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* From the Medizinische Universitätsklinik und Poliklinik Bonn (Dr. Ewig), Bonn, Germany; Dreifaltigkeits-Krankenhaus Wesseling (Drs. Schlochtermeier and Göke), Wesseling, Germany; and Winthrop University Hospital (Dr. Niederman), Mineola, NY.
Correspondence to: Santiago Ewig, MD, Medizinische Universitätsklinik und Poliklinik Bonn, Innere Medizin/Kardiologie und Pneumologie, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany; e-mail: santiago.ewig{at}ukb.uni-bonn.de
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Abstract |
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Design and interventions: A diagnostic strategy using regular collection of sputum samples, Gram staining in a local laboratory, and mailing of samples to a commercial laboratory for culture analysis.
Setting: A 200-bed primary-care hospital without subspeciality physicians.
Patients: One hundred sixteen consecutive patients with a diagnosis of CAP were prospectively evaluated during a 12-month period.
Results: Of 116 patients, 42 patients (36%) were capable of producing a sputum sample. Age 
75 years (odds ratio [OR], 0.4; 95% confidence interval [CI], 0.18 to 0.93) and prior ambulatory antimicrobial treatment (OR, 3.2; 95% CI, 1.2 to 8.4) were independent predictors of sputum production. A delay in collection and processing of sputum samples of > 24 h was present in 31% and 39%, respectively. A delay in collection yielded an increased number of Gram-negative enteric bacilli and nonfermenters (44% vs 7%, p = 0.056). A delay in processing was associated with an increased number of Candida spp isolates (33% vs 9%, p = 0.16). The overall diagnostic yield was low (10 of 116 patients, 9%) due to a limited number of valid samples (n = 23 of 42 patients, 55%) and a limited number of definitely or probably positive samples on Gram’s stain and culture (n = 10 of 42 patients, 24%). Prior ambulatory antimicrobial treatment was associated with a reduction in diagnostic yield (14% vs 56%, p = 0.09). The impact of diagnostic results on antimicrobial treatment decisions was minimal, with antimicrobial treatment directed to diagnostic results in only one patient.
Conclusions: We conclude that in this setting representative of primary-care hospitals in Germany, sputum had a low diagnostic yield and did not contribute significantly to patient management.
Key Words: antimicrobial treatment • diagnosis • Gram stain • outcome • pneumonia • sputum
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Introduction |
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Any standardized approach to patients with CAP must be adapted to local needs and limitations. Since the vast majority of patients with CAP in Germany are treated in primary-care hospitals, this is an important setting to validate any diagnostic approach. The value of collecting sputum samples is limited by the absence of a microbiology laboratory in most German primary-care hospitals. Therefore, in order to evaluate the role of sputum in the management of patients with CAP in this setting, we implemented a program of regular collection of sputum samples and Gram staining at the local, on-site laboratory as a diagnostic strategy. At the same time, we relied on the European Respiratory Society (ERS) guidelines adapted to current German susceptibility data for the selection of empiric antimicrobial treatment in the absence of a conclusive diagnostic result.6
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Materials and Methods |
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Setting
The main characteristics of this hospital are the absence of any subspecialists within the Department of Internal Medicine, and the absence of a microbiology laboratory, resulting in the practice of mailing all diagnostic samples to a commercial laboratory for analysis.
Patients
Between June 1999 and May 2000, a total of 116 consecutive patients with a diagnosis of CAP were prospectively evaluated. The diagnosis of CAP was based on finding a new infiltrate on chest radiography, symptoms suggestive of a lower respiratory tract infection, and no alternative diagnosis made during follow-up. All patients were nonimmunosuppressed, and had not been hospitalized during the preceding month. Exclusion criteria were as follows: (1) the presence of severe immunosuppression (HIV infection, neutropenia < 1 x 109/L, and organ transplantation); (2) patients referred from another hospital after initiation of antimicrobial treatment; (3) patients with witnessed gross aspiration; and (4) patients with pulmonary tuberculosis. The severity of pneumonia was classified according to the pneumonia severity index of Fine et al.17
All patients were intended to be treated according to the ERS guidelines with modifications made in accordance with current German susceptibility patterns.
Interventions
An attempt to collect a sputum sample was made in all patients as soon as possible. The procedure of expectoration was explained in detail by the attending nurse, and the sputum sample was collected in a sterile tube. The nurse also documented the reasons for a failure to produce sputum.
Immediately after obtaining the sample, it was processed in the local hospital laboratory. The macroscopic appearance was graded as mucoid or purulent. Then it underwent Gram staining and read at low (x 100) magnification by the local hospital laboratory technicians. Thereafter, samples meeting microscopic validity criteria were mailed to a commercial laboratory for culture. Otherwise, samples were discarded. The regular mailing time was 24 h. Antimicrobial treatment was never delayed in order to obtain a sample from any patient.
Definitons
A sample was judged macroscopically valid when the appearance was purulent. Following the criteria of Lentino and Lucks,9
stained specimens were then scored 0, + 1, or + 2 according to the number of leukocytes, and 0, - 1, and - 2 according to the number of squamous epithelial cells seen per low power field. Specimen with scores of 1 were considered microscopically valid.9
Gram stain was graded "positive" in the presence of a predominant organism, "negative" in the absence of any microorganism, and "mixed flora" in the absence of a predominant microorganism. A sputum sample was considered as definitely diagnostic for a cultured bacterial isolate when the following criteria were met: (1) the sample was macroscopically purulent and microscopically valid, (2) the Gram stain result was positive, (3) the same microorganism grew in culture as was seen on Gram stain, and (4) there were moderate-to-high amounts of growth according to semiquantitative evaluation criteria used by the laboratory. The sample was considered probably diagnostic in the presence of mixed flora on Gram stain, while meeting all other criteria. Candida spp were not considered an etiologic pathogen.
Delay in collection or processing of sputum was referred to as a delay in obtaining or processing a sample for > 24 h. Nonresponse to antimicrobial treatment was defined as persistent temperature 38 C and/or persistent clinical symptoms (malaise, cough, expectoration, or dyspnea) or clinical deterioration (development of acute respiratory failure requiring ventilatory support and/or septic shock) after 72 h of in-hospital antimicrobial treatment.
Measurements
The following end points were recorded: the number of patients capable of producing sputum, reasons for failure to produce sputum, macroscopic and microscopic validity of sputum samples and the association of both criteria, and the number of definite and probably diagnostic samples. In addition, the influence of the presence of COPD, prior ambulatory antimicrobial treatment, and delays in sampling and laboratory processing of samples on diagnostic results was analyzed. Finally, the impact of diagnostic results on antimicrobial treatment decisions was investigated, ie, the rate of using a targeted antimicrobial treatment according to diagnostic results, instead of using an empiric regimen. This assessment was done retrospectively, correlating treatment decisions to diagnostic results.
Statistics
Results are expressed as mean ± SD. Continuous variables were compared by Student’s t test, and categorical variables were compared by 
2 test or by Fisher Exact Test where appropriate. Predictors of productive cough were evaluated by a multivariate stepwise forward logistic regression analysis. The level of significance was set at p < 0.05.
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Results |
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65 years) of whom 50 patients (43%) were very elderly (age 75 years). Twenty-four patients (21%) were admitted to the hospital from nursing homes. At least one comorbidity (cardiac, pulmonary, hepatic, renal, CNS, diabetes mellitus, or neoplastic as previously defined18
) was present in 103 patients (89%). Using the classification according to the pneumonia severity score, there were 13 patients (11%) in risk class I, 7 patients in risk class II (6%), 11 patients in risk class III (10%), 48 patients in risk class IV (41%), and 37 patients in risk class V (32%). Initial antimicrobial treatment corresponded to the ERS guidelines in 85 cases (83%) and was inadequate treatment (according to guideline standards) in 17 cases (17%). Fourteen patients were not rated for adequacy of therapy because of decisions to limit treatment. Twenty-seven patients received monotherapy (aminopenicillin/ß-lactamase-inhibitor [n = 10], second-generation cephalosporin [n = 5], macrolide [n = 5], and levofloxacin [n = 7]), and 89 patients received combination treatment (aminopenicillin/ß-lactamase-inhibitor plus macrolide [n = 71], aminopenicillin/ß-lactamase-inhibitor plus levofloxacin [n = 1], second-generation cephalosporin plus macrolide [n = 9], and third-generation cephalosporin plus macrolide [n = 8]). Twenty-two patients (19%) did not respond to initial antimicrobial treatment. Twenty patients (17%) were admitted at the ICU. Mortality rate was 15% (17 patients; 5 patients [10%] from risk class IV and 12 patients [32%] from risk class V).
Sampling of Sputum
Overall, 42 of 116 patients (36%) produced a sputum sample. Of these, 13 samples (31%) were not collected at hospital admission but 1 day after (n = 10), 2 days after (n = 2), and 3 days after (n = 1). Reasons for failure to produce a sputum sample included unproductive cough efforts (n = 31, 27%), weakness (n = 23, 20%), and noncompliance (n = 20, 17%).
Age 75 years (odds ratio [OR], 0.45; 95% confidence interval [CI], 0.2 to 0.99; p = 0.046), admission to the hospital from a nursing home (OR, 0.39; 95% CI, 0.13 to 1.1; p = 0.078), prior ambulatory antimicrobial treatment (OR, 2.9; 95% CI, 1.1 to 7.3; p = 0.024), and pulmonary comorbidity (OR, 2.0; 95% CI, 0.9 to 4.4; p = 0.07) were the only variables predictive of sputum production at a level of significance of p < 0.1. In particular, the pneumonia severity score was not associated with the probability of producing sputum (32% in pneumonia severity score classes 1 to 3 as compared to 38% in classes 4 and 5). In a multivariate analysis including the four variables with p < 0.1, only age 75 years (OR, 0.4; 95% CI, 0.18 to 0.93; p = 0.034) and prior ambulatory antimicrobial treatment (OR, 3.2; 95% CI, 1.2 to 8.4; p = 0.019) remained as independent predictors of sputum production.
Validity of Sputum Samples
Of 42 samples, 35 samples (83%) were purulent according to macroscopic judgment. All 12 bacterial isolates cultured in moderate or high amounts in 10 patients were found in purulent sputum samples. Overall, macroscopic appearance was 100% (10 of 10 samples) sensitive and 22% (7 of 32 samples) specific for the prediction of growth in culture.
Only 23 of 42 samples (55%) were considered microscopically valid as defined above. Macroscopic judgement predicted microscopic validity with a sensitivity of 91% (21 of 23 samples) and a specificity of 26% (5 of 19 samples).
Gram Stains of Microscopically Valid Samples
Gram stains were positive in 5 samples (22%) [with Gram-positive cocci in all cases] and negative in 1 sample (4%); the remaining 17 samples (74%) revealed a mixed flora.
Sputum Cultures of Microbiologically Valid Samples
Sputum samples were processed in the laboratory within the first 24 h in 11 cases (48%), within 48 h in another 10 cases (44%), and within 72 h and 96 h in 1 case each (4%). Overall, 16 pathogens (excluding 5 Candida spp) were cultured from 14 patients, including Streptococcus pneumoniae (n = 4), Staphylococcus aureus (n = 2), Haemophilus influenzae (n = 4), Gram-negative enteric bacilli (GNEB; n = 3), Pseudomonas aeruginosa (n = 2), and Stenotrophomonas maltophilia (n = 1). Twelve pathogens were present in moderate-to-high amounts. All four pathogens isolated in low amounts were either GNEB (n = 2), P aeruginosa (n = 1) or S maltophilia (n = 1). However, of 23 samples, only 5 samples had a predominant organism on Gram stain; of these 5 samples, only 3 samples had concomitant growth in culture (2 samples with S pneumoniae and 1 sample with S aureus). The remaining two cases may have been false-negative results because of prior ambulatory antimicrobial treatment. Thus, applying strict criteria for the validity of a given isolate, overall 10 of 42 patients (24%) had a definite or probable diagnostic result in sputum samples (10 of 23 patients [44%] with valid sputum samples), with 12 pathogens isolated (Table 1
).
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Impact of COPD on Diagnostic Results
In patients with a valid sputum sample, the presence of COPD was associated with a diagnostic yield twice as high as patients without COPD (7 of 12 patients [58%] with COPD vs 3 of 11 patients [27%] without COPD; OR, 3.7; 95% CI, 0.65 to 21.6; p = 0.13), but this difference did not reach significance.
Impact of Ambulatory Antimicrobial Treatment on Diagnostic Results
Prior ambulatory antimicrobial treatment was associated with a fourfold reduction in diagnostic yield, although this difference did not achieve significance (1 of 7 patients [14%] vs 9 of 16 patients [56%]; OR, 0.13; 95% CI, 0.13 to 1.3; p = 0.06).
Impact of Diagnostic Results on Antimicrobial Treatment Decisions
Only one patient with a positive result in a valid sample (S aureus) who did not respond to initial empiric antimicrobial treatment received a targeted treatment according to culture results that differed from the ERS guideline-recommended empiric treatment. This directed treatment was successful.
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Discussion |
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Of the 42 sputum samples collected from this population of 116 patients, only 23 samples (55%) were valid when standard microscopic criteria were applied, thereby substantially reducing the number of evaluable patients. Using these criteria, a macroscopic purulent appearance had a high false-positive rate of predicting validity. The same was true for predictions of subsequent growth in culture based on macroscopic appearance. These observations confirm and extend previous data.8 Thus, it is hardly possible to replace microscopic validation by the use of more readily available macroscopic criteria.
Only a minority of patients (36%) were able to produce a sputum sample. Failures were due to nonproductive cough, weakness, and noncompliance. An age 75 years was the most important predictor of a failure to produce sputum. The positive association between prior ambulatory antimicrobial treatment and ability to produce a sample may simply reflect the fact that general practitioners believed that patients with productive cough were more likely to have bacterial pneumonia and need antibiotic therapy. Our findings show a generally lower frequency of collecting sputum samples than in previous studies, which reported failure in 20 to 70% of patients,19
20
21
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with particularly low rates in the elderly.23
24
Since the low rate of collecting a sample is unlikely to be increased by any intervention, sputum sampling is unable to be part of the initial microbial investigation in a considerable proportion of hospitalized patients with CAP.
The delay in collection and laboratory processing of sputum samples was considerable, with 31% collected and 52% processed > 24 h after hospital admission. These delays are mostly explained by weekends and nonworking days, and may represent a problem even in prospective studies.25 Delays in collection resulted in antimicrobial pretreatment, thereby affecting the specificity of culture results, which demonstrated an increased recovery of GNEB and nonfermenters. Although we are not able to define exactly the impact of processing delays on the sensitivity of sputum cultures, it is known that common respiratory pathogens such as S pneumoniae and H influenzae are easily missed when samples are processed after > 4 h. In addition, it was evident that delays in processing were associated with an increase in the isolation of Candida spp. Thus, the isolation of Candida spp in sputum samples of nonimmunosuppressed patients may be regarded as marker of overgrowth with colonizing organisms and not true pathogens.
Gram stains had a low diagnostic yield, and a low number of positive samples had a corresponding growth in culture. One explanation may be the lack of investigators who were familiar with the evaluation of Gram stains. In fact, the yield of Gram stains has proven to be highly dependent on a skilled investigator applying strict criteria.26 27 In one study, 15% of the samples prepared by a house officer were technically inadequate, and the interpretations were often incorrect, with 50% of the pneumococcal readings being false-positive, and many of the H influenzae samples being false-negative.27 However, if experienced laboratory technicians are not able to examine specimens, it is highly improbable that Gram stains can be accurately used in primary-care hospitals.
In a study correlating Gram stain with the culture recovery of S pneumoniae from culture, it could be shown that applying liberal criteria such as "any Gram-positive diplococcus" resulted in a sensitivity of 83%, but with a specificity of only 38%. If the criterion for positive was a "preponderance of Gram-positive cocci," then the sensitivity dropped to 48% while specificity rose to 100%.7 The updated American Thoracic Society guidelines advise that if a Gram stain is used to guide initial antimicrobial treatment, it should be with highly sensitive criteria, with the primary purpose being to visualize a microorganism that was not anticipated by the clinical scenario.5 In our study, the yield of sputum was limited, even when liberal criteria were applied. It provided diagnostic results in only 10 of 116 patients (9%), 10 of 42 patients (24%) who produced sputum, and 10 of 23 patients (44%) with a microscopically valid sputum sample, respectively. The yield was somewhat higher in COPD patients, but since colonization with high bacterial loads may be present in up to 25%, it may be difficult to account for the effect of colonizing pathogens in the interpretation of sputum culture results.28 29 Clearly, prior ambulatory antimicrobial treatment decreased the diagnostic yield, but in view of data30 31 suggesting that any delay in treatment may be harmful in terms of outcome, it is not appropriate to discourage ambulatory treatment in order to increase diagnostic yield.
The impact of sputum sample data on therapeutic decisions was negligible. Only one patient had a benefit from the identification of the underlying pathogen in sputum. This patient might have been diagnosed equally if he was reinvestigated after the failure of the initial antimicrobial treatment. Similar results have also been reported when evaluating the value of routine microbial investigation in different hospital settings.32 33 34 35 In these studies, sputum smears and cultures added very little to the management and outcome of patients who received an appropriate initial antimicrobial regimen. In patients with treatment failures, mortality was not different, regardless of whether treatment was changed empirically or changed on the basis of diagnostic tests.
We are unsure to what extent the results of the present study can be applied to other hospital settings. In fact, it has been repeatedly demonstrated that higher diagnostic yields can be achieved in different hospital settings and patient populations.18 20 21 22 25 However, even in the most favorable report, originating from an experienced, university tertiary-care hospital, valid sputum samples could only be obtained in 39% of patients, with a predominant microorganism on Gram stain in 31% of patients. Moreover, the final difference in broad-spectrum vs pathogen-directed antimicrobial treatment, in the groups with and without diagnostic Gram stain, was only 14%.36 Thus, the impact of diagnostic testing on therapeutic decisions also seems limited in settings interested in the study of pneumonia. However, data37 highlighting an improved outcome for patients treated with a cephalosporin/macrolide combination or a quinolone, compared to a cephalosporin monotherapy regimen, raise serious doubts about the value of using focused antimicrobial treatment according to sputum findings.
We believe that our results, reflecting implementation of a diagnostic strategy in a primary-care hospital not particularly interested in the field of respiratory infections, are representative of comparable hospitals in Germany. Moreover, our findings demonstrate that the yield and impact of sputum samples should be evaluated in each particular setting in order to establish a management approach for CAP that is designed according to local capabilities and facilities. As a result, we conclude that sputum collection cannot be recommended as part of a management algorithm in German patients with CAP treated in a primary-care hospital that does not have on-site microbiology facilities.
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Footnotes |
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Received for publication February 22, 2001. Accepted for publication November 1, 2001.
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