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For patients with community-acquired pneumonia (CAP), clinical response during the first days of treatment is predictive of clinical outcome. As risk assessments can improve the efficiency of pneumonia management, a prospective cohort study to assess clinical, biochemical and microbiological predictors of early clinical failure was conducted in patients with severe CAP (pneumonia severity index score of >90 or according to the American Thoracic Society definition). Failure was assessed at day 3 and was defined as death, a need for mechanical ventilation, respiratory rate >25/min, PaO2 <55 mm Hg, oxygen saturation <90%, haemodynamic instability, temperature >38°C or confusion. Of 260 patients, 80 (31%) had early clinical failure, associated mainly with a respiratory rate >25/minute (n = 34), oxygen saturation <90% (n = 28) and confusion (n = 20). In multivariate logistic regression analysis, failure was associated independently with altered mental state (OR 3.19, 95% CI 1.75–5.80), arterial PaH <7.35 mm Hg (OR 4.29, 95% CI 1.53–12.05) and PaO2 <60 mm Hg (OR 1.75, 95% CI 0.97–3.15). A history of heart failure was associated inversely with clinical failure (OR 0.30, 95% CI 0.10–0.96). Patients who failed to respond had a higher 28-day mortality rate and a longer hospital stay. It was concluded that routine clinical and biochemical information can be used to predict early clinical failure in patients with severe CAP.
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- Patients and methods
Community-acquired pneumonia (CAP) is a common disease that is associated with serious complications such as respiratory insufficiency, sepsis and death. CAP requires hospitalisation of 15–50% of patients, and 5–10% of patients require management in an intensive care unit (ICU) [1–7]. Despite advances in antimicrobial therapy, the mortality rate among hospitalised patients is still high, ranging from 2% to 30%. Clinical response during the first 2–3 days of treatment appears to predict outcome [9–11]. Non-response is associated with increased morbidity and mortality, but once clinical stability has been achieved, clinical deterioration caused by pneumonia is rare . Risk assessments could help physicians to improve the efficiency of pneumonia treatment, with optimal monitoring of high-risk patients preventing unnecessary complications, ICU admissions or deaths; patients at low risk for treatment failure may be switched from parenteral to oral antibiotics early in the treatment process, thereby potentially reducing the length of hospital stay and leading to more efficient use of available healthcare resources.
There is currently an absence of data to predict the response (or failure to respond) to therapy of patients treated for severe CAP. Recent studies have analysed risk-factors for early clinical failure in patient cohorts with mild-to-severe CAP, and found that independent factors associated with early clinical failure were multilobar pneumonia, pleural effusion, a pneumonia severity index (PSI) score >90, Legionella pneumonia, Gram-negative pneumonia, liver disease, leukopenia, dyspnoea and confusion [13–15]. Current criteria, such as the APACHE II and PSI scores, only predict mortality, and do not seem to be sufficiently accurate to guide clinical care. Moreover, these algorithms include >15 variables and are impractical to use routinely [16–20]. Therefore, the aim of the present study was to assess clinical, biochemical and microbiological predictors of early clinical failure in patients hospitalised with severe CAP.
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- Patients and methods
Between July 2000 and June 2003, 273 consecutive patients with severe CAP were included in the study. Thirteen patients were subsequently excluded from analysis: six patients withdrew informed consent; six patients had other infections outside the respiratory tract that required antibiotic treatment; and data concerning early failure were incomplete for one patient. Of the 260 remaining patients, 180 (69%) were responders and 80 (31%) had early clinical failure. Reasons for failure are shown in Table 1. A single failure criterion at day 3 was present in 46 (57%) patients, while multiple failure criteria were present in 34 (43%) patients.
Table 1. Reasons for early clinical failure
|Reasons for failure (evaluated at third day of hospitalisation)||Failure n = 80 (31%)|
|Need for mechanical ventilation||5 (6%)|
|Respiratory rate >25/min||34 (42%)|
|Oxygen saturation <90%||28 (35%)|
|Altered mental state||20 (25%)|
|Haemodynamically unstable||4 (5%)|
|Multiple features||34 (43%)|
In univariate analysis, total PSI score, APACHE II score, lower Glasgow Coma Score, presence of a changed mental state, arterial pH <7.35 and arterial PaO2 <60 mm Hg (variables of the PSI score) were significantly more predictive of early failure. A history of chronic heart failure was found more often among early responders (Table 2). Causative microorganisms were identified in 134 (52%) patients, in 90 (50%) responders and in 45 (56%) patients with early failure (Table 3). The most frequently isolated microorganism in both groups was S. pneumoniae. Gram-negative microorganisms were identified more often among inpatients with early failure (OR 2.21, 95% CI 1.04–4.69). The initial therapy instituted most frequently was β-lactam monotherapy (Table 4). Initial therapy with macrolide/β-lactam combinations was associated with early clinical failure in univariate analysis.
Table 2. Characteristics of patients included in the study
|Characteristic||Responder n = 180||Early failure n = 80||OR|| 95% CI||p|
|Age||67.9 (16.0%)||69.15 (16.8%)||1.01||1.00–1.02||0.57|
|Pneumonia severity index score||108.3 (23.9%)||123.9 (26.2%)||1.03||1.01–1.04||<0.001|
|APACHE score||13.3 (4.4%)||14.8 (5.1%)||1.07||1.01–1.13||0.03|
|Glasgow coma score||14.7 (1.1%)||14.4 (1.1%)||0.80||0.62–1.02||0.07|
|Female gender||57 (32%)||23 (29%)||0.87||0.49–1.55||0.69|
|Nursing home||5 (3%)||4 (5%)||1.80||0.48–7.05||0.37|
|Mental state change||39 (22%)||36 (45%)||2.96||1.68–5.21||<0.001|
|Pleural effusion X-ray||30 (17%)||17 (21%)||1.03||0.96–1.10||0.38|
|Temperature <35°C or >40°C||24 (13%)||11 (14%)||1.00||0.95–1.06||0.93|
|Systolic BP <90 mm Hg||4 (2%)||3 (4%)||1.03||0.95–1.11||0.48|
|Heart rate >125/min||39 (22%)||21 (26%)||1.03||0.97–1.09||0.41|
|Respiratory rate >30/min||55 (31%)||31 (39%)||1.03||0.99–1.05||0.20|
|Arterial PaH <7.35 mm Hg||7 (4%)||12 (15%)||4.36||1.65–11.55||0.003|
|Arterial Pa02 <60 mm Hg||56 (31%)||35 (44%)||1.72||1.00–2.96||0.05|
|PaO2||66.9 (19.5%)||69.3 (27.9%)||1.01||0.99–1.02||0.43|
|pH||7.45 (0.06%)||7.43 (0.08%)||0.03||0.00–0.18||0.006|
|Systolic blood pressure||134.3 (24.5%)||138.5 (30.8%)||1.01||1.00–1.02||0.24|
|Temperature||38.6 (1.2%)||38.3 (1.2%)||0.85||0.68–1.06||0.15|
|Respiratory rate||26.3 (8.1%)||28.1 (9.8%)||1.02||0.99–1.06||0.16|
|Heart rate||105.5 (22.0%)||106.7 (24.5%)||1.00||0.99–1.01||0.71|
| Chronic heart failure||27 (15%)||4 (5%)||0.30||0.10–0.88||0.03|
| Neoplasm||44 (24%)||18 (23%)||1.00||0.98–1.02||0.73|
| Cerebrovascular incident||13 (7%)||7 (9%)||1.02||0.93–1.12||0.67|
| Kidney disease||17 (9%)||6 (8%)||0.98||0.89–1.08||0.61|
Table 3. Microorganisms associated with severe community-acquired pneumonia
|Aetiology||Responders n = 180||Failures n = 80||OR|| 95% CI||p|
|Streptococcus pneumoniae||49 (27%)||20 (25%)||0.89||0.49–1.63||0.71|
|Haemophilus influenzae||11 (6%)||3 (4%)||0.60||0.16–2.21||0.44|
|Other Gram-negative bacteria||17 (9%)||15 (19%)||2.21||1.04–4.69||0.04|
|Escherichia coli||3||6|| || || |
|Enterobacter spp.||2||2|| || || |
|Klebsiella spp.||5||1|| || || |
|Pseudomonas spp.||0||2|| || || |
|Othera||7||4|| || || |
|Chlamydia pneumoniae||10 (6%)||8 (10%)||1.89||0.72–4.98||0.20|
|Legionella pneumophila||7 (4%)||3 (4%)||0.96||0.24–3.82||0.96|
|Mycoplasma pneumoniae||4 (2%)||4 (5%)||2.32||0.56–9.50||0.24|
|Multiple pathogens||20 (11%)||9 (11%)||1.01||0.44–2.34||0.97|
|Other pathogensb||12 (7%)||5 (6%)||0.88||0.32–2.44||0.81|
|Unknown aetiology||90 (50%)||35 (44%)||0.85||0.49–1.50||0.56|
Table 4. Initial therapy for patients with community-acquired pneumonia
|Therapy||Responders n = 180||Failures n = 80||OR|| 95% CI||p|
|β-lactam monotherapy||109 (61%)||44 (55%)||0.80||0.47–1.36||0.40|
|Macrolide monotherapy||3 (1%)||1 (1%)||0.75||0.08–7.29||0.80|
|Cephalosporin monotherapy||33 (18%)||13 (16%)||0.86||0.43–1.75||0.69|
|Other monotherapya||14 (8%)||3 (4%)||0.46||0.13–1.66||0.24|
|β-lactam/macrolide combination||12 (7%)||12 (15%)||2.47||1.06–5.77||0.04|
|Cephalosporin/macrolide combination||6 (3%)||5 (6%)||1.93||0.57–6.53||0.29|
|Macrolide/other combination||3 (2%)||2 (3%)||1.51||0.25–9.23||0.65|
|Inappropriate treatmentb||18 (20%)||10 (22%)||1.43||0.60–3.40||0.42|
In multivariate analysis, the simplest predictive model with the highest predictive value included altered mental state, arterial PaH <7.35, PaO2 <60 mm Hg and an absence of a history of heart failure as independent predictors of early clinical failure (area under the ROC curve 0.70, 95% CI 0.63–0.77; Table 5). As the results of microbiological investigations of sputum are not available upon admission, those results were not included in the analysis.
Table 5. Results of multivariate analysis
|Altered mental status||3.19||1.75–5.80||<0.001|
From the multivariate model, a prediction rule was derived in which a score was assigned to the presence of each variable. The predicted probability of outcome was determined as 1/(1 + e-LP), where the linear predictor (LP) = −1.41 + (1.16 altered mental status) + (1.46 × pH <7.35) + (−1.19 × heart failure) + (0.56 × arterial PaO2 <60 mm Hg). A prognostic score for each patient (minimum −2 to maximum 6 points), reflecting the probability of early failure, was calculated by adding the scores of relevant characteristics. Patients with a cut-off of <1 point had an 18% possibility of early clinical failure, whereas patients with a cut-off point of >3 points had a 75% possibility of failure (Table 6).
Table 6. Cut-off points of prediction rule for early failure in patients hospitalised with community-acquired pneumonia
|Points scorea||Responders (%)||Failures (%)||Total (patients)|
Ten (22%) patients with early clinical failure and 18 (20%) patients who responded to treatment received inappropriate therapy, based on the results of microbiological culture (OR 1.43, 95% CI 0.60–3.40). All patients who received inappropriate therapy remained alive at day 28 (Table 7). Of ten patients who experienced early failure and received inappropriate therapy, four had Gram-negative bacteria (two Pseudomonas aeruginosa and two Enterobacter cloacae) isolated from sputum samples, in one case in combination with S. pneumoniae. The other six patients had serological evidence of infection with an atypical pathogen, including two cases with S. pneumoniae isolated from sputum samples (one in combination with pneumococcal bacteraemia). In all patients, empirical therapy was appropriate for S. pneumoniae as a probable cause of CAP.
Table 7. Characteristics of patients receiving inappropriate therapy for community-acquired pneumonia (CAP)
|Patient||Early clinical failure||Microbial cause of CAP||Basis of diagnosis||Co-infection (if any)||Therapy at day 1||Criteria of early clinical failure at day 3||Mortality at day 28|
| 1||Yes||Pseudomonas aeruginosa||Sputum|| ||Amoxycillin||Fever||No|
| 2||Yes||Chlamydia pneumoniae||Serology|| ||Amoxycillin||Fever||No|
| 3||Yes||C. pneumoniae||Serology|| ||Amoxycillin||Fever||No|
| 4||Yes||C. pneumoniae/Mycoplasma pneumoniae||Serology||Escherichia coli/Streptococcus pneumoniae (sputum)||Ceftriaxone||Respiratory rate > 25/min||No|
| 5||Yes||Enterobacter cloacae||Sputum|| ||Amoxycillin||Oxygen saturation < 90% + respiratory rate > 25/min||No|
| 6||Yes||E. cloacae||Sputum|| ||Amoxycillin||Respiratory rate > 25/min||No|
| 7||Yes||C. pneumoniae||Serology||S. pneumoniae (blood culture + sputum)||Amoxycillin||Oxygen saturation < 90%||No|
| 8||Yes||P. aeruginosa||Sputum||S. pneumoniae (sputum)||Amoxycillin||Oxygen saturation < 90% + PaO2 < 55||No|
| 9||Yes||M. pneumoniae||Serology|| ||Amoxycillin||Fever||No|
|10||Yes||M. pneumoniae||Serology|| ||Ceftriaxone||Oxygen saturation < 90% + PaO2 < 55||No|
|11||No||Legionella pneumophila/C. pneumoniae||Serology|| ||Amoxycillin|| ||No|
|12||No||C. pneumoniae/M. pneumoniae||Serology|| ||Amoxycillin|| ||No|
|13||No||E. cloacae||Sputum||S. pneumoniae (sputum)||Amoxycillin|| ||No|
|14||No||C. pneumoniae||Serology||Haemophilus influenzae (sputum)||Amoxycillin|| ||No|
|15||No||C. pneumoniae||Serology|| ||Ceftriaxone|| ||No|
|16||No||Citrobacter freundii||Blood culture|| ||Amoxycillin|| ||No|
|17||No||L. pneumophila||Serology||Corynebacterium spp. (blood culture)||Ceftriaxone|| ||No|
|18||No||C. pneumoniae||Serology|| ||Amoxycillin|| ||No|
|19||No||Aspergillus spp.||Sputum||S. pneumoniae (sputum)||Ceftriaxone|| ||No|
|20||No||C. pneumoniae||Serology|| ||Ceftriaxone|| ||No|
|21||No||L. pneumophila||Serology|| ||Amoxycillin|| ||No|
|22||No||L. pneumophila||Serology + UAT||S. pneumoniae||Penicillin|| ||No|
|23||No||M. pneumoniae||Serology|| ||Amoxycillin|| ||No|
|24||No||L. pneumophila||Serology||S. pneumoniae (blood culture)||Amoxycillin|| ||No|
|25||No||P. aeruginosa||Sputum||E. coli (sputum + blood culture)||Cefuroxime|| ||No|
|26||No||Acinetobacter spp.||Sputum|| ||Amoxycillin|| ||No|
|27||No||M. pneumoniae||Serology|| ||Cefuroxime|| ||No|
|28||No||C. pneumoniae||Serology||S. pneumoniae (blood culture)||Ceftriaxone|| ||No|
Of 18 patients who responded and received inappropriate therapy, three had Gram-negative bacteria (P. aeruginosa, E. cloacae and Acinetobacter spp.) isolated from sputum samples, in one case in combination with S. pneumoniae. One patient had a blood culture positive for Citrobacter freundii, with no other cause for CAP identified, but responded clinically after receiving amoxycillin at day 3. Another patient had Aspergillus isolated from sputum samples (together with S. pneumoniae), but had no apparent risk-factors for yeast infection. One patient had a positive urinary antigen test for L. pneumophila, and had S. pneumoniae isolated from tracheal aspirates. This patient showed a rapid clinical response with penicillin therapy. The remaining 12 patients had serological evidence of infection with an atypical pathogen, but all showed a good clinical response with β-lactam therapy at day 3. None of the patients receiving inappropriate therapy had been switched to appropriate therapy at day 3.
During the follow-up period of 28 days (inpatients and outpatients), patients with early clinical failure had a significantly higher chance of all-cause death and had longer lengths of hospital stay. Nine (12%) patients with early clinical failure died, not including the five patients who died before day 3, whereas eight (4.4%) patients who responded early died (OR 2.93, 95% CI 1.09–7.92). The length of hospital stay of patients with early clinical failure was 13.4 ± 5.3 days, compared with 9.6 ± 4.7 days for early responders (mean difference 3.8 days, 95% CI 2.6–5.4 days).
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Clinical and biochemical data that are assessed routinely for patients with CAP can be used to determine the likelihood of early clinical failure in patients hospitalised with severe CAP. Early clinical failure is associated with increased mortality and a longer stay in hospital. Close monitoring of patients at high risk for treatment failure may prevent unnecessary deaths, ICU admissions and associated costs.
The strengths of the present study were the prospectively collected data, strict criteria for inclusion, and the focus on patients with a high risk for early clinical failure. In addition, early failure was evaluated according to previously defined and generally accepted criteria. Until now, no studies have analysed prognostic factors for early clinical failure in patients with severe CAP. Arterial PaH <7.35 mm Hg, arterial Pa02 <60 mm Hg, altered mental state upon admission, and an absence of a history of chronic heart failure, were independent predictors of early clinical failure in patients treated for severe CAP. Isolation of Gram-negative pathogens was also a strong predictor for early clinical failure, but as culture results from sputum are not available at the time of admission, this variable was excluded from the final analysis.
Hypoxaemia, acidosis and confusion may all indicate tissue hypoperfusion caused by oxygen deficiency, and are associated with high mortality in patients with CAP . As hypoxaemia and acidosis can be determined only with proper arterial blood-gas analysis, the importance of performing this diagnostic procedure at admission should be emphasised. In contrast to the Glasgow Coma Score, confusion, defined as an acute alteration in the mental state of patients, as observed by family or treating physicians, was an independent predictor for clinical failure. However, this definition does not use an objective scale, which limits the internal validity of the model and its applicability in other settings.
Remarkably, a history of chronic heart failure was related inversely to early clinical failure. Although it is possible that some patients with a history of heart failure were admitted because of congestive heart failure, which is sometimes difficult to differentiate from pneumonia on a chest X-ray, all patients had evidence of new or progressive infiltrates on chest X-ray, fulfilled the clinical criteria for pneumonia, and had a PSI score of >90, or fulfilled the ATS criteria for severe CAP. Although heart failure has been associated with an adverse clinical outcome in patients with CAP, it has also been associated with a high risk for viral pneumonia [31,32]. It is, therefore, possible that viral respiratory infections with a less severe course were more prevalent among patients with heart failure. Indeed, no pathogenic bacteria were isolated from 68% of patients with heart failure, compared with 45% of patients without heart failure (p 0.02).
In univariate analysis, treatment with a combination of β-lactams and macrolides was associated with early failure. In The Netherlands, most patients hospitalised with severe CAP on regular wards are treated with β-lactam monotherapy, although combination therapy is sometimes used for more severe cases of CAP, as judged by the treating physician. There was no statistically significant difference in the prevalence of inappropriate treatment prescribed for failing and responding patients. An atypical pathogen was detected in the majority of patients who received inappropriate treatment and who were not treated with a macrolide or fluoroquinolone. The most common pathogens isolated from these patients were C. pneumoniae and M. pneumoniae, both of which usually cause mild infections. Moreover, diagnosis of atypical infections by means of serological investigations is difficult, especially for C. pneumoniae, with high rates of false-positives . The possible influence of penicillin resistance in S. pneumoniae on early clinical failure could not be investigated, as pneumococcal resistance to penicillins in The Netherlands is <1%.
The present study has a number of limitations. First, evaluation of patients included in a clinical trial risks selecting patients who differ from those encountered in daily clinical practice. However, analysis of a sample of 56 consecutive patients meeting the inclusion criteria who were unable or unwilling to provide informed consent showed a similar disease severity (average PSI score of 106.45) and age (average age 68.4 years) compared with the study population. Therefore, generalisation of the results to immunocompetent patients admitted to non-ICU wards because of severe CAP seems justified. Second, while explicit definitions of clinical response are absent, criteria for clinical stability usually include normalisation of heart rate, systolic blood pressure, respiratory rate, temperature, oxygenation and mental status [12,34]. Therefore, these criteria were used to define clinical failure, although the use of other criteria may lead to different outcomes. This is illustrated by the lower rates of failure in other studies in which different criteria for early failure were used, including lack of response or worsening of clinical and/or radiological status after 48–72 h, a requirement for changes in therapy, and/or performance of invasive procedures for diagnostic and therapeutic purposes [14,35]. Furthermore, the higher failure rate in the present study was probably also related to the strict selection of severe CAP. Third, the definition used for severity of disease can be questioned. Severe CAP was defined on the basis of higher PSI scores and ATS criteria. In the present cohort, only 19% of patients were in Fine class V, which probably explains the relatively low mortality rate in the study in comparison with the original derivation cohort. In addition, patients who were admitted directly to an ICU were not included in the analysis, which probably influenced mortality rates in the cohort when compared with Fine's original derivation cohort .
In patients who do not respond to initial therapy, the possibility of an incorrect diagnosis, an inadequate host-related response, and drug-related or pathogen-related problems, e.g., antibiotic-resistant pathogens, should be considered. However, the feature that is most important in early clinical failure has not yet been determined. In the present study, strict diagnostic criteria for CAP were used for inclusion, discordant therapy appeared not to be associated with early clinical failure, and all isolates of S. pneumoniae were susceptible to β-lactam antibiotics. Nevertheless, 31% of patients still fulfilled the criteria for early clinical failure. Therefore, an inadequate host response was probably the most important factor in early treatment failure in the study cohort. Whether genetic predisposition, as suggested recently [36–38], contributes to early failure remains to be determined.
In summary, clinical and biochemical data that are usually assessed routinely in patients with CAP can be used to indicate the possibility of early clinical failure in patients hospitalised with severe CAP. Close monitoring of patients at high risk for treatment failure may prevent unnecessary deaths, ICU admissions and associated costs. Early identification of patients at low risk for early failure may assist physicians in scheduling treatment strategies, e.g., whether or not to switch to oral antibiotics early in the treatment programme. The prognostic variables identified in the present study are easy to assess and might be helpful in reaching these treatment decisions. The PSI score predicted early clinical failure in multivariate analysis nearly as accurately as the combination of the four variables mentioned above. Therefore, these variables seem to be more practical for daily use. Nevertheless, the prediction rules derived from the data require validation in external cohorts of severe CAP to evaluate their general applicability.