparatively ignored but important diseases. Aims And Objectives: To study the clinical profile, disease complications and short-term outcomes of patients over a period of two years with Suspected primary immunodeficiency Disorders (PID) to ascertain the association of immunoglobulin levels and CD counts with PID. Materials And Methods: This Prospective observational study was conducted in the Department of Pediatrics, Government Medical College, Srinagar. A detailed history was taken from each patients attendant after confirming the reliability of the attendant (ideally mother or father) with special reference to the presence/ absence of manifestation of Primary immunodeficiency disorders. A thorough clinical examination was done after obtaining written informed consent from all patients for their inclusion in the study. In this study, 30 patients ,0-18 years of age, who met the inclusion criteria were included.: The duration of the study was two years and three months starting from September 2020-December 2022 (The first 3 months for patient recruitment). Data was compiled using Microsoft 2016 Excel spreadsheet and analyzed by IBMSPSS V.23. Descriptive statistics was computed to describe the sociodemographic characteristics of participants and to summarize the distribution of each of the dependent (outcome) and independent variables. Results: In this study, 30 patients with suspected Primary immunodeficiency disorders (PIDs) were recruited for three months and each patient was followed for two years as per study protocol. About 47% of the patients were products of 3rd degree consanguineous marriage, 33.3% of patients had a family history of Primary immunodeficiency disorders and 6.7% had received blood transfusions presently or in the past.Serum immunoglobulins profile was deranged in more than half of the patients. IgM was seen to be low in 60% of the patients, IgG and IgA were low in 36.7 % of the patients and IgE was high in 26% of the patients with suspected primary immunodeficiency disorder. CD4 and CD19 counts were seen to be low in 20% of patients and 16.7% of patients reported low CD8 count. Other diagnostic tests like Broncho-alveolar lavage (BAL) showed growth in 3.3% of patients, WAS protein was low in 16.7 % of the patients.The association of CD4 Counts was found to be statistically significant with p value <0.002 by Fishers Exact test. Patients with low CD4 count had 83.3% mortality as compared to those having normal counts. There was a strong association seen in patients with low CD8 counts with mortality among PID patients and p valve was highly significant (p valve <0.0005).

265. Cryptococcal disease in Covid-19 infection: Case series from South Texas

Abstract Background Covid-19 infection is associated with a lack of immune resilience that may be magnified using immunomodulators to suppress the cytokine storm, facilitating the emergence of opportunistic infections. We describe five cases of cryptococcal infection complications among Covid-19 hospitalized patients. Methods This was a retrospective cohort study based on chart review performed at the Audie Murphy Veteran Affairs Hospital from 8/2020 to 8/2021; a level 1A facility with 232 beds and an active bone marrow transplantation program. We included patients aged ≥ 18 with a diagnosis of Covid-19 and subsequent Cryptococcal infection based on cultures or antigen testing. Results Our patients were all male with ages ranging between 64 to 80 years. Three had underlying type II diabetes, hypertension, and two had end-stage renal disease. Only one had underlying immunosuppression with hydroxychloroquine for rheumatoid arthritis and one had underlying cirrhosis. Four patients had disseminated disease/fungemia while one had localized pulmonary disease. All the cases had low CD4 counts (158-300) and low CD8 counts (92-290). Two of the fungemia cases were diagnosed by blood culture and the other two by serum cryptococcus antigen test. All the patients had received corticosteroids with or without remdesivir, while one received additional tocilizumab, one baricitinib and one convalescent plasma infusion. Four cases of fungemia received liposomal amphotericin B and three of them received additional flucytosine. The patient with cryptococcal pulmonary disease received only fluconazole. Four patients expired at 28 days after diagnosis, only one recovered and is still alive at 1-year follow up. Table 1.Case details. ESRD: end stage renal disease; DM-2: diabetes mellitus type ; HTN: hypertension; A-fib: Atrial Fibrillation; HFpEF: heart failure with preserved ejection fraction; PVD: peripheral vascular disease; RA: rheumatoid arthritis; PTSD: post traumatic stress disorder; BPH: benign prostatic hyperplasia; CAD: coronary artery disease; HLD: hyperlipidemia; CVA: cerebrovascular accident. Conclusion Cryptococcus infection has been described among patients with Covid-19 during the pandemic. This may be due to immunosuppression caused by the Covid-19 infection and its related-treatments. Most of our patients presented with disseminated cryptococcus infection complicating covid-19 with resulting high mortality rates. Low CD4/CD8 counts and corticosteroid use were documented in all cases. Further studies are needed to better characterize at-risk patients for cryptococcal infection that may benefit from cryptococcal prophylaxis. Disclosures All Authors: No reported disclosures.

Immunologic Abnormalities Associated With Health Status of Heart Recipients Long Term After Transplantation

With improvements in survival rates, health-related quality of life is an important outcome parameter to evaluate the effectiveness of transplantation. We aimed to identify potential immunologic abnormalities as factors associated with poorer health-related quality of life at distinct scales of the 36-Item Short Form Health Survey in heart transplant recipients long term after transplantation. One hundred heart transplant recipients were evaluated in a single center. Short-form 36 questionnaires were sent by mail to participants. All patients were clinically and immunologically evaluated after the first year of heart transplantation. A high prevalence of several immunologic abnormalities persisted even after the first year of transplantation, including IgG hypogammaglobulinemia, low IgG-specific antipneumococcal antibodies, C4 hypocomplementemia, CD8 T-cell lymphocytopenia, and CD19 B-cell lymphocytopenia. Older recipients (>55 years), posttransplant diabetes, digestive complications, and posttransplant infections were associated with lower physical functioning scores (scale < 60). Older recipients (>55 years), pretransplant diabetes, pretransplant arterial hypertension, posttransplant digestive complications, and lower CD8 counts were associated with lower physical role scores (scale <25). In a single center study, lower CD8 cell counts were found to be associated with poorer health status in heart recipients after the first year of transplantation.

Digital Image Analysis of CD8+ and CD3+ Tumor-Infiltrating Lymphocytes in Tongue Squamous Cell Carcinoma.

PurposeThe presence of CD8+ tumor-infiltrating lymphocytes (TILs) has been reported to be associated with treatment outcomes in many types of solid tumors. However, the results vary due to the various methods of visual estimation and subjective interpretation. The current study is the first to use digital image analyses to evaluate the density of CD8+/CD3+ TILs in tongue squamous cell carcinoma (TSCC).Patients and MethodsFrom 2005 to 2015, a cohort of 258 TSCC patients were consecutively enrolled in this study. After immunohistochemistry on representative sections, the density of CD8+/CD3+ TILs at tumor invasive margins was evaluated by digital image analysis. The subjects were stratified by the median values of CD3+ cell density, CD8+ cell density, CD8/CD3, and scores (0, 1, and 2) to demonstrate the association with various clinicopathological manifestations.ResultsLow CD8+ TIL counts were associated with advanced tumor stages (p=0.034), and low CD8/CD3 ratios were associated with perineural invasion (p=0.043). Both parameters were also associated with increased tumor depths (p=0.034 and 0.004, respectively). Univariate analyses revealed that advanced tumor stages, perineural invasion, extranodal extension, tumor depth, lower CD8 counts, and lower scores (score 0 vs 2) were associated with poorer overall survival, and multivariate analysis further indicated that extranodal extension and low scores (score 0 vs 2) were both independent factors for overall survival (p < 0.0001 and p = 0.0369, respectively).ConclusionThe use of digital image analysis to assess CD8+ TILs at the invasive margins provides an objective indicator of prognoses including overall survival.

Clinical and pathological associations of PTEN expression in ovarian cancer: a multicentre study from the Ovarian Tumour Tissue Analysis Consortium

BackgroundPTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study.MethodsTumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests.ResultsDownregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients; p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression (p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC (p value < 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC (p value = 0.019) and associated with higher CD8 counts (p value = 0.0016).ConclusionsPTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.

Compromised CD4:CD8 ratio recovery in people living with HIV agedover 50 years: an observational study.

ObjectivesPersistent CD4:CD8 ratio inversion (< 1) is associated with mortality in older people. We investigated the interaction of the effects of baseline CD8 count and age at HIV diagnosis on CD4:CD8 ratio recovery with antiretroviral therapy (ART).MethodsAn observational study (1 January 2007 to 31 December 2016) was carried out using routinely collected data from the HIV outpatient services at Imperial College Healthcare NHS Trust, London, UK. CD4 and CD8 counts, prior to and during ART, treatment during primary HIV infection (PHI) and HIV‐1 viral load were included in univariate and multivariate analyses using Cox proportional hazard regression.ResultsData were included for 876 patients starting ART, where HIV suppression was achieved. Of these patients, 741 of 876 (84.6%) were male and 507 of 876 (57.9%) were Caucasian. The median time on ART was 38 [interquartile range (IQR) 17–66] months. CD8 count change on ART was bidirectional; low CD8 counts (≤ 600 cells/μL) increased and high CD8 counts (> 900 cells/μL) decreased. The median pre‐ART CD4:CD8 ratio was 0.41 (IQR 0.24–0.63), and recovery (≥ 1) occurred in 274 of 876 patients (31.3%). Pre‐ and post‐ART CD4:CD8 ratios were lower in those aged > 50 years compared with young adults aged 18–30 years (P < 0.001 and P = 0.002, respectively). After adjustment, younger age at HIV diagnosis (P < 0.001) and treatment during PHI (P < 0.001) were favourable for CD4:CD8 ratio normalization.ConclusionsOlder age (> 50 years) at HIV diagnosis was associated with persistent CD4:CD8 ratio inversion, whereas treatment of PHI was protective. These findings confirm the need for testing and early treatment of people aged > 50 years, and could be used in a risk management algorithm for enhanced surveillance.

Innate and Adaptive Immune Defects in Chronic Pulmonary Aspergillosis.

We evaluated the expression of biomarkers of innate and adaptive immune response in correlation with underlying conditions in 144 patients with chronic pulmonary aspergillosis (CPA). Patients with complete medical and radiological records, white cell counts, and a complete panel of CD3, CD4, CD8, CD19, and CD56 lymphocyte subsets were included. Eighty-four (58%) patients had lymphopenia. Six (4%) patients had lymphopenia in all five CD variables. There were 62 (43%) patients with low CD56 and 62 (43%) patients with low CD19. Ten (7%) patients had isolated CD19 lymphopenia, 18 (13%) had isolated CD56 lymphopenia, and 15 (10%) had combined CD19 and CD56 lymphopenia only. Forty-eight (33%) patients had low CD3 and 46 (32%) had low CD8 counts. Twenty-five (17%) patients had low CD4, 15 (10%) of whom had absolute CD4 counts <200/μL. Multivariable logistic regression showed associations between: low CD19 and pulmonary sarcoidosis (Odds Ratio (OR), 5.53; 95% Confidence Interval (CI), 1.43–21.33; p = 0.013), and emphysema (OR, 4.58; 95% CI; 1.36–15.38; p = 0.014), low CD56 and no bronchiectasis (OR, 0.27; 95% CI, 0.10–0.77; p = 0.014), low CD3 and both multicavitary CPA disease (OR, 2.95; 95% CI, 1.30–6.72; p = 0.010) and pulmonary sarcoidosis (OR, 4.94; 95% CI, 1.39–17.57; p = 0.014). Several subtle immune defects are found in CPA.

A Parameter for IL-10 and TGF-ß Mediated Regulation of HIV-1 Specific T Cell Activation Provides Novel Information and Relates to Progression Markers

HIV replication is only partially controlled by HIV-specific activated effector T cells in chronic HIV infection and strategies are warranted to improve their efficacy. Chronic T cell activation is generally accompanied by regulation of antigen-specific T cell responses which may impair an effective control of chronic infections. The impact of HIV-induced T cell regulation on individual patients’ disease progression is largely unknown, since classical T cell activation assays reflect net activation with regulation as unknown contributing factor. We here explore a quantitative parameter for antigen-induced cytokine-mediated regulation (RAC) of HIV-specific effector T cell activation by functional antibody-blockade of IL-10 and transforming growth factor-β. HIV Env- and Gag-specific T cell activation and RAC were estimated in peripheral blood mononuclear cells from 30 treatment-naïve asymptomatic HIV-infected progressors (CD4 count 472/µl, HIV RNA 37500 copies/ml) stimulated with overlapping peptide panels for 6 days. RAC was estimated from differences in T cell activation between normal and blocked cultures, and related to annual CD4 loss, immune activation (CD38) and microbial translocation (plasma lipopolysaccharides). RAC was heterogeneously distributed between individual patients and the two HIV antigens. Notably, RAC did not correlate to corresponding classical activation. Env RAC correlated with CD38 and CD4 loss rates (r> = 0.37, p = <0.046) whereas classical Gag activation tended to correlate with HIV RNA (r = −0.35, p = 0.06). 14 patients (47%) with low RAC’s to both Env and Gag had higher CD8 counts (p = 0.014) and trends towards lower annual CD4 loss (p = 0.056) and later start with antiretroviral treatment (p = 0.07) than the others. In contrast, patients with high RAC to both Env and Gag (n = 8) had higher annual CD4 loss (p = 0.034) and lower CD8 counts (p = 0.014). RAC to Env and Gag was not predicted by classical activation parameters and may thus provide additional information on HIV-specific immunity. RAC and other assessments of regulation deserve further in-depth exploration.

The Chemokine Receptor CXCR4 is More Frequently Expressed in Breast Compared to Other Metastatic Adenocarcinomas in Effusions

This objective of this study was to investigate the expression of chemokine receptors in tumor cells and leukocytes in breast carcinoma effusions. The expression of leukocyte markers (CD3/4/8/14/16/19) and chemokine receptors (CXCR1/4, CCR2/5/7) was studied in 21 breast carcinoma effusions using flow cytometry. Breast carcinoma cells expressed CXCR4 in 7/21 (33%) effusions, with less frequent expression of CXCR1, CCR5, and CCR7. CXCR2 and CCR2 were absent. Lymphocytes showed frequent CXCR4, CCR5, and CCR7 expression, while CXCR1, CXCR2, CCR2 were rarely or never detected. Macrophages expressed all six receptors except for CXCR2. Comparative analysis of breast carcinoma effusions with previously studied ovarian and cervical/endometrial adenocarcinomas (ACs) showed significantly higher CXCR4 expression in breast carcinoma cells compared to the other gynecological ACs (p = 0.001). Breast and cervical/endometrial carcinoma effusions showed different expression of chemokine receptors in lymphocytes (lower CXCR1, higher CXCR4 and CCR7 levels; p = 0.012, p = 0.005, p < 0.001, respectively) and macrophages (higher CCR7 levels; p < 0.001), as well as lower CD8 counts (p < 0.001) and higher CD19 counts (p = 0.001) compared to ovarian carcinoma effusions. Higher numbers of CD8-positive lymphocytes (p = 0.080) and higher CCR7 monocyte expression (p = 0.087) were associated with a trend for shorter disease-free survival. In conclusion, breast carcinoma cells express CXCR4, a unique feature among metastatic ACs in effusions, with rare expression of other chemokine receptors. Chemokine receptor expression in leukocytes and lymphocyte counts significantly differ from those of ovarian carcinoma effusions. The prognostic role of CCR7 expression in monocytes and CD8 counts in breast carcinoma effusions merits further research.

Significant alterations in peripheral blood lymphocyte subsets in patients with somatoform disorder.

Previous studies have suggested that somatoform disorders (SFD) might be associated with changes in the function of the central and autonomic nervous systems. The aim of this study was to examine the possible immunological differences between SFD and healthy controls. Twenty-four patients with SFD and 13 healthy individuals completed the psychological questionnaires to assess symptom reporting [Symptom Checklist-90 Revised (SCL-90-R)] and to diagnose for SFD [Screening for Somatoform Symptoms scale (SOMS-scale)]. Participants also provided a blood sample taken in the morning, which was analysed with an automated cell counter to determine the number of leucocytes per μl and with flow cytometry to determine lymphocyte subsets. With the exception of a higher T4/T8 ratio in the patient group, which was mainly because of lower CD8 counts, there were no significant differences in the absolute number of lymphocytes (subsets) between patients with SFD and healthy subjects. A positive correlation between B-lymphocyte subsets (CD19+CD22+, CD19+CD5+, CD19+CD3-) to all scales of the SCL-90-R, except somatisation, were found in SFD. Additionally, a positive correlation was found in SFD between CD14+CD16+ monocytes and somatisation (0.573) on the SCL-90-R scale. These data indicate that patients with SFD have an enhanced humoral immunity as shown by increased B-cell numbers and furthermore an elevated T4/T8 ratio because of lower CD8 suppressor cells. Further studies will be required to determine whether these alterations in lymphocyte subsets are directly involved in the pathophysiology of SFD.