Etiology and Pathogenesis

The host defenses of the lung are constantly challenged by a variety of organisms, including both viruses and bacteria (see Chapter 22). Viruses in particular are likely to avoid or overwhelm some of the upper respiratory tract defenses, causing a transient, relatively mild clinical illness with symptoms limited to the upper respiratory tract. When host defense mechanisms of the upper and lower respiratory tracts are overwhelmed, microorganisms may establish residence, proliferate, and cause a frank infectious process within the pulmonary parenchyma. With particularly virulent organisms, no major impairment of host defense mechanisms is needed; pneumonia may occur even in normal and otherwise healthy individuals. At the other extreme, if host defense mechanisms are quite impaired, microorganisms that are not particularly virulent and unlikely to cause disease in a healthy host may produce a life-threatening pneumonia.

In practice, several factors frequently cause enough impairment of host defenses to contribute to the development of pneumonia, even though individuals with such impairment are not considered “immunosuppressed.” Viral upper respiratory tract infections, ethanol abuse, cigarette smoking, heart failure, and preexisting chronic obstructive pulmonary disease (COPD) are a few of the contributing factors. More severe impairment of host defenses is caused by diseases associated with immunosuppression (e.g., advanced AIDS), various underlying malignancies (particularly leukemia and lymphoma), and use of corticosteroids and other immunosuppressive or cytotoxic drugs. In these cases associated with impairment of host defenses, individuals are susceptible to both bacterial and more unusual nonbacterial infections (see Chapters 24 to 26).

Microorganisms, especially bacteria, find their way to the lower respiratory tract in two major ways. The first is by inhalation, whereby organisms are usually carried in small droplet particles inhaled into the tracheobronchial tree. The second is by aspiration, whereby secretions from the oropharynx pass through the larynx and into the tracheobronchial tree. Aspiration is usually thought of as a process occurring in individuals unable to protect their airways from secretions by glottic closure and coughing. Although clinically significant aspiration is more likely to occur in such individuals, everyone is subject to aspirating small amounts of oropharyngeal secretions, particularly during sleep. Defense mechanisms seem able to cope with this nightly onslaught of bacteria, and frequent bouts of aspiration pneumonia are not experienced.

Less commonly, bacteria reach the pulmonary parenchyma through the bloodstream rather than by the airways. This route is important for the spread of certain organisms, particularly Staphylococcus. When pneumonia results in this way from bacteremia, the implication is that a distant primary source of bacterial infection is present or that bacteria were introduced directly into the bloodstream (e.g., with intravenous drug abuse).

Many individual infectious agents are associated with development of pneumonia. The frequency with which each agent is involved is difficult to assess and depends to a large extent on the specific population studied. The largest single category of agents is probably bacteria. The other two major categories are viruses and Mycoplasma. Of the bacteria, the organism most frequently associated with pneumonia is Streptococcus pneumoniae, in common parlance often called pneumococcus. It has been estimated that in adults, approximately one-half of all pneumonias serious enough to require hospitalization are pneumococcal in origin.

Pathology

The pathologic process common to all pneumonias is infection and inflammation of the distal pulmonary parenchyma. An influx of polymorphonuclear leukocytes (PMNs), edema fluid, erythrocytes, mononuclear cells, and fibrin is seen to a variable extent in all cases. Bacterial pneumonias in particular are characterized by an exuberant outpouring of PMNs into alveolar spaces as they attempt to limit proliferation of the invading bacteria.

Individual types of pneumonia may differ in exact location and mode of spread of the infection. In the past, a distinction was often made between pneumonias that follow a “lobar” distribution, those that behave more like a “bronchopneumonia,” and those with the pattern of an “interstitial pneumonia.” However, these distinctions are often difficult to make because individual cases of pneumonia frequently do not adhere to any one particular pattern but have mixtures of the three patterns in varying proportions. Given this limitation, a brief mention of the three major types follows.

Interstitial pneumonias are characterized by an inflammatory process within the interstitial walls rather than alveolar spaces. Although viral pneumonias classically start as interstitial pneumonias, severe cases generally show extension of the inflammatory process to alveolar spaces as well.

Pathophysiology

Infections of the pulmonary parenchyma produce their clinical sequelae not only by altering the normal functioning of the lung parenchyma but also by inducing a more generalized systemic response to invading microorganisms. The major pathophysiologic consequence of inflammation and infection involving the distal air spaces is decreased ventilation to affected areas. If perfusion is relatively maintained, as it often is because of the vasodilatory effects of inflammatory mediators, ventilation-perfusion mismatch results, with low ventilation-perfusion ratios in diseased regions. When alveoli are totally filled with inflammatory exudate, there may be no ventilation to these regions, and extreme ventilation-perfusion inequality (i.e., shunt) results.

Ventilation-perfusion inequality generally manifests as hypoxemia. Although frank shunting may explain part of the hypoxemia, ventilation-perfusion mismatch with areas of low ventilation-perfusion ratio is usually a more important factor. Carbon dioxide retention is not a feature of pneumonia unless the patient already has an extremely limited reserve, especially from underlying COPD. In fact, patients with pneumonia frequently hyperventilate and have a PCO₂ less than 40 mm Hg.

The systemic response to pneumonia is not unique but rather is a reflection of the body’s response to serious infection. Perhaps the most apparent aspects of this response are fever, an outpouring of PMNs into the circulation (particularly with bacterial pneumonia), and often a “toxic” appearance of the patient. These indirect systemic responses can be clues that an infectious process is the cause of a new pulmonary infiltrate.

Clinical Features

In many ways the clinical manifestations of pneumonia are similar, even when different infectious agents are involved. In other ways the presentations and manifestations are quite different. Although recognition of subtle clinical differences sometimes allows the astute clinician to suggest an etiologic diagnosis, methods for identifying a specific infectious agent play an equally if not more important role in the final diagnosis. However, in many cases, a specific agent cannot be clearly identified, and patients often are managed in an empirical way based on the setting in which they present.

Perhaps the most important constellation of symptoms in almost any type of pneumonia consists of fever, cough, and often shortness of breath. The cough is nonproductive in some cases, particularly in pneumonias due to viruses or mycoplasma; in others, especially bacterial pneumonias, sputum production is a prominent feature. When the inflammatory process in the pulmonary parenchyma extends out to the pleural surface, the patient often reports pleuritic chest pain. If the fever is high and “spiking,” patients frequently experience shaking chills associated with the rapid rise in body temperature.

Physical examination reflects the systemic response to infection and the ongoing inflammatory process in the lung. Patients often have tachycardia, tachypnea, and fever. Examination of the chest typically reveals crackles or rales overlying the region of the pneumonia. If dense consolidation is present and the bronchus supplying the area is patent, sound transmission is greatly increased through the consolidated pneumonic area. As a result, breath sounds may be bronchial in quality, fremitus is increased, and egophony is present. The consolidated area is characteristically dull to percussion of the overlying chest wall. Examination of peripheral blood generally shows an increase in white blood cell count (leukocytosis). Especially in patients with bacterial pneumonia, the leukocytosis is composed primarily of PMNs, and a shift toward immature younger neutrophils (i.e., bands) may be seen.

In pneumococcal pneumonia, the onset of the clinical illness often is relatively abrupt, with sudden development of shaking chills and high fever. Cough may be productive of yellow, green, or blood-tinged (rusty-colored) sputum. Before the development of pneumonia, patients often experience a viral upper respiratory tract infection, which can be an important predisposing feature.

Mycoplasmal pneumonia, in contrast to pneumococcal pneumonia, characteristically has a somewhat slower, more insidious onset. Cough is a particularly prominent symptom, but it often is nonproductive. Fever is not as high, and shaking chills are uncommon. Young adults are the individuals most likely to have mycoplasmal pneumonia, although the disease is not limited to this age group.

Patients with either staphylococcal or gram-negative bacillary pneumonias are often quite ill. Frequently these patients have complex underlying medical problems and have already been hospitalized. Many have impaired defense mechanisms or have recently received antibiotics. Staphylococcal pneumonia may be seen as a secondary complication of influenza infection or as a result of dissemination of the organism through the bloodstream.

Pneumonia with anaerobic organisms generally occurs in patients with impaired consciousness or difficulty swallowing who cannot adequately protect the airway from aspiration of oropharyngeal secretions. Dentition often is poor, and patients frequently have gingivitis or periodontal abscesses. Clinical onset of the pneumonia tends to be gradual, and sputum may have a foul odor, suggesting anaerobic infection. Because the organisms are likely to cause substantial tissue destruction, necrosis of affected tissue and abscess formation are relatively common sequelae.

Pneumonia caused by L. pneumophila, commonly called Legionnaires’ disease, can be seen as isolated cases or localized outbreaks. Otherwise healthy hosts may be affected, but patients with impaired respiratory defense mechanisms appear to be predisposed. Patients are often extremely ill, not only with respiratory compromise and even respiratory failure but also with nonrespiratory manifestations; specifically, gastrointestinal, central nervous system, hepatic, and renal abnormalities may accompany the pneumonia.

Diagnostic Approach

As with other disorders affecting the pulmonary parenchyma, the single most useful tool for assessing pneumonia at the macroscopic level is the chest radiograph. The radiograph not only confirms the presence of a pneumonia, it also shows the distribution and extent of disease and sometimes gives clues about the nature of the etiologic agent. The classic pattern for S. pneumoniae (pneumococcus) and K. pneumoniae is a lobar pneumonia (Fig. 23-1). Staphylococcal and many of the gram-negative pneumonias may be localized or extensive and often follow a patchy distribution (Fig. 23-2). Mycoplasma organisms can produce a variety of radiographic presentations, classically described as being more impressive than the clinical picture would suggest. Pneumonias caused by aspiration of oropharyngeal secretions characteristically involve the dependent regions of lung: the lower lobe in the upright patient or the posterior segment of the upper lobe or superior segment of the lower lobe in the supine patient (Fig. 23-3).

The chest radiograph is useful for demonstrating the presence of pleural fluid, which frequently accompanies pneumonia, particularly of bacterial origin. The pleural fluid can be either thin and serous or thick and purulent; in the latter case, the term empyema is used (discussed later under Empyema).

Microscopic examination of sputum may play an important role in evaluating patients with pneumonia. However, the importance of obtaining a sputum specimen and using it as a guide to treatment, as opposed to treating the patient empirically without a sputum specimen, is an issue of substantial controversy. Most authorities now recommend basing initial treatment on clinical presentation, in many cases without substantial efforts at identifying a causative organism. In cases in which a sputum specimen is obtained, it is important to evaluate the quality of the specimen because a poor-quality specimen may provide inadequate or inaccurate information. In a good sputum specimen (i.e., one that contains few squamous epithelial cells picked up in transit through the oropharynx), inflammatory cells and bacteria can be seen.

In most bacterial pneumonias, large numbers of PMNs are seen in the sputum. In contrast, mycoplasmal and viral pneumonias have fewer PMNs and more mononuclear inflammatory cells. Pneumococcal, staphylococcal, and gram-negative bacillary pneumonias commonly demonstrate a relatively homogeneous population of the infecting bacteria. Anaerobic aspiration pneumonias, caused by a mixture of organisms from the oropharynx, show a mixed population of bacteria of many different morphologies. In Legionnaires’ disease, the bacterium does not stain well with the usual Gram stain reagent and therefore is not seen with conventional staining techniques. In mycoplasmal and viral pneumonia, the infecting agent is not visualized by light microscopy, and only the predominantly mononuclear cell inflammatory response is seen.

In conjunction with the initial Gram stain and microscopic examination of sputum, the specimen is cultured for bacteria. However, some bacteria are relatively difficult to grow, and in many if not most cases, the initial Gram stain is just as important in making the etiologic diagnosis. Special culture media are available to facilitate the growth of Legionella species.

When sputum is not spontaneously expectorated by the patient, other methods for obtaining respiratory secretions (or even material directly from the lung parenchyma) may be necessary. Techniques that have been used—flexible bronchoscopy, needle aspiration of the lung, and occasionally surgical lung biopsy—are described in greater detail in Chapter 3. Techniques for testing urine for the presence of pneumococcal antigens are becoming increasingly useful.

Routine stains and cultures of sputum are not useful for three of the important causes of pneumonia: Mycoplasma, Chlamydophila, and Legionella. Sometimes the diagnosis can be confirmed by a variety of serologic techniques that demonstrate a rise in antibody titer against the organism, but these techniques provide a retrospective diagnosis and are not useful clinically. Several newer methods are seeing increasing clinical usefulness over time. For example, direct fluorescent antibody staining can be performed for Legionella, especially on tissue specimens, but more recent methods include culture on special supplemented media and a commonly used urinary antigen radioimmunoassay (only for certain L. pneumophila serotypes). Polymerase chain reaction methods are being investigated for all three organisms and may have an important role in the future.

Functional assessment of patients with acute infectious pneumonia is usually limited to evaluating gas exchange. Arterial blood gas values characteristically demonstrate hypoxemia accompanied by normal or decreased PCO₂. Pulmonary function tests have little usefulness in this setting.

Therapeutic Approach: General Principles and Antibiotic Susceptibility

The cornerstone of treatment of bacterial pneumonia is antibiotic therapy directed at the infecting organism. However, because the causative organism often is not known when the pneumonia is first diagnosed and, in fact, frequently is not identified at any point during the clinical course, initial treatment strategies have been developed on the basis of the clinical setting (e.g., community-acquired vs. hospital-acquired pneumonia). These initial treatment strategies are outlined later under Initial Management Strategies Based on Clinical Setting of Pneumonia. If and when an organism is identified, the regimen may be changed to allow for more focused or more effective antibiotic coverage. Because knowledge of antibiotic susceptibility of specific organisms helps with understanding the rationale behind initial treatment strategies, this section first considers some of the general patterns of antibiotic susceptibility for the major organisms causing pneumonia.

In the case of pneumococcal pneumonia, penicillin traditionally has been the most appropriate agent, assuming the patient is not allergic to penicillin, although cases with various degrees of resistance to penicillin are now being encountered with increasing frequency. In addition, because penicillin is not effective against some of the other common causes of community-acquired pneumonia (e.g., Mycoplasma pneumoniae, C. pneumoniae), other classes of antibiotics with a broader spectrum against agents causing community-acquired pneumonia are typically used when antibiotics are initiated. They include macrolides (erythromycin or a derivative, such as azithromycin) and quinolones (e.g., levofloxacin). When high-level resistance of pneumococcus to penicillin is found, either a quinolone or vancomycin is typically necessary. Intermediately resistant strains can often be treated with ceftriaxone.

Staphylococci generally produce penicillinase, which requires use of a penicillinase-resistant derivative of penicillin, such as oxacillin or nafcillin. Some staphylococci are also resistant to these derivatives, in which case vancomycin is the antibiotic of choice. H. influenzae may be sensitive to ampicillin, but the high frequency of organisms resistant to this antibiotic generally justifies alternative coverage, such as a second- or third-generation cephalosporin, an extended spectrum macrolide, trimethoprim-sulfamethoxazole, or a quinolone. Many of the other gram-negative bacillary pneumonias often display resistance to a variety of antibiotics. Aminoglycosides (e.g., gentamicin and tobramycin), third- or fourth-generation cephalosporins, quinolones, carbapenems (e.g., meropenem), or an extended-spectrum penicillin with a β-lactamase inhibitor (e.g., piperacillin/tazobactam) may be used initially while antibiotic sensitivity testing is performed. Pneumonia caused by anaerobes is treated most commonly with either penicillin or clindamycin. A macrolide or a quinolone is the antibiotic of choice for pneumonias caused by either Legionella or Mycoplasma.

No definitive forms of therapy are available for most viral pneumonias, although rapid advances in this field may lead to development of more clinically useful therapeutic agents. Influenza vaccine (see Chapter 22) is effective in preventing influenza in the majority of individuals who receive it, whereas antiviral agents (amantadine or rimantadine for influenza A, a neuraminidase inhibitor such as zanamivir or oseltamivir for influenza A or B) may reduce the duration or severity of the illness if given soon after onset of clinical symptoms.

Other modalities of therapy are mainly supportive. Chest physical therapy and other measures to assist clearance of respiratory secretions are useful for some patients with pneumonia, particularly if neuromuscular disease or other factors impair the effectiveness of the patient’s cough. If patients have inadequate gas exchange as demonstrated by significant hypoxemia, administration of supplemental O₂ is beneficial. Occasionally, frank respiratory failure develops, and appropriate supportive measures are instituted (see Chapter 29).

Initial Management Strategies Based on Clinical Setting of Pneumonia

During the past 2 decades, greater emphasis on cost-effective use of medical resources has spurred development of algorithms and guidelines for the clinician approaching common clinical problems. Pneumonia is a particularly good example of an important clinical problem for which such management strategies have been developed, relating to both diagnostic evaluation and initiation of therapy. Separate strategies are being promulgated for two distinct groups of patients with pneumonia, depending on the setting where the pneumonia developed: community-acquired or nosocomial (hospital-acquired). Guidelines apply to patients who do not have significant underlying impairment of systemic host defense mechanisms, such as patients with AIDS or those receiving immunosuppressive drugs or cancer chemotherapy.

Intrathoracic Complications of Pneumonia

As part of the discussion of pneumonia, two specific intrathoracic complications of pneumonia—lung abscess and empyema—are briefly considered because they represent important clinical sequelae.

Respiratory Infections Associated with Bioterrorism

The magnitude of society’s concerns about bioterrorism changed abruptly after September 11, 2001, following the terrorist attacks on the World Trade Center and the Pentagon. Subsequent recognition of cases of both cutaneous and inhalational anthrax contracted by handling mail containing anthrax spores illustrated all too vividly not only the danger posed by some previously uncommon biological agents but also the widespread fear elicited by the threat of bioterrorism. This section briefly discusses three biological agents with life-threatening effects that can be mediated by infection involving the respiratory system: Bacillus anthracis, Yersinia pestis, and Francisella tularensis.

References