Colonization of humans with Staphylococcus aureus is a critical prerequisite of subsequent clinical infection of the skin, blood, lung, heart and other deep tissues. S. aureus persistently or ...intermittently colonizes the nares of approximately 50% of healthy adults, whereas approximately 50% of the general population is rarely or never colonized by this pathogen. Because microbial consortia within the nasal cavity may be an important determinant of S. aureus colonization we determined the composition and dynamics of the nasal microbiota and correlated specific microorganisms with S. aureus colonization.
Nasal specimens were collected longitudinally from five healthy adults and a cross-section of hospitalized patients (26 S. aureus carriers and 16 non-carriers). Culture-independent analysis of 16S rRNA sequences revealed that the nasal microbiota of healthy subjects consists primarily of members of the phylum Actinobacteria (e.g., Propionibacterium spp. and Corynebacterium spp.), with proportionally less representation of other phyla, including Firmicutes (e.g., Staphylococcus spp.) and Proteobacteria (e.g. Enterobacter spp). In contrast, inpatient nasal microbiotas were enriched in S. aureus or Staphylococcus epidermidis and diminished in several actinobacterial groups, most notably Propionibacterium acnes. Moreover, within the inpatient population S. aureus colonization was negatively correlated with the abundances of several microbial groups, including S. epidermidis (p = 0.004).
The nares environment is colonized by a temporally stable microbiota that is distinct from other regions of the integument. Negative association between S. aureus, S. epidermidis, and other groups suggests microbial competition during colonization of the nares, a finding that could be exploited to limit S. aureus colonization.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Patients that are immunosuppressed might be at risk of serious influenza-associated complications. As a result, multiple guidelines recommend influenza vaccination for patients infected with ...HIV, who have received solid-organ transplants, who have received haemopoietic stem-cell transplants, and patients on haemodialysis. However, immunosuppression might also limit vaccine responses. To better inform policy, we reviewed the published work relevant to incidence, outcomes, and prevention of influenza infection in these patients, and in patients being treated chemotherapy and with systemic corticosteroids. Available data suggest that most immunosuppressed populations are indeed at higher risk of influenza-associated complications, have a general trend toward impaired humoral vaccine responses (although these data are mixed), and can be safely vaccinated—although longitudinal data are largely lacking. Randomised clinical trial data were limited to one study of HIV-infected patients with high vaccine efficacy. Better trial data would inform vaccination recommendations on the basis of efficacy and cost in these at-risk populations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Although antiretroviral therapy (ART) improves survival in persons with cryptococcal meningitis (CM) and AIDS, ART frequently elicits HIV immune reconstitution inflammatory syndrome (IRIS), an ...exaggerated and frequently deadly inflammatory reaction that complicates recovery from immunodeficiency. The pathogenesis of IRIS is poorly understood and prediction of IRIS is not possible.
We prospectively followed 101 ART-naïve Ugandans with AIDS and recent CM for one year after initiating ART, and used Luminex multiplex assays to compare serum cytokine levels in participants who did or did not develop IRIS. IRIS occurred in 45% of participants with recent CM on ART, including 30% with central nervous system (CNS) manifestations. The median time to CM-IRIS was 8.8 wk on ART. Overall mortality on ART was 36% with IRIS and 21% without IRIS. CM-IRIS was independently associated with death (HR = 2.3, 95% CI 1.1-5.1, p = 0.04). Patients experiencing subsequent CM-IRIS had 4-fold higher median serum cryptococcal antigen (CRAG) levels pre-ART (p = 0.006). Higher pre-ART levels of interleukin (IL)-4 and IL-17 as well as lower tumor necrosis factor (TNF)-α, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and vascular endothelial growth factor (VEGF) predicted future IRIS in multivariate analyses (area under the curve AUC = 0.82). An algorithm based on seven pre-ART serum biomarkers was a robust tool for stratifying high (83%), moderate (48%), and low risk (23%) for IRIS in the cohort. After ART was initiated, increasing levels of C-reactive protein (CRP), D-dimer, IL-6, IL-7, IL-13, G-CSF, or IL-1RA were associated with increasing hazard of IRIS by time-to-event analysis (each p≤0.001). At the time of IRIS onset, multiple proinflammatory cytokine responses were present, including CRP and IL-6. Mortality was predicted by pre-ART increasing IL-17, decreasing GM-CSF, and CRP level >32 mg/l (highest quartile). Pre-ART CRP level >32 mg/l alone was associated with future death (OR = 8.3, 95% CI 2.7-25.6, p<0.001).
Pre-ART increases in Th(17) and Th(2) responses (e.g., IL-17, IL-4) and lack of proinflammatory cytokine responses (e.g., TNF-α, G-CSF, GM-CSF, VEGF) predispose individuals to subsequent IRIS, perhaps as biomarkers of immune dysfunction and poor initial clearance of CRAG. Although requiring validation, these biomarkers might be an objective tool to stratify the risk of CM-IRIS and death, and could be used clinically to guide when to start ART or use prophylactic interventions.
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Data continue to emerge that suggest treating HIV infection as early as possible is beneficial. In this trial assessing the timing of antiretroviral therapy initiation in patients with acute ...cryptococcal meningitis and newly diagnosed HIV infection, early initiation was associated with increased mortality.
Cryptococcus neoformans
is the most common cause of meningitis in adults in sub-Saharan Africa,
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5
and meningitis caused by
C. neoformans
accounts for approximately 20 to 25% of deaths from the acquired immunodeficiency syndrome (AIDS) in Africa.
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9
Determining when antiretroviral therapy (ART) should be initiated after a diagnosis of cryptococcal meningitis involves balancing the survival benefit conferred by ART against the risk of the immune reconstitution inflammatory syndrome (IRIS), a paradoxical reaction that occurs during immunologic recovery with ART despite effective therapy for the opportunistic infection. Since 2009, the international standard of care has shifted toward earlier ART . . .
Background. Cryptococcal meningitis (CM) is the proximate cause of death in 20%–30% of persons with acquired immunodeficiency syndrome in Africa. Methods. Two prospective, observational cohorts ...enrolled human immunodeficiency virus (HIV)—infected, antiretroviral-naive persons with CM in Kampala, Uganda. The first cohort was enrolled in 2001–2002 (n=92), prior to the availability of highly active antiretroviral therapy (HAART), and the second was enrolled in 2006–2007 (n=44), when HAART was available. Results. Ugandans presented with prolonged CM symptoms (median duration, 14 days; interquartile range, 7–21 days). The 14-day survival rates were 49% in 2001–2002 and 80% in 2006 (P<.001). HAART was started 35±13 days after CM diagnosis and does not explain the improved 14-day survival rate in 2006. In 2006–2007, the survival rate continued to decrease after hospitalization, with only 55% surviving to initiate HAART as an outpatient. Probable cryptococcal-related immune reconstitution inflammatory syndrome occurred in 42% of patients, with 4 deaths. At 6 months after CM diagnosis, 18 persons (41%) were alive and receiving HAART in 2007. The median cerebral spinal fluid (CSF) opening pressure was 330 mm H2O; 81% of patients had elevated pressure (>200 mm H2O). Only 5 patients consented to therapeutic lumbar puncture. There was a trend for higher mortality for pressures >250 mm H2O (odds ratio OR, 2.1; 95% confidence interval CI, 0.9–5.2; P=.09). Initial CSF WBC counts of <5 cells/mL were associated with failure of CSF sterilization (OR, 17.3; 95% CI, 3.1–94.3; P<.001), and protein levels <35 mg/dL were associated with higher mortality (OR, 2.0; 95% CI, 1.2–3.3; P=.007). Conclusions. Significant CM-associated mortality persists, despite the administration of amphotericin B and HIV therapy, because of the high mortality rate before receipt of HAART and because of immune reconstitution inflammatory syndrome—related complications after HAART initiation. Approaches to increase acceptance of therapeutic lumbar punctures are needed.
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Summary The immune reconstitution inflammatory syndrome (IRIS) has emerged as an important early complication of antiretroviral therapy (ART) in resource-limited settings, especially in patients with ...tuberculosis. However, there are no consensus case definitions for IRIS or tuberculosis-associated IRIS. Moreover, previously proposed case definitions are not readily applicable in settings where laboratory resources are limited. As a result, existing studies on tuberculosis-associated IRIS have used a variety of non-standardised general case definitions. To rectify this problem, around 100 researchers, including microbiologists, immunologists, clinicians, epidemiologists, clinical trialists, and public-health specialists from 16 countries met in Kampala, Uganda, in November, 2006. At this meeting, consensus case definitions for paradoxical tuberculosis-associated IRIS, ART-associated tuberculosis, and unmasking tuberculosis-associated IRIS were derived, which can be used in high-income and resource-limited settings. It is envisaged that these definitions could be used by clinicians and researchers in a variety of settings to promote standardisation and comparability of data.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Background. Cryptococcal meningitis (CM)-related immune reconstitution inflammatory syndrome (IRIS) complicates antiretroviral therapy (ART) in 20%–40% of ART-naive persons with AIDS and prior CM. ...Pathogenesis is unknown. Methods. We compared initial cerebrospinal fluid (CSF) cultures, inflammatory markers, and cytokine profiles in ART-naive patients with AIDS who did or did not subsequently develop IRIS after starting ART. We also compared results obtained at IRIS events or CM relapse. Results. Of 85 subjects with CM, 33 (39%) developed CM-related IRIS and 5 (6%) developed culture-positive CM relapse. At CM diagnosis, subjects subsequently developing IRIS had less inflammation, with decreased CSF leukocytes, protein, interferon-γ, interleukin-6, interleukin-8, and tumor necrosis factor-α, compared with subjects not developing IRIS (P<.05, for each). Initial CSF white blood cell counts ⩽25 cells/µL and protein levels ⩽50 mg/dL were associated with development of IRIS (odds ratio, 7.2 95% confidence interval, 2.7–18.7; P < .001). Compared with baseline levels, we identified CSF elevations of interferon-γ, tumor necrosis factor-α, granulocyte colony-stimulating factor, vascular-endothelial growth factor, and eotaxin (CCL11) (P < .05, for each) at the time of IRIS but minimal inflammatory changes in those with CM relapse. Conclusion. Patients who subsequently develop CM-related IRIS exhibit less initial CSF inflammation at the time of CM diagnosis, compared with those who do not develop IRIS. The inflammatory CSF cytokine profiles observed at time of IRIS can distinguish IRIS from CM relapse.
Abstract Background The substantial risk for respiratory and invasive infections with Streptococcus pneumoniae (Spn) among people with HIV-1 (PWH) begins with asymptomatic colonization. The frequency ...of Spn colonization among US adults with and without HIV-1 infection is not well characterized in the conjugate vaccine era. Methods We determined Spn colonization frequency by culture and specific lytA gene quantitative polymerase chain reaction (PCR) and microbiota profile by 16S ribosomal RNA gene sequencing in nasopharyngeal (NP) and oropharyngeal (OP) DNA from 138 PWH and 93 control adults and associated clinical characteristics. Results The frequencies of Spn colonization among PWH and controls did not differ (11.6% vs 8.6%, respectively; P = .46) using combined results of culture and PCR, independent of vaccination or behavioral risks. PWH showed altered microbiota composition (ie, β-diversity; NP: P = .0028, OP: P = .0098), decreased α-diversity (NP: P = .024, OP: P = .0045), and differences in the relative abundance of multiple bacterial taxa. Spn colonization was associated with altered β-diversity in the nasopharynx (P = .011) but not oropharynx (P = .21). Conclusions Despite widespread conjugate vaccine and antiretroviral use, frequencies of Spn colonization among PWH and controls are currently consistent with those reported in the preconjugate era. The persistently increased risk of pneumococcal disease despite antiretroviral therapy may relate to behavioral and immunologic variables other than colonization.
The cell surface serine protease Transmembrane Protease 2 (TMPRSS2) is required to cleave the spike protein of SARS-CoV-2 for viral entry into cells. We determined whether negatively-charged heparin ...enhanced TMPRSS2 inhibition by alpha-1-antitrypsin (AAT). TMPRSS2 activity was determined in HEK293T cells overexpressing TMPRSS2. We quantified infection of primary human airway epithelial cells (hAEc) with human coronavirus 229E (HCoV-229E) by immunostaining for the nucleocapsid protein and by the plaque assay. Detailed molecular modeling was undertaken with the heparin-TMPRSS2-AAT ternary complex. Enoxaparin enhanced AAT inhibition of both TMPRSS2 activity and infection of hAEc with HCoV-229E. Underlying these findings, detailed molecular modeling revealed that: (i) the reactive center loop of AAT adopts an inhibitory-competent conformation compared with the crystal structure of TMPRSS2 bound to an exogenous (nafamostat) or endogenous (HAI-2) TMPRSS2 inhibitor and (ii) negatively-charged heparin bridges adjacent electropositive patches at the TMPRSS2-AAT interface, neutralizing otherwise repulsive forces. In conclusion, enoxaparin enhances AAT inhibition of both TMPRSS2 and coronavirus infection. Such host-directed therapy is less likely to be affected by SARS-CoV-2 mutations. Furthermore, given the known anti-inflammatory activities of both AAT and heparin, this form of treatment may target both the virus and the excessive inflammatory consequences of severe COVID-19.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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