Adjuvant potential of low dose all-trans retinoic acid during oral typhoid vaccination in Zambian men.

There is an urgent need to identify ways of enhancing the mucosal immune response to oral vaccines. Rotavirus vaccine protection is much lower in Africa and Asia than in industrialized countries, and no oral vaccine has efficacy approaching the best systemic vaccines. All-trans retinoic acid (ATRA) up-regulates expression of α4ß7 integrin and CCR9 on lymphocytes in laboratory animals, increasing their gut tropism. The aim of this study was to establish the feasibility of using ATRA as an oral adjuvant for oral typhoid vaccination. In order to establish that standard doses of oral ATRA can achieve serum concentrations greater than 10 nmol/l, we measured ATRA, 9-cis and 13-cis retinoic acid in serum of 14 male volunteers before and 3 h after 10 mg ATRA. We then evaluated the effect of 10 mg ATRA given 1 h before, and for 7 days following, oral typhoid vaccine in eight men, and in 24 men given various control interventions. We measured immunoglobulin (Ig)A directed against lipopolysaccharide (LPS)and protein preparations of vaccine antigens in whole gut lavage fluid (WGLF) and both IgA and IgG in serum, 1 day prior to vaccination and on day 14. Median [interquartile range (IQR)] C(max) was 26·2 (11·7-39·5) nmol/l, with no evidence of cumulation over 8 days. No adverse events were observed. Specific IgA responses to LPS (P = 0·02) and protein (P = 0·04) were enhanced in WGLF, but no effect was seen on IgA or IgG in serum. ATRA was well absorbed, well tolerated and may be a promising candidate oral adjuvant.

In a trial of the use of miltefosine to treat HIV-related cryptosporidiosis in Zambian adults, extreme metabolic disturbances contribute to high mortality.

There is still no effective treatment for cryptosporidiosis even though the disease has a significant impact on HIV-infected adults and children. Following evidence of the drug's promising efficacy in vitro, a phase-1-phase-2 study of miltefosine (given at 2.5 mg/kg for 14 days, with the dose capped at 100 mg/day) was recently initiated among Zambian adults with HIV-related cryptosporidiosis. Seven patients were recruited before the trial was terminated prematurely because of lack of efficacy and the development of severe adverse events. The latter may have been entirely drug-related or the result of extreme metabolic abnormalities already present in the patients enrolled in the trial. In future trials of miltefosine, attention will have to be paid to the possibility of metabolic abnormalities in the subjects investigated.

Presence of Schistomiasis in Genital Biopsies from Patients at the University Teaching Hospital in Lusaka; Zambia

Background: Ectopic localizations of the adult Schistosomes and ova in the genital tract of individuals living in schistosoma endemic areas are common. The infection can affect both male and female reproductive organs; and although it is predominant in adult women; case reports in girls younger than 15 years of age have been documented. Objective: The objective of this review was to determine and document the presence of genital schistosomiasis from biopsy specimens. Methods: Patients' laboratory records at the University Teaching Hospital histopathology laboratory for the period 2001 to 2007 were retrieved and reviewed for reports on the presence of schistosomiasis. Data were analysed by age; sex and biopsy site. Results: Thirty eight (65.5) of the 58 specimens with schistosomiasis were from the genital organs. Female genital tract schistosomiasis was more prevalent (84.2) than male genital schistosomiasis (15.8); p0.001. Schistosomiasis was high in biopsy specimens collected from the cervix

Nitazoxanide for persistent diarrhoea in Zambian acquired immune deficiency syndrome patients: a randomized-controlled trial.

BACKGROUND: Adults with acquired immune deficiency syndrome and persistent diarrhoea in Zambia have intestinal infection, predominantly protozoa. AIM: To search for treatment which can be offered with minimal investigation, we carried out a double-blind, randomized-controlled trial of nitazoxanide (a drug with a range of activity against parasites and bacteria). METHODS: Patients with diarrhoea of 1 month duration or longer were randomized to receive nitazoxanide (1000 mg twice daily) or placebo for 2 weeks. End-points were clinical response, parasitological clearance and mortality. RESULTS: Two hundred and seven adults were randomized; 42 died during the study. The primary assessment of efficacy was made after 17 days. Clinical response was observed in 56 (75%) of 75 patients receiving nitazoxanide and 45 (58%) of 77 patients receiving placebo (P = 0.03). The rate of improvement was markedly higher in patients with CD4 counts under 50 cells/microL receiving nitazoxanide (P = 0.007). The benefit was largely restricted to the period when the drug was being administered. No difference was seen in parasitological clearance between the two groups. Mortality was 19% by 4 weeks of follow-up and did not differ with treatment allocation. CONCLUSIONS: Nitazoxanide given orally for 14 days was associated with clinical improvement in Zambian acquired immune deficiency syndrome patients with diarrhoea, especially those with very low CD4 counts.

Albendazole chemotherapy for AIDS-related diarrhoea in Zambia--clinical, parasitological and mucosal responses.

BACKGROUND: Albendazole reduces diarrhoea in African AIDS patients, but it is unclear if the clinical response to treatment reflects pathogen eradication and/or mucosal recovery. METHODS: Adults with HIV-related persistent diarrhoea were treated with albendazole 800 mg twice daily for 14 days. Clearance of parasites was evaluated at 3 and 6 weeks by stool microscopy. At baseline and at 6 weeks duodenal biopsies were taken for electron microscopy (EM) and morphometry. RESULTS: Ten (7%) of 153 patients had cryptosporidiosis, 54 (37%) had isosporiasis and 23 (16%) had microsporidiosis. By 3 weeks, these protozoa were cleared in 27 (46%) of 59 patients initially positive. By 6 weeks, 34 (39%) of 87 patients experienced complete clinical response, 18 (21%) partial response and 35 (40%) no response. Crypt depth increased by 15% over 6 weeks (P < 0.001), but villous height increased only in patients with complete response (median + 50 microm, interquartile range (IQR) 2-90, compared to patients with partial (+ 4 microm, IQR -15,41) or no response (-13 microm, IQR -2,12; P=0.008)). Fifteen patients died: body mass index < 17.5 kg/m(2) and crypt depth < 180 microm independently predicted death. CONCLUSIONS: Albendazole therapy reduced the burden of protozoal infection and promoted mucosal recovery in patients with a complete clinical response.

Intestinal and systemic infection, HIV, and mortality in Zambian children with persistent diarrhea and malnutrition.

BACKGROUND: Persistent diarrhea-malnutrition syndrome is a complex of infection and immune failure that involves protein, calorie and micronutrient depletion, and metabolic disturbances. We report an analysis of the impact of HIV infection on infectious disease, clinical presentation, and mortality in Zambian children with persistent diarrhea and malnutrition. METHODS: Two hundred children (94 boys and 106 girls, 6-24 months old) were examined on admission to the malnutrition ward of University Teaching Hospital in Lusaka, Zambia. There was then 1 month of follow-up. RESULTS: Antibodies to HIV were found in 108 of the children (54%). The common intestinal infections (Cryptosporidium parvum [26%] and nontyphoid Salmonella spp [18%]), septicemia (17%), and pulmonary tuberculosis confirmed by gastric lavage (13.5%) were not significantly more common in HIV-seropositive than in HIV-seronegative children. HIV-seropositive children were more likely to have marasmus whereas HIV-seronegative children were more likely to have kwashiorkor. Weight-for-age z scores at nadir (postedema) were lower in HIV-seropositive children (median, -4.4; interquartile range [IQR], -5.0 to -3.8) than in HIV-seronegative children (median, -3.7; IQR, -4.2 to -3.1; P < 0.0001). Height-for-age and weight-for-height z scores and mid-upper arm circumference showed a similar difference. Of the 200 children, 39 (19.5%) died within 28 days; cryptosporidiosis and marasmus were the only independent predictors of death. CONCLUSIONS: Although intestinal and systemic infections did not differ for HIV-seropositive and HIV-seronegative children, HIV influenced nutritional states of all children. Cryptosporidiosis and marasmus were associated with higher mortality.

A method for diagnosis of microsporidiosis adapted for use in developing countries.

Microsporidiosis in AIDS patients has emerged as an important cause of morbidity, but diagnosis requires special stains, equipment and expertise. Here we describe a modification to an existing staining technique to allow more rapid preparation, without additional equipment, facilitating research in the tropics into these important pathogens.

Cryptosporidiosis in urban Zambian children: an analysis of risk factors.

In four crowded townships of Lusaka, Zambia, the prevalence of cryptosporidiosis in 222 children with diarrhea was 18%, with marked temporal and geographic variation over the course of one rainy season. Using data on the finding of oocysts of Cryptosporidium parvum in urban water supplies, the areas under study were categorized as high or low risk. Prevalence of cryptosporidiosis in children with diarrhea was higher in high risk areas after stratification by early/late stage of the rains (Mantel-Haenszel odds ratio [OR] = 2.9, 95% confidence interval [CI] = 1.3, 6.7; P = 0.008). Cryptosporidiosis was not associated with keeping animals, nutritional status, or parental education, but was apparently more common in breast fed children (OR = 2.7, 95% CI = 1.1, 6.9; P = 0.01), although the proportion of exclusively breast fed children was not measured. Since most of these infections were of short duration, we conclude that transmission of C. parvum can vary dynamically within one city and over short periods of time, and that water-borne contamination may be a substantial influence.