Infections caused by other Legionella species
Since 1943, unusual, fastidious Rickettsia-like organisms have been identified as causes of isolated cases of pneumonia. Long considered medical curiosities, these organisms were named after their discoverers or the patients from whom they were isolated. Such obscure nomenclature (e.g., TATLOCK, OLDA, HEBA, and WIGA) reflected the absence of knowledge concerning these agents. Subsequent studies of these organisms led to their reclassification as Legionella species. Of the more than 30 Le-gionella species that have been identified, at least 19 have been recognized as causes of pneumonia, particularly in immunosup-pressed hosts.
The clinical picture is not distinctive. Fever is the most common feature, cough is variable in severity, and sputum production is absent or scant. Pleurisy or dyspnea may develop, and chest x-rays show a patchy or nodular, progressive broncho-pneumonia. L. micdadei is the most important of these organisms. Previously known as TATLOCK and HEBA, this organism was rediscovered as the Pittsburgh pneumonia agent that caused acute suppurative pneumonia in 13 immunosuppressed patients from two centers. L. micdadei can also cause pneumonia in immunologically intact hosts and extrathoracic infections in immunologically impaired hosts. It has been isolated from hospital water supplies and can cause nosocomial infections in im-munosuppressed patients.
In the first 13 patients with Pittsburgh pneumonia, the diagnosis was established through a lung biopsy or autopsy that revealed acute alveolar inflammation and short, weakly acid-fast, gram-negative bacilli. More recent cases have been diagnosed by culturing the agent on charcoal-yeast extract agar or by sero-logic means. Erythromycin has been used with success. Unlike L. pneumophila, L. micdadei is susceptible to penicillins and cephalosporins in vitro; however, there are no data on the use of these drugs in clinical L. micdadei infection.
Many other Legionella species have been identified as causes of pneumonia. These organisms grow on charcoal-yeast extract agar. Some cases in which Legionella species have been implicated share common features: patients have been exposed to infected water and have COPD or are immunosuppressed.70 Therapy with erythromycin, alone or with rifampin, has been suggested.
Chlamydophia (Chlamydia) Pneumoniae
C. pneumoniae, initially known as the Taiwan acute respiratory disease (TWAR) agent, is an important pathogen, accounting for up to 10% of all pneumonias in the United States.71 Serologic surveys suggest that a majority of adults have been infected at some point, indicating that most cases are mild or subclinical.
Unlike psittacosis, which is a true zoonosis that spreads only from animals to humans,72 C. pneumoniae spreads from person to person via respiratory droplets. The incubation period of C. pneumoniae is long. Unlike C. trachomatis, which causes neonatal pneumonia, C. pneumoniae infects mainly older children and young adults; however, older patients (especially those with COPD) can also be affected. Clinically, C. pneumoniae pneumonia in young patients resembles M. pneumoniae pneumonia73; after a prodrome of pharyngitis that lasts no more than 2 weeks, nonproductive cough and fever occur. Pulmonary infiltrates are mild. The infection is usually self-limited. In older patients with underlying COPD, C. pneumoniae can cause bronchitis that may be mild or very persistent. Bronchospasm may be prominent.74 This organism can sometimes cause severe pneumonia in patients with COPD, and fatalities have been reported in debilitated patients. A macrolide, a tetracycline, or a fluoroquinolone is recommended for therapy.
Recurrent Pneumonia
Patients with recurrent pneumonia present a diagnostic and therapeutic challenge. Anatomic abnormalities should be carefully sought in all such patients and should be suspected particularly when the infections recur in one bronchopulmonary segment. Examples of anatomic abnormalities include cysts, blebs, abscess cavities, bronchiectasis, and bronchial obstruction by tumors, foreign bodies, or bronchiostenosis. If shifting locations are involved, systemic abnormalities may be present. Examples include defects of leukocyte function, immunoglobulin deficiencies, a1-antitrypsin globulin deficiency, and cystic fibrosis. Recurrent aspiration may be responsible, in which case a carefully performed neurologic examination and a barium swallow may reveal the proper diagnosis. It is important to remember that noninfectious processes may produce recurrent pulmonary infiltrates that may be accompanied by cough and fever [see 14:V Chronic Diffuse Infiltrative Lung Disease]. Examples of such processes include organizing pneumonia, eosinophilic pneumonia, hypersensitivity pneumonitis, vasculitis, pulmonary hemo-siderosis, and pulmonary emboli.
Chronic Pneumonia
Often, bacterial pneumonias exhibit delayed resolution, in which radiographic abnormalities persist for weeks or even months after clinical recovery. Infrequently, pyogenic infection pursues a slow but progressively destructive course despite antibiotic therapy; K. pneumoniae and other gram-negative bacilli have been implicated in some patients with such chronic bacterial pneumonias. Mycobacteria and Actinomyces are common causes of chronic pulmonary infection; fungi are particularly common in patients treated with corticosteroids. Persistent infiltration caused by neoplasia, sarcoidosis, pulmonary hemorrhage, vasculitis, fibrosing alveolitis, alveolar proteinosis, lipoid pneumonia, toxins, and other processes may mimic chronic pulmonary infection. Fiberoptic bronchoscopy is very useful for diagnosis, but lung biopsy may be needed.
Aspiration Pneumonia
Epidemiology and etiology
Although aspiration is probably the mechanism responsible for most bacterial pneumonias, the term aspiration pneumonia is best reserved for infection caused by mixed mouth flora. Seventy percent of patients with depressed consciousness have demonstrable pharyngeal aspiration, often involving much larger volumes of material than that aspirated by healthy persons. Because of the larger volumes of aspirated material, underlying diseases impairing host defenses, and alterations in oropharyn-geal flora, patients with altered consciousness are most prone to aspiration pneumonia. In clinical practice, aspiration pneumonia most often results from alcoholism, drug abuse, administration of sedatives or anesthesia, head trauma, and seizures or other neurologic disorders. In addition, aspiration of GI contents is more frequent in patients with abnormalities of deglutition or esophageal motility resulting from placement of nasogastric tubes, esophageal carcinoma, bowel obstruction, or repeated vomiting from any cause. Poor oral hygiene and periodontal disease predispose to aspiration pneumonia because of the increased bacterial flora in these patients.
The clinical results of pulmonary aspiration depend in large part on the nature and volume of material aspirated. Aspiration of gastric contents is a common problem that may produce Mendelson syndrome, a fulminating illness, if a large volume of acidic gastric juice is aspirated.75 Aspiration of particulate material can produce acute airway obstruction and death by asphyxiation; aspiration of smaller particles may produce atelectasis of a pulmonary segment or even of an entire lung, resulting in dyspnea, wheezing, and cyanosis. Characteristic pulmonary injuries and distinctive clinical syndromes are produced by aspiration of smoke, freshwater or saltwater, and fats or oils (lipoid pneumonitis).
Diagnosis
Clinical Features
Patients with mixed aspiration pneumonia may present with an acute febrile illness, or the illness may follow a more indolent course, extending over many days or even weeks. Fever, cough, and sputum production are the dominant symptoms; the sputum may be copious, foul smelling, or both. Physical examination typically discloses rales and signs of pulmonary consolidation. An evaluation of dental hygiene and of the gag reflex is helpful; disordered pharyngeal sensation is a better predictor of vulnerability than is an absent gag reflex.
Laboratory Studies
Radiographically, infiltrates are most common in dependent areas of the lung, especially the apical segments of the lower lobes and the posterior segments of the upper lobes. Tissue necrosis can occur. Without treatment, aspiration pneumonia may produce multiple small cavities, which reflect a necrotizing pneumonitis. Lung abscesses or empyemas may ensue.
The sputum of patients with classic aspiration pneumonia contains abundant polymorphonuclear leukocytes and mixed mouth flora. If specimens are obtained by transtracheal aspiration or other procedures that avoid contamination of sputum by organisms from the oral cavity, aerobic and anaerobic bacterio-logic techniques can reveal the specific causative bacteria. Because anaerobes are the dominant flora of the upper respiratory tract (outnumbering aerobic or facultative bacteria by 10 to 1), it is not surprising that anaerobes are the dominant organisms in aspiration pneumonia. Of particular importance are Prevotella melaninogenica and other Prevotella (formerly, oral strains of Bac-teroides) species (slender, pleomorphic, pale gram-negative rods), Fusobacterium nucleatum (slender gram-negative rods with pointed ends), and anaerobic or microaerophilic streptococci and Peptostreptococcus (small gram-positive cocci in chains or clumps). As expected, multiple organisms are recovered from most patients.
Treatment
With the exception of B. fragilis, which can be identified along with other anaerobic species in 17% of patients with classic aspiration pneumonia, all the anaerobes found are penicillin sensitive. Penicillin is effective when B. fragilis is present in combination with penicillin-sensitive organisms, suggesting that aspiration pneumonias are synergistic infections that can be treated successfully by elimination of most but not necessarily all of the organisms involved. Penicillin dosages of 2.4 to 6.0 million units daily are generally effective. Parenteral therapy is advisable initially, but a 10- to 14-day course of treatment can be concluded with orally administered antibiotics if the patient responds well. Clindamycin represents an excellent alternative agent and may even be superior to penicillin for treatment of necrotizing aspiration pneumonias and lung abscesses.
Hospitalization or antibiotic therapy alters the usual oropha-ryngeal bacterial flora, so that staphylococci, facultative gram-negative bacilli, or both may be identified in patients. As a result, aspiration pneumonia in hospitalized patients often involves pathogens that are uncommon in community-acquired pneumonias. Gram stains and cultures of sputum are especially important for identifying gram-negative bacilli and staphylococ-ci in the hospital setting. Broad antimicrobial coverage is required until specific pathogens have been identified by culture and sensitivity testing. Although tube feedings are often recommended to prevent aspiration pneumonia, there is no evidence that they are effective.
Other Pulmonary Infections
Acute bronchitis
Cough is the chief complaint responsible for an estimated 30 million physician office visits in the United States annually. For about 12 million of these patients, the clinical diagnosis is acute bronchitis.
Acute bronchitis is commonly defined as an acute respiratory tract infection in which cough, with or without sputum production, is a prominent feature. In most cases, an etiologic diagnosis is not established. When sputum is absent or scant, the illness is often attributed to a respiratory tract virus; when purulent sputum is present, the bacteria that cause community-acquired pneumonias are considered likely causes.
Most otherwise healthy persons recover from acute bronchitis in 1 to 3 weeks, but the cough can linger for more than a month in up to 20% of patients.77 Although 70% to 90% of patients are treated with antibiotics, published trials demonstrate little clinical benefit, even if purulent sputum is present.77-79 Guidelines of the Infectious Disease Society of America, the American College of Physicians-American Society of Internal Medicine, and the American Academy of Family Physicians state, "Routine antibiotic treatment of uncomplicated acute bronchitis is not recommended, regardless of duration of cough."80 Suspected cases of pertussis constitute an exception.81 Clinicians who are confronted with demands for antibiotics may find a delayed prescription strategy useful.82,83 This strategy involves providing patients with a prescription, but instructing them to fill it only if their symptoms fail to improve within the next few days. Patients with high fever, chills, respiratory distress, underlying pulmonary or immunosuppressive disorders, or physical signs of pulmonary parenchymal infection should be evaluated for pneumonia and treated according to the guidelines for community-acquired pneumonia (see above).
Chronic bronchitis
Patients with chronic bronchitis characteristically produce sputum on most days for at least 3 months each year for more than 2 years. The sputum is frequently colonized by H. influenzae (nontypable), S. pneumoniae, or M. catarrhalis, singly or in combination. Although it is not certain whether the bacteria themselves produce additional airway damage, heavy bacterial loads correlate with increased inflammation.84 Patients who acquire a new strain of bacteria are at increased risk for symptomatic exacerbations of their chronic bronchitis.85 The role of long-term prophylactic antibiotic therapy in chronic bronchitis is controversial. Long-term antibiotic therapy may provide symptomatic relief in certain patients who experience multiple exacerbations of bronchitis during the winter, but it is not useful in improving or preserving pulmonary function. However, short-term antibiotic therapy is effective in treating acute exacerbations of chronic bronchitis.
Bronchiectasis
True saccular, or cystic, bronchiectasis involves both dilatation of the bronchi and destruction of the bronchial walls. Bronchiectasis results most often from neglected or recurrent infection, especially in childhood; therefore, bronchiectasis has become much less common since the introduction of antibiotics. Aggressive medical therapy has greatly improved the prognosis.
Symptoms include cough that may be dry or productive of copious foul sputum, recurrent lower respiratory tract infection, and hemoptysis. In rare instances, bronchiectasis can present as pleuritic chest pain. In advanced cases, fibrosis can lead to cor pulmonale and respiratory failure. The chest x-ray may show increased lung markings, honeycombing, atelectasis, or pleural changes, but high-resolution or helical chest CT is required for definitive diagnosis87 [see 14:III Chronic Obstructive Diseases of the Lung].
Lung Abscess
Epidemiology and etiology
In the antibiotic era, lung abscesses have become less common and less serious. The most common variety has been termed the primary, simple, nonspecific, or putrid abscess. Primary lung abscess accounts for about 60% of all lung abscesses and originates from a necrotizing suppurative bronchopneumo-nia caused by the aspiration of mixed oropharyngeal bacteria. Thus, both the predisposing factors and the causative organisms are similar to those identified in aspiration pneumonia. Patients with primary lung abscesses typically have alterations of consciousness because of underlying problems such as alcoholism and neurologic disorders; periodontal disease is often present. The organisms causing the abscess are much more reliably identified by transtracheal aspirates than by sputum cultures, which are invariably contaminated with anaerobes and other mouth flora. Percutaneous lung aspiration and bronchoalveolar lavage may also be useful for bacteriologic diagnosis. Mixed anaerobic bacteria are seen in most cases; F. nucleatum, P. melaninogenica, Peptostreptococcus, and anaerobic or microaerophilic streptococci predominate. B. fragilis is recovered with other organisms in 15% of cases.
Many other conditions can lead to lung abscess. Necrotizing bacterial pneumonias caused by S. aureus, K. pneumoniae, or other gram-negative bacilli can lead to abscess formation. In other patients, abscess develops as a result of bronchial obstruction caused by tumors, foreign bodies, or bronchial stenosis. Septic pulmonary embolization is a cause of abscess formation. Pulmonary tuberculosis, fungal infection, or actinomycosis often leads to cavity formation. In the immunosuppressed host, No-cardia and other opportunistic organisms may also produce cav-itation. Lung abscesses in patients with AIDS are caused by a wide array of organisms and respond poorly to therapy.
Noninfectious processes can produce cavitary lung lesions. Primary and metastatic tumors, bullae, cysts, intralobar pulmonary sequestration, pulmonary infarcts, vasculitis (including Wegener granulomatosis), and rheumatoid lung disease must be considered in the differential diagnosis of lung abscess.
Diagnosis
Clinical Features
The clinical presentation of the patient with a lung abscess depends on the type of abscess. Patients with abscesses resulting from necrotizing staphylococcal or gram-negative bacillary pneumonias are usually acutely ill and exhibit clinical features of the underlying pneumonia. Although patients with primary lung abscess may also present acutely with aspiration pneumonia, they more often experience insidiously progressive symptoms for weeks or even months before diagnosis. Cough is present in almost all patients; when the abscess drains into the bronchial tree, production of copious foul-smelling sputum is characteristic. Hemoptysis is present in approximately one third of cases and may occasionally reach life-threatening proportions. Chest pain consisting of either a dull ache or a true pleurisy is common. Most patients have fever, but frank rigors are unusual. Often, patients with a chronic course of lung abscess lasting many weeks have anorexia, weight loss, and debility.
Physical Examination and Imaging
Physical examination of a patient with a lung abscess may disclose pulmonary rales, signs of consolidation, or, rarely, clubbing of the nails. These findings are not diagnostic, however, and chest x-rays or CT scans are required to establish the presence of an abscess. Although any lung segment may be involved, abscesses are most common in the posterior segments of the upper lobes and the apical segments of the lower lobes, because these areas are dependent when a person is recumbent. Abscesses may be single or, less often, multiple. The finding of air-fluid levels signifies rupture into the bronchial tree.
Laboratory Studies
As is the case with other pulmonary infections, examination of the sputum is crucial to the diagnosis of lung abscess. In patients with primary lung abscesses, the sputum is often putrid and contains numerous polymorphonuclear leukocytes and an abundant mixed microbial flora. Sputum cultures reveal only normal mouth flora. Meaningful anaerobic bacteriology depends on obtaining, either by transtracheal aspiration or by bronchoscopy, specimens that have not traversed the orophar-ynx. Percutaneous needle aspiration can also be very helpful, both diagnostically and therapeutically. In a typical case of aspi-rational putrid lung abscess, these invasive procedures may not be necessary. They are important, however, if the diagnosis is uncertain. The indications for bronchoscopy in patients with lung abscess are debatable. Although some physicians advocate bronchoscopy in all such patients, other physicians reserve the procedure for patients in whom there is a suspicion of bronchial obstruction by a foreign body or tumor, for patients who fail to respond to medical therapy, and for patients from whom specimens are required to rule out tuberculosis, fungal infection, or carcinoma. Bronchoscopy may be helpful therapeutically by promoting bronchial drainage from cavities that incompletely communicate with the bronchial tree.
Treatment
If specific pathogens such as S. aureus or Klebsiella are present in reliable specimens, therapy should be directed at the causative pathogen. In primary lung abscesses caused by mixed oral flora, penicillin has been the drug of choice. Prospective studies comparing penicillin therapy with clindamycin therapy in 66 patients with lung abscess found clindamycin to be the superior agent; however, the long clinical experience with penicillin warrants retaining it as the drug of choice, with clindamycin an excellent alternative for patients who are allergic to penicillin or who respond poorly to that drug. Despite its excellent bactericidal activity against anaerobic bacteria, metronidazole appears less effective in treating lung abscess. Most centers initiate treatment with I.V. penicillin in a dosage range of 6 to 12 million units a day or with I.V. clindamycin in a dosage of 600 mg every 8 hours. After a clear-cut clinical response is observed, oral penicillin V in a dosage of 750 mg four times a day or oral clindamycin in a dosage of 300 mg every 6 hours can be substituted. Parenteral therapy is often required for 2 to 4 weeks before the occurrence of defervescence, diminished sputum production, and reduction in cavity size. The duration of therapy depends on the clinical course, but prolonged treatment for 4 to 8 weeks is usually required.
In addition to administration of antibiotics, adequate drainage is essential and can usually be achieved with intensive pulmonary physiotherapy and postural drainage. Bron-choscopy can be very useful in promoting drainage and for excluding the diagnosis of cancer. Although surgery was once the mainstay of treatment for lung abscess, antibiotics are now almost always able to control infection, and surgery is needed only when complications occur. Massive hemoptysis is an indication for lung resection. Uncontrolled sepsis may occasionally necessitate lobectomy. CT-guided percutaneous tube drainage may be very helpful in patients who are too ill to tolerate thora-cotomy and may be the treatment of choice for lung abscesses that are refractory to medical management. Empyema, another complication of lung abscess, requires external drainage by tho-racentesis, chest tube, or rib resection. The persistence of a thin-walled cavity after otherwise successful medical treatment, however, is not an indication for surgery. Recurrent or persistent infection, recurrent hemoptysis, or the suspicion of tumor may mandate operative intervention. Shaggy, thick-walled cavities may be suggestive of tumor. Complications of lung abscess that have become uncommon because of antibiotic therapy include bronchogenic spread of infection to other pulmonary segments, bronchiectasis, and bacteremia with metastatic infection such as brain abscess.
Whereas patients with gram-negative or staphylococcal bacil-lary pneumonias or serious underlying diseases have a substantial mortality, the prognosis for patients with primary lung abscess is quite good. It is important to prevent recurrent pulmonary infection by treating dental disease and by avoiding factors that predispose to pulmonary aspiration.
Empyema
Etiology
Bacteria can reach the pleural space by many routes. Most often, empyema results from the direct spread of bronchopul-monary infections, including pneumonias, lung abscesses, and bronchiectasis.88 Less often, empyema develops as a complication of thoracotomy or, rarely, thoracentesis. Open chest trauma provides another means for the direct introduction of microorganisms. Intra-abdominal infections, especially subphrenic abscesses, can penetrate the diaphragm to cause empyemas. Uncommonly, esophageal rupture can cause spread of infection from the mediastinum to the pleural space. Finally, hematogenous seeding is an infrequent mechanism of empyema formation.
S. aureus, various species of Streptococcus, and gram-negative bacilli are the most common causes of empyema; among the gram-negative bacilli, K. pneumoniae has been linked with dia-betes.89 Many infections are mixed. Anaerobes have been recognized in 25% to 76% of empyemas and may occur in pure culture or in combination with aerobic or facultative organisms. Fu-sobacterium, Prevotella, and anaerobic gram-positive cocci are the anaerobes most often seen. M. tuberculosis has become a relatively rare cause of pleural space infections, and fungi are implicated uncommonly.90 Transdiaphragmatic rupture of a liver abscess occasionally produces amebic empyema.
Diagnosis
In most patients, the clinical presentation of empyemas includes fever, dyspnea, chest pain, and cough. Hemoptysis is less common than these other symptoms. If diagnosis and treatment are delayed, weight loss and debility may be prominent. The physical findings in patients with empyemas are no different from those in other patients with pleural effusions. In addition, chest wall tenderness may be present, and there may be signs of an underlying pneumonia or intra-abdominal infection. Tachy-pnea and respiratory distress may occur, and septic shock may complicate advanced cases. Polymorphonuclear leukocytosis is common; other laboratory findings may include anemia and hy-poxia. Chest x-rays reveal pleural effusions that are free flowing in early disease but frequently loculated in late cases. Ultra-sonography may be necessary to distinguish fluid from pleural fibrosis. Unless surgery or thoracentesis has been performed, air-fluid levels in the pleural space suggest a bronchopleural fistula.
Differential diagnosis
In the differential diagnosis of empyema, it is important to consider the many causes of noninfected pleural effusions.91 Most important is the distinction between sterile parapneumon-ic effusions and true empyemas. Thoracentesis is mandatory for the diagnosis of empyema. Several thoracenteses may be needed if the fluid is loculated; CT or ultrasound guidance is very helpful in these circumstances. Gross purulence is diagnostic for empyema, but the absence of frank pus does not rule out infection. Like other inflammatory effusions, empyema fluids have the characteristics of exudates: protein levels greater than 3 g/dl and lactic dehydrogenase values in excess of 550 units. Pleural fluid acidosis is characteristic of empyemas, but alkalosis can occur if the infection is caused by a urea-splitting organism such as Proteus. Pleural fluid glucose levels are depressed in empyemas, and although white cell counts are variable, counts above 5,000/mm3 are common, with polymorphonuclear leukocytes predominating. Gram stains of the pleural fluid will often reveal the causative organisms. Both aerobic and anaerobic cultures are mandatory; a foul odor suggests anaerobic infection. Stains and cultures for mycobacteria and fungi are important in selected cases.
Treatment
Treatment of empyemas involves both antibiotics and drainage. Antibiotics should be selected on the basis of the causative pathogens. High-dose parenteral therapy is required, and prolonged courses of 3 weeks or more are often needed. Adequate drainage is of paramount importance. In acute empyemas, the pleural cavity is lined by acute fibrinous inflammation, and percutaneous drainage of free-flowing fluid may be possible by repeated thoracentesis or tube thoracostomy. Closed chest tube drainage is the traditional method for draining empyemas, but image-guided catheter drainage is also effective, particularly when the fluid is loculated. Resolution of fever generally signifies satisfactory drainage. If complete drainage cannot be achieved with chest tubes, video-assisted thoracoscopic surgery (VATS) can often disrupt intrapleural adhesions and achieve excellent drainage of loculated effusions92; although VATS requires endotracheal intubation and general anesthesia, it is less invasive than the next alternative, rib resection with tho-racotomy for decortication. Enzymatic debridement with strep-tokinase may enable some patients to avoid surgery.
Septic Pulmonary Embolism
Although once uncommon, septic pulmonary embolism is now encountered because of I.V. drug abuse, which accounts for more than 75% of cases; tricuspid valve endocarditis and direct injection of infected material cause most of these cases. S. aureus and gram-negative bacilli are the predominant etiologic agents in I.V. drug abusers. Septic pulmonary embolism may also develop in patients with septic phlebitis of peripheral veins (especially phlebitis related to I.V. lines or pelvic infections), abscesses, or other bacteremic infections.
Unlike bland emboli, septic pulmonary emboli produce pulmonary infarction in most instances. Small emboli produce flame-shaped or patchy infiltrates that may shift in location; these manifestations generally resolve with antibiotic therapy. Larger emboli often cavitate and may lead to lung abscess, empyema, or bronchopleural fistula formation. In addition to antibiotics, surgical drainage may be required for such complications. Operative intervention may be needed to control the source of emboli in some patients. Heparin can be useful in patients with septic phlebitis.
