Aleksandra Leligdowicz

Association between Source of Infection and Hospital Mortality in Patients Who Have Septic Shock

RATIONALE Mortality caused by septic shock may be determined by a systemic inflammatory response, independent of the inciting infection, but it may also be influenced by the anatomic source of infection. OBJECTIVES To determine the association between the anatomic source of infection and hospital mortality in critically ill patients who have septic shock. METHODS This was a retrospective, multicenter cohort study of 7,974 patients who had septic shock in 29 academic and community intensive care units in Canada, the United States, and Saudi Arabia from January 1989 to May 2008. MEASUREMENTS AND MAIN RESULTS Subjects were assigned 1 of 20 anatomic sources of infection based on clinical diagnosis and/or isolation of pathogens. The primary outcome was hospital mortality. Overall crude hospital mortality was 52% (21-85% across sources of infection). Variation in mortality remained after adjusting for year of admission, geographic source of admission, age, sex, comorbidities, community- versus hospital-acquired infection, and organism type. The source of infection with the highest standardized hospital mortality was ischemic bowel (75%); the lowest was obstructive uropathy-associated urinary tract infection (26%). Residual variation in adjusted hospital mortality was not explained by Acute Physiology and Chronic Health Evaluation II score, number of Day 1 organ failures, bacteremia, appropriateness of empiric antimicrobials, or adjunct therapies. In patients who received appropriate antimicrobials after onset of hypotension, source of infection was associated with death after adjustment for both predisposing and downstream factors. CONCLUSIONS Anatomic source of infection should be considered in future trial designs and analyses, and in development of prognostic scoring systems.

Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection

HIV-2 infection in the majority of infected subjects follows an attenuated disease course that distinguishes it from infection with HIV-1. Antigen-specific T cells are pivotal in the management of chronic viral infections but are not sufficient to control viral replication in HIV-1-positive subjects, and their function in HIV-2 infection is not fully established. In a community-based cohort of HIV-2 long-term nonprogressors in rural Guinea-Bissau, we performed what we believe is the first comprehensive analysis of HIV-2-specific immune responses. We demonstrate that Gag is the most immunogenic protein. The magnitude of the IFN-gamma immune response to the HIV-2 proteome was inversely correlated with HIV-2 viremia, and this relationship was specifically due to the targeting of Gag. Furthermore, patients with undetectable viremia had greater Gag-specific responses compared with patients with high viral replication. The most frequently recognized peptides clustered within a defined region of Gag, and responses to a single peptide in this region were associated with low viral burden. The consistent relationship between Gag-specific immune responses and viremia control suggests that T cell responses are vital in determining the superior outcome of HIV-2 infection. A better understanding of how HIV-2 infection is controlled may identify correlates of effective protective immunity essential for the design of HIV vaccines.

Two Distinct Epidemics: The Rise of HIV-1 and Decline of HIV-2 Infection Between 1990 and 2007 in Rural Guinea-Bissau

Objectives:To assess changes in HIV incidence and prevalence in Caió, a rural area of Guinea-Bissau, between 1990 and 2007. Design:Three cross-sectional community surveys. Methods:In 1990, 1997, and 2007, surveys were conducted among adults. The prevalence of HIV-1 and of HIV-2 was estimated for each survey, and incidence rates were calculated for the first (1990-1997) and second period (1997-2007). Results:The HIV-1 incidence was approximately 4.5/1000 person-years in the two periods, whereas the HIV-2 incidence decreased from 4.7 (95% confidence interval 3.6-6.2) in the first to 2.0 (95% confidence interval 1.4-3.0) per 1000 person-years in the second period (P < 0.001). HIV-1 prevalence rose from 0.5% in 1990 to 3.6% in 2007, and HIV-2 prevalence decreased from 8.3% in 1990 to 4.7% in 2007. HIV-1 prevalence was less than 2% in 15 to 24 year olds in all surveys and was highest (7.2%) in 2007 among 45 to 54 year olds. The HIV-2 prevalence was fivefold higher in older subjects (≥45 yr) compared with those less than 45 years in both sexes in 2007. Conclusions:HIV-1 incidence is stable, and its prevalence is increasing, whereas HIV-2 incidence and prevalence are both declining. In contrast with what has been observed in other sub-Saharan countries, HIV-1 prevalence is lower in younger age groups than older age groups.

Undetectable plasma viral load predicts normal survival in HIV-2-infected people in a West African village

BackgroundThere have been no previous studies of the long-term survival and temporal changes in plasma viral load among HIV-2 infected subjects.Methods133 HIV-2 infected and 158 HIV-uninfected subjects from a rural area in North-west Guinea-Bissau, West Africa were enrolled into a prospective cohort study in 1991 and followed-up to mid-2009. Data were collected on four occasions during that period on HIV antibodies, CD4% and HIV-2 plasma viral load.ResultsMedian age (interquartile range [IQR]) of HIV-2 infected subjects at time of enrollment was 47 (36, 60) years, similar to that of HIV-uninfected control subjects, 49 (38, 62) (p = 0.4). Median (IQR) plasma viral load and CD4 percentage were 347 (50, 4,300) copies/ml and 29 (22, 35) respectively.Overall loss to follow-up to assess vital status was small, at 6.7% and 6.3% for HIV-2 infected and uninfected subjects respectively. An additional 17 (12.8%) and 16 (10.1%) of HIV-2 infected and uninfected subjects respectively were censored during follow-up due to infection with HIV-1. The mortality rate per 100 person-years (95% CI) was 4.5 (3.6, 5.8) among HIV-2 infected subjects compared to 2.1 (1.6, 2.9) among HIV-uninfected (age-sex adjusted rate ratio 1.9 (1.3, 2.8, p < 0.001) representing a 2-fold excess mortality rate associated with HIV-2 infection.Viral load measurements were available for 98%, 78%, 77% and 61% HIV-2 infected subjects who were alive and had not become super-infected with HIV-1, in 1991, 1996, 2003 and 2006 respectively. Median plasma viral load (RNA copies per ml) (IQR) did not change significantly over time, being 150 (50, 1,554; n = 77) in 1996, 203 (50, 2,837; n = 47) in 2003 and 171 (50, 497; n = 31) in 2006. Thirty seven percent of HIV-2 subjects had undetectable viraemia (<100 copies/ml) at baseline: strikingly, mortality in this group was similar to that of the general population.ConclusionsA substantial proportion of HIV-2 infected subjects in this cohort have stable plasma viral load, and those with an undetectable viral load (37%) at study entry had a normal survival rate. However, the sequential laboratory findings need to be interpreted with caution given the number of individuals who could not be re-examined.

Direct Relationship between Virus Load and Systemic Immune Activation in HIV-2 Infection

Immune activation is a hallmark of disease progression in human immunodeficiency virus (HIV) type 1 (HIV-1) and HIV type 2 (HIV-2) infection. However, the relationship between viremia and systemic immune activation is unclear. We assessed the relationship between HIV-2 plasma virus load and immune system activation in a cross-sectional study in a community cohort of HIV-1-positive, HIV-2-positive, and HIV-negative patients, in which many HIV-2-positive patients had nonprogressing infection. HLA-DR and CD38 expression on CD4(+) and CD8(+) T cells was measured, as were plasma beta(2)-microglobulin levels. These markers were related to clinical (virus load and CD4(+) cell count) and immunological (HIV-2-specific interferon gamma secretion) correlates of delayed disease progression. A consistent positive correlation was identified between the level of HIV-2 viremia and immune activation. We propose that increasing virus load may contribute to systemic immune activation in HIV-2 infection.

Intensive Care Unit Capacity in Low-Income Countries: A Systematic Review

Purpose Access to critical care is a crucial component of healthcare systems. In low-income countries, the burden of critical illness is substantial, but the capacity to provide care for critically ill patients in intensive care units (ICUs) is unknown. Our aim was to systematically review the published literature to estimate the current ICU capacity in low-income countries. Methods We searched 11 databases and included studies of any design, published 2004-August 2014, with data on ICU capacity for pediatric and adult patients in 36 low-income countries (as defined by World Bank criteria; population 850 million). Neonatal, temporary, and military ICUs were excluded. We extracted data on ICU bed numbers, capacity for mechanical ventilation, and information about the hospital, including referral population size, public accessibility, and the source of funding. Analyses were descriptive. Results Of 1,759 citations, 43 studies from 15 low-income countries met inclusion criteria. They described 36 individual ICUs in 31 cities, of which 16 had population greater than 500,000, and 14 were capital cities. The median annual ICU admission rate was 401 (IQR 234-711; 24 ICUs with data) and median ICU size was 8 beds (IQR 5-10; 32 ICUs with data). The mean ratio of adult and pediatric ICU beds to hospital beds was 1.5% (SD 0.9%; 15 hospitals with data). Nepal and Uganda, the only countries with national ICU bed data, had 16.7 and 1.0 ICU beds per million population, respectively. National data from other countries were not available. Conclusions Low-income countries lack ICU beds, and more than 50% of these countries lack any published data on ICU capacity. Most ICUs in low-income countries are located in large referral hospitals in cities. A central database of ICU resources is required to evaluate health system performance, both within and between countries, and may help to develop related health policy.

Altered innate immune development in HIV-exposed uninfected infants.

Background:Early in life, HIV-exposed uninfected (HEU) infants are at an increased risk of morbidity and mortality from infectious disease compared with HIV-unexposed (UE) infants. To improve our understanding of the mechanisms underlying their increased risk, we contrasted innate immune development between HEU and UE infants in a developing world setting, where early life infectious disease risk is exceptionally high. Methods:A prospective longitudinal cohort of HEU and UE newborns was established, and the most detailed characterization to date of HEU infant immune development was performed. Single-cell cytokine production was analyzed by flow cytometry after stimulation of whole blood with pathogen-associated molecular patterns (PAMPs). Results:Monocyte, classical dendritic cell, and plasmacytoid dendritic cell composition was similar between HEU and UE infants throughout the first year of life. However, HEU mononuclear cells mounted an enhanced pro-inflammatory response to PAMP stimulation, both in quantity of cytokine produced per cell and in proportion of responder cells. Significant differences in cytokine production were detected on the single-cell level in a PAMP-specific pattern, but only at 2 and 6 weeks of age; all differences normalized by 12 months of age. Conclusions:This time course of innate immune deviation early in life corresponds to the clinical window of vulnerability to infections in HEU infants and may be at least partially responsible for their increased morbidity and mortality from infectious disease.

HIV-2 capsids distinguish high and low virus load patients in a West African community cohort.

HIV-2 causes AIDS similar to HIV-1, however a considerable proportion of HIV-2 infected patients show no disease and have low plasma virus load (VL). An analysis of HIV-2 capsid (p26) variation demonstrated that proline at p26 positions 119, 159 and 178 are more frequent in lower VL subjects while non-proline residues at all three sites are more frequent in subjects with high VL. In vitro replication levels of viruses bearing changes at the three sites suggested that these three residues influence virus replication by altering susceptibility to TRIM5alpha. These results provide new insights into HIV-2 pathogenesis.

Influence of HLA Class I and HLA-KIR Compound Genotypes on HIV-2 Infection and Markers of Disease Progression in a Manjako Community in West Africa

ABSTRACT Overall, the time to AIDS after HIV-2 infection is longer than with HIV-1, and many individuals infected with HIV-2 virus remain healthy throughout their lives. Multiple HLA and KIR gene products have been implicated in the control of HIV-1, but the effect of variation at these loci on HIV-2 disease is unknown. We show here for the first time that HLA-B*1503 is associated significantly with poor prognosis after HIV-2 infection and that HLA-B*0801 is associated with susceptibility to infection. Interestingly, previous data indicate that HLA-B*1503 is associated with low viral loads in HIV-1 clade B infection but has no significant effect on viral load in clade C infection. In general, alleles strongly associated with HIV-1 disease showed no effect in HIV-2 disease. These data emphasize the unique nature of the effects of HLA and HLA/KIR combinations on HIV-2 immune responses relative to HIV-1, which could be related to their distinct clinical course.

Multilayered defense in HLA-B51-associated HIV viral control

Polymorphism in the HLA region of a chromosome is the major source of host genetic variability in HIV-1 outcome, but there is limited understanding of the mechanisms underlying the beneficial effect of protective class I alleles such as HLA-B57, -B27, and -B51. Taking advantage of a unique cohort infected with clade B’ HIV-1 through contaminated blood, in which many variables such as the length of infection, the infecting viral strain, and host genetic background are controlled, we performed a comprehensive study to understand HLA-B51–associated HIV-1 control. We focused on the T cell responses against three dominant HLA-B51–restricted epitopes: Gag327-345(NI9) NANPDCKTI, Pol743-751(LI9) LPPVVAKEI, and Pol283-289(TI8) TAFTIPSI. Mutations in all three dominant epitopes were significantly associated with HLA-B51 in the cohort. A clear hierarchy in selection of epitope mutations was observed through epitope sequencing. L743I in position 1 of epitope LI9 was seen in most B51+ individuals, followed by V289X in position 8 of the TI8, and then, A328S, in position 2 of the NI9 epitope, was also seen in some B51+ individuals. Good control of viral load and higher CD4+ counts were significantly associated with at least one detectable T cell response to unmutated epitopes, whereas lower CD4+ counts and higher viral loads were observed in patients who had developed escape mutations in all three epitopes or who lacked T cell responses specific to these epitope(s). We propose that patients with HLA-B51 benefit from having multiple layers of effective defense against the development of immune escape mutations.