8Miscellaneous infection
8.1Introduction
Besides several main topics, thoracic surgery also covers a diversity of diseases and procedures, which cannot be summarized under one single heading. Among those, Juan Tovar from Madrid updates the variety of treatment options for pleural empyema. Marija Stojkovic and Thomas Junghanss from the Department of Clinical Tropical Medicine in Heidelberg comment on the topic of lung echinococcosis, which is contributed by Akin Kuzucu from Turkey. The age-related etiology of chylothorax requires different measures in terms of diagnosis and treatment. The German neonatologists Anja Bialkowski and Christian F. Poets discuss the congenital chylothorax, while the pediatric surgeons Bethany J. Slater and Steven S. Rothenberg focus on the aquired variant. Open as well as video-assisted procedures for thymus-related diseases are presented by Lan Vu and Hanmin Lee from San Francisco. Jose Ribas Milanez de Campos and Hugo Veiga Sampaio da Fonseca share their experiences in treating hyperhidrosis, while Markus Krüger adds comments to this particular chapter of the two Brazilian thoracic surgeons.
Juan A. Tovar
8.2Empyema (including lung abcess)
Pleural surfaces are lubricated by a minimal amount of clear fluid that facilitates displacement with minimal friction during respiration. This fluid is filtered from the pleural capillary network and reabsorbed by the lymphatic vessels. Disturbances in the balance between secretion and reabsorption cause pleural effusion and this can happen in various clinical conditions. In the presence of infection, the effusion turns into “empyema” and the fluid becomes purulent with bacteria, fibrin and other debris.
In most cases pneumonia is at the origin of empyema that, for this reason is known as “parapneumonic”. Purulent effusions can also have other origins like esophageal perforation, mediastinitis, subphrenic sepsis or postoperative infection. These are not considered in the present chapter.
In the past, pneumonia was a leading cause of morbidity and mortality both in adults and children and, although the advent of antibiotics dramatically changed the results of its treatment, it still remains a serious problem. A proportion of children with pneumonia develop pleural effusions that may evolve into empyema. For unknown reasons, the incidence of empyema is increasing in industrialized countries and the etiology of the infection shifted from Streptococcus pneumoniae, the more common germ isolated in the past, to Staphylococcus aureus, Streptococcus pyogenes or Pseudomonas aeruginosa, Klebsiella or other Gram negative and anerobic bacteria that became more prevalent due to the widespread use of antibiotics [1]. The nature of the pleural infection with abundant bacteriolysis and the frequent use of antibiotics prior to thoracentesis explain why the majority of samples recovered do not yield positive cultures. PCR studies, however, have shown that Streptococcus pneumoniae and Staphylococcus aureus remain the most prevalent germs in children [1].
Bacteria reach the pleural space from the infected lung (rarely from a ruptured lung abscess) and attract leukocytes that secrete pro-inflammatory cytokines, particularly Interleukin-8 (IL-8) and Tumor Necrosis Factor-α (TNF-α). These further permeabilize capillaries and pleural surfaces and cause imbalance of the sequence secretion/reabsorption.
In a first, exudative stage (stage I), pleural fluid is clear or thin, has a pH above 7.20, glucose above 60 mg/dL and a lactic dehydrogenase (LDH) less than three times the maximum normal serum level (<1000 U/ L). Unless adequately treated, pleural effusion progresses into the fibrinopurulent stage (stage II). Bacteria coming from the infected lung are more abundant in the fluid and massive migration of leukocytes occurs. This stage is characterized by progressive secretion of inflammatory mediators with increased pro-coagulant activity and decreased fibrinolysis. The fluid becomes purulent and fibrin clots and peels line the surfaces creating isolated spaces with progressively thicker walls or septa. At this stage, the fluid has a pH below 7.20, glucose below 60 mg/dL and LDH higher than three times the maximum normal serum level (>1000 U/L) [2].
Finally, if still not successfully treated, empyema enters into stage III or the organization stage in which proliferation of fibroblasts in the fibrin depositions takes place and collagen synthesis generates thick scar tissue that perpetuates pleural septation while entrapping the lung and limiting its expansion and function [3].
Probably all patients with pneumonia have pleural effusions but in the vast majority of them these resolve under appropriate treatment without further complications. However, in some cases, fever does not go away under antibiotic therapy and pleuritic pain and/or respiratory difficulty may appear. Percussion and auscultation may indicate pleural involvement and plain X-rays of the thorax demonstrate the presence of fluid in the pleural space, particularly when they are taken in lateral decubitus (Fig. 8.2.1). In cases in which bronchopleural fistula has occurred as a consequence of lung necrosis and abscess, pyo-pneumothorax is apparent. Pleural thickening and scoliosis are also visible in the late phases of the process. Round hollow areas delimited by a thin shell (pneumatoceles) are visible in the parenchyma in some cases of Staphylococcus pneumonia.
The introduction of intercostal ultrasonography (US) facilitated early detection and assessment of the amount of clear pleural fluid during the exudative stage. US imaging also demonstrates thick strands of fibrin and loculations during the fibrinopurulent stage (Fig. 8.2.2) and lung entrapment in the late, organization stage.
Fig. 8.2.1: Plain X-ray of the thorax showing basal pneumonia with parapneumonic Stage I effusion on the left in a 3-year old boy. (a) at presentation, (b) 48 hours later. The amount of fluid increased greatly, as better shown by the film taken lying on the left side (c). Intercostal ultrasonography or US (d) shows a fluid rim of more than 10 mm.
Other imaging procedures may occasionally be indicated, but certainly not in all patients and not in the early phases of the disease [4]. A CT-scan is useful for accurately locating closed spaces difficult to drain percutaneously, but it involves considerable irradiation (equivalent to 20–400 plain X-rays films) and tends to overrate the severity of the disease. It should hence be restricted to complicated cases and to those in which drainage is difficult because of multiple loculation [1, 5].
Knowledge of the natural course of pleural empyema should guide the therapeutic decisions. The exudative phase is reversible and can respond to appropriate antibiotic treatment alone. This should be directed empirically to the usual germs: i.v. Ampicillin 250–300 mg/kg/day in four doses or G-Sodium Penicillin, 300,000– 400,000 IU/ kg/day in six doses are preferred at the beginning, adjusting drugs to bacteriologic findings when available [6].
Fig. 8.2.2: Intercostal US in a child with pleural fibrinopurulent, Stage II parapneumonic effusion. Large rim, thick peel and loculation are clearly shown.
In most children with simple parapneumonic effusion, pyrexia and fever disappear and little attention is given to the pleural fluid. Only if the fever persists, pleuritic pain and/ or respiratory difficulty develop, is assessment of the amount of fluid by plain X-rays or US indicated. When the rim between the thoracic wall and the lung exceeds 10 mm, thoracentesis at this stage may help to assess the nature of the effusion. Falling pH, glucose in the fluid and the presence of germs upon Gram staining are suggestive of progression towards fibrinopurulent stages and may indicate, together with clinical signs, dyspnea and persisting fever, drainage during this phase of “simple empyema”. However, thoracentesis is indicated only in a proportion of patients and therefore, measurements of pH, glucose, LDH or Gram staining are of little help in many other cases.
When, in spite of adequate treatment, pyrexia and fluid persist, more than one thoracentesis would be necessary. In these cases, intercostal drainage is certainly preferable to multiple taps [1]. Pediatricians, pneumologists, intensive care specialists or invasive radiologists take charge more often in these first phases of the treatment of empyema, and pediatric surgeons are rarely involved at this stage. US-guided insertion of Fr10–12 soft drains using a guide wire introduced through a needle (Seldinger technique) is preferred. Unidirectional drainage with underwater seal is mandatory, and meticulous care of the tube is applied.
When the effusion reaches the fibrinopurulent stage, the empyema is considered “complicated” and requires more active treatment since, unless drained and cleansed, it might end up causing fibrosis and lung entrapment. Intravenous antibiotic therapy should then be based on Cefotaxime (200–300 mg/kg/day in four doses in addition to either Cloxacillin 150–200 mg/kg/day in four doses or Clyndamycin 30–40 mg/kg/day in four doses) [6]. Intercostal insertion of a 10–14 F drain is often sufficient for adequate drainage. It is generally placed in the midaxillary line at the level of the fifth or sixth intercostal space in order not to interfere with the comfort of the child. US or CT-scan information may indicate other locations or more drains.
The ideal setting for insertion of the drain is the operating room and sedation or general anesthesia is mandatory. The tube should be connected to an underwater seal and aspiration of no more than −20 cm H2O is considered to be beneficial. Milking and irrigation of the tube are necessary to clear out the debris that might otherwise obstruct it. The tube is removed when there is minimal drainage and the symptoms fade away. This happens in most fibrinopurulent empyemas although in some cases drainage and hospitalization have to be maintained for a relatively long period of time.
For this reason and because drainage alone may be insufficient due to loculation and drain obstruction, the treatment of stage II and stage III “complicated” empyema evolved into other modalities of treatment: video-assisted thoracoscopic surgical (VATS) drainage and cleansing of the pleural space or fluidification of the fibrin inflammatory debris by chemical treatment (fibrinolysis).
The introduction of VATS in the 90s had a huge impact in the treatment of empyema in adults and children. Direct view of the inflammatory lesions facilitated taking down the septa, extracting the peels, reducing the bacterial charge and appropriately irrigating and draining the thorax. A 5-mm port located at the mid-axillary line on the fifth or sixth intercostal space (unless imaging indicates a better location) is used for the 30° lens, and aspirator-irrigator and forceps are introduced by two or more 10-mm additional ports. The septa are taken down, the peel is separated (Fig. 8.2.3) and extracted, the pleural space is generously irrigated and the lung is freed, creating, if possible, a single cavity in which to optimally locate the drain or drains.
The advocators of VATS claimed that, since general anesthesia was most often used for simple intercostal drain insertion, accurate pleural cleansing and positioning of the tubes were better achieved under vision with a relatively minor invasion. In spite of VATS being a formal thoracic operation under general anesthesia with the consequent risks of hemorrhage, nerve or lung lesions and air leaks, this approach rapidly gained the favor of pediatric surgeons and pediatricians, who for the first time had the opportunity to view the nature and the extent of the pleural inflammatory environment. In addition, some randomized pediatric studies showed that VATS was superior to simple drainage in terms of length of drainage, hospital stay and need for additional fibrinolysis [7, 8].
Fig. 8.2.3: Picture taken during thoracoscopy for Stage II fibrinopurulent pleural empyema in a child. The thick peels and inflammatory material are being irrigated, aspirated and prepared for extraction. The involvement of both parietal and visceral pleural surfaces is clearly displayed.
However, fluidification and cleansing of the exudates has been widely attempted in the past by irrigating the infected pleural space with diluted bleach and other antiseptics and the availability of new and more effective agents able to dissolve fibrin clots (fibrinolytics) rejuvenated this approach. After draining the fluid through the intercostal tube, a solution of streptokinase, urokinase or human tissue plasminogen activator (alteplase) is injected and left for some hours with the tube clamped. After a new period of drainage, the procedure is repeated several times in the ensuing days.
Streptokinase is an enzyme secreted by several species of Streptococcus that is able to activate human plasminogen and trigger plasmin proteolytic cascade that lyses fibrin clots. For the treatment of empyema it is injected at doses of 70–120 mL of a solution of 250,000 IU/100 mL, clamping the tube for the ensuing 4 hours, re-establishing the drainage under suction and repeating the procedure daily for 4 or 5 days.
Urokinase is another plasminogen activator originally isolated from human urine that is administered as a solution containing 1000 IU/mL in sterile saline in boluses of 40 mL (10 mL in patients below 10 kg). The tube is clamped for 4 hours and drainage resumed under negative pressure for the next hours. The treatment is repeated twice a day for 3 days. Unfortunately, urokinase is not available in all countries and particularly, not in the US.
A recombinant version of human tissue plasminogen activator (alteplase) is injected through the tube at a dose of 4 mg in 40 mL of sterile saline, followed by tube clamping for 1 hour and re-establishment of the drainage under suction until the next day. The procedure is repeated two more times.
Only a few randomized studies addressed the issue of the superiority of fibrinolysis over drainage and cleansing alone in children with pleural empyema. One of them did not show substantial advantage using streptokinase but the other one showed significantly better results with urokinase [9, 10].
It appears therefore that both fibrinolysis and VATS are more effective than drainage and irrigation alone as the first approach for complicated empyema in children. A retrospective analysis of the existing evidence showed that VATS could have some advantages but the degree of evidence met by randomized comparisons was not met by such analysis [11]. Level-A evidence-based studies were therefore mandatory to compare these approaches.
To our knowledge, only four controlled, prospective, randomized studies have been carried out in children to this day. The first one included 30 patients each in two VATS and urokinase fibrinolysis branches and concluded that there were no differences in the results but also that VATS was significantly more costly [12]. The second one studied 27 patients in each of the streptokinase or VATS branches and showed that VATS was significantly superior in terms of time until removal of the chest tube, hospital stay and duration of symptoms. In exchange, VATS was again significantly more costly [13]. The third study used either alteplase fibrinolysis or VATS in two groups of 18 patients each and could not demonstrate any difference between both groups except for the hospital costs, which were again higher in the VATS branch [14]. Finally, the fourth multicenter study was carried out on children below 15 years with septated empyema and included 53 treated by VATS and 50 with urokinase fibrinolysis. There were no differences between groups and the overall hospital stay was longer than in the other previously quoted studies probably because only stage III patients were included [15].
Therefore, in the present state of knowledge, both fibrinolysis and VATS are equally effective for the treatment of pleural empyema in children. However, taking into account that VATS is a major and more costly operation, drainage and fibrinolysis should be the preferred first approach for this condition [16]. VATS may still be indicated when drainage cannot be accomplished after appropriate fibrinolytic treatment.
Persistent broncho-pleural fistula or lung abscess should be treated whenever possible with antibiotics, appropriate drainage and fibrinolysis. Operative measures may be unsuccessful due to the necrotic-inflammatory environment met in such cases [5].
Major open operations for decortications are very rarely indicated in children except in cases in which multiple loculations with sepsis and severe lung encasing, a very unlikely event, compromise survival. In rare instances, persistent bronchopleural fistula might justify such treatments. Under such circumstances, thoracotomy, cleansing, closure of fistula and appropriate drainage achieved good results [17, 18]. With the current therapeutic protocols this is an extremely rare event.
The plasticity of the thorax and intra-thoracic organs in children accounts for the scarcity of functional sequelae in cases of empyema. A recent study on lung function in children treated for empyema showed only minimal FVC%, FEV1 and FEV1/FVC in comparison with controls. Empyema children did not show any difference in maximal exercise capacity [19]. In another study performed on 26 children after a mean of 8 years post-empyema treatment, there was no functional impairment, spirometry was normal in 80% and although X-rays were minimally abnormal in 36% and minimal MRI residuals were found in 82%, the functional significance was negligible [20].
8.3Echinococcosis
8.3.1Introduction
Parasitic diseases are important causes of morbidity and mortality in humans worldwide. Although most parasites that affect the lung are endemic to tropical and subtropical regions, immigration and travel practices have resulted in transfer of these diseases to other areas. Echinococcosis is one of the most geographically widespread zoonoses in the world. Human echinococcosis occurs as a result of infection by cestodes of the genus Echinococcus. Four Echinococcus species are known to be pathogenic for humans. The two most important of these are E. granulosus and E. multilocularis, which cause cystic echinococcosis (CE) and alveolar echinococcosis (AE), respectively. The other two species that affect humans are E. vogeli and E. oligarthus. These cause an infestation known as “polycystic echinococcosis” and are of minor importance.
8.3.2Cystic echinococcosis
The most common tapeworm condition of the lung is cystic echinococcosis (CE), or “hydatid disease,” caused by E. granulosus. This illness is concentrated in sheep-raising areas, such as the Mediterranean region, eastern Europe, Africa, South America, the Middle East, Australia, New Zealand and China (Fig. 8.3.1). Although,
Fig. 8.3.1: Distribution of Echinococcus granulosus worldwide (Copyright© WHO). the numbers of infections in animals and humans have decreased with time as a result of education and various control measures, CE continues to be an important public health problem in many countries.
8.3.2.1Life cycle and morphology
Like all cestodes, E. granulosus requires two different host species to complete its life cycle. The definitive hosts are dogs and other canine carnivores, and the intermediate hosts are a variety of warm-blooded vertebrates (e.g. sheep, cattle, goats, pigs, camels and humans). The adult worms inhabit the small intestine of the definitive host and do not make the host ill. The adult worm releases eggs within the intestine, and these pass out with the definitive host’s feces. Humans may become infected with E. granulosus accidentally through contact with this final host (usually a dog), particularly during playful close contact between children and dogs, or via ingestion of food or fluids that are contaminated with egg-containing feces. After an Echinococcus egg is ingested by the intermediate host, the embryo (known as the oncosphere, or first larval stage) is released into the host’s gastrointestinal tract. Embryos then embed in the lining of the tract, and ultimately penetrate the mucosa and enter the mesenteric vascular system. They undergo blood-borne distribution in the portal circulation, and most embryos lodge in the intermediate host’s liver. Each embryo then transforms to a cystic metacestode (second larval stage) filled with fluid. Each of these cysts is surrounded by the host’s reactive tissue, known as a pericyst. Inside the pericyst, the cystic metacestode (endocyst) has an acellular outer wall or “laminated membrane” and an inner layer or “germinative membrane” that is a monolayer of viable pluripotent cells. While embedded in the viscera, brood capsules and protoscolices bud from the germinative membrane of some metacestodes (Fig. 8.3.2).
When a dog (or other definitive/ final host) ingests a cyst in viscera of the intermediate host, the protoscolices are released from the cyst. These attach to the dog’s intestinal wall, develop into mature adult tapeworms, and complete the life cycle. Since the life cycle relies on carnivores eating infected herbivores, humans are usually a “dead end” for the parasite and do not play a role in the biological cycle.
8.3.2.2Pulmonary involvement
Most embriyos become trapped in the hepatic sinusoids, and therefore 70% of echinococcal cysts form in the liver. Embryos that bypass hepatic filtration enter the lung via the right circulation (hepatic vein, inferior vena cava, and pulmonary arteries). They either complete their cystic transformation in the lung or else pass through via the pulmonary vascular system and develop in another organ. Alternative pathways for this parasite to enter the lung are the lymphatic circulation or via a portocaval anastomosis in the portal system. As well, pulmonary or intrathoracic extrapulmonary involvement can occur secondary to intrathoracic rupture of cysts from the dome of the liver.
Fig. 8.3.2: Echinococcal cyst and its components.
The lung is the second most common site of E. granulosus lodgment, with incidence varying between 15% and 30% [21, 22]. Much less frequent sites are the spleen, kidneys, orbit, heart, brain and bone, which account for approximately 10% to 15% of cases combined [22]. E. granulosus infestations may be acquired in childhood; however, because of the slow-growing nature of echinococcal cysts, most liver and lung cysts become symptomatic and are diagnosed in adulthood.
Most patients with CE have single-organ involvement and harbor a solitary cyst. In rare cases, primary echinococcosis develops in intrathoracic extrapulmonary structures, such as the pleural cavity, mediastinum, and chest wall. If a echinococcal cyst in the liver ruptures into the inferior vena cava, or a echinococcal cyst in the right ventricle ruptures, this can lead to secondary echinococcosis in the form of cyst/ s, and potentially subsequent embolism and endovascular echinococcosis [21, 23, 24]. In rare cases, massive embolism of the pulmonary arteries occurs [21].
8.3.2.3Clinical presentation
The clinical presentation of pulmonary CE depends on the size and location of the cyst/ s, and whether these structures are intact or ruptured. Most small intact echinococcal cysts in pulmonary tissue remain asymptomatic. Large echinococcal cysts are more likely to cause chest pain, cough, or dyspnea by compressing the lung parenchyma and surrounding tissues. In young patients, the lesions can expand asymptomatically until they reach giant size (>10 cm in diameter) because the remaining healthy lung tissue is able to provide sufficient ventilation.
With complicated pulmonary CE (i.e. ruptured cysts), the clinical picture is variable and depends on the nature of the perforation. Echinococcal cysts in lung tissue can rupture into the pleural space or into a bronchus. Perforation into a bronchus can lead to expectoration of vomit-like cystic fluid and remnants of parasite-derived cyst wall. Rarely, complete expectoration of the cystic contents can result in spontaneous cure. However, in most cases, solid remnants of the collapsed endocyst are left in the cavity and become a source of recurrent bacterial infection. Purulent sputum and fever are strong indicators of bacterial infection of the cyst cavity, including pericystic lung tissue or abscess formation, situations that can result in sepsis. In some cases, ruptured CE causes severe complications, such as massive hemoptysis or anaphylactic shock.
In contrast to perforation into a bronchus, rupture of a echinococcal cyst into the pleural cavity usually causes pneumothorax, pleural effusion, or empyema. Cyst rupture into the pleural cavity can also result in tension pneumothorax, secondary larval spread, or allergic and anaphylactic reaction [25]. Pneumothorax almost always indicates the presence of a bronchopleural fistula.
8.3.2.4Diagnosis
Cystic echinococcosis is usually diagnosed based on a combination of (1) identification of the cyst/ s through various imaging techniques, (2) results of serological tests, (3) identification of protoscolices or hooks of E. granulosus by microscopic examination, (4) analysis of DNA markers in the cyst fluid or cyst wall (e.g. by polymerase chain reaction [PCR]), (5) macroscopic or histopathological detection of the pathognomonic structure of a cyst obtained through surgery or biopsy, and (6) history of possible exposure. Most cases of pulmonary CE are diagnosed from incidental radiographic findings on routine chest radiography.
8.3.2.5Imaging-based approach
Most cases of CE are initially detected by finding cysts using different imaging techniques. Ultrasonography plays an important role in the diagnosis of abdominal CE. For this reason, ultrasonography-based classification systems have been developed to correlate CE cyst stages with natural history. According to the staging system of the WHO Informal Working Group (WHO-IWG), these cysts are classified as active (CE1 and CE2), transitional (CE3) or inactive (CE4 and CE5) [26]. Even though CE cyst staging systems have been developed for liver cysts, this classification also applies for echinococcal cysts in other organs. Today, the terms “complicated” (ruptured) and “uncomplicated” (unruptured) have been widely adopted for CE cysts of the lung. The WHO-IWG CE staging system may be used to replace these terms and help standardize clinical trials and treatment recommendations. Many radiologic findings of CE of the lung are similar to those of CE of the liver. However, in CE of the lung, chest radiography and chest computed tomography are preferred over ultrasonography for staging, and in contrast to hepatic cysts, pulmonary cysts usually do not calcify, and daughter cyst formation is rare.
On X-ray films, uncomplicated (CE1 stage) cysts appear as homogeneous, dense, round or oval lesions that have well-defined borders, are between 1 cm and 20 cm in diameter, and are surrounded by normal lung tissue (Fig. 8.3.3 A). Computed tomography (CT) reveals the fluid contents within an intact echinococcal cyst (CE1 stage) (Fig. 8.3.3 B). On CT images, the cyst wall, which represents the combined pericyst and endocystic wall, ranges in thickness from 2 mm to 1 cm. Cyst fluid usually appears close to the attenuation of water.
If the pericyst communicates with the tracheobronchial tree, air enters and dissects the pericyst and endocyst structures, producing radiographically visible air between the pericyst and the detached wall of the endocyst. This radiological appearance is known as a meniscus or air crescent sign (Fig. 8.3.4 A), an inverse crescent sign, or a signet ring sign. Each of these indicates detachment and is believed to be a harbinger of impending rupture of the endocyst (CE3a stage). If the cyst has ruptured, separation of the cystic membrane creates a wide spectrum of radiologic images. If the ruptured cyst communicates with the tracheobronchial tree, some of the fluid evacuates and air enters the space between the pericyst and the laminated membrane causing an air-fluid level. In some cases, the cyst wall appears to be crumpled and floating on top of the residual fluid, resulting in the well-recognized water lily or camalote sign (CE3a stage) (Fig. 8.3.4 B). The appearance of collapsed membranes inside the cyst with a serpentine configuration or with a twirled and twisted configuration after partial expectoration of cyst fluid is called the serpent (or snake) sign or spin (or whirl) sign, respectively (CE3a stage) (Fig. 8.3.5). Several other radiological signs of CE on CT and magnetic resonance imaging (MRI) have also been described. These include the rim sign, air bubble sign, Cumbo’s sign, cyst wall sign, ring enhancement sign, and halo sign.
Fig. 8.3.3: (a): Chest radiograph showing a well-defined, circular opacity surrounded by normal lung tissue in the left lower lung lobe (CE1 stage). (b): A computed tomography scan demonstrating a large solitary cyst and atelectasis in the pericystic lung tissue (CE1 stage).
Fig. 8.3.4: Chest radiograph revealing the air crescent sign (CE3 stage) (a) and a ruptured echinococcal cyst with a water lily sign (CE3a stage) (b).
A ruptured cyst may not have the characteristic imaging appearance of an echinococcal cyst. The inflammatory reaction in tissue adjacent to the lesion may mask the ruptured cyst, and the overall radiologic appearance may not be indicative of the lesion. In some cases, the cyst membranes liquefy and the pericyst thickens (CE4 and CE5 stages). In this situation, the typical cystic nature may be lost and the radiological appearance on plain films may be similar to that of a bacterial lung abscess. CE4 stage cysts may give an appearance of a ball of wool sign, indicating the degenerative nature of the cyst (Fig. 8.3.6).
Fig. 8.3.5: A computed tomography scan showing a ruptured echinococcal cyst containing detached membranes inside the cystic cavity (the as whirl (or spin) sign (CE3a stage).
On MRI, T1-weighted images of echinococcal cysts show hypointense cystic content and an isointense wall relative to cyst content, whereas T2-weighted images show hyperintense cystic content and a hypointense wall [22]. However, currently, MRI is not frequently used for diagnosing pulmonary CE.
Bronchoscopy can be a useful diagnostic tool in challenging cases where a ruptured pulmonary echinococcal cyst does not have the characteristic clinical and radiologic appearance (CE4 and CE5 stages), [27]. If a ruptured cyst membrane causes occlusion in the bronchial system, it may be possible to visualize and eliminate the cyst remnants using bronchoscopy.
8.3.2.6Laboratory tests
In the diagnosis of echinococcosis, laboratory tests are complementary to clinical findings and radiological studies. In most instances, eosinophilia can be normal or slightly increased and generally only occurs if the cyst is ruptured and there is leakage of antigenic material. As therapeutic puncture or diagnostic puncture are contraindicated in CE of the lung, direct diagnostic methods, such as examination of cyst contents/fluid, are not performed frequently. Direct examination can only be done after surgical intervention or fine-needle biopsy in suspected cases of complicated cases that have not been definitively diagnosed.
Fig. 8.3.6: A cyst with heterogeneous contents, in particular the so-called “ball of wool sign” (CE4 stage).
In the past, intradermal testing (Casoni and Weinberg’s respective complement fixation tests) was widely used to diagnose echinococcal disease, but these assays are rarely used currently because of low sensitivity and specificity. Today, several immunodiagnostic tests are available that can be used to confirm a clinical diagnosis; however, there are two main categories of problems with test methods that involve crude E. granulosus antigens: (1) false-positive results occur in the presence of other helminth infections, cancer, and immune disorders, and (2) false-negative results occur due to poor antigen presentations. Serology is less likely to be positive if the cysts are intact, calcified or nonviable, and children more frequently exhibit negative serology. False-negative results can also occur because of the location of a lesion. It is important to note that CE of the lung is more likely to be accompanied by false-negative serology than CE of the liver [28]. The most widely available tests confirm the diagnosis in 80% to 94% of hepatic CE cases, and in 65% of pulmonary CE cases [29].
Enzyme-linked immunosorbent assays for immunoglobulin G (IgG-ELISA), indirect hemagglutination antibody test (IHAT), latex agglutination test (LAT), and immunofluorescence antibody test (IFAT) are the immunological methods most commonly used in diagnosing echinococcosis. In all of these tests, cross-reactivity may be observed, particularly in cases of CE and alveolar echinococcosis (AE). The Echinococcus western blot IgG may be used to exclude cross-reactivity in positive sera. This assay correctly differentiates between CE and AE; however, cross-reactivity is not completely excluded [30].
It is accepted that immunodiagnostic tests do not replace clinical and radiological diagnosis; these tests are considered helpful diagnostic adjuncts and are useful, if necessary, for follow-up of operated or medically treated patients. Increased antibody titers may be detected even in patients with active cysts (CE1 and CE2 stages) who are negative prior to surgical intervention. Specific antibodies are known to increase as early as the first week after surgery and generally reaching a maximum toward the end of the first month [31]. In such cases, the titers decrease slowly over 12–18 months post-surgery [29].
8.3.2.7Surgical treatment
Surgery is the main treatment for pulmonary CE, as the parasite must be eliminated to achieve a complete cure. In patients with pulmonary CE, the principle of surgery is to preserve as much lung tissue as possible. It is important to always use the most conservative surgical methods possible, and removal of all parasitic material and closure of bronchial openings is usually adequate treatment, even if a patient presents with giant cysts, multiple cysts, or lung abscess. Radical resection of the lung must be avoided unless the pulmonary parenchyma is seriously damaged or infected, or atelectatic areas are assessed as irrecoverable. In some cases, it can be difficult to determine the optimal surgical procedure when a giant echinococcal cyst has compressed a considerable amount of lung parenchyma for a long period. Such a decision may have to be made in the operating room. The parenchyma around an echinococcal cyst is often affected by the lesion and may exhibit chronic congestion, hemorrhage, bronchopneumonia, or interstitial pneumonia. These inflammatory changes in the lung tissue often resolve after surgical cyst removal. Patients with cystic lesions tend to show good recovery of lung tissue after surgery. Considering this, the size of cyst/ s, number of lesions, and presence of infection should not be considered indications for radical resection, such as lobectomy. In particular, children and adolescents with CE usually have excellent pulmonary tissue capacity for lung expansion after surgery.
Lung-conserving approaches when treating pulmonary CE include pericystotomy and enucleation of the endocyst, aspiration-pericystotomy and removal of the endocyst with or without capitonnage, or pericystectomy. Regardless of the surgical procedure performed, spillage of cyst contents must be avoided to prevent intraoperative dissemination of protoscolices and eventual recurrence. During surgery, once a cyst is identified it is surrounded by pads soaked in 10% povidone-iodine or hypertonic saline solution to protect the operatory field from spillage and subsequent seeding of new cysts. Hypertonic saline solution is the preferred agent, as it is considered to have scolicidal properties. If enucleation is planned, the pericyst is opened, careful blunt dissection is performed between the pericyst and the endocyst, and the cyst is enucleated entirely. During the dissection, the airway pressure is lowered to prevent the cyst from protruding through the pericystic opening. This procedure carries high risk for cyst rupture and dissemination, and is generally preferred when treating small cysts only.
Another option once a cyst is identified is to aspirate the echinococcal fluid with a wide-bore needle. In this procedure, the pericyst is opened after aspiration, and then the entire cystic membrane is removed. In both of the two approaches, once the surgeon is certain that all cystic membrane has been removed, large bronchial openings are closed, the cavity is irrigated with normal saline solution, and the cavity is obliterated with separate purse-string sutures. These are placed from the deepest level to the surface of the cavity (i.e. capitonnage). Some authors suggest that capitonnage offers no benefit with respect to outcome [32], but this technique is the safest way to avoid prolonged air leakage and to protect the cavity from infection and abscess formation. In pericystectomy, endocysts are removed together with the hostderived capsule (pericyst). This procedure carries high risk of intra and postoperative complications such as bleeding or prolonged air leakage, and greater loss of parenchyma in which the cyst is situated.
Bilateral pulmonary CE can be managed with either a one- or two-stage surgery involving bilateral thoracotomy, or with median sternotomy. When bilateral thoracotomy is performed in patients with bilateral uncomplicated pulmonary CE (i.e. no ruptured cysts), it is best to first treat the side with the larger cyst/ s or greater number of cysts. If there is a ruptured cyst on one side and an intact cyst on the other side, the intact cyst is treated first unless the ruptured lesion is causing urgent serious symptoms. In selected cases, lung and liver cysts may be treated during the same operation via thoraco-phrenotomy.
Recently, some reports have described video-assisted thoracic surgery in the treatment of pulmonary CE in selected patients [33, 34]. In these cases, the thoracoscopic approach is performed using the same principles as are followed with the open technique: protecting tissues from contamination, completely removing all parasitic contents, and closing any bronchial openings that are present. Patients who have small cysts or ruptured cysts that pose minimal risk of spillage may be favorable candidates for video-assisted thoracic surgery. The main advantage offered by thoracoscopy is less trauma and discomfort for the patient. However, information about long-term outcomes is needed before this procedure can become widely accepted.
8.3.2.8Medical treatment
According to WHO Informal Working Group on Echinococcosis (WHO-IWGE) guidelines [35], chemotherapy is indicated for inoperable primary liver or lung CE, for patients with multiple cysts in two or more organs, for patients with peritoneal cysts, and to prevent secondary echinococcosis. Two benzimidazole compounds, mebendazole and albendazole, are the only effective drugs for treating uncomplicated echinococcal cysts, and as an alternative to surgery. Mebendazole is given at a dose of 40–50 mg/ kg/day in three divided doses after meals (maximum daily dose 6 g). Albendazole is given at a dose of 10–15 mg/kg/day in two divided doses (maximum dose 800 mg daily). These two drugs are benzimidazole carbamates, and this treatment is most often administered in 3- to 6-month cycles [35]. Benzimidazole carbamates have inhibitory effects on glucose uptake, which leads to depletion of glycogen storage, degenerative alteration in the germinal layer, and cellular autolysis. Albendazole is usually preferred for chemotherapy owing to its higher bioavailability, the lower daily doses required, and its better efficacy overall. Praziquantel, an isoquinolone, has also been proposed as a treatment for CE at a dose of 40 mg/kg orally once weekly, and concomitant with benzimidazoles [35]. Praziquantel has been used alone and in combination with albendazole; however, the efficacy of praziquantel as primary chemotherapy for CE is not clearly defined [36].
In general, small isolated cysts surrounded by minimal adventitial reaction respond best to medical therapy, whereas complicated cysts that have multiple compartments or daughter cysts, or those that have thick or calcified surrounding adventitial reactions are relatively refractory to treatment. Drug penetration of echinococcal cysts is negatively correlated with the thickness of the pericystic fibrous capsule. For this reason, children respond to medical treatment better than adults do. Research has shown that 50% to 70% of patients with CE show some degree of response to medical management [30]; however, the reported cure rates in this patient group are only 10% to 30% [30]. It has been suggested that the larger the diameter of the cyst, the greater the possibility that medical treatment will fail and tend to be complicated. Relapses after chemotherapy have been observed in 14% to 25% of patients with pulmonary CE [30]. Some authors have noted that pulmonary CE and cysts in younger patients relapsed less frequently than hepatic cysts and cysts in older patients [37].
Overall, medical treatment is generally not considered a reliable way of eradicating E. granulosus and is a long and tedious process that carries considerable risk. Anthelmintic therapy causes degenerative changes in the endocyst wall, which could increase the likelihood of rupture. The incidence of degenerative changes in pulmonary CE treated with albendazole is approximately 80% [37, 38]. The fundamental issue is not the efficacy of anthelmintic therapy for pulmonary CE, but whether this form of treatment leads to complications. In some cases, if a cyst does rupture but the cyst membrane and contents are completely expectorated, then the patient may be cured. Even if the parasite dies due to the drug and there is no acute, serious complication, the cyst membrane will usually remain in the cavity. This cavity often leads to secondary bacterial infection and other complications, which are associated with more problematic surgeries and postoperative courses, and longer hospital stays than uncomplicated cases [25, 39].
The timing of pulmonary CE cyst rupture after initiation of anthelmintic treatment is reported to vary considerably, from 10 days to 2 months [39, 40]. Clearly, any patient who receives medical therapy for these cysts must be followed closely for at least 2 months with careful monitoring for serious complications that could require emergent intervention. The WHO-IWGE also suggests that medical and laboratory examinations should be conducted for adverse reactions such as neutropenia, alopecia, and liver dysfunction [35]. These problems can be severe and irreversible, and the WHO-IWGE recommends that these assessments be done every 2 weeks initially, and then monthly [35]. It is important to note that close follow-up is usually not possible in cases of CE because these patients tend to be from rural areas where medical care is distant and often inadequate. When considering how to proceed with a case, all the potential problems with medical treatment should be weighed carefully.
Several reports have suggested percutaneous treatment of pulmonary CE as an effective alternative to surgical treatment in selected patients with this disease. However, in general, percutaneous aspiration of pulmonary cysts has been considered too high-risk because of (1) the possibility of cyst rupture associated with any puncture, and (2) complications related to rupture. According to WHO-IWGE guidelines, percutaneous drainage of an echinococcal cyst (a procedure referred to as PAIR: puncture, aspiration, injection, re-aspiration) is considered to be contraindicated for pulmonary CE [35]. The safety and efficacy of percutaneous treatment are related to the anatomical site of the cyst. The PAIR method is mainly used in the treatment of hepatic and extrahepatic abdominal echinococcal cysts.
Each organ afflicted with CE has its own associated symptoms and therapeutic requirements. It is generally agreed that, regardless of whether symptoms are present, the first-line treatment for pulmonary CE is surgical, and medical therapy should only be used to prevent recurrence or in patients who cannot tolerate surgery. Close follow-up is recommended at 6-month intervals for at least 5 years [21].
8.3.3Alveolar echinococcosis
There is less human exposure to E. multilocularis than to E. granulosus, but the precise extent of AE is unknown. For humans, E. multilocularis is the most pathogenic species of Echinococcus, and causes a potentially fatal, chronically progressive infestation. The life cycle is similar to that of E. granulosus, but the definitive and intermediate hosts involved are usually wild animals. The life cycle of E. multilocularis involves wild canines, usually foxes and wolves, as definitive hosts, and mainly rodents as intermediate hosts. Despite this parasite’s predominantly sylvatic life cycle, domestic animals, such as dogs and cats, may also become infested and can transmit this agent to humans.
E. multilocularis, also known as alveolar echinococcosis, is more common in colder areas, such as the Arctic and some regions of Asia and west-central Europe. The primary anatomical location of this agent is the liver. Isolated extrahepatic locations (e.g. spleen, peritoneum, lung, vertebra, brain, kidney, heart, adrenal gland, and muscle) account for only 2% to 4% of all cases [41, 42]. Primary lung involvement is reported to be extremely rare [41–43]; however, E. multilocularis tends to spread to the lung and other organs in approximately one-third of affected patients via infiltration and metastatic formation [41].
A characteristic feature of AE is its exogenous, tumor-like proliferation that leads to infiltration of the affected organ/ s, and to severe disease and even death in progressive cases. The prevalence of this disease is lower among children. Based on case data that the European Echinococcosis Registry (EurEchinoReg) surveillance network collected from 11 countries of western and central Europe and Turkey, the proportion of affected patients younger than 20 years is 2.1% (12/559) and the median age is 56 years (range, 5–86 years) [41].
Clinical symptoms of AE usually follow a long asymptomatic period (i.e. 5 to 15 years), and primarily include some clinical patterns that typically suggest digestive and hepatic disorders. Pulmonary symptoms, such as chronic cough, chest pain, hemoptysis, almost always occur after hepatic involvement.
Essentially the same radiological and serological procedures are used to diagnose CE and AE. Treugut et al. studied 20 cases of pulmonary involvement of E. multilocularis and described two radiological forms [44]: (1) a form with multiple ill-defined irregular lesions (up to 3-cm diameter) lying peripherally, some with stippled calcification; and (2) a form caused by liver disease penetrating the diaphragm and giving rise to various changes in the right lung base. Serological tests are more reliable for diagnosing AE than CE. The diagnosis can be confirmed by parasite identification in surgical or biopsy material.
When possible, the treatment for AE is total resection (i.e. removing the entire lesion from the liver and other affected organs by following the rules of radical tumor surgery). In cases where this is not feasible, long-term medical treatment with albendazole (in most cases lifelong) is the alternative. Even after complete excision, a minimum 2-year course of chemotherapy is recommended, and a minimum of 10 years of monitoring for possible recurrence is advised [35].
Marija Stojkovic, Thomas Junghanss
Comment
Echinococcosis is filed under the so-called Neglected Tropical Diseases (NTSs). Where the disease is prevalent, patients have limited access to care; where it is rare – in most rich countries – patients continue to encounter health care facilities with limited experience in the management of echinococcosis [45, 46].
Worth reiterating over decades because of its importance for patient management: Echinococcus (E.) granulosus and E. alveolaris are taxonomically close relatives, they cause, however, entirely different diseases: Cystic echinococcosis (CE) grows by pressure atrophy, alveolar echinococcosis (AE) by cancer-like infiltration and necrosis of surrounding tissues. Of importance for thoracic surgeons: AE of the lungs is extremely rare and almost entirely due to distant metastases or infiltrative expansion of hepatic AE [45].
Not much progress has been made over the years in CE/AE serological diagnostics. Lack of sensitivity of serological tests – very prominently in pulmonary CE – and cross-reactivity between CE and AE still causes mis- and over-interpretation of serological results. Differentiation between CE and AE may be possible with specific immunoblot patterns, but largely relies on imaging. If this fails, confirmation requires material of the lesion for microscopy, molecular methods, and histopathology which is a problem in pulmonary CE/AE. On imaging of the liver AE pseudocysts (large necrotic cavities) with transdiaphragmatic growth should not be confused with true CE cysts (which have a cyst wall with a smooth inner lining). Among the differential diagnoses of pulmonary air-filled space, occupying lesions TB caverns are worth mentioning. Asymptomatic pulmonary CE cysts are regularly discovered through CXR screening for active TB in immigrants.
Search for antigens suited for serological follow-up of CE-patients after interventions, e.g. surgery, has so far been unsuccessful. Follow-up to confirm cure or detect relapses remains in the realm of imaging.
In imaging substantial progress has been achieved, most importantly in staging CE cysts. The WHO cyst classification is increasingly valued as a tool for treatment decision and criteria have been developed to assign treatment modalities to cyst stages [45, 47]. Of major benefit to patients is accumulating evidence that WHO CE 4 and CE 5 cysts do not need any treatment at all if uncomplicated and yearly follow-up is guaranteed for 5–10 years (watch & wait) [45, 47].
WHO cyst classification is ultrasound-based and was primarily developed for hepatic CE cysts. By and large it can, however, be translated into CE cysts of any organ including the lungs. With the known limitations of ultrasound in the assessment of pulmonary pathology, computed tomography (CT) is the commonly used alternative. CT does not, however, reproduce the critical features of CE cysts, most importantly pathognomonic signs for diagnosis and staging and fistulas [48, 49]. The shortcomings of CT have been shown for hepatic CE cysts (see figures below; from [48]) and are equally applicable to CE cysts of the lungs. In assessing pulmonary CE MRI is clearly superior to CT.
