Comparing clinical outcomes in HIV-infected and uninfected older men hospitalized with community-acquired pneumonia.

OBJECTIVES: Outcomes of community-acquired pneumonia (CAP) among HIV-infected older adults are unclear. METHODS: Associations between HIV infection and three CAP outcomes (30-day mortality, readmission within 30 days post-discharge, and hospital length of stay [LOS]) were examined in the Veterans Aging Cohort Study (VACS) of male Veterans, age ≥ 50 years, hospitalized for CAP from 10/1/2002 through 08/31/2010. Associations between the VACS Index and CAP outcomes were assessed in multivariable models. RESULTS: Among 117 557 Veterans (36 922 HIV-infected and 80 635 uninfected), 1203 met our eligibility criteria. The 30-day mortality rate was 5.3%, the mean LOS was 7.3 days, and 13.2% were readmitted within 30 days of discharge. In unadjusted analyses, there were no significant differences between HIV-infected and uninfected participants regarding the three CAP outcomes (P > 0.2). A higher VACS Index was associated with increased 30-day mortality, readmission, and LOS in both HIV-infected and uninfected groups. Generic organ system components of the VACS Index were associated with adverse CAP outcomes; HIV-specific components were not. Among HIV-infected participants, those not on antiretroviral therapy (ART) had a higher 30-day mortality (HR 2.94 [95% CI 1.51, 5.72]; P = 0.002) and a longer LOS (slope 2.69 days [95% CI 0.65, 4.73]; P = 0.008), after accounting for VACS Index. Readmission was not associated with ART use (OR 1.12 [95% CI 0.62, 2.00] P = 0.714). CONCLUSION: Among HIV-infected and uninfected older adults hospitalized for CAP, organ system components of the VACS Index were associated with adverse CAP outcomes. Among HIV-infected individuals, ART was associated with decreased 30-day mortality and LOS.

Ultrastructural localization of albumin transport across the cerebral microvasculature during experimental meningitis in the rat.

Injury to the blood brain barrier (BBB) is a fundamental sequela of bacterial meningitis, yet the precise mechanism facilitating exudation of albumin across the endothelium of the cerebral microvasculature remains conjectural. After intracisternal inoculation of Escherichia coli (0111:B4) lipopolysaccharide in rats to elicit a reversible meningitis and BBB injury, we utilized in situ tracer perfusion and immunolabeling procedures to identify by transmission electron microscopy the precise topography and microvascular exit pathway(s) of bovine serum albumin (BSA). Results revealed that during meningitis there was: (a) an inducible increase in immunodetectable monomeric BSA binding to the luminal membrane of all microvascular segments in the pia-arachnoid and superficial brain cortex; (b) similar uptake of both colloidal Au-BSA (as well as monomeric BSA) by plasmalemmal vesicles but no detectable transcytosis to the abluminal side; and (c) predominant exit of both perfused Au-BSA and immunodetectable monomeric BSA through open intercellular junctions of venules in the pia-arachnoid. This was corroborated in separate experiments documenting focal pial venular leaks of in situ perfused 0.01% colloidal carbon black during experimental meningitis. These results provide precise localization of BBB injury in meningitis to meningeal venules, confirm a paracellular exit pathway of albumin via open intercellular junctions, and suggest an injury mechanism amenable to specific therapeutic intervention.

Morphologic alterations of the blood-brain barrier with experimental meningitis in the rat. Temporal sequence and role of encapsulation.

The cerebral capillary endothelium is unique and functions as an effective blood-brain barrier (BBB) owing to its intercellular tight junctions and rare pinocytotic vesicles. To assess how bacterial meningitis alters the BBB, rats were inoculated intracisternally with three encapsulated meningeal pathogens (Escherichia coli K1+, Streptococcus pneumoniae type III, Haemophilus influenzae type b) and an unencapsulated mutant strain (H. influenzae Rd). After defined infection durations, the morphologic alterations of the cerebral capillary endothelium were quantitatively assessed by transmission electron microscopy. Results revealed a significant increase in pinocytotic vesicle formation (P less than 0.001) early after meningitis induction (4 h) that was sustained with longer infection durations (10 h, 18 h) for all encapsulated strains tested. In addition, there was a progressive increase in completely separated intercellular junctions with increasing infection duration, (P less than 0.05). 4 h after induction of meningitis with H. influenzae Rd, cerebrospinal fluid (CSF) bacterial concentrations, cerebral capillary morphologic changes, and functional BBB permeability to circulating 125I-albumin were similar to those observed with H. influenzae type b. However, prolonging the H. influenzae Rd infection to 18 h allowed for CSF clearance of the organism, thereby precluding the significant increase in separated junctions or progression of functional BBB permeability seen with the encapsulated H. influenzae type b. These data suggest a uniform morphologic explanation for altered BBB permeability in meningitis with a reproducible temporal sequence. Encapsulation does not appear essential for BBB injury, but may facilitate its progression by allowing the organism to evade host clearance.

Recombinant human interleukin-1 induces meningitis and blood-brain barrier injury in the rat. Characterization and comparison with tumor necrosis factor.

The diversity of infectious agents capable of inducing meningitis and blood-brain barrier (BBB) injury suggests the potential for a common host mediator. The inflammatory polypeptides, IL-1 and TNF, were tested in an experimental rat model as candidate mediators for induction of meningitis and BBB injury. Intracisternal challenge of rIL-1 beta into rats induced neutrophil emigration into cerebrospinal fluid (CSF) and significantly increased BBB permeability to systemically administered 125I-BSA as early as 3 h later (P less than 0.05). This injury was reversible, dose dependent and significantly inhibited by prior induction of systemic neutropenia (via intraperitoneal cyclophosphamide) or preincubation of the rIL-1 beta inoculum (50 U) with an IgG monoclonal antibody to rIL-1 beta. Similar kinetics and reversibility of CSF inflammation and BSA permeability were observed using equivalent dose inocula of rIL-1 alpha. rTNF-alpha was less effective as an independent inducer of meningitis or BBB injury over an inoculum range of 10(1) U (0.0016 micrograms/kg)-10(6) U (160 micrograms/kg) when injected intracisternally, but inoculum combinations of low concentrations of rTNF alpha (10(3) U) and rIL-1 beta (0.0005-5.0 U) were synergistic in inducing both meningitis and BBB permeability to systemic 125I-BSA. These data suggest that in situ generation of interleukin-1 within CSF (with or without TNF) is capable of mediating both meningeal inflammation and BBB injury seen in various central nervous system infections.

Acute meningitis with a negative Gram's stain: clinical and management outcomes in 171 episodes.

PURPOSE: To characterize the diagnostic spectrum and physician management decisions of patients presenting to an emergency department with an acute, community-acquired illness, cerebrospinal fluid (CSF) white blood cell count > 5/mm3, and a negative Gram's stain for bacteria. PATIENTS AND METHODS: In this retrospective cohort study over a 2-year period, symptoms, examination findings, paraclinical data, physician management, and clinical outcomes were assessed for each patient. RESULTS: One hundred sixty-eight patients (171 patient episodes) were evaluated. Almost half of the cohort presented in nonsummer months (48%); 20% of concurrent comorbid disease, and 15% had identified immunocompromising conditions. The reported examination findings were diverse, with diverse, with fever [49%] and neck stiffness [39%] being the most frequent findings. The majority were hospitalized (70%), with a median stay of 4 days. Approximately one half underwent computed tomography or magnetic resonance imaging (49%), and received empiric treatment with antibiotics (52%). A diagnostic cause was established in 23%, with the majority being inherently treatable diseases (including syphilis, bacteremia, Lyme disease). Variables significantly associated with a subsequent proven diagnostic cause included: age > 60 years; presence of comorbid disease (especially immunodeficiency); and presentation in winter months. CONCLUSIONS: A large proportion of patients presenting with acute meningitis and a negative CSF Gram's stain undergo hospitalization, noninvasive cranial imaging, and receive empiric antibiotic therapy. Better clinical guidelines are needed to identify the diagnostic and management decisions that benefit patient outcome.

A prognostic rule for elderly patients admitted with community-acquired pneumonia.

PURPOSE: We sought to identify admission characteristics predicting mortality in elderly patients hospitalized with community-acquired pneumonia and to develop a prognostic staging system and discriminant rule. PATIENTS AND METHODS: We retrospectively analyzed data from 2,356 patients aged > or = 65 years admitted with community-acquired pneumonia. Multivariable analyses of a derivation cohort (n = 1,000) identified characteristics associated with hospital mortality. A staging system and discriminant rule based on these characteristics were tested in a validation cohort (n = 1,356). Our discriminant rule was compared with a rule formulated from a heterogeneous adult population with community-acquired pneumonia. RESULTS: Hospital mortality rates were 9% (derivation cohort) and 12% (validation cohort). We identified five independent predictors of mortality: age > or = 85 years [odds ratio 1.8 (95% confidence interval 1.1-3.1)], comorbid disease [odds ratio 4.1 (2.1-8.1)], impaired motor response [odds ratio 2.3 (1.4-3.7)], vital sign abnormality [odds ratio 3.4 (2.1-5.4)], and creatinine level > or = 1.5 mg/dL [odds ratio 2.5 (1.5-4.2)]. These variables stratified patients into four distinct stages with increasing mortality in the derivation cohort (Stage 1, 2%; Stage 2, 7%; Stage 3, 22%; Stage 4, 45%; P = 0.001) as well as in the validation cohort (Stage 1, 4%; Stage 2, 11%; Stage 3, 23%; Stage 4, 41%; P = 0.001). The discriminant rule developed from the derivation cohort had greater overall accuracy (77.1%) in the validation cohort than a rule formulated from a heterogeneous adult population (68.0%, P = 0.001). CONCLUSION: Elderly patients with community-acquired pneumonia have characteristics at admission that can predict mortality. Our staging system and discriminant rule improve prognostic stratification of these patients.

Recent advances in the pathogenesis and pathophysiology of bacterial meningitis.

Bacterial meningitis continues to account for worldwide morbidity and mortality despite the advent of effective bactericidal antibiotic therapy. Recent advances over the past 10 years in the development of experimental animal models as well as basic investigation into critical bacterial surface virulence factors have begun to clarify a conceptual framework for understanding the mechanism of meningitis development in humans. Basic observations regarding competing host defenses and bacterial virulence factors have supported a pathogenetic sequence of mucosal colonization with a meningeal pathogen; systemic host invasion with intravascular replication; blood brain barrier penetration and unimpeded CSF proliferation amid the impaired host defenses in the CSF milieu; and pathophysiologic sequelae including vasogenic, cytotoxic, and interstitial brain edema (and other processes) accounting for irreversible neuronal injury and death. Only through continued basic investigation into each of these pathogenetic steps will significant reductions in morbidity and mortality ensue.

Utility of prognostic stratification in adults with community-acquired bacterial meningitis.

Prognostic stratification uses baseline clinical features to subdivide patients into subgroups with different risks for a particular outcome. We review the importance of prognostic stratification in internal medicine, in infectious diseases, and in adults with community-acquired bacterial meningitis.

Treatment of bacterial meningitis.

Major epidemiological changes have altered the empiric therapy of patients with bacterial meningitis, a disease with significant morbidity and mortality. We offer recommendations for empiric management decisions and specific antibiotic choices for patients with bacterial meningitis.

Yeast perinephric abscess: report of a case and review.

We report a case of yeast perinephric abscess and review 11 other published cases. This rare entity occurs primarily in patients who have diabetes mellitus, who have recently undergone surgery, or who have urinary tract obstruction. The clinical illness is often subacute or chronic with nonspecific symptoms. Candida and Torulopsis species are the reported etiologic agents. Successful therapy usually consists of percutaneous or surgical drainage of the abscess. Overall mortality is 25%; however, no patient in this series died as a direct result of perinephric infection.

Computed tomography of the head before lumbar puncture in adults with suspected meningitis.

BACKGROUND: In adults with suspected meningitis clinicians routinely order computed tomography (CT) of the head before performing a lumbar puncture. METHODS: We prospectively studied 301 adults with suspected meningitis to determine whether clinical characteristics that were present before CT of the head was performed could be used to identify patients who were unlikely to have abnormalities on CT. The Modified National Institutes of Health Stroke Scale was used to identify neurologic abnormalities. RESULTS: Of the 301 patients with suspected meningitis, 235 (78 percent) underwent CT of the head before undergoing lumbar puncture. In 56 of the 235 patients (24 percent), the results of CT were abnormal; 11 patients (5 percent) had evidence of a mass effect. The clinical features at base line that were associated with an abnormal finding on CT of the head were an age of at least 60 years, immunocompromise, a history of central nervous system disease, and a history of seizure within one week before presentation, as well as the following neurologic abnormalities: an abnormal level of consciousness, an inability to answer two consecutive questions correctly or to follow two consecutive commands, gaze palsy, abnormal visual fields, facial palsy, arm drift, leg drift, and abnormal language (e.g., aphasia). None of these features were present at base line in 96 of the 235 patients who underwent CT scanning of the head (41 percent). The CT scan was normal in 93 of these 96 patients, yielding a negative predictive value of 97 percent. Of the three misclassified patients, only one had a mild mass effect on CT, and all three subsequently underwent lumbar puncture, with no evidence of brain herniation one week later. CONCLUSIONS: In adults with suspected meningitis, clinical features can be used to identify those who are unlikely to have abnormal findings on CT of the head.

Community-acquired bacterial meningitis: risk stratification for adverse clinical outcome and effect of antibiotic timing.

BACKGROUND: Community-acquired bacterial meningitis causes substantial morbidity and mortality in adults. OBJECTIVE: To create and test a prognostic model for persons with community-acquired bacterial meningitis and to determine whether antibiotic timing influences clinical outcome. DESIGN: Retrospective cohort study; patients were divided into derivation and validation samples. SETTING: Four hospitals in Connecticut. PATIENTS: 269 persons who, between 1970 and 1995, had community-acquired bacterial meningitis microbiologically proven by a lumbar puncture done within 24 hours of presentation in the emergency department. MEASUREMENTS: Baseline clinical and laboratory features and times of arrival in the emergency department, performance of lumbar puncture, and administration of antibiotics. The target end point was the development of an adverse clinical outcome (death or neurologic deficit at discharge). RESULTS: For the total group, the hospital mortality rate was 27%. Fifty-six of 269 patients (21 %) developed a neurologic deficit, and in 9% the neurologic deficit persisted at discharge. Three baseline clinical features (hypotension, altered mental status, and seizures) were independently associated with adverse clinical outcome and were used to create a prognostic model from the derivation sample. The prediction accuracy of the model was determined by using the concordance index (c-index). For both the derivation sample (c-index, 0.73 [95% CI, 0.65 to 0.81]) and the validation sample (c-index, 0.81 [CI, 0.71 to 0.92]), the model predicted adverse clinical outcome significantly better than chance. For the total group, the model stratified patients into three prognostic stages: low risk for adverse clinical outcome (9%; stage I), intermediate risk (33%; stage II), and high risk (56%; stage III) (P=0.001). Adverse clinical outcome was more common for patients in whom the prognostic stage advanced from low risk (P=0.008) or intermediate risk (P=0.003) at arrival in the emergency department to high risk before administration of antibiotics. CONCLUSIONS: In persons with community-acquired bacterial meningitis, three baseline clinical features of disease severity predicted adverse clinical outcome and stratified patients into three stages of prognostic severity. Delay in therapy after arrival in the emergency department was associated with adverse clinical outcome when the patient's condition advanced to the highest stage of prognostic severity before the initial antibiotic dose was given.

Primary prevention of cryptococcal meningitis by fluconazole in HIV-infected patients.

To evaluate whether oral fluconazole reduces the risk of a first episode of cryptococcal meningitis in HIV-infected patients, we conducted a case-control study of patients cared for in a university teaching hospital and two urban HIV-outpatient clinics. Cases consisted of HIV-infected patients with CD4 cell counts less than 250/microL who developed a first episode of cryptococcal meningitis between July 1, 1990, and June 30, 1993. For each case (n = 18), 4 control subjects were chosen from HIV-infected patients (CD4 count < 250/microL) whose cerebrospinal fluid was negative for cryptococcal antigen and culture, and who were matched by age, sex, and time of lumbar puncture. There were no significant differences between cases and controls in age, sex, insurance status, mean CD4 count, history of oral candidosis, presence of a previous AIDS-defining illness, the number of visits to the HIV-outpatient clinic, or use of antiretroviral therapy. In the 6 months before lumbar puncture, 2 of 18 cases (11%) and 26 of 72 controls (36%) were exposed to fluconazole, a finding that gives a matched odds ratio (adjusted for race, route of HIV infection, and CD4 count) of 0.08 (95% CI 0.01-0.84; p = 0.035) and indicates a 92% protective efficacy. We conclude that fluconazole reduces the risk of a first episode of cryptococcal meningitis in HIV-infected patients with a CD4 count less than 250/microL. Although the optimum dose and duration of fluconazole could not be determined, our results suggest that less than daily use was effective in the prevention of cryptococcal meningitis.

Community-acquired bacterial meningitis in adults: categorization of causes and timing of death.

The relationship between cause and timing of death in 294 adults who had been hospitalized with community-acquired bacterial meningitis was investigated. For 74 patients with community-acquired bacterial meningitis who died during hospitalization, the underlying and immediate causes of death were identified according to the criteria of the World Health Organization and National Center for Health Statistics. Patients were classified into 3 groups: category I, in which meningitis was the underlying and immediate cause of death (59% of patients; median duration of survival, 5 days); category II, in which meningitis was the underlying but not immediate cause of death (18%; median duration of survival, 10 days); and category III, in which meningitis was neither the underlying nor immediate cause of death (23%; median duration of survival, 32 days). In a substantial proportion of adults hospitalized with community-acquired bacterial meningitis, meningitis was neither the immediate nor the underlying cause of death. A 14-day survival end point discriminated between deaths attributable to meningitis and those with another cause.