gammadelta T lymphocytes in the peripheral blood of patients with tuberculosis with and without HIV co-infection.

BACKGROUND: Several recent studies suggest that gammadelta T lymphocytes play an important role in immunity against Mycobacterium tuberculosis. However, the dynamics of these cells in the peripheral blood of patients with tuberculosis (TB) with and without HIV infection is not fully understood. A study was undertaken to evaluate the profile of the gammadelta T cell population in patients at the time the diagnosis of TB was established. METHODS: A cross sectional study was performed in consecutive TB patients from the Department of Infectious Diseases, Spedali Civili, Brescia. CD4+, CD8+ and Vdelta1 and Vdelta2 T cell counts were analysed. Lymphocyte surface membrane expression was evaluated with the FITC-TCRgammadelta, -Vdelta1, -Vdelta2 and PE-Vdelta1 monoclonal antibodies. Blood donors and HIV seropositive asymptomatic individuals acted as controls. RESULTS: Seventy four TB patients were evaluated, 20 of whom (27%) were co-infected with HIV. HIV seronegative TB patients (n=54) had total gammadelta T cells and Vdelta1 subsets comparable to those in blood donors (n=39). However, the percentage with the Vdelta2 subset was significantly lower in patients with TB than in controls (median 1.5 v 2.1; p=0.05). Responsiveness to PPD was not associated with predominance of a specific gammadelta T cell subset. HIV seropositive individuals had a decreased percentage of circulating Vdelta2 cells at a level similar to that in HIV seronegative TB patients, regardless of the presence of active TB. CONCLUSIONS: HIV seronegative TB patients and HIV infected individuals (with or without active TB) have a reduced number of circulating Vdelta2 T cells compared with healthy individuals. Whether TB and HIV infection share a common mechanism causing Vdelta2 T cell depletion still needs to be established.

Hodgkin disease developing in patients infected by human immunodeficiency virus results in clinical features and a prognosis similar to those in patients with human immunodeficiency virus-related non-Hodgkin lymphoma.

BACKGROUND: Unlike aggressive non-Hodgkin lymphoma (NHL), Hodgkin disease (HD) develops rarely in patients who are infected by human immunodeficiency virus (HIV), and its characteristics are not well defined. The authors analyzed the clinicopathologic and prognostic features from a consecutive series of patients with HIV-associated HD who were observed at their institution and compared them with the features observed in a concurrent series of patients with systemic HIV-related NHL. METHODS: Eighteen patients with HIV infection who were diagnosed and treated uniformly from 1985 to 1999 at a single primary referral center were analyzed. Their demographic, immunologic, and clinicopathologic features; responses to treatment; and outcomes were compared with those of 98 patients with systemic NHL of aggressive histology who were diagnosed during the same period and with 165 HIV negative patients with HD. RESULTS: HIV-associated HD and NHL occurred in patients with similar age, gender, HIV risk factors, degree of immunodeficiency, and incidence of previous acquired immunodeficiency syndrome. The clinical presentation of HIV-associated HD was atypical and was more aggressive than in HIV negative patients (mediastinal involvement, 11%; Stage III-IV, 84%; B symptoms, 83%). It was similar to HIV-related NHL, except for the frequency of extralymph node disease, which was seen less frequently in patients who had HD (56%) compared with patients who had NHL (82%; P = 0.025), and the frequency of bone marrow involvement, which was unexpectedly higher in patients who had HD (50%) compared with patients who had NHL (20%; P = 0.011). Potentially curative treatment was administered to 77% of patients with HD and 66% of patients with NHL. Complete remission and disease recurrence rates as well as disease free and overall survival rates did not differ significantly, with estimated overall survival at 5 years of 24% in patients with HD and 23% in patients with NHL. CONCLUSIONS: HIV-associated HD is an aggressive disease with demographic, clinical, and prognostic features nearly identical to those of HIV-related NHL.

Secondary mutations in the protease region of human immunodeficiency virus and virologic failure in drug-naive patients treated with protease inhibitor-based therapy.

The role of mutations in protease (PR) and reverse-transcriptase (RT) of human immunodeficiency virus (HIV) in predicting virologic failure was assessed in 248 antiretroviral-naive HIV-positive patients who began a PR inhibitor-containing antiretroviral regimen. Genotypic testing was performed on plasma samples stored before the start of therapy. Twenty-seven patients (10.9%) had mutations in the RT, 5 (2%) carried primary mutations in the PR, and 131 (52.8%) showed only secondary PR mutations. Virologic failure at week 24 occurred in 62 (25.0%) of 248 patients. There was a statistically significant correlation between virologic failure and the number of PR mutations (P= .04, chi(2) test). Mutations at codons 10 and 36 of PR (present in 39.3% and 40.0% of patients in whom treatment failed, respectively) were identified by stepwise logistic regression as the strongest predictors of virologic failure (odds ratio, 2.20; 95% confidence interval, 1.30-3.75; P= .004). If confirmed in independent studies, this result may justify the increased use of HIV genotyping in drug-naive patients requiring antiretroviral therapy.

Pilot dose-finding trial on interferon alpha in combination with ribavirin for the treatment of chronic hepatitis C in patients not responding to interferon alone.

BACKGROUND: Effectiveness of combination therapy with standard interferon alpha doses and ribavirin is far from being demonstrated in patients with hepatitis C non responders to interferon alpha monotherapy. Recent kinetic studies revealed that these doses may be suboptimal. AIMS: To find the criteria for optimisation of the interferon dose, to be used in combination with ribavirin in patients with hepatitis C non responders to interferon alpha monotherapy. PATIENTS: Sixty-three patients enrolled in a pilot controlled trial were treated for 6 months with ribavirin ([1000-1200 mg daily) and were randomised to concurrently receive interferon alpha 2b for 6 months at: 3 Million Units thrice weekly [group A (21 patients)], 5 MU thrice weekly [group B (21 patients)] and 5 million units daily [group C (21 patients)]. RESULTS: A sustained virological response was observed in: 1 patient from group A (5%), 2 patients from group B (9%) and 8 patients from group C (38%; p=0.02 vs group A; p=0.03 vs group B). Side-effects were not significantly different between the 3 groups. Multivariate analysis showed that infection by hepatitis C virus genotypes 2 or 3 and interferon alpha dosage of 5 million units daily were independent predictors of sustained response. CONCLUSIONS: These results suggest that higher interferon doses administered daily in combination with ribavirin could be more effective in those patients with hepatitis C who had not responded to interferon alone.

Tolerability of twice-weekly rifabutin-isoniazid combinations versus daily isoniazid for latent tuberculosis in HIV-infected subjects: a pilot study.

The tolerability of and adherence to intermittent short-term rifabutin-isoniazid preventive treatment was assessed in subjects dually infected with Mycobacterium tuberculosis and the human immunodeficiency virus (HIV). In a randomised, open-label, phase II pilot study, 44 subjects received either rifabutin 300 mg and isoniazid 750 mg twice weekly for 3 months (group A, n = 16) or the same regimen with rifabutin at 600 mg (group B, n = 14), or isoniazid 300 mg/day for 6 months (group C, n = 14). Three, two and four subjects in groups A, B, and C, respectively, did not complete their treatment (one case of flu-like syndrome in group B; one methadone withdrawal syndrome in group A; and patient decision in two cases in group A and four in group C). Overall, adverse events were reported by four, nine, and seven subjects in groups A, B and C, respectively. Intermittent combined rifabutin + isoniazid for 3 months had lower default rates than daily standard isoniazid for 6 months. The regimen with rifabutin at 300 mg dose compared favourably to standard isoniazid, and warrants larger efficacy studies to assess its role for the prevention of latent tuberculosis in HIV-infected subjects.

The International Prognostic Index can be used as a guide to treatment decisions regarding patients with human immunodeficiency virus-related systemic non-Hodgkin lymphoma.

BACKGROUND: The International Prognostic Index (IPI) effectively separates aggressive lymphomas into four groups with significantly different responses to therapy and survival. The authors have applied the IPI to evaluate a series of patients with human immunodeficiency virus (HIV) related lymphoma, a disease for which treatment strategies are still controversial and prognostic indicators are therefore particularly important. METHODS: Sixty-nine consecutive evaluable patients with HIV-related systemic non-Hodgkin lymphoma (NHL) diagnosed at a single Institution during a 10-year period were analyzed. Primary cerebral lymphoma was not considered. Forty-nine patients (71%) received aggressive combination chemotherapy (CT), 45 of whom were treated with the same program: cyclophosphamide, doxorubicin, etoposide, cytarabine, bleomycin, vincristine, and methotrexate with lecuovorin and prednisone (ProMACE-CytaBOM). Univariate and multivariate methods were used for statistical analysis. End points were response to treatment in patients receiving aggressive CT and survival of treated patients and all patients. RESULTS: According to age-adjusted IPI, 5 patients (7%) belonged to the low risk group, 12 (17%) to the low-intermediate risk group, 16 (23%) to the high-intermediate risk group, and 36 (52%) to the high risk group. Among the four groups with increasing IPI scores, the mean CD4 cell count at NHL diagnosis was 313, 230, 151, and 72/microL, respectively (P = 0.0085). The complete response (CR) rates were 100%, 88%, 50%, and 32% (P = 0. 0001) and the median survival of all patients was >60, 17, 10.9, and 6.8 months (P = 0.0002) for patients with low, low-intermediate, high-intermediate, and high risk IPI scores, respectively. In multivariate analysis, among patients receiving aggressive CT, high risk IPI (P = 0.013) and systemic symptoms (P = 0.014) were the only parameters related to CR, and high risk IPI (P = 0.016) and achievement of CR (P < 0.001) were the only parameters related to survival. When all patients were considered, high risk IPI had significant prognostic value for overall survival (P = 0.01), as did age (P = 0.019) and achievement of CR (P < 0.001). CONCLUSIONS: IPI was a reliable prognostic indicator in an unselected series of patients with HIV-related systemic NHL. The outcomes of patients without high risk IPI treated with aggressive CT were similar to those expected for HIV negative patients with lymphoma. However more than half of patients with HIV-related NHL had IPI high risk disease, and their outcomes were poor even after aggressive CT. The degree of immunodeficiency was related to increasing IPI score, suggesting that immunodeficiency may be an important factor contributing to the aggressive clinical presentation of lymphoma.

Prognostic factors correlated with survival in AIDS patients.

The authors present the AIDS cases (CDC '93) observed in Brescia from 1983 to 1994. They observed 1189 subjects (M 84%, F 16%) with a mean age of 32.7 years (intra-venous drug users 75.1%, heterosexuals 14%, homosexuals 9.6%). The mean survival observed was 56.7 weeks from the diagnosis of AIDS (mortality per year 78%). The most frequent AIDS-defining events were Visceral Candidiasis, P. carinii Pneumonia (PCP) and Neurotoxoplasmosis, while the longest and shortest mean survival was for Kaposi's Sarcoma (89 weeks) and Wasting Syndrome (8.4). The mean value of CD4+ lymphocyte counts on AIDS diagnosis was 72.6/microl (1166 cases) and the highest and lowest were in non-Hodgkin's Lymphoma (NHL; 147.6/microl) and Cryptosporidiosis (18.8/microl). Antiretroviral therapy had been given for at least a month in 41.4% subjects (mean treatment duration of 74.8 weeks). The Cox model has demonstrated the favourable effect on survival of high CD4+ lymphocyte counts on diagnosis, antiretroviral therapy, the diagnosis of Tuberculosis (TBC) and PCP as initial markers and the diagnosis of TBC, PCP or Cytomegalovirus infection (CMV) during the entire clinical evolution. Moreover, the unfavourable effect of high age, diagnosis of Progressive Multifocal Leucoencephalopathy (PML), Wasting Syndrome and NHL as initial markers and diagnosis of PML or NHL in any moment of the disease has been demonstrated.

Pediatric migration and hepatitis A risk in host population.

Hepatitis A virus (HAV) circulation in a given area is closely related to socioeconomic standards. Following the improvement of living conditions, HAV seroprevalence rates in the population have decreased steadily during the last decades in many Western European countries, including Italy, thereby leading to a shift of risk of disease towards older age groups. Since the severity of the disease closely parallels age, a higher incidence of symptomatic cases in adults is now reported in Europe and the United States, being travel-related to a large extent. Intrafamilial person-to-person spread is also an important source of infection and transmission from children to parents may occur due to the lack of immunity in the general population. In the last two decades, Italy has been the destination of an increasing number of migrants from developing countries, where HAV is highly endemic. Furthermore, international adoption programmes cause pediatric populations from HAV endemic countries to increase in low endemic areas, possibly leading to secondary cases in close contacts.7 The aim of this paper is to report the epidemic HAV outbreak which occurred among the voluntary nursing staff of a pediatric Rwandan refugee community hosted in a village of the Brescia Province, in northern Italy.

Ultrasound evaluation of hepatic lymph nodes in patients with anti-hepatitis C virus antibody reactivity.

BACKGROUND: Portal lymphadenopathy is frequently found in inflammatory liver diseases. However, the mechanisms underlying portal lymphadenopathy are unknown. AIMS: To evaluate the prevalence of portal lymphadenopathy in patients with serum anti-hepatitis C Virus antibody reactivity and its relationship to clinical parameters. PATIENTS AND METHODS: The presence of portal lymphadenopathy was evaluated by upper abdominal Ultrasound by the same examiner in 114 patients with anti-hepatitis C Virus reactivity: 56 patients with normal liver enzyme activity and 58 randomly selected patients with increased liver enzyme activity undergoing liver biopsy. Laboratory tests were then performed in all patients the following day. RESULTS: Portal lymph nodes were found in a significantly higher percentage of patients with increased liver enzymes (74%) than in patients with persistently normal liver enzymes (29%: p < 0.01). Aminotransferases, gamma glutamyl transpeptidase levels and the percentage of patients with HCVRNA in serum and histological scores for piecemeal and lobular necrosis were significantly higher in patients showing hepatic lymph nodes. Multivariate analysis showed that only alanine aminotransferase and lobular necrosis were independently related to the presence of hepatic lymph nodes. A significant correlation was found between lymph node size, aminotransferase activity and lobular necrosis. CONCLUSION: Ultrasound-proven portal lymph node enlargement is an indirect sign of hepatocellular damage in patients with positive serum anti-hepatitis C Virus antibodies.

Effects of recombinant granulocyte colony-stimulating factor (G-CSF) in patients treated with ProMACE-CytaBOM for HIV-related non-Hodgkin's lymphoma (NHL).

BACKGROUND AND OBJECTIVE: The use of hematopoietic growth factors in association with chemotherapy in human immunodeficiency virus (HIV)-related non-Hodgkin's lymphoma (NHL) has been recommended, but few studies have evaluated its cost-effectiveness. DESIGN AND METHODS: The effects of recombinant granulocyte colony-stimulating factor (G-CSF) were analyzed in 33 consecutive patients with HIV-related NHL treated at a single institution with the same chemotherapy program, ProMACE-CytaBOM, with G-CSF, in 21 cases diagnosed after December 31, 1991, or without G-CSF, in 12 cases diagnosed earlier. Pearson's chi-square analysis and the two-sided Student's t-test were used for statistical comparisons. The method of Kaplan-Meyer and the log-rank-test were used for survival analyses. RESULTS: G-CSF support significantly reduced the frequency of day-1 drug dose reductions (p < 0.001) and of chemotherapy delays (p < 0.001), and improved the actual delivered doses of adriamycin, cyclophosphamide and etoposide (p < 0.02). In patients with a CD4+ count < 0.01 x 10(9)/L, chemotherapy could be given at full doses in 90% of cycles with G-CSF compared to only 20% without it. G-CSF affected neither the frequency and duration of fever and hospitalization nor the complete remission and survival rates after stratification according to the CD4+ count. INTERPRETATION AND CONCLUSIONS: G-CSF support significantly improved dose-intensity in patients with HIV-related NHL treated with aggressive chemotherapy, particularly in the subgroup with a CD4+ count < 0.1 x 10(9)/L, but it did not improve their clinical outcome.

Changing patterns of HIV transmission and better targeting for intervention strategies.

We considered the HIV population of our area, comparing demographic characteristics between 2 consecutive 6-year periods to assess the current patterns of HIV transmission. All HIV-positive patients referred to our hospital from January 1985 to December 1996 were included in the study and were classified into 2 periods: A (January 1985 to December 1990) and B (anuary 1991 to December 1996). The variables analysed were: sex, age at first visit, HIV risk category. A total of 4284 HIV subjects were observed, 2306 in period A vs 1978 in period B (P=ns). Males were 76.3% vs 75.2% (P=ns). Mean age for males was 27.4 vs 32.4 years (P < 0.001) and for females 25.4 vs 30.1 years (P < 0.001). Intravenous drug users (IVDUs) were 88.4% vs 65.4% (P < 0.001), 'heterosexuals' 14.3% vs 24.8% (P < 0.001), 'men who have sex with men' 2.4% vs 4.8% (P < 0.001). Mean age by the main risk groups was: IVDUs 25.9 vs 29.7 years (P < 0.001); heterosexuals 30.4 vs 36 years (P=0.007); 'men who have sex with men' 35 vs 35 years. In conclusion, our study confirms the emerging role of heterosexuals in the current HIV epidemic. People older than teenagers seem to have misperceived their own risk of HIV infection, given the increase in the mean age occurred in the most recent years. This trend suggests the need for prevention strategies focusing more on heterosexual transmission and older people.

Detection of clonal T cell populations with closely related T cell receptor junctional sequences in persons at high risk for human immunodeficiency virus (HIV) infection and in patients acutely infected with HIV.

The T cell repertoires were characterized for CD4+ and CD4 lymphocytes derived from 2 patients with acute human immunodeficiency virus (HIV) infection and from 25 HIV-seronegative persons at high risk for acquiring HIV. Oligoclonal expansions of CD4 cells were detected in the HIV-infected patients and in 2 of 3 uninfected high-risk subjects with a reduced number of CD4+ lymphocytes. Furthermore, nucleotide sequencing revealed that some of the T cell receptor (TCR) beta variable segments (TCRBV), which were highly selected in the high-risk subjects, shared closely related junctional sequences, with the TCRBV predominantly expanded in the HIV-infected patients. Since the likelihood that these similarities occurred by chance is extremely low, these data provide direct molecular evidence in support of several cellular and serologic studies suggesting that some persons remain uninfected despite exposure to HIV.

Detection of Mycoplasma genitalium from urethral swabs of human immunodeficiency virus-infected patients.

Mycoplasma have been suggested as co-factors in the pathogenesis of acquired immune deficiency syndrome (AIDS). The prevalence of urethral infection by Mycoplasma genitalium was determined by polymerase chain reaction (PCR) with urethral swabs from 35 HIV-infected patients at different stages of the disease (all of them were heterosexual men). M genitalium was detected in 2 out of 19 non-AIDS (stage A and B) patients and in a similar proportion (1 out of 14; 7.1%) of samples from healthy individuals. A dramatic increase in the frequency of M. genitalium detection was observed in samples of AIDS (stage C) patients. In fact, 9 out of 16 (56.2%) specimens tested positive by PCR. We found no association in AIDS patients between M. genitalium infection and CD4 count, Human Immunodeficiency Virus (HIV) p24 antigenemia or opportunistic infection.

High prevalence of GB virus C infection in a group of Italian patients with hepatitis of unknown etiology.

Prevalence of the recently discovered GB virus C(GBV-C) was evaluated in a cohort of 49 Italian patients with acute or chronic hepatitis of unknown etiology (non-A-E hepatitis) and in a control group of 100 healthy blood donors. The GBV-C genomes could be detected by polymerase chain reaction (PCR) with reverse transcription in 35% of the acute and 39% of the chronic hepatitis patients; only 1 of the control subjects had a positive response. All PCR products hybridized with a specific probe in a colorimetric assay, and the analysis of the sequences of the amplified cDNAs fully confirmed the specificity of the assay. Furthermore, the alignment of the predicted translation products identified two recurrent amino acid substitutions in 6 patients, suggesting the possible existence of at least 2 different GBV-C subtypes. Thus, GBV-C may be an important agent, contributing, at least in Italy, to a significant number of the cases of hepatitis of unknown etiology.

Rhodococcus equi infection in HIV-infected patients.

OBJECTIVE: To report clinical and microbiological features and response to treatment in HIV patients with Rhodococcus equi infection. DESIGN: Retrospective study. SETTING: Inpatients admitted to two Infectious Diseases Departments in a community-based hospital. PATIENTS: A total of 12 HIV-positive patients with R. equi infection. MAIN OUTCOME MEASURES: Clinical status, radiological finding, microbiological, haematochemical and immunological tests, and response to treatment. RESULTS: Twelve patients (11 men, six injecting drug users) were diagnosed with R. equi infection. Fever and cough were the principal clinical signs on presentation. Mean CD4+ count at the time of diagnosis was 47.67 x 10(6)/l (SD, 49.2 x 10(6)/l). In 58.3% of the cases the diagnosis of R. equi infection followed the appearance of an AIDS-defining illness. The most frequent radiological findings were cavitary lesions (41.7%) and lung consolidation (33.3%). In 83% of cases, R. equi was isolated from blood and in 33.3% cases from sputum. Test of chemosensitivity showed sensitivity to vancomycin (100%), teicoplanin (100%), ceftriaxone (80%), erythromycin (71%) and ciprofloxacin (66%). Clinical response alone with the disappearance of the presenting signs was observed in nine of the 12 cases (75%); complete response was observed in two cases. Seven patients died with a mortality rate of 58.3% and a mean survival of 5.75 months (SD, 6.48 x 10(6)/l). CONCLUSIONS: R. equi should be considered in the differential diagnosis of pulmonary of disseminated infections in patients with HIV infection. Blood culture may be the most sensitive means of diagnosis. Other studies are needed to determine the most effective choice and duration of antibiotic therapy.

Transmission of HIV-associated tuberculosis to healthcare workers.

OBJECTIVE: A retrospective investigation was made to compare the occupational risk of tuberculosis in personnel assisting human immunodeficiency virus (HIV)-infected and uninfected subjects with active tuberculosis. DESIGN: We retrospectively reviewed 6 years of hospital activity in 3 units where HIV-infected patients with tuberculosis are hospitalized and in 2 units where non-HIV-infected tuberculosis patients are hospitalized. The risk of occupational tuberculosis in healthcare workers who assisted HIV-infected and non-HIV-infected patients with tuberculosis was investigated. PARTICIPANTS: The risk of occupational tuberculosis in healthcare workers was studied by considering the numbers of potential source cases (hospitalized patients with tuberculosis) in the two conditions investigated (HIV-positive and HIV-negative). Both potential source cases and cases of tuberculosis in healthcare workers had to be microbiologically proven in order to be considered. RESULTS: Seven cases of tuberculosis occurred in persons who cared for 85 HIV-infected subjects with tuberculosis, while only 2 cases occurred in staff members who took care of 1,079 HIV-negative tuberculosis patients over the same period (relative risk = 44.4; 95% confidence interval = 8.5-438). CONCLUSIONS: Tuberculosis seems no longer to be a neglectable risk in healthcare workers assisting patients with HIV infection. Further study is urgently needed to see whether such unexpectedly high dissemination of tuberculosis also is demonstrable in the community.

Incidence and clinicopathological heterogeneity of HIV-related non-Hodgkin's lymphoma.

The characteristics of 14 HIV-seropositive patients with NHL consecutively observed between 1984 and 1988 at our Institution are described. Patients belonged to a known population of 1242 HIV-seropositive individuals in whom the incidence of NHL was 1.13%, significantly higher than in age-matched controls (P less than .0001). Within this population, a previous diagnosis of ARC or AIDS, but not of LAS, was the only significant risk factor for the development of NHL (P less than .0001). According to the status of HIV infection at the time of NHL diagnosis, two groups of patients could be clearly identified with different clinicopathological features and prognosis. In fact, NHL developing in 7 patients previously affected by ARC or AIDS, presented as localized, extranodal disease, predominantly in the CNS; large cell histology, peripheral blood cytopenia, severe immunodeficiency and poor prognosis further distinguished this subgroup. Conversely, NHL developing in 7 patients with either asymptomatic HIV-seropositivity or LAS, more often presented as disseminated disease both in nodal and extranodal sites, with Burkitt's-type histology. Cytopenia was uncommon and immunodeficiency was significantly less severe. In this subgroup complete remission (CR) was achieved with aggressive treatment in 6 of 7 patients. No relapses occurred but two opportunistic infection-related deaths were observed. Four patients are alive 6-34 months after CR, two of whom show newly developed opportunistic infections.