0
Original Research: COMMUNITY-ACQUIRED PNEUMONIA |

Severity of Pneumococcal Pneumonia Associated With Genomic Bacterial Load FREE TO VIEW

Jordi Rello, MD, PhD; Thiago Lisboa, MD; Manel Lujan, MD; Miguel Gallego, MD; Cordelia Kee, PhD; Ian Kay, BSc, MBSc; Diego Lopez, MD; Grant W. Waterer, MBBS, PhD, FCCP; for the DNA-Neumococo Study Group
Author and Funding Information

Affiliations: From the Critical Care Department (Drs. Rello and Lisboa), Hospital Universitari Joan XXIII, Tarragona, Spain; University Rovira i Virgili (Drs. Rello and Lisboa), IISPV, Tarragona, Spain; Centro de Investigacíon Biomedica en Red Enfermedades Respiratorias (CIBERes) [Drs. Rello, Lisboa, Lujan, Gallego, and Lopez], Tarragona, Spain; Hospital de Sabadell (Drs. Lujan and Gallego), Sabadell, Spain; School of Medicine and Pharmacology (Drs. Kee and Waterer), University of Western Australia, Perth, WA, Australia; the Department of Microbiology and Infectious Diseases (Mr. Kay), Royal Perth Hospital, Perth, WA, Australia; and Fundación Jimenez Diaz (Dr. Lopez), Madrid, Spain.

Correspondence to: Jordi Rello, MD, PhD, Critical Care Department, Joan XXIII University Hospital, Carrer Dr. Mallafre Guasch 4, 43007 Tarragona, Spain; e-mail: jrello.hj23.ics@gencat.cat

*A complete list of members of the DNA-Neumococo Study Group is located in the Appendix.


Presented in part at the 2008 American Thoracic Society Conference, Toronto, ON, Canada.

This study was funded by FIS 04/1500, Fondo de Investigaciones Sanitarias, CIBER Enfermedades Respiratorias (CIBERes 06/06/0036), and AGAUR (2005/SGR/920). Dr. Waterer is supported by the National Health and Medical Research Council of Australia.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.xhtml).


© 2009 American College of Chest Physicians


Chest. 2009;136(3):832-840. doi:10.1378/chest.09-0258
Text Size: A A A
Published online

Background:  There is a clinical need for more objective methods of identifying patients at risk for septic shock and poorer outcomes among those with community-acquired pneumonia (CAP). As viral load is useful in viral infections, we hypothesized that bacterial load may be associated with outcomes in patients with pneumococcal pneumonia.

Methods:  Quantification of Streptococcus pneumoniae DNA level by real-time polymerase chain reaction (rt-PCR) was prospectively conducted on whole-blood samples from a cohort of 353 patients who were displaying CAP symptoms upon their admission to the ED.

Results:  CAP caused by S pneumoniae was documented in 93 patients (36.5% with positive blood culture findings). A positive S pneumoniae rt-PCR assay finding was associated with a statistically significant higher mortality (odds ratio [OR], 7.08), risk for shock (OR, 6.29), and the need for mechanical ventilation (MV) [OR, 7.96]. Logistic regression, adjusted for age, sex, comorbidities, and pneumonia severity index class, revealed bacterial load as independently associated with septic shock (adjusted odds ratio [aOR], 2.42; 95% CI, 1.10 to 5.80) and the need for MV (aOR, 2.71; 95% CI, 1.17 to 6.27). An S pneumoniae bacterial load of ≥ 103 copies per milliliter occurred in 29.0% of patients (27 of 93 patients; 95% CI, 20.8 to 38.9%) being associated with a statistically significant higher risk for septic shock (OR, 8.00), the need for MV (OR, 10.50), and hospital mortality (OR, 5.43).

Conclusion:  In patients with pneumococcal pneumonia, bacterial load is associated with the likelihood of death, the risk of septic shock, and the need for MV. High genomic bacterial load for S pneumoniae may be a useful tool for severity assessment.

Figures in this Article

Streptococcus pneumoniae is the leading cause of community-acquired pneumonia (CAP) worldwide.1,2 Currently available microbiological tests (eg, sputum and blood cultures) have limited clinical utility due to both low sensitivity and the delay for culture results to be available.36 Although urinary antigen testing for S pneumoniae is quicker, this test has significant limitations including a significant rate of false-positive results.7,8 Non-culture-based diagnostic polymerase chain reaction (PCR) techniques allowed the accurate and rapid quantification of bacterial load (consisting of both viable and nonviable bacteria).9

The major challenges associated with CAP include identifying patients at risk of septic shock and death, and identifying those patients who could benefit more from intensive care or adjuvant therapy. Patients are commonly stratified into risk groups by using scoring systems (eg, pneumonia severity index [PSI])10 or confusion, urea ≥ 7 mmol/L, respiratory rate ≥ 30 breaths/min, BP < 90 mm Hg systolic or < 60 mm Hg diastolic, age ≥ 65 years (or CURB-65)11 scores. While these scoring systems perform reasonably well when studied in large cohorts, they should not be used for clinical decisions at an individual patient level. Currently, no microbiological information is helpful for severity assessment.

ICU admission decisions are still based mainly on the clinical judgment of attending physicians and are exposed to important variability. The American Thoracic Society/Infectious Diseases Society of America guidelines1 suggest the following two major criteria for ICU admission: septic shock and the need of mechanical ventilation (MV). Liapikou et al12 reported that invasive MV was the main determinant for ICU admission, followed by septic shock. In the absence of these two major criteria, ICU admission was not related to survival. Identifying patients at higher risk for septic shock and the need for invasive MV could be a useful surrogate for ICU admission.13

Although diagnosis may benefit from quantitative real-time PCR (rt-PCR) for S pneumoniae in whole-blood samples,14,15 the relationship between pneumococcal bacterial load and clinical outcomes has not been investigated. In this study, we analyzed the quantitative bacterial load of S pneumoniae in a cohort of patients admitted to the hospital with CAP. These data were correlated with clinical data and outcomes of disease to determine the following: (1) the relationship between bacterial load and the development of septic shock, and the need for MV; and (2) whether mortality and secondary outcomes, such as acute kidney injury (AKI) and ARDS, were associated with higher bacterial loads.

Study Design

This was a prospective study of adult patients hospitalized with CAP. Data and blood samples were collected in the ED. Data were entered into an electronic database for analysis. Patients were observed for the development of the predefined end points of septic shock development and the need for MV from the time they were admitted to the ED until they were discharged from the hospital. Secondary outcomes were the development of AKI and ARDS, and in-hospital mortality.

Study Population

Adult patients admitted to the ED with a diagnosis of CAP were included in the study. CAP was defined as the presence of a new pulmonary infiltrate on the chest radiograph at the time of hospitalization, plus either a new or increased cough with or without sputum production, or an abnormal temperature (< 35.6°C or > 37.8°C), or an abnormal serum leukocyte count (ie, leukocytosis, left shift, or leukopenia) as defined by local laboratory standards. Two sets of blood cultures and 4 mL of an ethylenediaminetetraacetic acid-treated blood sample for rt-PCR were obtained in the ED at the time the patients were hospitalized, before starting antibiotic treatment. Patients receiving outpatient antimicrobial therapy prior to admission to the hospital were not included in the study. The study was approved by the Joan XXIII University hospital ethics board, and all patients or next of kin signed an informed consent.

Study Variables

The variables considered in each patient included in the study were as follows: demographics (ie, age and sex); underlying comorbidities (ie, chronic heart disease, neoplasia, liver disease, diabetes mellitus, COPD, HIV infection, alcoholism, corticotherapy, and obesity); results of laboratory cultures (ie, blood culture, respiratory sample culture, and urinary antigen); severity of CAP (ie, risk class according to the PSI, the need for MV, the development of septic shock, AKI, and ARDS); and in-hospital mortality.

Definitions

A diagnosis of CAP due to S pneumoniae was considered to be definite when this microorganism was isolated from an uncontaminated sample (pleural fluid or blood culture) or significant growth in a respiratory fluid sample obtained by endotracheal aspiration (> 105 colony-forming units per milliliter) or BAL (> 104 colony-forming units per milliliter). It was considered to be probable when a positive sputum sample culture, positive urinary antigen test, or positive rt-PCR findings were obtained. Underlying comorbidity was defined as the presence of one of the following chronic conditions: immuncompromise, defined as primary immunodeficiency or immunodeficiency secondary to splenectomy, hematologic malignancy, autoimmune disorder, radiation treatment, use of cytotoxic drugs, or cancer chemotherapy within 4 weeks before the episode; chronic heart disease, which was considered in patients admitted to the hospital with New York Heart Association class III and IV symptoms of heart failure; liver disease, which was considered in patients with documented biopsy-proven cirrhosis, documented portal hypertension, episodes of past upper GI bleeding attributed to portal hypertension, or previous episodes of hepatic encephalopathy; corticosteroid therapy, which was defined as using daily doses of > 20 mg of prednisolone (or equivalent) for > 2 weeks; COPD, which was defined as a disease state characterized by the presence of airflow limitation due to chronic bronchitis or emphysema; obesity, which was considered in patients with a body mass index > 30 kg/m2; septic shock, which was defined as systolic BP < 90 mm Hg despite fluid resuscitation of > 20 mL/kg and the need for vasopressor agents; ARDS, which was diagnosed according to the criteria of the American-European Consensus Conference Committee16; and AKI, which was defined as an urine output of < 20 mL/h or a total urine output of < 80 mL in 4 h. Rapid radiologic spread was defined by an increase in the size of the opacities by > 50% at 48 h after presentation. Blood cultures were processed using a standard system (Versa TREK Instrument System 220/240; TREK Diagnostic Systems; Cleveland, OH). Bacterial identification and susceptibility testing were performed using standard methods.

Quantification of the Pneumococcal Load

Quantification of the S pneumoniae bacterial load was performed in frozen samples at the University of Western Australia laboratory (Perth, WA, Australia), as previously described elsewhere.14,15 The assay targets the autolysin-A (lytA) gene, which has been shown to be specific for S pneumoniae, and provides an accurate reproducibility of 95% in whole blood samples if the bacterial load is more than eight copies per milliliter.15 Because lytA is a single-copy gene, the number of copies measured is equivalent to the bacterial load number.

Statistical Analysis

Statistical analysis was performed using statistical software package (SPSS, version 11.0 for Windows; SPSS, Inc; Chicago, IL). Categorical data were analyzed by using the χ2 test or Fisher exact test and were described as proportions. Continuous variables were compared by using the t test or the Mann-Whitney U test and were described as the mean (SD) or median (interquartile range [IQR]) according to the presence of normal distribution. The number of copies of the lytA gene (and therefore the quantity of S pneumoniae DNA in copies per milliliter) was analyzed after logarithmic transformation. The area under the receiver operating characteristic curve (AUROC) was considered to be an index of discrimination. Logistic regression models were used to identify factors associated with the primary outcomes. Potential risk factors included age, sex, the presence of comorbidities, the severity of pneumonia episode (PSI class), and bacterial load measurements. The results are expressed as odds ratios (ORs) with 95% CIs. Statistical significance was defined as a two-tailed p value < 0.05.

Study Population

A total of 353 white patients with CAP were included in the study, of whom 93 were documented as a having a diagnosis of definite CAP (n = 44) or probable CAP (n = 49) caused by S pneumoniae, and 260 patients had no evidence of S pneumoniae and a negative rt-PCR result. A description of the techniques used to detect S pneumoniae is shown in Table A1 (in the online supplemental material). Clinical characteristics of the 260 patients with negative bacterial load and no evidence of S pneumoniae are described in Table A2 (in the online supplemental material). Further analysis is restricted to 93 patients with documented pneumococcal CAP.

Among the 93 pneumococcal CAP patients, the mean (± SD) age was 63.0 ± 18.6 years. Comorbidities were present in 86.0% of patients, and the most frequent were tobacco use, heart disease, diabetes mellitus, and COPD. The baseline characteristics of these patients are detailed in Table 1. There were no patients presenting with splenectomy, functional asplenia, or hypogammaglobulinemia.

Table Graphic Jump Location
Table 1 Clinical Characteristics of 93 Patients With Pneumococcal Pneumonia According to PCR Results

Data are presented as No. (%) unless otherwise stated. RX = radiologic.

*Values are given as the median (IQR).

Qualitative rt-PCR Analysis

No difference was found in the clinical characteristics or the prevalence of comorbidities between patients with positive and negative bacterial loads (Table 1). Patients with positive rt-PCR results were more likely to have positive blood culture findings (OR, 5.87; 95% CI, 1.90 to 17.91). The documentation of bacterial load was associated with AKI (OR, 4.40; 95% CI, 1.42 to 13.50), septic shock development (OR, 6.29; 95% CI, 1.49 to 26.06), the need for MV (OR, 7.96; 95% CI, 1.24 to 49.66), and higher in-hospital mortality (OR, 7.08; 95% CI, 1.10 to 44.45).

The S pneumoniae rt-PCR assay was compared with blood cultures (Table A3 in the online supplemental material). rt-PCR detected S pneumoniae DNA in 85.3% of patients with positive blood culture findings, whereas blood culture findings were positive in only 50% of the patients with detectable S pneumoniae DNA. All of the five patients with a positive blood culture but no DNA detectable by using rt-PCR survived and did not have nonfatal complications of sepsis (ie, septic shock or the need for MV). In all patients with a positive S pneumoniae rt-PCR assay result but no other test positive for S pneumoniae, no other pathogen was detected on sputum or blood cultures.

Bacterial Genomic Load and Clinical Outcomes

In patients with documented bacterial load, the number of copies of S pneumoniae DNA per milliliter in whole blood samples (or S pneumoniae bacterial load) was significantly associated with worse clinical outcomes. S pneumoniae bacterial load ranged from 10 to 1,474,000 copies per milliliter (median, 1,075 copies per milliliter; IQR, 25 to 75% or 410 to 10,715 copies per milliliter). The distribution of patients according to the logarithm of the number of copies of S pneumoniae DNA is shown in Table 2. Median S pneumoniae bacterial load values were significantly higher in patients in whom septic shock developed (13,520 copies per milliliter [IQR, 25 to 75%/1,093 to 30,500 copies per milliliter] vs 690 copies per milliliter [IQR, 25 to 75%/366 to 6,550 copies/mL], respectively; p < 0.05).

Table Graphic Jump Location
Table 2 Distribution of S pneumoniae Bacterial Loads in Patients With S pneumoniae CAP as Detected by rt-PCR
Effect of Bacterial Load on Septic Shock and the Need for MV

Figure 1 shows the predicted probability of septic shock, and Figure 2 shows the predicted probability of the need for MV as a function of S pneumoniae bacterial load. Each log increase in the bacterial load was associated with an increase of 2.5 times in the probability of septic shock and a two times higher risk for needing MV.

Figure Jump LinkFigure 1 Predicted probability of septic shock as a function of S pneumoniae bacterial load detected by quantitative rt-PCR.Grahic Jump Location
Figure Jump LinkFigure 2 Predicted probability of the need for MV as a function of S pneumoniae bacterial load detected by quantitative rt-PCR.Grahic Jump Location

A logistic regression model adjusted for age, sex, the presence of comorbidities, and severity index (PSI class I to III or IV to V) identified that the S pneumoniae bacterial load was independently associated with septic shock (adjusted OR, 2.42; 95% CI, 1.10 to 5.80; [Hosmer-Lemeshow goodness of fit p value = 0.43]) and the need for MV (adjusted OR, 2.71; 95% CI, 1.17 to 6.27; [Hosmer-Lemeshow goodness of fit p value = 0.25]).

Discrimination Assessment: AUROC Analysis

The discriminative ability of bacterial load to assess clinical outcomes in patients with pneumococcal pneumonia was evaluated with AUROC analysis. rt-PCR performance was acceptable for septic shock (AUROC, 0.79; 95% CI, 0.67 to 0.92; p < 0.05) and the need for MV (AUROC, 0.77; 95% CI, 0.64 to 0.91; p < 0.05).

Effect of Bacterial Load on Clinical Outcomes

High S pneumoniae bacterial load, using a “breakpoint” of ≥ 103 copies per milliliter, was associated with a specificity of around 80% for septic shock development and the need for MV. Sensitivities and specificities for septic shock and the need for MV for different breakpoints of S pneumoniae bacterial load are also detailed in Table A4 (in the online supplemental material). When comparing patients with a high S pneumoniae bacterial load (≥ 103 copies per milliliter) and low S pneumoniae bacterial load (< 103 copies per milliliter or undetectable) [Table A5 in the online supplemental material, Table 3 in the article], a significant difference was found in relevant clinical outcomes such as bacteremia (OR, 6.25; 95% CI, 2.38 to 16.40), rapid radiologic spread (OR, 22.75; 95% CI, 3.36 to 148.37), AKI (OR, 7.00; 95% CI, 2.57 to 19.07), ARDS (OR, 14.77; 95% CI, 2.12 to 99.49), the need for MV (OR, 10.50; 95% CI, 2.74 to 39.63), and septic shock (OR, 8.00; 95% CI, 2.65 to 24.12) [Fig 3]. The documentation of a bacterial load > 1,000 copies per milliliter was associated with a higher risk for hospital mortality (OR, 5.43; 95% CI, 1.52 to 19.24) [Fig 4].

Table Graphic Jump Location
Table 3 Characteristics of Patients With Pneumococcal Pneumonia According to Quantitative S pneumoniae rt-PCR Results

Data are presented as No. (%), unless otherwise stated. See Table 1 for abbreviation not used in the text.

Figure Jump LinkFigure 3 Septic shock development according to quantitative rt-PCR results in patients with pneumococcal pneumonia.Grahic Jump Location
Figure Jump LinkFigure 4 Mortality according to quantitative rt-PCR results in patients with pneumococcal pneumonia.Grahic Jump Location

This study confirms the association between a high quantitative bacterial genomic load of S pneumoniae in blood samples and increased mortality. It also reveals an association between bacterial load and the development of septic shock or the need for MV. The implication of these findings is that a sample obtained for bacterial load measurement will provide valuable prognostic information. Our observations also reveal some insight into the mechanisms that underlie the risk factors associated with death and shock in patients with pneumococcal pneumonia.

Our data demonstrate that patients with CAP with ≥ 103 copies per milliliter S pneumoniae DNA in their blood at the time of ED presentation are an easily and specifically defined high-risk group for septic shock, the need for MV,12,13 and death. Moreover, the detection of bacterial load is nearly twice as sensitive as blood cultures for the detection of pneumococcal bacteremia. This new assay has the potential to greatly increase our ability to accurately stratify the severity of pneumonia in patients in the ED, and may be of interest for the stratification of patients enrolling in clinical trials for adjuvant therapies, as well as increasing our understanding of the biology of sepsis.

This study documents that a S pneumoniae quantitative rt-PCR assay of whole blood exceeds the sensitivity of blood cultures.17 With improved DNA extraction techniques and other assay refinements, the assay used in this study compared very favorably with blood cultures. In addition, the quantitative rt-PCR assay can deliver a result within a few hours (4 to 6 h), unlike blood cultures, with the potential to have an impact on the critical phase of early clinical care.

While the rt-PCR assay did not detect S pneumoniae DNA in five patients with positive blood culture findings, all of these patients had a very benign clinical course. It is quite possible that these patients had very low levels of bacteremia, beyond the current sensitivity of the rt-PCR assay but detectable after several days of growth in cultures. Further refinements in DNA extraction and in the rt-PCR assay may further improve the sensitivity of this test. A further advantage of the lytA assay is that, unlike urinary antigen tests, positive results have not been seen in healthy control subjects.7,8,18

The strong correlation we observed between clinical outcomes and S pneumoniae bacterial load might modify the current paradigm of management for patients with pneumococcal CAP. Invasive pneumococcal disease is associated with a high mortality despite antimicrobial therapy,19 and our findings are consistent with those of a smaller study20 in children with invasive pneumococcal disease. Currently, hospital admission and site-of-care decisions are largely based on scoring systems that assign weights to different predictive variables such as age, sex, comorbid diseases, and features of physiologic compromise. While these predictive scoring systems perform relatively well in large cohorts, at an individual patient level they are only crude predictors of outcome. Adding bacterial load to the predictive algorithms may allow a much more accurate determination of clinical outcome in individual patients.

ICU admission criteria are quite variable in different institutions and depend largely on the availability of resources. There is no “gold standard” with which to decide the need for ICU admission. Despite the use of severity scores, ICU admission decisions are still based mainly on the clinical judgment of attending physicians. In 2007, Valencia et al21 reported that most patients with CAP who were in PSI class V were treated on a hospital ward. In that study,21 69% of the patients admitted to the ICU required intubation and MV, and/or presented with shock. Bacterial load identified patients who were at higher risk for septic shock and the need for MV, the major criteria for ICU admission of the American Thoracic Society/Infectious Diseases Society of America guidelines,1 as separate outcomes. Bacterial load could be useful as a stratification tool for identifying patients at higher risk for ICU admission.

Aside from the significant implications for therapy in patients with pneumococcal CAP, our findings open up new insights into the biology of sepsis. The prevailing sepsis paradigm suggests that the primary driver is an excessive host inflammatory response to bacterial pathogens.22 Our data demonstrate that, at least in patients with pneumococcal pneumonia, a major determining factor for shock and organ failures was bacterial load in the bloodstream. The correlation of bacterial load, with age, proinflammatory genotypes, and specific serotypes should be evaluated in further studies.

Our study has some limitations. While the number of patients is relatively large for pneumonia cohort studies, the total number of important outcomes (eg, shock) is not large. Wide CIs are due to the small sample size. Another limitation is that this assay is valid only for pneumococcal pneumonia. In addition, this assay cannot be used to exclude S pneumoniae, because negative results may occur with pneumococcal disease with a low degree of systemic invasion. However, S pneumoniae is the major pathogen in CAP,1,2 and prior reports23 have suggested that a large proportion of patients with CAP with negative culture findings actually have S pneumoniae. Another potential limitation is the absence of information regarding the time elapsed from the onset of infection to diagnosis. Although samples were transported to a central laboratory, it is unlikely that the transport caused significant DNA degradation. Previous studies have reported a relatively long persistence of DNA in ethylenediaminetetraacetic acid-treated whole-blood samples. Moreover, studies with meningococcal disease24,25 have documented that bacterial load measurements are unaffected by the delay in sample submission or by the administration of antibiotics before hospital admission. The implication of these findings is that a sample obtained for bacterial load measurement will provide valuable prognostic information.

In conclusion, the intensity of bacteremia in patients with pneumococcal pneumonia is associated with poor outcome. In addition, this assay has a greater sensitivity than the current methods used to identify S pneumoniae in patients with CAP who have been admitted to the ED. In patients with pneumococcal pneumonia, high bacterial load has the potential to be an early and objective marker of prognosis to identify candidates for ICU admission or adjuvant therapy in randomized clinical trials.

AKI

acute kidney injury

AUROC

area under the receiver operating characteristic curve

CAP

community-acquired pneumonia

IQR

interquartile range

lyt A

autolysin-A

MV

mechanical ventilation

OR

odds ratio

PCR

polymerase chain reaction

PSI

pneumonia severity index

rt-PCR

real-time PCR

Author contributions: Drs. Rello and Lisboa were responsible for analysis of data and writing the first draft of the article; all remaining authors contributed scientifically to the final version of the article. Drs. Rello, Gallego, Lujan, Lopez, and Lisboa enrolled patients, recorded variables, conducted the follow-up, and collected samples. Drs. Waterer and Kee, and Mr. Kay were responsible for performing the quantitative reverse transcription PCR assay.

Financial/nonfinancial disclosures: The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Appendix
The DNA-Neumococo Study Group

Jordi Rello, Thiago Lisboa, Frederic Gomez, Guillermo Cañardo, Monica Magret, and Alejandro Rodriguez (Microbiology, Critical Care and Emergency Departments, Hospital Universitari Joan XXIII, Tarragona, Spain); Miguel Gallego, Manel Luján, Dionisia Fontanals, and Dolors Mariscal (Pneumology and Microbiology Departments, Corporacio Parc Tauli, Sabadell, Spain); Grant Waterer and Cordelia Kee (School of Medicine and Pharmacology, University of Western Australia, Perth, Australia); Todd M. Pryce, Silvano Palladino, Ian Kay, and Ronan Murray (Department of Microbiology and Infectious Diseases, Royal Perth Hospital, Perth, Australia); Diego Lopez (Critical Care Department, Fundación Jimenez Diaz, Madrid, Spain); Diego Guerrero (Emergency Department, Hospital Dr Negrin, Las Palmas de Gran Canarias, Spain); Jose Valles and Rosario Menendez (Respiratory Department Hospital La Fe, Valencia, Spain).

Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44suppl:S27-S72. [PubMed] [CrossRef]
 
Garau J, Calbo E. Community-acquired pneumonia. Lancet. 2008;371:455-458. [PubMed]
 
Campbell SG, Marrie TJ, Anstey R, et al. Utility of blood cultures in the management of adults with community acquired pneumonia discharged from the emergency department. Emerg Med J. 2003;20:521-523. [PubMed]
 
Waterer GW, Jennings SG, Wunderink RG. The impact of blood cultures on antibiotic therapy in pneumococcal pneumonia. Chest. 1999;116:1278-1281. [PubMed]
 
Chalasani NP, Valdecanas MA, Gopal AK, et al. Clinical utility of blood cultures in adult patients with community-acquired pneumonia without defined underlying risks. Chest. 1995;108:932-936. [PubMed]
 
Theerthakarai R, El-Halees W, Ismail M, et al. Nonvalue of the initial microbiological studies in the management of nonsevere community-acquired pneumonia. Chest. 2001;119:181-184. [PubMed]
 
Gutierrez F, Masia M, Rodriguez JC, et al. Evaluation of the immunochromatographic Binax NOW assay for detection ofStreptococcus pneumoniaeurinary antigen in a prospective study of community-acquired pneumonia in Spain. Clin Infect Dis. 2003;36:286-292. [PubMed]
 
Lasocki S, Scanvic A, Le Turdu F, et al. Evaluation of the Binax NOWStreptococcus pneumoniaeurinary antigen assay in intensive care patients hospitalized for pneumonia. Intensive Care Med. 2006;32:1766-1772. [PubMed]
 
Murdoch DR. Nucleic acid amplification tests for the diagnosis of pneumonia. Clin Infect Dis. 2003;36:1162-1170. [PubMed]
 
Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243-250. [PubMed]
 
Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58:377-382. [PubMed]
 
Liapikou A, Ferrer M, Polverino E, et al. Severe community-acquired pneumonia: validation of the Infectious Diseases Society America/American Thoracic Society guidelines to predict an intensive care unit admission. Clin Infect Dis. 2009;48:377-385. [PubMed]
 
Charles PG, Wolfe R, Whitby M, et al. SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia. Clin Infect Dis. 2008;47:375-384. [PubMed]
 
van Haeften R, Palladino S, Kay I, et al. A quantitative LightCycler PCR to detectStreptococcus pneumoniaein blood and CSF. Diagn Microbiol Infect Dis. 2003;47:407-414. [PubMed]
 
Kee C, Palladino S, Kay I, et al. Feasibility of real-time polymerase chain reaction in whole blood to identifyStreptococcus pneumoniaein patients with community-acquired pneumonia. Diagn Microbiol Infect Dis. 2008;61:72-75. [PubMed]
 
Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818-824. [PubMed]
 
Murdoch DR. Impact of rapid microbiological testing on the management of lower respiratory tract infection. Clin Infect Dis. 2005;41:1445-1447. [PubMed]
 
Ishida T, Hashimoto T, Arita M, et al. A 3-year prospective study of a urinary antigen-detection test forStreptococcus pneumoniaein community-acquired pneumonia: utility and clinical impact on the reported etiology. J Infect Chemother. 2004;10:359-363. [PubMed]
 
Parsons HK, Metcalf SC, Tomlin K, et al. Invasive pneumococcal disease and the potential for prevention by vaccination in the United Kingdom. J Infect. 2007;54:435-438. [PubMed]
 
Carrol ED, Guiver M, Nkhoma S, et al. High pneumococcal DNA loads are associated with mortality in Malawian children with invasive pneumococcal disease. Pediatr Infect Dis J. 2007;26:416-422. [PubMed]
 
Valencia M, Badia JR, Cavalcanti M, et al. Pneumonia severity index class V patients with community-acquired pneumonia: characteristics, outcomes and value of severity scores. Chest. 2007;132:515-522. [PubMed]
 
Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420:885-891. [PubMed]
 
Ruiz-Gonzalez A, Falquera M, Nogués A, et al. IsStreptococcus pneumoniaethe leading cause of pneumonia of unknown etiology? A microbiologic study of lung aspirates in consecutive patients with community acquired pneumonia. Am J Med. 1999;106:385-390. [PubMed]
 
Darton T, Guiver M, Naylor S, et al. Severity of meningococal disease associated with genomic bacterial load. Clin Infect Dis. 2009;48:587-594. [PubMed]
 
Corless CE, Guiver M, Borrow R, et al. Simultaneous detection ofNeisseria meningitidis,Haemophilus influenzae, andStreptococcus pneumoniaein suspected cases of meningitis and septicemia using real-time PCR. J Clin Microbiol. 2001;39:1553-1558. [PubMed]
 

Figures

Figure Jump LinkFigure 1 Predicted probability of septic shock as a function of S pneumoniae bacterial load detected by quantitative rt-PCR.Grahic Jump Location
Figure Jump LinkFigure 2 Predicted probability of the need for MV as a function of S pneumoniae bacterial load detected by quantitative rt-PCR.Grahic Jump Location
Figure Jump LinkFigure 3 Septic shock development according to quantitative rt-PCR results in patients with pneumococcal pneumonia.Grahic Jump Location
Figure Jump LinkFigure 4 Mortality according to quantitative rt-PCR results in patients with pneumococcal pneumonia.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 Clinical Characteristics of 93 Patients With Pneumococcal Pneumonia According to PCR Results

Data are presented as No. (%) unless otherwise stated. RX = radiologic.

*Values are given as the median (IQR).

Table Graphic Jump Location
Table 2 Distribution of S pneumoniae Bacterial Loads in Patients With S pneumoniae CAP as Detected by rt-PCR
Table Graphic Jump Location
Table 3 Characteristics of Patients With Pneumococcal Pneumonia According to Quantitative S pneumoniae rt-PCR Results

Data are presented as No. (%), unless otherwise stated. See Table 1 for abbreviation not used in the text.

References

Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007;44suppl:S27-S72. [PubMed] [CrossRef]
 
Garau J, Calbo E. Community-acquired pneumonia. Lancet. 2008;371:455-458. [PubMed]
 
Campbell SG, Marrie TJ, Anstey R, et al. Utility of blood cultures in the management of adults with community acquired pneumonia discharged from the emergency department. Emerg Med J. 2003;20:521-523. [PubMed]
 
Waterer GW, Jennings SG, Wunderink RG. The impact of blood cultures on antibiotic therapy in pneumococcal pneumonia. Chest. 1999;116:1278-1281. [PubMed]
 
Chalasani NP, Valdecanas MA, Gopal AK, et al. Clinical utility of blood cultures in adult patients with community-acquired pneumonia without defined underlying risks. Chest. 1995;108:932-936. [PubMed]
 
Theerthakarai R, El-Halees W, Ismail M, et al. Nonvalue of the initial microbiological studies in the management of nonsevere community-acquired pneumonia. Chest. 2001;119:181-184. [PubMed]
 
Gutierrez F, Masia M, Rodriguez JC, et al. Evaluation of the immunochromatographic Binax NOW assay for detection ofStreptococcus pneumoniaeurinary antigen in a prospective study of community-acquired pneumonia in Spain. Clin Infect Dis. 2003;36:286-292. [PubMed]
 
Lasocki S, Scanvic A, Le Turdu F, et al. Evaluation of the Binax NOWStreptococcus pneumoniaeurinary antigen assay in intensive care patients hospitalized for pneumonia. Intensive Care Med. 2006;32:1766-1772. [PubMed]
 
Murdoch DR. Nucleic acid amplification tests for the diagnosis of pneumonia. Clin Infect Dis. 2003;36:1162-1170. [PubMed]
 
Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med. 1997;336:243-250. [PubMed]
 
Lim WS, van der Eerden MM, Laing R, et al. Defining community acquired pneumonia severity on presentation to hospital: an international derivation and validation study. Thorax. 2003;58:377-382. [PubMed]
 
Liapikou A, Ferrer M, Polverino E, et al. Severe community-acquired pneumonia: validation of the Infectious Diseases Society America/American Thoracic Society guidelines to predict an intensive care unit admission. Clin Infect Dis. 2009;48:377-385. [PubMed]
 
Charles PG, Wolfe R, Whitby M, et al. SMART-COP: a tool for predicting the need for intensive respiratory or vasopressor support in community-acquired pneumonia. Clin Infect Dis. 2008;47:375-384. [PubMed]
 
van Haeften R, Palladino S, Kay I, et al. A quantitative LightCycler PCR to detectStreptococcus pneumoniaein blood and CSF. Diagn Microbiol Infect Dis. 2003;47:407-414. [PubMed]
 
Kee C, Palladino S, Kay I, et al. Feasibility of real-time polymerase chain reaction in whole blood to identifyStreptococcus pneumoniaein patients with community-acquired pneumonia. Diagn Microbiol Infect Dis. 2008;61:72-75. [PubMed]
 
Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS: definitions, mechanisms, relevant outcomes, and clinical trial coordination. Am J Respir Crit Care Med. 1994;149:818-824. [PubMed]
 
Murdoch DR. Impact of rapid microbiological testing on the management of lower respiratory tract infection. Clin Infect Dis. 2005;41:1445-1447. [PubMed]
 
Ishida T, Hashimoto T, Arita M, et al. A 3-year prospective study of a urinary antigen-detection test forStreptococcus pneumoniaein community-acquired pneumonia: utility and clinical impact on the reported etiology. J Infect Chemother. 2004;10:359-363. [PubMed]
 
Parsons HK, Metcalf SC, Tomlin K, et al. Invasive pneumococcal disease and the potential for prevention by vaccination in the United Kingdom. J Infect. 2007;54:435-438. [PubMed]
 
Carrol ED, Guiver M, Nkhoma S, et al. High pneumococcal DNA loads are associated with mortality in Malawian children with invasive pneumococcal disease. Pediatr Infect Dis J. 2007;26:416-422. [PubMed]
 
Valencia M, Badia JR, Cavalcanti M, et al. Pneumonia severity index class V patients with community-acquired pneumonia: characteristics, outcomes and value of severity scores. Chest. 2007;132:515-522. [PubMed]
 
Cohen J. The immunopathogenesis of sepsis. Nature. 2002;420:885-891. [PubMed]
 
Ruiz-Gonzalez A, Falquera M, Nogués A, et al. IsStreptococcus pneumoniaethe leading cause of pneumonia of unknown etiology? A microbiologic study of lung aspirates in consecutive patients with community acquired pneumonia. Am J Med. 1999;106:385-390. [PubMed]
 
Darton T, Guiver M, Naylor S, et al. Severity of meningococal disease associated with genomic bacterial load. Clin Infect Dis. 2009;48:587-594. [PubMed]
 
Corless CE, Guiver M, Borrow R, et al. Simultaneous detection ofNeisseria meningitidis,Haemophilus influenzae, andStreptococcus pneumoniaein suspected cases of meningitis and septicemia using real-time PCR. J Clin Microbiol. 2001;39:1553-1558. [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Supporting Data
Data Supplement

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543