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.

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.

The effect of C. burnetii infection on the quality of life of patients following an outbreak of Q fever.

Sixty-six cases of Q fever were diagnosed in people affiliated with a goat-farming co-operative in rural Newfoundland in the spring of 1999. Follow-up studies which included administration of the Short Form 36 Health Survey (SF-36) were conducted 3 and 27 months after the initial outbreak to prospectively follow the effects of acute Q fever on the quality of life of the participants. Twenty-seven months after the outbreak 51% of those who had Q fever reported persistent symptoms including seven participants whose symptoms had initially resolved 3 months after the outbreak. Individuals with Q fever had significantly lower scores on five of the eight scales in the SF-36 and lower scores in the mental and physical summary scales compared to uninfected controls. Although this supports the hypothesis of a 'post Q fever fatigue syndrome' (QFFS), further study is warranted.

Goat-associated Q fever: a new disease in Newfoundland.

In the spring of 1999 in rural Newfoundland, abortions in goats were associated with illness in goat workers. An epidemiologic investigation and a serologic survey were conducted in April 1999 to determine the number of infections, nature of illness, and risk factors for infection. Thirty-seven percent of the outbreak cohort had antibody titers to phase II Coxiella burnetii antigen >1:64, suggesting recent infection. The predominant clinical manifestation of Q fever was an acute febrile illness. Independent risk factors for infection included contact with goat placenta, smoking tobacco, and eating cheese made from pasteurized goat milk. This outbreak raises questions about management of such outbreaks, interprovincial sale and movement of domestic ungulates, and the need for discussion between public health practitioners and the dairy industry on control of this highly infectious organism.

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.

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.

Determinants of rifabutin-associated uveitis in patients treated with rifabutin, clarithromycin, and ethambutol for Mycobacterium avium complex bacteremia: a multivariate analysis. Canadian HIV Trials Network Protocol 010 Study Group.

Uveitis occurred in a substantial proportion of AIDS patients receiving rifabutin, 600 mg daily, together with clarithromycin and ethambutol for treatment of Mycobacterium avium complex bacteremia. A case-control study was undertaken to examine potential risk factors for developing uveitis. Of eight parameters examined, only baseline body weight predicted the development of uveitis by both univariate and multivariate analyses (P = .001). The incidence of uveitis was 14% in patients weighing >65 kg, 45% in patients between 55 and 65 kg, and 64% in patients <55 kg. Concomitant therapy with fluconazole, a drug known to raise serum rifabutin concentrations, was not associated with an increased incidence of uveitis. The risk of uveitis was markedly reduced when rifabutin was given at 300 mg daily in combination with clarithromycin and ethambutol.

Topical undecylenic acid for herpes simplex labialis: a multicenter, placebo-controlled trial.

A multicenter, patient-initiated, double-blind, placebo-controlled trial of 15% undecylenic acid cream was conducted with 573 patients with recurrent herpes labialis. Treatment was applied 5 or 6 times daily until crusting and then thrice daily until healing. Patients were assessed daily until 48 h after crusting and then every other day until healing. Undecylenic acid significantly reduced the incidence and duration of viral shedding and the duration and severity of itching but did not increase abortive episodes or reduce times to healing, crusting, or progression of lesion size. When treatment was initiated during the prodrome, the time to crusting was reduced (P = .02) and the area under the symptom-time curve for pain and tenderness was reduced, approaching statistical significance (P = .06). Active treatment was well tolerated but caused dysgeusia and local irritation. Undecylenic acid 15% cream reduces viral shedding in recurrent herpes labialis, but clinical benefits are minimal and largely restricted to patients initiating therapy during the prodrome.

Pathogenesis and immunology of Listeria monocytogenes.

Listeriosis is primarily a foodborne disease and the pathogenesis of infection is determined by passage of the organism from the gastrointestinal lumen to the reticuloendothelial cells of the liver and spleen. Subsequent invasive events such as sepsis and meningitis develop. The immune response to Listeria is characterized by early macrophage mediated killing followed by the development of a brisk cell mediated immune response. Humoral immunity appears to play no role in infection in the protected response. Organism specific virulence factors such as hemolysin and actin polymerization factor may play important roles in pathogenesis and also illicit specific immune responses. Immunization against listeriosis has been carried in animals but does not appear feasible for this rare infection in human populations.

The practice of infectious diseases in the 1990s: the Canadian experience.

A survey of the members of the Canadian Infectious Disease Society was carried out to determine the content of an infectious diseases consultative practice in the 1990s. Respondents were asked to identify all new inpatient, outpatient, and telephone consultations during a 1-week period in 1990. Consultations were categorized by the infectious disease syndrome of the patient and by the microorganism that was identified. Bacterial infections were the most common cause of inpatient consultations, while viral infections were more common in outpatients. Consultations for parasitic infections were primarily for Pneumocystis carinii pneumonia related to infection with the human immunodeficiency virus (HIV). "Newer" infectious disease syndromes such as chronic fatigue syndrome, toxic shock syndrome, and Lyme disease were all represented in the responses for the 1-week study period. The significant impact of HIV infection on the overall consultative load suggests that there will be a continuing need for newly trained infectious disease consultants into the 21st century.

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.

Interaction of Listeria species with human cell monolayers.

In foodborne listeriosis, the first step of infection must be attachment to, and invasion of, the gastrointestinal epithelium by virulent Listeria monocytogenes. Virulence factors affecting this invasion are only now being determined. We examined the interaction of L. monocytogenes, serotypes 4b and 1/2a strains with "smooth" and "rough" characteristics. In addition, flagellated and non-flagellated isogenic strains altered by transposon mutagenesis were examined to study the effect of flagellae on virulence. Strains of Listeria ivanovii and Listeria innocua were also studied. L. ivanovii demonstrated the greatest degree of internalization and L. innocua, the least. L. monocytogenes strains were intermediate and there were no significant differences between "rough" and "smooth" isolates. The presence or absence of flagellae did not effect cell association in this model. Minor differences between cell lines for the same strains were demonstrated. Variations in cell association for differing inocula temperatures (4 degrees, 22 degrees, 37 degrees) were also noted for all strains. The interaction of Listeria species with human cell monolayers appears to be complex. Hemolysin clearly play a significant role but other virulence factors may also be important.

Measuring the functional impact of fatigue: initial validation of the fatigue impact scale.

The fatigue impact scale (FIS) was developed to improve our understanding of the effects of fatigue on quality of life. The FIS examines patients' perceptions of the functional limitations that fatigue has caused over the past month. FIS items reflect perceived impact on cognitive, physical, and psychosocial functioning. This study compared 145 patients referred for investigation of chronic fatigue (ChF) with 105 patients with multiple sclerosis (MS) and 34 patients with mild hypertension (HT). Internal consistency for the FIS and its three subscales was > .87 for all analyses. Fatigue impact was highest for the ChF group although the MS group's reported fatigue also exceeded that of the HT group. Discriminant function analysis correctly classified 80.0% of the ChF group and 78.1% of the MS group when these groups were compared. This initial validation study indicates that the FIS has considerable merit as a measure of patient's attribution of functional limitations to symptoms of fatigue.

An animal model of foodborne Listeria monocytogenes virulence: effect of alterations in local and systemic immunity on invasive infection.

Development of foodborne listeriosis is dependent on an interplay between organism-specific virulence factors and host susceptibility. Gastric inoculation of Sprague-Dawley rats was used as a model to explore Listeria-specific virulence and host susceptibility. Gastric inoculation leads to invasive infection with "smooth" hemolytic Listeria monocytogenes but not with "rough" L. monocytogenes or other Listeria species. Infection is dose-dependent with an ID50 of 10(6) virulent Listeria monocytogenes. In these experiments, the ID50 was not altered by pregnancy but invasive infection led to abnormal reproductive outcomes including stillbirth and reabsorption of fetuses. Immunosuppression by cyclosporin A led to more prolonged infection but did not alter the ID50. Manipulation of intestinal flora with antibiotics suggested increased rates of infection with antibiotics that decreased anaerobic flora. Growth of virulent Listeria in milk at varying temperatures did not enhance virulence. No differences in invasive potential of flagellated vs. non-flagellated L. monocytogenes were found. Oral models of invasive Listeria monocytogenes infection provide a useful tool for studying organism virulence and host susceptibility.

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.

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.