Theodore Kordossis

Circulating Autoantibodies to Erythropoietin Are Associated with Human Immunodeficiency Virus Type 1—Related Anemia

In a cohort of 204 unselected consecutive human immunodeficiency virus type 1 (HIV-1)-infected patients, the association of circulating autoantibodies to endogenous erythropoietin (EPO) with HIV-1-related anemia was studied. Circulating autoantibodies to EPO were present in 48 (23.5%) of the 204 patients studied. Circulating autoantibodies were an independent predictor of anemia (odds ratio [OR]=5.0; 95% confidence interval [CI], 2.5-9.9), as strong as other known causes of anemia. The association of anti-EPO antibodies with anemia became stronger when the analysis was limited to the group of patients without any medical condition causing anemia (OR=10.4; 95% CI, 3.2-33.9). Moreover, the effect on hemoglobin levels remained significant even after adjusting for other anemia parameters. Anti-EPO autoantibodies were associated with higher EPO levels (r=.25, P=.012) and with a more prominent EPO response to anemia. Our findings suggest that autoimmunity, among other factors, may contribute to the pathogenesis of HIV-1-related anemia.

Mixed Cryoglobulinemia in HIV-1 Infection: The Role of HIV-1

BACKGROUND: Cryoglobulins are associated with chronic infections. OBJECTIVE: To investigate the prevalence of mixed cryoglobulinemia in patients with HIV-1 infection, the clinical spectrum of cryoglobulinemia in these patients, and the possible role of HIV-1 in cryoglobulin formation. DESIGN: Prospective cohort study. SETTING: Laiko Hospital, Athens, Greece. PATIENTS: 89 patients with HIV-1 infection. MEASUREMENTS: Serum and cryoglobulins were evaluated for antibodies to HIV and hepatitis C virus (HCV), HIV-1, and HCV viral load. RESULTS: Mixed cryoglobulins were detected in 24 patients with HIV-1 infection (27% [95% CI, 18% to 36%]). The HIV-1 viral load was higher in cryoglobulin-positive patients (median, 38.25 x 10(3) copies/mL [25th, 75th percentiles: 13.8 x 10(3) copies/mL, 78.55 x 10(3) copies/mL]) than in cryoglobulin-negative patients (median, 5.3 x 10(3) copies/mL [25th, 75th percentiles: 0.7 x 10(3) copies/mL, 27.2 x 10(3) copies/mL]) (P = 0.001). Antibodies to HIV were detected in all cryoprecipitates, and HIV-1 RNA sequences were identified in 22 of the 23 cryoprecipitates examined. Nine cryoglobulin-positive patients (38% [CI, 19% to 54%]) had clinical manifestations compatible with cryoglobulinemia. CONCLUSIONS: Mixed cryoglobulinemia is common in patients with HIV-1 infection.

Levels of Soluble CD40 Ligand (CD154) in Serum Are Increased in Human Immunodeficiency Virus Type 1-Infected Patients and Correlate with CD4+ T-Cell Counts

ABSTRACT CD40 ligand (CD40L or CD154) is a costimulatory molecule expressed mainly on activated CD4+ T cells. Concentrations of the soluble form of CD40L (sCD40L) in serum were determined for a cohort of 77 human immunodeficiency virus type 1 (HIV-1)-infected patients before and after initiation of highly active antiretroviral treatment (HAART) by a quantitative enzyme-linked immunosorbent assay. Circulating sCD40L levels were higher by twofold in untreated patients than in healthy controls (means ± standard deviations [SD]: 1.41 ± 1.48 versus 0.69 ± 0.59 ng/ml; P < 0.001). HIV-1-infected patients classified as CD4 T-cell category 1 had significantly higher sCD40L levels than patients classified as CD4 categories 2 and 3 (mean ± SD: 2.08 ± 1.46 ng/ml versus 1.57 ± 1.58 [category 2] and 0.94 ± 1.25 ng/ml [category 3]; P = 0.046), while no correlation with clinical categories A, B, and C was found. Individual serum sCD40L levels correlated with CD4+ T-cell counts (P = 0.039) but not with viral load, gamma globulin levels, or acute-inflammatory-response markers. After 8 to 12 months of HAART, a further threefold increase of serum sCD40L levels, which paralleled the increase of CD4+ T-cell counts, was observed. These novel findings suggest that sCD40L measurement in HIV-1-infected patients could serve as a new surrogate marker useful in the assessment of treatment efficacy, especially in settings where well-equipped laboratories and funding required for CD4+ T-cell count and viral load measurements are not available.

An unusual case of brucellar spondylitis involving both the cervical and lumbar spine

We report an unusual case of brucellar spondylitis, involving both the cervical and lumbar spine. Diagnosis was established using magnetic resonance imaging (MRI). An initial plain radiograph of the lumbar spine, showing mild degenerative lesions, was misleading. Therefore, institution of a proper treatment was delayed.

Safety of Lactobacillus Strains Used as Probiotic Agents

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Polyneuropathy induced by HIV disease and antiretroviral therapy

OBJECTIVE To investigate the underlying mechanisms of polyneuropathy induced by HIV infection or antiretroviral drugs. METHODS We tested 100 HIV patients (59 with AIDS). Ninety-three patients received antiretroviral drugs. Forty-four were treated with neurotoxic compounds (ddI, ddC, d4T). Nerve conduction velocities and the sympathetic skin response (SSR) in palms and soles were measured in all patients. In skin biopsies (ankle and thigh), the intraepidermal nerve fiber density (IENFD) and the number of epidermal fibers without contact to the basal membrane (fragments) were quantified using PGP9.5 staining. RESULTS Severity of the disease (CD4 +count) correlated to conduction velocities of peroneal (p < 0.01, Spearmans rank correlation), sural (p < 0.01) and median nerves (p < 0.05/p < 0.001, sensory/motor). In contrast, the duration of neurotoxic treatment did not impair conduction velocities (p > 0.3) but correlated to reduced IENFD in the ankle (r = -0.24, p < 0.05). Despite their reduced IENFD, patients with long neurotoxic treatment had a high number of fragments irrespective of their CD4 +count. CONCLUSIONS Neurotoxic treatment appears to primarily impair thin fiber conduction, whereas HIV neuropathy is linked to large fiber impairment and reduction of fragments of nerve fibers. SIGNIFICANCE These findings emphasize the differential pattern of polyneuropathy in HIV patients caused by the infection or induced by antiretroviral treatment.

Sternal tuberculosis after coronary artery bypass graft surgery.

We report a case of sternal tuberculosis following sternotomy, which was performed during coronary artery bypass graft surgery. Although pre-operative evaluation revealed signs of asymptomatic tuberculosis of the lung, isoniazid chemoprophylaxis was not instituted, and the patient developed active tuberculosis in both the lung and sternum 5 y later.We report a case of sternal tuberculosis following sternotomy, which was performed during coronary artery bypass graft surgery. Although pre-operative evaluation revealed signs of asymptomatic tuberculosis of the lung, isoniazid chemoprophylaxis was not instituted, and the patient developed active tuberculosis in both the lung and sternum 5 y later.

Fine Epitope Specificity of Anti-erythropoietin Antibodies Reveals Molecular Mimicry With HIV-1 p17 Protein: A Pathogenetic Mechanism for HIV-1–Related Anemia

BACKGROUND Circulating autoantibodies to endogenous erythropoietin (anti-Epo) are detected in human immunodeficiency virus type 1 (HIV-1)-infected patients and represent a risk factor for anemia. The aim of this study was to map the B-cell epitopes on the Epo molecule. METHODS Serum samples from HIV-1-positive patients and healthy individuals were tested against overlapping peptides covering the entire sequence of Epo. RESULTS Serum samples from anti-Epo-positive patients exhibited significant binding to Epo epitopes spanning the following sequences: amino acids 1-20 (Ep1), amino acids 54-72 (Ep5), and amino acids 147-166 (Ep12). Structural analysis of erythropoietin revealed that the immunodominant epitopes, Ep1 and Ep12, comprise the interaction interface with Epo receptor (EpoR). Autoantibodies binding to this specific region are anticipated to inhibit the Epo-EpoR interaction, resulting in blunted erythropoiesis; this phenomenon is indicated by the significantly higher Epo levels and lower hemoglobin levels of anti-Ep1-positive patients compared with anti-Ep1-negative individuals. The region corresponding to the Ep1 epitope exhibited a 63% sequence homology with the ³⁴LVCASRELERFAVNPGLLE⁵² fragment of the HIV-1 p17 matrix protein. CONCLUSIONS These results suggest that the main body of anti-Epo is directed against a functional domain of Epo, and that the presence of anti-Epo can be considered to be a result of a molecular mimicry mechanism, which is caused by the similarity between the Ep1 region and the p17 protein.

Elevated Serum Levels of Soluble Immune Activation Markers Are Associated with Increased Risk for Death in HAART-Naive HIV-1–Infected Patients

The aim of this study was to determine the serum levels of soluble markers reflecting different aspects of immune activation in HIV-1-infected patients, and assess their prognostic significance for occurrence of AIDS-related death before the advent of the highly active antiretroviral treatment (HAART). Serum concentrations of the soluble forms of interleukin-2 receptors (sIL-2R), intercellular adhesion molecule-1 (sICAM-1), and E-selectin (sEs) have been determined in a cohort of 64 HIV-1-infected patients, between 1990-1993. The patients were followed prospectively with regular visits at the outpatient department. Follow-up time was censored at January 1, 1997, the date after which HAART was introduced. The median follow-up time was 46 months (range, 2-78 months). By the end of follow-up, 34 subjects had died. Baseline levels of all three soluble markers were significantly lower in subjects who remained alive during the follow-up compared to subjects who died. Univariate analysis showed that individual sIL-2R and sICAM-1, but not sEs measurements, were significantly associated with time to death (p = 0.008 and 0.003, respectively). Even after adjustment for age and CD4+ T-cell counts sIL-2R measurements remained significantly prognostic. Sensitivity analysis using follow-up time to year 2000 confirmed these results. Our data suggest that assessment of the immune activation status using the easily measured levels of circulating markers may provide additional information about the risk of AIDS-related death. Further studies are needed to assess the effect of HAART on the levels of immune activation markers and their prognostic value.

Virological and Immunological Response to HAART Therapy in a Community-Based Cohort of HIV-1-Positive Individuals

Abstract Purpose: To determine virological and immunological response to highly active antiretroviral therapy (HAART) and to investigate factors influencing response in a community-based setting. Method: Plasma HIV RNA levels and CD4 cell counts were studied in 168 unselected individuals starting HAART including indinavir or ritonavir or hard-gel saquinavir-containing regimens. Results: Overall, 60% of the patients reduced their HIV RNA to below 500 Eq/mL, but half of them experienced a subsequent virologic rebound. Patients with higher baseline HIV RNA, higher baseline CD4 cell count, and simultaneous initiation of combination therapy and patients on indinavir or ritonavir regimen were more likely to have virologic response within 6 months since HAART initiation. Patients with lower baseline CD4 cell count and with lower rates of viral clearance had a higher probability of a subsequent virologic rebound. Forty percent of the patients had increased their CD4 cell counts by more than 100 cells/μL (immunologic response). The probability of immunologic response was independent of baseline HIV RNA levels and CD4 cell count; however, the more complete the virologic suppression, the higher the probability of immunologic response. Thirty percent of the patients had discordance between virologic and immunologic responses. Conclusion: The rate of virologic failure in this unselected group of patients was higher than that observed in randomized clinical trials, but only a minority (11%) of the patients were treatment naïve. Starting combination therapy simultaneously and initiating antiretroviral therapy before advanced HIV disease has developed predict virologic response, whereas the magnitude of viral suppression predicts mid to long immunological response.