Predicting Lymph Node Metastasis in Non-small Cell Lung Cancer: Prospective External and Temporal Validation of the HAL and HOMER Models.

BACKGROUND: Two models, the Help with the Assessment of Adenopathy in Lung cancer (HAL) and Help with Oncologic Mediastinal Evaluation for Radiation (HOMER), were recently developed to estimate the probability of nodal disease in patients with non-small cell lung cancer (NSCLC) as determined by endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA). The objective of this study was to prospectively externally validate both models at multiple centers. RESEARCH QUESTION: Are the HAL and HOMER models valid across multiple centers? STUDY DESIGN AND METHODS: This multicenter prospective observational cohort study enrolled consecutive patients with PET-CT clinical-radiographic stages T1-3, N0-3, M0 NSCLC undergoing EBUS-TBNA staging. HOMER was used to predict the probability of N0 vs N1 vs N2 or N3 (N2|3) disease, and HAL was used to predict the probability of N2|3 (vs N0 or N1) disease. Model discrimination was assessed using the area under the receiver operating characteristics curve (ROC-AUC), and calibration was assessed using the Brier score, calibration plots, and the Hosmer-Lemeshow test. RESULTS: Thirteen centers enrolled 1,799 patients. HAL and HOMER demonstrated good discrimination: HAL ROC-AUC = 0.873 (95%CI, 0.856-0.891) and HOMER ROC-AUC = 0.837 (95%CI, 0.814-0.859) for predicting N1 disease or higher (N1|2|3) and 0.876 (95%CI, 0.855-0.897) for predicting N2|3 disease. Brier scores were 0.117 and 0.349, respectively. Calibration plots demonstrated good calibration for both models. For HAL, the difference between forecast and observed probability of N2|3 disease was +0.012; for HOMER, the difference for N1|2|3 was -0.018 and for N2|3 was +0.002. The Hosmer-Lemeshow test was significant for both models (P = .034 and .002), indicating a small but statistically significant calibration error. INTERPRETATION: HAL and HOMER demonstrated good discrimination and calibration in multiple centers. Although calibration error was present, the magnitude of the error is small, such that the models are informative.

Acute Onset of Pneumococcal Pneumonia Following Instrumentation of the Respiratory Tract.

We describe 22 patients who developed pneumococcal pneumonia within 96 hours of respiratory tract instrumentation. In 59% of cases, the time to onset of symptoms was <24 hours. Instrumentation bypasses normal protective barriers and carries organisms directly to the lower airways, leading to the rapid development of pneumonia.

White Blood Cell Counts, Alcoholism, and Cirrhosis in Pneumococcal Pneumonia.

BACKGROUND: An elevated white blood cell (WBC) count is a characteristic finding in pneumococcal pneumonia. Very low WBC counts, occurring in some cases, are often associated with overwhelming pneumonia and have been attributed to alcohol-induced suppression of bone marrow. However, a systematic study of neutropenia, leukocytosis, alcohol ingestion, and cirrhosis in pneumococcal pneumonia has not been previously reported. METHODS: Using a database of patients with pneumococcal pneumonia at our medical center, we extracted data on WBC counts at admission, differential counts, alcohol ingestion, and cirrhosis, and we related these to 7-day and 30-day mortality. RESULTS: White blood cell counts were <6000/mm3 in 49 of 481 patients (10.2%) with pneumococcal pneumonia and >25000/mm3 in 40 (8.3%). Mortality at 7 days was 18.4% and 12.5%, respectively, 5-fold and 3-fold greater in patients with WBC <6000 or >25000 than in those with WBC counts between 6000 and 25000 (P < .001). Increased band forms were not associated with a worse outcome (P = .12). Alcohol use and cirrhosis were not associated with WBC counts <6000 (P = .63 and P = .41, respectively). CONCLUSIONS: In a large series of cases of pneumococcal pneumonia, WBC counts <6000 or >25000 correlated significantly with increased 7-day mortality. More than 10% band forms was not associated with a poor outcome. Alcohol abuse was not associated with low WBC or increased mortality. Our findings suggest that greater consideration be given to more intense care for patients with bacterial pneumonia who have very high or very low WBC counts at the time of hospital admission.

Quantitative and Qualitative Antibody Responses to Immunization With the Pneumococcal Polysaccharide Vaccine in HIV-Infected Patients After Initiation of Antiretroviral Treatment: Results From a Randomized Clinical Trial.

BACKGROUND: Pneumococcal vaccination is recommended for human immunodeficiency virus-infected (HIV+) persons; the best timing for immunization with respect to initiation of antiretroviral therapy (ART) is unknown. METHODS: Double-blind, placebo-controlled trial in HIV+ with CD4(+) T cells/µL (CD4) ≥ 200 randomized to receive the 23-valent pneumococcal polysaccharide vaccine (PPV23) or placebo at enrollment, followed by placebo or PPV23, respectively, 9-12 months later (after ≥6 months of ART). Capsular polysaccharide-specific immunoglobin (Ig) G and IgM levels to serotypes 1, 3, 4, 6B, and 23F, and opsonophagocytic killing activity (OPA) to serotypes 6B and 23F were evaluated 1 month postvaccination. RESULTS: One hundred seven subjects were enrolled, 72 (67.3%) were evaluable (36/group). Both groups had significant increases in pre- to 1-month postvaccination IgG levels, but negligible to IgM, and significant increases in OPA titers to serotype 6B but not to 23F. There were no significant differences between groups in serotype-specific IgM or IgG levels or OPA titers. For the combined groups, there was a significant correlation between serotype-specific IgG and OPA titers to 23F but not to 6B. There was no correlation between CD4, viral load and IgG responses. CONCLUSIONS: In HIV+ with CD4 ≥ 200, delaying PPV23 until ≥6 months of ART does not improve responses and may lead to missed opportunities for immunization.

Long-term survival following pneumococcal pneumonia.

We studied the long-term survival of patients who recovered from pneumococcal pneumonia. Mortality was increased for up to 10 years after documented pneumococcal pneumonia and was greater in proportion to the PORT score at admission and among persons who had bacteremic disease.

The impact of statin and macrolide use on early survival in patients with pneumococcal pneumonia.

BACKGROUND: Mortality in pneumococcal pneumonia remains high despite early antibiotic eradication of bacteria. Most deaths occur within the first week, the time of peak inflammatory responses. Statins and macrolides have broad immunosuppressive activity; their impact, separately and together, on survival in patients with pneumococcal pneumonia was evaluated. METHODS: All patients with pneumococcal pneumonia seen at a single medical center from 2000 through 2010 were included in this retrospective cohort study. A multivariate-adjusted Cox proportional hazard model was used to evaluate survival. RESULTS: Of 347 patients with pneumococcal pneumonia, 90 (26%) were taking a statin at presentation and 126 (36%) were started on treatment with a macrolide. Thirty-two (9%) statin users were treated with a macrolide. Statin users were older than non-statin users, with a higher prevalence of diabetes, coronary artery disease and chronic kidney disease and a lower prevalence of alcohol consumption and liver disease. Statin users had higher mean Pneumonia Patient Outcomes Research Team scores. Patients treated with a macrolide were not different from those who received other antibiotics. The risk of mortality among statin users was reduced at 7, 14, 20 and 30 days after admission. Mortality was not reduced in patients treated with a macrolide or with a macrolide plus a statin compared with those who did not receive a macrolide. CONCLUSIONS: Patients who are receiving statins at the time of admission for pneumococcal pneumonia have better clinical outcomes than those who are not. Treatment with a macrolide does not appear to confer a survival benefit.

The incidence of necrotizing changes in adults with pneumococcal pneumonia.

BACKGROUND: Necrotizing pneumonia is generally considered a rare complication of pneumococcal infection in adults. We systematically studied the incidence of necrotizing changes in adult patients with pneumococcal pneumonia and examined the severity of infection, role of causative serotypes, and association with bacteremia. METHODS: We used a database of all pneumococcal infections identified at our medical center between 2000 and 2010. Original readings of chest X-rays (CXR) and computerized tomography (CT) were noted. Images were then independently reevaluated by 2 radiologists. The severity of disease at admission was assessed using SMART-COP and Pneumonia Outcomes Research Team (PORT) scoring systems. RESULTS: In 351 cases of pneumococcal pneumonia, necrosis was reported in no (0%) original CXR readings and in 6 of 136 (4.4%) CTs. With rereading, 8 of 351 (2.3%) CXR and 15 of 136 (11.0%) CT had necrotizing changes. Overall, these changes were identified in 23 of 351 (6.6%) patients. The incidence of bacteremia and the admitting SMART-COP and PORT scores were similar in patients with and without necrosis (P = 1.00, P = .32, and P = .54, respectively). Type 3 pneumococcus was more commonly isolated from patients with necrosis than from patients without necrosis (P = .05), but 10 other serotypes were also implicated in 16 cases for which the organism was available for typing. CONCLUSIONS: Necrotizing changes in the lungs were seen in 6.6% of a large series of adults with pneumococcal pneumonia but were often overlooked on initial readings. Patients with necrosis were not more likely to have bacteremia or more severe disease. Type 3 pneumococcus was the most commonly identified serotype.

Antibody persistence ten years after first and second doses of 23-valent pneumococcal polysaccharide vaccine, and immunogenicity and safety of second and third doses in older adults.

In a study of older adults, first and second doses of 23-valent pneumococcal polysaccharide vaccine (PN23) induced IgG increases for all 8 vaccine serotypes tested. Participants (N=143, mean age 76 years) were re-enrolled to study antibody levels after ten years, and safety and immunogenicity of another PN23 dose. Ten years after first or second doses, mean IgG concentrations exceeded vaccine-naïve levels for 7 of 8 serotypes tested. Second and third doses administered at this time were generally well tolerated and were immunogenic, inducing similar postvaccination levels. Immunogenicity is preserved after multiple PN23 doses without evidence of a lower than expected immune response (i.e., without hyporesponsiveness).

The obesity paradox in community-acquired bacterial pneumonia.

BACKGROUND: The impact of obesity on the outcome of pneumonia is uncertain. METHODS: We retrospectively identified 266 hospitalized patients with proven pneumococcal or Haemophilus community-acquired pneumonia who had at least one body mass index (BMI, kg/m²) value documented in the 3 months before admission. Patients were classified as underweight (BMI <18.5), normal weight (BMI 18.5 to <25), overweight (BMI 25 to <30), or obese (BMI ≥30). The association of absolute BMI values and BMI categories with the mortality at 30 days after admission for pneumonia was investigated. RESULTS: Increasing BMI values were associated with reduced 30-day mortality, even after adjustment for significant covariates (odds ratio 0.88, confidence interval 0.81-0.96; p<0.01). There was a significant trend towards lower mortality in the overweight and obese (non-parametric trend, p=0.02). CONCLUSIONS: Our data suggest that obesity may exert a protective effect against 30-day mortality from community-acquired bacterial pneumonia.

The spectrum of invasive pneumococcal disease at an adult tertiary care hospital in the early 21st century.

Despite widespread pneumococcal vaccination of children and adults, invasive pneumococcal disease (IPD) remains prominent. Using our database of all Streptococcus pneumoniae infections at the Veterans Affairs Medical Center, Houston, Texas, since 2000, we reviewed cases of IPD, defined as the isolation of pneumococci from any normally sterile body site. In 136 cases, the mean age of patients was 63 years; 43% were African American, a higher proportion than the 30% served by our hospital. One hundred sixteen patients (85%) had pneumonia, of whom 3 also had empyema. Seven had bacteremia with no apparent source, 5 meningitis, 5 spontaneous bacterial peritonitis, 3 septic arthritis, 2 endocarditis, and individual patients had osteomyelitis and/or localized abscesses. One hundred twenty-one patients (89%) had > or =1 underlying condition associated with susceptibility to pneumococcal infection, and another 8 (6%) were aged >65 years old. Thus only 5% of patients lacked a condition for which 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended. Fifty-five percent had been vaccinated; similar proportions of vaccine serotypes infected previously vaccinated and nonvaccinated patients. All but 2 isolates were fully susceptible to penicillin and cefotaxime as currently defined. Consistent with substantial replacement of infecting serotypes since the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), none of the predominant infecting serotypes was included in PCV7, although all except for 6A were contained in PPV23. The overall mortality at 30 days was 16% and was similar in vaccinated and nonvaccinated subjects. IPD causes a wide spectrum of disease. Mortality is substantial. PPV23 is clearly not fully protective.

Hyperglycemia in diabetics and non-diabetics: effect on the risk for and severity of pneumococcal pneumonia.

OBJECTIVES: We sought to determine whether poor glucose control among diabetics is associated with increased risk for pneumococcal pneumonia and whether elevated admitting plasma glucose (APG) levels are associated with increased severity of this infection in diabetic and non-diabetic patients. METHODS: We compared hemoglobin A(1c) (HbA(1c)) in diabetics who had pneumococcal pneumonia with diabetic case-controls who did not have pneumonia. In patients with pneumococcal pneumonia, we related APG to disease severity as determined by SMART-COP score, need for ICU admission, and mortality at 7 and 30 days. RESULTS: Fifty-three of 233 patients with pneumococcal pneumonia (22.7%) were diabetic. Diabetics with pneumonia had poorer glycemic control than diabetic case-controls (HbA(1c) 8.2% vs. 7.2%, respectively, P<0.01). In pneumococcal pneumonia patients, SMART-COP scores, need for ICU admission, and mortality increased in proportion to the APG. These findings were attributable to the significant association between hyperglycemia and severity in non-diabetics. CONCLUSIONS: Poor glycemic control predisposes diabetics to pneumococcal pneumonia but, among diabetics, the degree of hyperglycemia at admission is not associated with increased disease severity. In contrast, among non-diabetics with pneumococcal pneumonia, hyperglycemia is a marker for severe disease and increased mortality, perhaps reflecting massive release of cytokines and glucocorticosteroids in overwhelming infection.

Acute bacterial pneumonia is associated with the occurrence of acute coronary syndromes.

A link between acute infections and the development of acute coronary syndromes (ACS) has been proposed. We used retrospective cohort and self-controlled case series analyses to define the closeness of the association between acute bacterial pneumonia due to Streptococcus pneumoniae or Haemophilus influenzae and ACS. For the retrospective cohort analysis we included a control group of patients with admission diagnoses other than pneumonia or ACS. For the self-controlled case series analysis, we made within-person comparisons of the risk for ACS during the 15 days after admission for pneumonia with that of 365 days before and after that event. In 206 pneumonia patients (144 S. pneumoniae, 62 H. influenzae) we identified 22 (10.7%) cases of ACS, which compared to 6 (1.5%) among 395 controls resulted in an odds ratio (OR) of 7.8 (95% confidence interval [CI], 3.1-19.4). With multivariate logistic regression analysis, the OR for ACS in the pneumonia group remained elevated (OR, 8.5; 95% CI, 3.4-22.2). By the self-controlled case series method, the risk of ACS remarkably increased during the first 15 days after the diagnosis of pneumonia (incidence rate ratio, 47.6; 95% CI, 24.5-92.5). The characteristics and strength of these associations suggest a causal role for the acute infection in this relationship.

Initial and subsequent response to pneumococcal polysaccharide and protein-conjugate vaccines administered sequentially to adults who have recovered from pneumococcal pneumonia.

BACKGROUND: Controversy persists over the benefits of pneumococcal polysaccharide vaccine (PPV) for adults at high risk for pneumococcal disease. We studied PPV, protein-conjugate pneumococcal vaccine (PCV), and immunologic "priming" with PCV followed by "boosting" with PPV in adults who had recovered from pneumococcal pneumonia. METHODS: Subjects received PPV followed by PCV 6 months later, or vice versa. The levels of IgG to capsular polysaccharide and opsonophagocytic killing activity (OPK) were studied at baseline and at 4-8 weeks and 6 months after each vaccination. RESULTS: PPV and PCV stimulated similar IgG levels and OPK at 4-8 weeks after vaccination. Six months after receipt of PPV, the antibody levels declined to baseline but remained modestly elevated after receipt of PCV. PCV administered 6 months after PPV stimulated modest increases in IgG level that failed to reach the peaks observed after receipt of PPV. In contrast, PPV administered 6 months after PCV caused dramatic increases in the levels of IgG and OPK for all polysaccharides at 4-8 weeks, consistent with a booster effect. Six months after receipt of the second vaccination, however, levels of IgG and OPK fell precipitously in all patients, approaching baseline levels. CONCLUSIONS: In these high-risk subjects who have recovered after treatment for pneumonia, the effect of PPV is short-lived; PCV stimulates a more prolonged response. The use of PPV as a booster following PCV causes early increases in antibody levels, but the level of IgG declines rapidly thereafter, consistent with induction of suppressor cells or tolerance. Protein vaccines may be needed for high-risk adults.

Multiple-dose granulocyte-macrophage-colony-stimulating factor plus 23-valent polysaccharide pneumococcal vaccine in patients with chronic lymphocytic leukemia: a prospective, randomized trial of safety and immunogenicity.

BACKGROUND: For the current study, the authors sought to determine whether administration of multiple-dose granulocyte-macrophage-colony-stimulating factor (GM-CSF) could improve response to standard 23-valent polysaccharide pneumococcal vaccine (PPV) in patients with chronic lymphocytic leukemia (CLL). METHODS: Patients were allocated randomly to receive PPV either alone or with 3 doses of GM-CSF (250 microg) given before or after vaccination. Serum was obtained before, 4 weeks after, and 12 weeks after vaccination for antibody determination. Thirty-two patients with CLL were given PPV. They were randomized to receive 3 doses of GM-CSF either before or after vaccination or to receive no GM-CSF. RESULTS: A 4-fold rise in immunoglobulin G (IgG) to capsular polysaccharides from Streptococcus pneumoniae types 4, 6B, 9V, 14, 19F, and 23F occurred in <10% of patients in each of the 3 groups. There were no differences in geometric mean IgG levels in any of the 3 groups 4 weeks or 12 weeks after vaccination. CONCLUSIONS: In patients with CLL, the response to pure polysaccharide pneumococcal vaccine was low despite immune enhancement with multiple doses of GM-CSF. In all patients, reactogenicity was minor.

The association between pneumococcal pneumonia and acute cardiac events.

BACKGROUND: Increased cardiac stress, hypoxemia, and inflammation may contribute to acute cardiac events, such as myocardial infarction (MI), arrhythmia, and/or congestive heart failure (CHF). We sought to determine the incidence of such events in patients who were hospitalized for community-acquired pneumococcal pneumonia. METHODS: We studied the medical records of all patients who were admitted for pneumococcal pneumonia during a 5-year period (2001-2005) to identify those who had MI, atrial fibrillation or ventricular tachycardia, or new-onset or worsening CHF at the time of hospital admission. RESULTS: Of 170 patients, 33 (19.4%) had > or =1 of these major cardiac events. Twelve had MI, of whom 2 also had arrhythmia and 5 had new-onset or worsening CHF. Eight had new-onset atrial fibrillation or ventricular tachycardia; 6 of these also had new CHF. Thirteen had newly diagnosed or worsening CHF, without MI or new arrhythmias. Hypoxemia and anemia were prominent. Importantly, patients with concurrent pneumococcal pneumonia and cardiac events had a significantly higher mortality than those with pneumococcal pneumonia alone (P<.008). The coexistence of pulmonary and cardiac disease was often overlooked by admitting physicians who, seeking a unifying diagnosis, emphasized one diagnosis to the exclusion of the other. CONCLUSIONS: Patients with pneumococcal pneumonia are at substantial risk for a concurrent acute cardiac event, such as MI, serious arrhythmia, or new or worsening CHF. This concurrence significantly increases mortality due to pneumonia. Admitting physicians tend to seek a unifying diagnosis, but the frequent coexistence of pneumonia and cardiac events indicates the importance of considering multiple diagnoses.

Community-associated strains of methicillin-resistant Staphylococccus aureus as the cause of healthcare-associated infection.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients with community-associated infection have been described as strains genetically distinct from the strains isolated from patients with healthcare-associated infection. This study examines the hypothesis that community-associated MRSA (CA-MRSA) strains now cause serious infections in hospitalized patients. METHODS: Thirty-seven clinical MRSA isolates were randomly selected from blood isolates obtained from July 2003 through June 2004. Strains were tested for staphylococcal chromosomal cassette mec (SCCmec) type, pulsed-field gel electrophoresis (PFGE) type, and presence of Panton-Valentine leukocidin (PVL) genes. Medical records review and epidemiologic classification was performed by an investigator blinded to the results of the bacterial strain analysis. Episodes of bloodstream infection were independently classified as either community-associated or healthcare-associated infections, and bacterial isolates were independently classified as either CA-MRSA strains or healthcare-associated MRSA (HA-MRSA) strains, according to established definitions. SETTING: A tertiary care Veterans Affairs Medical Center. RESULTS: Twenty-four (65%) of 37 MRSA isolates were SCCmec type IV, a genetic type characteristic of CA-MRSA strains; 22 of these 24 isolates belonged to the CA-MRSA clone USA300 and carried PVL genes. Thirteen (35%) of the 37 strains were SCCmec type II, of which 12 were USA100-ST5 and 12 lacked PVL genes. Thirty patients (81%) had healthcare-associated infections; 18 (60%) of these 30 were infected with isolates carrying markers of CA-MRSA strains. Of 7 patients with CA-MRSA infections, 6 were infected with isolates belonging to the USA300 clone. Patients with healthcare-associated bloodstream infections were as likely to be infected with a CA-MRSA strain as patients with a community-associated infection (P = .38). CONCLUSIONS: MRSA strains with molecular characteristics of CA-MRSA strains have emerged as an important cause of serious healthcare-associated infection in our hospital.

Bactericidal activity of orally available agents against methicillin-resistant Staphylococcus aureus.

BACKGROUND: The recent proliferation of community-acquired (CA) methicillin-resistant Staphylococcus aureus (MRSA) has led to a marked increase in the need for outpatient treatment of MRSA infections. Many oral agents active against MRSA have been available for years, and a paucity of literature compares them, leaving physicians with little guidance for choosing among them. The purpose of the present study was to compare the bactericidal effects of orally available antibiotics against MRSA and to determine whether there were differences in antimicrobial killing activity against CA-MRSA and hospital-acquired (HA) MRSA isolates. METHODS: A total of 12 unique patient MRSA isolates were studied. Six strains were CA, carrying the staphylococcal chromosomal cassette (SCCmec) type IVa, while six were HA and carried SCCmec type II. Time-kill methods were used to study the bactericidal activity of the orally available antimicrobials linezolid, rifampicin, trimethoprim/sulfamethoxazole, clindamycin, minocycline, and moxifloxacin alone and in combination in vitro. RESULTS: Trimethoprim/sulfamethoxazole was rapidly bactericidal resulting in >2 log(10) cfu/mL decrease at 8 h and >3 log(10) cfu/mL decrease at 24 h in vitro. No antibiotic combination exhibited better killing than trimethoprim/sulfamethoxazole alone. Adding rifampicin to trimethoprim/sulfamethoxazole showed a trend towards antagonism in vitro. There were no differences in the bactericidal activity of any antimicrobial or antimicrobial combination against MRSA isolates carrying SCCmec type IVa versus those carrying SCCmec type II. CONCLUSION: Trimethoprim/sulfamethoxazole is rapidly bactericidal against MRSA in vitro when compared with most other orally available antimicrobials. No differences in bactericidal activity were detected when activities against CA-MRSA and HA-MRSA were compared.

Nontypeable Haemophilus influenzae as a cause of spontaneous bacterial peritonitis.

Haemophilus influenzae rarely causes spontaneous bacterial peritonitis. We describe a typical case of spontaneous bacterial peritonitis in which the causative organism was identified as nontypeable H. influenzae, biotype III. Infection progressed despite the presence of adequate serum bactericidal antibody, probably due to the absence of complement in ascites fluid.