A clinical diagnosis of pneumonia was adjudicated in 322 out of 505 participants in the cohort study following blinded chart review. Bacterial etiology was determined in 64 (19.8%) of those cases, and 5 (1.6%) patients had viral pneumonias. Given the goal of this study, subsequent analyses focused solely on bacterial etiologies of pneumonia. Table 1 shows the bacteria identified, and for each, the number of patients who met a composite severity endpoint of bacteremia, admission to an Intensive Care Unit (ICU), or death.
Table 1. Distribution of the bacterial etiology of pneumonia with number of corresponding cases that met a composite severity endpoint of bacteremia, admission to the ICU or death
Etiology
|
Total number
|
Number of cases meeting composite endpoint of bacteremia, ICU admission or death
|
Methicillin-Resistant Staphylococcus aureus
|
12
|
7
|
Methicillin-Susceptible Staphylococcus aureus (MSSA)
|
7
|
3
|
Pseudomonas aeruginosa
|
12
|
4
|
Streptococcus pneumoniae
|
6
|
3
|
Haemophilus influenza
|
5
|
2
|
Serratia marcescens
|
3
|
2
|
Escherichia coli
|
3
|
2
|
Legionella pneumophilia
|
2
|
1
|
Stenotrophomonas maltophilia
|
1
|
1
|
Streptococcus gordonii
|
1
|
1
|
Actinomyces odontolyticus
|
1
|
0
|
Mixed infections
|
11
|
8
|
Total with Bacterial Etiology for Pneumonia Identified
|
64
|
34
|
No Bacterial Etiology for Pneumonia Identified
|
258
|
46
|
Total
|
322
|
80
|
Predominant bacterial pathogens were Staphylococcus aureus (n=19; 12 Methicillin Resistant (MRSA) and 7 Methicillin Susceptible (MSSA)), Pseudomonas aeruginosa (n = 12), Streptococcus pneumoniae (n=6), and Haemophilus influenza (n=5). Pneumonias due to Serratia marcescens (n=3), Escherichia coli (n=3), Legionella pneumophilia (n=2), Stenotrophomonas maltophilia (n=1), Streptococcus gordonii (n=1) and Actinomyces odontolyticus (n=1) were also identified. Eleven infections were characterized as mixed, with 9 of the combinations involving S. aureus (5 MRSA and 4 MSSA) in combination with Acinetobacter baumanii (n=2), P. aeruginosa (n=2), E. coli (n=2), Klebsiella pneumoniae (n=1), H. influenzae (n=1), and Streptococcus anginosus (n=1). Other combinations included S. pneumoniae with Moraxella catarrhalis and one that involved E. coli, Proteus mirabilis and K. pneumoniae. The relative contribution of different microbiological samples to identifying each bacterial etiology of pneumonia is available in Supplementary Table 1 (Table S1). While there was no statistically significant difference between the rates at which pneumonia due to particular bacterial etiologies met the composite severity endpoint (p=0.79), patients who had specific bacterial etiologies identified as the causative agent of their pneumonia were more likely to meet the severity endpoint than those who did not (p=3.5e-08)Subsequent analyses focused on comparing PCT levels for S. pneumoniae, H. influenzae, MSSA, MRSA, P. aeruginosa, the Enterobacteriaceae (E. coli and S. marcescens) and mixed infections. This approach was chosen for two reasons: (i) to maximize comparisons between the largest groups, and (ii) to provide comparisons between microbial etiologies that prompt consideration for adjustment in therapy from typical CAP regimens. Demographic information for patients belonging to these groups is shown in Table 2.
Table 2. Demographic and Clinical Characteristics of Patients with different etiologies of pneumonia
Population Characteristics
|
Microbial Etiology of pneumonia
|
|
MRSA
|
MSSA
|
Pseudomonas aeruginosa
|
Streptococcus pneumoniae
|
Haemophilus influenzae
|
Enterobacteriacae
|
Mixed infections
|
No Bacterial etiology identified
|
P value
|
Age
|
69 (22-89)
|
64 (49-83)
|
68 (48-82)
|
59 (37-77)
|
52 (23-81)
|
69 (53-94)
|
54 (23-87)
|
68 (22-99)
|
0.082
|
Male Gender
|
8 (66)
|
5 (71)
|
7 (58)
|
4 (67)
|
2 (40)
|
4 (67)
|
8 (73)
|
153 (59)
|
0.95
|
Active smoker
|
1 (8)
|
0
|
2 (17)
|
3 (50)
|
2 (40)
|
1 (17)
|
4 (36)
|
61 (24)
|
0.29
|
Medical comorbidities
|
|
Diabetes
|
3 (25)
|
4 (57)
|
3 (25)
|
1 (17)
|
1 (20)
|
1 (17)
|
2 (18)
|
59 (23)
|
0.70
|
Heart Failure
|
5 (42)
|
0
|
2 (17)
|
1 (17)
|
1 (20)
|
1 (17)
|
2 (18)
|
54 (21)
|
0.68
|
Renal Failure
|
4 (33)
|
0
|
2 (17)
|
2 (33)
|
0
|
0
|
1 (9)
|
57 (22)
|
0.47
|
Cirrhosis
|
1 (8)
|
0
|
0
|
0
|
0
|
1 (17)
|
0
|
12 (5)
|
0.66
|
Malignancy
|
5 (42)
|
3 (43)
|
6 (50)
|
5 (83)
|
5 (100)
|
4 (67)
|
5 (45)
|
79 (31)
|
0.0013
|
Underlying lung disease (Asthma, COPD, Pulmonary Hypertension or Interstitial Lung Disease)
|
6 (50)
|
3 (43)
|
9 (75)
|
4 (67)
|
4 (80)
|
5 (83)
|
5 (45)
|
138 (53)
|
0.50
|
Data are presented as mean (range) or n (%). Percentages may not total 100 because of rounding.
There were no statistically significant differences in age, gender and smoking status of patients with pneumonia caused by different bacteria or those from whom the causative bacterial etiology was not identified. Similarly, patients with diabetes, renal failure, cirrhosis and underlying chronic lung conditions including asthma, COPD, pulmonary hypertension and interstitial lung disease were equivalently represented in the patient groups. In a notable exception, there was a statistically significant difference in the prevalence of malignancy in the different patient groups (p=0.0013), driven by the finding that there was a smaller percentage of patients with malignancy in the group for which a bacterial etiology for pneumonia was not identified.
PCT values were available for all patients on hospital day 1, 91% on day 2, 86% on day 3, and 78% of patients on hospital day 4. We constructed boxplots for all available PCT data showing median and interquartile values for different bacterial etiologies from hospital days 1-4 (Figures 1a – 1d respectively).
Median PCT value the time of admission was highest for S. pneumoniae (3.7 ng/mL) and lowest for mixed infections (0.05 ng/mL), with intermediate values for S. aureus (0.47 and 0.12 ng/mL for MRSA and MSSA respectively), H. influenzae (0.12 ng/mL) and P. aeruginosa (0.065 ng/mL). Significant differences were observed between mixed infections compared to S. pneumoniae (p=0.014) and to MRSA (p=0.018).
Day 2 PCT values increased from levels obtained on admission for S. pneumoniae (a 71% increase to 6.34 ng/mL), P. aeruginosa (a 407% increase to 0.33 ng/mL), and MSSA (doubling to 0.24 ng/mL). PCT values were relatively stable for H. influenzae and mixed infections, and decreased for MRSA (by 64%). Pneumococcal pneumonias resulted in significantly higher PCT values when compared to P. aeruginosa (p=0.0043), H. influenzae (p=0.036) and mixed infections (p=0.0016). Significant differences were observed between median PCT values for mixed infections when compared to P. aeruginosa (p= 0.044), Enterobacteriaceae (p=0.024) as well as both MSSA and MRSA (p=0.018 and p=0.031 respectively),
Median PCT values on hospital day 3 almost tripled for MSSA in comparison to values from day 2, but decreased by 64% for S. pneumoniae, and by 57% for Enterobacteriaceae. The PCT values for other pathogens were relatively stable. The significant differences between PCT levels for pneumococcus compared to mixed infections (p=0.008) and P. aeruginosa (p=0.032) persisted into day 3 of assessment, as did the comparison between mixed infections and MSSA (p= 0.039). PCT values for pneumococcal infections were also higher than those for MRSA (p= 0.043). Notably, the values for infections due to MRSA and MSSA diverged the most on day 3, but did not reach statistical significance (p=0.27).
On hospital day 4, median PCT values for all pathogens fell within a narrow range (0.05 ng/mL to 0.47 ng/mL). Pseudomonal infections had very low PCT values, and were significantly lower than values for S. pneumoniae (p= 0.047) and MSSA (p= 0.017).