Thoracic surgeons occasionally must be involved in the diagnosis and treatment of respiratory tract infections. In addition to the complication of postoperative pneumonia in surgical patients, assistance may be needed for diagnosing radiographic abnormalities, community-acquired pneumonia (CAP), nosocomial pneumonia, ventilator-associated pneumonia (VAP), and pneumonia in the immunocompromised host. Although most clinically significant infections can be identified with respiratory cultures and microbiologic analysis, a small percentage of infections require a surgical pathologist for definitive diagnosis. 1 The spectrum and burden of etiologic organisms are affected by host risk factors and immune status. [2] [3] [4] [5] [6] [7] Because organisms are found less often in the lung tissue of patients with normal immunity, diagnosis can be facilitated by cultures, serologic studies, and epidemiologic data. 8 In the immunocompromised host, a broader differential must be considered, including the possibility of multiple simultaneous infections.
In addition to infection, other disorders should be considered, such as pulmonary involvement by preexisting disease, drug-induced or treatmentrelated injury, noninfectious interstitial pneumonias, and malignancy. Appropriate chest imaging may help narrow the differential. This information, when combined with clinical history and the timing of the disease (acute, subacute, or chronic), is critical to a successful treatment strategy. This article reviews the current diagnostic modalities and medical treatment recommendations for pulmonary infections.
The successful treatment of pulmonary infections depends on accurate identification of the precipitating pathogen. In contemporary medical practice, distinction of the genus or species of an infectious organism can have important prognostic and therapeutic implications. Suspected pulmonary infections should be defined by (1) signs and symptoms consistent for diagnosing a pneumonia, (2) clinical setting consistent with acquisition of pneumonia, (3) host susceptibility predisposing to pneumonia, and (4) exposure and risk factors of specific pathogens. 9 For pneumonia, sputum collection with microscopic examination and culture of expectorant is the mainstay of laboratory evaluation. Although simple, quick, and inexpensive, sputum cultures are nonetheless negative for growth 50% of the time despite proven infections. Contamination with oropharynx secretions is also a frequent issue. If sputum evaluation fails to identify causative factors and definitive identification is required for successful patient treatment, more invasive sampling techniques are available, including bronchoscopy, transthoracic needle aspiration or core biopsy, and surgical wedge biopsy of peripheral lung using a transthoracic approach. [10] [11] [12] [13] [14] [15] [16] [17] Specimens Obtained Through the Flexible Bronchoscope Current pulmonary endoscopy is dominated by the flexible bronchoscope. Its flexibility provides the advantage of better access to more distal airways. 18, 19 Lavage and washings can be aspirated and the fluid sample of suspended cells can be sent to the laboratory for millipore filtration or cytocentrifuge-type application onto slides (Fig. 1) . 14, 17, [20] [21] [22] Clinical guidelines confirm the value of a bronchoscopic approach to diagnosis, particularly in patients with VAP, in whom it has been shown to reduce 14-day mortality. 23, 24 Endobronchial ultrasound has also added to the available diagnostic options (Fig. 2) . Both transbronchial lung biopsy of peripheral pulmonary lesions and sampling of mediastinal and hilar lymph nodes may provide access to infectious pathogens that cannot be identified otherwise. 25, 26 The transbronchial biopsy technique allows obtainment of samples of alveolar lung parenchyma beyond the cartilaginous bronchi. 17, 19, 20, 27 Endoscopic transbronchial biopsies taken blindly are intended to represent alveolar lung parenchyma. Sometimes these samples have bronchial mucosa and cartilage if a branch point, such as a minor carina, is sampled directly (Fig. 3) . Many types of pulmonary infections can be diagnosed using fine needle aspiration and cytologic evaluation. [28] [29] [30] [31] Fine needle aspiration is an especially useful technique, because respiratory secretions (eg, sputum, bronchial washings, brushings, bronchoalveolar lavage) are often limited by the need to differentiate true pathogens from contaminant organisms. Nevertheless, these diagnostic tools are complementary and both remain excellent options in the diagnosis of localized or diffuse pulmonary infection. Electromagnetic navigation bronchoscopy has proven effective in assessing pulmonary nodules accurately with low complication rates. Electromagnetic navigation bronchoscopy uses computer guidance to enable bronchoscopic access to pulmonary lesions (Fig. 4) . 32 
Contamination can be minimized when the upper respiratory tract can be bypassed. With either transtracheal or transthoracic needle aspiration, the presence of bacteria becomes much more significant, especially when sheets of neutrophils and/or necroinflammatory debris are present (Fig. 5) , as would be the case with a typical lobar or lobular consolidation, lung abscess, or other complex pneumonia (Fig. 6) . [34] [35] [36] [37] In this context, transthoracic needle aspiration can establish the etiologic diagnosis of CAP and nosocomial pneumonia when coupled with contemporary microbiologic methods. [38] [39] [40] [41] In current practice, the use of transthoracic needle aspiration biopsy has become commonplace, 16, [42] [43] [44] [45] [46] [47] and it is often used to target well-circumscribed nodules when an infectious process must be ruled out (Fig. 7) . Besides the morphologic features of the microorganism, important cytologic clues to the diagnosis include the accompanying cellular response and the presence and character of any necrotic debris. Anaerobic pulmonary infections, typically in the form of a lung abscess, can also be approached in this way or with transthoracic needle aspiration (Fig. 8) . 48 In some cases, core biopsy is preferable to an aspirate. Needle core biopsies may provide better and more abundant diagnostic tissue, whereas aspirate is preferred when evaluating suspected bacterial abscess. Based on the microscopic features of the organism obtained, this technique may yield rapid diagnostic results. 39 In addition to respiratory samples, pleural fluid can be tapped when effusions are present. Positive cultures of these normally sterile fluids circumvent the interpretive problems associated with bacterial growth in sputum samples. Persistent effusions and suspected empyema can be easily analyzed with thoracentesis ( Fig. 9 ). [49] [50] [51] Specimens Obtained Through Thoracoscopy Surgical biopsy of lung parenchyma is indicated to distinguish infection from interstitial and inflammatory lung disease. The introduction of high-resolution video equipment has changed elective thoracic surgery. With small incisions and a thoracoscopic video camera (Fig. 10) , surgeons can directly biopsy affected lung tissue, with large quantities of parenchyma available for both microbiologic and pathologic evaluation (Fig. 11) . Video-assisted thoracic surgery has become the standard approach for most surgical biopsies. Mortality is low and length of hospital stay and recovery are improved over those with the standard thoracotomy. 52 When the same thoracic access ports are used, ipsilateral lymph nodes that may contain disease or abnormalities can be biopsied simultaneously. Before a wedge lung biopsy is performed, consultation among the radiologist, chest physician, and thoracic surgeon is essential to identify ideal locations for biopsy.
Pneumonia may be classified according to several parameters, including pathogenesis, epidemiology, anatomic pattern (see Fig. 4 ), clinical course, and organism. 53 In this article, pulmonary bacterial infection is divided into CAP, health care-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), and VAP. Mycobacterial, fungal, and viral infections are also addressed because these entities require special diagnostic and treatment considerations. The pathologic patterns and agents of the most common pulmonary infections are listed in Table 1 .
CAP is defined as pneumonia acquired in an outpatient setting by patients in whom common lower respiratory pathogens are suspected. Although viruses (Fig. 12) and endemic fungi may cause CAP, the definition and treatment regimens presuppose a bacterial origin. The most common origins are listed in Table 2 (Figs. 13 and 14A, B). Coverage of these agents forms the basis for initial empiric treatment of CAP. However, clinicians must be aware of factors that predispose patients to pneumonia caused by drug-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa; antibiotic selection for these patients should take into consideration additional breadth of spectrum (Box 1). 23 
The American Thoracic Society and the Infectious Disease Society of America have published joint guidelines on the diagnosis and management of CAP. Box 2 55 summarizes the recommended empiric antibiotics for CAP. Recommended treatment regimens vary based on severity of illness and setting (eg, outpatient, inpatient, intensive care). For empiric inpatient therapy, strong evidence supports use of either a respiratory fluoroquinolone or a combination of a b-lactam plus a macrolide. 56 In patients requiring intensive care, guidelines recommend a b-lactam plus a fluoroquinolone. 55 However, in this critically ill population, in whom the margin for error is low, many clinicians favor an initial broad-spectrum regimen that includes anti-MRSA and antipseudomonal coverage.
If an etiologic agent is identified, antimicrobial therapy should be narrowed to target that pathogen ( Table 3) . Guidelines recommend that before discontinuation of therapy, a minimum of 5 days of treatment should occur, and patients should have achieved clinical stability as evidenced by the absence of fever for greater than 48 hours, hypoxia, tachypnea, tachycardia, and hypotension. Patients can be safely switched from intravenous to oral therapy when they are hemodynamically stable and able to absorb oral medication. 58, 59 A longer duration of therapy may be necessary if the patient does not experience improvement, the identified pathogen was not sensitive to initial empiric therapy, or an extrapulmonary infection is present.
A subset of patients presenting with pneumonia acquired in the community will have risk factors for disease caused by drug-resistant pathogens (DRP). In the 2005 guidelines from the American Thoracic Society and the Infectious Diseases Society of America (ATS/IDSA) for HAP and VAP, an additional category, HCAP, was proposed to the existing paradigm. 23 These patients share risk factors for DRP with those susceptible to HAP and VAP, including exposure to P aeruginosa, extended spectrum b-lactamase producing Escherichia coli and Klebsiella, Acinetobacter, Burkholderia, drug-resistant Enterobacteriaceae, and MRSA. Included in the new classification are patients hospitalized within the past 90 days; those receiving chemotherapy, wound care, or intravenous antibiotics; residents of nursing homes or long-term facilities; and patients undergoing hemodialysis. For these patients, the guidelines recommend a more aggressive empiric antibiotic regimen, including an antipseudomonal blactam plus either an aminoglycoside or an Table 4 ).
Nosocomial pneumonia is generally subdivided into HAP, including postoperative pneumonia, and VAP. HAP is defined as pneumonia occurring in patients hospitalized for longer than 48 hours before onset and is associated with high mortality rates. 23 The treatment algorithm for HAP is based on individual risk for DRP (see Box 1) and time of onset. Patients with no preexisting risk factors for DRP in whom early HAP develops (within the first four hospital days) may be treated with a b-lactam such as a third-generation cephalosporin, ampicillin-sulbactam, or ertapenem, or with a respiratory fluoroquinolone such as levofloxacin. Patients with late-onset HAP (five or more inpatient days) or with risk factors for DRP should be treated with a broad-spectrum regimen (see Table 4 ). 23 VAP VAP is defined as pneumonia occurring more than 48 hours after initiation of endotracheal intubation and mechanical ventilation. 60 Prior hospitalization within the past 90 days or prior antibiotic therapy predisposes to colonization and infection with antibiotic-resistant pathogens. 61 Suspected cases of VAP should be reviewed for risk factors and signs of antibiotic multidrug resistance (MDR) (Fig. 15) .
VAP is the most frequently acquired infection in intensive care units (ICUs), with an incidence of 6% to 52%. 60 Generally, VAP is more prevalent in surgical ICUs than in medical ICUs. 60 Risk factors for VAP include both host and intervention factors ( Table 5 ). The microbes commonly associated with VAP are similar to those that cause HAP ( Table 6) . VAP caused by more than one pathogen was identified in 30% to 70% of cases. 60, 61 Treatment with initial empiric therapy should be guided by the risk for MDR pathogens as described earlier for HCAP and HAP ( Table 7) . A strategy for deescalation from an empiric broad-spectrum, multidrug regimen to a targeted therapy with a narrower spectrum is recommended to reduce antibiotic use and the selective pressure for MDR bacteria. 62, 63 Aerosolized Antibiotic Therapy in the ICU A growing body of data suggests that aerosolized antibiotics may have a role in the treatment of pulmonary infections in mechanically ventilated patients. 64 Table 8 .
With proper delivery, antimicrobial therapy may be targeted directly at the site of infection, increasing concentrations in the lung while minimizing systemic toxicity ( Table 9 ). 64 Delivery mechanisms range from atomizers to jet and ultrasonic nebulizers, and vibrating mesh technology. Given the rise in incidence of DRPs in the ICU, large multicenter trials are needed to validate these novel treatment options. The current guidelines from the American Thoracic Society do not recommend routine use of aerosolized antibiotic therapy but do state that aerosolized antibiotics may be considered for treatment of microorganisms with a high minimum inhibitory concentration to parenteral antibiotics. 23 
Mycobacterial infection may manifest clinically with vast variation. Pulmonary infection is common and may be diagnostically challenging because of significant overlap in presenting symptoms with other pulmonary infections. Therefore, diagnosis is often delayed until confirmation with an invasive procedure, such as transbronchial biopsy, transthoracic needle biopsy, or surgical lung biopsy. 69, 70 Direct acid-fast bacillus smears of respiratory specimens are negative in approximately 50% of cases, 71 and a biopsy may be the first suggestion of a mycobacterial infection (Fig. 16) . 72 Mycobacterial species can be categorized into two clinically relevant groups: Mycobacterium tuberculosis complex and nontuberculous mycobacteria (NTM).
M tuberculosis is the most virulent mycobacterial species and is the etiologic agent of Table 2 and MDR pathogens Pseudomonas aeruginosa Klebsiella pneumoniae (ESBL1) b Acinetobacter spp b
Antipseudomonal cephalosporin (cefepime, ceftazidime) or Antipseudomonal carbapenem (imipenem or meropenem) or b-Lactam/b-lactamase inhibitor (piperacillin-tazobactam) plus Antipseudomonal fluoroquinolone b (ciprofloxacin or levofloxacin) or Aminoglycoside (amikacin, gentamicin, or tobramycin) plus Linezolid or vancomycin c Abbreviation: ESBL, extended-spectrum b-lactamase.
a Initial antibiotic therapy should be adjusted or streamlined based on microbiologic data and clinical response to therapy.
b If an ESBL 1 strain, such as K pneumoniae or an Acinetobacter sp is suspected, a carbapenem is a reliable choice. If L pneumophila is suspected, the combination antibiotic regimen should include a macrolide (eg, azithromycin) or a fluoroquinolone (eg, ciprofloxacin or levofloxacin) should be used rather than an aminoglycoside. c If MRSA risk factors are present or there is a high incidence locally. tuberculosis worldwide in its various forms. This organism is responsible for more deaths worldwide than any other single microbe. Postprimary tuberculosis, the most common form in adults, typically involves the apices of the upper lobes, producing granulomatous lesions with cavities and variable degrees of fibrosis and retraction of the parenchyma. [73] [74] [75] In a minority of patients, the lesions enlarge and progress secondary to increased necrosis and/or liquefaction. 76 NTM include more than 125 species 77,78 ; however, relatively few cause pulmonary disease. 72,79-81 NTM species are subdivided according to growth rates. Of the rapid growers, M abscessus is the most frequently recovered pulmonary pathogen, whereas M fortuitum and M chelonae are more often associated with wound infection and soft tissue disease. 68 Among the slow growers, M avium-intracellulare complex is the most common NTM respiratory pathogen, followed by M kansasii in the United States and M xenopi in Europe. NTM may cause a wide spectrum of pulmonary and extrapulmonary disease, but most frequently cause fibronodular bronchiectasis or cavitation. 68 
Treatment of mycobacterial disease is generally more complicated than that for other bacteria because of the slow growth of the organisms, mechanisms of drug resistance (eg, the unique cell wall characteristics of the genus), and poor drug tolerability. Multidrug regimens are required for extended duration. Once the diagnosis of active pulmonary tuberculosis is confirmed, initial recommended treatment comprises a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin, according to local patterns of susceptibility. 82 Duration of therapy depends on the drug susceptibility of the isolate, presence of extrapulmonary involvement, and immune status of the patient. Although acquired resistance does occur, the more common cause of treatment failure is medication nonadherence. For this reason, evidence strongly supports direct observational therapy. Confirmation of clearance of sputum acid-fast bacilli is recommended at 3 months. Given the increase in MDR and extensively drug-resistant M tuberculosis strains, repeat susceptibility testing is warranted with documented treatment failure. If drug-resistant strains are identified, expert consultation is recommended, and a regimen composed of at least four agents should be selected in a stepwise approach from the following classes: (1) all first-line agents to which the strain is sensitive: isoniazid, rifampin, pyrazinamide, and ethambutol; (2) one fluoroquinolone, if susceptible; (3) one injectable aminoglycoside, such as streptomycin or kanamycin; (4) less effective second-line antituberculous drugs, such as ethionamide or cycloserine; and (5) second-line agents for which few data are available: linezolid, clarithromycin, amoxicillinclavulanate, or clofazamine. 83 Treatment of pulmonary NTM is less well defined. Although the principles of management are similar to those for M tuberculosis, antibiotic regimens vary by species. 68 For M avium complex, ATS/IDSA guidelines recommend a combination of clarithromycin, rifampicin, and ethambutol, whereas for M kansasii, the initial regimen comprises isoniazid, rifampicin, and ethambutol. 72 For localized pulmonary M abscessus infection, medical management alone is not effective and surgical resection is required.
Tuberculosis remains the most common cause of hemoptysis worldwide; however, in the United States, invasive fungal infections, chronic granulomatous disease, bronchiectasis, and bronchitis account for most cases. 84, 85 Conservative management can often control bleeding. The current recommended strategy for hemoptysis is initial nonoperative management and stabilization, with surgery reserved for isolated cases. [86] [87] [88] For a patient presenting with massive hemoptysis, the immediate goals of the surgeon are to preserve life through protecting the healthy lung from aspiration, to stabilize the patient hemodynamically, and to correct any coagulopathy. 85 Bronchoscopy can often be effective if bleeding is mild. 89 More than 80% of patients can be treated successfully with bronchoscopic localization. 84, 89 The bleeding site can be controlled with balloon tamponade, laser ablation, and local vasopressor therapy. The decision to intervene angiographically should be made based on the clinical examination, imaging results, bronchoscopic findings, and physician expertise. Transcatheter arterial embolization is successful in most patients. 84, 85, [90] [91] [92] [93] [94] Although bronchial embolization is the mainstay of treatment, emergency surgery can be considered if initial attempts to control bleeding and stabilize the patient prove unsuccessful. The decision to take the patient to the operating room requires at a minimum known laterality of the lesion and, optimally, lobar location (Fig. 17) . 85 
With the rapid increase in bone marrow and solid organ transplantation, invasive fungal infection has become a significant cause of morbidity and mortality. Although nearly 100 fungi have been recovered from respiratory infections, 95 only a small number are consistently implicated as pathogenic (Box 4). Broadly, fungal pathogens that infect the lung include yeasts such as Candida spp and Cryptococcus; endemic dimorphic fungi such as Histoplasma and Coccidioides; filamentous molds, of which Aspergillus is most common; and members of the family Mucorales.
The most effective method of diagnosis is often identification of fungi in tissue sections or cytologic samples (Fig. 18) . 31, 96, 97 The patient may present with a wide spectrum of radiographic pulmonary disease. In the healthy host, fungal pathogens typically produce one or more nodular lesions (Fig. 19) , which, in turn, may become cavitary as the lesions evolve (Fig. 20) . However, clinical presentation may vary widely and may include solitary or multiple and bilateral nodular lesions; segmental or lobar consolidation; cavitary lesions, fistulas, infarcts; direct extension into mediastinal, thoracic soft tissue, chest wall, and diaphragm; chronic tracheal and endobronchial infection; and fungus ball such as aspergilloma. 98 Proximal endobronchial disease mimicking a neoplasm has also been described for various fungal species. 99 
Until recently, effective treatment options for invasive fungal infection were largely limited to amphotericin B deoxycholate, which is well known for its potential for systemic toxicity. However, the development of lipid, liposomal, and aerosolized formulations of amphotericin B, and newer triazole and echinocandin antifungal agents, has greatly expanded treatment options for these diseases. Because of differences in antifungal susceptibility and prognosis between dimorphic endemic fungi, filamentous fungi, and other molds (eg, Mucor), a definitive microbiologic or pathologic diagnosis is strongly preferred before treatment.
For invasive Aspergillus infection, a large randomized controlled trial showed the superiority of voriconazole over amphotericin B, 100 treatment of invasive pulmonary aspergillosis in most patients. 101 Limited data suggest that in certain populations, such as heart transplant recipients, voriconazole in combination therapy with caspofungin may contribute to improved outcomes; additional data are anticipated. 102, 103 In lung transplant recipients, aerosolized amphotericin B has been used for antifungal prophylaxis and as adjunct therapy in invasive fungal disease. 104 In pulmonary mucormycosis, however, voriconazole is ineffective. The preferred treatment remains amphotericin B, although some data suggest that liposomal amphotericin B may be more efficacious than the deoxycholate formulation. 105 A novel triazole, posaconazole, has also been approved for salvage therapy, but it is limited by its availability in oral formulation only and its inconsistent bioavailability. 105 Limited evidence also suggests improved outcomes with a combination therapy of amphotericin B and posaconazole or an echinocandin. 105 When empiric therapy is required in critically ill patients in whom hemodynamic instability or cytopenia may prevent invasive diagnostic procedures, the logical approach is combination therapy with voriconazole and amphotericin B.
Viruses cause more infections in the respiratory tract than all other types of microorganisms combined. 106 The viruses that commonly infect the lung are presented in Box 5. The common respiratory viruses (eg, influenza, parainfluenza, respiratory syncytial virus, adenovirus) cause outbreaks of respiratory illness in the general population each year. Fortunately, most viral respiratory infections are mild and self-limited. However, viruses are also capable of producing serious or life-threatening infections, such as in the case of primary varicella-zoster pneumonia 107 or respiratory disease caused by highly pathogenic strains of influenza. 108, 109 In addition, viralmediated bronchial epithelial damage predisposes susceptible patients to secondary bacterial infection, which is associated with significant morbidity and mortality. 110 Recent outbreaks of the H1N1 strain of influenza A have served to highlight the increased risk of mortality associated with influenza complicated by secondary bacterial infection, especially with S aureus. 111, 112 In immunocompromised hosts, less common viral agents may cause severe clinical disease. In these patients, diagnosis may be made through respiratory cytologic specimens, from which herpes simplex, Cytomegalovirus, and adenovirus are the most commonly identified viral pathogens. 113 The cytologic features of viral infections in the respiratory tract are most likely to be found in exfoliative specimens, such as bronchial washings and bronchoalveolar lavage. 114, 115 Treatment of Viral Pulmonary Infection
In most respiratory infection caused by viruses, no treatment is necessary. No consensus exists on prophylactic antibiotic treatment of influenza-like illness. However, when secondary bacterial pneumonia is suspected, antibacterial agents targeting the most common causative pathogens (S pneumoniae and S aureus, including MRSA) should be initiated. Treatment options for primary viral respiratory tract infections are limited. For influenza A, early treatment with oseltamivir or zanamivir within 48 hours of the onset of symptoms has been shown to decrease complications, especially in the very young, elderly individuals, and patients with impaired immune status or comorbid conditions. Table 10 116 summarizes the possible for antiviral treatments for prevention of severe viral pneumonia.