Biomedical subjects

S P Blatt

Publications and source records attributed to S P Blatt.

At least 19 recordsLinked to original sources

PubMed1998

Size and duration of zidovudine benefit in 1003 HIV-infected patients: U.S. Army, Navy, and Air Force natural history data. Military Medical Consortium for Applied Retroviral Research.

OBJECTIVES: The study's objectives were to determine the size and duration of benefits of early versus delayed versus late treatment with zidovudine (ZDV) on disease progression and mortality in HIV-infected patients, and whether patients rapidly progressing before ZDV treatment had a different outcome from those not rapidly progressing before ZDV. DESIGN: The design was an inception cohort of 1003 HIV-infected patients. One hundred and seventy-four of the 1003 patients were treated before CD4 counts fell to <400 x 10(9)/L, ("early treatment"); 183 of 1003 patients were treated after CD4 counts fell to <400 x 10(9)/L but before clinical disease developed ("delayed treatment"); and 646 of the 1003 patients had either been treated after clinical disease developed or had not been treated at all by the end of follow-up ("late treatment"). Outcomes were progression to clinical HIV disease and mortality. RESULTS: The relative risk (RR) of progression for early versus delayed treatment was 0.58 (p < .03), and durability of ZDV benefits on progression was estimated at no more than 2.0 years; however, this estimate had wide confidence intervals. The RR of progression for delayed versus late treatment was 0.54 p < .0001, and durability of ZDV benefits was estimated at 1.74 years; this estimate had narrow confidence intervals. Survival was better for the early versus delayed treatment (RR = 0.55), but this difference was not statistically significant. In the subgroup of patients with more rapid CD4 decline prior to ZDV therapy, significant benefits on progression were observed for early versus delayed ZDV therapy (RR = 0.42, p = .02) and delayed versus late ZDV therapy (RR = 0.51; p = .0004). Duration of benefit was estimated to be 4.5 years (early versus delayed) and 1.7 years (delayed versus late). For patients with less rapid pre-ZDV decline in CD4 levels, a significant progression benefit was observed for delayed versus late therapy (RR = 0.50; p = .02). Duration of benefit in this subgroup was estimated to be 1.8 years. No significant benefit was found for early versus delayed treatment (RR = 1.12) in the less rapid pre-ZDV CD4 cell decline subgroup. CONCLUSIONS: Early treatment compared with delayed treatment was associated with a sizable reduction in HIV progression, but the duration of benefits was estimated to last only about 2 years. Delayed treatment compared with late treatment with ZDV was associated with substantial reduction of progression, but this reduction was also clearly limited in duration. Benefits on progression and mortality for the early treatment group were heavily dependent on the pre-ZDV CD4 slope. In the subgroup of patients with the most rapid pre-ZDV CD4 cell declines, the duration of benefit was much longer, possibly as long as 4 years.

Adult↗

PubMed1996

Cytomegalovirus polyradiculopathy in HIV-infected patients.

Cytomegalovirus polyradiculopathy, a late complication of HIV infection, is characterized by lower extremity weakness, urinary retention, and sacral dysesthesias. We describe four patients (mean CD4 T-cell count = 25 cells/mm3) who developed this "infectious cauda equina syndrome." The characteristic cerebrospinal fluid (CSF) findings, notably atypical for a viral infection, included polymorphonuclear leukocytosis (mean white blood cell count = 1512 cells/mm3, 72% polymorphonuclear leukocytes), elevated protein level (mean = 370 mg/dl), and hypoglycorrhacia (mean = 28 mg/dl). Physicians who treat patients with HIV should be familiar with this syndrome because early intervention, prior to microbiologic confirmation, provides the best hope for improving neurologic function.

AIDS-Related Opportunistic Infections↗

PubMed1996

Antigen-stimulated apoptotic T-cell death in HIV infection is selective for CD4+ T cells, modulated by cytokines and effected by lymphotoxin.

OBJECTIVE: To characterize the mechanism of in vitro antigen-induced apoptotic T-cell death in the peripheral blood mononuclear cells (PBMC) of HIV-1-infected individuals. DESIGN AND METHODS: PBMC from HIV-1 infected and uninfected individuals were unstimulated or stimulated with HIV-1 envelope synthetic peptides (Env) or influenza A virus to determine the extent of antigen-stimulated apoptotic T-cell death, whether this death was limited to the CD4+ subset, and the effects of cytokines on T-cell death. Death was assessed by apoptotic nuclear morphology after 7 days of culture by fluorescence microscopy using a DNA-specific dye. Transwell cultures and supernatant transfers were utilized to test whether a soluble factor produced by HIV-positive PBMC induced death of HIV-negative T cells. Exogenous cytokines [interleukin (IL)-12, interferon (IFN)-gamma, IL-4 and IL-10], as well as antibodies against endogenously produced cytokines (IL-4, IL-10, IL-12, and lymphotoxin) were tested for their ability to modulate death. RESULTS: Antigenic stimulation induced death in PBMC from HIV-positive donors, but not in PBMC from HIV-negative donors. Antigen-stimulated death was seen in CD4+ but not CD8+ T-cell subset from the HIV-positive patients. Apoptotic death was blocked by IL-12, IFN-gamma, anti-IL-4, anti-IL-10, and anti-lymphotoxin, but not by anti-IL-12. Transwell and supernatant transfer experiment indicated that antigen-stimulated HIV-positive PBMC produced a factor that killed T-cell blasts. The factor was inhibited by anti-lymphotoxin, but not by anti-IL-10. CONCLUSIONS: Stimulation of HIV-positive PBMC with CD4-dependent antigens results in selective death of CD4+ T cells that is modulated by cytokines. Our results suggest that apoptotic death is not limited to HIV-infected or HIV-specific T cells, but occurs in bystander cells. Lymphotoxin is a mediator of antigen-stimulated T-cell death in this in vitro model.

Antibodies↗

PubMed1995

Multivariate models for predicting progression to AIDS and survival in human immunodeficiency virus-infected persons.

Nine hundred thirty persons enrolled in the US Air Force Human Immunodeficiency Virus (HIV) Natural History Study were evaluated with a standard battery of 30 potential surrogate markers of disease progression. A risk score for predicting progression to AIDS was then calculated for each patient in the cohort by using the four highest-ranking variables from multivariate analysis: percentage of CD4 CD29 cells, anergy status, age, and hemoglobin. For predicting survival, beta 2-microglobulin replaced age in the Cox model. Stratification according to the risk score demonstrated that rates of progression to AIDS and survival were significantly different between risk groups (P < .0001). The novel combination of these markers results in extremely accurate risk scores, which may serve as the basis for the development of true surrogate markers of disease progression.

Acquired Immunodeficiency Syndrome↗

PubMed1995

In vitro T cell function, delayed-type hypersensitivity skin testing, and CD4+ T cell subset phenotyping independently predict survival time in patients infected with human immunodeficiency virus.

Human immunodeficiency virus type 1 (HIV-1)-infected patients (n = 335) in the US Air Force HIV Natural History Program were followed for 3 years (mean) after skin testing, immunophenotyping of CD4+ cell subsets, and measurement of in vitro interleukin-2 production after stimulation by phytohemagglutinin, alloantigens, tetanus toxoid, and influenza A virus. The T cell functional assay predicted survival time (P < .001) and time for progression to AIDS (P = .014). Skin testing for tetanus, mumps, and Candida antigen and the total number of positive tests (P < .001 for each) stratified patients for survival time. In a multivariable proportional hazards model, the T cell functional assay (P = .008), the absolute number of CD4+ T cells (P = .001), the percentage of CD4+ CD29+ cells (P = .06), and the number of reactive skin tests (P < .001) predicted survival time. Thus, cellular immune functional tests have significant predictive value for survival time in HIV-1-infected patients independent of CD4+ cell count.

Acquired Immunodeficiency Syndrome↗

PubMed1995

Presence of neutralizing antibodies to heterologous human immunodeficiency virus type 1 isolates in sera of infected individuals is not predictive of rate of disease progression.

These studies were undertaken to examine whether the presence of human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies in sera of infected individuals would alter the rate of disease progression. HIV-1-infected individuals (n = 87) were initially examined for neutralizing activity in vitro against both laboratory and tissue culture-adapted clinical heterologous HIV-1 isolates. The neutralizing activities of sera were determined by a 90% or greater reduction in HIV-1 p24 levels in vitro. In a cross-sectional analysis of all infected individuals, we observed that sera from asymptomatic individuals neutralized a significantly greater number of heterologous HIV-1 isolates than sera from symptomatic patients. Patients who could be followed up longitudinally (n = 24) were then studied to determine the impact of neutralizing antibodies on the rate of disease progression. We observed no significant difference between the numbers of HIV-1 isolates neutralized in vitro by sera from patients who remained clinically stable and by those from patients who progressed rapidly. Our data indicated that the presence or absence of neutralizing antibodies to heterologous HIV-1 isolates was not associated with the rate of disease progression.

Adult↗

PubMed1995

Serologic evaluation of human immunodeficiency virus type 1-infected individuals from Argentina and the United States indicates a similar distribution of subgroup B isolates.

Utilizing peptides based on the V3 region of gp120, we undertook a serologic examination of human immunodeficiency virus type 1 (HIV-1)-infected individuals from Argentina to determine if prevalent HIV-1 isolates could be identified in this population. Our findings suggest that a similar pool of HIV-1 subgroup B isolates exists in both Argentina and the United States.

Amino Acid Sequence↗

PubMed1995

The significance of hematuria in patients infected with the human immunodeficiency virus.

PURPOSE: We determined the importance of hematuria in patients infected with the human immunodeficiency virus (HIV). MATERIALS AND METHODS: The records of 1,326 HIV infected patients with yearly evaluations were reviewed for hematuria and evaluation results. Mean followup was 2.1 years. RESULTS: A total of 331 patients (25.0%) had 1 episode of hematuria and 67 were evaluated with 5 significant diagnoses made. Management was affected in only 3 of these patients. No occult genitourinary tumors were found. CONCLUSIONS: In young, asymptomatic, HIV infected patients with microscopic hematuria a urological evaluation can be safely omitted in the presence of normal renal function and a benign urological history.

Adult↗

PubMed1995

Rates of p24 antigenemia and viral isolation in comparable white and black HIV-infected subjects. Military Medical Consortium for Applied Retroviral Research.

OBJECTIVE: To determine the relative frequencies of HIV-1 p24 antigen and culture positivity in white and black patients. DESIGN: Volunteers in the US military's HIV natural history study were 46% white, 44% black, 7% Hispanic and 3% other. Focusing on the comparable groups of whites and blacks, a retrospective analysis was performed of the results of virologic assays collected over a 2-year period. METHODS: p24 antigen was quantitated in sera with and without immune complex dissociation (ICD); viral isolation was performed by coculture of peripheral blood mononuclear cells. RESULTS: Results of the two virologic assays were very similar in the two racial groups, both overall and after stratification by CD4 cell count. As reported previously, the concentration of serum immunoglobulin G was found to be greater in black than white subjects. In contrast to results with ICD, sera tested without ICD resulted in differing (higher) rates of antigenemia in whites than blacks (P = 0.002). CONCLUSIONS: The frequencies of p24 antigen and culture positivity were found to be independent of race. Previously observed racial differences in antigen positivity were likely to be due to more extensive antibody binding in blacks than in whites.

Adult↗

PubMed1994

Type 1/type 2 cytokine modulation of T-cell programmed cell death as a model for human immunodeficiency virus pathogenesis.

In vitro T-cell receptor-induced programmed cell death in both activated T cells from human immunodeficiency virus-seronegative (HIV-) donors and resting T cells from HIV+ donors was substantially influenced by cytokines. Addition of exogenous recombinant "type 1" lymphokines interferon gamma and interleukin 2 (IL-2), as well as the macrophage-produced IL-12, which favor cell-mediated T-cell responses, blocks both systems of T-lymphocyte programmed cell death. In contrast, the "type 2" lymphokines IL-4 and IL-10, which favor antibody responses, either had no effect or enhanced these systems of in vitro T-cell programmed cell death. A role for endogenously produced cytokines was suggested by the inhibition of T-cell receptor-mediated death by antibodies against IL-4 and IL-10 and its enhancement by anti-IL-12 in cultures containing monocytes. These results demonstrate that the functional properties of type 1 and type 2 cytokine classes may be further extended to include their effects on T-cell programmed cell death and their possible role in the pathogenesis of HIV infection.

Apoptosis↗

PubMed1994

Inhibition of activation-induced programmed cell death and restoration of defective immune responses of HIV+ donors by cysteine protease inhibitors.

In vitro activation of PBLs from HIV+ individuals resulted in programmed cell death (PCD) within 2 days in 58 of 95 HIV+ blood donors, in contrast to only two of 30 control HIV- donors. CD4+ and CD8+ T cells from HIV+ donors died under these conditions, and these cells showed apoptotic nuclear morphology and DNA fragmentation. To test the hypothesis that this cell death shares a common biochemical pathway with that induced by TCR cross-linking in normal dividing T cells, inhibitors of the calcium-activated cysteine protease calpain were tested for their ability to block the activation-induced PCD of HIV+ donors. The E-64 (epoxysuccinyl) class of cysteine protease inhibitors gave 40% to 60% inhibition of HIV+ PCD responses, while the aldehyde inhibitors, leupeptin and calpain inhibitor II, gave 60% to 67% inhibition. The involvement of this calpain-dependent death pathway in HIV-induced functional T helper cell deficiency was tested by examining the effect of calpain inhibitors on the defective Ag- and mitogen-dependent proliferative responses of HIV+ donors. Twenty to fifty percent of such defective responses were significantly restored toward normal levels by calpain inhibitors, whereas control responses by normal donors were largely unaffected. These data suggest that a calpain-dependent PCD pathway contributes to HIV-associated immunodeficiency and suggest the use of calpain inhibitors as a possible route to therapy of HIV infection.

Apoptosis↗

PubMed1994

Legionnaires' disease in human immunodeficiency virus-infected patients: eight cases and review.

Despite being a well-known pathogen for immunocompromised patients, Legionella pneumophila has infrequently been described in persons with infection due to human immunodeficiency virus (HIV). Since 1986, we have identified eight cases of legionella pneumonia among seven HIV-infected persons enrolled in the HIV Natural History Study of the U.S. Air Force. The median CD4+ T cell count for these patients was 83/mm3; 50% of the cases occurred in persons for whom AIDS was previously diagnosed, and five of the cases were nosocomial. Six of the patients had coexistent pulmonary infections. None of the cases occurred among persons receiving prophylactic therapy with trimethoprim-sulfamethoxazole. Therapeutically, all patients appeared to respond well to standard antilegionella therapy or high doses of trimethoprim-sulfamethoxazole. Overall, these seven patients represent 1.7% of the patients with late-stage HIV infection (Walter Reed stage 5 or 6) in this cohort. L. pneumophila, although remaining an uncommon pathogen for HIV-infected patients, may produce serious disease in this population. HIV-infected persons should be considered at risk for legionnaires' disease, particularly in institutions where potable water supplies have become contaminated.

AIDS-Related Opportunistic Infections↗

PubMed1994

False-positive rapid plasma reagin tests in human immunodeficiency virus infection and relationship to anti-cardiolipin antibody and serum immunoglobulin levels.

The incidence of biologic false-positive rapid plasma reagin (RPR) tests may be increased in human immunodeficiency virus (HIV) infection; however, injecting drug use has not been excluded as the cause. Review of 3371 periodic syphilis serology results from 1077 HIV-seropositive patients in the United States Air Force HIV Natural History Study between January 1986 and June 1992 revealed a cumulative biologic false-positive RPR rate of 1%. Most (6/9) were transient low-titer results associated with a recent acute infectious process. False-positive RPR tests did not appear to correlate with anticardiolipin antibody levels or serum IgG or IgA levels, which are increased in HIV infection. Although not statistically significant, there was a trend toward higher IgM levels in patients with biologic false-positive tests. Thus, the incidence of false-positive RPR in an HIV-infected population with a low risk of injecting drug use is similar to that in the general population, and the mechanism may correlate with elevated serum IgM levels.

Analysis of Variance↗

PubMed1994

Role of interleukin-10 in T helper cell dysfunction in asymptomatic individuals infected with the human immunodeficiency virus.

The loss of T helper cell (TH) function in asymptomatic HIV type 1-infected individuals occurs before the decline in CD4+ T cells. At least part of the loss in TH function results from changes in immunoregulatory cytokine profiles. To investigate the role of IL-10 in such dysregulation, we tested whether: (a) expression of IL-10-specific mRNA would be upregulated in PBMC from asymptomatic, HIV-infected (HIV+) individuals; (b) PBMC from these same individuals would produce increased levels of IL-10 when stimulated in vitro with phytohemagglutinin; and (c) defective antigen-specific TH function could be restored by anti-IL-10 antibody. We observed that IL-10-specific mRNA was marginally upregulated, and increased levels of IL-10 were produced by PBMC from HIV+ individuals compared with PBMC from uninfected individuals. Those individuals whose TH function was more severely compromised produced higher levels of IL-10. Additionally, defective antigen-specific TH function in vitro could be reversed by anti-IL-10 antibody, including the response to HIV envelope synthetic peptides. Furthermore, the antigen-specific TH responses of HIV-uninfected PBMC could be reduced with IL-10, a process reversed by anti-IL-10. These results confirm that the early loss of TH function in HIV+ individuals is due at least in part to cytokine-induced immune dysregulation, and support the hypothesis of a switch from a predominant type 1 state to a predominant type 2 condition in HIV infection.

Antigens, CD↗

PubMed1994

A case of Pott's disease in a 20-year-old military dependent.

Tuberculous spondylitis (Pott's disease) is an uncommon complication of Mycobacterium tuberculosis infection that may have serious consequences if the diagnosis is missed or delayed. A case of tuberculous spondylitis in a military dependent is presented. Clinical presentation, radiologic findings, laboratory findings, and treatment are discussed.

Adult↗

PubMed1993

Restoration of HIV-specific cell-mediated immune responses by interleukin-12 in vitro.

Peripheral blood mononuclear cells (PBMCs) from many asymptomatic individuals infected with human immunodeficiency virus-type 1 (HIV) are unresponsive as measured by in vitro T cell proliferation and interleukin-2 (IL-2) production to influenza virus and synthetic peptides of HIV envelope (Env). Strong influenza virus- and Env-stimulated IL-2 responses and T cell proliferation were restored when cultures were stimulated in the presence of IL-12. Interferon-gamma production by PBMCs from HIV seropositive (HIV+) patients was also restored with IL-12. Furthermore, in vitro antigen-specific production of IL-2 and proliferation of PBMCs from HIV- donors were suppressed by antibody to IL-12, but were not enhanced by addition of exogenous IL-12. Thus, IL-12 may be limiting in PBMCs from HIV+ but not HIV- individuals. These findings demonstrate that IL-12 can restore HIV-specific cell-mediated immunity in vitro in HIV-infected individuals and suggest a potential use of IL-12 in augmenting the diminished immunologic functions associated with HIV infection.

Cells, Cultured↗

PubMed1993

Delayed-type hypersensitivity skin testing predicts progression to AIDS in HIV-infected patients.

OBJECTIVE: To evaluate the prognostic significance of cutaneous delayed-type hypersensitivity (DTH) skin testing in persons infected with HIV. DESIGN: Cohort study. SETTING: United States Air Force (USAF) Medical Center. PATIENTS: Consecutive sample of 889 HIV-infected USAF personnel or dependents undergoing their first staging evaluation from 1985 through August 1990 in the USAF HIV Natural History Study. MEASUREMENTS: All patients were evaluated with DTH skin testing including purified protein derivative and four control skin test antigens: mumps, candida, tetanus toxoid, and trichophyton. In addition, all patients underwent CD4+ T-cell surface marker determinations. The relation between DTH skin test response at first evaluation and progression to Walter Reed stage 6 (presence of an AIDS-defining opportunistic infection) was evaluated using Kaplan-Meier survival analysis. RESULTS: Patients with more than 400 CD4+ T cells/mm3 are more likely than those having fewer than 400 CD4+ T cells per mm3 to respond to at least one (94% compared with 67%, P < 0.001) or at least two (86% compared with 45%, P < 0.001) DTH skin tests. Mean CD4 counts are lower for anergic compared with nonanergic patients and for patients responding to a single control skin test compared with those responding to two or more skin tests (P < 0.05). The DTH skin test response at first evaluation was also found to predict progression to AIDS; the relative risk at 5 years of follow-up was 2.5 (95% CI, 1.2 to 5.2) for anergy compared with a single positive skin test and 3.0 (CI, 1.4 to 6.2) for a single compared with two or more skin test responses. The DTH skin test response at first evaluation was a predictor of progression (P < 0.001) when controlling for initial CD4 count and Walter Reed stage in a Cox proportional hazards regression analysis. CONCLUSIONS: The DTH skin test response, a functional measure of cellular immunity, is an independent predictor of progression to AIDS in persons with HIV.

Acquired Immunodeficiency Syndrome↗

PubMed1993

Total lymphocyte count as a predictor of absolute CD4+ count and CD4+ percentage in HIV-infected persons.

OBJECTIVE: To determine whether the total lymphocyte count (TLC) accurately predicts a low absolute CD4+ T-cell count and CD4+ percentage in persons infected with human immunodeficiency virus (HIV). DESIGN: Retrospective analysis of data collected in the US Air Force HIV Natural History Study. SETTING: Military medical center that performs annual medical evaluation of all HIV-infected US Air Force personnel. PATIENTS: A total of 828 consecutive patients with no prior history of zidovudine use, evaluated from January 1985 through July 1991. For patients with multiple observations over time, a single data point within each 6-month interval was included in the analysis (N = 2866). MEASUREMENTS AND MAIN RESULTS: The sensitivity, specificity, and likelihood ratio (LR) of the TLC, in the range of 1.00 x 10(9)/L to 2.00 x 10(9)/L, in predicting an absolute CD4+ T-cell count less than 0.20 x 10(9)/L or a CD4+ percentage less than 20% were calculated. In addition, the LR and pretest probability of significant immunosuppression were used to calculate posttest probabilities of a low CD4+ count for a given TLC value. The LR of the TLC in predicting an absolute CD4+ count < 0.20 x 10(9)/L increased from 2.4 (95% confidence interval, 2.2 to 2.5) for all TLCs less than 2.00 x 10(9)/L, to 33.2 (95% confidence interval, 24.1 to 45.7) for all TLCs less than 1.00 x 10(9)/L. The specificity for this prediction increased from 57% to 97% over this range. The LR also increased from 1.4 (95% confidence interval, 1.3 to 1.6) for all TLCs less than 2.00 x 10(9)/L to 9.7 (95% confidence interval, 7.1 to 13.1) for all TLCs less than 1.00 x 10(9)/L in predicting a CD4+ percentage less than 20%. CONCLUSIONS: The TLC, between 1.00 x 10(9)/L and 2.00 x 10(9)/L, appears to be a useful predictor of significant immunosuppression as measured by a CD4+ T-cell count less than 0.20 x 10(9)/L in HIV-infected persons. The LR for a given TLC value and the pretest probability of immunosuppression can be used to determine the posttest probability of significant immunosuppression in individual patients. For example, in a patient with a TLC less than 1.50 x 10(9)/L and a pretest probability of 16%, the posttest probability of a low CD4+ T-cell count increases to 53%. In contrast, a TLC greater than 2.00 x 10(9)/L in an individual with a pretest probability of 30% will decrease the posttest probability of a low CD4+ T-cell count to less than 4%. Physicians should find these data useful to help predict the risk for opportunistic infection among HIV-infected persons who present with syndromes that are potentially compatible with opportunistic infection but who have not had recent or prior CD4+ T-cell analysis.

Adolescent↗