Very early mortality in patients starting antiretroviral treatment at primary health centres in rural Malawi.

OBJECTIVES: To report on the cumulative proportion of deaths occurring within 3 months of starting antiretroviral treatment (ART) and to identify factors associated with such deaths, among adults at primary health centres in a rural district of Malawi. METHODS: Retrospective cohort study: from June 2006 to April 2008, deaths occurring over a 3-month period were determined and risk factors examined. RESULTS: A total of 2316 adults (706 men and 1610 women; median age 35 years) were included in the analysis and followed up for a total of 1588 person-years (PY); 277 (12%) people died, of whom 206 (74%) people died within 3 months of initiating ART (cumulative incidence: 13.0; 95% confidence interval: 11.3-14.8 per 100 PY of follow-up). Significant risk factors associated with early deaths included male sex, WHO stage 4 disease, oesophageal or persistent oral candidiasis and unexplained presumed or measured weight loss >10%. One in every 3 patients who either died or was lost to follow up had unexplained weight loss >10%, and survival in this group was significantly different from patients without this condition. CONCLUSIONS: Seven in 10 individuals initiating ART at primary health centres die early. Specific groups of patients are at higher risk of such mortality and should receive priority attention, care and support.

A URA3 null mutant of Candida albicans (CAI-4) causes oro-oesophageal and gastric candidiasis and is lethal for gnotobiotic, transgenic mice (Tgepsilon26) that are deficient in both natural killer and T cells.

Current data suggest that functional URA3 genes are necessary for the full pathogenesis of Candida albicans. Herein it is shown that a putatively avirulent URA3/URA3 null mutant of C. albicans (CAI-4) can colonize the murine alimentary tract, invade oro-oesophageal and gastric tissues with yeasts and hyphae, evoke a granulocyte-dominated inflammatory response, and kill transgenic mice that are deficient for both natural killer cells and T cells. Because C. albicans-colonized (gnotobiotic) mice lack a viable prokaryotic microbiota, this study also demonstrates that the gut microbiome is not required to supply the mutant's nutritional needs. The gnotobiotic murine model described herein can be used to assess the capacity of C. albicans mutants to colonize and infect cutaneous, mucosal and systemic tissues and kill the susceptible host via a clinically common, natural route of infection; namely the alimentary tract.

Brief Report: Cofactors of Mortality Among Hospitalized HIV-Infected Children Initiating Antiretroviral Therapy in Kenya.

OBJECTIVES: Identifying factors associated with mortality among acutely ill HIV-infected children presenting with advanced HIV disease may help clinicians optimize care for those at highest risk of death. DESIGN: Using data from a randomized controlled trial (NCT02063880), we determined baseline sociodemographic, clinical, and laboratory cofactors of mortality among HIV-infected children in Kenya. METHODS: We enrolled hospitalized, HIV-infected, antiretroviral therapy-naive children (0-12 years), initiated antiretroviral therapy, and followed up them for 6 months. We used Cox proportional hazards regression to estimate hazard ratios (HRs) for death and 95% confidence intervals (CIs). RESULTS: Of 181 enrolled children, 39 (22%) died. Common diagnoses at death were pneumonia or suspected pulmonary tuberculosis [23 (59%)] and gastroenteritis [7 (18%)]. Factors associated with mortality in univariate analysis included age <2 years [HR 3.08 (95% CI: 1.50 to 6.33)], orphaned or vulnerable child (OVC) [HR 2.05 (95% CI: 1.09 to 3.84)], weight-for-age Z score <-2 [HR 2.29 (95% CI: 1.05 to 5.00)], diagnosis of pneumonia with hypoxia [HR 5.25 (95% CI: 2.00 to 13.84)], oral thrush [HR 2.17 (95% CI: 1.15 to 4.09)], persistent diarrhea [HR 3.81 (95% CI: 1.89 to 7.69)], and higher log10 HIV-1 viral load [HR 2.16 (95% CI: 1.35 to 3.46)] (all P < 0.05). In multivariable analysis, age <2 years and OVC status remained significantly associated with mortality. CONCLUSIONS: Young age and OVC status independently predicted mortality. Hypoxic pneumonia, oral thrush, and persistent diarrhea are important clinical features that predict mortality. Strategies to enhance early diagnosis in children and improve hospital management of critically ill HIV-infected children are needed.

The association between cigarette smoking and selected HIV-related medical conditions.

OBJECTIVE: To clarify the effect of cigarette smoking on the development of conditions associated with HIV infection. DESIGN: Prospective and retrospective cohort study, with interview and examination twice a year since 1988. METHODS: Data on 516 HIV-infected men from cohorts of homosexual and bisexual men in San Francisco, Denver and Chicago, who were repeatedly interviewed and examined between 1988 and 1992, were analysed. After excluding men who did not have well-defined dates of seroconversion and those who were classified as ex- or intermittent smokers, 232 men remained for analysis: 106 were smokers and 126 were non-smokers. Univariate and Kaplan-Meier survival analyses were performed to assess the relationship between cigarette smoking and loss of CD4+ T-lymphocytes, diagnosis of any AIDS-defining illness, and specific diagnosis of Kaposi's sarcoma, Pneumocystis carinii pneumonia (PCP), oral candidiasis, hairy leukoplakia, and community-acquired pneumonia. RESULTS: By univariate analyses, cigarette smoking was not associated with clinical AIDS, loss of CD4+ cells, Kaposi's sarcoma or PCP, but was significantly associated with oral candidiasis [relative risk (RR), 1.32; 95% confidence interval (CI), 1.02-1.70], hairy leukoplakia (RR, 1.51; 95% CI, 1.15-1.99), and community-acquired pneumonia (RR, 2.62; 95% CI, 1.30-5.27). Dose-response effect was also evident for these three conditions (all P < 0.01). Kaplan-Meier survival analysis indicated no association between cigarette smoking and time of progression to clinical AIDS, Kaposi's sarcoma (KS), or PCP (P = 0.62, 0.54 and 0.11, respectively) but showed that cigarette smokers developed oral candidiasis, hairy leukoplakia, and pneumonia more quickly than non-smokers (P = 0.031, 0.006 and 0.009, respectively). CONCLUSIONS: Cigarette smoking was not associated with an increased likelihood or rate of developing KS, PCP or AIDS, but was associated with developing community-acquired pneumonia, oral candidiasis, and hairy leukoplakia in these HIV-infected men.

An open multicentre comparative study of the efficacy, safety and tolerance of fluconazole and itraconazole in the treatment of cancer patients with oropharyngeal candidiasis.

Oropharyngeal candidiasis is a frequent infection in cancer patients who receive cytotoxic drugs. In this study, the efficacy, safety and tolerance of fluconazole and itraconazole were compared in non-neutropenic cancer patients with oropharyngeal candidiasis. Of 279 patients who were randomised between the two treatment groups, 252 patients were considered to be eligible (126 in each group). The clinical cure rate was 74% for fluconazole and 62% for itraconazole (P=0.04, 95% Confidence Interval (CI): 0.5-23.3%). The mycological cure rate was 80% for fluconazole and 68% for itraconazole (P=0.03, 95% CI: 1.2-22.6%). The safety and tolerance profile of both drugs were comparable. This study has shown that in patients with cancer and oropharyngeal candidiasis, fluconazole has a significantly better clinical and mycological cure rate compared with itraconazole.

The role of oral candidiasis in survival and hospitalization patterns: analysis of an inner city hospital human immunodeficiency virus/acquired immune deficiency syndrome registry.

To assess the effect of oral candidiasis (OC) associated with human immunodeficiency virus (HIV) at initial hospital admission on both survival and hospital use, a retrospective analysis was performed in 1,172 hospitalized patients identified by an HIV surveillance program at an inner city public hospital in East Harlem, New York. Survival times were compared using three different HIV staging schemes placing patients with OC into either a common stage with adenopathy patients (Scheme IHS-URV), a common stage with acquired immune deficiency syndrome patients (AIDS; Scheme WRCDC), or an intermediate stage between AIDS patients and all others (Scheme ORAL). Patients without AIDS demonstrated a significantly increased risk of dying (relative risk, 2.61; 95% confidence interval [CI], 1.69, 4.03) if they were initially admitted with OC. Survival times for different stages of disease showed the best between-stage distinction for a Scheme ORAL, with the OC stage having a median survival of 643 days. Mean days of hospitalization also showed best distinctions for Scheme ORAL. Other staging schemes did not distinguish patients as well in terms of both survival times or mean hospitalization days. HIV-infected patients admitted with OC but without AIDS had a discrete survival prognosis and hospitalization course. Therefore, presence of OC even without other immunologic data has implications for institutional resource allocation and planning. These data support, in this context, a separate clinical designation for OC patients.

[Candidiasis in AIDS patients]. / Candidíase em pacientes aidéticos.

UNLABELLED: A total of 35 in patients admitted at Emilio Ribas Hospital--São Paulo, Brazil, with digestive candidiasis and AIDS clinical diagnostic were evaluated 10 month later, being 29 male and 6 female; white outnumbering black with age ranged from 30 to 50 years old. Agar Sabouraud culture and tube germinative tests identified 28 (80%) Candida albicans out 35 strains. Minimum inhibitory concentration (MIC) 50% was against azoles (ketoconazole = 2.2 micrograms/ml; itraconazole = 21.0 micrograms/ml and fluconazole = 19.0 micrograms/ml); polyenes (nystatin = 50.0 micrograms/ml and amphotericin B = 0.12 micrograms/ml) and 5 fluorocytosine = 1.6 micrograms/ml. Siegel tests showed significant Candida albicans proportions in strains isolated from 35 AIDS patients. There was no significant relation between AMB doses and early or late death. CONCLUSIONS: candidiasis in AIDS patients showed high MIC 50% to azoles and nystatin and significant Candida albicans proportion in all strains isolated from AIDS patients. Previous amphotericin B therapy had no influence in early or late death in 30 patients. Previous therapy possibly explained MIC 50% increases in Candida strains.

Factors associated with time free of oral candidiasis in children living with HIV/AIDS, São Paulo, Brazil.

In clinical practice, recurrence of thrush is common in children living with HIV/AIDS. The aim of this study was to determine the factors associated with time spent free of oral candidiasis using survival analysis for recurrent events. A retrospective cohort study was carried out with 287 children treated between 1985 and 2009 at a reference center in the city of São Paulo, Brazil. The Prentice, Williams and Peterson model for recurrent events was used for the investigation of factors associated with the time free of oral candidiasis. The following factors were associated with the time patients were free of oral candidiasis: moderate immunodepression (HR = 2.5; p = 0.005), severe immunodepression (HR = 3.5; p < 0.001), anemia (HR = 3.3; p < 0.001), malnutrition (HR = 2.6; p = 0.004), hospitalization (HR = 2.2; p < 0.001), monotherapy (HR = 0.5; p = 0.006), dual therapy (HR = 0.3; p < 0.001) and triple therapy/highly active antiretroviral therapy (HR = 0.1; p < 0.001). The method analyzed in the present study proved useful for the investigation of recurrent events in patients living with HIV/AIDS.

Thrush - nightmare of the foundling hospitals.

Before safe artificial nutrition, refrigeration, and microorganisms became known, thrush was a severe and frequently lethal disease in foundling hospitals. Overcrowded and understaffed, these institutions were the ideal breeding ground for this disease. Malnutrition, especially when breastfeeding was denied, contributed to the fatal course. Nosocomial infections and high mortality led to a prejudice against infant hospitals in the late 19th century. Candida albicans was discovered in 1840 when a cooperation at the Paris Foundling Hospital between the Hungarian emigrant David Gruby and the Swede Frederik Berg led to this organism being the first pathogen to be identified. After World War II, Candida infections increased with the use of antibiotics. The disease became less threatening after the development of nystatin, the result of an interdisciplinary cooperation in New York between the microbiologist Elizabeth Hazen and the biochemist Rachel Brown.

Risk factors for mortality among HIV-positive patients with and without active tuberculosis in Dar es Salaam, Tanzania.

BACKGROUND: The aim of this study was to describe risk factors for mortality and clinical characteristics of HIV-infected patients with and without tuberculosis (TB) coinfection. METHODS: A cohort of HIV-infected patients with CD4(+) T-cell counts of ≤200 cells/µl was recruited, consisting of 255 HIV-infected patients without active TB and 231 patients with active TB. All received a well-supervised treatment with an efavirenz-based HAART, and those coinfected with TB received appropriate anti-TB treatment. They were followed up for 48 weeks after HAART initiation. RESULTS: Common presenting symptoms in HIV-only patients were fever (36.5%), headache (34.5%), skin rash (34.5%) and weight loss (32%), while in HIV-TB patients the symptoms were weight loss (58%), cough (57.6%), night sweats (44.6%) and fever (34.2%). HIV-TB patients had significantly lower body mass index, Karnofsky scores and haemoglobin levels compared to those infected with HIV only, despite similar baseline CD4(+) T-cell counts. Overall, 12 (4.7%) HIV patients developed TB and 7 (3%) HIV-TB patients had worsening of their TB symptoms during the study period. Mortality was similar in the two groups, being 10.9% (16 deaths per 100 person years) and 11.3% (17 deaths per 100 person years) in HIV-only and HIV-TB patients, respectively. Overall, more males (13.1%) died compared to females (9.6%). Predictors of mortality were presence of oral candidiasis, Kaposi's sarcoma, low Karnofsky score, and low baseline white blood cell and CD4(+) T-cell counts. CONCLUSIONS: The outcomes following well-supervised treatment of HIV-TB patients are similar to those in patients with HIV alone. Predictors of mortality were those of advanced disease.

Factors associated with time free of oral candidiasis in children living with HIV/AIDS, São Paulo, Brazil / Fatores associados ao tempo livre de candidíase oral em crianças vivendo com HIV/AIDS, São Paulo, Brasil / Factores asociados al tiempo libre y la candidiasis oral en niños que viven con VIH/SIDA, São Paulo, Brasil

In clinical practice, recurrence of thrush is common in children living with HIV/AIDS. The aim of this study was to determine the factors associated with time spent free of oral candidiasis using survival analysis for recurrent events. A retrospective cohort study was carried out with 287 children treated between 1985 and 2009 at a reference center in the city of São Paulo, Brazil. The Prentice, Williams and Peterson model for recurrent events was used for the investigation of factors associated with the time free of oral candidiasis. The following factors were associated with the time patients were free of oral candidiasis: moderate immunodepression (HR = 2.5; p = 0.005), severe immunodepression (HR = 3.5; p < 0.001), anemia (HR = 3.3; p < 0.001), malnutrition (HR = 2.6; p = 0.004), hospitalization (HR = 2.2; p < 0.001), monotherapy (HR = 0.5; p = 0.006), dual therapy (HR = 0.3; p < 0.001) and triple therapy/highly active antiretroviral therapy (HR = 0.1; p < 0.001). The method analyzed in the present study proved useful for the investigation of recurrent events in patients living with HIV/AIDS.

A recorrência da candidíase oral em crianças vivendo com HIV/AIDS é um acontecimento muito comum na prática clínica. O objetivo foi verificar os fatores associados ao tempo livre de candidíase oral, utilizando técnica de análise de sobrevida para eventos recorrentes. Estudo de coorte retrospectivo com 287 crianças, atendidas entre 1985 e 2009, em um serviço de saúde de São Paulo, Brasil. Foi utilizado o modelo marginal para eventos recorrentes de Prentice, Williams e Peterson para investigação dos fatores associados ao tempo livre de candidíase oral. Imunodepressão moderada (HR = 2,5; p = 0,005) ou grave (HR = 3,5; p < 0,001), anemia (HR = 3,3; p < 0,001), desnutrição (HR = 2,6; p = 0,004) e internação (HR = 2,2; p < 0,001), monoterapia (HR = 0,5; p = 0,006), terapia dupla (HR = 0,3; p < 0,001) e terapia tripla/HAART (HR = 0,1; p < 0,001) foram associados ao tempo livre de candidíase oral. A metodologia apresentada neste artigo pode ser bastante útil em pesquisas na área de HIV/AIDS, quando pretende-se estudar eventos com comportamento de recorrência.

La repetición de candidiasis oral en los niños que viven con VIH/SIDA es muy común en la práctica clínica. El objetivo fue verificar los factores asociados al tiempo libre y la candidiasis oral, usando la técnica de análisis de supervivencia para eventos recurrentes. Se realizó un estudio de cohorte retrospectiva con 287 niños que visitaron entre 1985 y 2009 un servicio de salud de São Paulo, Brasil. Se usó el modelo marginal para eventos recurrentes de Prentice, Williams y Peterson, con el fin de investigar los factores asociados. Moderada inmunodepresión (HR = 2,5; p = 0,005) o grave (HR = 3,5; p < 0,001), anemia (HR = 3,3; p < 0,001), desnutrición (HR = 2,6; p = 0,004) y hospitalización (HR = 2,2; p < 0,001), monoterapia (HR = 0,5; p = 0, 006), terapia dual (HR = 0,3; p < 0,001) y triple terapia/TARGA (HR = 0,1; p < 0,001) se asociaron al tiempo libre y la candidiasis oral. La metodología presentada en este artículo puede ser útil para la investigación en el área de VIH/SIDA, cuando se pretenda estudiar el comportamiento de la repetición del evento.

Oroesophageal candidiasis is lethal for transgenic mice with combined natural killer and T-cell defects.

Germfree transgenic epsilon 26 (Tgepsilon26) mice, which express the full-length human CD3epsilon gene, have combined defects in natural killer (NK) cells and T cells were found to be extremely susceptible to oroesophageal (palate, tongue, esophagus) and gastric (cardia-antrum section) candidiasis. The gnotobiotic Tgepsilon26 mice die, apparently from severe oroesophageal candidiasis, within 2-4 weeks after their alimentary tracts are colonized with Candida albicans. The Tgepsilon26 mice manifest resistance to acute systemic candidiasis (intravenous injection) and to systemic candidiasis of endogenous origin for the first 2 weeks after their alimentary tracts are colonized with C. albicans. Granulocyte depletion data suggest that granulocytes, in the absence of functional NK cells and T cells, can protect Tgepsilon26 mice from acute systemic candidiasis and from systemic candidiasis of endogenous origin, for at least 14 days after alimentary tract colonization. Granulocytes and macrophages, in the absence of NK cells and T cells, are unable to protect Tgepsilon26 mice from lethal oroesophageal candidiasis and systemic candidiasis of endogenous origin which was evident in moribund Tgepsilon26 mice 2-4 weeks after colonization. Thus, non-T cells (i.e., NK cells) and T cells play important roles in resistance to oroesophageal and systemic (acute and of endogenous origin) candidiasis.

Biotherapeutic effects of probiotic bacteria on candidiasis in immunodeficient mice.

Four species of probiotic bacteria were assessed for their capacities to protect athymic bg/bg-nu/nu and euthymic bg/bg-nu/+ mice from mucosal and systemic candidiasis. Each bacterial species and Candida albicans colonized the gastrointestinal tracts of both strains of mice. The presence of probiotic bacteria (Lactobacillus acidophilus, Lactobacillus reuteri, Lactobacillus casei GG, or Bifidobacterium animalis) in the gastrointestinal tracts prolonged the survival of adult and neonatal bg/bg-nu/nu mice compared to that of isogenic mice colonized with C. albicans alone. The incidence of systemic candidiasis in bg/bg-nu/nu mice was significantly reduced by each of the four probiotic bacterial species. The numbers of C. albicans present in the alimentary tracts of euthymic bg/bg-nu/+ mice were significantly reduced by L. casei GG and B. animalis. None of the probiotic bacteria species completely prevented mucosal candidiasis, but B. animalis reduced its incidence and severity. Probiotic bacteria also modulated antibody- and cell-mediated immune responses to C. albicans. The prolonged survival of mice, decreased severity of mucosal and systemic candidiasis, modulation of immune responses, decreased number of C. albicans in the alimentary tract, and reduced numbers of orogastric infections demonstrated not only that probiotic bacteria have biotherapeutic potential for prophylaxis against and therapy of this fungal disease but also that probiotic bacteria protect mice from candidiasis by a variety of immunologic (thymic and extrathymic) and nonimmunologic mechanisms in this model.

Essential role of the Candida albicans transglutaminase substrate, hyphal wall protein 1, in lethal oroesophageal candidiasis in immunodeficient mice.

Oroesophageal candidiasis is caused by the combined action of fungal virulence factors and host inflammatory responses when protective immunity is absent. Hyphal wall protein 1 (Hwp1) on germ tubes and true hyphae of Candida albicans forms covalent cross-links to buccal epithelial cells in vitro by functioning as a substrate for mammalian transglutaminases. In this study, beige-athymic (bg/bg-nu/nu) or transgenic epsilon 26 mice that have combined natural killer and T cell defects did not succumb to candidiasis after oral administration of C. albicans strains with inactivated HWP1 genes, whereas mice given isogenic strains of C. albicans that had a single copy of HWP1 survived only 2-3 weeks. Illness correlated with extensive alterations of the lingual and esophageal mucosa that were absent in mice given the hwp1/hwp1 mutant. HWP1 is a promising target for development of antifungal drugs for treatment of oroesophageal candidiasis.