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CD4+ T-lymphocyte counts in HIV infection: are European standards applicable to African patients?

CD4+ lymphocyte count (CD4+ LC) is a widely used marker of Human Immunodeficiency Virus (HIV) immune impairment. Physiological lymphocytosis is frequently encountered in Africans. Therefore, we tried to determine if given CD4+ LC levels are of similar significance in European versus African HIV-infected individuals. Lymphocyte phenotyping of 750 HIV-infected adults was retrospectively analyzed. Three hundred and seventy patients were consecutively selected in Paris, France; 185 in Abidjan, Côte d'Ivoire; and 195 in Bobo-Dioulasso, Burkina Faso. In the three settings, lymphocyte phenotyping was performed by flow cytometry using similar protocols. Data from Abidjan and Bobo-Dioulasso were combined on the basis of geographic proximity and contrasted with those from Paris. Geometric mean levels of Total Lymphocyte Count (TLC), CD4+ LC, CD8+ lymphocyte count (CD8+ LC), and CD4:CD8 ratio, adjusted for percentage of CD4+ T-cells (%CD4+), were compared between Africans and Europeans. For a given %CD4+, TLC and CD4+ LC but not CD8+ LC tended to be about one third higher in West African than in French adults (p < 0.0001). Approximate equivalencies of absolute CD4+ counts in French and West African HIV-infected adults suggest that where thresholds of 200 and 500 CD4+ cells/microliter are applied in Europe, it might be appropriate to apply a threshold of approximately 250 and 700 CD4+ cells/microliter in West Africa, respectively. Establishing indicators of progression of HIV infection with locally appropriate thresholds may represent important steps toward improvement of HIV disease management in Africa.

Adult↗

Quantification of the variation due to laboratory and physiologic sources in CD4 lymphocyte counts of clinically stable HIV-infected individuals.

We have conducted a study to quantify the amount of variation in the CD4 lymphocyte counts of HIV-infected individuals due to laboratory and physiological factors. Thirty HIV-infected male volunteers had blood drawn on six occasions: three times in each of 2 weeks, 4 weeks apart. Two tubes of blood were drawn at each visit, and duplicate measurements were obtained from one of the tubes of blood. Differences between duplicate measurements from a single tube of blood and between CD4 counts obtained from two tubes of blood drawn on the same day were attributed to laboratory factors. Differences between CD4 counts obtained on different days were attributed to a combination of laboratory factors and physiologic factors, which included the effects of exercise, tobacco, and the consumption of alcohol and caffeine. The mean absolute CD4 count at the first visit was 450 (range 86-1,081). The short-term coefficient of variation of CD4 count was 13.7 (95% CI: 12.9, 14.6). Physiologic and laboratory factors accounted for 85% and 15% of the variation in CD4 counts, respectively. Variation in the absolute white blood cell count, lymphocyte percentage, and CD4 percentage accounted fo 52%, 29%, and 19% of the physiologic variation in CD4 counts, respectively. Our results confirm a high degree of short-term variability of CD4 counts among HIV-infected individuals, which can be largely attributed to physiological factors. This variability can be minimized more effectively by repeating CD4 counts over time than by repeating measurements at a single visit.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Intraepithelial lymphocyte count and crypt hyperplasia measure the mucosal component of the graft-versus-host reaction in mouse small intestine.

We have used measurements of intestinal epithelial cell kinetics and counts of intraepithelial lymphocytes and mucosal mast cells to measure small intestinal mucosal changes during the proliferative and recovery phases of graft-vs.-host reaction in neonatal mice. Unirradiated (CBA x BALB/c)F1 mice were injected with parental spleen cells or with culture medium at 6-8 days of age, and followed up for 9 wk thereafter. The spleen index was used as a measure of the graft-vs.-host reaction, a stathmokinetic technique with microdissection was used to measure villus and crypt lengths and crypt cell production rate, and intraepithelial lymphocytes and mucosal mast cells were counted in histologic sections. Intraepithelial lymphocyte count rose within 24 h of induction of the graft-vs.-host reaction and increases in crypt length and in crypt cell production rate occurred within 3 days. These indices exactly parallel the spleen index during the proliferative phase of the graft-vs.-host reaction and the changes occurred in the absence of any villus damage. Mucosal mast cell numbers also increased, but the rise was delayed and sustained when compared with other mucosal changes. These results show that measurements of mucosal architecture and intraepithelial lymphocyte counts can be used to quantify mucosal cell-mediated immune reactions. In addition, this study provides further evidence to support our hypothesis that the mechanism of these changes is due to a delayed-type hypersensitivity reaction in the intestinal mucosa rather than to the action of cytotoxic T lymphocytes.

Animals↗

The prognostic significance of peripheral lymphocyte counts in patients with breast carcinoma.

A retrospective study evaluating five-year survival rates in relation to pretreatment lymphocyte counts was undertaken in 453 patients with breast carcinoma. Patients with early tumor stages had higher pretreatment lymphocyte counts than those with advanced tumors: five-year survival in patients with pretreatment counts above 2000 per mm3 was 87% in Stage I, 67% in Stage II, and 57% in Stage III, while the comparable figures in patients with lower counts were 82%, 51%, and 29%. The differences in five-year survival rates for Stage II and III were significant: z equals 1.6955, p equals 0.046 and z equals 1.8841, p equals 0.03. Similar differences were noted in the disease-free, five-year survival rates. The corresponding figures in the three tumor stages for patients with counts above 2000/mm3 were 80%, 63%, and 53%, while those for patients with lower counts were 74%, 44%, and 18%. The differences in Stage II and III were also statistically significant: z equals 1.8430, p equals 0.33 and z equals 2.592, p equals 0.005 respectively. The possibility that the presence of suppressant factors related to the thymus may influence levels of lymphocytes was evaluated. Comparison of pre-thymectomy and postthymectomy lymphocyte counts in a control group of patients who had thymectomy for myasthenia gravis revealed a gradual increase of lymphocytes following thymectomy. The increase was significant at the second year following thymectomy. These observations indicate that lymphocyte counts may serve as prognostic indicators in patients with breast cancer. Low lymphocyte counts may be related to the presence of suppressor substances.

Adult↗

Total lymphocyte count as a possible surrogate of CD4 cell count to prioritize eligibility for antiretroviral therapy among HIV-infected individuals in resource-limited settings.

OBJECTIVE: To characterize the value of total lymphocyte counts in predicting risk of death among patients initiating triple combination antiretroviral therapy. METHODS: Study subjects included antiretroviral-naive persons aged 18 years or older who initiated treatment with triple combination therapy between August 1 1996 and September 30 1999 in a population-based observational cohort of HIV-infected individuals. Total lymphocyte counts as well as CD4 count and plasma viral load were assessed at baseline. Separate Cox proportional hazards models were devised to evaluate the effect on survival of total lymphocyte count in lieu of or with CD4 count after adjustment for other prognostic factors including plasma viral load. RESULTS: A total of 733 antiretroviral-naive persons initiated triple drug combination antiretroviral therapy over the study period with a median follow-up of 29.5 months. In the first analysis, only baseline CD4 cell counts of 50-199 cells/microl or less than 50 microl were associated with an increased risk of mortality [adjusted relative risk (ARR) 2.90; 95% CI: 1.40, 5.98] and (ARR 6.30; 95% CI: 2.93, 13.54), respectively. When CD4 counts were excluded from the analysis as if unavailable, total lymphocyte count of between 0.8 and 1.4 G/I, and less than 0.8 G/I were both significantly associated with an increased risk of mortality (ARR 2.36; 95% CI: 1.16, 4.78) and (ARR 6.17; 95% CI: 2.93, 13.01), respectively. CONCLUSION: Total lymphocyte count may provide a simple and cost-effective alternative for prioritizing therapy initiation in resource-limited settings. Our results suggest that, if appropriately validated, judicious application of total lymphocyte counts could overcome one of the practical obstacles to more widespread provision of antiretroviral therapy in resource-poor settings.

Adolescent↗

Blood lymphocyte counts with subset analysis in operable breast cancer. Relation to the extent of tumor disease and prognosis.

Blood lymphocyte counts and various lymphocyte subsets, as defined by rosette tests, were examined in breast cancer patients and correlated to the extent of tumor disease and prognosis. One hundred sixty-six patients tested before or shortly after surgery were included. It was observed that the frequency of E-rosette-forming lymphocytes correlated to the development of distant metastases (P = 0.007) and survival (P = 0.022). A high frequency of E-rosette-forming cells was associated with a poor prognosis. The well-known prognostic value of clinical tumor stage and axillary lymph node involvement was also confirmed. A possible relation between the tumor disease and other immune variables was indicated by the finding that the frequency of EAC-rosette-forming lymphocytes (mainly B-cells) was reduced in patients with relatively large primary tumors. This relation was most pronounced in patients without axillary node involvement (P less than 0.01). In addition, it was observed that the blood lymphocyte counts were significantly higher in patients with three or more tumor-involved axillary nodes than in those with zero to two (P less than 0.005). Our results seem to stand in contrast to the generally held view that low lymphocyte counts and a low proportion of E-rosette-forming cells in the blood are associated with a large tumor burden and a poor prognosis.

Adult↗

Stability of peripheral blood lymphocyte count and E-rosette forming lymphocytes in healthy adults.

Highly reproducible peripheral blood lymphocyte (PBL) count and percent E-rosette forming lymphocyte (%E-RFL) assays were developed by modifying existing procedures. PBL count assay variation was reduced by using replicate electronic white blood cell (WBC) counting and 2,000 WBC differentials. The %E-RFL assay modifications reduced variation and include the use of: (a) a capillary buffy coat isolation procedure that recovered more than 85% of the PBL without the use of chemical separation media, (b) centrifugation temperatures of 20--22 degrees C, and (c) toluidine blue staining that allowed enumeration of %E-RFL and not E-rosette forming cells, by exclusion of nonlymphoid cells. Day-to-day variation of PBL count and %E-RFL was defined by making serial determinations over a period of months. The data indicate that healthy adults maintain PBL counts and %E-RFL within narrow ranges that are specific for each individual.

Adolescent↗

Peripheral blood lymphocyte counts and survival in breast cancer.

The lymphocytes in the peripheral blood of patients with breast cancer were studied. Peripheral blood lymphocyte counts were found to be significantly lower in the short-survivors when compared with the long survivors. Lymphocyte count may be a host factor, that influences survival in breast cancer.

Breast Neoplasms↗

CD4 T-lymphocyte counts and Pneumocystis carinii pneumonia in pediatric HIV infection.

The relationship between CD4 T-lymphocyte counts and infection with the human immunodeficiency virus (HIV) is retrospectively investigated for 266 HIV-infected and uninfected children who were born to infected women, including 39 with Pneumocystis carinii pneumonia (PCP), in a population-based surveillance study. Of 21 perinatally HIV-infected children with PCP only 10 (48%) had CD4 T-lymphocyte counts that were less than 500 x 10(6) cells/L (500 cells/mm3), compared with all 18 who were infected via blood transfusions or clotting factors. Among 68 children who were 1 year or younger, 18 (90%) of 20 PCP cases had CD4 T-lymphocyte counts that were less than 1500 x 10(6) cells/L (1500 cells/mm3) compared with only five (10%) of 48 children who did not have the acquired immunodeficiency syndrome (odds ratio, 77.4; 95% confidence interval, 19.7 to 313.4). The mean CD4 T-lymphocyte count was lower for the 39 PCP cases when compared with the 188 children who were at different stages of HIV infection and did not have the acquired immunodeficiency syndrome (AIDS) independent of age. The majority of perinatally HIV-infected children with PCP were 6 months or younger and 50% were previously unknown to be infected. Thus, HIV-positive children should be identified early and followed closely. CD4 T-lymphocyte counts may be useful in monitoring HIV-positive children and determining when to begin PCP prophylaxis.

Acquired Immunodeficiency Syndrome↗

Clinical and genetic heterogeneity in hereditary haemochromatosis: association between lymphocyte counts and expression of iron overload.

To identify a new marker of expression of disease, independent of HFE genotype in patients with hereditary haemochromatosis (HHC), the total peripheral blood lymphocyte counts were analysed according to iron status in two groups of subjects with HFE mutations. The groups consisted of 38 homozygotes for C282Y, and 107 heterozygotes for the C282Y or compound heterozygotes for C282Y and H63D. For control purposes, total lymphocyte counts and iron status were also examined in 20 index patients with African dietary iron overload, a condition not associated with HFE mutations, and in 144 members of their families and communities. Mean lymphocyte numbers were lower in C282Y homozygous HHC index subjects with cirrhosis and higher iron stores than in those without cirrhosis and with lower iron burdens [(1.65 +/- 0.43) x 10(6)/mL vs. (2.27 +/- 0.49) x 10(6)/mL; p = 0.008]. Similarly, mean lymphocyte counts were significantly lower in C282Y heterozygotes and C282Y/H63D compound heterozygotes with iron overload and increased serum ferritin concentrations compared to those with normal serum ferritin concentrations (p < 0.05). Statistically significant negative correlations were found, in males, between lymphocyte counts and the total body iron stores, either in C282Y homozygous HHC patients (p = 0.031 in a multiple regression model dependent on age) and in C282Y heterozygotes or C282Y/H63D compound heterozygotes with iron overload (p = 0.029 in a simple linear model). In contrast, lymphocyte counts increased with increasing serum ferritin concentrations among the index subjects with African iron overload (r = 0.324, not statistically significant) and among the members of their families and communities (r = 0.170, p = 0.042). These results suggest that a lower peripheral blood lymphocyte count is associated with a greater degree of iron loading in HFE haemochromatosis but not in African iron overload, and they support the notion that the lymphocyte count may serve as a marker of a non-HFE gene that influences the clinical expression of HFE haemochromatosis.

Adult↗

Decrease in CD4 lymphocyte counts with rest; implications for the monitoring of HIV infection.

Measurement of the CD4 lymphocyte count is widely used as a prognostic marker and guide for the institution of antiretroviral therapy in patients infected with HIV (human immunodeficiency virus). CD4 counts are known to fluctuate with strenuous physical activity and diurnal variation but there is no information on the effects of rest or normal daily activity. We investigated the effects of rest on the absolute CD4 lymphocyte count in 20 healthy laboratory workers. Blood samples were obtained in 20 subjects upon arrival in the laboratory (CD4 0), following 30 and 60 min rest (CD4 30 and CD4 60 respectively) and 8 h into a normal working day (CD4 8). A significant decrease in the CD4 lymphocyte count was observed following 60 min rest; mean CD4 count at 0 min 1060 x 10(6)/L, mean CD4 count at 60 min 660 x 10(6)/L (P = 0.0017). These results demonstrate a significant effect of rest on CD4 lymphocyte counts in healthy volunteers. This biological variation may be important in HIV-infected patients and needs to be addressed by further studies.

Activities of Daily Living↗

Effect of operation on B and T lymphocyte counts.

Preoperative and postoperative studies of peripheral B and T lymphocyte counts were accomplished in 21 patients. Diagnoses included 10 carcinoma of the breast, 3 sarcoma, and 8 benign diseases. On postoperative day one and two, an increase in B-cell percentage was observed in the majority of patients tested. However, there was a decrease in total lymphocyte count and fast-reacting T lymphocyte numbers on postoperative day one, especially in patients who had intraabdominal operations. All the lymphocyte counts returned to preoperative range within one week. Pertinent reports in the literature were reviewed and discussed.

Adult↗

Changes in total lymphocyte count as a surrogate for changes in CD4 count following initiation of HAART: implications for monitoring in resource-limited settings.

BACKGROUND: A major obstacle to the administration of highly active antiretroviral therapy (HAART) in resource-limited settings is the high cost of CD4 count testing. The total lymphocyte count (TLC) has been proposed as a surrogate marker to monitor immune response to therapy. OBJECTIVE: To assess, in a developed country setting, the capability and clinical utility of TLC change as a surrogate marker for CD4 count change in monitoring patients on HAART. METHODS: Longitudinal co-variation between changes in TLC and concomitant changes in CD4 count following the initiation of HAART was examined using a retrospective cohort study of 126 HIV-positive patients attending The Miriam Hospital, Brown University, Providence, RI. Analyses included evaluation of the direction of TLC change as a marker for direction of CD4 change, using sensitivity and specificity; evaluation of absolute change in TLC as a marker for benchmark changes in CD4 (> or =50 over 6 months, > or =100 over 12 months), using receiver-operator characteristic (ROC) curves; and a regression model of change in TLC as a function of change in CD4, to understand within-individual variation of longitudinal TLC measures. RESULTS: In the first 24 months of HAART, the sensitivity of a TLC increase as a marker for CD4 count increase over the same time period ranged from 86-94%, and the specificity ranged from 80-85%. The median change in TLC among patients with a CD4 count rise of > or =100 cells/mm at 1 year of HAART was +766 cells/mm while that of patients with a CD4 count rise of <100 cells/m was +100 cells/mm. The area under the corresponding ROC curve was 0.89, suggesting that change in TLC discriminates well between those with 1-year CD4 change of > or =100 vs. those with change <+100. From a regression analysis, we found that mean change in TLC per 1 cell/mm change in CD4 count was 7.3 (SE 1.2, P < 0.001). The degree of this association varied from individual to individual but was positive for all individuals. CONCLUSIONS: Within the first 2 years of HAART, the direction of change in TLC appears to be a strong marker for direction of concomitant change in CD4 count (sensitivity 86-94% and specificity 80-85%, depending on length of interval). Positive and negative predictive values depend on the proportion of CD4 changes that are positive. In this cohort, that proportion is 87.9%, which yields high positive predictive value (96-98%) but lower negative predictive value (43-63%). Findings from the regression model suggest that taking multiple measurements of TLC at more frequent intervals may reduce variability and potentially improve predictive accuracy.

Adolescent↗

Cytomegalovirus (CMV) viremia and the CD4+ lymphocyte count as predictors of CMV disease in patients infected with human immunodeficiency virus.

We screened 192 patients infected with human immunodeficiency virus (HIV) to examine the relation between CD4+ lymphocyte counts and cytomegalovirus (CMV) viremia and the occurrence of CMV disease and subsequent duration of survival. When we stratified the viremic patients by CD4+ lymphocyte counts, the proportions were as follows: <50/mm3, 20 (25%) of 80 patients; 50-100/mm3, 2 (5.5%) of 36; 101-150/mm3, none of 14; and >150/mm3, 1 (1.5%) of 62. After a mean follow-up period of 8.5 months, 21 (11%) of 192 patients developed CMV disease. The probability of developing CMV disease at 6 months was 13% when the CD4+ lymphocyte count was <50/mm3, 3% when the CD4+ lymphocyte count was 50-100/mm3, and 0 when the CD4+ lymphocyte count was >100/mm3; this probability was 46% for viremic patients and 1% for nonviremic patients. In a multivariate analysis, CMV viremia was independently prognostic of CMV disease (relative risk, 22.03; 95% confidence interval, 6.49-78.97; P < .001), whereas a CD4+ lymphocyte count of <50/mm3 was not (P = .26). These results support the value of CMV viremia for predicting which HIV-infected patients are at risk of developing CMV disease and should therefore receive primary prophylaxis.

AIDS-Related Opportunistic Infections↗

Do HIV type 1 RNA levels provide additional prognostic value to CD4(+) T lymphocyte counts in patients with advanced HIV type 1 infection?

Our objective was to assess whether HIV-1 RNA levels provide additional prognostic information beyond CD4(+) T lymphocyte counts in the prediction of subsequent HIV-1 disease progression among patients with advanced HIV-1 disease. In a nested case-control study conducted in patients with baseline CD4(+) T lymphocyte counts < 300 cells/mm(3) and receiving nucleoside reverse transcriptase inhibitors, 102 patients who progressed to an AIDS-defining event or death were matched within 10 CD4(+) T lymphocyte cells/mm(3) to patients who did not progress. The relationship between plasma HIV-1 RNA levels and HIV-1 disease progression was studied using conditional logistic regression analysis, which adjusts for the matching by baseline CD4(+) T lymphocytes. We observed a 0.10 log(10) copies/ml difference in baseline HIV-1 RNA levels between cases and their matched controls (p = 0.027). The relative risk for HIV-1 disease progression increased with increasing baseline HIV-1 RNA levels (odds ratio [OR] for a 3-fold higher HIV-1 RNA level, 1.42; 95% confidence interval [CI], 1.08--1.86), and remained important when also controlling for clinical status at baseline and CD4(+) T lymphocytes at 2 months (p = 0.038). Higher baseline HIV-1 RNA levels were associated with HIV-1 disease progression among patients with a baseline CD4(+) T lymphocyte count of 100 cells/mm(3) or greater (OR, 1.80; 95% CI, 1.15--2.81), but not among patients with a baseline CD4(+) T lymphocyte count < 100 cells/mm(3) (OR, 1.09; 95% CI, 0.73--1.63). We concluded that HIV-1 RNA levels predict subsequent HIV-1 disease progression independent of CD4(+) T lymphocyte counts. The magnitude and importance of the prognostic information contained in the HIV-1 RNA levels appear to depend on the CD4(+) T lymphocyte counts.

Adult↗

Effect of beta-adrenergic stimulation on the circulatory lymphocyte count: studies in normals and in patients with chronic airflow obstruction.

In eight non-allergic patients with chronic airflow obstruction (CAO) and eight age and sex matched, healthy control subjects the circadian variation in circulatory lymphocyte count was studied in relation to serum cortisol and urinary epinephrine levels. In addition, we investigated the effect of the beta-adrenergic agent terbutaline on the lymphocyte count in two ways: as a long-term effect after 8 days of oral slow-release terbutaline with constant diurnal and nocturnal serum levels in patients, and as a short-term effect by a constant rate infusion of 0.2 micrograms/min over 4 hr in normals. Both patients and controls showed similar circadian patterns of urinary epinephrine excretion and lymphocyte counts. Patients with CAO, however, had significantly lower epinephrine levels and significantly higher lymphocyte counts at all hours of observation (every 4 hr from 0800 to 0800 hr the next day), as compared with normal controls. After 8 days of slow-release terbutaline the lymphocyte count in the patient group decreased to levels not significantly different from that of normals. The circadian rhythm of the lymphocytes, however, persisted under terbutaline therapy. No correlation existed between the lymphocyte count modulating factor, serum cortisol and the lymphocyte count over 24 hr. On placebo infusion in the control persons an increase of lymphocytes over 4 hr occurred, as a consequence of circadian rhythmicity. On terbutaline infusion a significant increase of lymphocytes after 1 hr was followed by a decrease to levels significantly below those on the placebo day. The same pattern was found in the leucocyte count. From this study it is concluded that beta-adrenergic stimulation corrects the relative lymphocytosis to counts comparable with normals. Other coinciding factors must regulate, however, the circadian rhythmicity.

Adult↗

Modelling progression of CD4-lymphocyte count and its relationship to survival time.

The purpose of this article is to model the progression of CD4-lymphocyte count and the relationship between different features of this progression and survival time. The complicating factors in this analysis are that the CD4-lymphocyte count is observed only at certain fixed times and with a high degree of measurement error, and that the length of the vector of observations is determined, in part, by the length of survival. If probability of death depends on the true, unobserved CD4-lymphocyte count, then the survival process must be modelled. Wu and Carroll (1988, Biometrics 44, 175-188) proposed a random effects model for two-sample longitudinal data in the presence of informative censoring, in which the individual effects included only slopes and intercepts. We propose methods for fitting a broad class of models of this type, in which both the repeated CD4-lymphocyte counts and the survival time are modelled using random effects. These methods permit us to estimate parameters describing the progression of CD4-lymphocyte count as well as the effect of differences in the CD4 trajectory on survival. We apply these methods to results of AIDS clinical trials.

Acquired Immunodeficiency Syndrome↗

Factors associated with the CD4+ lymphocyte count at diagnosis of acquired immunodeficiency syndrome. The AIDS IN EUROPE Study Group.

To assess which factors are associated with the CD4+ lymphocyte count at the time of AIDS diagnosis we studied 3046 patients in the AIDS IN EUROPE study who were diagnosed with AIDS in 1 of 17 European countries between 1979 and 1989 and for whom the CD4 count at AIDS diagnosis was known. Data were extracted retrospectively from patient case notes, using a standardized form. There was a wide range of average CD4+ lymphocyte counts at AID diagnosis, according to which diseases were present at diagnosis. The highest geometric mean CD4+ lymphocyte counts at AIDS diagnosis were associated with the diagnosis of extrapulmonary tuberculosis, Kaposi's sarcoma, and non-Hodgkin's lymphoma while the lowest counts were found when histoplasmosis and cytomegalovirus (CMV) retinitis were present. There were no appreciable differences between CD4+ lymphocyte counts at AIDS in patients according to the three major transmission route categories (sex, age, or region of diagnosis) but there was a marked trend (p < 0.005) toward lower CD4+ lymphocyte counts at AIDS diagnosis in more recent years. These associations remained largely unchanged after adjustment for other factors.

AIDS-Related Opportunistic Infections↗