CONGENITAL CYSTIC ANOMALIES OF THE LUNG
Congenital lesions of the lung include primarily tracheobronchial atresia, bronchogenic cysts, pulmonary dysplasia, pulmonary sequestration, congenital cystic adenomatoid malformations (CCAM), and congenital lobar emphysema (CLE). Although many of these lesions present early in life with dramatic symptoms and physical findings, most remain occult until late childhood and even into adult life. These uncommon lesions arise from aberrations in normal aerodigestive tract development, which begins during the fourth week of fetal life when the lung bud forms at the caudal end of a groove in the primordial pharynx. An initial phase of sequential airway branching occurs until as many as 20-25 generations are reached by the sixteenth week of fetal life. These branches are divided into three zones: a proximal conductive zone (branches 1-16), an intermediate transitional zone (branches 17-19), and a distal respiratory zone (branches 20-25). A second canalicular phase is then entered as capillaries develop in the distal air passages. Finally, the alveolar phase begins at approximately 26 weeks of fetal life as prototype alveolar air sacs appear complete with both type I and type II pneumocytes. The number and size of alveoli continue to increase until the total alveolar surface reaches the adult size of nearly 100 m2.
A. Tracheobronchial Atresia
Atresia of the tracheobronchial tree can occur at any level and may involve an isolated segment or multiple diffuse areas of the airway. Tracheal atresia is associated with polyhydramnios, prematurity, esophageal atresia, and tracheoesophageal fistula. Typically, neonates present with intractable cyanosis and despite a normal-appearing larynx are unable to be intubated. Emergency tracheostomy can be life-sustaining in babies with isolated subglottic atresia; in other infants with more diffuse disease, mask ventilation can achieve some palliation through anomalous esophagobronchial connections. Diffuse airway involvement, however, is invariably fatal.
Isolated bronchial atresia results in a bronchus that ends in a blind pouch. A mucocele develops distal to the obstruction and, as a result of compression of neighboring normal bronchial structures, causes emphysematous changes in the surrounding lung. Since children frequently develop wheezing, stridor, and pulmonary infections in the involved segments, resection is almost always indicated. Like bronchial atresia, true congenital bronchial stenosis is rare, although right main stem bronchial stenosis occurs not infrequently from iatrogenic airway trauma in chronically ventilated patients.
Related anomalies of the tracheobronchial tree include anomalous tracheal or esophageal bronchi and tracheal diverticula. These rare lesions often present with symptoms of bronchial obstruction and in many cases require resection of involved lung tissue due to chronic infection and the development of bronchiectasis (see section on Bronchiectasis). Similar to pulmonary sequestration, these lesions can have a dominant systemic arterial blood supply that must be kept in mind if operation is contemplated.
Bronchogenic cysts are the most common cystic lesions of the mediastinum and arise from abnormal budding of the foregut during development. The cyst wall consists of fibroelastic tissue, smooth muscle, and cartilage, whereas the cyst itself is lined with respiratory tract epithelia. It may also contain mucus-producing cuboidal cells, which contribute to enlargement of the cyst with mucus. They may occur anywhere along the tracheobronchial tree but occur most commonly in the vicinity of the right pulmonary hilum and subcarinal region. Less frequently, they present in the neck, lower lobes of the lung, pleura, pericardium, or below the diaphragm. When large, cysts can compress surrounding vital structures, including the aerodigestive tract causing dysphagia, pneumothorax, cough, or hemoptysis or become infected. The diagnosis is confirmed by CT as a spherical fluid- or mucus-filled nonenhancing mass. An air-fluid level may be present thus suggesting communication with the airway. Cysts within the pulmonary parenchyma more commonly communicate with a bronchus, as opposed to those in the mediastinum. In general, mediastinal bronchogenic cysts present with airway compression and parenchymal cysts are manifested by pulmonary infection. Some cysts have been noted to enlarge rapidly and rupture into the pleural space, causing tension pneumothorax. Rare cases of malignant transformation have been reported. All bronchogenic cysts—regardless of location—are best treated with either simple or segmental resection by VATS or thoracotomy. Rarely, lobectomy is required.
et al.. Congenital lung lesions underlying molecular mechanisms. Semin Pediatr Surg 2010;19(3):171.
IB: Congenital airway lesions and lung disease. Pediatr Clin North Am 2009;56(1):227.
C. Bronchopulmonary Dysplasia
Bronchopulmonary dysplasia (BPD) is a form of chronic lung disease that occurs in infants, usually in preterm infants receiving respiratory support with mechanical ventilation or prolonged oxygen supplementation. With the introduction of positive pressure ventilation in newborn infants Northway et al originally described a pattern of lung injury characterized by airway injury, inflammation, and parenchymal fibrosis in preterm infants who had received mechanical ventilation. Since the introduction and implementation of antenatal corticosteroids and postnatal surfactant replacement BPD now more commonly affects those of extremely low birth weight and born less than 26 weeks of gestation. BPD nowadays is fundamentally viewed as the result of abnormal reparative processes in response to injury and inflammation occurring in an immature lung of a genetically susceptible infant. The pathogenesis of BPD begins with a very immature lung complicated by iatrogenic damage from therapy with oxygen and volume ventilation with superimposed infection and inflammation as well as pulmonary edema complicated by poor nutrition. Treatment is supportive combining new approaches to ventilation (nasal CPAP and inhaled nitric oxide) with vitamin A. The American Thoracic Society has recently published a position paper on the care of the child with chronic lung disease of infancy and childhood that addresses many of these issues.
D. Pulmonary Aplasia and Agenesis
Pulmonary hypoplasia is a relatively common abnormality of lung development and is defined pathologically as an abnormally low radial alveolus count and low ratio of lung weight to body weight. Pulmonary hypoplasia is termed primary pulmonary hypoplasia when no inciting cause is identified and is likely caused by abnormalities of the transcription factors that regulate early lung morphogenesis. These neonates present with tachypnea and hypoxemia resistant to administration of supplemental oxygen due to abnormal thickening of the pulmonary arteriolar wall. Persistent fetal circulation, hypoxemia, hypercapnia, and acidosis lead to early death in over 75% of patients. Secondary pulmonary hypoplasia is associated with a restriction of lung growth or the absence of fetal breathing. Any reduction of the chest cavity by a mass, effusion, or external compression can impact lung growth. The most common of these abnormalities is congenital diaphragmatic hernia (see Chapter 43). Other conditions associated with secondary pulmonary hypoplasia include those that produce oligohydramnios and direct chest compression (eg, bilateral renal agenesis [Potter syndrome], renal dysplasia, and amniotic fluid leaks); those with abnormal bone development and small rigid chest walls (eg, achondroplasia, chondrodystrophia fetalis calcificans, osteogenesis imperfecta, and spondyloepiphyseal dysplasia); those with decreased fetal respiratory movements (eg, phrenic nerve agenesis, abdominal masses or ascites with elevation of the diaphragm, arthrogryposis multiplex congenita, camptodactyly, and congenial myotonic dystrophy); those with intrathoracic mass lesions (eg, CCAM, cystic hygroma, esophageal duplication cysts); and those with pulmonary vascular abnormalities (eg, scimitar syndrome, pulmonary artery agenesis).
Unilateral pulmonary agenesis occurs when one lung and the associated vascular structures fail to develop. Neonates with pulmonary agenesis may present with tachypnea and cyanosis, particularly if associated cardiac anomalies exist (50% of cases). Some patients, however, remain asymptomatic until childhood, when they complain of dyspnea and wheezing suggestive of asthma. Physical examination in these patients reveals marked tracheal deviation toward the side of the agenesis, and chest x-ray, barium esophagography, and chest CT may be required to exclude other diagnostic possibilities such as total lung atelectasis from foreign body aspiration, total lung sequestration, and esophageal bronchus.
E. Pulmonary Sequestration
Pulmonary sequestration describes a mass of lung parenchyma that arises through abnormal budding of the caudal embryonic foregut and consequently has no bronchial communication with the otherwise normal tracheobronchial tree. Sequestration may occur either within normal lung tissue, termed intralobar sequestration, or as separate masses with their own visceral pleura, referred to as extralobar sequestration. The majority (85%) of sequestrations are of the intralobar type. Intralobar sequestrations receive their blood supply from the thoracic or abdominal aorta and splenic artery and their venous drainage from the pulmonary veins. In some cases this may be associated with anomalous venous drainage of the normal lung. Intralobar sequestrations are most commonly found on the left side in the lower lobe. Extralobar sequestrations are less common and receive their blood supply from the thoracic or abdominal aorta and the venous drainage via the systemic veins such as the hemiazygos or azygous veins or inferior vena cava. Both are associated with foregut communications but more commonly in extralobar sequestrations.
Intralobar sequestrations are usually diagnosed later in childhood or adolescence with multiple episodes of pneumonia. Common symptoms include a chronic or recurrent cough. Extralobar sequestrations usually present in infancy with respiratory distress and chronic cough or manifest as gastrointestinal symptoms if a communication with the gastrointestinal tract exists. In rare instances, patients may present with hemoptysis or congestive heart failure from large left-to-right shunts through the sequestration. The diagnosis is usually suspected on chest x-ray and confirmed with a CT scan of the chest delineating the arterial and venous drainage. Angiography can be used to confirm the diagnosis and elucidate aberrant vascular anatomy. Treatment consists of segmental resection or, if necessary, lobectomy via thoracotomy or video-assisted procedure. Great care must be taken to identify the nature of both the arterial blood supply and the venous drainage to avoid exsanguinating hemorrhage from division of an unrecognized systemic artery or venous infarction of the normal lung from ligation of the common draining vein. Following successful resection, the prognosis is favorable.
F. Congenital Cystic Adenomatoid Malformation
CCAM is the second most common cause of newborn respiratory distress, secondary to structural problems. CCAM is a discrete, space-occupying intrapulmonary mass that contain variable-sized cysts. These lesions do not function in normal gas exchange yet airspaces within these masses communicate with the tracheobronchial tree. Histologically, CCAM is distinguished from other lesions and normal lung by polypoid projections of the mucosa, an increase in smooth muscle and elastic tissue within cyst walls, an absence of cartilage, the presence of mucus-secreting cells, and the absence of inflammation. The classification system described by Stocker organizes these lesions on pathologic appearance and clinical outcome. Class I consists of large cysts greater than 2 cm; class II consists of small cysts less than 2 cm; class III consists of solid lesions without cysts. Children will present either at birth or in early childhood with recurrent respiratory infections. The growth of CCAMs usually plateaus between 25 and 28 weeks, at which time the fetus appears to grow around the lesion. The vast majority of small- to moderate-sized CCAMs remain asymptomatic during fetal life. Approximately 15% of CCAMs will shrink significantly before birth. However, large lesions represent 5%-10% of CCAMs and may produce significant mass effect, which can lead to pulmonary hypoplasia, impaired fetal swallowing and polyhydramnios, and impaired venous return and heart failure. Fetal hydrops can result and appears to depend on the size and rate of growth of the mass, and result from compression of the superior vena cava and impaired venous return. As therapeutic fetal interventions have become feasible, the ability to predict which infants will progress to hydrops has become critical. High-resolution fetal MRI can calculate a cyst volume ratio which is useful in predicting progression to hydrops. Fetal interventions including a short course of maternal betamethasone for microcystic CCAM and minimally invasive in utero thoracoamniotic shunting for macrocystic CCAM have been shown to be successful. If fetal development is uncomplicated, early delivery is not encouraged. At birth, the infants are stratified based on symptoms. Critically ill infants require immediate resection of the involved lobe. An asymptomatic neonate should be initially evaluated with chest radiography. While surgery can be delayed in those patients with small lesions, any patient with known CCAM should undergo elective resection due to possible future complications including pneumonia and malignant transformation.
G. Congenital Lobar Emphysema
CLE is the cause of half of the episodes of newborn respiratory distress due to structural abnormalities and is defined as an overdistended lobe resulting from the obstruction of a lobar bronchus. Obstruction can arise from abnormal cartilage development or an ischemic event during bronchial development. CLE also can develop as the result of meconium aspiration, lobar torsion, or an extrinsic cause such as obstructing lymph nodes. The left upper lobe is most commonly involved, and with the right middle lobe next in prevalence. In addition, neonates who require prolonged mechanical ventilation (eg, those with hyaline membrane disease) can develop lobar emphysema from a combination of suction catheter trauma and barotrauma. The right lower lobe is most frequently affected in such patients. Most infants present within the first 6 months of life with respiratory distress. In some patients, severe respiratory distress may occur in the neonatal period, requiring emergency evaluation and treatment. Almost all infants present with tracheal and mediastinal deviation away from the affected side, hyperresonance and decreased breath sounds on the affected side, and a chest radiograph demonstrating hyperlucency in the area of the affected lobe with compression of adjacent lung. A chest radiograph often is sufficient before proceeding with operation. Occasional patients, particularly older children, may require chest CT scans to exclude other pathology (eg, bronchogenic cysts, anomalous pulmonary vessels, and hilar lymphadenopathy). Bronchoscopy also may be necessary to rule out the presence of a foreign body causing ball-valve airway obstruction. Successful therapy in all patients requires pulmonary resection, which almost uniformly consists of lobectomy. Great care is necessary with airway management at the time of induction of general anesthesia in these patients as positive-pressure ventilation can result in further shifting of the mediastinum resulting in impaired venous return and cardiovascular collapse. If such a situation arises, an emergent thoracotomy should be preformed to allow for the affected lobe to “herniate out” of the incision decompressing mediastinal pressure. Even after lung resection, patients may have bronchomalacia and a tendency toward bronchospasm.
CONGENITAL VASCULAR LESIONS OF THE LUNG
Vascular diseases of the lung include two main processes: arteriovenous malformations and vascular rings. Arteriovenous malformations are uncommon congenital lesions that develop as a result of abnormal capillary formation during the canalicular phase of development. Most arise from the pulmonary artery, but occasionally a systemic arterial source can be involved similar to that in pulmonary sequestration. Rarely, an arteriovenous malformation can arise from a coronary artery, with the right coronary artery involved 55% of the time. Coronary arteriovenous fistulas drain into the right ventricle (40%), right atrium (25%), pulmonary artery (20%), coronary sinus (7%), superior vena cava (1%), or left-sided heart chambers (7%). Patients are either asymptomatic or develop signs of congestive heart failure. Myocardial infarction is rare. A continuous murmur and signs of reduced left ventricular afterload may be present. Although the diagnosis often can be established with echocardiography and color Doppler imaging, the definitive diagnosis, shunt fraction, and complete preoperative planning require catheterization and angiography. Operation is indicated for symptomatic patients and for those asymptomatic patients with large shunts.
Vascular rings occur from abnormal development of the aortic arches and major branches, with resulting compression of the trachea and esophagus. In normal fetal development, a dual system of six aortic arches regresses in such a way that the left fourth arch becomes the main left-sided aorta, the left sixth arch develops as the ductus arteriosus, and the right fourth arch persists as the right innominate artery and subclavian artery. Most vascular rings, however, are associated with a right-sided aortic arch and are classified as complete vascular rings or incomplete rings (arterial slings). Complete vascular rings include a double aortic arch (67%, the most common complete ring), a right aortic arch with a left subclavian and left ductus arteriosus (30%), a right aortic arch with mirror-image branching and a left ductus arteriosus (rare), and a left aortic arch with an aberrant right subclavian and right ductus arteriosus (very rare). Incomplete rings consist of an aberrant right subclavian artery that originates on the left side and passes posterior to the esophagus (most common incomplete ring) and an anomalous left pulmonary artery arising from the right pulmonary artery and passing between the trachea and the esophagus (pulmonary artery sling).
Most patients present with symptoms of tracheal or esophageal compression. Patients with an anomalous right subclavian artery may present later in life with obstructive symptoms (dysphagia lusoria), while those with complete vascular rings and pulmonary artery slings typically present early in life (within 6 months) with symptoms of respiratory distress (often frank stridor), particularly with neck flexion and poor feeding. The diagnosis is often suggested by characteristic findings on barium esophagogram. Bilateral indentations imply double aortic arch. A posterior indentation suggests an aberrant right subclavian artery, large right-sided indentations suggest complete rings associated with a right aortic arch, and an anterior impression is typical of a pulmonary artery sling. Often, the diagnosis can be confirmed by echocardiography. MRI/MRA often provides useful anatomic details. Surgical repair of these lesions is indicated once the diagnosis is established and is accomplished by dividing the vascular ring usually through a left thoracotomy. With double aortic arches, the smaller of the two arches is divided distal to the subclavian artery, while other complete rings generally are treated by division of the ligamentum arteriosum. Aberrant right subclavian arteries may be simply divided or, if necessary, divided and transposed to the right side. Pulmonary artery slings require reimplantation of the left pulmonary artery and often resection of the compressed trachea, which often has severe tracheomalacia and stenosis. Rarely, tracheomalacia secondary to vascular ring compression necessitates suspension of the aortic arch from the sternum.
SUPPURATIVE DISEASES OF THE LUNG
A lung abscess usually begins as a necrotizing pneumonia progessing to liquefactive necrosis of the lung parenchyma. The liquefied necrotic material eventually empties into a draining bronchus, forming a necrotic cavity of pus containing an air-fluid level. With rupture, the infection can extend into the pleural space, producing an empyema. Arbitrarily, abscesses are termed acute if the duration is less than 6 weeks and chronic if more than 6 weeks. Although the incidence of lung abscesses fell dramatically following the introduction of effective antibiotics in the 1940s and 1950s, a recent increase in the number of immunocompromised individuals secondary to organ transplantation, chemotherapy, and AIDS has resulted in a resurgence in the numbers of lung abscesses requiring treatment.
Lung abscesses can be divided into two major categories based on etiology: primary and secondary. Lung abscesses are termed primary when they arise in a previously healthy individual or secondary to an underlying cause. Most commonly a primary abscess occurs as a result of aspiration owing to impaired consciousness or swallowing dysfunction due to neuromuscular or esophageal diseases. Sixty to seventy percent of lung abscesses present in the right lung in the dependent posterior segment of the right-upper lobe and superior segment of the lower lobe. They are most commonly polymicrobial with a predominance of anaerobic organisms including Peptostreptococcus, Bacteroides fragilis, and Fusobacterium. Conditions that predispose to aspiration include anesthesia (both general and monitored), neurologic disorders (cerebrovascular accidents, seizures, diabetic coma, head trauma, etc), drug ingestion (alcohol, narcotics, etc), normal sleep, poor oral hygiene (increases bacterial load), and esophageal disease (gastroesophageal reflux, achalasia, cancer, tracheoesophageal fistula). Secondary causes include bronchial obstruction (tumor, foreign body, hilar lymphadenopathy), necrotizing pneumonia (S auerus, K pneumoniae), chronic pneumonia (due to fungi, tubercle bacilli), and opportunistic infection in an immunodeficient host. Over the years the incidence of secondary lung abscess arising in the setting of an immunocompromised state has increased. As a result, virulent aerobic species such as Klebsiella, Pseudomonas, Proteus, Enterobacter, and S aureus now comprise the majority of these infections as opposed to anaerobic species. Gram-negative lung abscess occurs in elderly and immunocompromised patients with nosocomial pneumonia. Cavitating lesions may arise in the setting of a malignancy or pulmonary infarct. Direct extension of a localized infection such as amebiasis or subphrenic abscess may also progress to a secondary lung abscess. Blood-borne infections can give rise to multiple lung abscesses in the periphery of the lung and are the result of septic emboli from bacteria, endocarditis, septic thrombophlebitis, or subphrenic infection. It should be noted that secondary infections of congenital or acquired cystic lesions, such as bronchogenic cysts, bullae, tuberculous cavities, and hydatid cysts, are not true pulmonary abscesses because they occur in a preformed space.
Clinical Findings & Diagnosis
Patients with lung abscesses typically reports symptoms of cough, fever, putrid sputum, hemoptysis, dyspnea, pleuritic chest pain, and weight loss. Symptoms are often insidious in onset and associated with malaise and weight loss if chronic. Complications include rupture into a bronchus, with initial hemoptysis followed by the production of foul-smelling, purulent sputum (and the potential for life-threatening pneumonia from aspiration of pus into normal lung); rupture into the pleural space with resulting pyopneumothorax, sepsis, and possibly empyema necessitatis; and, rarely, massive hemoptysis requiring emergent pulmonary resection. On physical examination, signs of lobar consolidation predominate; but clubbing, signs of pleural effusion, cachexia, and rarely a draining chest wound (empyema necessitatis) can be present. Laboratory studies should include a differential white blood cell count and sputum culture. Chest radiography and CT scan of the thorax are usually sufficient to aid diagnosis and differentiate between empyema and abscess. Cavitation is generally apparent on chest radiographs 2 weeks after the onset of symptoms. Radiological resolution lags behind clinical and biochemical improvement, taking up to 3 months to resolve in up to 70%. In cases of suspected bronchial obstruction or in all patients with unexplained lung abscesses, bronchoscopy is indicated. Fine-needle aspiration of the abscess cavity for diagnostic culture has been shown to isolate the offending pathogens in 94% of patients compared with only 11% and 3% from sputum culture and bronchoalveolar lavage, respectively. Early fine-needle aspiration can prompt a change of the antibiotic regimen in 43% of cases and can be life-saving in immunocompromised patients with unusual organisms.
Antibiotic administration has been the mainstay of therapy following general resuscitation measures. First-line treatment should include aerobic and anaerobic coverage for a period of 4-6 weeks. Once the acute sepsis subsides (after up to 2 weeks), therapy can frequently be changed to an oral outpatient regimen and continued until complete resolution of the abscess occurs (3-5 months). Important adjuncts to antibiotic administration include chest physiotherapy, postural drainage, bronchoscopy (may require repeated examinations to maintain bronchial drainage), and health maintenance measures (general nutrition, dental hygiene, etc).
In patients who do not respond to this initial regimen and who do not have surgical indications (see below), early percutaneous drainage has been shown to be a safe and effective procedure (mortality rate, 1.5%; morbidity rate, 10%). Specific proposed indications for percutaneous drainage include: (1) an abscess under tension as evidenced by mediastinal shift, displacement of fissures, or downward displacement of the diaphragm; (2) radiographic verification of contralateral lung contamination; (3) unremitting signs of sepsis after 72 hours of adequate antibiotic therapy; (4) abscess size larger than 4 cm or increasing abscess size; (5) rising fluid level; and (6) persistent ventilatory dependency.
In addition to drainage, intervention permits microbiological analysis of the aspirate. In up to 47% of patients, initial antibiotic regimens require adjustment based on microbial speciation and sensitivity analyses. Tube thoracostomy carries risk of parenchymal injury with resulting chronic air leak and/or bronchopleural fistula (BPF). Operative intervention is rarely indicated in the management of lung abscess but should be considered in patients with failure of clinical or radiological improvement after 4-6 weeks of antibiotic therapy, abscesses larger than 6 cm, massive or life-threatening hemoptysis (4%), empyema or BPF (4%), and bronchial obstruction (particularly if secondary to resectable cancer). Furthermore, acute rupture into the pleural space (pyopneumothorax) is still a surgical emergency. When surgery is indicated, either thoracoscopic or open lobectomy generally is the preferred procedure and can be accomplished with low morality (0%-2%) and morbidity. A double-lumen tube is mandatory to protect the airway due to the high risk of spillage of abscess into the contralateral lung. Routine buttressing of the bronchial stump with a vascularized pedicle (intercostal muscle or pericardial fat) is recommended to prevent BPF.
Antibiotics given over 4-6 weeks with percutaneous drainage is effective in 85%-95% of patients. Mortality for lung abscess has decreased from 30% to 40% in the preantibiotic era to 10% in the present era, but remains greater for elderly individuals, immunocompromised patients, or those who have abscess larger than 6 cm, bronchial obstruction, multiple abscesses, necrotizing pneumonia, or gram-negative pneumonia.
T. Results of surgery for bronchiectasis and pulmonary abscesses. Thorac Surg Clin 2012;22:333.
Bronchiectasis is defined as irreversible dilation of the peripheral airways secondary to damage of the structural components of the bronchial wall (elastin, muscles, and cartilage). Mechanisms of damage include bronchial wall injury, bronchial lumen obstruction, and traction from adjacent fibrosis seen in end-stage lung fibrosis. Cole’s “vicious cycle” hypothesizes that initial infection, in a background of genetic susceptibility or impaired mucosal clearance, results in retention of microorganisms in the bronchial tree. Overproduction of thick inflammatory mucus in the setting of persistent microbial colonization of dilated airways, together with impairment of mucociliary clearance mechanisms causes a vicious cycle of repeated and prolonged episodes of chronic inflammation resulting in progressive airway and lung damage.
The clinical syndrome manifests as chronic dilation of bronchi, a paroxysmal cough that produces variable amounts of fetid, mucopurulent sputum, and recurrent pulmonary infections. Aspirated foreign bodies, endobronchial neoplasms, and hilar lymphadenopathy (see section on Middle Lobe Syndrome, later) also can cause retention of secretions, infections, and progressive bronchiectasis. The presence of true established bronchiectasis, however, must be distinguished from pseudobronchiectasis, which is a cylindric bronchial dilation that is associated with acute bronchopneumonia. When left untreated, true bronchiectasis progresses, while pseudobronchiectasis reverses completely after weeks to months.
Most cases are related to acquired disorders and are caused by two factors: infection and bronchial obstruction. Acquired viral and bacterial infections in infancy and childhood (eg, pertussis, measles, influenza, tuberculosis, bronchopneumonia) were common predisposing conditions that led to bronchiectasis in the past and are still common in developing countries. With the reemergence of tuberculosis postinfectious bronchiectasis is also becoming more prevalent, and is seen 11% of patients. In developed countries, immune deficiency syndromes (hypogammaglobulinemia and leukocyte dysfunction), metabolic defects (cystic fibrosis, alspha-1 antitrypsin deficiency), ultrastructural defects (primary ciliary dyskinesia, Young syndrome, Kartagener syndrome, congenital defects of cartilage), and pulmonary sequestration are more common causes.
Reid categorized bronchiectasis into three main types based on pathologic appearance: (1) tubular or cylindrical, characterized by smooth dilation of the bronchi; (2) varicose, in which the bronchi are dilated with multiple indentations; and (3) cystic or saccular, in which dilated bronchi terminate in blind ending sacs of pus with no communication with the rest of the lung. Saccular bronchiectasis follows severe infections and cases of bronchial obstruction, while the cylindrical variant is associated with tuberculosis and immune disorders. Varicose consists of alternating areas of cylindrical and saccular types.
Bronchiectasis can be classified also as perfused or nonperfused types according to functional hemodynamic perfusion studies as described by Ashour. The perfused type has cylindrical bronchiectatic changes with intact pulmonary artery flow, whereas the nonperfused type involves cystic bronchiectasis with absent pulmonary artery flow and retrograde filling of the pulmonary artery through the systemic circulation.
Taken together, tubular or cylindric bronchiectasis tends to have better prognosis than cystic/varicose varieties, as the lung areas affected by the former tend to have good function and perfusion. Cystic bronchiectasis tends to indicate a completely destroyed, nonfunctional, and nonperfused lung. Additionally, all parameters of respiratory function are worse in the saccular type as compared with the tubular type. Saccular type bronchiectasis also is associated with higher bacterial loads with virulent strains, such as Pseudomonas.
In general, bronchiectasis involves the second-order to fourth-order branches of the segmental bronchi, and its distribution is largely characteristic of the underlying pathology. The left lung tends to be more involved than the right lung in 55%-80% of cases. This may be because the left mainstem bronchus is narrower and longer than the right and subject to greater compression pressures, especially by the aortic arch. The lower lobes are commonly affected owing to gravity-dependent retention of infected secretions. Congenital disorders, for example, are associated with diffuse bilateral bronchiectasis, while tuberculosis and granulomatous diseases are characterized by unilateral or bilateral disease, most commonly limited to the upper lobes and superior segments of the lower lobes. Furthermore, bronchiectasis following pyogenic and viral pneumonias usually involves only the lower lobes, middle lobe, and lingula, and postobstructive bronchiectasis is generally limited to the obstructed segments (see also Middle Lobe Syndrome, later). Common pathogens in patients with bronchiectasis include H influenzae, S aureus, K pneumoniae, E coli, and, in the chronic setting, Pseudomonas species. Mycobacteria, fungi, and Legionella should also be cultured.
Clinical Findings & Diagnosis
Patients with a history of recurrent febrile episodes often complain of a chronic or intermittent cough that produces variable amounts of foul-smelling sputum (up to 500 mL/d). Hemoptysis occurs in 41%-66%, but rarely is it massive. Bronchiectasis associated with granulomatous disease may not be associated with a productive cough (so-called dry bronchiectasis). Exacerbations and advanced disease are manifested by increased sputum production, fever, dyspnea, anorexia, fatigue, and weight loss. A history of sinus problems, infertility, or a family history of similar problems suggests the presence of an inherited disorder associated with bronchiectasis. Physical examination may reveal cyanosis, clubbing, pulmonary osteoarthropathy, evidence of malnutrition, and, in advanced disease, signs of cor pulmonale. Although bronchiectasis is suspected, an imaging study is usually required for confirmation. Bronchograms were at one time required, but high-resolution chest CT scans are now the imaging procedure of choice to document bronchial dilation, particularly with saccular disease. Even with the diagnosis of bronchiectasis, however, endobronchial neoplasm or foreign body must be excluded by flexible fiberoptic bronchoscopy.
In nearly all patients, conservative medical therapy is indicated and generally is sufficient. This includes broad-spectrum antibiotics, bronchodilators, humidification, expectorants, mucolytics, and effective routine postural drainage. In patients with continued infection, bronchoscopy with bronchoalveolar lavage should be considered to obtain more accurate culture results. Other adjunctive therapies include influenza and pneumococcal vaccines and, in some patients, chronic “prophylactic” antibiotic administration with trimethoprim-sulfamethoxazole, erythromycin, or ciprofloxacin. A recent advance in controlling underlying bacterial (especially pseudomonas) infection and symptoms associated with bronchiectasis has been the use of inhaled antibiotics. In the cystic fibrosis and chronic bronchiectasis population, nebulized tobramycin or gentamicin has proven effective in controlling infection, sputum production, and symptoms in a significant proportion of patients.
Patients who fail intensive medical therapy may be candidates for surgical resection if the following criteria are met: (1) the disease must be localized and completely resectable; (2) pulmonary reserve must be adequate; (3) the process must be irreversible (ie, not pseudobronchiectasis, bronchial stricture, foreign body, etc); and (4) significant symptoms must persist. Preoperative assessment requires a high-resolution chest CT scan, although some surgeons still prefer a bronchogram as a “road map.” Pulmonary function studies generally are not necessary, since the involved segments do not function.
The goals of surgery are to remove all active disease and to preserve as much functioning lung parenchyma as possible. The surgical approach includes complete segmental resection of the involved areas. Partial resection almost always ends in recurrence. Resection most commonly involves all basal segments (unilaterally or bilaterally) along with the middle lobe or lingula. With tuberculosis, however, removal of the upper lobe or lobes with or without the superior segment of the lower lobes is more likely. During operation, meticulous maintenance of a clear airway devoid of mucopurulent secretions and blood is essential. Careful dissection of the bronchovascular structures is difficult in patients with chronic inflammation and scarring but is essential to avoid complications.
Although most patients are successfully treated with medical therapy, some require operation. The results of pulmonary resection depend on the cause and type of parenchymal involvement. Success with elimination of symptoms occurs in up to 80% of patients with limited localized disease but only 36% of those with diffuse disease. Prognostic factors include: (1) unilateral disease restricted to the basal segments; (2) young age; (3) absence of sinusitis and rhinitis; (4) history of pneumonia; and (5) no major airway obstruction. Overall morbidity and mortality rates are surprisingly low at 3%-5% and less than 1%, respectively.
Middle lobe syndrome (MLS) is characterized by recurrent or chronic collapse of the middle lobe of the right lung but can also involve the lingula of the left lung. There are two forms of MLS: obstructive and nonobstructive. Obstructive MLS occurs as a result of an endobronchial lesion or extrinsic compression of the middle lobe bronchus from hilar lymphadenopathy or tumor causing postobstructive atelectasis and pneumonitis. The most common cause of extrinsic compression of the right-middle lobe bronchus is enlargement of peribronchial lymph nodes due to fungal infections such as histoplasmosis or atypical mycobacterial infections. Adenopathy due to sarcoidosis or lymph node metastases has also been described in obstructive MLS. Less common causes include aspirated foreign objects, broncholiths, inspissated mucus (associated with cystic fibrosis), and endoluminal granulomas associated with sarcoidosis.
Nonobstructive MLS is characterized by the absence of a mechanical obstruction of the middle lobe bronchus on bronchoscopy and/or CT of the chest. Though poorly understood the narrow diameter and long length of the middle lobe bronchus, combined with an acute angle at its origin, create poor conditions for adequate drainage. This form of MLS is the most common cause and commonly occurs in adults and children with recurrent pneumonia. It is often related to asthma, bronchitis, and cystic fibrosis.
The diagnosis of MLS should be entertained in a patient with repeated episodes of right-sided pneumonia, only after other causes of obstruction (bronchogenic cancer, foreign body, etc), have been ruled out. Evaluation includes chest radiography, bronchoscopy and CT of the chest. Most patients respond to intensive medical therapy including bronchodilators, mucolytics, and broad spectrum antibiotics in addition to therapeutic bronchoscopy. Those who do not respond should be offered resection of the right-middle lobe and/or debulking lymphadenopathy, which is associated with a low mortality rate and favorable outcome. Other indications for surgery include bronchiectasis, fibrosis (bronchial stenosis), abscess, unresolved or intractable recurrent pneumonia, hemoptysis, and suspicion of neoplasm.
et al.: Middle lobe syndrome: a review of clinicopathological features, diagnosis and treatment. Respiration 2012;84:80.
Broncholithiasis is defined as the presence of calculi (broncholiths) within the tracheobronchial tree. In most cases, a broncholith is formed by erosion and extrusion of a calcified adjacent lymph node into the bronchial lumen and is usually associated with long-standing foci of necrotizing granulomatous lymphadenitis. Calcified lymph nodes can remain attached to the bronchial wall, lodge in a bronchus, or be expectorated (lithoptysis). The most common cause of broncholithiasis in the United States is histoplasmosis. Tuberculosis is another frequent cause in some parts of the world.
Patients with broncholithiasis often complain of hemoptysis, lithoptysis (30%), cough, sputum production, fever, chills, and pleuritic chest pain. The hemoptysis is characteristically sudden and self-limited, though rarely it may be massive. Symptoms of pneumonia may indicate bronchial obstruction from an impacted broncholith. Signs suggesting broncholithiasis include localized wheezing on physical examination, evidence of hilar calcifications or segmental atelectasis and pneumonia on chest x-ray, and bronchoscopic evidence of peribronchial disease. The diagnosis is confirmed by documentation of lithoptysis or the presence of an endobronchial “lung stone.”
The complications of broncholithiasis include hemoptysis, which on occasion can be massive and life threatening; suppurative lung diseases (eg, pneumonia and bronchiectasis); midesophageal traction diverticula; and, rarely, tracheobronchoesophageal fistula.
In addition to instituting appropriate therapy for underlying pulmonary diseases, treatment is primarily directed at removal of endobronchial stones. This can be accomplished at the time of bronchoscopy if the broncholith is freely floating within the tracheobronchial tree or if it extends well into the bronchial lumen and can be removed without excessive force or traction (20% of cases). The main danger of transbronchoscopic removal of broncholiths is the risk for massive hemorrhage. This results during inappropriate removal of broncholiths that remain substantially attached to the parabronchial tissues. Because of intense peribronchial fibrosis in this situation, the broncholith not infrequently becomes adherent to vascular structures such as the pulmonary artery, which may be torn with vigorous attempts at broncholith removal.
Nearly 80% of patients with broncholiths that remain in situ require surgical removal. The goal of surgery in this disease is preservation of lung function. The broncholith may be removed safely with bronchotomy; however, most patients require segmentectomy or lobectomy, particularly if destruction of lung parenchyma has occurred from postobstruction suppurative lung disease. Fistulas between the airway and the esophagus should be repaired with interposition of normal tissue (intercostal muscle flap, etc) between the two structures to prevent recurrence. Following surgery, the prognosis is excellent.
et al.: Rigid bronchoscopy and surgical resection for broncholithiasis and calcified mediastinal lymph nodes. J Thorac Cardiovasc Surg 2008;136:186.
5. Cystic Fibrosis and Mucoid Impaction of the Bronchi
Cystic fibrosis is an autosomal recessive multisystem congenital disorder that is characterized by chronic airway obstruction and infection and by exocrine pancreatic insufficiency and gastrointestinal tract dysfunction with consequent effects on nutrition, growth, and maturation. The disorder is the result of several characterized mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, most commonly the ΔF508 mutation. Such mutations cause abnormalities of chloride and likely sodium transport leading to abnormal regulation and reduction of airway surface liquid volume. The result is a viscous and tenacious mucus that adheres to the airway surface epithelium resulting in airflow obstruction and bacterial infection (S auerus, P aeruginosa, and Burkholderia cepacia). Once established, infection of the CF lung is rarely eradicated. Pulmonary manifestations of the disorder include mucoid impaction, bronchitis, bronchiectasis, pulmonary fibrosis, emphysema, and lung abscess. Mucoid plugs are rubbery, semisolid, gray to greenish-yellow in color, and round, oval, or elongated in shape. There is often a history of recurrent upper respiratory infection, fever, and chest pain. Expectoration of hard mucus plugs or hemoptysis may occur.
The earliest manifestation of CF lung disease is a cough that progressively worsens to becoming a daily event and productive. It often becomes paroxymal and associated with gagging and emesis. Sputum is usually tenacious, purulent, and often green, reflecting bacterial infection. Hyperinflation of the lungs due to airway obstruction is noted early in the progression of lung disease. Asthmatic or bronchiolitic-type wheezing is common. CF patients typically have mild bronchitis symptoms for long periods of time punctuated by increasingly frequent acute exacerbations of symptoms that include increased intensity of cough, tachypnea, shortness of breath, decreased activity and appetite, and weight loss. Intense antibiotic therapy and assistance with clearance of mucus are usually required to reduce lung symptoms and improve lung function. End-stage lung disease is characterized by substantial hypoxemia, pulmonary hypertension, cor pulmonale, and death.
The primary objectives of CF treatment are to control infection, promote mucus clearance, and improve nutrition. Therapy includes postural drainage with chest percussion, expectorants, detergents, bronchodilators, antibiotics, and aerosol inhalation. More novel therapies include inhaled hypertonic saline which osmotically draws water onto the airway surface thereby “rehydrating” the airway mucus allowing for easier expectoration, aerosolized rhDNase which lyses the viscous DNA contained within airway mucus and ibuprofen which has been shown to slow the decline in lung function. Surgery including partial lung resection is indicated for apparently localized disease (lung abscess and bronchiectasis) and recurrent severe exacerbations. Lobectomy is occasionally indicated for massive hemoptysis that is refractory to bronchial artery embolization.
Double lung transplantation has become an accepted therapy for respiratory failure secondary to CF. Patients should be referred when their prognosis is about equal to the waiting time for donor lungs, currently about 2 years after acceptance as a lung transplant candidate. Relative contraindications to transplant include severe malnutrition (ideal body weight < 70%), chronic steroid use greater than 20 mg of prednisone daily and mechanical ventilation (center dependent). Multiresistant P aeruginosa infection is not a contraindication for transplantation although pan-resistant P aeruginosa is considered, at some centers, to be a contraindication. Burkholderia cepacia is viewed by some to be a contraindication to lung transplantation. The transplanted lungs remain free of CF, but are subject to secondary infection, acute rejection, and chronic rejection (bronchiolitis obliterans syndrome). The 5-year survival following lung transplantation is 48%. The median survival in all CF patients now exceeds 31 years.
et al.: Cystic fibrosis. Lancet 2009;373:1891.
Tuberculosis markedly declined as a cause of death between 1953 and 1984, but since 1985, this disease has experienced resurgence due to increased immigration of infected individuals and HIV infection. A reservoir of about 5000-8000 clinical cases exists, and an additional 25,000 new cases occur annually. Multidrug-resistant tuberculosis (MDR-TB) and, most recently, extensively drug-resistant tuberculosis (XDR-TB) have emerged over the last 20 years. MDR-TB is defined as those strains resistant to at least isoniazid and rifampicin. XDR-TB strains are defined as those resistant to rifampicin, isoniazid, flurooquinolones, and any of capreomycin, kanamycin, or amikacin. Resistance to these antituberclar drugs is the result of spontaneous mutations in the genome and is due to a myriad of factors most commonly inadequate treatment of active pulmonary tuberculosis. Less than 20% of the United States population is tuberculin-positive, but tuberculosis remains a common infectious cause of death worldwide. It is estimated that there are 440,000 new MDR-TB cases identified each year worldwide, many of these arising in previously treated patients. Nearly 50% of cases occur in India and China. The prognosis of treatment of MDR-TB or XDR-TB is significantly worse than for drug-susceptible disease.
Several species of the genus mycobacterium may cause lung disease, but 95% of cases of lung disease are due to Mycobacterium tuberculosis. Several “atypical” species of Mycobacterium, such as Mycobacterium bovis and Mycobacterium avium, that are chiefly soil-dwellers, have become clinically more important in recent years because they are less responsive to preventive and therapeutic measures. Mycobacteria are nonmotile, nonsporulating, weakly gram-positive rods classified in the order Actinomycetales. Dormant organisms remain alive for the life of the host.
The initial infection often involves pulmonary parenchyma in the midzone of the lungs. When hypersensitivity develops after several weeks, the typical caseation appears. Regional hilar lymph nodes become enlarged. Most cases arrest spontaneously at this stage. Should the infection progress, caseation necrosis develops and giant cells produce a typical tubercle. A cause of latent disease in the elderly or debilitated patient is dormant reactivation tubercles. Sites in the apical and posterior segments of the upper lobes and superior segments of the lower lobes are the usual areas of infection.
Patients may present with minimal symptoms, including fever, cough, anorexia, weight loss, night sweats, excessive perspiration, chest pain, lethargy, and dyspnea. Extrapulmonary disease may be associated with more severe symptoms, such as involvement of the pericardium, bones, joints, urinary tract, meninges, lymph nodes, or pleural space. Erythema nodosum is seen occasionally in patients with active disease.
False-negative tests with intermediate-strength PPD are usually due to anergy, improper testing, or outdated tuberculin. Anergy is sometimes associated with disseminated tuberculosis, measles, sarcoidosis, lymphomas, or recent vaccination with live viruses (eg, poliomyelitis, measles, rubella, mumps, influenza, or yellow fever). Immunosuppressive drugs (eg, corticosteroids, azathioprine) and disease states (eg, AIDS, organ transplantation) may also cause false-negative responses. Mumps skin tests are negative in patients taking immunosuppressive drugs. Culture of sputum, gastric aspirates, and tracheal washings as well as pleural fluid and pleural and lung biopsies may establish the diagnosis.
Radiographic findings include involvement of the apical and posterior segments of the upper lobes (85%) or the superior segments of the lower lobes (10%). Seldom is the anterior segment of the upper lobe solely involved, as in other granulomatous diseases such as histoplasmosis. Involvement of the basal segments of the lower lobes is uncommon except in women, blacks, and diabetics, but endobronchial disease usually involves the lower lobes, producing atelectasis or consolidation. Differing x-ray patterns correspond to the pathologic variations of the disease: the local exudative lesion, the local productive lesion, cavitation, acute tuberculous pneumonia, miliary tuberculosis, Rasmussen aneurysm, bronchiectasis, bronchostenosis, and tuberculoma.
It is critical to distinguish the x-ray findings from bronchogenic carcinoma, particularly when there is tuberculoma without calcification.
Active disease should be treated with one of the chemotherapeutic regimens that have recently been shown to shorten the period of treatment while maintaining their potency. Such drugs include isoniazid, streptomycin, rifampin, and ethambutol.
Treatment of MDR-TB and XDR-TB is less well defined. The World Health Organization (WHO) recently updated and put forth recommendations for treating MDR-TB. This includes:
Rapid drug-susceptibility testing of isonizaid and rifampicin should be performed at the initial diagnosis of tuberculosis.
The use of sputum microscopy and culture should be used instead of microscopy alone.
Later generation flurooquinolones, as well as ethionamide, should be used in patients with MDR-TB.
The treatment of MDR-TB should include at least pyrazinamide, a flouroquinolone, a parenteral agent (kanamycin, amikacin, or capreomycin), ethionamide, and either cycloserine or p-aminosalicyclic acid.
An intensive treatment of at least 8-months duration is recommended.
The success of MDR-TB therapy ranges from 36% to 79% with a mortality rate of 11%. It is estimated that less than 10% of people with MDR-TB are receiving appropriate treatment according to international guidelines.
The role of surgery in treatment of tuberculosis has diminished dramatically since chemotherapy became available. It is now confined to the following indications: (1) failure of chemotherapy; (2) performance of diagnostic procedures; (3) destroyed lung; (4) postsurgical complications; (5) persistent bronchopleural fistula; and (6) intractable hemorrhage. The most common parenchymal resections include lobectomy, followed by pneumonectomy. Muscle flap coverage is strongly recommended. The infectious process often involves the pleural space and it is useful to perform an extrapleural dissection to minimize contamination or bacterial superinfection of the resection cavity.
Pulmonary resection is adjunctive to chemotherapy. The rationale for lung resection of parenchyma affected by MDR-TB is to remove a large focal burden of organisms present in destroyed nonviable lung tissue. The destroyed lung parenchyma and associated cavities are an ideal environment for the bacillus to grow due to its isolation from the circulation and therefore the host’s defenses. Surgery is recommended in MDR-TB patients with extensive drug resistance—those with localized disease amenable to resection and those with high drug activity. Pretreatment with chemotherapeutic regimens for at least 2 months is required before operation to reduce the bacterial burden, followed by 12-24 months of treatment after surgery.
Diagnostic lung resection may be necessary to rule out other diseases, such as cancer, or to obtain material for cultures. Patients with destroyed lobes or cavitary tuberculosis of the right-upper lobe containing large infected foci may sometimes be candidates for resection.
The disease can become reactivated in some patients who have had thoracoplasty, plombage, or resection, and a few will require reoperation. The most common indications for surgery after plombage therapy are pleural infection (pyogenic or tuberculous) and migration of the plombage material, causing pain or compression of other organs. Following pulmonary resection, tuberculous empyema may develop in the postpneumonectomy space, sometimes associated with a bronchopleural fistula or bony sequestration. Persistent bronchopleural fistula after chemotherapy and closed tube drainage may require direct operative closure. Use of muscle flaps (intercostal, etc) is highly recommended to cover any bronchial stumps, especially in the setting of pneumonectomy.
Tuberculous empyema poses unique problems of management. Treatment depends on whether the empyema is: (1) associated with parenchymal disease; (2) mixed tuberculous and pyogenic or purely tuberculous; and (3) associated with bronchopleural fistula. The ultimate objective is complete expansion of the lung and obliteration of the empyema space. Pulmonary decortication or resection may be used for tuberculosis, but open or closed drainage is necessary when the process is complicated by pyogenic infection or bronchopleural fistula.
The prognosis is excellent in most cases treated medically; the death rate decreased from 25% in 1945 to less than 10% currently. Perioperative mortality for pulmonary resections for tuberculosis ranges from 10% for pneumonectomy to 3% for lobectomy and 1% for segmentectomy and subsegmental resections.
The morbidity of surgical resection ranges from 12% to 39% with the most common complications being bleeding, empyema, wound complications, and bronchopleural fistula. The rate of sputum sterilization ranges from 78% to 96% in MDR-TB patients. Factors leading to poorer outcomes include retreatment cases, XDR-TB, bilateral disease, and low body mass index.
et al.: WHO guidelines for the programmatic management of drug-resistant tuberculosis: 2011 update. Eur Respir J 2011;38:516–528.
et al.: Surgical treatment for multidrug-resistant and extensive drug-resistant tuberculosis. Ann Thorac Surg 2010;89:1597–1602.
et al.: Surgical treatment of drug-resistant tuberculosis. Lancet Infect Dis 2012;12(2):157–166.
et al.: Surgery for the sequelae of postprimary tuberculosis. Thorac Surg Clin 2012;22(3):287–300.
FUNGAL INFECTIONS OF THE LUNG
Pulmonary fungal infections are increasing due to the widespread use of broad-spectrum antibiotics, the use of corticosteroids and other immunosuppressive drugs, and the spread of HIV infection. However, infection can occur in immunocompetent hosts. Fungal infections frequently involve the respiratory tract and include histoplasmosis, coccidioidomycosis, blastomycosis, cryptococcosis, aspergillosis, mucormycosis, and candidiasis. Fungal infections, though ubiquitous, are notable for several characteristic endemic areas. Candidiasis rarely if ever requires operative treatment and thus will not be discussed here.
Histoplasma capsulatum is a dimorphic soil fungus found in soil enriched by the nitrogen contained in bird and bat guano. Abandoned buildings, attics, lofts, and areas under trees that serve as bird and bat roosts and caves are especially likely to contain high concentrations. In endemic areas, exposure is common, and most infections are sporadic. Outbreaks have been traced to spelunking, demolition of buildings, and activities that disrupt contaminated soil. This organism is found primarily in the Ohio and Mississippi River valleys and in Central America. Mammals, including humans, inhale the organism and macrophages engulf the fungus. It then transforms into the budding yeast form, causing activation of inflammatory cytokines. Over several months the ongoing inflammation causes granuloma formation in lymph nodes with resulting caseation, necrosis, fibrosis, and calcification. The diagnosis of histoplasmosis is made definitively by growth of the organism from either sputum, BAL fluid, lung tissue, or mediastinal lymph nodes—though incubation periods of 4-6 weeks are required. Serology also plays an important role in the diagnosis. Both complement fixation and immunodiffusion tests should be ordered. Serology is not useful in immunosuppressed patients who are unable to mount an antibody response. The Histoplasma EIA has been under development as a diagnostic aid and detects the galactomannan component of the cell wall of H capsulatum. The original assay was marked by poor sensitivity; however, with modifications its sensitivity has increased to 65% in patients with acute pulmonary histoplasmosis.
Most infections in immunocompetent individuals are asymptomatic. Infections are classified as acute, chronic, or disseminated. Acute infections are manifested: (1) as a flu-like syndrome with fever, chills, dry cough, headache, retrosternal discomfort, arthralgias, and a rash suggesting erythema nodosum; (2) with symptoms similar to a flu-like syndrome but limited to the lungs and occasionally accompanied by a productive cough; or (3) as an acute diffuse nodular disease with mild symptoms. Radiographic findings in these three acute syndromes typically demonstrate ill-defined upper lobe nonsegmental opacities; nonsegmental areas of consolidation that tend to change; and diffuse, discrete 3- to 4-mm nodules, respectively. Hilar adenopathy on chest x-ray is common. Physical examination can be normal or may reveal signs of pneumonia.
In contrast, chronic infections include: (1) an asymptomatic solitary, discrete nodule less than 3 cm in diameter known as a histoplasmoma (most common), often with central and concentric calcifications (“target lesion”) and frequently located in the lower lobes; (2) chronic cavitary histoplasmosis, which typically occurs in patients with underlying obstructive disease, characteristically mild symptoms, fibronodular upper lobe infiltrates, and centrilobular emphysematous spaces; (3) mediastinal granulomas that may result in broncholithiasis, esophageal traction diverticula, superior vena cava compression, and tracheobronchoesophageal fistulas; and (4) fibrosing mediastinitis, which can produce compression of the superior vena cava, tracheobronchial tree, or esophagus.
Disseminated disease includes an acute, subacute, and chronic form. These infections occur in children (acute and subacute) as well as adults (subacute and chronic). Fever and abdominal pain are common. Other findings include hepatosplenomegaly, pancytopenia, meningitis, endocarditis, adrenocortical insufficiency, and oropharyngeal ulceration (chronic form).
Radiographic imaging in disseminated disease may demonstrate diffuse interstitial pneumonitis (25%) or minimal findings. The symptoms and roentgenographic findings of histoplasmosis resemble those of tuberculosis, although the disease appears to progress more slowly. There may be cough, malaise, hemoptysis, low-grade fever, and weight loss. As many as 30% of cases coexist with tuberculosis. Pulmonary fibrosis, bulla formation, and pulmonary insufficiency occur in advanced cases of histoplasmosis. Mediastinal involvement is quite frequent and may take the form of granuloma formation, or dysphagia. Furthermore, mediastinal fibrosis is among the most common benign causes of superior vena caval syndrome (discussed earlier in the chapter). Erosion of inflammatory lymph nodes into bronchi may cause expectoration of broncholiths, hemoptysis, wheezing, or bronchiectasis. Traction diverticula of the esophagus may lead to development of tracheoesophageal fistula. Pericardial involvement may lead to constrictive pericarditis.
In lesions that present as solitary pulmonary nodules, histoplasmosis is diagnosed in about 15%-20% of cases. Radiologically, early infections appear as diffuse mottled parenchymal infiltrations surrounding the hila, with enlargement of hilar lymph nodes. Cavitation indicates advanced infection and is the complication about which the surgeon is most often consulted. The diagnosis rests on finding a positive skin test or complement fixation test and culturing the fungus from sputum or a bronchial aspirate.
Medical therapy of histoplasmosis is indicated only in cavitary and severe disease and for most infections in immunocompromised hosts. Azoles are recommended as first-line treatment for patients who have mild to moderate pulmonary histoplasmosis. Itraconazole (200-400 mg/d for 6 months) is the drug of choice for cavitary disease, while amphotericin B (1-2 g total dose) is reserved for patients with more serious infections and infections in immunocompromised patients. Reflecting increasing use of corticosteroids for ARDS in the last decade, the current American Thoracic Society Guidelines recommend the use of intravenous methylprednisilone as adjunctive therapy for severe acute pulmonary histoplasmosis. Operative intervention is reserved for treatment of complications and to rule out neoplastic disease in the case of suspicious pulmonary nodules. Broncholithectomy via rigid bronchoscopy with or without pulmonary resection, repair of tracheobronchoesophageal fistulas, decompression of mediastinal granulomas, and spiral saphenous vein bypass of severe symptomatic superior vena cava obstruction are typical examples. The Infectious Diseases Society of America recommends pericardiectomy for recurrent pericardial effusions. In cases of vascular fibrosis of the superior vena cava and pulmonary vessels percutaneous intravascular dilation and stenting is recommended as first-line treatment.
Coccidioides immitis is a dimorphic soil fungus endemic to the Sonoran life zone (Utah, Arizona, California, Nevada, and New Mexico) and is associated with creosote brush. Dry heat with brief intense rain is essential for this fungus, which is spread by strong winds. Infection occurs through inhalation of as few as 1-10 arthrospores, which then germinate as parasitic spherules. Spherules have a double refractile cell wall and produce endospores that cause the spherule to rupture, spreading the infection to the surrounding tissues. Caseation, suppuration, abscess formation, and fibrosis follow. The diagnosis of coccidioidomycosis relies on the detection of acutely elevated titers of immunoglobulin M (IgM) antibodies (by latex agglutination and confirmed by immunodiffusion tube precipitin tests) or rising serum immunoglobulin G (IgG) antibody complement fixation titers (seroconversion or fourfold rise) in the appropriate clinical context. The coccidioidin and Spherulin skin tests, which become positive 3-21 days following infection, are generally useful only for epidemiologic studies and not for the diagnosis of acute disease. C immitis grows well in culture, but it is extremely hazardous to handle and requires a laminar flow hood due to the highly infectious nature of the arthrospores. Identification of the spherules in tissue, lavage samples, and fine-needle aspirates is helpful in making the diagnosis in some patients. Although many stains can be used, including routine fungal (potassium hydroxide, KOH) preparations, Pap staining is most sensitive. Gram stains, however, fail to demonstrate spherules.
Primary infection is asymptomatic in 60% of patients, while most others develop desert fever, with fever, productive cough, pleuritic chest pain, pneumonitis, and a rash typical of erythema nodosum or erythema multiforme. Disease that includes arthralgias is known as desert rheumatism. Radiographic findings demonstrate segmental or nonsegmental, homogeneous or mottled infiltrates with a predilection for the lower lobes. Physical examination is often unrevealing, but rales and rhonchi may be present. Other findings include eosinophilia (66%), hilar adenopathy (20%), and small exudative pleural effusions (2%-20%). Symptomatic persistent infection associated with chest x-ray findings 6-8 weeks after primary infection is classified as one of five types: persistent pneumonia, chronic progressive pneumonia, miliary coccidioidomycosis, coccidioidal nodules, or pulmonary cavities. Persistent pneumonia manifests with symptoms of fever, productive cough, and pleuritic chest pain in association with protracted infiltrates and consolidation on chest x-ray generally resolving within 8 months. Patients with chronic progressive pneumonia complain of fever, cough, dyspnea, hemoptysis, and weight loss, with bilateral apical nodular densities and multiple cavities lasting years. This presentation closely resembles tuberculosis and chronic histoplasmosis. Miliary coccidioidomycosis occurs early and rapidly, associated with bilateral diffuse infiltrates. This form of disease implies the presence of impaired immunity and has an associated mortality rate of 50%. Nearly half of patients with coccidioidal nodules are asymptomatic. These nodular densities (coccidiomas) appear in the middle and upper lung fields, often within 5 cm of the hilum; range from 1 to 4 cm in size; and do not calcify, making it hard to distinguish them from malignancy. In endemic areas, 30%-50% of all nodules are coccidiomas. Patients develop pulmonary cavities in 10%-15% of cases of coccidioidomycosis. Typically, these are solitary (90%), thin-walled, located in the upper lobes (70%), less than 6 cm in size (90%), and close spontaneously within 2 years (50%). Some cavities, however, cross fissures; cause hemoptysis (25%-50%), usually mild; rupture, producing a pyopneumothorax with a bronchopleural fistula; or become infected with Aspergillus. Uncommonly, dissemination can occur, particularly in immunocompromised individuals, in pregnancy (third trimester), and in non-Caucasian individuals. Although pulmonary symptoms in disseminated disease are mild, meningeal involvement is common and the mortality rate is high (50%).
Medical therapy is not indicated in asymptomatic, immunocompetent individuals. Patients with persistent or chronic pneumonia, miliary disease, and those at risk for dissemination should be treated with antifungal therapy. Amphotericin B (0.5-2.5 g intravenously as total dose) is the standard treatment, though the newer azole compounds (fluconazole, ketoconazole, and itraconazole) may be used for long-term maintenance therapy, since the relapse rate may be as high as 25%-50%. Surgery is reserved for patients with coccidiomas when cancer is a concern and in patients with cavities that have an associated radiographic abnormality suggesting carcinoma (ie, thick wall) or that develop a complication (eg, hemoptysis and pyopneumothorax from rupture). Resection should include all diseased tissue and most often requires lobectomy.
Blastomyces dermatitidis is a dimorphic soil fungus found in warm, wet, nitrogen-rich soil in an endemic area that extends east of a line from the Texas Gulf coast to the border between Minnesota and North Dakota (except Florida and New England). Infection occurs characteristically in males (male-to-female ratio 6:1-15:1) from 30-60 years of age through inhalation of conidia (asexual spores). At 37°C, the conidia germinate as yeasts, producing caseation in a manner similar to tuberculosis. Rarely, infection may develop through direct skin inoculation. Risk factors include poor hygiene, exposure to dust and wood, manual labor, and poor housing conditions. Since no accurate skin or serologic tests exist, the diagnosis depends on culture or histologic identification of the yeast form. Culture of the mycelial form can be hazardous. B dermatitidis grows as white to tan colonies of septate hyphae at room temperature but changes to budding yeast at 37°C. This temperature-dependent change reflects the uncoupling of oxidative phosphorylation. The yeast form can be found in sputum (33%), bronchoalveolar lavage specimens (38%), lung biopsies (21%), and fine-needle aspirates (7%) and can be demonstrated with standard KOH preparations or many other histologic stains (but not Gram stain). The yeast, however, does not have a large capsule (distinguishes it from Cryptococcus neoformans) and does not grow intracellularly (differentiates it from H capsulatum).
Manifestations of blastomycosis can occur in many organ systems, including the lungs, skin, bone, genitourinary tract (prostatitis and epididymo-orchitis), and central nervous system. Pulmonary infection can be asymptomatic or may present with flu-like symptoms, evidence of pneumonia, or pleurisy. Cough (36%), weight loss (20%), pleuritic pain (26%), fever (23%), hemoptysis (21%), erythema nodosum, and ulcerative bronchitis are common. Radiographic findings include homogeneous or patchy consolidation in a nonsegmental distribution with pleural effusions or thickening or cavitation (15%-35%). In some patients, the appearance of pulmonary masses may mimic carcinoma. A predilection for the upper lobes has been noted; however, unlike histoplasmosis and coccidioidomycosis, in blastomycosis, hilar and mediastinal adenopathy is unusual.
Limited disease in asymptomatic immunocompetent patients requires no specific therapy. Itraconazole, 100-200 mg/d orally for at least 2-3 months, is now the therapy of choice for nonmeningeal disease, with a response rate of over 80%. Amphotericin B (0.5-2 g), however, is indicated in patients with meningeal disease or failed therapy. Surgical resection is rarely necessary except when the possibility of malignancy cannot be excluded.
Cryptococcus neoformans is an encapsulated yeast-like budding fungus. It is a saprophyte existing on the skin, nasopharynx, gastrointestinal tract, and vagina of humans as well as in pigeon excreta, grasses, trees, plants, fruits, bees, wasps, insects (cockroaches), birds, milk products, pickle brine, and soil. Cryptococcal infection generally indicates the presence of an underlying debilitating disease in an immunocompromised host. Infection occurs from inhalation of the yeast form. The diagnosis can be established by the detection of serum antigen (via complement fixation tests) in patients with appropriate clinical and radiographic findings. More commonly, however, histologic identification with India ink stains is used; routine cultures are not performed because they are extremely time-consuming and require multiple biochemical tests for differentiation of cryptococcus from other fungi. No accurate skin test exists for cryptococcosis.
The most common sites of infection are the lungs and central nervous system. Pulmonary infection may remain asymptomatic, or patients may complain of cough, pleuritic chest pain, and fever. Radiographically, cryptococcus can appear as a localized, well-defined 3-10-cm pleural-based mass without smooth borders; as single or multiple areas of consolidation, usually within one lobe but in nonsegmental distribution; or as a disseminated miliary nodular infiltrate. A predilection for the lower lobes has been noted. Central nervous system infection usually follows an asymptomatic pulmonary infection. Central nervous system symptoms are highly variable, since many patients are severely immunocompromised and do not manifest the usual signs and symptoms of meningitis or cerebritis.
Medical therapy is indicated in most cases of pulmonary infection except for rare cases of limited localized disease. Amphotericin B (0.5-2 g) remains the treatment of choice and is often combined with flucytosine (150/mg/kg/d) for synergy. New azole compounds (eg, fluconazole, itraconazole, and voriconazole) have been used with increasing frequency as first-line therapy both as single agents and in combination. Surgery is rarely indicated and is useful only to exclude the possibility of malignancy or to determine the etiology of an undiagnosed diffuse pulmonary infiltrate by open lung biopsy.
Aspergillus species are ubiquitous dimorphic soil fungi found in soil and decaying organic matter. The most common pathogenic species include Aspergillus fumigatus (most common), Aspergillus niger, Aspergillus flavus, and Aspergillus glaucus. In culture, these fungi resemble an aspergillum, which is a brush used to sprinkle holy water. Aspergillosis represents the second-most common (after candidiasis) opportunistic fungal infection in immunocompromised hosts and the third-most common systemic fungal infection requiring hospital care. Infection occurs almost exclusively through inhalation of conidia into areas of lung with impaired mucociliary function (eg, tuberculous cavities). Although the diagnosis is supported by demonstrating immediate and delayed-type hypersensitivity skin reactions, by culturing uniform septate hyphae with dichotomous branching at 45 degrees, and by detecting specific IgG and IgE antibodies, a definitive diagnosis requires demonstration of hyphal tissue invasion or documentation of hyphae on methenamine silver stain in a suspected aspergilloma. Galactomannan enzyme-linked immunosorbent assays have recently become available and serve as a sensitive serum measure of invasive infection.
Infection with Aspergillus species usually takes one of three forms: allergic bronchopulmonary aspergillosis, invasive aspergillosis, and aspergilloma. Allergic bronchopulmonary aspergillosis occurs in patients who are atopic (asthmatics) and in patients with cystic fibrosis. Endobronchial fungal growth leads to dilated airways filled with mucus and fungus. Continuous exposure to fungal antigens results in precipitating antibodies, increased IgE levels (which correlate with disease activity), and both immediate and delayed-type hypersensitivity. Patients complain of cough, fever, wheezing, dyspnea, pleuritic pain, and hemoptysis. Chest x-ray shows homogeneous densities in a “gloved-finger,” inverted Y, or “cluster of grapes” pattern. Five stages have been defined depending on disease activity and steroid dependency: Stage 1 includes acute infection with characteristic x-ray and laboratory evidence of disease; stage 2 occurs with steroid-induced remission; stage 3 is characterized by asymptomatic exacerbations of laboratory and x-ray findings; steroid-dependent asthma with worsening laboratory tests (total IgE, precipitins, etc) is indicative of stage 4 disease; and end-stage fibrosis, bronchiectasis, and obstruction define stage 5.
Invasive aspergillosis is found exclusively in immunocompromised patients, particularly in patients with leukemia (50%-70% of cases). Dissemination occurs frequently, and three types of pulmonary disease have been described: tracheobronchitis (uncommon), necrotizing bronchopneumonia, and hemorrhagic infarction (most common). In tracheobronchitis, disease is usually limited to the larger airways (bronchus more so than trachea) with little parenchymal involvement. Focal or diffuse mucosal ulceration, pseudomembranes, and intraluminal fungal plugs are common. Patients often present with cough, dyspnea, wheezing, and hemoptysis. Occasionally, patchy areas of atelectasis secondary to bronchial obstruction can be seen on chest x-ray. Necrotizing bronchopneumonia should be suspected in patients with unremitting fever, dyspnea, tachypnea, radiologic evidence of bronchopneumonia, and a poor response to standard antibiotic therapy. Finally, hemorrhagic infarction due to vascular permeation with nonthrombotic occlusion of small- to medium-sized arteries and necrosis typically results in either a well-defined nodule or a wedge-shaped, pleura-based density. Symptoms are nonspecific and include fever, dyspnea, dry cough, pleuritic chest pain, and hemoptysis. Cavitation is common, and radiologic examination may reveal “round” pneumonia or “air crescents” of a mycotic lung sequestrum.
Aspergillomas (“fungus balls” or mycetomas) are divided into two types: simple, thin-walled cysts lined with ciliated epithelium and surrounded by normal parenchyma; and complex cavities associated with markedly abnormal surrounding lung tissue. Aspergillomas most often occur in the upper lobes and in the superior segments of the lower lobes. Although they may be multiple (22%), calcification and air-fluid levels are rare. Most aspergillomas—particularly complex ones—are associated with cavitary lung disease, that is, tuberculosis (most common), histoplasmosis, sarcoidosis, bronchiectasis, and others. Hemoptysis occurs in 50%-80% and can present with frequent minor episodes (30% subsequently have massive bleeding), repeated moderate episodes, or a single episode of massive hemoptysis. Chest x-ray may reveal a 3- to 6-cm round, mobile density with a crescent of air.
Corticosteroids are indicated in patients with allergic bronchopulmonary aspergillosis in addition to measures to relieve bronchospasm (inhaled β-agonists or anticholinergics). In invasive aspergillosis, amphotericin B (0.5-2 g intravenously as total dose) has been standard therapy despite a mortality of 90%. In addition, some patients with complex aspergillomas and severe pulmonary disease are not candidates for surgical resection, and intracavitary amphotericin has been used with modest success. Surgery is indicated for complications of Aspergillus infection. Hemoptysis due to aspergillomas is usually best treated by surgical resection. Furthermore, hemoptysis associated with localized invasive aspergillosis (particularly once cavitation has occurred) can be treated by resection and amphotericin B. Generally, wide excision (lobectomy) is required; however, in some high-risk patients with aspergillomas, cavernostomy, and muscle flap closure is an alternative.
Infection with Rhizopus arrhizus, Absidia species, and Rhizomucor species of the class Zygomycetes and the order Mucorales occurs in certain distinct immunosuppressed patient populations: people with poorly controlled diabetes and leukemia patients. These fungi are ubiquitous organisms that are found in decaying fruit, vegetable matter, soil, and manure. Infection occurs following inhalation of sporangiospores, which germinate in a hyphal form. The diagnosis is made by demonstrating the organism in symptomatic patients. No accurate skin or serologic tests exist. Although the fungi do grow in culture as broad, irregular nonseptate hyphae that branch at angles up to 90 degrees (occasionally being confused with Aspergillus species), most commonly the diagnosis is made on histologic examination. The sine qua non for mucormycosis is hyphal vascular invasion between the internal elastic membrane and the media of blood vessels, causing thrombosis, infarction, and necrosis.
In addition to pulmonary infections, mucormycosis manifests as distinct clinical syndromes such as rhinocerebral infection (direct extension into the central nervous system from paranasal sinus infection), cutaneous infection (burn patients), gastrointestinal infection (children with protein-calorie malnutrition), and disseminated infection (uremic patients receiving deferoxamine therapy). Patients with pulmonary infection complain of fever, cough, pleuritic chest pain, and hemoptysis. Frequently, this type of infection occurs in immunocompromised hosts and follows a fulminant course. Three patterns of infection are noted on chest x-ray: limited disease with involvement of a single lobe or segment, diffuse or disseminated disease with involvement of both lungs and the mediastinum, and endobronchial disease with bronchial obstruction and secondary bacterial infection. Characteristic CT findings include a halo sign (area of low attenuation around a dense infiltrate), ring enhancement, and an air-crescent sign (area of contrast between normal lung and a radiodense cavitating lesion). Amphotericin B is the standard treatment. In nonneutropenic patients, the newer azole compounds may be useful; however, infection with these fungi remains highly lethal, with a mortality of 90%. The cause of death in these patients is often fungal sepsis, progressive pulmonary dysfunction, and hemoptysis. In the small group of patients with limited disease, aggressive surgical resection in combination with amphotericin B has lowered the mortality to only 50%. In contrast, the endobronchial form can be effectively treated with transbronchoscopic resection (using the Nd:YAG laser) in a large proportion of patients.
Pneumocystis carinii is a fungal organism that has been found in the lungs of a variety of domesticated and wild mammals and is distributed worldwide in humans. Pulmonary involvement leads to progressive pneumonia and respiratory insufficiency. Disease has been seen with increasing frequency in recipients of organ transplants who are undergoing immunosuppressive therapy. Diagnosis is made by open lung biopsy. Without treatment with trimethoprim-sulfamethoxazole, pentamidine, or inhaled antimicrobial therapy, the course is one of relentless progression. With improved antiviral therapy for HIV infections, the incidence of pneumocystosis has been declining.
et al.: Surgery for other pulmonary fungal infections, Actinomyces, and Nocardia. Thorac Surg Clin 2012;22:363–374.
et al.: Pulmonary fungal infections. Respirology 2012;17:913–926.
SARCOIDOSIS (BOECK SARCOID, BENIGN LYMPHOGRANULOMATOSIS)
Sarcoidosis is a noncaseating granulomatous disease of unknown cause involving the lungs, liver, spleen, lymph nodes, skin, and bones. The highest incidence is reported in Scandinavia, England, and the United States. The incidence in blacks is 10-17 times that in whites. Half of patients are between ages 20 and 40 years, with women more frequently affected than men.
Sarcoidosis may present with symptoms of pulmonary infection, but usually these are insidious and nonspecific. Erythema nodosum may herald the onset, and weight loss, fatigue, weakness, and malaise may appear later. Fever occurs in approximately 15% of cases. Pulmonary symptoms occur in 20%-30% and include dry cough and dyspnea. Hemoptysis is rare. One-fifth of patients with sarcoidosis have myocardial involvement, and heart block or failure may occur. Peripheral lymph nodes are enlarged in 75%, scalene lymph nodes are microscopically involved in 80% and mediastinal nodes in 90%, and cutaneous involvement is present in 30%. Hepatic and splenic involvement can be shown by biopsy in 70% of cases. There may be migratory or persistent polyarthritis, and central nervous involvement occurs in a few patients.
The x-ray findings in sarcoidosis are classified into five descriptive categories or stages (Table 18–5). Pulmonary disease can manifest as a reticulonodular infiltrate, an acinar pattern of opacities, or large nodules with or without mediastinal adenopathy. Mediastinal lymph node involvement characteristically includes bilateral symmetric hilar and paratracheal lymphadenopathy. Anterior or posterior mediastinal adenopathy or asymmetric hilar involvement should prompt a suspicion of other diseases, particularly Hodgkin disease and non-Hodgkin lymphomas. Pleural effusions and cavitation are rare and, if present, necessitate an evaluation for tuberculosis, congestive heart failure, and coincidental pneumonia.
Table 18–5.Radiographic stages of sarcoidosis. ||Download (.pdf) Table 18–5. Radiographic stages of sarcoidosis.
Stage 0: No x-ray abnormality
Stage 1: Hilar and mediastinal lymph node enlargement without pulmonary abnormalities
Stage 2: Hilar and mediastinal lymph node enlargement with pulmonary abnormalities
Stage 3: Diffuse pulmonary disease without adenopathy
Stage 4: Pulmonary fibrosis
Although no single test exists to confirm absolutely the diagnosis of sarcoidosis (the diagnosis remains one of exclusion), it may be suggested by the characteristic radiographic appearance of bilateral hilar and mediastinal lymphadenopathy, by gallium 67 scanning, and by elevated serum and bronchoalveolar fluid levels of angiotensin-converting enzyme and lysozyme. Pathologic documentation of noncaseating granulomas should normally be obtained either via transbronchial biopsy or mediastinoscopy (more reliable, with > 95% success rate). Culture for mycobacteria, fungi, and other atypical infections must also be negative.
Asymptomatic patients and those with minimal clinical disease may require no therapy. Corticosteroids have been used in patients with pulmonary impairment and symptomatic disease with good success. Despite the indolent nature of the disease and steroid therapy, long-term mortality is reported as high as 10%. Lung transplantation has been utilized with success in patients refractory to medical management.