A community randomized controlled clinical trial of mixed carotenoids and micronutrient supplementation of patients with acquired immunodeficiency syndrome.

OBJECTIVE: This clinical trial aims to evaluate if natural mixed carotenoids supplementation can improve the health and survival of acquired immunodeficiency syndrome (AIDS) patients. DESIGN: A placebo-controlled, prospective, randomized, double-blind, multicenter clinical trial. SETTING: Community, tertiary care human immunodeficiency virus (HIV) clinics of the Canadian HIV Trials Network (CTN). PARTICIPANTS: Three hundred and thirty-one adults with advanced AIDS on conventional management were recruited during routine clinic visits. INTERVENTIONS: All participants, including 166 controls, received daily oral specially formulated multivitamins including vitamin A and trace elements; 165 treatment group participants received additional daily oral natural mixed carotenoids, equivalent to 120,000 IU (72 mg) of beta-carotene daily. Follow-up was quarterly at routine clinic visits. RESULTS: Mean (s.d.) follow-up was for 13 (6) months. Thirty-six participants died by 18 months. Serum carotene concentration <1.0 micromol/l was present in 16% participants at baseline. Despite variation in carotene content of the treatment medication, serum carotene concentrations increased significantly to twice the baseline levels to 18 months follow-up in participants who received carotenoids treatment compared with controls (P < 0.0001). Although not statistically significant, mortality was increased in participants who did not receive carotenoids treatment compared with those who did (HR time to death 1.76, 95% CI 0.89, 3.47, P = 0.11). In multivariate analysis, survival was significantly and independently improved in those with higher baseline serum carotene concentrations (P = 0.04) or higher baseline CD4 T-lymphocyte counts (P = 0.005). Adjusted mortality was also significantly and independently increased in those who did not receive carotenoids treatment compared with those who did (HR time to death 3.15, 95% CI 1.10, 8.98, P = 0.03). CONCLUSIONS: Low serum carotene concentration is common in AIDS patients and predicts death. Supplementation with micronutrients and natural mixed carotenoids may improve survival by correction of a micronutrient deficiency. Further studies are needed to corroborate findings and elucidate mechanism of action.

Legionnaires' disease in the Caribbean. An outbreak associated with a resort hotel.

Outbreaks of legionnaires' disease (LD) in tourists visiting Italian and Spanish resorts have been recently reported. An unusual number of reports of LD in tourists visiting the US Virgin Islands prompted an investigation of risk factors for development of LD in this area. Twenty-seven cases of LD were identified between 1979 and 1982 through press reports, personal communication, the national LD surveillance system, a review of hospital records, and a mail survey. Twenty-four of 27 persons with the disease had visited St Croix and 12 of them had stayed at a single hotel in 1981. Available evidence suggested that infection was due to Legionella pneumophila serogroup 1; L pneumophila serogroups 1 and 3 and several new Legionella species were isolated from the potable water system at the hotel. Following hyperchlorination of the potable water system, no further cases of LD in hotel visitors have been identified to date.

Predictors of survival and eradication of Mycobacterium avium complex bacteremia (MAC) in AIDS patients in the Canadian randomized MAC treatment trial. Canadian HIV Trials Network Protocol 010 Study Group.

OBJECTIVE: To assess the importance of baseline characteristics including medical history, indicators of current disease status, therapeutic drug use, in vitro drug susceptibility, immune status and mycobacterial load on bacteriologic response and survival in HIV-positive patients with Mycobacterium avium complex (MAC) bacteremia. DESIGN: An observational substudy of an open-label randomized controlled trial of two alternative therapeutic regimens for MAC. SETTING: Twenty-four hospital-based HIV clinics in 16 Canadian cities. MAIN OUTCOME MEASURES: The main outcome measures were survival and bacteriologic response, defined by consecutive negative blood cultures for MAC at least 2 weeks apart within 16 weeks of study entry. RESULTS: Prior AIDS diagnosis, low Karnofsky score, active unstable AIDS-related conditions, absence of antiretroviral therapy and absence of Pneumocystis carinii pneumonia prophylaxis were associated with shorter survival by univariate regression using the proportional hazards model. On multivariate analysis, antiretroviral therapy was not an independent predictor of mortality, and previous rifabutin prophylaxis was independently associated with poor survival outcomes, a result consistent across study treatment. Using a logistic regression model, baseline quantitative mycobacterial load [relative odds of clearing, 1.97 for a decrease of 1 log10 colony forming count; 95% confidence interval (CI), 1.36-2.87; P < 0.001] and Karnofsky score were the only statistically significant univariate predictors of clearance, although previous prophylaxis with rifabutin was also a significant predictor in a multivariate model (relative odds of clearing, 0.39; 95% CI, 0.17-0.88; P < 0.05). CONCLUSIONS: This study indicates that although the level of MAC bacteremia is an important predictor of clearance, it is not associated with survival.

Pyomyositis: tropical disease in a temperate climate.

Two cases of pyomyositis or bacterial abscess of striated muscle in adults are presented. One patient was initially diagnosed as having acute thrombophlebitis of the lower extremity. Computerized tomography was helpful in establishing the correct diagnosis. The other patient presented with a closed compartment syndrome following blunt trauma. Both patients responded to open drainage and antibiotic therapy, although the diagnosis was delayed for over three weeks in one patient. Although common in the tropics, pyomyositis is unusual in the temperate zone. Unfamiliarity with this entity remains the major obstacle to appropriate management.

Lowbury Lecture. Listeriosis: epidemiology, virulence and the significance of contaminated foodstuffs.

Recent epidemiological evidence confirms that sporadic, as well as outbreak-associated, cases of listeriosis are primarily foodborne in origin. Implicated foodstuffs include meat products, dairy products, fruit, seafood and raw and processed vegetables. Large community-acquired outbreaks in North America and Europe have been complemented by smaller outbreaks involving hospitalized patients. Anecdotal reports and case clusters of nosocomial cases also support foodborne transmission. Cross-infection may be a major mode of transmission as demonstrated in a recent outbreak in Costa Rica. The sporadic nature of outbreaks of listeriosis are more consistent with changes in organism virulence rather than host susceptibility. The population of patients at risk for listeriosis (pregnant women and immunocompromised hosts) may not vary greatly. Establishment of infection is probably dose-dependent and gastric acidity may be protective. However, other organism-specific virulence factors, such as haemolysin production, may affect the post-intestinal phase of infection. Virulence factors other than haemolysins have not been characterized as yet. In summary, acquisition of Listeria monocytogenes infection from the environment by susceptible hosts may be widespread but invasive infection remains rare and the determinants of invasion require further elucidation.

An outbreak of Candida parapsilosis prosthetic valve endocarditis following cardiac surgery.

Five of 34 (15%) patients who received prosthetic cardiac valves between May and August 1982 at the Victoria General Hospital in Halifax, Nova Scotia, developed Candida parapsilosis prosthetic valve endocarditis. The clustering of these cases pointed to a common source outbreak. In a retrospective cohort study, no significant differences were found between infected and uninfected patients in terms of pre-, intra-, and postoperative risk factors. Environmental investigations suggested intraoperative contamination through the cardiac bypass equipment as the source of infection but a causal relationship could not be established. The outcome for the cases was uniformly fatal, emphasizing the need for prevention of such serious nosocomial infections.

A model of food-borne Listeria monocytogenes infection in the Sprague-Dawley rat using gastric inoculation: development and effect of gastric acidity on infective dose.

Recent epidemiological evidence suggests that Listeria monocytogenes (LM) is a food-borne pathogen in humans. A model of LM infection was developed using the Sprague-Dawley (SD) rat to study the interaction of LM with gastrointestinal epithelium as the first step in the pathogenesis of invasive listeriosis. Conventionally raised, juvenile female SD rats were given 10(2)-10(9) virulent L. monocytogenes, serotype 4b or nonpathogenic Listeria species. Only rats given virulent LM developed dose-dependent invasive infection of the liver and spleen. Light and electron microscopic studies suggested attachment to and invasion of the gastrointestinal mucosa by virulent LM. Because the development of invasive listeriosis in humans has been epidemiologically associated with a decrease in gastric acidity, the effect of decreasing gastric acidity on dose-dependent infection was studied. Rats were pretreated with cimetidine (50 mg/kg) by intraperitoneal injection prior to oral inoculation of 10(2)-10(9) virulent L. monocytogenes. Cimetidine significantly lowered the infective dose of virulent L. monocytogenes (P < 0.05). This oral model should allow further study of host and organism-specific virulence factors mediating the gastrointestinal phase of invasive LM infection, an increasingly important public health problem.

Pneumococcal vaccination practices among private physicians.

It is estimated that less than 10 percent of patients thought to be at high risk of invasive pneumococcal diseases have received 14-valent pneumococcal polysaccharide vaccine. To determine if any of these groups are more likely to be vaccinated than others, 893 private, primary-care physicians were surveyed nationwide. Although there was general agreement that the vaccine is indicated for the high-risk groups, patients with cardiorespiratory diseases were the only ones usually immunized by more than half of the survey respondents. The discrepancy between attitudes and practices could not be attributed to any specific factor.

The epidemiology of immune thrombocytopenia.

Three cases of immune thrombocytopenia (ITP) associated with human immunodeficiency virus (HIV) infection prompted a review of community-acquired thrombocytopenia in Nova Scotia from January 1980 to December 1987. Two hundred and seven patients meeting the case definition of ITP were identified. The incidence of ITP rose from 2.0×10(5) in 1980 to 3.3×10(5) in 1987. More cases of ITP in the sexually active population occurred between 1984 and 1987 than in the previous four years (P=0.034). All three cases of known HIV associated ITP were captured in the retrospective surveillance system. The study concluded that increases in community-acquired ITP in a sexually active population may be a surrogate marker of the HIV epidemic, even in geographic areas with a low seroprevalence for HIV. Serological tests for HIV infection should be a routine part of the diagnostic investigation of ITP in all sexually active patients or those with other potential risk factors for HIV infection.

A randomized double-blind placebo controlled trial of oral acyclovir in renal allograft recipients.

Fifty renal transplant patients were randomized to receive either 800 mg acyclovir by mouth four times daily or identical placebo tablets for prophylaxis of herpes simplex infection. Patients were followed weekly to assess reactivation of herpes simplex, varicella zoster virus, Epstein-Barr virus or cytomegalovirus (CMV) infections. The patients received standard immunosuppressive regimens including cyclosporine A. Acyclovir suppressed secretion of herpes simplex virus in treated patients (P=0.001). Three episodes of mucocutaneous herpes simplex virus occurred in placebo recipients and one in a noncompliant acyclovir recipient. A clinically important difference in graft survival was demonstrated, but because of sample size failed to reach statistical significance (P=0.11). No reactivation of varicella zoster virus, Epstein-Barr virus or CMV infection was detected in either group. Toxicity was limited to central nervous irritability. The authors conclude that high dose oral acyclovir provides effective prophylaxis for prevention of herpes simplex virus infections in renal transplantation and may be associated with increased graft survival, perhaps from suppression of CMV infection.

Immunization against pneumococcal disease in HIV-infected patients: conjugate versus polysaccharide vaccine before or after reconstitution of the immune system (CTN-147).

To investigate whether patients should be immunized immediately or delay immunization until after reconstitution of the immune system and whether a conjugate or polysaccharide vaccine results in a better immunologic response. Seventy-nine patients were randomly assigned, utilizing a two by two factorial design to receive immediate immunization or delay immunization. Baseline characteristics were similar for the four arms: 78% men, median age 41 years, median time since HIV diagnosis 0.3 years, median CD4 60 cells/mm(3) and median HIV viral load 5.02 log copies/mL. Results in favour of delayed immunization were observed for those serotypes showing a response. The proportional odds ratios for delayed versus immediate immunization were 0.341 (P = 0.04) and 0.204 (P = 0.004) at months 6 and 12, respectively. No differences in immunological response were observed between the two individual vaccines for the shared serotypes studied. HIV-infected adults produced a higher immunological response to pneumococcal vaccine after reconstitution of the immune system.

Hepatotoxicity from first line antiretroviral therapy: an experience from a resource limited setting.

BACKGROUND: Highly active antiretroviral therapy (HAART) has been associated with liver toxicity. The role of monitoring for liver toxicity has not been well studied in resource-limited settings (RLS). OBJECTIVES: To determine the background prevalence and incidence of liver injury and describe the associated signs and symptoms of acute hepatitis after initiating HAART; and to determine the role of liver enzyme tests in monitoring hepatotoxicity. METHODS: In this prospective study, in Mulago Hospital AIDS Clinics, we consecutively enrolled adult patients initiated on one of three first line HAART regimens [Stavudine (d4T)-Lamivudine (3TC) and nevirapine (NVP); Zidovudine (AZT)-3TC and Efavirenz (EFV) or d4T-3TC-EFV]. We monitored ALT (alanine aminotransferase) and clinical evidence of acute hepatitis at baseline, 2(nd), 6(th), 10(th) and 14(th) week of therapy. RESULTS: Two hundred and forty HIV-positive HAART- naïve patients were enrolled in the study. The baseline prevalence of transaminitis was 1.7% with an incidence of 4.2% at 14 weeks. Grade 3-4 hepatotoxicity was documented in 1.3%. Jaundice was seen in grade 2-4 ALT elevations. Being on concurrent HAART and antituberculous drugs was associated with grade 2-4 toxicity compared to those who were only on HAART [OR; 16.0 (95% CI; 2.4-104.2)]. CONCLUSIONS: Incidence of severe hepatotoxicity within three months of first-line antiretroviral therapy was low, suggesting that routine measurement of transaminases may not be necessary in all patients initiating HAART in RLS. Routine measurement may be important in following patients on HAART and concurrent TB treatment as well as those with jaundice to avoid missing hepatotoxicity.

New perspectives on the gastrointestinal mode of transmission in invasive Listeria monocytogenes infection.

The route or mechanism of transmission of Listeria monocytogenes from its rural veterinary reservoir to newborn and older human populations has been obscure. Anecdotal reports of milk-borne infection from cows with Listeria mastitis have been published, but intensive investigations of small outbreaks of L. monocytogenes infections in humans have not supported a gastrointestinal mode of infection. Several recent studies, however, strongly suggest this possibility, and case-control studies of epidemic listeriosis in the Canadian Maritime provinces in 1981 documented an association between ingestion of uncooked vegetables and the development of illness (p = 0.02). In that study, coleslaw from a regional producer which was distributed throughout the Maritimes was considered to be the vehicle of transmission. Cabbage, the raw product in the production of coleslaw, was contaminated at a farm prior to arrival at the plant. Contamination occurred through fertilization with raw manure from a flock of sheep known to harbour L. monocytogenes. Therefore, an indirect link was established between Listeria monocytogenes infection of sheep on a cabbage farm and subsequent development of invasive listeriosis in humans. This study supports findings from other epidemiologic studies of human listeriosis and is consistent with results of investigations into the mode of transmission of natural and laboratory-acquired listeriosis in animals.

Foodborne listeriosis.

Listeria monocytogenes emerged as an important foodborne pathogen in the latter part of the 20th century. Clinical syndromes caused by this microorganism include sepsis in the immunocompromised patient, meningoencephalitis in infants and adults, and febrile gastroenteritis. Focal infections at other sites are less frequent. Listeria species are commonly found in raw and unprocessed food products. Major outbreaks of listeriosis, with high morbidity and mortality, have been caused by a variety of foods, including soft cheeses, delicatessen meats, and vegetable products. Improved detection methods, dietary recommendations, and, in some cases, preemptive antibiotic treatment or prophylaxis have reduced the incidence of sporadic listeriosis infections in the United States. Microbial virulence factors distinguishing environmental strains of L. monocytogenes from invasive strains causing foodborne illness and host factors promoting human infection remain incompletely understood.