Nosocomial pneumonia

Abstract Nosocomial pneumonia, or terminal pneumonia as it was for- merly called, results from the repeti- tive microaspiration of contaminated oropharyngeal secretions into the lungs in the presence of impaired host defenses. This pathophysiologic sequence was suggested by the ob- servations of Osler but clarified by the seminal work of Rouby and col- leagues. The enormous impact of an- timicrobial agents on the organisms responsible for nosocomial pneumo- nias was first identified by Kneeland and Price who found that organisms of the normal pharyngeal flora virtu- ally disappeared in terminal pneumo- nias following administration of these drugs, being replaced by gram- negative bacilli. The remarkable sus- ceptibility of seriously ill patients to becoming colonized by exogenous organisms, even in the absence of antimicrobial therapy, was shown by Johanson et al. These factors, antibi-

otics and the change in bacterial binding receptors in the airways as- sociated with illness, lead to infec- tions caused by exogenous organ- isms that are frequently resistant to antimicrobial agents. Clinical find- ings that usually identify patients with respiratory infections are unre- liable for the diagnosis of nosocomi- al pneumonias as shown by Andrews et al. Invasive techniques, especially the protected specimen brush (PSB) technique, avoid contamination of the specimen by proximal secretions and accurately reflect the bacterial burden of the lung, as first shown by Chastre et al. Quantitation of such specimens serves as an excellent proxy for direct cultures of the lung and are the current gold standard for diagnosis.

Keywords Nosocomial pneumonia · Protected specimen brush ·

Aspiration

Introduction

The development of pneumonia in patients who are al- ready seriously ill with a different process is not a new phenomenon but one that has long been recognized with the phrase “Pneumonia is the old man’s friend” – the im- plication being that pneumonia is the mode of exit from this worldly life when continued existence becomes problematic. Sir William Osler honed his world- renowned clinical skills at the autopsy table where he had the opportunity to correlate his clinical findings di- rectly with anatomical findings, an opportunity very

largely lost to today’s physicians, at least in the United States. In his classic text, “The Principles and Practice of Medicine” [1], Osler discusses at length the differences between lobar pneumonia and forms of pneumonia that occurred in other settings such as complications of other diseases, post-operatively, especially following ether an- esthesia, or as in so-called “terminal pneumonias”.

He thought that no physician could miss the diagnosis

of lobar pneumonia, based on the presenting signs and

symptoms, even without a chest radiograph. In contrast,

the other forms of pneumonia were easily overlooked,

leading to Osler’s comment that there was a much great-

er incidence of terminal pneumonia in the autopsy room than on the wards. These pneumonias were lobular ini- tially, consisting of an intense neutrophilic inflammatory exudate centered on a small bronchiole located in a de- pendent portion of the lung. This infection was then, and still is today, caused by the microaspiration of small quantities of contaminated oropharyngeal secretions in the presence of host defenses that are unable to eliminate the challenge. We will review two aspects of these infec- tions; the pathophysiology and the methods of diagnosis in the midst of confounding factors.

Pathophysiology of nosocomial pneumonia

It is now understood that nosocomial pneumonia is usu- ally initiated by colonization of the upper respiratory tract by potentially pathogenic bacteria. Secretions con- taminated by these bacteria are aspirated in small quanti- ties into the lungs–around the cuff of an endotracheal tube if present. The lung’s antibacterial defenses try to inactivate this bacterial bolus. If these defenses are suc- cessful, pneumonia will not result. If they are unsuccess- ful, infection occurs, beginning as bronchiolitis and pro- gressing to bronchopneumonia that may extend to in- volve adjacent regions of lung in a confluent pneumonia with or without abscess formation. Osler [1] understood the outlines of this process when he wrote about ether weakening the lining of the lungs to allow postoperative pneumonias to develop.

Studies of the pathophysiology of complex clinical processes are usually difficult and the work of any one group of investigators is often incomplete. Every now and then a particularly important study is completed that brings much of the field into focus. Such was the case with the paper published in 1992 by Rouby et al. [2].

These investigators utilized a French law that enables re- searchers to perform an autopsy shortly after the patient’s death to obtain specimens for research if not expressly forbidden by the patient. They performed a bedside thora- cotomy and removed either the left or right lung of 83 pa- tients who died while receiving mechanical ventilation for respiratory failure. The removed lungs were serially sec- tioned so that five to ten samples were obtained from each bronchopulmonary segment for histologic examination.

Additional sections from each lobe were submitted for mi- crobiologic study. In 69 of the 83 patients a bronchoalveo- lar lavage (BAL) procedure had been performed within 48 h prior to death as part of a prospective study of pneu- monias. Thus, the key features that make this such an im- portant study are (1) a large sample size; (2) prospective data collection for some elements; (3) meticulous patho- logic techniques, especially serial sectioning of the lungs and (4) sampling performed immediately after death.

Infection was found in 60 of 83 (72%) lungs and oc- curred predominantly in dependent lung segments indi-

cating the aspirational nature of this process. Stages of severity from bronchiolitis alone, to bronchopneumonia, to lung abscess were readily recognized and lesions at varying stages usually co-existed in the same lung, sug- gesting a recurring process. Foci of infection were wide- ly dispersed among areas of either normal lung or lung tissue involved with other pathologic processes such as diffuse alveolar damage. Without serial sectioning, many foci of infection would have been missed and the patient wrongly categorized as uninfected. The correlation be- tween microbiologic results and histology was imperfect but illuminating (Table 1). In general, higher bacterial counts were associated with more advanced lesions of infection, i.e. bronchopneumonia and abscess. No micro- bial growth was observed in lobes free of infectious le- sions histologically. However, 30–40% of lobes that showed infectious lesions had no bacterial growth but over 90% of these patients were receiving intravenous antibiotics.

These findings indicate that nosocomial bronchopneu- monia occurs in most patients undergoing prolonged me- chanical ventilation, when defined by histologic criteria.

Foci of bronchopneumonia may become sterile either as a result of successful host defenses or the effect of pow- erful antibiotics, or both. Alternatively, progressive lung infection with systemic manifestations results if host de- fenses, with or without antibiotics, are unable to rise to the challenge posed by colonization of distal airways [3].

The source of organisms that colonize the distal airways remains somewhat controversial, with some investigators finding that colonization of the stomach precedes coloni- zation of the airways [4]. In most cases, colonization of the stomach is the result of swallowing contaminated secretions [5]. Airway colonization by Pseudomonas aeruginosa and related organisms seems to differ from the usual pattern with colonization of the distal airways occurring first, before any more proximal site [6]. That may be because receptors to bind P. aeruginosa are more readily available in the trachea and more distal sites. Alternatively, it may suggest that colonization is the result of aerosol contamination by P. aeruginosa and other organisms that thrive in water, such as Serratia marcescens.

Many studies of nosocomial pneumonia have failed to reproduce one or another of the key features of the Rouby study. Most are readily explained by a careful evaluation of the data and study design. For example, many studies have found a lower prevalence of pneumo- nia–in some cases much lower. As Rouby et al. [2]

pointed out, the prevalence they found was due to serial sectioning of the lungs, enabling them to identify small focal lesions that would have been missed by the less rigorous sampling techniques that are generally used.

Some have suggested that sterile inflammatory lesions

cannot be bacterial pneumonias and argue that a histo-

logic gold standard overestimates the incidence of pneu-

monia. However, sterile lesions usually co-exist with other lesions with positive cultures. As with the presence of positive cultures in regions that do not show histolog- ic pneumonias, these findings are likely explained by sampling errors induced by the focal nature of this pro- cess.

Historical perspective

Colonization, or the persistence of a bacterial species at a particular site over time, is a root cause of nosocomial pneumonia. The upper airways of healthy individuals contain a limited bacterial flora, including a number that are potentially pathogenic. In fact, the organisms that we regard as being highly pathogenic for the respiratory tract, such as Streptococcus pneumoniae, are members of the normal flora. In the pre-antibiotic era, these were the organisms that caused pneumonia, whether nosocomial or community-acquired.

Smillie and Duerschner [7] reported, in 1947, their findings in an autopsy study of 109 subjects with termi- nal pneumonia and 98 people who died but did not have pneumonia at post-mortem. Specimens of peripheral lung and nasopharyngeal swabs were cultured (Table 2).

These results were interpreted as showing that terminal bronchopneumonias were caused by organisms that were members of the normal nasopharyngeal flora and that colonization of the upper respiratory tract with the same organisms found in the lungs was readily demonstrated at the time of autopsy. Nasopharyngeal colonization was also common among patients who did not have pneumo- nia. The role of Staphylococcus aureus was uncertain,

primarily because it so often colonized the nasopharynx of patients who did not have pneumonia. Gram-negative bacilli (GNB) were found in “some” patients, but were not felt to play an important role.

By 1960 the situation had changed dramatically.

Kneeland and Price [8] duplicated the earlier study in an autopsy series of 200 consecutive patients; 110 were found to have terminal, or nosocomial, pneumonia. The authors compared the causative organisms to those re- ported by Smillie and Duerschner [7] 10 years earlier (Table 3). Clearly, an enormous shift in the bacteria asso- ciated with nosocomial pneumonia had occurred in this 10-year period. Kneeland and Price [8] were far more convinced about the pathogenicity of S. aureus than had been their predecessors, thinking that it was “probably a pathogen”. This impression was influenced by the im- pact of the influenza pandemic in the late 1950s. Pneu- monias due to normal flora, e.g. S. pneumoniae, H. in- fluenzae, and Group A streptococci, were seen only in patients who had not received antimicrobial therapy.

The reason for the predominance of the normal flora organisms as the cause of pneumonia is simply that they are more pathogenic for the lungs than other organisms.

However, serious illness or surgery causes a shift in the availability of receptors for other bacterial species in the respiratory tract so that colonization by GNB, S. aureus and other organisms may occur. In 1969, Johanson et al.

[9] reported that the pharyngeal flora of hospitalized, ill patients underwent a dramatic and swift alteration. GNB that rarely colonized the throats of healthy individuals appeared quickly in throat swabs of sick patients, with their prevalence being proportional to the severity of ill- ness. Antibiotics alone were not responsible. For exam- Table 1 Correlation of lung

histology and microbiology [2] Histologic grading Number Quantitative colony counts in lung tissue (cfu/g)

of severity of lobes

No growth <10

Colonies ≥10

Colonies

No infection 43 43 (100%) 0 0

Bronchiolitis 20 6 (30%) 14 (70%) 0

Bronchopneumonia 15 6 (40%) 4 (27%) 5 (33%)

Confluent pneumonia 18 7 (39%) 5 (28%) 6 (33%)

Total 96 62 23 11

Table 2 Post-mortem culture results in the pre-antibiotic era [7]

Organism Bronchopneumonia ( n =109) No bronchopneumonia ( n =98)

Lung isolates (%) Nasopharyngeal Lung isolates (%) Nasopharyngeal

colonization (%) colonization (%)

Streptococcus pneumoniae 37 78 11 39

Group A streptococci 7 80 6 50

Haemophilus influenzae 21 78 4 20

Staphylococcus aureus 41 58 24 44

ple, GNB colonization ranged from 0–2% among hospi- talized patients who were not physically ill (psychiatry patients) and non-hospitalized healthy people, but was found in 62% of moribund patients in the absence of an- tibiotic therapy. Antibiotic therapy increased GNB colo- nization to 80% in the latter patients. This study showed that underlying disease was an important determinant of GNB colonization in addition to antibiotic therapy.

Seriously ill patients are remarkably susceptible to ac- quiring exogenous organisms from their environment, a susceptibility not shared by healthy individuals. Antibi- otics, either given to the patient or present in the pa- tient’s environment, cause strong pressure on the bacteri- al flora and select resistant strains. Trouillet et al. [10]

analyzed the factors associated with potentially drug- resistant (PDR) bacteria in nosocomial pneumonias and found that prior antibiotic therapy, prior broad spectrum antibiotic use and the duration of mechanical ventilation were each associated with an increasing prevalence of PDR infections. Pneumonias that occurred early in the hospital course or before antibiotics had been given were usually caused by antibiotic-susceptible organisms.

It is fortunate that members of the normal bacterial flora of the respiratory tract have remained susceptible to most antibiotics so that administration of almost any an- tibiotic leads to the swift elimination of these organisms.

The result of these two factors, the change in bacterial binding sites in the airways and the elimination of the normal flora by antibiotics, is that the airways of sick in- dividuals become colonized by organisms that are not normally present, such as GNB. However, members of the normal flora are acquiring antimicrobial genes in greater numbers. Clinicians soon may be faced with the specter of pneumonias caused by normal flora organisms that are resistant to common, if not all, antibiotics. Given the greater pathogenicity of these organisms, such a re- sistance pattern could potentially recreate the pre-antibi- otic era.

Diagnosis of nosocomial pneumonia

The shortcomings of a histologic gold standard have led to a variety of studies exploring the usefulness of surro- gate measures. Osler, of course, relied entirely on his

findings at autopsy to make the diagnosis of terminal, or nosocomial, pneumonia. In the absence of antibiotics, the evolution of pneumonia follows a predictable histo- logic course that is closely correlated with quantitative microbiologic findings in both experimental animals and humans. Following the inoculation of pathogenic bacte- ria into the lungs resident alveolar macrophages phago- cytose and kill the invading bacteria. If they are unable to do so, neutrophils are recruited from the blood into al- veolar spaces, a sequence that has been known for over 100 years [11]. This process begins in the region of ter- minal bronchioles because of the rapid increase in cross- sectional area of the airways at that level with the resul- tant deposition of inhaled materials. Inflammation spreads quickly to adjacent alveoli if not contained. In acute situations, and in the absence of antibiotics, recog- nizable foci of bronchopneumonia require bacterial den- sities of approximately 10

cfu/g [12]. Confluent pneu- monias are associated with approximately 10

cfu/g and abscesses even greater numbers. However, the associa- tion between histology and quantitative microbiology be- comes much less tight over time as lung defenses kill or- ganisms and the milieu of the consolidated lung no lon- ger supports bacterial multiplication [13].

Nevertheless, histologic findings remain the principal

“gold standard” for nosocomial pneumonia, even though regarded as unreliable by some investigators, due to poor agreement among multiple reviewers [14]. Factors that contribute to uncertainty about the recognition of pneu- monia histologically include the presence of underlying lung disease, especially diffuse alveolar damage and pul- monary edema, and certain systemic processes, notably marked leukopenia. However, the major confounding factor is antibiotic therapy that has the capacity to steril- ize pneumonic lesions long before they resolve histologi- cally leading to the often-observed disparity between histology and microbiology and limiting the usefulness of histology as a gold standard. At least that problem is well understood. The problem that is not understood is the extent of histologic pneumonia that must be present to be important clinically. Since aspiration presumably occurs on a daily basis in mechanically ventilated pa- tients, new foci of potential bronchopneumonia are being initiated every day. Within a few days, there are foci at the stage of bronchiolitis, some at the early broncho- Table 3 Etiologies of terminal

pneumonia, 1947 and 1957 Organism 1946–47 [7] ( n =109; %) 1956–57 [8] ( n =110; %)

Streptococcus pneumoniae 37 6

Group A streptococci 7 0

Haemophilus influenzae 21 4

Staphylococcus aureus 41 50

Pseudomonas aeruginosa 0 24

Klebsiella pneumoniae 0 25

Other Gram-negative bacilli “Some” 19

pneumonia stage and perhaps others at the confluent stage. How many of what types of lesions are necessary to produce clinical signs of pneumonia is not known.

A number of investigators have examined the rela- tionship between histologic evidence of nosocomial pneumonia and clinical signs of infection. Andrews and coworkers [15] studied 24 patients who died while en- rolled in a prospective study of acute respiratory failure.

Multiple sections through both lungs were examined by a pathologist who was blinded to the clinical history of the patient. Similarly, clinicians made the determination of whether or not pneumonia was present at the time of the patient’s death based on the clinical findings while blinded to the pathologic findings. Foci of bronchopneu- monia were found in 14 (58%) patients in at least one lung segment and these were classified as having histo- logic pneumonias. Only 9 of these 14 patients (64%) were classified by the clinicians as having clinical pneu- monia at the time of death. Similarly, two of ten patients (20%) who had only diffuse alveolar damage without pneumonia histologically were diagnosed clinically as having pneumonia. These findings have been reproduced in a number of studies [16, 17, 18] and it is clear that clinical findings are not reliable indicators of the pres- ence or absence of histologic pneumonia in mechanically ventilated patients, especially those with ARDS.

Since nosocomial pneumonia is caused by the pres- ence of bacteria in normally sterile regions of the lungs, it seems obvious that appropriate cultures should provide a useful surrogate for a histologic diagnostic standard.

The value of expectorated sputum, analogous to a trache- al aspirate in an intubated patient for this purpose, has been debated for nearly 100 years [19, 20]. Sputum has the great advantages of ready availability and lack of ex- pense. However, colonization of proximal airways, in- cluding the oropharynx, with multiple species of bacteria causes contamination of specimens passing through, so that potentially pathogenic bacteria are present in expec- torated sputum or tracheal aspirates from most patients, whether or not they have pneumonia.

An often-overlooked aspect of sputum or tracheal as- pirates as a source of material is the handling of the specimen. A previous generation of physicians was taught to inspect the sample carefully, preferably in a petri dish, and to select the most purulent portion with sterile scissors or a loop. Another recommended ap- proach was to have the patient rinse his mouth with ster- ile water prior to expectoration [21, 22] or to wash the specimen repeatedly with sterile water in a container [23]. This was shown to remove a significant number of oral bacteria in subsequent culture, presumably from the surface of the specimen. Another technique is to homog- enize the sample as is done for quantitative cultures. It is believed that organisms present in sputum at high con- centrations are more likely to be important than those present at low concentrations. An organism present in

sputum at a concentration of 10

cfu/ml or more has long been believed to be the cause of community-acquired pneumonia [23], a notion based on the premise that pneumonias were caused by single organisms.

The protected specimen brush (PSB) technique is a highly selective approach to the sampling of secretions in the distal airways while avoiding contamination by proximal secretions [24]. Chastre et al. [25] performed a landmark study in 26 patients who died while receiving mechanical ventilation. While ventilation was continued, bronchoscopy was performed and PSB samples were ob- tained from the anterior segment of the left lower lobe (LLL). A mini-thoracotomy was then performed and multiple samples of lung tissue were obtained from the same segment for histology and quantitative cultures.

Six patients had histologic pneumonias in the anterior segment of the LLL, 20 did not. Lung tissue cultures yielded 10

cfu/g or more of lung tissue in all six patients with pneumonia. In four (67%) patients these infections were polymicrobial with multiple organisms present at concentrations of 10

cfu/g or more. Interestingly, none of these four patients had received antibiotics in the week before their death and the predominant organisms were members of the normal oropharyngeal flora, such as S. pneumoniae. In the two pneumonia patients who had received antibiotics, the predominant organisms were P. aeruginosa and Proteus mirabilis. Overall there was a highly significant correlation between lung tissue cultures and PSB cultures. A cut-off value for the PSB of 10

cfu/ml identified all patients with pneumonia. As ex- pected, some patients whose PSB cultures yielded 10

cfu/ml or more did not have pneumonia in the anteri- or segment of the LLL.

The Rouby study would predict that a focal pneumonia would have been found in a nearby segment [2]. This is a drawback of the sampling strategy used by Chastre et al.

[25]. A total of 30 organisms were recovered from cul- tures of lung tissue from the 26 patients while 51 organ- isms were recovered from PSB samples. Virtually all of the excess PSB yield was accounted for by GNB and fun- gi, suggesting that contamination by proximal colonizing organisms was an additional contributing factor to the dis- crepancy between PSB and tissue cultures. Nevertheless, this study showed that the PSB technique closely reflects the bacterial burden of the lung segment sampled and that a quantitative value of 10

cfu/ml or more provides a reli- able cut-off to identify patients with pneumonia. Selection of an anterior segment may explain the relatively low prevalence of pneumonia in this study. Overall, this study showed that PSB samples do meet the objective of finding a usable surrogate for the histologic gold standard.

It is important to understand the mechanics of PSB

sampling. The PSB samples approximately 0.001 ml of

secretions. Virtually all investigators who have utilized

this technique have placed the PSB in 1.0 ml of sterile

water or saline for vigorous shaking or vortexing. Sam-

ples of this 1.0 ml are then plated in various dilutions. A final result of 10

cfu/ml would indicate that the original material sampled in the airway contained a concentration of bacteria of 10

cfu/ml. Many studies have verified these findings and have found that bronchoalveolar la- vage (BAL) provides similar information although with a cut-off value of 10

cfu/ml or more [26, 27, 28, 29].

Studies that have failed to support the findings of Chastre et al. [25] generally suffer from one or more crit- ical faults, the most important of which is failure to ac- count for antibiotic therapy appropriately. It has become clear that changes in therapy within 72 h of invasive sampling renders the results unpredictable and often not interpretable [30]. A second consideration is the failure to match histologic and PSB samples sources closely.

Several recent studies have reported that quantitative cultures of tracheal aspirates have greater sensitivity than more invasive PSB or BAL samples [31, 32]. This would be expected from the pathophysiology of these infec- tions, in which colonization precedes infection and many more organisms colonize proximal ways than cause pneumonia. The specificity of BAL and PSB remain greater than that of tracheal aspirates [31, 32]. These findings have been reproduced in a non-human primate model of respiratory failure as well [33].

Attempts to diagnose pneumonia by non-microbiolog- ic techniques have been generally unsuccessful. Elastin fragments have been identified in the sputum of patients with pneumonias caused by GNB [34, 35]. The source of

the elastin is presumably necrosis of alveolar walls or airways, but it is not found in the sputum of patients with other types of pneumonia and, hence, has limited useful- ness. Endotoxin is also found in the sputum of patients with GNB pneumonias but it may be difficult to distin- guish colonization from infection [36, 37]. Various anti- gens unique to organisms found in the lungs, such as pneumococcal polysaccharide capsular material, confirm the fact that the organism is present but do not distin- guish between colonization and infection.

Summary

Critically ill patients are remarkably susceptible to colo- nization by exogenous bacteria which, in the hospital en- vironment, are often antibiotic-resistant. Differences in hospital environments account for the widely varying bacterial etiologies among different hospitals and the ne- cessity of knowing current antibiotic susceptibility pat- terns for each hospital. PSB and BAL provide useful sur- rogates for histology in the diagnosis of nosocomial pneumonia as long as certain precautions are followed.

Most important is the avoidance of obtaining cultures shortly after changing antibiotics. Finally, the pathophys- iology of nosocomial pneumonia as explained by Rouby and colleagues [2] provides a framework for the under- standing of this process that is extremely useful in the in- terpretation of new research findings.

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