Scholarly article on topic 'Enhancing the etiologic diagnosis of community-acquired pneumonia in adults using the urinary antigen assay (Binax NOW)'

Enhancing the etiologic diagnosis of community-acquired pneumonia in adults using the urinary antigen assay (Binax NOW) Academic research paper on "Biological sciences"

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{"Community-acquired pneumonia" / Etiology / Diagnosis / " Streptococcus pneumoniae " / "Urinary antigen test"}

Abstract of research paper on Biological sciences, author of scientific article — Daniel Genné, Hans H. Siegrist, Reto Lienhard

Summary Objectives Approximately 40% of community-acquired pneumonia (CAP) remains of unknown etiology. To improve the rate of detection of the causative microbiologic agent, the Binax NOW Streptococcus pneumoniae urinary antigen test (UAT) was evaluated. Design In this prospective study, 67 adults with CAP were compared with 81 healthy patients to determine sensitivity and specificity of the UAT and its role in improving the etiologic diagnosis of CAP. Results An etiology could be found for 22 patients (33%) using conventional methods (14 S. pneumoniae, sensitivity 64.3%, 1/81 positive UAT control urine samples, specificity 98.8%). This proportion increased to 33 patients (49%) with the addition of the urinary antigen test (p =0.039). Pneumococcal infection was diagnosed by the UAT in 24% of our patients without an etiologic identification by conventional methods. Conclusions Given its excellent specificity, this test can be considered an important tool for detecting S. pneumoniae in CAP of unknown etiology, enabling the diagnosis of pneumococcal pneumonia in a quarter of cases.

Academic research paper on topic "Enhancing the etiologic diagnosis of community-acquired pneumonia in adults using the urinary antigen assay (Binax NOW)"

International Journal of Infectious Diseases (2006) 10, 124—128

http://intl.elsevierhealth.com/journals/ijid

Enhancing the etiologic diagnosis of community-acquired pneumonia in adults using the urinary antigen assay (Binax NOW)

Daniel Gennea *, Hans H. Siegristb, Reto Lienhardb

a Service de Médecine Interne de l'Hôpital de la Ville,

rue du Chasseral 20, 2300 La Chaux-de-Fonds, Switzerland

b Institut Neuchatelois de Microbiologie, La Chaux-de-Fonds, Switzerland

Received 13 July 2004; received in revised form 16 December 2004; accepted 7 March 2005 Corresponding Editor: Jonathan Cohen, Brighton, UK

KEYWORDS Summary

Community-acquired

pneumonia; Objectives: Approximately 40% of community-acquired pneumonia (CAP) remains of

Etiology; unknown etiology. To improve the rate of detection of the causative microbiologic

Diagnosis; agent, the Binax NOW Streptococcus pneumoniae urinary antigen test (UAT) was

Streptococcus evaluated.

pneumoniae; Design: In this prospective study, 67 adults with CAP were compared with 81 healthy

Urinary antigen test patients to determine sensitivity and specificity of the UAT and its role in improving

the etiologic diagnosis of CAP.

Results: An etiology could be found for 22 patients (33%) using conventional methods (14 S. pneumoniae, sensitivity 64.3%, 1/81 positive UAT control urine samples, specificity 98.8%). This proportion increased to 33 patients (49%) with the addition of the urinary antigen test (p = 0.039). Pneumococcal infection was diagnosed by the UAT in 24% of our patients without an etiologic identification by conventional methods.

Conclusions: Given its excellent specificity, this test can be considered an important tool for detecting S. pneumoniae in CAP of unknown etiology, enabling the diagnosis of pneumococcal pneumonia in a quarter of cases.

# 2005 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Introduction

* Corresponding author. Tel.: +41 32 9672111; fax: +41 32 9672729.

E-mail address: daniel.genne@ne.ch (D. Genné).

Diagnosis of community-acquired pneumonia (CAP) relies on clinical criteria and on microbiological results consisting of blood culture and culture of

1201-9712/$32.00 © 2005 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2005.03.006

an appropriate sputum sample, including Gram stain.1 Many cases of CAP are of unknown etiology; the sensitivity of blood culture is around 10-15%, and that of sputum culture varies between 10 and 30%. Even when invasive sampling techniques such as broncho-alveolar lavage or transthoracic aspiration are used, 40% of CAP remain of unknown etiology.2 Community-acquired pneumonia presents a challenge to the physician and its treatment is often empirical. The need for a new rapid and specific test for the detection of Streptococcus pneumoniae is growing as pneumococcal pneumonia is considered to be the main etiology due to cultivable bacteria. In an era of increasing prevalence of antimicrobial resistance, quick and unequivocal identification of the etiology of pneumonia would considerably improve patient management. The evaluation of a new rapid urinary antigen test for the detection of S. pneumoniae in adults suffering from CAP has been carried out in previous studies.3-5 This rapid immu-nochromatographic test detects the pneumococcal C-polysaccharide antigen specific for the pneumo-coccal cell wall and could facilitate the diagnosis of S. pneumoniae pneumonia. We evaluated this new test to determine its sensitivity, specificity and contribution to the microbiologic diagnosis of CAP of unknown cause in adults.

Materials and methods

This was a prospective controlled study undertaken at the La Chaux-de-Fonds Hospital, Switzerland.

Pneumonia group

The study was performed during one winter period from October 1999 to May 2000. All patients aged over 18 years presenting at hospital admission with CAP were prospectively included in the study. Community-acquired pneumonia was defined by a new infiltrate on chest X-ray associated with a leukocytosis (>10 x 109/l) or leukopenia (<4 x 109/l), and with one of the following: fever, dyspnea, cough, chest pain or new sputum production.

Microbiological analysis for these patients included blood cultures and culture of a sputum sample. The presence of pathogens in blood or sputum was assessed by conventional procedures. Sputum Gram staining was performed on a purulent portion of each sample. Samples were considered to be of good quality when >25 polymorphonuclear cells and <10 squamous cells were observed under low-power (i.e., 100x) magnification. Only good quality sputum samples were accepted.

An etiologic diagnosis of CAP was established in accordance with the following conventional criteria: recovery of a respiratory pathogen from culture of a specimen with normally sterile culture results, and high yield of a respiratory pathogen in a culture of a good-quality sputum sample with a predominant morphotype on Gram stain. Uncon-centrated urine samples were tested using the immunochromatographic assay Binax NOW S. pneumoniae antigen (Portland, Maine, USA). This test detects the C-polysaccharide antigen from the cell wall of S. pneumoniae that is believed to be specific for all pneumococcal serotypes.6 The test was performed in accordance with the manufacturer's instructions. A swab was dipped into the urine sample and then inserted into the test device. A buffer solution was added, and the device was closed, bringing the sample into contact with the test strip. The test was read at 15min and was interpreted by noting the presence or absence of visually detectable pink lines. A positive test result was indicated by the detection of both sample and control lines, and a negative result was indicated by the detection of a control line only.

A urine sample was collected at admission but could be accepted within the first 6 days following admission. Patients were excluded if they received an antibiotic more than one day prior to hospitalization.

Control group

The control group consisted of random patients who had urine sent for bacteriological culture for suspected urinary tract infection. These urine samples were collected during a period of low prevalence of community-acquired pneumonia (August and September 2000). If the urinary antigen test was positive, the patient was medically evaluated to exclude any history of pneumococcal infection or S. pneumoniae vaccination within 14 days prior to testing.

We also evaluated the place of the urinary antigen test by calculating the likelihood ratio (LR).7The LR determines the performance of a test in a standardized fashion. It expresses the ratio of the probability that a given diagnostic test result would be observed for a patient with the target disease versus the probability for a patient without the disease. A positive LR is calculated as follows: sensitivity/(1 -specificity). A negative LR corresponds to: (1 - sen-sitivity)/specificity. Tests with a positive LRof >10 or a negative LRof <0.1 are considered excellent.8 We chose this approach to clearly and simply assess the validity of this test by use of evidence-based clinical microbiology principles and, in addition, to detect more pneumococcal causes in community-acquired pneumonia of unknown origin.

Table 1 Microbiological tests and etiology of community-acquired pneumonia in 67 adult patients.

Sputum

Blood culture

Urinary test

Streptococcus pneumoniae Haemophilus influenzae Escherichia coli Pasteurella multocida Moraxella catarrhalis Unknown

14 3 3 1 1

67 (100%)

4a 3 3 1 1 0

12 (18%)

0 0 0 0 0

11 (16%)

9 0 0 0 0 11

20 (30%)

One patient had blood and sputum positive cultures.

Results

A total of 67 patients were enrolled in the pneumonia group; their mean age was 68 years (range: 34 to 91 years) and 29 (43%) were women. Forty-eight (72%) had fever on admission and all of the patients had a new infiltrate, mostly in the right lower lobe. Leukocytosis was present in 63 (94%) patients. The mean Pneumonia Severity Index9 was 106 (range: 30-231).

The control group consisted of 81 urine samples, of which 25 were positive on culture (13 Escherichia coli, six Staphylococcus spp., five other enterobac-teriaceae and one Enterococcus faecalis); the mean age of these patients was 64 years (range: 24 to 100 years) and 38 (47%) were women. Both groups were comparable for age (p = 0.3, Mann-Whitney test) and sex ratio (p = 0.74, Fisher's exact test).

Twenty-two bacteria were identified from sputum and/or blood cultures in 22 patients (33%) out of 67 from the pneumonia group (Table 1). No serolo-gical test was performed. This explains the smaller number of determined causes of pneumonia. Fourteen pneumonia cases were attributed to S. pneumoniae according to sputum (four cases) and/or blood culture results (11 cases). Of the 14 cases, the urinary antigen test was positive in nine, giving a sensitivity of 64.3% (Table 2). Of the 81 control urine samples only one had a positive urinary antigen test resulting in a high specificity of 98.8% (Table 2). The positive LR was 53.6 and the negative LR 0.36.

The urinary antigen test was negative in all pneumonia patients with a non-pneumococcal etiology (eight cases), which confirms its high specificity,

and positive in 11 (24%) of the CAP patients with negative blood or sputum cultures (45 cases). An etiology was found for 22 patients (33%) without the urinary antigen test and this proportion was increased to 33 patients (49%) with the addition of the urinary antigen test ( p = 0.039 Fisher's one-sided exact test) (Figure 1).

Discussion

Streptococcus pneumoniae is the most common cause of CAP but is undoubtedly under-diagnosed.2 Isolation of S. pneumoniae from blood is specific but lacks sensitivity, while isolation of S. pneumoniae from sputum may represent colonization. The urinary antigen test is a major new tool for determining the etiology of CAP in adults.

Contrary to the first published papers, the sensitivity of the urinary antigen test in our study (64%) is much lower than that found by Dominguez et al.3 and Burel et al.4 (between 78% and 86%) maybe because the urine samples in our study could be collected within the first 6 days compared to collections on the first day only in the other papers.3,4 Indeed, in patients with an initial positive urinary antigen test, Murdoch and coworkers showed that the test remained positive after 6 weeks in nearly 50% of them.10 Only Rosón et al. found the same limited sensitivity (66%) in their study as we did, but the time period between admission and urine collection is not stated in their paper.11 The specificity was confirmed to be very high (>98%), comparable to previous reports (>95%).3—5,12 This means that a

Table 2 Sensitivity and specificity of the S. pneumoniae urinary antigen test.

Positive test Negative test Total

Pneumococcal pneumonia 9 5 14 Sensitivity: 64.3%

Control without pneumonia 1 80 81 Specificity: 98.8%

Total 10 85 95

Positive predictive Negative predictive

value: 90% value: 94.1%

ra 40-

TO iso-

JD O 20-

P= 0.039

Conventional methods + Urinary antigen test

Figure 1 Improved rate of detection of causative agent in CAP of unknown etiology.

negative test could not rule out pneumococcal pneumonia. On the other hand, a positive test renders pneumococcal etiology for pneumonia highly probable. This information is very useful for those who work in areas where penicillin-resistant S. pneumoniae is common because in cases with a positive urinary antigen test it helps in the choice of empiric antibiotic therapy.

Ruiz-Gonzalez et al. showed that using transthoracic needle aspiration analysed by culture, capsular antigen detection and PCR, to document most efficiently the etiology of pneumonia cases, the number of S. pneumoniae identified increased from 8.2% to 30%.2 Our study leads to similar results without the need for an invasive sample using a simple and quick method. Fourteen cases of S. pneumoniae were identified by conventional methods and 11 additional cases solely by the urinary antigen test, which represents an increase of 16% (21% to 37%) to reach a final number of 25 cases of S. pneumoniae infection. Compared with sputum and blood culture, the urinary antigen test was the most efficient test giving an etiology for almost one third of the community-acquired pneumonia cases (30%) (Table 1).

With a rate of 11 positive blood cultures for S. pneumoniae out of 20 CAP cases caused by S. pneumoniae (positive urinary antigen tests) (52%), our results are much higher than those commonly found in the literature (between 15% and 30%). Two reasons may explain this difference: firstly, the published rates have been measured for all patients with a community-acquired pneumonia. If one considers only those with a pneumo-coccal pneumonia as a denominator, these rates are probably much higher, as those found in our study (52%). If we consider positive pneumococcal bacteremia for all patients included in our study, the rate (11/67, 16%) remains in the expected range. Secondly, a previous study performed in the same region, showed that fewer than 10% of patients suffering from CAP were hospitalized.13 As the

study population considered only hospitalized patients, we included the most severe cases (mean Pneumonia Severity Index 106), which could explain why we found more bacteremia.

Previous studies failed to find a causative agent in about one-half of patients with CAP, and it has been suggested that other causative agents remain to be discovered.14-16 An alternative hypothesis is that most of these patients have undetected pneumo-coccal pneumonia.1,17 Our results are in accordance with the latter explanation, because 24% of our patients without an etiologic identification by conventional methods had pneumococcal infection detected by the urinary antigen test. These results are in accordance with a recent published series where about 25% of pneumonia with no pathogen identified had a positive urinary antigen test.18 Roson et al. also showed that this urinary antigen testing permitted early diagnosis of pneumococcal pneumonia in 26% more patients than Gram stain-ing.11

Unfortunately, this test cannot be used forenhan-cing the detection rate of etiologies of community-acquired pneumonia in children because of their high percentage of S. pneumoniae nasopharyngeal carriage, which is not the case in adults unless they live with young children.19

This study has four main limitations: (1) As no serological tests or virological cultures were performed, the total number of determined causes of pneumonia was low (33%). However, several other investigators have reported a low rate of pathogen isolation if no other tests than culture were per-formed.20 (2) No bronchoscopy or other invasive procedure has been done to prove the presence of S. pneumoniae in patients with negative blood and sputum cultures but with positive urinary antigen test. In common practice, however, the use of more invasive methods for sampling of lower-airway secretions is impractical and not commonly performed. (3) If patients had taken an antibiotic before entering the study, they could have had negative cultures while the urinary antigen test still remained positive. (4) As the study was performed during only one winter period the sample size was rather small which could explain the significant increase of etiologic diagnosis when using the urinary antigen test. A large prospective study should attempt to better define the place of this test in CAP without a microbiological etiology.

This study confirms that the urinary antigen test has a high specificity among patients with CAP and significantly increases the diagnosis of a pneumo-coccal origin beyond standard microbiological cultures. The urinary antigen test raises the interesting possibility that significantly more cases of CAP are

caused by S. pneumoniae than conventional tests can currently confirm.

Acknowledgments

Presented at the 11th European Congress of Clinical Microbiology and Infectious Diseases, Istanbul, Turkey 1-4 April 2001 (abstract P584).

We are indebted to Michel Procopiou MD and Laurent Kaiser MD for helpful comments.

Conflict of interest: This study was supported in part by a grant from Binax, Portland, Maine, USA.

References

1. Bartlett JG, Mundy LM. Community-acquired pneumonia: current concept. N Engl J Med 1995;333:1618-824.

2. Ruiz-Gonzalez A, FalgueraM, NoguesA, Rubio-Caballero M. Is Streptococcus pneumoniae the leading cause of pneumonia of unknown etiology? A microbiological study of lung aspirates in consecutive patients with community-acquired pneumonia. Am J Med 1999;106:385-90.

3. Domínguez J, Gall N, Blanco S, Pedroso P, Prat C, Matas L, et al. Detection of Streptococcus pneumoniae antigen by a rapid immunochromatographic assay in urine samples. Chest 2001;119:243-9.

4. Burel E, Dufour P, Gauduchon V, Jarraud S, Etienne J. Evaluation of a rapid immunochromatographic assay for detection of Streptococcus pneumoniae antigen in urine samples. Eur J Clin Microbiol Infect Dis 2001;20:840-1.

5. Murdoch DR, Laing RT, Mills GD, Karalus NC, Town GI, Mirret S, et al. Evaluation of a rapid immunochromatographic test for detection of Streptococcus pneumoniae antigen in urine samples from adults with community-acquired pneumonia. J Clin Microbiol 2001;39:3495-8.

6. Marcos MA, Martinez E, Almela M, Mensa J, Jimenez de Anta MT. New rapid antigen test for diagnosis of pneumococcal meningitis. Lancet 2001;357:1499-500.

7. Jaeschke R, Guyatt GH, Sackett DL. Users' guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me caring for my patients? Evidence-Based Medicine Working Group. JAMA 1994;271:703-7.

8. Giocoli G. Evidence-based clinical microbiology. J Clin Microbiol 2000;38:3520-1.

9. Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, Singer DE, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med 1997;336: 243-50.

10. Murdoch DR, Laing RT, Cook JM. The NOW Streptococcus pneumoniae urinary antigen test positivity rate 6 weeks after pneumonia onset and among patients with COPD. Clin Infect Dis 2003;37:153-4.

11. Rosén B, Fernandez-Sabé N, Carratala J, Verdaguer R, Dorca J, Manresa F, et al. Contribution of a urinary antigen assay (Binax NOW) to the early diagnosis of pneumococcal pneumonia. Clin Infect Dis 2004;38:222-6.

12. Yu VL, Kellog JA, Plouffe JF. Evaluation of the Binax urinary, Gram stain and sputum culture for Streptococcus pneumo-niae in patients with community-acquired pneumonia [abstract 262]. In: Program and abstracts of the 38th Annual Meeting of the Infectious Society of America (New Orleans). American Society of Microbiology; 2000.

13. Bochud PY, Moser F, Erard P, Verdon F, Studer JP, Villard G, et al. Community-acquired pneumonia: a prospective outpatient study. Medicine 2001;80:75-87.

14. Woodhead MA, Macfarlane JT. Prospective study of the etiology and outcome of pneumonia in the community. Lancet 1987;21:671-4.

15. Fang GD, Fine M, Orloff J, Arisumi D, Yu VL, Kapoor W, et al. New and emerging etiologies for community-acquired pneumonia with implications for therapy. A prospective multicenter study of 359 cases. Medicine 1990;69:307-16.

16. Karalus NC, Cursons RT, Leng RA, Mahood CB, Rothwell RP, Hancock B, et al. Community-acquired pneumonia: etiology and prognostic index evaluation. Thorax 1991;46: 902-6.

17. Jimenez P, Meneses M, Saldias F, Velasquez M. Pneumococcal antigen detection in bronchoalveolar lavage fluid from patients with pneumonia. Thorax 1994;49:872-4.

18. Gutiérrez F, Masia M, Rodriguez JC, Ayelo A, Soldan B, Cebrian L, et al. Evaluation of the immunochromatographic Binax NOW assay for detection of Streptococcus pneumoniae urinary antigen in a prospective study of community-acquired pneumonia in Spain. Clin Infect Dis 2003;36:286-92.

19. Hamer DH, Egas J, Bertha E, Macleod WB, Griffiths JK, Sempertegui F. Assessment of the Binax NOW S. pneumoniae urinary antigen test in children with nasopharyngeal pneumococcal carriage. Clin Infect Dis 2002;34:1025-8.

20. Marrie TJ, Peeling RW, Fine MJ, Singer DE, Coley CM, Kapoor WN. Ambulatory patients with community-acquired pneumonia: the frequency of atypical agents and clinical course. Am J Med 1996;101:508-15.

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