Pulmonary infections span a wide spectrum, ranging from self-limited to life-threatening and from acute to chronic. This topic details the pathophysiology, epidemiology, general features, and treatment of pulmonary infections, particularly bacterial pneumonia [see Table 1].
Pneumonia
Although overall hospitalization rates are declining, hospital-izations for acute lower respiratory tract infections have increased steadily since 1980.1 Taken together, pneumonia and influenza rank as the sixth leading cause of death in the United States and lead all other infectious diseases in this respect. Antibiotics have greatly modified the natural history of pneumonia and have sharply reduced the overall case-fatality rate. At the same time, the widespread use of antimicrobial agents has led to the emergence of drug-resistant strains, thereby altering and expanding the range of pathogens responsible for pneumonia, especially in hospitalized patients. The growing population of patients with chronic obstructive pulmonary disease (COPD) and other debilitating illnesses and the use of respiratory therapy and immunosuppressive drugs have contributed to the increasing incidence of nosocomial and opportunistic pneumonias, which have a very high mortality.
Pathophysiology
Host Defense Mechanisms
The lung is normally sterile. In healthy people, an intricate series of defense mechanisms maintain that sterility in the face of heavy bacterial colonization of the upper respiratory tract, inhalation of thousands of bacteria in droplet nuclei each day, and nearly universal aspiration of upper airway secretions during normal sleep each night.2,3 Defects in host defense mechanisms account for most cases of pneumonia [see Table 2].
Transmission of Organisms to Lungs
Inhalation of aerosolized droplets accounts for the transmission of respiratory viruses, such as influenza virus, which cause highly contagious infections that often occur in epidemics.4 Other nonviral agents produce pneumonia through similar means of spread. Such agents include mycoplasmas, which are transmitted from person to person and cause primary atypical pneumonia; Coxiella burnetii, which is transmitted from livestock and causes Q fever; and Chlamydophila (formerly Chlamydia), which is transmitted from birds (C. psittaci) or humans (C. pneumoniae). Mycobacterium tuberculosis is spread from person to person by aerosolized droplets. The organisms that are responsible for causing the systemic mycoses are probably inhaled from sources in nature. Of bacteria that cause pneumonia, Legionella pneumo-phila is the species most likely to be spread by inhalation of aerosolized organisms that originate in contaminated fresh water.
Pneumococci are spread from person to person by aerosolized droplets, but pneumococcal pneumonia is not highly contagious and is caused in many cases by aspiration of na-sopharyngeal organisms, the second major mechanism of infec-tion.4 Aspiration of nasopharyngeal organisms occurs in nearly all persons during sleep and is probably responsible for most bacterial pneumonias, including staphylococcal and gram-negative bacillary pneumonias; it certainly accounts for the necrotiz-ing pneumonitis that results from the aspiration of mixed mouth flora.
Hematogenous seeding, the third and least common mechanism for pneumonia, accounts for occasional cases of staphylo-coccal pneumonia that complicate tricuspid valve endocarditis or septic thrombophlebitis. This mechanism is also responsible for various gram-negative bacillary pneumonias in patients with bacteremia.
Tissue Responses
Once organisms succeed in bypassing host defense mechanisms to arrive at the alveoli, a variety of tissue responses may ensue, depending on the nature of the pathogen and on the integrity of the host inflammatory response. Although the inflammatory response is essential for the control of infection, it can produce tissue damage, impair ciliary action, and impede phagocytosis.
The inflammatory response to Streptococcus pneumoniae or Haemophilus influenzae often produces lobar consolidation, but these infections rarely result in tissue necrosis. In contrast, staphylococci and many gram-negative bacilli often produce necrosis, which can lead to cavitation and even frank abscess formation; a peribronchial distribution is characteristic, but lo-bar consolidation may occur. Viruses generally produce interstitial inflammation rather than air-space exudates. The infection is usually bilateral and causes diffuse alveolar damage and interstitial edema. Similar tissue responses may be initiated by My- coplasma, Chlamydophila, and Legionella species; by gram-negative bacteremia (shock lung); and by other causes of the acute respiratory distress syndrome. Mycobacteria and fungi typically evoke a slow granulomatous response.
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Table 1 Major Causes of Pulmonary Infection |
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Gram-positive cocci: Streptococcus pneumoniae, S. pyogenes, other streptococci, staphylococci |
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Gram-positive bacilli: Bacillus anthracis |
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Gram-negative cocci: Neisseria meningitidis, Moraxella catarrhalis |
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Gram-negative coccobacilli: Haemophilus influenzae |
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Gram-negative bacilli: Klebsiella pneumoniae, Pseudomonas species, Escherichia coli, Proteus, Serratia species, Acinetobacter, Yersinia pestis, Francisella tularensis, Enterobacter species, Prevotella, Legionella species |
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Mixed flora (aspiration pneumonia) |
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Mycobacteria: Mycobacterium tuberculosis, M. avium complex |
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Fungi: Histoplasma, Coccidioides, Blastomyces, Cryptococcus, Candida, Aspergillus, Mucoraceae |
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Parasites: Pneumocystis carinii, Toxoplasma gondii |
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Mycoplasmas: Mycoplasma pneumoniae |
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Chlamydophila (chlamydiae): C. pneumoniae, C. psittaci, C. trachomatis |
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Rickettsia-like organisms: Coxiella burnetii |
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Viruses: influenza virus, parainfluenza virus, adenovirus, respiratory syncytial virus, rhinovirus, measles virus, varicella-zoster virus, cytomegalovirus |
Table 2 Host Defense Mechanisms against Pulmonary Infection
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Mechanism |
Modifying Factors |
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Normal flora of upper respiratory tract |
Antibiotic therapy, respiratory therapy, hospitalization |
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Aerodynamic properties of upper respiratory tract |
Tracheal intubation |
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Protective reflexes (e.g., cough, sneeze, gag, bronchoconstrictor) |
Sedatives and hypnotics, alcohol and drug abuse, neurologic disorders, age and debility, tracheal intubation (gastrointestinal disorders) |
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Mucous carpet that entraps particles |
Viral infections, smoking, chemical irritants, dehydration |
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Ciliary action, mucociliary transport |
Smoking, viral infections, advanced age, aspirin (?) |
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Antibacterial substances in respiratory secretions (e.g., lysozyme, lactoferrin, ^-antitrypsin, IgA) |
None |
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Fibronectin in respiratory secretions (competitively inhibits adherence |
Decreased fibronectin levels in seriously ill patients |
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of gram-negative bacilli) |
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Free drainage of tracheobronchial tree |
Foreign bodies, obstructing tumors, bronchostenosis |
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Rich blood supply |
Vascular obstruction (e.g., emboli) |
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Alveolar macrophages |
Viral infections, smoking (both increase macrophage numbers but impair function) |
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Lymphatic tissue |
Cytotoxic therapy |
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Humoral immunity (B cells, IgG and IgA antibodies, complement, polymorphonuclear neutrophils) |
Immunosuppressive disorders and therapy |
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Cellular immunity (T cells, lymphokines, mononuclear phagocytes) |
Immunosuppressive disorders and therapy |
Epidemiology and etiology
Community-Acquired Pneumonia
Like other respiratory tract illnesses, pneumonia is most common in the winter because of the seasonal increase in viral infections and the close contact of persons confined indoors. Community-acquired pneumonias are a major problem in the United States, with an estimated four million cases occurring annually.5 About one million cases require hospitalization,5 and at least 60,000 result in death.6 The mortality of community-acquired pneumonia ranges from less than 1% in patients who are not ill enough to require hospitalization to 13.7% for hospitalized patients, 19.6% for bacteremic patients, and 36.5% for patients admitted to intensive care units.7 Clinical and laboratory data can be used to determine which patients are at greatest risk for death and thus require hospitalization and aggressive therapy. Co-morbidity is the strongest risk factor, with neoplastic disease, neurologic disease, and alcoholism being particularly worri-some.8 Advanced age is another strong predictor of risk,6 in part because older patients often underreport symptoms.7-10 Physical findings of high fever, tachypnea, confusion, hypoxia, and hypotension also portend an adverse result.11 The presence of extensive radiographic abnormalities, especially bilateral pleural effusions, is associated with higher risk, as are laboratory abnormalities such as hypoxia, azotemia, acidosis, hyponatremia, and hypophosphatemia. Postobstructive, aspiration, gram-negative, and staphylococcal pneumonias produce a high mortality. Patients lacking these adverse prognostic indicators have a low risk of death and can usually be treated successfully as outpatients. Patients hospitalized for pneumonia have a greater than fivefold likelihood of requiring subsequent hospitalization for pneumonia than patients with other serious illnesses. They also have substantially higher long-term mortality than age-matched control subjects.
In the preantibiotic era, pneumonia was nearly synonymous with S. pneumoniae infection. Pneumococci still account for 30% to 60% of all community-acquired pneumonias for which an etiology can be determined.14 Pneumococci are particularly likely to be responsible for community-acquired pneumonias severe enough to require hospitalization and for pneumonia in persons older than 60 years.
The second most common bacterial cause of community-acquired pneumonia is H. influenzae, which accounts for about 10% of cases14; patients with COPD are particularly vulnerable. Although infection with Moraxella catarrhalis is much less common than infection with H. influenzae, it is being recognized increasingly as a cause of community-acquired pneumonia. Like H. influenzae, M. catarrhalis has a predilection for patients with cardiopulmonary disease. In rare cases, M. catarrhalis causes fulminant pneumonia, bacteremia, or both.
Staphylococci and gram-negative bacilli are much less common but more serious causes of community-acquired respiratory infections. Significant predisposing conditions are required for these organisms to produce pneumonia. In the community setting, staphylococcal pneumonia usually follows influenza. Gram-negative pneumonias in the community setting are most common in patients who have recently been hospitalized and treated with antibiotics, in smokers and others with chronic lung disease, and in immunosuppressed patients.2,16 Exposure to aerosols of contaminated water is an additional risk factor for infection with Pseudomonas aeruginosa,17 and alcoholism predisposes to Klebsiella pneumonia. Meningococcal pneumonia is rare.18 A variety of other bacteria, including L. pneumophila, can cause pneumonia in the community setting.15 Aspiration of mixed mouth flora is responsible for infection in some patients.
In about half the patients with community-acquired pneumonia, the etiologic agent cannot be identified.19 Especially in younger patients, many of these infections result from so-called atypical agents, which lack the cell wall structure that characterizes ordinary bacteria. In a study of patients with a mean age of 41 years, for example, M. pneumoniae accounted for 22.8% of community-acquired pneumonias, and C. pneumoniae for 10.7%; in addition, influenza A accounted for 2.7% .19 C. pneumoniae is also increasingly being recognized as a cause of community-acquired pneumonia in adults with COPD [see 14:III Chronic Obstructive Diseases of the Lung]. Respiratory tract viruses, including respiratory syncytial virus, adenoviruses, and influenza or parainfluenza viruses,20 can also cause community-acquired pneumonias in persons of all ages.
Hospital-Acquired Pneumonia
Pneumonia is the second most common nosocomial infection in the United States21; about 200,000 cases occur annually, accounting for 17.8% of all hospital-acquired infections and 40,000 to 70,000 deaths. Risk factors for nosocomial infections include aspiration, COPD or other chronic severe illnesses, thoracic and upper abdominal surgery, and treatment in an ICU. Patients who require mechanical ventilation are particularly at risk; pneumonia develops in 9% to 24% of patients who require intubation for more than 48 hours.22 Ventilated patients who acquire nosocomial pneumonia have a much higher mortality (54%) than comparably ill ventilated patients who do not acquire pneumonia (27%).
The bacterial etiologies of hospital-acquired pneumonias are very different from those of community-acquired pneumonias. Many nosocomial pneumonias are polymicrobial; gram-negative bacilli are isolated in 47% of patients, anaerobes in 35%, and Staphylococcus aureus in 26%. In contrast, pneumococci account for no more than 10% of hospital-acquired pneumonias. Other organisms that are associated with community-acquired infections can occasionally cause pneumonia in the hospital setting; such organisms include Legionella species, M. pneumoniae, and C. pneumoniae.23
Pseudomonas, Klebsiella, and Escherichia coli are the most commonly implicated causes of gram-negative pneumonias. Noso-comial gram-negative pneumonias often occur in patients with serious underlying diseases; as a result, mortality is as high as 30% to 50%. Previous antibiotic administration, respiratory therapy, chronic illness, and confinement to bed predispose to oropharyngeal colonization with gram-negative bacilli, which occurs in up to 45% of ICU patients and precedes pneumonia in most cases. Upper intestinal colonization has also been implicated, but its importance is uncertain. Although most nursing home residents are elderly and chronically ill, only 14% of them become colonized with gram-negative bacilli; oropharyngeal colonization in this population is transient and does not appear to predispose to gram-negative pneumonia. Hence, pneumonia in these patients can be approached as a community-acquired infection rather than a hospital-acquired infection.
Pneumonia in Immunosuppressed Patients
Immunosuppressed patients, particularly those with AIDS,26,27 are vulnerable to a broad range of pulmonary pathogens. In addition to being susceptible to the many organisms that produce community- and hospital-acquired pneumonias, these patients are susceptible to many opportunistic microbes that are unlikely to cause pneumonia in immunologically competent hosts.28 Such organisms include bacteria (e.g., Pseudomonas, Nocardia, and Legionella species), mycobacteria (e.g., M. avium complex), viruses (e.g., cytomegalovirus and herpesvirus), fungi (e.g., Candida, Aspergillus, and Mucor species), and protozoa (e.g., Pneumocystis carinii and Toxoplasma gondii). As a result, immunosuppressed patients require an aggressive approach to diagnosis and therapy [see 7:X Infections Due to Haemophilus, Moraxella, Legionella, Bordetella, and Pseudomonas, 7:XI Infections Due to Brucella, Fran-cisella, Yersinia pestis, and Bartonella, and 7:XXXVIII Mycotic Infections in the Compromised Host].
Diagnosis
Clinical Features
Classic signs and symptoms of pneumonia include cough, sputum production, chest pain, fever, chills, hypoxia, and dyspnea. Although the results of physical examination in patients with typical pneumonias are often nonspecific, the examination may reveal rales, rhonchi, or bronchial breath sounds, as well as percussion dullness over the involved segments of the lung. Pleural effusions may accompany pneumonia. The chest x-ray shows infiltrates.
Nonbacterial and bacterial pneumonias have differing clinical presentations. Although both types of pneumonia can affect persons of all ages, nonbacterial pneumonias are most common in older children and young adults. Patients with viral, my-coplasmal, or chlamydial pneumonias will often complain of a severe hacking cough, but substantial sputum production is unusual. Sputum production is also minimal in Legionnaires disease, but these patients are usually sicker than those with non-bacterial pneumonias [see 7:X Infections Due to Haemophilus, Moraxella, Legionella, Bordetella, and Pseudomonas].
Patients with bacterial pneumonias are more likely to have copious sputum production—as well as an abrupt onset of illness, high temperatures, chills, and development of significant pleural effusions—than are patients with nonbacterial pneumonias.
On physical examination, a patient with bacterial pneumonia generally looks sicker than a patient with nonbacterial pneumonia, and chest examination of patients with bacterial pneumonia usually reveals signs of consolidation or at least localized rales and rhonchi. In contrast, the chest examination of patients with nonbacterial pneumonias typically shows only fine rales, and often, the physical findings are less extensive than the radiologic abnormalities.
Laboratory Studies
Patients with bacterial pneumonias are more likely to have polymorphonuclear leukocytosis. If the chest x-ray reveals lobar or segmental consolidation, abscess formation, or significant pleural effusion, bacterial pneumonia is more likely. A patchy infiltrate can occur in either process, but a true interstitial infiltrate suggests a nonbacterial etiology. Computed tomography is extremely helpful in patients with complex infections.
The sputum examination is central to the etiologic diagnosis of pneumonia.29 The sputum of patients with bacterial pneumonia is typically thick and either green or brownish and is sometimes blood tinged. A good sputum specimen for microscopic examination and culture is crucial.30 If the patient cannot expectorate spontaneously, pulmonary physiotherapy, intermittent positive pressure ventilation with humidified air, or nasotra-cheal suction may be used to obtain the specimen. The Gram stain of sputum from patients with bacterial pneumonia usually reveals abundant polymorphonuclear leukocytes and will often disclose the primary pathogens. Patients with nonbacterial pneumonias or Legionnaires disease generally produce only scant quantities of thin sputum. In influenzal pneumonia, the sputum may be bloody. The Gram stain of sputum from patients with pneumonia from atypical agents reveals an absence of bacteria and a scant cellular response; in patients with my-coplasmal pneumonia, mononuclear cells may predominate.31 It can be difficult to determine the etiology in patients with noso-comial pneumonias; prolonged hospitalization, antibiotic administration, and ventilatory therapy predispose to colonization with organisms that contaminate sputum specimens but can also cause pneumonia. Bronchoalveolar lavage is effective in identifying the responsible pathogen.32
Kits for the detection of nucleic acids from Legionella, My-coplasma, and mycobacterial species in sputum are currently available, and similar tests may soon be available for the detection of other pathogens.33 Urinary antigen assays may assist in the diagnosis of Legionella34 and pneumococcal35 pneumonias. Blood cultures are of limited value in the management of patients with community-acquired pneumonias.
Invasive Studies
In immunocompromised patients, numerous opportunistic agents can cause pneumonia, and aggressive techniques may be required to obtain a satisfactory specimen. Although invasive procedures rarely are necessary in immunocompetent patients, they may be required in patients who present with unusual features, are critically ill, or fail to respond to conventional therapy. Procedures such as transtracheal aspiration, bronchoscopy (sometimes including transbronchial biopsies), bronchial brushing, or percutaneous lung taps37 may be necessary; bronchoalve-olar lavage is a particularly useful technique and is generally well tolerated. If these less invasive techniques fail to produce a diagnosis, open lung biopsy should be considered.
Diagnosis of Ventilator-Associated Pneumonia
The diagnosis of ventilator-associated pneumonias may be based on clinical criteria, Gram stains and cultures of tracheal aspirates, and pulmonary infection scores or invasive tech-niques.38,39 Even with bronchoscopy and lavage, the diagnosis can be difficult; the detection of a marker called soluble triggering receptor expressed on myeloid cells (sTREM-1) in lavage fluid may be an indication of ventilator-associated pneumonia.
