The etiology and clinical manifestations of pneumonia depend on the environment where the disease is acquired and the host characteristics.
Treatment of pneumonia is based on an assessment of place of therapy (outpatient, hospital ward, or ICU), the presence of coexisting cardiopulmonary diseases, and the presence of modifying factors.
Although prompt initiation of antibiotics is critical in patients with nosocomial pneumonia, all patients with suspected pneumonia should have a sampling done of lower respiratory tract secretions to better guide the therapy.
Lung abscess should be managed initially with appropriate medical therapy and/or percutaneous drainage.
Owing to the presence of branching hyphae, infections due to actinomycosis and nocardiosis may be mistaken for fungal infections. It is important to make the distinction because actinomycotic infections do not respond to antifungal therapy but rather to antibiotics.
Surgical consultation is regularly requested for the diagnosis and treatment of pulmonary complications of the endemic mycoses: Histoplasma capsulatum, Blastomyces dermatitidis and Coccidioidomycosis immitis, and the yeast Cryptococcus neoformans. All resemble pulmonary malignancies.
Histoplasmosis causes pericarditis, mediastinal fibrosis, and mediastinal granuloma, which can cause entrapment of vascular structures, the esophagus, and the trachea.
Coccidioidomycosis can cause both spontaneous pneumothorax associated with effusion and thin-walled cavities that can become superinfected with tuberculosis and aspergillosis.
Cryptococcosis can result in organ damage from tissue distortion secondary to an expanding fungal burden.
Most patients with pulmonary aspergillosis have either impaired immunity or underlying preexisting chronic lung disease. Aspergillomas may develop in preexisting cavities. Surgery is indicated for complications of the disease, such as massive hemoptysis.
Surgery has largely been supplanted by multiple-regimen medical therapy for tuberculous and nontuberculous mycobacterial infections. There is still a role for pulmonary resection in multidrug-resistant infection, cavitary lesions, and lung destruction.
Lower respiratory tract infections are important in the practice of the thoracic surgeon because their complications may require surgical intervention and they may complicate thoracic surgical procedures.
Pneumonia is an infection of the lower respiratory tract that involves the terminal airways: respiratory bronchioles, alveolar ducts, and alveoli. The infection develops when the sterility of the tracheobronchial tree is breached by the introduction of a virulent pathogen or a defect in the host immunologic defense. Symptoms of acute lower respiratory infection may include fever or hypothermia, rigors, sweats, new cough with or without sputum production or change in color of respiratory secretions in a patient with chronic cough, chest discomfort, or shortness of breath. Most patients also have nonspecific symptoms, such as fatigue, myalgias, abdominal pain, anorexia, and headache.
Despite advancements in the diagnosis and treatment of pneumonia in the past century, it is listed by the Centers for Disease Control and Prevention as the sixth leading cause of death in the United States and the leading cause of death from infectious diseases.1 Contemporary management of pneumonia is based on whether the infection was acquired in the community versus in the hospital, including any care facility, the severity of illness, and the patient’s comorbid conditions, including immune status.
Community-acquired pneumonia (CAP) is commonly defined as an acute infection of the pulmonary parenchyma in a patient not hospitalized or residing in a long-term-care facility for ≥14 days before the onset of symptoms. CAP is among the leading causes of death in the United States, accounting for some 65,000 deaths in 20022; it is responsible for more than 10 million physician visits a year and some 1.4 million hospital discharges. The most common etiologic agent of CAP is Streptococcus pneumoniae, which accounts for about two-thirds of all cases of bacteremic pneumonia.2 Other pathogens include Haemophilus influenzae, Mycoplasma pneumoniae, Chlamydia pneumoniae, Staphylococcus aureus, Streptococcus pyogenes, Neisseria meningitidis, Moraxella catarrhalis, Klebsiella pneumoniae and other gram-negative rods, Legionella species, influenza virus (depending on the season), respiratory syncytial virus, adenovirus, and parainfluenza virus. Gram-negative bacilli (Enterobacteriaceae and Pseudomonas) are the cause of CAP in some patients (those who have had previous antimicrobial treatment or who have pulmonary comorbidities). The frequency of other causes, such as Mycobacterium tuberculosis, Chlamydophila psittaci (psittacosis), Coxiella burnetii (Q fever), Francisella tularensis (tularemia), and endemic fungi (Histoplasma, Coccidioides, Blastomyces) vary between epidemiologic settings.3 Certain pathogens cause pneumonia more commonly among persons with specific risk factors. For instance, pneumococcal pneumonia is especially likely to occur in the elderly and in patients with a variety of medical conditions, including alcoholism, chronic obstructive airway disease, immune-deficiency, etc. Legionella is an opportunistic pathogen that is rarely recognized in healthy young children and young adults. It is an important cause of pneumonia in organ transplant recipients and in patients with renal failure.
All patients suspected to have pneumonia should undergo chest radiography for the following reasons: to confirm the diagnosis, to provide information on the location and extent of the disease, to explore the possibility of complications such as pleural effusion, multilobar disease, and cavitation; to detect underlying pulmonary disease or alternative diagnoses; and to monitor the progression or resolution of the disease.4 Other appropriate tests for hospitalized patients with CAP include a complete blood cell count and differential, serum creatinine, blood urea nitrogen, glucose, electrolytes, and liver function tests. Oxygen saturation should be assessed by pulse oximetry in all admitted patients and arterial blood gas in sicker patients. There should be two pretreatment blood cultures as well as Gram’s staining and culture of expectorated sputum.4,5
Other tests that should not be performed routinely but might be useful in some patients admitted to the hospital include the urinary antigen assays for Legionella species and Strep. pneumoniae and a direct stain (i.e., acid-fast) for the detection of mycobacterial infections in patients who are in high-risk categories for tuberculosis.3,5 HIV serology with informed consent should also be considered, especially for persons aged 15 to 54 years.3 Serologic testing may also include tests for viral agents, endemic fungi, and other unusual pathogens in appropriate clinical settings. Invasive diagnostic techniques (transtracheal aspiration, bronchoscopy with a protected brush catheter, bronchoalveolar lavage [BAL], and direct percutaneous fine-needle aspiration of the lung) are used to obtain lower airway specimens uncontaminated by oropharyngeal flora. These procedures may help to obtain early accurate diagnosis and are reserved for occasional patients who are severely ill.1,5 Potentially infected body fluids from other anatomic sites—including pleural fluid, joint fluid, and cerebrospinal fluid (CSF)—should be obtained for chemistry, Gram’s staining, and culture if warranted by the clinical presentation.
Pathogen-directed antimicrobial therapy is ideal, but this is usually not feasible because no etiology can be identified in more than 50 percent of cases. Empiric antibiotic regimens should include coverage of “atypical pathogens” and should be changed when results of culture and in vitro sensitivity tests become available.3 All admitted patients should receive their first dose of antibiotic therapy within 8 h of arrival at the hospital. This has been shown to reduce mortality at 30 days.6 The American Thoracic Society (ATS) currently makes recommendations based on an assessment of place of therapy (outpatient, hospital ward, or ICU), the presence of coexisting cardiopulmonary disease (chronic obstructive pulmonary disease [COPD], congestive heart failure), and the presence of modifying factors such as age, immune status, other comorbid factors, etc. Most patients can be treated using monotherapy with antipneumococcal fluoroquinolone except for ICU-admitted patients who should receive β-lactam plus either a macrolide or a quinolone. Appropriate at-risk patients should receive a regimen with two antipseudomonal agents.
Hospital-acquired pneumonia (HAP) is defined as pneumonia that occurs 48 h or more after admission and that was not incubating at the time of admission. According to the report from the National Center for Infectious Diseases, nosocomial pneumonia is the most frequent hospital-acquired infection in the combined medical and surgical ICUs, which accounts for 31 percent of all infections in the ICU.7 Risk factors for HAP include mechanical ventilation for >48 h, residence in an ICU, duration of ICU or hospital stay, severity of underlying illness, and presence of comorbidities. Generally, loss of mechanical host defense and suppression of normal flora probably explain a major component of the increased risk of pneumonia in hospitalized patients. The most obvious compromise of normal host immunity in hospitalized patients is alteration of the mechanical components of lung defenses.
Nearly half of the HAP cases are polymicrobial. Early-onset HAP (occurring in the first 4 days of hospitalization) is often caused by community-acquired pathogens such as H. influenzae, Strep. pneumoniae, or methicillin-susceptible Staph. aureus (MSSA). HAP developing ≥5 days after hospitalization (“late onset”) is often caused by aerobic gram-negative bacilli (e.g., Pseudomonas aeruginosa, Enterobacteriaceae, or Acinetobacter) or methicillin-resistant Staph. aureus (MRSA).8 In patients receiving mechanical ventilation, these antibiotic-resistant pathogens assume increasing importance. Other gram-negative rods, such as Escherichia coli and Klebsiella species, are also common pathogens. Nosocomial viral and fungal infections are uncommon causes of HAP in immunocompetent patients.
Ventilator-associated pneumonia (VAP) is a pneumonia that arises more than 48 to 72 h after endotracheal intubation. VAP accounts for as much as 83 percent of nosocomial pneumonia and carries a particularly poor prognosis, with a reported mortality rate of up to 50 percent. Aspiration of oropharyngeal or gastric contents contaminated with colonizing flora is important in the pathogenesis of VAP. Several factors that lead to impairments in level of consciousness and/or swallowing and cough reflexes (e.g., related to cerebrovascular disease) increase the risk for the development of aspiration pneumonia. The oropharynx appears to be the most important source of microorganisms. Continuous aspiration of subglottic secretions has been associated with significant reductions in the incidence of VAP in two randomized trials.9 Supine patient positioning may also facilitate aspiration, which may be decreased by a semirecumbent positioning.10 Enteral nutrition has been considered a risk factor for the development of pneumonia mainly because of an increased risk of aspiration of gastric contents. However, its alternative, parenteral nutrition, is associated with higher risks for infections associated with intravascular devices, complications of line insertions, higher costs, and loss of intestinal villous architecture, which may facilitate enteral microbial translocation. Nasogastric intubation and gastroparesis are other known risk factors for aspiration.
The diagnosis of HAP is suspected if the hospitalized patient has a radiographic infiltrate that is new or progressive along with clinical findings suggesting infection, which include the new onset of fever, purulent sputum, leukocytosis, and decline in oxygenation. Most studies of nonintubated patients have involved clinical diagnosis with sputum culture. A recent meta-analysis showed that the most acceptable standards for the diagnosis of VAP require quantitative cultures of BAL fluid or protected specimen brush samples. BAL is also recommended if the patient is already receiving antibiotics.
Initial inadequate antimicrobial therapy for HAP is an independent risk factor for increased mortality. Initial therapy (while awaiting results of cultures) must be empiric and cover a broad spectrum of possible pathogens. Demographics, host factors (e.g., severity and acuity of illness, comorbidities), duration of hospitalization, prior antibiotic use, and antimicrobial resistance patterns within the hospital or ICU must be taken into account in selecting antibiotics for empiric treatment. Rates of resistance are influenced by type and size of hospital, ICU or non-ICU setting, anatomic site of isolation, and patterns of prior antibiotic use within individual patients or institutions. Empiric treatment for pneumonia occurring within the first 4 days of hospitalization in patients without severe comorbidities or exposure to antibiotics need not encompass P. aeruginosa or potentially resistant pathogens. However, broader-spectrum coverage (to include these pathogens) is advised for critically ill ICU patients requiring prolonged mechanical ventilation or those who have received prior antibiotics. In this context, a combination of antipseudomonal β-lactam (e.g., cefotetan) plus an aminoglycoside (if no contraindications to aminoglycoside use exist) can be used. Alternatively, a fluoroquinolone can be substituted for the aminoglycoside. Linezolid is an alternative to vancomycin for the treatment of MRSA. The Study Group on Aspiration Pneumonia found that ampicillin plus the β-lactamase inhibitor sulbactam, when compared with clindamycin with the optional addition of a second- or third-generation cephalosporin, was equally effective in terms of clinical response.10 Antibiotic therapy should be tailored appropriately when culture results become available.
Lung abscess is defined as necrosis of the pulmonary tissue caused by microbial infection and the formation of cavities containing necrotic debris or fluid. The process usually begins as a localized pneumonitis. Liquefaction necrosis of the lung tissue eventually communicates with the bronchial tree. This partial internal drainage results in the classic cavity with an air-fluid level. The formation of multiple small (<2 cm) abscesses is occasionally referred to as necrotizing pneumonia or lung gangrene. Both lung abscess and necrotizing pneumonia are manifestations of a similar pathologic process.
Aspiration of infectious material is the most frequent etiologic mechanism in the development of primary lung abscess. Poor oral hygiene, dental infections, and gingival disease are common in these patients. Some of the factors that predispose to aspiration include states of compromised consciousness (e.g., cerebrovascular accident, seizure, alcoholism, anesthesia, head trauma, and coma) and esophageal disease (e.g., achalasia, reflux disease, and various causes of esophageal obstruction). Immunocompromised hosts—including patients on various chemotherapies, malnourished patients, and those with multiple trauma—are also at risk. Secondary lung abscess can occur from a hematogenous source; bronchial obstruction by tumor, stricture, or foreign body; or extension from an extrapulmonary site, such as mediastinal, subdiaphragmatic, or hepatic abscesses.11
The posterior segment of the right upper lobe and the superior segment of the right lower lobe are the most common locations for lung abscess. This is due to gravitation of the infectious material from the oropharynx into these dependent areas of the lung. Lung abscesses have numerous infectious causes. The dominant pathogens are Peptostreptococcus, Bacteroides, Prevotella, and Fusobacterium species.12 A primary lung abscess may be caused by Strep. pneumoniae, Strep. viridans, K. pneumoniae, and H. influenzae. Selected nonbacterial pathogens that can produce lung abscess include parasites (e.g., Entamoeba histolytica), many fungi (e.g., Aspergillus species, Histoplasma capsulatum), and mycobacteria. A number of opportunistic infections, such as nocardiosis and aspergillosis, can dominate in lung abscess in immunocompromised hosts.
One unique mechanism for the development of lung abscesses occurs in Lemierre syndrome, or jugular vein suppurative thrombophlebitis.13 This infection begins in the pharynx (sometimes with an overt tonsillar or peritonsillar abscess) but spreads to involve spaces in the neck and the carotid sheath, which contains the internal jugular vein. Bacteremia, due to Fusobacterium necrophorum, and septic emboli to the lungs, which subsequently cavitate, are all characteristic complications of this process once the vessels are involved. Tricuspid valve endocarditis, usually due to Staph. aureus, also typically causes septic emboli that are widely distributed in both lungs. This is a common feature of endocarditis complicating injection drug use and an infrequent complication of septic venous thrombosis in other settings.
Most of these patients present with a subacute onset of illness and do not seek medical attention for 2 weeks or more after the onset of illness. Early symptoms are often those of pneumonia—that is, malaise, anorexia, sputum-producing cough, sweats, and fever. Initially, foul sputum is not observed in the course of the infection; however, after cavitation occurs, putrid expectorations are quite prevalent. The odor of breath and sputum of a patient with an anaerobic lung abscess is often quite pronounced and noxious and may provide a clue to the diagnosis. Hemoptysis may occasionally follow the expectoration of the putrid sputum. The sputum may contain gangrenous lung tissue. Chest pain, if present, usually indicates pleural involvement.
On physical examination, a small area of dullness, indicating localized pneumonic consolidation, is found, and usually suppressed (rather than bronchial) breath sounds. Fine or medium moist crackles may be present. If the cavity is large, there may be tympany and amphoric breath sounds. Signs of pulmonary suppuration generally disappear with appropriate antibiotic therapy, but this disappearance does not necessarily denote cure. If the abscess becomes chronic, weight loss, anemia, and hypertrophic pulmonary osteoarthropathy may occur. Physical examination of the chest may be negative in the chronic phase, but rales and rhonchi are usually present.
Chest x-rays early in the course may show a segmental or lobar consolidation, which sometimes becomes globular as pus distends it. The distinctive characteristic of lung abscess, the air-fluid level, can be observed only on a chest x-ray film taken with the patient upright or in the lateral decubitus position (Fig. 6-1). In the presence of associated pleural thickening, atelectasis, or pneumothorax, the air-fluid level may be obscured. A computed tomography (CT) scan of the chest is valuable for better anatomic interpretation. It can demonstrate cavitation within an area of consolidation, the thickness and regularity of the abscess wall, and the exact position of the abscess with regard to the chest wall and bronchus.
The indications and comparative benefits of invasive procedures such as transtracheal aspirates, transthoracic aspirates, and fiberoptic bronchoscopy are controversial and depend to a great extent on operator ability. The use of these methods to obtain appropriate culture specimens should be strongly considered in patients who do not respond to medical therapy within 2 weeks. However, dependable microbiologic data can be obtained only if these procedures are performed prior to the institution of antibiotic therapy. Most pulmonologists believe that these diagnostic procedures should not be performed routinely in all patients but should be reserved for patients with atypical presentations or unclear diagnoses. Bronchoscopy may also be used to exclude the presence of a foreign body or neoplasm and can provide drainage. These invasive procedures should be avoided in patients with coagulation disorders or bleeding tendencies and in those for whom it is difficult to provide adequate oxygenation.
Lesions that simulate bacterial lung abscess include cavitating bronchogenic carcinoma, bronchiectasis, empyema secondary to a bronchopleural fistula, tuberculosis, coccidioidomycosis and other mycotic lung infections, infected pulmonary bullae or air cysts, pulmonary sequestration, silicotic nodules with central necrosis, subphrenic or hepatic (amebic or hydatid) abscesses with perforation into a bronchus, and Wegener’s granulomatosis. Detailed history, repeated clinical evaluation, and the procedures described above can usually differentiate these disorders from simple lung abscess.
Appropriate use of antibiotics determines morbidity and mortality in patients with lung abscess. Clindamycin is currently the first choice for the treatment of anaerobic infections; penicillin is a less-favored alternative. The Study Group on Aspiration Pneumonia14 also included patients with primary abscesses and found that ampicillin plus the β-lactamase inhibitor sulbactam, as opposed to clindamycin, with the optional addition of a second- or third-generation cephalosporin, was equally effective in terms of clinical response. For gram-negative organisms as well as Pseudomonas, aminoglycosides and quinolones or cephalosporins can be used. Nafcillin or oxacillin or cephalexin is recommended as a first-line agent for gram-positive organisms. The supportive treatment should include chest physiotherapy with postural drainage as well as nutritional support. Serial radiographs have limited use in the evaluation of response to therapy.
The availability of effective antibiotic therapy for primary lung abscess has drastically modified the natural history of the disease and diminished the role of surgery. Operative indications are less frequent in current practice, and these procedures are undertaken electively for chronic illnesses only after medical therapy has been unsuccessful. Prior to any surgical intervention, major considerations in patients with a delayed medical response include:
An associated condition that precludes response, such as obstruction with a foreign body or neoplasm
Erroneous microbial diagnosis with infection due to bacteria, mycobacteria, or fungi that have not been suspected and are not being treated
Large cavity size (usually >6 cm in diameter) that may require prolonged therapy or empyema, which necessitates drainage
An alternative, nonbacterial cause of cavitary lung disease, such as cavitating neoplasm, vasculitis, or pulmonary sequestration
Other causes of persistent fever, such as drug fever or Clostridium difficile–associated colitis
Indications for drainage include ongoing sepsis despite adequate antimicrobial therapy, progressively enlarging lung abscess in imminent danger of rupture, failure to wean from mechanical ventilation, and contamination of the opposite lung. In current practice, due to advances in interventional radiology, most of these lung abscesses are drained percutaneously under CT, ultrasound, or fluoroscopic guidance with acceptable success rates and morbidity.15 This approach may be problematic in patients with coagulopathies if a significant amount of lung tissue must be traversed and other anatomic structures do not allow for unimpeded access to the cavity; another difficulty is posed by the presence of material within the abscess that cannot be effectively evacuated through a drainage tube. In addition, there is always a concern for soiling the pleural space with abscess contents. Direct tube drainage may be indicated in severely ill patients with large abscesses. Safe and effective pneumonostomy or cavernostomy with direct drainage (Monaldi procedure) depends on accurate topical localization of the abscess and a high degree of certainty that the underlying lung is firmly adherent to the overlying parietal pleura.
Endoscopic drainage of lung abscesses has also been reported with acceptable outcomes.16 The procedure is performed by placing a pigtail catheter into the abscess cavity under bronchoscopic visualization and leaving the catheter in place until the cavity has drained. It can be considered in selected patients who have an airway connection to the abscess or in whom an endobronchial obstruction that prevents drainage is present.
Surgical resection is now required in less than 10 percent of the cases of lung abscess. Indications for surgical intervention include unsuccessful medical management over a period of 8 weeks; complications such as bronchopleural fistula, empyema, massive or significant recurrent hemoptysis, and the persistence of a cavity larger than 6 cm after 8 weeks of treatment; necrotizing infection associated with multiple abscesses; and rupture into the pleural cavity with pyopneumothorax. Surgical intervention may also be indicated when there is a strong suspicion of carcinoma present. Intraoperatively, the patient will require double-lumen intubation or a bronchial blocker to help prevent spillage of pus into the contralateral lung, and rigid bronchoscopy may be indicated. Careful dissection and meticulous hemostasis are very important because of the adhesions and distorted anatomy caused by the abscess. Suction decompression of large cavities prior to dissection is usually helpful. Lobectomy is typically required, as segmentectomy may be inadequate and pneumonectomy is rarely necessary. Complete resection of involved areas as well as placement of two large-caliber tubes will help to speed recovery, prevent recurrence, and avoid the development of empyema.
Owing to the presence of branching hyphae, infections due to actinomycosis and nocardiosis may be mistaken for fungal infections. It is important to make the distinction because actinomycotic infections do not respond to antifungal therapy but rather antibiotics.
Actinomycosis is a relatively uncommon subacute-to-chronic disease characterized by the production of suppurative abscesses or granulomas that eventually develop draining sinuses and dense scarring. These lesions discharge pus containing the organisms, which are filamentous, gram-positive, anaerobic-to-microaerophilic bacteria that are not acid fast. The branching form of the bacterium allows it to be recognized by the presence of “sulfur granules,” or masses of hyphae, in the pus. In humans, actinomycosis is usually caused by Actinomyces israelii, which is a commensal in the normal human oropharyngeal flora. Areas of clinical manifestations of actinomycosis include cervicofacial, thoracic, and abdominal sites. Cervicofacial is the most common, comprising up to 50 percent of reported cases. Infections in the soft tissues of the mouth and throat can manifest themselves as submandibular masses with chronic draining sinuses. The infection can spread by direct extension from the neck across fascial planes into the mediastinum. Interestingly, there does not seem to be any greater incidence of the disease in patients who are immunocompromised, including those with HIV, patients who have undergone organ transplantation, or those on steroids.17 Lung infection can result from dental surgery or aspiration and after trauma, including introduction of the organism from esophageal perforation. Hematogenous spread from distant lesions is also possible and can infect preexisting cavitary disease in the lung.
Thoracic actinomycosis commonly presents as a pulmonary infiltrate or mass that, if left untreated, can spread to involve the pleura, pericardium, and chest wall with rib osteomyelitis. The patient may have any combination of the nonspecific symptoms, such as fever, dry or productive cough, blood-streaked sputum, shortness of breath, chest pain, weight loss, fatigue, and anorexia. Physical examination may reveal abnormal breath sounds. The presence of sinus tracts with drainage from the chest wall (i.e., pleurocutaneous fistula) should raise very high clinical suspicion.
Definite diagnosis can be made by histopathologic examination and anaerobic culture of material from draining sinuses and abscesses. The “sulfur granules” are practically pathognomonic; they are approximately 1 mm in diameter and can be seen by the naked eye as yellowish particles. Microscopically, they are composed of branching filamentous rods that stain positive on Gram’s stain (Fig. 6-2). On chest x-ray, the presence of a mass-like lesion that extends across fissures or pleura, invades into the adjacent chest wall or thoracic vertebrae, or causes local destruction of the ribs or sternum suggests thoracic actinomycosis. CT scans usually reveal an infiltrative mass with focal areas of decreased attenuation that enhance with contrast. This infiltrative mass has a tendency to invade surrounding tissues, and lymphadenopathy is uncommon.
High-dose penicillin, administered over a prolonged period, is the cornerstone of therapy for actinomycosis. Prolonged treatment is necessary owing to the presence of surrounding dense fibrous tissues. Lack of a clinical response from a patient receiving penicillin therapy may also indicate the presence of resistant companion bacteria, which may require modification of the antibiotic regimen.
Surgical intervention may be implemented for drainage of an abscess or empyema and for radical excision of sinus tracts when feasible. The most common indication for surgery is exploratory thoracotomy to rule out carcinoma.18 Rarely, actinomycosis may be complicated by an unusual but significant hemoptysis—another indication for surgery—although selective bronchial artery embolization is a viable option in this setting. Even if histology suggests complete resection, it must still be followed by prolonged antibiotic therapy, as surgery alone is usually not curative. Inadequate antibiotic therapy postoperatively may result in complications such as bronchopleural fistulas and empyema.
Nocardiosis is an acute, subacute, or chronic suppurative infection caused by weakly gram-positive, filamentous bacteria found worldwide in soils. Nocardia asteroides (80 percent) and Nocardia brasiliensis are the principal causes of human disease. Nocardia farcinica is being recognized with increasing frequency. The disease has a pronounced tendency toward remission and exacerbation, and infections are localized or disseminated. Localized infection usually manifests itself as primary cutaneous or, rarely, lymphocutaneous disease. Nocardiosis is an opportunistic infection, and disseminated or fulminant disease mainly occurs in immunocompromised hosts with underlying illnesses such as chronic granulomatous disease and HIV infection as well as patients on immunosuppressive therapy.19 Lung transplant recipients have a particularly high incidence. Inhalation of the free-living organism is the likely route of infection. Introduction of N. asteroides via the respiratory tract results in pulmonary lesions, most often manifest as multiple abscesses. Nocardia abscesses are characteristically confluent, with little evidence of encapsulation, which probably accounts for the ready dissemination from the initial pulmonary focus. This organism also evades the host’s bactericidal mechanisms. The primary disease, which occurs in the pulmonary system, may mimic tuberculous, staphylococcal, or mycotic infection. Hematogenous dissemination to the brain, kidneys, and liver are the most common metastatic sites.
Symptoms in patients with nocardiosis are indistinguishable from those in patients with similar pulmonary infections of other microbial etiology. Cough with sputum production and fever are the dominant symptoms. Subcutaneous abscesses and draining sinuses near the chest wall that contain sulfur granules, similar to those observed in actinomycosis, are characteristic. Lung examination may reveal diffuse or localized abnormal breath sounds.
The diagnosis of nocardiosis is established by aerobic culture of the causative organism from the site(s) of infection. Because Nocardia organisms grow more slowly than common bacteria, the microbiology laboratory should always be notified when nocardiosis is clinically suspected, especially if sputum is submitted. Bronchial brushings or percutaneous transthoracic needle aspiration biopsy of the lung may help to obtain appropriate samples and avoid the need for thoracotomy. Nocardia organisms are not demonstrated with routine hematoxylin and eosin (H&E) stain and may be seen only by a careful search of sections stained with Gram’s, Gomori methenamine silver (GMS), or acid-fast bacillus stain.
Possible findings on chest x-ray and/or CT scan include irregular nodules (which may cavitate), reticulonodular or diffuse alveolar pulmonary infiltrates, lung abscess formation, and pleural effusion. All patients with pulmonary nocardiosis should have brain imaging by either CT scan or magnetic resonance imaging (MRI).20
Sulfonamides are first-line antimicrobial therapy and sulfadiazine is generally preferred because of its central nervous system (CNS) and CSF penetration. The combination of trimethoprim/sulfamethoxazole (TMP/SMX) or minocycline in high doses is an acceptable alternative. Treatment for a minimum of 2 to 3 months is recommended; treatment for as long as 12 months may be necessary, especially for systemic disease. Prophylactic TMP/SMX should be considered in transplant centers with excess rates of nocardial infection.21
Surgical intervention may be required for the drainage of lung abscess or empyema or when the diagnosis of a lung lesion is unclear. Pulmonary resection for previously diagnosed Nocardia infection is rarely indicated.
Pulmonary manifestations are the hallmark of histoplasmosis, as this, also known as Darling disease, is probably the most common of all fungal infections of the lungs. Clinical syndromes range from asymptomatic infection to diffuse alveolar disease causing respiratory difficulty and occasionally death. H. capsulatum is a dimorphic fungus that remains in a mycelial form at ambient temperatures and grows as yeast at body temperature in mammals. Although the fungus can be found in temperate climates throughout the world, it is endemic to the Ohio, Missouri, and Mississippi River valleys in the United States. Farmers, construction workers, and people who enjoy outdoor activities are the most at risk. The disease results from aerosolization of conidial and mycelial fragments from contaminated soil due to the excreta of chickens, pigeons, and bats, which are then deposited in the alveoli. Conversion from the mycelial to the pathogenic yeast form occurs intracellularly. The host defense includes the fungistatic properties of neutrophils and macrophages. T-lymphocytes are crucial in limiting the extent of infection. Susceptibility to dissemination is increased markedly with impaired cellular host defenses.
There is a wide spectrum of pulmonary histoplasmosis syndromes. The extent of disease and mode of presentation following initial exposure correlate with the size of the inoculum that was inhaled and the Histoplasma-specific immunity of the exposed subject. Pulmonary auscultation reveals nonspecific rales, wheezes, or findings consistent with the extent of underlying pneumonitis, consolidation, or cavitation.
Approximately 85 to 90 percent of infected immunocompetent individuals are asymptomatic. As the cell-mediated host immunity matures, delayed-type hypersensitivity to histoplasmal antigens occurs (3 to 6 weeks after exposure). The skin antigen test for Histoplasma species turns positive. Over weeks to months, the inflammatory response produces calcified fibrinous granulomas with areas of caseous necrosis. Most asymptomatic cases are now identified by the incidental finding of enlarged mediastinal or hilar lymph nodes or pulmonary nodules seen on radiographs or CT scans obtained for the evaluation of other conditions. Perhaps the main significance of such findings is the need to differentiate them from malignancy (Fig. 6-3).
Inhalation of a large amount of inoculums results in an inflammatory response in the lung and adjacent lymph nodes, similar to the Ghon complex of pulmonary tuberculosis.22 This can be due to primary infection or reinfection. Nonimmune subjects usually present within 2 weeks with respiratory symptoms and diffuse pulmonary involvement radiographically. Fever, headache, malaise, myalgia, abdominal pain, and chills are common symptoms. Enlarged hilar and mediastinal lymph nodes (mediastinal lymphadenitis) are present in 5 to 10 percent of patients. Mediastinal histoplasmosis results in fibrosing mediastinitis, which can cause symptoms of compression and is the most frequent benign etiology of superior vena cava (SVC) obstruction. Cough, hemoptysis, dyspnea, and/or chest pain may be present; these are related to the degree of compression imposed on the pulmonary airway and circulation. Rarely, compression of the esophagus occurs, which causes dysphagia.
This form occurs mostly in middle-aged men with underlying pulmonary disease (e.g., COPD); it is rare in children and represents 10 percent of symptomatic cases. Chronic pulmonary histoplasmosis (CPH) resembles reactivation tuberculosis, which is a common misdiagnosis. It is associated with cough, dyspnea, chest pain, weight loss, fevers, malaise, and night sweats. The clinical course of untreated CPH is progressive, with spread to contiguous lung. Complications, such as hemoptysis and bronchopleural fistulas, may ensue. Other infections can coexist, such as mycobacterial and other fungal infections (e.g., aspergillosis). Concurrent neoplasia is not uncommon.
Radiographs typically show changes of emphysema. Airspace opacities are present and may surround preexisting bullae, producing the appearance of cavitation with air-fluid levels. In severe cases the lung disease may progress and produce diffuse confluent airspace disease. As the patient recovers, the opacities on chest x-ray become more defined and nodular in appearance. The disease is almost always in the upper lobes and may be bilateral or unilateral in distribution. The inflammatory process progressively destroys lung tissue and retracts the hilar structures upward as a consequence of the loss of lung volume. Pleural thickening adjacent to the lung disease is often present. Untreated cases may lead to progressive pulmonary fibrosis, which may result in respiratory and cardiac failure and recurrent infections.
This form occurs mostly in hosts who are immunocompromised and probably results from a failure to develop protective cellular immunity following the acute infection. Symptoms vary depending on the duration of illness. Evidence for dissemination includes hepatosplenomegaly, extrapulmonary lymphadenopathy, mucosal or skin lesions, anemia, leukopenia, thrombocytopenia, or hepatic enzyme elevation. Furthermore, gastrointestinal involvement may produce diarrhea and abdominal pain. Cardiac involvement resulting in valvular disease, cardiac insufficiency, or vegetations may cause dyspnea, peripheral edema, angina, and fever. CNS involvement may produce headache, visual and gait disturbances, confusion, seizures, altered consciousness, and neck stiffness or pain. Note that subacute progressive disseminated histoplasmosis results in adrenal infection in 80 percent of patients. Radiographically, localized, cavitary, or miliary infiltrates as well as mediastinal lymphadenopathy may be present. The presence of calcified lymph nodes and lung granulomas suggests that disseminated disease has resulted from reinfection. Diffuse nodular opacities can be seen on CT scan (Fig. 6-4).
Histoplasmin skin testing is not recommended for diagnostic purposes because of the high rate of positive reactions in endemic areas and the wide variability of response. H. capsulatum can be recovered from sputum, BAL fluid, lesions, blood, or bone marrow on routine fungal cultures; but the organism grows slowly and plates must be kept up to 12 weeks. The combination of blood and bone marrow cultures increases the likelihood of positive results. In chronic or severe acute pulmonary disease, organisms can be cultured from sputum or bronchial washings. Multiple specimens increase yield. Antibody testing can be performed using immunodiffusion, complement fixation, and radioimmunoassay in increasing order of sensitivity.
Antibody levels peak 6 weeks following exposure and decline over a 2- to 5-year period. Antigen detection in serum and urine is useful in immunocompromised individuals, whose ability to produce antibodies may be impaired. Cross-reactivity with antigens from Blastomyces dermatitidis and Coccidioides immitis may cause a false-positive test result. Urine specimens have higher sensitivity, up to 90 percent for disseminated disease. Paired urine and serum specimens have the highest yield. Note that some patients with acute histoplasmosis may have high serum levels of angiotensin-converting enzyme. This may cause a diagnostic confusion with sarcoidosis, especially if the patient also has hilar adenopathy.
Tissue may have to be obtained from pulmonary lesions and lymph nodes by bronchoscopy, percutaneous needle biopsies, or rarely, thoracoscopy in order to make the diagnosis. Histologic findings in pulmonary histoplasmosis demonstrate a predominantly mononuclear infiltrate. Multiple caseating granulomas are characteristic, with multinucleated giant cells and possible peripheral fibrosis and central calcification. On H&E staining, the yeast form of H. capsulatum has a false capsule. Special stains, such as GMS or periodic acid-Schiff (PAS), may reveal budding yeast, but the organisms can be mistaken for Pneumocystis carinii and other fungal organisms. In chronic pulmonary forms—in addition to underlying lung disease—vascular involvement, tissue necrosis, and scarring are present. Extensive fibrosis with collagen deposition is observed in fibrosing mediastinitis.
Echocardiography, CT scan of the abdomen, as well as CT scan and MRI of the brain should be performed when involvement of these areas is suspected. Lumbar puncture (LP) in CNS histoplasmosis demonstrates a lymphocytic pleocytosis, with elevated protein and normal or low glucose.
No treatment is needed for asymptomatic immunocompetent individuals without serious underlying disease. The antifungal therapy of choice is amphotericin B or its liposomal formulation for disseminated disease. The recommended duration of therapy is 12 weeks for acute and subacute histoplasmosis, 12 to 24 months for chronic disease, and 6 to 18 months for disseminated progressive disease. Patients with disseminated disease and HIV should be on treatment for life. Itraconazole can be used for those with moderate illness and for completion of therapy after response to amphotericin. In those who are hypoxic corticosteroids should be added. Mediastinal and hilar lymphadenopathies usually resolve. Granulomatous inflammation causes extensive enlargement with caseating necrosis, which may fibrose with progressive healing. Occasionally, the lymph nodes may remain enlarged, compressing surrounding structures and distorting anatomic architecture.
Indications for surgery include:
The presence of persistent or progressive cavitations with repeated relapses despite multiple courses of intensive medical treatment
Medical therapy is insufficient to alleviate the compressive effects of progressive fibrosis, calcification, and scarring:
Life-threatening tracheobronchial and esophageal obstruction and bronchoesophageal fistula
SVC syndrome, pulmonary vascular obstruction, or middle-lobe syndrome associated with fibrosing mediastinitis
Severe valvular insufficiency due to involvement in disseminated histoplasmosis
Symptomatic broncholithiasis (which occurs when a calcified node erodes into a bronchus) if bronchoscopic extraction was unsuccessful
During surgery, care should be taken to avoid spilling necrotic material into the mediastinum and initiating a further fibrotic reaction.
Pulmonary aspergillosis comprises a spectrum of mycotic diseases caused by Aspergillus species. Human illness is usually caused by Aspergillus fumigatus and Aspergillus niger and, less frequently, by Aspergillus flavus and Aspergillus clavatus. The transmission of fungal spores to the human host is via inhalation. A. fumigatus exists in two forms: (1) conidiophores, the reproductive forms that produce and release thousands of spores and (2) hyphae, which represent mature spores characterized by a 45-degree dichotomous branching pattern. The fungus grows widely in soil, water, and decaying vegetable or animal material. The spores are readily inhaled, and the fungus is commonly found in the sputum of healthy individuals.23 Most patients with pulmonary aspergillosis have either impaired immunity or underlying preexisting chronic lung disease such as bronchiectasis, COPD, or tuberculosis. Impaired immunity may be secondary to alcoholism, advanced age, poorly controlled diabetes mellitus, underlying malignancy, cirrhosis, malnutrition, sepsis, AIDS, or organ transplantation.
Pulmonary aspergillosis may present as any of three distinctive clinical syndromes: allergic bronchopulmonary aspergillosis, aspergilloma, and invasive aspergillosis.
Allergic bronchopulmonary aspergillosis (ABPA) represents a hypersensitivity reaction to A. fumigatus in patients with poorly controlled asthma or cystic fibrosis. It is associated with a type I, III, or IV allergic response to Aspergillus antigens. Excessive mucus production in association with impaired ciliary function leads to mucoid impaction of the airways. The plugs of inspissated mucus contain hyphal elements of A. fumigatus and eosinophils, but the organisms remain within the bronchial lumen; this feature differentiates ABPA from invasive aspergillosis. The inflammatory response results in damage to the bronchial wall with airway destruction and the subsequent development of bronchiectasis. ABPA was initially described as a disease characterized by episodic wheezing, pulmonary infiltrates, pyrexia, sputum and blood eosinophilia, and sputum containing brown flecks or plugs. Almost all ABPA patients have clinical asthma. The disease may progress through various stages based on clinical, serologic, and radiographic findings. These stages need not occur in order. The first four stages—which are acute, remission, recurrent exacerbation, and corticosteroid-dependent asthma—are potentially reversible with no long-term sequelae. However, the fifth stage, fibrotic lung disease, in which bronchiectasis or fibrosis develops, is irreversible.24
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