Pierre Peters

Double-Blind Placebo-Controlled Study of Concurrent Administration of Albendazole and Praziquantel in Schoolchildren with Schistosomiasis and Geohelminths

A double-blind placebo-controlled study of the concurrent administration of albendazole and praziquantel was conducted in>1500 children with high prevalences of geohelminths and schistosomiasis. The study sites were in China and the Philippines, including 2 strains of Schistosoma japonicum, and 2 different regions of Kenya, 1 each with endemic Schistosoma mansoni or Schistosoma haematobium. Neither medication affected the cure rate of the other. There was no difference between the side effect rate from albendazole or the double placebo. Praziquantel-treated children had more nausea, abdominal pain, and headache but these side effects were statistically more common in children with schistosomiasis, suggesting a strong influence of dying parasites. The subjects were followed for 6 months for changes in infection status, growth parameters, hemoglobin, and schistosomiasis morbidity. In all 4 sites, a significant 6-month increase in serum hemoglobin was observed in children who received praziquantel, strongly supporting population-based mass treatment.

Apoptosis and T Cell Hyporesponsiveness in Pulmonary Tuberculosis

Mycobacterium tuberculosis (MTB)-induced T cell responses are depressed in peripheral blood mononuclear cells of persons with newly diagnosed pulmonary tuberculosis (TB), and levels of interferon (IFN)-gamma remain low even after completion of antituberculous therapy. Loss of MTB-reactive T cells through apoptotic mechanisms could account for this prolonged T cell hyporesponsiveness. T cell apoptosis was studied in TB patients and healthy control subjects. Both spontaneous and MTB-induced apoptosis (in CD4 and non-CD4 T cells) from TB patients was increased when compared with healthy control subjects, whereas coculture with control antigen (candida) had no effect on T cell apoptosis in either group of study subjects. An inverse correlation existed between increased MTB-induced T cell apoptosis and IFN-gamma and interleukin (IL)-2 immunoreactivities. Successful antituberculous chemotherapy resulted in a 50% reduction in both spontaneous and MTB-induced apoptosis, which coincided with 3- and 8-fold increases in levels of MTB-stimulated IL-2 and IFN-gamma, respectively. These data indicate that apoptotic pathways are operant during active MTB infection and may contribute to deletion of MTB-reactive T cells and the immunopathogenesis of this disease.

Augmentation of Apoptosis and Interferon-γ Production at Sites of Active Mycobacterium tuberculosis Infection in Human Tuberculosis

Pleural tuberculosis (TB) was employed as a model to study T cell apoptosis at sites of active Mycobacterium tuberculosis (MTB) infection in human immunodeficiency virus (HIV)-coinfected (HIV/TB) patients and patients infected with TB alone. Apoptosis in blood and in pleural fluid mononuclear cells and cytokine immunoreactivities in plasma and in pleural fluid were evaluated. T cells were expanded at the site of MTB infection, irrespective of HIV status. Apoptosis of CD4 and non-CD4 T cells in the pleural space occurred in both HIV/TB and TB. Interferon (IFN)-gamma levels were increased in pleural fluid, compared with plasma. Spontaneous apoptosis correlated with specific loss of MTB-reactive, IFN-gamma-producing pleural T cells. Immunoreactivities of molecules potentially involved in apoptosis, such as tumor necrosis factor-alpha, Fas-ligand, and Fas, were increased in pleural fluid, compared with plasma. These data suggest that continued exposure of immunoreactive cells to MTB at sites of infection may initiate a vicious cycle in which immune activation and loss of antigen-responsive T cells occur concomitantly, thus favoring persistence of MTB infection.

Increased Replication of HIV-1 at Sites of Mycobacterium tuberculosis Infection: Potential Mechanisms of Viral Activation

&NA; Tuberculosis (TB) enhances HIV‐1 replication and the progression to AIDS in dually infected patients. We employed pleural TB as a model to understand the interaction of the host with HIV‐1 during active TB, at sites of Mycobacterium tuberculosis (MTB) infection. HIV‐1 replication was enhanced both in the cellular (pleural compared with blood mononuclear cells) and acellular (pleural fluid compared with plasma) compartments of the pleural space. Several potential mechanisms for expansion of HIV‐1 in situ were found, including augmentation in expression of tumor necrosis factor (TNF)‐&agr; and the HIV‐1 noninhibitory &bgr;‐chemokine (MCP‐1), low presence of HIV‐1 inhibitory &bgr;‐chemokines (MIP‐1&agr;, MIP‐1&bgr;, and RANTES [regulated on activation, normal T expressed and secreted]), and upregulation in expression of the HIV‐1 coreceptor, CCR5, by pleural fluid mononuclear cells. Thus, at sites of MTB infection, conditions are propitious both for transcriptional activation cf HIV‐1 in latently infected mononuclear cells, and facilitation of viral infection of newly recruited cells. These mechanisms may contribute to enhanced viral burden and dissemination during TB infection.

Morbidity due to schistosomiasis japonica in the People's Republic of China

Transmission and morbidity induced by Schistosoma japonicum were evaluated in 825 individuals undergoing periodic treatment with praziquantel on Jishan island, Jiangxi Providence, in the Peoples Republic of China. Eggs of S. japonicum were found in the stools of 39.4% of the population; 70% of those infected were less than 20 years of age. Hepatomegaly greater than 3 cm in the midsternal line was detected by physical examination and ultrasonography in 75% and 90% of individuals, respectively, regardless of infection status. Symmers clay pipe-stem fibrosis of the liver was detected by ultrasonography in 20% of all individuals. Hepatitis B surface antigen and antibody to hepatitis C were found in 11% and less than 1% of the population, respectively. Our study suggests that, despite intermittent chemotherapy, morbidity due to S. japonicum is still a significant problem in China.

Activation of β-chemokines and CCR5 in persons infected with human immunodeficiency virus type 1 and tuberculosis

Tuberculosis (TB) in human immunodeficiency virus type 1 (HIV-1)-infected persons is associated with progression of HIV-1 disease. The expression of macrophage inflammatory protein (MIP)-1alpha and CCR5 was assessed in HIV-1-infected patients with pulmonary TB (HIV-1/PTB) and without PTB (HIV-1/C), PTB patients not infected with HIV-1 (PTB), and control subjects. Mycobacterium tuberculosis (MTB)-induced MIP-1alpha production was lower in peripheral blood mononuclear cells (PBMC) of HIV-1/PTB patients than in those of PTB patients (P< .05) and was lower in PBMC of HIV-1/C patients than in those of control subjects (P< .005). However, MIP-1alpha production was higher in PBMC of HIV/PTB patients than in those of HIV-1/C patients (P< .01). The pattern of MTB-induced RANTES production was similar to that of MIP-1alpha. However, MTB induced greater expression of mRNA for CCR5 in PBMC of HIV-1/PTB patients than in those of HIV-1/C patients (P< .04). Furthermore, the MTB-induced HIV p24 antigen level in PBMC of HIV-1/PTB patients with a CD4 cell count <500 cells/microL was higher (P< .05) than that in HIV-1/C patients. Thus, perturbations in chemokine pathways in HIV-1/PTB patients may accelerate HIV-1 disease.

Mechanisms of apoptosis of T-cells in human tuberculosis.

The role of TGF-β TNF-α FasL and Bcl-2 in apoptosis of CD4 T-cells during active TB was studied. Coculture of PBMC from TB patients with neutralizing antibodies to TGF-β or TNF-α decreased spontaneous (P ≤ 0.05) and MTB-induced (P≤ 0.02) T-cell apoptosis by 50–90%, but effects were not additive. Interestingly, only levels of TGF-β in supernatants correlated with rates of spontaneous and MTB-induced apoptosis. FasL surface and mRNA expression were higher in unstimulated and MTB-stimulated PBMC from patients than controls, and neutralization of FasL abrogated apoptosis of T-cells from patients only. Intracellular Bcl-2 protein was lower among unstimulated CD4 T-cells from patients than those from controls (P ≤ 0.02), and MTB stimulation reduced intracellular Bcl-2 content in CD4 T-cells from patients only (P ≤ 0.001). These findings may indicate that, during TB, predisposition of CD4 T-cells to apoptosis may involve both low expression of Bcl-2, and excessive expression of TGF-β TNF-α and FasL.

Schistosomiasis japonica on Jishan Island, Jiangxi Province, People's Republic of China: persistence of hepatic fibrosis after reduction of the prevalence of infection with age

Hepatic fibrosis due to schistosomiasis japonica was examined by ultrasonography in a cross-sectional community study of 825 individuals on Jishan Island, Jiangxi Province, China. The prevalence of active infection was 39.4% with peak infection in the 10-19.9 years age group followed by a significant decline. A similar pattern was observed for intensity of infection. The prevalence of hepatomegaly in the midsternal line > or = 6 cm peaked at 60% in the fourth decade and remained elevated. A progressive increase in the severity of hepatic periportal fibrosis was observed with age, with advanced fibrosis peaking in the fifth decade. The proportion of individuals with advanced fibrosis was significantly greater in males than in females despite equivalent prevalence and intensity of schistosome infection. In addition, a positive association (P < 0.01) was found between periportal fibrosis and both hepatomegaly > or = 6 cm and splenomegaly. This study suggests that the natural history of schistosomiasis japonica in this hyperendemic community in China is marked by persistence of hepatomegaly and schistosome-induced periportal fibrosis in adults despite a decrease in the prevalence of infection.

Macrophage-Activating Cytokines in Human Immununodeficiency Virus Type 1–Infected and –Uninfected Patients with Pulmonary Tuberculosis

Tuberculosis (TB) is the most common opportunistic infection in human immunodeficiency virus type 1 (HIV-1)-infected patients globally and occurs throughout the course of HIV-1 disease. Here the production of interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha by peripheral blood mononuclear cells (PBMC) of HIV-1-infected versus -uninfected patients with newly diagnosed pulmonary TB (PTB) was compared. Findings were correlated with cytokine profiles, clinical presentation, and expression of inducible nitric oxide (iNOS). Most HIV-1/PTB patients with a CD4 cell count of 200-500 cells/microL had high IFN-gamma production and radiographic evidence of atypical PTB. Low IFN-gamma production and radiographic evidence of reactivated PTB characterized both HIV-1/PTB patients with a CD4 cell count >or=500 cells/microL and HIV-1-uninfected patients. TNF-alpha levels were similar in all HIV-1/PTB patients, regardless of CD4 cell count. Induction of iNOS in PBMC was low and was associated with low IFN-gamma production. These data underscore the potential pathogenic role of macrophage-activating cytokines in TB in HIV-1-infected patients.

Morbidity in schistosomiasis japonica in relation to intensity of infection. A study of two rural brigades in Anhui Province, China

Schistosomiasis japonica remains endemic in several provinces south of the Yangtze River in China because of relatively sparse populations of human beings and dense populations of snails. We studied two brigades in a rural commune in Gui-chi County, Anhui Province, to determine the prevalence, intensity, and morbidity associated with this infection before concerted control efforts were instituted. Quantitative fecal examinations, histories, and physical examinations relevant to schistosomiasis japonica were performed in 96 per cent of the available population 2 to 65 years of age. The prevalence was 26.3 per cent in Brigade A (778 persons) and 14.4 per cent in Brigade B (1532 persons). Clinical symptoms and signs were compared among uninfected persons and persons at three levels of infection as determined by fecal egg output. Some increased weakness was seen only at the heaviest levels of infection; abdominal pain was not an important symptom. Hepatomegaly was somewhat more frequent in moderate and heavy infections, but splenomegaly was rare and unrelated to intensity of infection. Neither stool consistency nor occult blood was related to the presence or intensity of infection. Approximately 50 per cent of the population had been treated for schistosomiasis japonica, 25 per cent repeatedly.