Epidemiology, vaccine effectiveness, and risk factors for mortality for pneumococcal disease among hospitalised adults in Singapore: a case-control study.

BACKGROUND: Streptococcus pneumoniae infections can lead to severe morbidity and mortality, especially in patients with invasive pneumococcal disease (IPD). This study evaluated factors associated with pneumococcal disease, pneumococcal vaccine effectiveness, and risk factors for all-cause mortality in hospitalised adults with pneumococcal disease in Singapore. METHODS: Retrospective case-control study of patients tested for pneumococcal disease with streptococcal urinary antigen testing and at least one sterile site culture, during their admission to a tertiary hospital in Singapore from 2015 to 2017. Patients were defined as cases of IPD or non-IPD, or as controls, based on laboratory results and clinical diagnoses. Multivariable models were constructed to determine factors associated with IPD/non-IPD, and risk factors for mortality from pneumococcal disease. Vaccine effectiveness against IPD/non-IPD was estimated using a variation of the test-negative design. RESULTS: We identified 496 pneumococcal disease cases, of whom 92 (18.5%) had IPD. The mean age of cases was 69.1 ± 15.4 years, and 65.5% were male. Compared with controls (N = 9181), IPD patients were younger (mean age 61.5 ± 16.3 years, vs 72.2 ± 16.1 years in controls; p < 0.001) and with less co-morbidities [median Charlson's score 1 (IQR 0-4), vs 3 (1-5) in controls; p < 0.001]. IPD patients also had the highest proportions with intensive care unit (ICU) admission (20.7%), inpatient mortality (26.1%) and longest median length of stay [9 (IQR 8-17) days]. On multivariable analysis, IPD was negatively associated with prior pneumococcal vaccination (adjusted relative risk ratio = 0.20, 95%CI 0.06-0.69; p = 0.011). Risk factors for mortality among pneumococcal disease patients were ICU admission, diagnosis of IPD, age ≥ 85 years and Charlson's score > 3. CONCLUSION: Patients with pneumococcal disease (especially IPD) were younger and had less co-morbidities than controls, but had higher risk of severe clinical outcomes and mortality. Pneumococcal vaccination effectiveness against IPD was estimated to be about 80%, and should be encouraged among high-risk patients.

A novel use of pneumococcal urinary antigen detection kits to identify Streptococcus pneumoniae cultures misidentified by the VITEK-2 system.

Streptococcus pneumoniae infections continue to be an important cause of morbidity and mortality in low-and middle-income countries. Differentiating S. pneumoniae from viridans group streptococci is essential to ensure appropriate antibiotic therapy. Conventional microbial identification tests can often misidentify the two groups. We used a common pneumococcal urinary antigen test to identify S. pneumoniae that were misidentified by the VITEK 2. The performance of the test was similar to the pneumococcal latex agglutination test.

A positive pneumococcal urinary antigen test promotes narrow spectrum antibiotic use in patients with non-invasive pneumococcal pneumonia.

BACKGROUND: We compared changes in antibiotics in patients diagnosed with noninvasive pneumococcal pneumonia (NPP) by pneumoccocal urinary antigen tests or respiratory cultures. METHODS: We compared patients diagnosed by pneumococcal urinary antigen tests or respiratory cultures that grew Streptococcus pneumoniae. We assessed the time from sample receipt to final result and antibiotic regimens, including an Antibiotic Spectrum Index (ASI). RESULTS: Seventy-two cases of NPP were diagnosed by pneumococcal urinary antigen and 87 by respiratory cultures, with a median time from sample receipt to final result of 0.21 days (interquartile range (IQR) 0.17-1.17) and 3.21 days (IQR 3.17-4.21 days), respectively. Among 123 cases without antibiotic allergies, between days 0 and 2, the ASI decreased in 36% (18/50) of cases diagnosed by urinary antigen compared to 10% (7/73) of cases diagnosed by respiratory culture (P < 0.01). CONCLUSIONS: Positive pneumococcal urinary antigen tests lead to early deescalation of antibiotics more frequently than respiratory cultures.

Evaluation of the Sofia S. pneumoniae FIA for Detection of Pneumococcal Antigen in Patients with Bloodstream Infection.

The usefulness of pneumococcal urinary antigen tests (UATs) in severe pneumococcal infection relies heavily on the performance in bacteremic patients. Fluorescence technology and automatic reading of test results may improve UAT performance. We evaluated the automatically read Sofia S. pneumoniae FIA for diagnosing pneumococcal bloodstream infection (BSI) in hospitalized adult patients. First, the Sofia FIA was evaluated on 97 patients with pneumococcal (n = 47) and nonpneumococcal (n = 50) BSI and compared with results by the visually read BinaxNOW S. pneumoniae immunochromatographic test (ICT) and ImmuView S. pneumoniae and Legionella pneumophila ICT. In four cases (4.1%), the Sofia FIA showed invalid test results, three of which showed invalid results by the ImmuView ICT previously. Based on 93 valid cases, the Sofia FIA showed similar sensitivity (for both comparisons: 68% versus 62%; P = 0.45) and specificity (for both comparisons: 91% versus 93%; P = 1.00) as the visually read UATs. Second, the Sofia FIA was prospectively evaluated on 82 consecutive nonfrozen urine samples, detecting pneumococcal antigen in 10 of 14 (sensitivity, 71%) pneumococcal BSI patients, similarly to the visually and automatically read BinaxNOW ICT (both 12 of 14; sensitivity, 86%; P = 0.50). Of five nonpneumococcal BSI cases, the Sofia FIA showed an invalid test result in one case, but no positive UAT results were obtained. Thus, the sensitivity and specificity of the Sofia FIA were similar to the performance rates of other UATs in patients with BSI, but invalid test results are of concern for the usefulness in pneumococcal BSI.

Protein Expression Analysis by Western Blot and Protein-Protein Interactions.

Western blot analysis is widely used for detecting protein expression, analysis of protein-protein interactions, and searching for new biomarkers. Also, it is a diagnostic tool used for detection of human diseases and microorganism infections.Some Streptococcus pneumoniae proteins are important virulence factors and a few of them are diagnostic markers. Here, we describe the detection of two pneumococcal proteins, pneumolysin and PpmA, in human urine by using monoclonal and polyclonal antibodies.

Pneumococcal Community-Acquired Pneumonia Detected by Serotype-Specific Urinary Antigen Detection Assays.

Background: Streptococcus pneumoniae is considered the leading bacterial cause of pneumonia in adults. Yet, it was not commonly detected by traditional culture-based and conventional urinary testing in a recent multicenter etiology study of adults hospitalized with community-acquired pneumonia (CAP). We used novel serotype-specific urinary antigen detection (SSUAD) assays to determine whether pneumococcal cases were missed by traditional testing. Methods: We studied adult patients hospitalized with CAP at 5 hospitals in Chicago and Nashville (2010-2012) and enrolled in the Etiology of Pneumonia in the Community (EPIC) study. Traditional diagnostic testing included blood and sputum cultures and conventional urine antigen detection (ie, BinaxNOW). We applied SSUAD assays that target serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13) to stored residual urine specimens. Results: Among 1736 patients with SSUAD and ≥1 traditional pneumococcal test performed, we identified 169 (9.7%) cases of pneumococcal CAP. Traditional tests identified 93 (5.4%) and SSUAD identified 76 (4.4%) additional cases. Among 14 PCV13-serotype cases identified by culture, SSUAD correctly identified the same serotype in all of them. Cases identified by SSUAD vs traditional tests were similar in most demographic and clinical characteristics, although disease severity and procalcitonin concentration were highest among those with positive blood cultures. The proportion of pneumonia cases caused by serotypes exclusively covered by PCV13 was not significantly different between the first and second July-June study periods (6.4% vs 4.0%). Conclusions: Although restricted to the detection of only 13 serotypes, SSUAD testing substantially increased the detection of pneumococcal pneumonia among adults hospitalized with CAP.

Cost effectiveness of pneumococcal urinary antigen in Emergency Department: a pragmatic real-life study.

Community-acquired pneumonia (CAP) is frequent and can be life-threatening. Streptococcus pneumoniae is the main bacteria involved, and is susceptible to penicillin A. Rapid microbiological diagnosis could then help reduce the antimicrobial spectrum. The pneumococcal urinary antigen (PUA) test is fast and easy to perform, but its impact on antimicrobial prescription and cost-effectiveness in emergency departments (ED) is not well known. We performed a pragmatic real life retrospective study in an adult ED to assess its usefulness: proportion of positive results, impact on antimicrobial prescriptions and cost-effectiveness. Over 3 years (from January 1st 2012 to December 31st 2014), 979 PUA tests were reutilized in our ED among 1224 patients who consulted for CAP; 51 (5.2%) were positive. Among them, 10 led to a modification of the antimicrobial treatment, but only 7 (14.3%) were in accordance with the results. The total cost of a PUA test is 27€. As only 7 PUA tests led to appropriate antimicrobial modification, we deemed that 972 had no impact, and the potential cost savings, if the test had not been used, would have been 26,244 € (972 × 27) during 3 years, that is 8748 € per year. Thus, it seems that the PUA test should not be generally used in the ED considering its low rate of positivity and the difficulties for physicians to adapt antibiotic treatment accordingly. This attitude change in utilization would lead to substantial cost savings.

Invasive Disease vs Urinary Antigen-Confirmed Pneumococcal Community-Acquired Pneumonia.

BACKGROUND: The burden of pneumococcal disease is measured only through patients with invasive pneumococcal disease. The urinary antigen test (UAT) for pneumococcus has exhibited high sensitivity and specificity. We aimed to compare the pneumococcal pneumonias diagnosed as invasive disease with pneumococcal pneumonias defined by UAT results. METHODS: A prospective observational study of consecutive nonimmunosuppressed patients with community-acquired pneumonia was performed from January 2000 to December 2014. Patients were stratified into two groups: invasive pneumococcal pneumonia (IPP) defined as a positive blood culture or pleural fluid culture result and noninvasive pneumococcal pneumonia (NIPP) defined as a positive UAT result with negative blood or pleural fluid culture result. RESULTS: We analyzed 779 patients (15%) of 5,132, where 361 (46%) had IPP and 418 (54%) had NIPP. Compared with the patients with IPP, those with NIPP presented more frequent chronic pulmonary disease and received previous antibiotics more frequently. Patients with IPP presented more severe community-acquired pneumonia, higher levels of inflammatory markers, and worse oxygenation at admission; more pulmonary complications; greater extrapulmonary complications; longer time to clinical stability; and longer length of hospital stay compared with the NIPP group. Age, chronic liver disease, mechanical ventilation, and acute renal failure were independent risk factors for 30-day crude mortality. Neither IPP nor NIPP was an independent risk factor for 30-day mortality. CONCLUSIONS: A high percentage of confirmed pneumococcal pneumonia is diagnosed by UAT. Despite differences in clinical characteristics and outcomes, IPP is not an independent risk factor for 30-day mortality compared with NIPP, reinforcing the importance of NIPP for pneumococcal pneumonia.

Utilidad práctica del antígeno neumocócico en orina / Practical use of pneumococcal antigen assessment in urine

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Usefulness of pneumococcal antigen urinary testing in the intensive care unit?

OBJECTIVES: The use of pneumococcal antigen urinary tests is substantially increasing and is associated with a significant cost. The relevant use of this test in the intensive care unit (ICU) should be better defined. Our aim was to define the role of this test in relation to other microbiological tests. We described a series of patients admitted to the ICU for an invasive pneumococcal disease (IPD). PATIENTS AND METHODS: We conducted a retrospective and descriptive study of the microbiological tests used to diagnose IPD in patients admitted to the ICU of the University Hospital in Bordeaux. Our aim was to measure the sensitivity of these bacteriological tests and of the BinaxNOWS. pneumoniae test. RESULTS: Between 2009 and 2013, 148 patients were admitted for an IPD. A lower respiratory tract infection was diagnosed in 96.6% of them (143 patients). The overall ICU case fatality rate was 17.6%. The sensitivity of the pneumococcal antigen urinary test, sputum bacteriological examination, and blood cultures was respectively 83%, 37.6%, and 29.7%. S. pneumoniae was isolated from at least one bacteriological sample in 48.6% of patients, but in 51.4%, the diagnosis was only based on the results of the pneumococcal antigen urinary test. CONCLUSION: We suggest performing a pneumococcal antigen urinary test when an IPD is suspected, only if the bacteriological tests are still negative after 48hours. This strategy would result in a substantial cost saving. Patients would not face any additional risks as the result of the pneumococcal antigen urinary test does not have any impact on the initially prescribed antibiotic therapy.

Sensitivity, Specificity, and Positivity Predictors of the Pneumococcal Urinary Antigen Test in Community-Acquired Pneumonia.

RATIONALE: Detection of the C-polysaccharide of Streptococcus pneumoniae in urine by an immune-chromatographic test is increasingly used to evaluate patients with community-acquired pneumonia. OBJECTIVES: We assessed the sensitivity and specificity of this test in the largest series of cases to date and used logistic regression models to determine predictors of positivity in patients hospitalized with community-acquired pneumonia. METHODS: We performed a multicenter, prospective, observational study of 4,374 patients hospitalized with community-acquired pneumonia. MEASUREMENTS AND MAIN RESULTS: The urinary antigen test was done in 3,874 cases. Pneumococcal infection was diagnosed in 916 cases (21%); 653 (71%) of these cases were diagnosed exclusively by the urinary antigen test. Sensitivity and specificity were 60 and 99.7%, respectively. Predictors of urinary antigen positivity were female sex; heart rate≥125 bpm, systolic blood pressure<90 mm Hg, and SaO2<90%; absence of antibiotic treatment; pleuritic chest pain; chills; pleural effusion; and blood urea nitrogen≥30 mg/dl. With at least six of all these predictors present, the probability of positivity was 52%. With only one factor present, the probability was only 12%. CONCLUSIONS: The urinary antigen test is a method with good sensitivity and excellent specificity in diagnosing pneumococcal pneumonia, and its use greatly increased the recognition of community-acquired pneumonia due to S. pneumoniae. With a specificity of 99.7%, this test could be used to direct simplified antibiotic therapy, thereby avoiding excess costs and risk for bacterial resistance that result from broad-spectrum antibiotics. We also identified predictors of positivity that could increase suspicion for pneumococcal infection or avoid the unnecessary use of this test.

Streptococcus pneumoniae as a uropathogen in children with urinary tract abnormalities.

We describe 3 children with urinary tract abnormalities and large numbers of Streptococcus pneumoniae in their urine, along with a brief review of previously reported cases. These findings strongly suggest that S. pneumoniae is a uropathogen, especially in children with urinary tract abnormalities.

Streptococcus pneumoniae urinary antigen test and acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Streptococcus pneumoniae is one of the most common bacteria identified in sputum obtained from subjects with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). PURPOSE: To examine the urinary pneumococcal antigen test in subjects admitted with AECOPD and subjects with COPD, and to evaluate its relationship with AECOPD. METHODS: Urine samples from 82 subjects with AECOPD involved in 122 consecutive hospitalizations were tested. Additionally, 196 consecutive subjects with stable COPD were tested a total of 607 times at intervals greater than 6 months. RESULTS: Pneumococcal antigen was positive in 14 (17.1%) out of all 82 subjects first hospitalized with AECOPD. It was positive in 7 (20.6%) out of the 34 subjects with pneumonic exacerbations of COPD, and in 7 (14.6%) out of the 48 subjects with non-pneumonic exacerbations of COPD. Two subjects with non-pneumonic S. pneumoniae-related AECOPD were identified, and they both tested positive. A total of 607 urinary antigen tests were performed on stable COPD subjects, and 16 (2.6%) specimens were positive. Colonization by S. pneumoniae was found in the sputum of only 25% of the COPD subjects with positive urinary pneumococcal antigen test results. CONCLUSION: The results of the pneumococcal urinary antigen test were similar for AECOPD subjects with and without pneumonia. This test may be a useful method for preventing the under-diagnosis of S. pneumoniae-related exacerbations of COPD. The detection of pneumococcal antigen in the urine is not related to the persistent colonization of the respiratory mucosa by S. pneumoniae.

Pneumococcal vertebral osteomyelitis and psoas abscess in a patient with systemic lupus erythematosus disclosing positivity of pneumococcal urinary antigen assay.

A 53-year-old woman with systemic lupus erythematosus presented with a 3-day history of fever and coughing. Diagnosis of pneumococcal bronchitis was made based on symptoms and positivity of pneumococcal urinary antigen test. On day 3, severe low back pain acutely occurred. Pneumococcal vertebral osteomyelitis and psoas abscess was diagnosed 17 days later by yield of penicillin-susceptible S. pneumoniae strain in blood cultures and drainage fluid. Although pneumococcal urinary antigen test is a useful tool for the diagnosis of pneumococcal pneumonia, we should consider the possibility of pneumococcal infections other than pneumonia or overwhelming bacteremia in immunosuppressive patients when urinary antigen test is positive.

Incidence and impact of false-positive urine pneumococcal antigen testing in hospitalized patients.

OBJECTIVES: Immunochromatographic urine pneumococcal antigen testing (ICT) has become a common diagnostic tool for those presenting with possible invasive pneumococcal disease. The incidence and clinical impact of ICT false-positivity on hospitalized patients has not been assessed outside of specific patient subpopulations. ICT performance needs to be assessed in a real-world clinical setting. This study aims to describe the incidence and clinical impact of ICT false-positivity in a hospital setting over a 19-month period. METHODS: A retrospective cohort study was performed to assess the incidence of false-positive (FP) ICT among hospitalized patients from November 21, 2007 to June 30, 2009. The primary objective was to describe the incidence of FP ICT results. The secondary objective was to describe what clinical impact, if any, could be attributed to FP ICT results. RESULTS: During the study period, 52 positive ICT results were obtained, of which 5 (9.6%) were deemed falsely positive. Interestingly, two of the 5 FP results were from patients who had received 23-valent pneumococcal vaccine (PPV) in the 2 days prior to ICT. The management of all 5 patients was impacted by the FP results through unnecessary antimicrobial treatment and/or deferral of further clinical evaluation. CONCLUSION: Health care providers should be aware of the potential for ICT FP and should order and interpret these tests within an informed clinical framework.

A prospective study of urinary pneumococcal antigen detection in healthy Karen mothers with high rates of pneumococcal nasopharyngeal carriage.

BACKGROUND: Detection of Streptococcus pneumoniae C-polysaccharide in urine is a useful rapid diagnostic test for pneumococcal infections in adults. In young children, high rates of false positive results have been documented due to detection of concurrent nasopharyngeal pneumococcal carriage. The relationship between pneumococcal carriage and urinary antigen detection in adults from developing countries with high pneumococcal carriage prevalence has not been well established. METHODS: We nested an evaluation of the BinaxNOW S. pneumoniae test within a longitudinal mother-infant pneumococcal carriage study in Karen refugees on the Thailand-Myanmar border. Paired urine and nasopharyngeal swab specimens were collected from 98 asymptomatic women at a routine study follow-up visit. The urine specimens were analyzed with the BinaxNOW test and the nasopharyngeal swabs were semi-quantitatively cultured to identify pneumococcal colonization. RESULTS: 24/98 (25%) women were colonized by S. pneumoniae but only three (3%) had a positive BinaxNOW urine test. The sensitivity of the BinaxNOW test for detection of pneumococcal colonization was 4.2% (95% CI: 0.1-21.1%) with a specificity of 97.3% (95% CI: 90.6-99.7%). Pneumococcal colonization was not associated with having a positive BinaxNOW test (odds ratio 1.6; 95% CI: 0.0-12.7; p=0.7). CONCLUSIONS: Significant numbers of false positive results are unlikely to be encountered when using the BinaxNOW test to diagnose pneumococcal infection in adults from countries with moderate to high rates of pneumococcal colonization.

Development of amperometric magnetogenosensors coupled to asymmetric PCR for the specific detection of Streptococcus pneumoniae.

A disposable magnetogenosensor for the rapid, specific and sensitive detection of Streptococcus pneumoniae is reported. The developed procedure involves the use of streptavidin-modified magnetic beads, a specific biotinylated capture probe that hybridizes with a specific region of lytA, the gene encoding the pneumococcal major autolysin, and appropriate primers for asymmetric polymerase chain reaction (PCR) amplification. Capture probes and amplicons specific for S. pneumoniae were selected by a careful analysis of all lytA alleles available. The selected primers amplify a 235-bp fragment of pneumococcal lytA. A detection limit (LOD) of 5.1 nM was obtained for a 20-mer synthetic target DNA without any amplification protocol, while the LOD for the asymmetric PCR amplicon was 1.1 nM. A RSD value of 6.9% was obtained for measurements carried out with seven different genosensors for 1.1-nM aPCR product. The strict specificity of the designed primers was demonstrated by aPCR amplification of genomic DNA prepared from different bacteria, including some closely related streptococci. Direct asymmetric PCR (daPCR), using cells directly from broth cultures of S. pneumoniae, showed that daPCR products could be prepared with as few as 2 colony-forming units (CFU). Furthermore, this methodology did not show any cross-reaction with closely related streptococci such as Streptococcus mitis (or Streptococcus pseudopneumoniae) even when present in the culture at concentrations up to 10(5) times higher than that of S. pneumoniae. Preliminary data for rapid detection of pneumococcus directly in clinical samples has shown that it is possible to discriminate between non-inoculated blood and urine samples and samples inoculated with only 10(3) CFU mL(-1) S. pneumoniae.

Disposable amperometric magnetoimmunosensors for the specific detection of Streptococcus pneumoniae.

Disposable amperometric magnetoimmunosensors, based on the use of functionalized magnetic beads and gold screen-printed electrodes, have been developed for the selective detection and quantification of Streptococcus pneumoniae. A specific antibody prepared against a serotype 37 S. pneumoniae strain, selected by flow cytometry among seven anticapsular or antisomatic antibodies, was linked to Protein A-modified magnetic beads and incubated with bacteria. The same antibody, conjugated with horseradish peroxidase, was attached to the bacteria and the resulting modified magnetic beads were captured by a magnetic field on the surface of tetrathiafulvalene-modified gold screen-printed electrodes. The amperometric response obtained at -0.15 V vs. the silver pseudoreference electrode of the Au/SPE after the addition of H(2)O(2) was used as transduction signal. Different assay formats were examined and the experimental variables optimized. The limits of detection achieved, without pre-concentration or pre-enrichment steps, were 1.5×10(4) cfu mL(-1) (colony forming unit) and 6.3×10(5) cfu mL(-1) for S. pneumoniae strains Dawn (serotype 37) and R6 (non-encapsulated), respectively. The developed methodology shows a good selectivity against closely related streptococci and its usefulness for the analysis of inoculated urine samples has been demonstrated. The total analysis time of 3.5 h from sampling to measurement, the possibility to prepare up to 30 sensors per day and the use of small amounts of test solution for S. pneumoniae identification, constitute important advantages that make the developed methodology a promising alternative for clinical diagnosis.