The Impact of Risk Factors on Treatment Outcomes of Nosocomial Pneumonia Due to Gram-Negative Bacteria in the Intensive Care Unit.

INTRODUCTION: Nosocomial pneumonia is a common infection associated with high mortality in hospitalized patients. Nosocomial pneumonia, caused by gram-negative bacteria, often occurs in the elderly and patients with co-morbid diseases. METHODS: Original research using a prospective cross-sectional design was conducted on 281 patients in an intensive care unit setting with nosocomial pneumonia between July 2015 and July 2019. For each nosocomial pneumonia case, data regarding comorbidities, risk factors, patient characteristics, Charlson comorbidity index (CCI), Systemic Inflammatory Response Syndrome (SIRS), and quick Sepsis-Related Organ Failure Assessment (qSOFA) points and treatment outcomes were collected. Data were analyzed by SPSS 22.0. RESULTS: Nosocomial pneumonia due to gram-negative bacteria occurred in patients with neurological disorders (34.87%), heart diseases (16.37%), chronic renal failure (7.12%), and post-surgery (10.68%). Worse outcomes attributed to nosocomial pneumonia were high at 75.8%. Mechanical ventilation, change of antibiotics, and CCI ≥ 3 and qSOFA ≥ 2 were significantly negative prognostic factors (p < 0.05) on outcomes of nosocomial pneumonia. There was no difference in treatment effects between gender, age, time of onset pneumonia, SIRS score (p > 0.05). The pathogens were significant factors that influence treatment effects, but they weren't independent risk factors for poor outcomes (p = 0.823). CONCLUSIONS: Patients with nosocomial pneumonia hospitalized in intensive care units are usually associated with many underlying diseases, including neurological diseases. Mechanical ventilation, a change in antibiotics, CCI ≥ 3, and qSOFA ≥ 2 are also associated with a worse prognosis of nosocomial pneumonia. CCI and qSOFA might be used in predicting the outcome of nosocomial pneumonia.

Innovative Use of Denver Shunt in a Child with Generalized Lymphatic Anomaly.

BACKGROUND: Denver® shunts have traditionally been used for palliation of refractory malignant and chylous peritoneal and pleural collections. We describe an innovative use of the Denver shunt in a child with generalized lymphatic anomaly. MATERIALS AND METHODS: Retrospective chart review of a 6-year-old girl with generalized lymphatic anomaly, who presented with refractory lymphorrhea from the labium majus, was performed. This was managed with innovative placement of the Denver shunt between a large abdominal wall cyst and the peritoneal cavity. RESULTS: There was progressive reduction in lymphorrhea with complete cessation at 11 months post shunt placement. At 33-month follow-up, the shunt remains patent with no further lymphorrhea. CONCLUSION: Denver shunts can be utilized for the creation of internal drainage pathways besides its traditional uses for draining peritoneal and pleural fluids.

Boosting of ALVAC-SIV Vaccine-Primed Macaques with the CD4-SIVgp120 Fusion Protein Elicits Antibodies to V2 Associated with a Decreased Risk of SIVmac251 Acquisition.

The recombinant ALVAC vaccine coupled with the monomeric gp120/alum protein have decreased the risk of HIV and SIV acquisition. Ab responses to the V1/V2 regions have correlated with a decreased risk of virus acquisition in both humans and macaques. We hypothesized that the breadth and functional profile of Abs induced by an ALVAC/envelope protein regimen could be improved by substituting the monomeric gp120 boost, with the full-length single-chain (FLSC) protein. FLSC is a CD4-gp120 fusion immunogen that exposes cryptic gp120 epitopes to the immune system. We compared the immunogenicity and relative efficiency of an ALVAC-SIV vaccine boosted either with bivalent FLSC proteins or with monomeric gp120 in alum. FLSC was superior to monomeric gp120 in directing Abs to the C3 α2 helix, the V5 loop, and the V3 region that contains the putative CCR5 binding site. In addition, FLSC boosting elicited significantly higher binding Abs to V2 and increased both the Ab-dependent cellular cytotoxicity activity and the breadth of neutralizing Abs. However, the FLSC vaccine regimen demonstrated only a trend in vaccine efficacy, whereas the monomeric gp120 regimen significantly decreased the risk of SIVmac251 acquisition. In both vaccine regimens, anti-V2 Abs correlated with a decreased risk of virus acquisition but differed with regard to systemic or mucosal origin. In the FLSC regimen, serum Abs to V2 correlated, whereas in the monomeric gp120 regimen, V2 Abs in rectal secretions, the site of viral challenge, were associated with efficacy.

Adjuvant-dependent innate and adaptive immune signatures of risk of SIVmac251 acquisition.

A recombinant vaccine containing Aventis Pasteur's canarypox vector (ALVAC)-HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC-simian immunodeficiency virus (SIV) and gp120 alum (ALVAC-SIV + gp120) equivalent vaccine, but not an ALVAC-SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

The Neonatal Fc receptor (FcRn) enhances human immunodeficiency virus type 1 (HIV-1) transcytosis across epithelial cells.

The mechanisms by which human immunodeficiency virus type 1 (HIV-1) crosses mucosal surfaces to establish infection are unknown. Acidic genital secretions of HIV-1-infected women contain HIV-1 likely coated by antibody. We found that the combination of acidic pH and Env-specific IgG, including that from cervicovaginal and seminal fluids of HIV-1-infected individuals, augmented transcytosis across epithelial cells as much as 20-fold compared with Env-specific IgG at neutral pH or non-specific IgG at either pH. Enhanced transcytosis was observed with clinical HIV-1 isolates, including transmitted/founder strains, and was eliminated in Fc neonatal receptor (FcRn)-knockdown epithelial cells. Non-neutralizing antibodies allowed similar or less transcytosis than neutralizing antibodies. However, the ratio of total:infectious virus was higher for neutralizing antibodies, indicating that they allowed transcytosis while blocking infectivity of transcytosed virus. Immunocytochemistry revealed abundant FcRn expression in columnar epithelia lining the human endocervix and penile urethra. Acidity and Env-specific IgG enhance transcytosis of virus across epithelial cells via FcRn and could facilitate translocation of virus to susceptible target cells following sexual exposure.

Association of Fcγ receptor IIIa genotype with the rate of HIV infection after gp120 vaccination.

We determined whether polymorphisms in Fcγ receptor (FcγR) IIa or FcγRIIIa genes were associated with outcomes in Vax004, a trial testing recombinant gp120 vaccination in preventing sexually acquired HIV infection. Male subjects (n = 1725), including infected and uninfected vaccinees and placebo recipients, were genotyped. We observed no association between FcγRIIa genotype and infection rate in vaccinees or placebo recipients. However, FcγRIIIa genotype was associated with infection rate among vaccinees (P = .035). Exploratory analyses revealed that vaccinees homozygous for the FcγRIIIa V allele in the lowest behavioral risk group had a greater rate of infection than low risk vaccinees with at least 1 F allele (hazard ratio [HR] = 3.52; P = .002). No such association was seen among vaccinees with high-risk behaviors or among placebo recipients in either risk stratum. Vaccinated low-risk VV subjects had a greater infection rate than low-risk VV placebo recipients (HR = 4.51; P = .17) or low-risk placebo recipients with any genotype (HR = 4.72; P = .002). Moreover, low-risk VV vaccinees had infection rates similar to individuals with high behavioral risk, irrespective of genotype. Our results generate the hypothesis that recombinant gp120 vaccine may have increased the likelihood of acquiring HIV infection in individuals with the VV genotype (present in ~ 10% of the population) at low behavioral risk of infection.

FcgammaRIIa genotype predicts progression of HIV infection.

Polymorphisms in FcgammaR genes are associated with susceptibility to or severity of a number of autoimmune and infectious diseases. We found that HIV-infected men in the Multicenter AIDS Cohort Study with the FcgammaRIIa RR genotype progressed to a CD4(+) cell count of <200/mm(3) at a faster rate than individuals with the RH or HH genotypes (relative hazard = 1.6; p = 0.0001). However, progression to AIDS (using the broad definition of either a CD4(+) cell count <200/mm(3) or development of an AIDS-defining illness) was less impacted by FcgammaRIIa genotype, largely because HH homozygotes had an increased risk of Pneumocystis jiroveci pneumonia as an AIDS-defining illness. We also showed that chronically infected subjects develop a substantial anti-gp120-specific IgG2 response. Moreover, HIV-1 immune complexes are more efficiently internalized by monocytes from HH subjects compared with RR subjects, likely because of the presence of IgG2 in the complexes. Finally, the FcgammaRIIIa F/V gene polymorphism was not associated with progression of HIV infection, but, as demonstrated previously, did predict the risk of Kaposi's sarcoma. These results demonstrate the importance of FcgammaRs in AIDS pathogenesis and point toward a critical role for interactions between FcgammaRs and immune complexes in disease progression.

Recombinant gp120 vaccine-induced antibodies inhibit clinical strains of HIV-1 in the presence of Fc receptor-bearing effector cells and correlate inversely with HIV infection rate.

Nonneutralizing Abs may play a role in protecting animals and humans from lentiviral infections. We explored the Ab-dependent, cell-mediated virus inhibition (ADCVI) Ab response to recombinant gp120 (rgp120) vaccination in sera from 530 participants in the Vax 004 trial. Serum ADCVI activity was measured against a clinical R5 strain of HIV-1 using peripheral blood mononuclear effector cells from healthy donors. The level of vaccine-induced ADCVI activity correlated inversely with the rate of acquiring HIV infection following vaccination, such that for every 10% increase in ADCVI activity, there was a 6.3% decrease in the hazard rate of infection (p=0.019). Some vaccinated individuals also mounted an ADCVI response against two other clinical R5 strains of HIV-1. However, ADCVI activity correlated poorly with neutralizing or CD4-gp120-blocking Ab activity measured against laboratory strains. Finally, the degree to which the ADCVI Ab response predicted the rate of infection was influenced by polymorphisms at the FcgammaRIIa and FcgammaRIIIa gene loci. These data indicate that rgp120 vaccination can elicit Abs with antiviral activity against clinical strains of HIV-1. However, such activity requires the presence of FcR-bearing effector cells. Our results provide further evidence that ADCVI may play a role in preventing HIV infection.