Abstract
Though less common in the developed world, parasitic infections, particularly those involving the lung, remain prevalent in resource poor countries. Current seroprevalence data place toxocariasis among the most common zoonotic infections worldwide; although the global prevalence varies widely depending on factors such as population density, sanitation, education, and enforcement of laws regarding proper disposal of waste matter. Other parasitic diseases, such as echinococcosis, strongyloidosis, and paragonimiasis, remain endemic in certain parts of the world, such as Africa, Asia, and South America, although are seen less frequently in developed countries, such as the United States. Both echinococcosis and strongyloidosis remain among the 17 most neglected tropical diseases as determined by the World Health Organization. Given the frequency of global travel, however, clinicians need to keep these diseases in mind when seeing patients particularly those with travel histories or those who are immunocompromised as in the case of strongyloidosis.
Keywords
parasitic infections of the lung, toxocariasis, strongyloidiasis, pulmonary paragonimiasis, hydatid disease of the lung
Toxocariasis
Toxocariasis is a soil-transmitted zoonotic roundworm infection transmitted to humans by contact with canine and feline feces. It causes two main diseases in humans: visceral toxocariasis (VT), formerly known as visceral larva migrans, and ocular toxocariasis (OT), formerly known as ocular larva migrans. VT results from an inflammatory response to the migration of immature, second-stage larvae through the viscera of a host that is not suitable for completion of the parasite’s life cycle. The lung parenchyma is commonly involved in this form of the disease.
Epidemiology
Toxocara species are found worldwide in domesticated and wild dogs and cats. Infection with Toxocara spp. is more prevalent than realized, because many individuals do not express the complete VT syndrome. Current seroprevalence data place toxocariasis among the most common zoonotic infections worldwide. The global prevalence of Toxocara spp. in humans varies widely and is dependent upon factors such as population density, sanitation, poverty, education, and enforcement of laws regarding proper disposal of animal excreta.
Toxocariasis is also endemic throughout the United States. In one seroprevalence study conducted more than 20 years ago by the Centers for Disease Control and Prevention (CDC), using a nationally represented set of banked sera from the First National Health and Nutrition Examination Survey (NHANES 1971–1973), the seroprevalence of Toxocara antibodies, as measured by enzyme-linked immunosorbent assay (ELISA), varied from 4.6% to 7.3%. However, rates approaching 30% were seen among black children of lower socioeconomic status. A second seroprevalence study, also conducted by the CDC (NHANES 1988–1994), found an overall prevalence of 13.9%. As in the prior survey, rates varied between different geographic regions and were influenced by socioeconomic conditions. Similarly, seroprevalence rates also vary in other industrialized countries, particularly those that are resource rich versus resource poor, with higher rates seen in rural or underserved areas with high rates of poverty, overcrowding, and poor hygiene.
Infection in the definitive host may be through multiple routes including vertical, transplacental (not in cats), and transmammary, as well as horizontal. The ability to survive and develop to sexual maturity in the intestinal tract of several vertebrate species has contributed to the worldwide propagation of the species. Puppies are especially dangerous, because transplacental infection results in 77%–100% of puppies becoming infected, and many pups are born with congenital canine toxocariasis. They can then shed millions of eggs into the environment depending on the immune status of the host as well as the intensity of the Toxocara canis infection. By the time the animals are 3 weeks old, mature egg-laying worms can be present. Adult female worms can produce and shed more than 200,000 ova per day, which are then passed unembryonated onto the soil in the feces of the infected animal. Under suitable soil conditions (temperature 10–30°C, availability of light, suitable pH and humidity), the ova become embryonated and infectious after a minimum of 2–3 weeks. Because of the thick shell, the embryonated ova can survive in moist soil for months or even a few years. Most infections in children affect those with a history of pica or individuals who have accidentally ingested contaminated soil. Children also become infected commonly while playing in backyards, parks, playgrounds, and sandboxes where it is easy to come in contact with infectious ova.
Etiology
Two species of the genus Toxocara are primarily responsible for most cases of VT: dogs, wolves, coyotes, and foxes are the definitive hosts for T. canis, whereas domestic cats are the host for T. cati. Other Toxocara spp. have been implicated in human infection, including T. vulpis (canine whipworm) and T. vitulorum (found in cattle). The role of T. lyncus (wild cats) and T. malaysiensis (domestic cats) in causing human infection is not clear. In addition, Baylisascaris procyonis (raccoon roundworm), Capillaria hepatica (rodent nematode), Ascaris suum (pig roundworm), and rarely Ascaris lumbricoides, hookworm larvae, as well as Strongyloides stercoralis can cause a VT-like syndrome.
Pathology/Pathogenesis
In the natural host, infectious ova are ingested and hatch in the upper alimentary tract. The second-stage larvae then migrate through the intestinal walls into the bloodstream and then into the liver and lungs of the infected animal. From the lungs, the larvae mature by migrating through the tracheobronchial tree and passing into the upper alimentary tract. There, the mature worm can begin laying eggs, which pass out in the feces to begin the cycle anew.
In aberrant hosts, such as humans, the initial stages of infection are identical: infectious second-stage larvae hatch in the small intestine and then begin migrating through blood and lymphatics to the liver, lung, brain, and other organs such as the eye. Before the larvae can complete their transtracheal passage and maturation to adult worms, however, host defenses block further migration of the larvae by encasing them within a granulomatous reaction, which is generally eosinophilic in nature. The pathogenesis of VT is the direct result of the immunologic response of the body to the dead and dying larvae. Multiple eosinophilic abscesses may develop in the infected tissues. The larvae remain alive and infective for an indefinite period of time, often as long as 7 years. The inflammation appears as an eosinophilic granuloma, and an open biopsy of a granulomatous lesion will often show the Toxocara larva. Host antibodies are generated against the Toxocara excretory-secretory (TES) antigens of the larvae. These glycoprotein antigens contain protease, acetylcholinesterase, and eosinophil-stimulating activity. They also elicit Th 2 immune responses and high levels of interleukins 4 and 5.
Clinical Features
Symptoms
It is the immediate hypersensitivity response to the larvae that manifests as symptoms of VT. The specific signs and symptoms depend on the organ affected. Toxocara is mainly an infection of young children, since they have a greater opportunity to ingest the infectious ova. The classic case occurs in a male child, younger than 6 years, with a history of pica and exposure to dogs. A child with fever of unknown etiology and eosinophilia with the appropriate epidemiological history should be assumed to have Toxocara infection until proven otherwise. The extent of signs and symptoms depends on the number and location of granulomatous lesions and the host’s immune response.
Pulmonary toxocariasis is generally asymptomatic or may present with symptoms such as mild cough and dyspnea. The initial symptoms may include a prodrome of anorexia, fever, and malaise. The so-called “covert toxocariasis” has been implicated as responsible for many subtle clinical manifestations. In a study of children in Ireland, a plethora of clinical manifestations were seen including fever, headache, anorexia, abdominal pain, nausea, vomiting, lethargy, sleep and behavior disorders, pharyngitis, pneumonia, cough, history of wheezing, limb pain, cervical lymphadenitis, and hepatomegaly. Another case-control study in French adults led to the term “common toxocariasis,” a syndrome comprising chronic dyspnea and weakness; cutaneous rash; pruritus and abdominal pain, often with eosinophilia; elevated levels of immunoglobulin E (IgE); and high titers of Toxocara -specific antibodies. Both “covert” and “common” toxocariasis probably represent variations in the clinical spectrum of mild Toxocara childhood and adult disease.
The time course for VT may be quite prolonged. The initial stage of the illness lasts several weeks, beginning with low-grade fevers and nonspecific symptoms and progressing to eosinophilia and hepatomegaly. Episodes of bronchitis, asthma, or pneumonia may occur. Over the next month, intermittent high fevers occur along with the major manifestations of the disease. Recovery may take as long as 1–2 years, during which time the eosinophilia resolves along with the hepatomegaly. Resolution of pulmonary infiltrates occurs more rapidly.
With more severe involvement, various combinations of abdominal pain, arthralgias, myalgias, weight loss, high intermittent fevers, and neurologic disturbance may be seen. Acute respiratory failure has been reported from Toxocara infection.
Other symptoms can include idiopathic seizure disorder, functional intestinal disorders, skin diseases (prurigo and chronic urticaria), eosinophilic and reactive arthritis, and angioedema.
Physical Findings
These depend on the extent of the infection, the organ system involved, and whether the disease is systemic or limited to a specific organ. The lung is one of the most common organs affected in children with toxocariasis. Cough, if present, is generally nonproductive. Wheezing is the most frequent finding on chest examination, although rhonchi and crackles also have been described. Because of the wheezing, some patients are diagnosed initially as suffering from asthma. Multiple studies have looked at the relationship between the seroprevalence of Toxocara infection and asthma and found that there is a significant positive correlation. In fact, toxocariasis is a well-recognized environmental risk factor for asthma in endemic regions. Apart from pulmonary involvement as noted previously, other symptoms in VT depend on organ involved; hepatomegaly of varying degrees is almost always present.
Imaging, Pulmonary Function Tests (PFTs), Laboratory Findings
There is no typical chest radiographic finding. Multiple pulmonary infiltrates or nodules may be seen; however, these are not pathognomonic. A recent study reported that all nodules seen in children with Toxocara infection on computed tomography (CT) scan, whether they were single or multiple, were in the peripheral area of the lungs. Less commonly pleural effusion has also been reported in association with the infection. Descriptions of imaging studies range from patchy airspace disease with pseudonodular infiltrates on CT scan to diffuse interstitial pneumonitis to an asymptomatic pulmonary mass. The latter may at times raise the suspicion for malignancy on initial evaluation. As with other eosinophilic pneumonias, pulmonary involvement in toxocariasis may present as patchy ground-glass opacities on initial CT scan findings. A recent study reported the presence of focal linear opacities on CT scan. A pattern similar to miliary tuberculosis (TB) has also been reported in severe cases. The varied radiologic patterns may reflect whether direct larval invasion of lung tissue or a hypersensitivity reaction to larval antigens is the primary pathologic process present in that particular patient.
Pulmonary function testing may reveal diminished lung function with decreased forced expiratory volumes in one second (FEV1). Bronchiectasis may result from chronic lung infection.
Neutrophilia occurs during the first few days but rapidly gives way to the eosinophilia classically seen in the disease. Eosinophilia can range up to 50%–90% of the total white blood cell count. Leukocytosis is generally present, with extreme values of over 100,000 cells/mm 3 occasionally reported.
Other laboratory findings also may be helpful in supporting a diagnosis of VT. Serum IgE levels are above 900 UI/mL in 60% of patients tested. Hypergammaglobulinemia is frequently reported and characterized by elevations of any one or all of the immunoglobulin classes. Because of cross-reactivity between larval and blood group antigens, many patients will develop high anti-A and anti-B isohemagglutinin titers that persist for months after the initial infection. Bronchoalveolar lavage fluid also may exhibit a relative eosinophilia.
Diagnosis and Differential Diagnosis
ELISA and Western blot (WB) using the larval TES antigens to detect the host’s antibodies are the most widely available and accepted tests for confirmation. If a titer above 1 : 32 is considered, the diagnostic sensitivity is approximately 78% with a specificity of over 92%. Because antibodies against Toxocara are present for years, an antigen-capture ELISA has been developed to separate acute from dormant infection. Most recently, polymerase chain reaction (PCR) tests and recombinant antigen based assays on the Luminex platform, have also been developed. The latter perform similarly to the existing TES-antigen WB and better than the TES-antigen ELISA method. However, they may not be widely available in underresourced countries where there is a high burden of disease.
Examination of the stool for ova and parasites is not helpful because the larvae rarely mature in humans. Before the ELISA against TES antibodies was developed, tissue biopsy to demonstrate the larvae in eosinophilic granulomas was the definitive test for diagnosis. Skin tests, other serologic testing, and fluorescent antibody techniques were troubled by low sensitivities and unacceptably high cross-reactivity with other parasitic infections.
Differential diagnosis should include the visceral lesions that may be produced by other nematode worms, as well as immature stages of certain nematodes and filarial worms. Invasion of the liver by Fasciola hepatica, a nematode worm, or Capillaria hepatica, a trematode, might be included. Also to be considered in this diagnosis are trichinosis, hepatitis, leukemia, other causes of intense eosinophilia, TB, asthma, lead poisoning, and the leukemoid reaction occurring in severe bacterial pneumonia.
Management and Treatment
Treatment depends on the severity and location of the infection. Albendazole or mebendazole are the treatments of choice for Toxocara infections, although albendazole is not approved by the Food and Drug Administration (FDA), for this particular indication, and mebendazole is no longer available in the United States ( Table 33.1 ). Thiabendazole and ivermectin have also been used. Most patients recover without any specific anthelmintic therapy. Corticosteroids along with antihelminthic treatment have been useful in patients with severe pulmonary and ocular involvement, possibly by also treating the hypersensitivity component of the disease as well. Surgery may be indicated in some cases with ocular disease. Otherwise, treatment is symptomatic.
| Disease | Drug | Dose and Duration |
|---|---|---|
| Toxocariasis | Albendazole | 400 mg by mouth twice a day for 5 days (adult & child) |
| Mebendazole | 100–200 mg by mouth twice a day for 5 days (adult & child) | |
| Echinococcosis | Albendazole | Adults: 400 mg by mouth twice a day for 1–6 months Children: 10–15 mg/kg/day (max 800 mg) by mouth twice a day for 1–6 months |
| Mebendazole | 50–60 mg/kg/day in three divided doses for 3–6 months up to 1 year a | |
| Strongyloides | Ivermectin b | 200 µg/kg given as a single dose for 1–2 days |
| Albendazole | 400 mg by mouth 2 times daily for 7 days | |
| Paragonimus | Praziquantel | 25 mg/kg given orally three times a day for 2 days c |
| Triclabendazole d | 10 mg/kg once or twice |
a 100–200 mg/kg/day for 3 months has also been used successfully in children without any serious complications reported.
b Oral Ivermectin is available for human use in the United States. Relative contraindications for the use of ivermectin include: pregnant women, confirmed or suspected Loa loa infection, and those weighing less than 15 kg. For Strongyloides associated hyperinfection syndrome, Ivermectin should be given until stool and sputum exams are negative for the parasite for 2 weeks.
c Safety of praziquantel not established in children less than 4 years old. In endemic areas, risks and benefits of treatment should be considered.
d Not available in the United States, not FDA approved.
e Contents of table adapted from the CDC and more information is available at the following websites:
http://www.cdc.gov/parasites/toxocariasis/health_professionals/index.html
http://www.cdc.gov/parasites/echinococcosis/health_professionals/index.html#tx
http://www.cdc.gov/parasites/strongyloides/health_professionals/index.html#tx
http://www.cdc.gov/parasites/paragonimus/health_professionals/index.html#tx .
Prognosis
Prognosis depends on the extent of the disease. The few deaths described with VT have resulted from myocardial, neurologic, or overwhelming systemic involvement. Neurologic disturbances have been described in severe cases because of invasion of the central nervous system (CNS) by larvae. Seizures, encephalopathy, meningoencephalitis, and transverse myelitis have all been reported. Manifestations of peripheral nervous system involvement include radiculitis and cranial nerve palsy. Renal, pancreatic, and cardiac invasion rarely occur. Cardiac involvement, while rare, can be a potentially life-threatening complication of the disease. T. canis also may produce the Pulmonary Infiltrates and Eosinophilia (PIE) syndrome. Finally, various dermatologic manifestations have been reported with toxocariasis. These include chronic urticaria, eczema, and pruritis.
Measures that decrease the ingestion of contaminated soil reduce the incidence of the disease. Anticipatory guidance should focus on the risks of pica and elimination of the behavior. Regular deworming of puppies and lactating or pregnant female dogs should be performed, and the risks of indiscriminate disposal of dog feces, especially in children’s play areas, should be emphasized.
Recently, the CDC announced an initiative to prioritize five neglected parasitic infections in the United States, including toxocariasis. Among the major priorities outlined are efforts to better define risk factors and further research to elucidate the natural history of toxocariasis and its complications. There is also a need to develop improved and easily available diagnostic tests for detecting active infection and studies to optimize current treatment regimens using anthelminthic drugs.
Echinococcosis (Hydatid Disease)
Epidemiology
Tapeworms of the genus Echinococcus are the causative agents of Echinococcosis, which has been recognized as one of the 17 neglected tropical diseases by the World Health Organization (WHO). The disease has a worldwide distribution. It is endemic in most parts of the world where sheep rearing is common including South America, the Mediterranean region, Central Asia, Western China, and East Africa.
There are three major forms of echinococcosis that affect humans: cystic echinococcosis, alveolar echinococcosis, and polycystic echinococcosis. Of these, cystic echinococcosis predominantly affects the lungs, whereas the latter two affect the liver and will not be discussed in detail. Polycystic echinococcosis is the least common form seen and is restricted to South and Central America.
Echinococcosis is known to affect all age groups and any body cavity, organ, or site, although it most frequently affects the liver and the lungs, with the lung more commonly affected in children. Infection occurs mostly during childhood, although years may elapse before manifestations are seen. While overall there is no gender preference, more cases are reported in males, and this slight difference in gender incidence is probably related to activity or occupation.
Etiology
Currently, nine species of Echinococcus have been identified with the two major species of medical importance being E. granulosus sensu lato (formerly recognized as a single species E. granulosus ) and E. multilocularis. Phylogenetic sequencing now shows that there are several different genotypes of E granulosus sensu lato, some of which are considered different species. Of these E. granulosus sensu stricto, E. equinus, E. ortleppi and E. Canadensis all cause cystic echinococcosis. Enterococcus multilocularis is the causative agent of alveolar echinococcosis, while E. vogeli and E. oligarthrus cause polycystic echinococcosis. In addition, another species E. shiquicus has been recently described in the Qinghai-Tibet highlands, and while no human disease has been described thus far, further studies are needed. Echinococcus granulosus sensu stricto is responsible for the majority (up to 88%) of human cases globally.
The parasites are maintained in nature by canines (primarily dogs, coyotes, dingoes, and wolves), which act as the definitive host. Herbivores (sheep, goats, or other livestock) are the intermediate hosts and harbor the larval stage. The life cycles of E. granulosus, E. multilocularis, and E. vogeli are similar, with the major difference being that the fox is the major definitive host for E. multilocularis and rodents are the intermediate hosts for both E. locularis and E. vogeli. For this review, we will be focusing primarily on E. granulosus (sensu lato).
Pathology/Pathogenesis
The first developmental stage is the tapeworm, which reaches sexual maturity only in the intestinal tract of its definitive mammalian host: dogs or other canines. Adult Echinococcus worms typically produce thousands of eggs each day that are extremely resistant to climatic conditions and survive for at least 2 years in northern regions. Infectious ova are released during defecation, contaminating fields, irrigated lands, and wells. Once the eggs are swallowed by humans, the outer shell is digested and the embryos penetrate the intestine and are hematogenously disseminated to various parts of the body, mostly to the liver and lung. In the lung, the embryos form fluid-filled cysts (hydatid cysts) ( Fig. 33.1 ).
Under ideal conditions, tapeworm heads, or protoscoleces, develop within the cysts. The minimum time for protoscoleces to develop has been estimated to be 10 months or longer after infection. Humans are accidental hosts and are highly unlikely to be involved in disease transmission. They can become infected from contaminated water and food or through close contact with infected dogs, sheep, or other livestock. Human-to-human transmission does not occur.
Lung cysts develop when embryos pass through the liver, through lymphatic ducts bypassing the liver, by contiguous extension from the liver, or through the bronchi. The cyst slowly enlarges, and its rate of growth is dependent on the distensibility of the tissue and the age of the host. It has also been suggested that different biological attributes such as the rate of attaining fertility as well as the size of a hydatid cyst can be related to the genotype. Pulmonary cysts grow faster in children. At a size of 1 cm, three layers can be identified within the cyst: (1) an inner layer of germinal epithelium or endocyst that is responsible for formation of daughter cysts by endogenous vesiculation; (2) a middle noncellular, laminated layer or ectocyst; and (3) an adventitia or pericyst, an outer capsule of fibrous tissue, vasculature, giant cells, and eosinophils resulting from a weak host reaction. With time, blood capsules and daughter cysts may develop and disintegrate, liberating free floating hooklets or “hydatid sand.”
Involvement of the diaphragm and transdiaphragmatic extension into the lung has been described in patients with primary hydatid cysts of the liver. Virtually any organ including the brain, eye, heart, mediastinum, blood vessels, pleura, diaphragm, pancreas, spleen, endocrine glands, bone, and genitourinary tract may be affected. The CNS is affected more often in children than in adults.
Clinical Features
Symptoms
Cyst size, location, and the potential for impairment of vital structures determine the clinical manifestations. The more common symptoms of pulmonary cysts are cough, chest pain, hemoptysis, fever, and malaise. Other manifestations include sputum production, chest discomfort, loss of appetite, dyspnea, vomiting of cyst elements, dysphagia, and hepatic pain. Bronchospasm has been reported with relief of “bronchial asthma” after removal of the cyst. Growth retardation patterns have been observed in many children.
A large proportion of pulmonary cases may be discovered incidentally on a routine chest radiograph. The intact cyst is most commonly asymptomatic and may account for a third of all cases. This is usually seen in children where the cyst may be an incidental finding. Most individuals harboring small lung cysts often remain asymptomatic 5–20 years after infection until the cyst enlarges sufficiently to cause symptoms. Awareness of symptoms is due to pressure from the enlarging cyst, secondary infection, and cyst rupture. Up to 30% of lung cysts may be complicated by rupture into the pleural space or bronchus, precipitated by coughing, sneezing, trauma, or increased abdominal pressure. Chills, fever, increased cough, mild hemoptysis, and change in appearance on radiographs suggest rupture.
Physical Findings
Physical examination is rarely definitive. Occasionally, a hydatid thrill (fluid wave) can be felt while percussing a large cyst. Demonstration of scoleces and hooklets of the parasite in vomitus, stool, urine, or sputum is pathognomonic but is rarely observed and may be seen only during surgery.
Children with echinococcosis may present to the emergency room because of complications of the disease. These complications may be mechanical, with hydatid growth affecting the bronchial tree or pleura; they also may result from hematogenous spread, infection, or allergic reaction. Cyst rupture, pneumothorax, atelectasis, bronchopleural fistula, empyema, saprophytic mycosis have been reported. A rare complication is rupture into the cardiovascular system with dissemination or sudden death.
Secondary hydatidosis in the pleura, acute asphyxia by bronchial obstruction, and allergic reactions, including anaphylaxis, may follow cyst rupture and leakage. Bronchobiliary fistula occurs in 2% of cases and is commonly, but not always, preceded by suppuration. The right side and posterior basal segment of the lung are most frequently affected. Pyrexia and weight loss may mimic malignancy, but bile expectoration is pathognomonic.
Imaging, PFT, Laboratory Findings
Lung cysts are readily detected on plain radiographical films, and the possibility of a hydatid cyst should always be considered in an endemic area. An intact cyst is seen as a round or oval homogeneous lesion with a sharply defined smooth border surrounded by normal lung or a zone of atelectasis. It may be located in the periphery, center, or hilum; be single or multiple; and unilateral or bilateral ( Fig. 33.2 ). The final form depends on the location and neighboring structures. With an increase in size, bronchial displacement occurs without obstruction, as has been demonstrated by CT or bronchography. On fluoroscopy, good elasticity of the cyst wall is demonstrable, and there is no interference with movement of the diaphragm.
As the cyst grows, air passages and surrounding vessels are eroded, producing bronchial air leaks into the cyst adventitia. The bronchial connection is actually nonpatent before rupture because of pressure of the endocyst against bronchial passages, and it may be recognized only during surgery. With varying stages of air dissection into the cyst, different classical radiologic signs may be seen. Pericystic emphysema is seen before rupture. A “meniscus sign” or “crescent sign” is a crescentic radiolucency above the homogeneous cyst shadow on deep inspiration that is seen when air penetrates between the adventitia and ectocyst. As air dissection continues, the parasite’s membrane is torn, and some hydatid fluid flows out. An air-fluid level is seen within the cyst lumen as well as an air cup between ectocyst and adventitia, known as “double air-layer appearance” or the Cumbo sign. This is also referred to as the onion peel or double arch sign and is pathognomonic for a ruptured pulmonary hydatid cyst. With free connection to a bronchus, the cyst wall is detached from the adventitia, crumbles, collapses, and floats on remaining cyst fluid. This result is seen on the radiograph as air between the collapsed floating cyst wall and the adventitia, known as the “water lily sign” or Camellote sign. The adventitial wall does not collapse at once, so the obliteration of the cyst cavity is not an immediate outcome.
Ultrasonography helps distinguish cystic lesions from solid tumors and has become the diagnostic study of choice for cystic and alveolar echinococcosis due to its low cost and high specificity and sensitivity. Pathognomonic signs on ultrasonography are multiple daughter cysts within a cyst, separation of the laminated membrane from the wall of the cyst, and collapsed cysts ( Fig. 33.3 ). A simple cyst with a thick wall in patients from an endemic area is suggestive. Abdominal ultrasonography is also recommended for liver cyst detection. Specific features identified on sonogram are similar to those seen on plain radiographs and include the double-walled cyst, water lily sign, honeycomb appearance, ball of wool sign, and cyst wall calcification with pseudosolid content. The honeycomb sign is caused by multivesiculated cysts in which the walls of adjacent cysts give the impression of “septa.” The ball of wool sign is caused by multiple degenerating hypoechoic cyst membranes folded inside the pseudosolid cyst content.
Cystic hydatidosis of the lung occurs most often as a single unilocular cyst. Only about 7%–38% occur as multiple unilocular cysts. The inferior lobes are most commonly affected. In children, the ratio of intact to ruptured cysts is 3 : 1, which is the inverse of that in adults. Unlike spleen and liver hydatid cysts, calcification of lung cysts is rare. A high right hemidiaphragm and right basal bronchiectasis suggest bronchobiliary fistula. A tract on sinogram or bronchogram is diagnostic. CT and magnetic resonance imaging (MRI) can also be used and may help with better documentation and definition of the vascular and biliary anatomy in complicated cases ( Fig. 33.4 ).
Hepatic function may be abnormal in one-half of patients with liver cysts. An increased specific serum IgE may be observed, but eosinophilia is more often absent than present and is completely unreliable in areas endemic for other parasites.
Diagnosis and Differential Diagnosis
The coughing up of hydatid cyst elements, described as “coughing up grape skins,” is diagnostic (see Fig. 33.1 ). Awareness of the disease is most important. Lung involvement is very likely if a cyst is present elsewhere in the body. Cystic hydatid disease is suspected based on a history of current or previous residence in an endemic area, clinical observations, and radiographic evidence. In 10% of cases, a diagnosis is suspected on routine radiographic study alone. A history of contact with possibly infected dogs may be obtained in only half the cases.
The Casoni skin test involves injection of hydatid fluid in the dermis, which produces an erythematous papule in 50%–80% of patients in less than 60 minutes ( Fig. 33.5 ). False-negative results, sometimes due to infected cysts, and false-positive results occur in 30% of those tested. With the development of improved serologic tests, the Casoni skin test is less commonly used.
Serologic tests include latex agglutination, indirect hemagglutination, complement fixation, agar gel diffusion, enzyme immunoassay, and immunoblot. Cross-reactivity between echinococcosis and cysticercosis ( Taenia solium infection) is a problem with any test that employs whole-cyst antigens. Serum antibody testing by indirect hemagglutination is 91% sensitive and 83% specific at a titer greater than or equal to 1 : 128. Immunoblot is 86% sensitive and 99% specific. It has been suggested that the Casoni test and indirect haemagglutination tests be used together in the diagnosis of hydatid disease to establish the diagnosis particularly in endemic areas where this remains a problem. Most recently, rapid diagnostic tests have been developed that may be useful and may complement ultrasound findings in uncertain cases.
After surgical removal of the cyst, there is generally a rapid decline in antibodies within 3 months although they may persist for years. Failure to observe the decline suggests incomplete cyst removal. Serum antibody tests can be referred to the CDC. False-negative results are more common in children and with pulmonary cysts. Up to 50% of patients with hydatid cysts in the lung or calcified cysts are seronegative. Laboratory tests may be more sensitive in complicated cysts, but at present, no single test is infallible, and there is still no serologic test that can effectively rule out the disease. Thus, disease awareness is most important.
Differential diagnosis of hydatid disease includes abscess, hamartoma, pulmonary arteriovenous fistula, benign granuloma, malignant tumor, metastases, and cysts of different origin. When present, the Cumbo sign is pathognomonic.
Management and Treatment
The treatment options for cystic echinococcosis include surgery, ultrasound-guided aspiration, and chemotherapy. Each method has limitations depending on the specific case. Spontaneous cure is possible after coughing out the cyst and its contents, but more commonly, infection and toxemia follow from the residual cyst. Up to two-thirds of symptomatic patients may die without intervention. Surgery used to be the treatment of choice along with antihelminthic treatment prior to the introduction of ultrasound guided percutaneous drainage, which is now used widely. Endoscopic retrograde cholangiopancreatography should be performed prior to the procedure to ensure that no connections exist with the biliary tree. The acronym PAIR has been used to describe the process that is puncture, aspiration, injection, and then reaspiration. This process has shown a percent reduction in cyst size of 73%–99%.
Once the diagnosis has been confirmed by serology, followed by imaging, the patient should be pretreated with albendazole for a few days prior to percutaneous removal of the cyst. Preoperative treatment has been reported to reduce intracystic pressure and simplify removal. However, it has also been reported that use of albendazole prior to surgery may itself contribute to rupture of the cyst. This is much more likely to occur with large cysts (>6 cm in diameter) due to degenerative changes that occur in the cyst wall. Presurgical use of albendazole or mebendazole can reduce the recurrence of cystic echinococcosis.
Use of albendazole following removal is also controversial. One group suggested treatment should continue for up to 1 month and less if the cyst is smaller (i.e., <6 cm in diameter). In another study, the authors reported that they only used albendazole if there was cyst spillage after surgery, partial cyst removal, or biliary rupture. Most would agree, however, that there is a risk of recurrence if not treated with albendazole as high as 11% in one older report.
Percutaneous removal of hydatid cysts has been reported, but has its limitations and generally cannot be used in the case of multiple cysts or cysts that appear solid, although successful percutaneous drainage of multiple cysts has been reported.
More recently, minimally invasive surgical techniques such as video assisted thoracoscopic surgery (VATS) as well as laparoscopic removal of cysts has also shown to be successful for uncomplicated cysts. In addition, techniques such as staged thoracotomy and pneumonostomy have been used for the treatment of multiple lung cysts as well as residual cavities in large complicated cysts.
When percutaneous drainage is not possible, surgery is recommended, although conservative management with benzimidazoles may be equally effective in asymptomatic patients. The success of surgery is dependent on the size and location of the cyst and on the skill of the surgeon. If surgery is indicated, it is important to perform surgery immediately after diagnosis, because a weak adventitial reaction and bronchial communications may lead to rupture with intrapulmonary dissemination. Only in the benign Alaskan-Canadian variant is conservative treatment recommended.
The aims of surgery are total eradication of the parasite with evacuation of the cyst and removal of the endocyst, prevention of cyst rupture and consequent dissemination during the operation, along with extirpation of the residual cavity. The lung parenchyma should be preserved and resection should be avoided in children if possible, because the damaged lung parenchyma has great capacity for recovery. Lung resection may be done in cases with bronchiectasis, severe inflammation, and large or multiple cysts that have destroyed lung parenchyma. The posterolateral approach is favored. Surgical techniques to eradicate the parasite may include puncture and aspiration of cysts in situ, excision of the entire cyst by enucleation, wedge resection, segmentectomy, lobectomy, or pneumonectomy. Surgical procedures such as enucleation with or without obliteration of the residual cavity by sutures (capitonnage) and cystectomy are mainly used for uncomplicated cysts. Lobectomy or segmental resection is reserved for lungs destroyed by large cysts or bronchobiliary and biliary-pleural fistulas.
The following YouTube video links show removal of hydatid lung cysts both using VATS and open surgical procedures:
Rupture and spillage may occur during surgery and lead to dissemination and anaphylaxis, which can be fatal. This complication, although uncommon even with spillage during surgery, is greatly feared. Anaphylaxis remains a concern, although an extensive literature search showed that lethal anaphylaxis has been a relatively rare event. The differences in surgical techniques therefore reflect the desire to prevent spillage of viable cyst contents. Commonly, the operative field is protected with saline-moistened gauzes, and the cysts are gently manipulated.
After extirpation of the parasite, bronchial fistulas are closed. To prevent recurrence, the residual cavity is injected with scolicidal agents, such as formalin, hypertonic saline, povidone-iodine, or absolute alcohol and albendazole. Because of extremely grave complications with the use of formalin and hypertonic solutions, some have used hydrogen peroxide with good results. The residual cavity is then either obliterated by sutures or left open to communicate with the pleural space. Alternatively, the pericystic membrane is resected with repair of bronchial leakage. Bronchobiliary fistulas may rarely occur following liver hydatid cyst disease. While the management was traditionally thought to be surgical, conservative management has been used with success in less severe cases.
Medical treatment alone has limited success, although results may vary according to the individual case. Between 30% and 50% of cases show some improvement after medical treatment based on imaging findings. Chemotherapy alone is indicated when percutaneous drainage and/or surgery is impractical or impossible, when patients have multiple cysts in two or more organs, when peritoneal cysts are present, and for recurrent disease.
According to the WHO guidelines, benzimidazoles (e.g., mebendazole or albendazole) are the chemotherapeutic agents of choice. Albendazole is the preferred treatment option in the United States, since mebendazole is no longer available in the United States. Albendazole differs from mebendazole in two respects: it is absorbed at a higher rate and it undergoes almost total first-pass metabolism to its effective protoscolicide metabolite, albendazole sulfoxide. Its plasma concentration in hydatid-infested patients is about 10–40 times higher than that achieved with mebendazole. Cyst fluid concentrations also are higher than those achieved with mebendazole. Further enhancement of drug concentration in target tissues may be possible with the concurrent use of cimetidine or administration with a fat-rich meal. Albendazole is usually well tolerated. Liver function may be abnormal in 10%–20% of patients during treatment, but side effects are rarely severe. Use of albendazole has been shown to be a safe and effective alternative to surgery for treating uncomplicated liver cystic Echinococcosis and requires a shorter hospital stay. Albendazole should not be used during the first trimester of pregnancy because it has teratogenic effects in animals, although these have not been observed in humans.
Mebendazole interferes with uptake of glucose by cestodes and disrupts their microtubule system, but it is poorly absorbed and produces low blood concentrations. Absorption is enhanced with meals. Repeated courses may be necessary. Cure of hydatid disease has been achieved in 35%–75% of patients, and recurrence rates have been low. Adverse reactions to mebendazole may occur within the first month and include fever and allergic reactions, alopecia, glomerulonephritis, and reversible leukopenia. With hepatobiliary disease, high blood levels and toxicity have been observed. Monitoring of clinical status, liver function, renal function, and complete blood count should be done weekly for the first month and biweekly thereafter.
Patients with chronic liver disease or bone marrow suppression should not undergo benzimidazole treatment. Another benzimidazole compound oxfendazole is available for use in veterinary practice only.
In addition to benzimidazoles, praziquantel may be added especially after surgery, when the risk of spillage is high. Praziquantel when given alone is not effective, but it does act synergistically with albendazole. Although limited data are available, the dose recommended is 40 mg/kg per week.
Prognosis
The more common surgical complications in children include atelectasis, hydropneumothorax, wound infection, pleural reaction, and hemothorax. Other reported complications from surgery are chest infection, abscess, empyema, septic shock, bronchial rupture, pneumothorax, bronchobiliary and/or biliary-pleural fistula, hemorrhage, massive aspiration, prolonged drainage, bronchiectasis, and allergic reactions, including anaphylactic shock and death with rupture.
The cysts’ unusual location is the cause of the following reported rarer complications: arterial emboli, portal hypertension, systemic venous obstruction, paraplegia, pleural effusion, phrenic nerve paralysis, transitory paralysis of cervical sympathetic chain, lower extremity thrombophlebitis, and stress ulcer.
Hydatid lung disease is preventable. The use of veterinary taeniacides for dogs; proper disposal of carcasses and entrails of animals to prevent dogs from gaining access; and the proper practice of hand, food, and drink hygiene to prevent contamination from dog excrement are appropriate preventive measures. Follow-up abdominal ultrasonography should be done annually for 5 years or more after successful treatment of hydatid disease. A cyst cavity may remain, and serologic findings may be positive for several years.
Sylvatic Alaskan-Canadian Variant
The Alaskan-Canadian Echinococcal species is clinically and morphologically distinct and has been named E. granulosus var. Canadensis. It is seen in the tundra and northern coniferous forests of North America, south to the Great Lakes, mainly among the native population, including the Eskimo, Aleut, and Native American Indians, 75% of whom live in areas where E. granulosus occurs. The wolf is the definitive host, and sometimes the dog, which ingests the tapeworm by eating the viscera of infected deer. Elk, reindeer, moose, and caribou also are intermediate hosts. Pig, sheep, and cattle resist the infection. In contrast, humans are not very suitable hosts.
The Alaskan-Canadian sylvatic infection is more benign; the cysts are smaller and more delicate, do not grow as rapidly, and produce fewer symptoms than the classic or pastoral E. granulosus. The risk of anaphylaxis with rupture is less, and the prospect for spontaneous cure without significant complications is excellent.
Most commonly affected organs are the liver and the lung, with lung involvement in 61% of the cases. Most cysts are simple, intact, and uninfected. For pulmonary cysts, the mean age is 22 years (5–77 years), and for liver cysts, it is 65.3 years (24–96 years). In patients with lung cysts, 71% are younger than 20 years. Only 6%–8% of cases are symptomatic, mostly because of cyst rupture, which occurs in some 26% of patients. Cough, purulent expectoration, and hemoptysis are usual complaints. Serious complications are rare, and no cases of anaphylaxis or seeding have been seen in the Alaskan or Canadian experience.
Diagnosis is based on a history of residence in an endemic area, exposure to dogs, and characteristic findings on routine radiographic study. Typically, a round or oval homogeneous waterlike density with clear-cut borders and no surrounding reaction is seen. Classic signs such as the water lily and crescent sign are rare. Laboratory tests are of little value. Eosinophilia is positive in only 29% of cases, hemagglutination in 10%, and the Casoni test in 56% of cases. With cyst leak or rupture, test results are usually but not always positive.
The surgical risk is minimal. Extrusion of the intact vesicle is not appropriate, and an open wedge resection of adventitia with intact cyst is favored. Gentleness is very important. The bronchial stump should be closed, and the defect in the lung obliterated. Alternatively, cystectomy may be performed.
Quite commonly, the cyst evacuates into the bronchi, and the symptoms disappear. Thus, surgery is not recommended for asymptomatic patients who are managed by observation. No serious morbidity and mortality have been reported with this approach.
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