Cystic echinococcosis (CE) is the larval cystic stage (called echinococcal cysts) of a small taeniid-type tapeworm (Echinococcus granulosus) that may cause illness in intermediate hosts, generally herbivorous animals and people who are infected accidentally. Ultrasonographic appearance of echinococcal cysts is seen in the image below.
View Image | WHO Informal Working Group on Echinococcosis standardized ultrasound classification of echinococcal cysts. Image courtesy of World Health Organization.... |
Three other species are recognized within the genus Echinococcus, and they may also develop in the human host and cause various forms of echinococcosis (hydatidosis). E granulosus is discussed separately from the other 3 species, notably Echinococcus multilocularis, which causes alveolar echinococcosis, because of marked differences in epidemiology, clinical features, diagnosis, and treatment.
In the normal life cycle of Echinococcus species, adult tapeworms (3-6 mm long) inhabit the small intestine of carnivorous definitive hosts, such as dogs, coyotes, or wolves, and echinococcal cyst stages occur in herbivorous intermediate hosts, such as sheep, cattle, and goats. A number of other suitable intermediate hosts, such as camels, pigs, and horses, are involved in the life cycle in many parts of the world.
In the typical dog-sheep cycle, tapeworm eggs are passed in the feces of an infected dog and may subsequently be ingested by grazing sheep; they hatch into embryos in the intestine, penetrate the intestinal lining, and are then picked up and carried by blood throughout the body to major filtering organs (mainly liver and/or lungs). After the developing embryos localize in a specific organ or site, they transform and develop into larval echinococcal cysts in which numerous tiny tapeworm heads (called protoscolices) are produced via asexual reproduction.
These protoscolices are infective to dogs that may ingest viscera containing echinococcal cysts (with protoscolices inside), mainly because of the habit in endemic countries of feeding dogs viscera of home-slaughtered sheep or other livestock. Protoscolices attach to the dog's intestinal lining and, in approximately 40-50 days, grow and develop into mature adult tapeworms, once again capable of producing infective eggs to be passed to the outside environment with the dog's feces.
Because humans play the same role of intermediate hosts in the tapeworm life cycle as sheep, humans also become infected by ingesting tapeworm eggs passed from an infected carnivore. This occurs most frequently when individuals handle or contact infected dogs or other infected carnivores or inadvertently ingest food or drink contaminated with fecal material containing tapeworm eggs.
In primary echinococcosis, metacestodes develop from oncospheres after peroral infection with E granulosus eggs. In secondary echinococcosis, larval tissue proliferates after being spread from the primary site of the metacestode. This can occur by spontaneous trauma such as induced rupture or during medical interventions.
In primary echinococcosis, larval cysts may develop in every organ. Most patients (as many as 80%) have single-organ involvement and harbor a solitary cyst. Approximately two thirds of patients experience liver echinococcosis. The second most common organ involved is the lung.
In each anatomic site, cysts are surrounded by the periparasitic host tissue (pericyst), which encompasses the endocyst of larval origin. Inside the laminated layer, or hyaline membrane, the cyst is covered by a multipotential germinal layer, giving rise to the production of brood capsules and protoscolices. The central cavities of cysts of E granulosus are filled with clear fluid, numerous brood capsules, and protoscolices. In addition, daughter cysts of variable size are often detected. The growth rate of cysts is highly variable and may depend on strain differences. Estimates of the average increase of cyst diameter vary (approximately 1-1.5 cm/y).
The clinical features of cystic echinococcosis are highly variable. The spectrum of symptoms depends on the following:
United States
Unfortunately, realistic national or international figures do not exist for total numbers of cases of cystic echinococcosis. The problem is that, until recently, the only basis for diagnosis was surgery, and few countries systematically reported cases. When they did report cases, uneven reporting occurred in different regions of countries. The groups most at risk of cystic echinococcosis are usually underserved by medical services.
However, the increasing use of mass screenings with ultrasonography in endemic countries is generating important epidemiological data. As different cyst stages have been classified according to their sonographic appearance, attempts are being made to match the cyst morphology with the natural history of the cyst. This is evident with the World Health Organization (WHO) standardized classification (see Imaging). At a community level, the relative proportions of cyst types can provide epidemiological information on disease transmission and help design effective control programs.[1]
In the United States, transmission of E granulosus in the dog-sheep cycle is known to occur most frequently in several western states, including California, Arizona, New Mexico, and Utah. In Arizona and New Mexico, cystic echinococcosis is known to occur in American Indians belonging to the Zuni, Navajo, and Santo Domingo tribes, whose members live in close proximity to their animals, kill many of their own animals each year, and generally have limited knowledge concerning the life cycle and transmissibility of the parasite. In the United States, Utah has had the highest number of surgical cases of those states involved, with approximately 45 cases from 1944-1994.
International
E granulosus is a cosmopolitan parasite, and endemic regions exist in each continent. Considerable public health problems occur in many areas, including countries of Central America and South America, Western and Southern/Southeastern Europe, the Middle East and North Africa, some sub-Saharan countries, Russia and adjacent countries, and China. Annual incidence rates of diagnosed human cases per 100,000 inhabitants vary widely, from less than 1 case per 100,000 to high levels. For example, rates in the indicated regions are as follows:
Cystic echinococcosis causes not only illness but also productivity losses in human and agricultural animal population, and it can have large societal impacts on endemic areas. Research is being conducted to evaluate the burden of disease, including nonmonetary costs.
Cystic echinococcosis is rarely fatal. Occasionally, deaths occur because of anaphylactic shock or cardiac tamponade in heart echinococcosis.[2]
Rare locations of the cyst (muscle, bone, brain, orbit) can cause dramatic and disabling symptoms (blindness, paralysis).[3, 4, 5, 6, 7, 8, 9, 10]
No racial predilection exists.
In some endemic countries, females are affected more than males because their lifestyle habits and practices bring them into contact with the parasite.
Individuals of all ages are affected. In some endemic countries, children have higher infection rates because they are most likely to play with dogs.
Prognosis is generally good and depends on the cyst location. For instance, neither surgery nor medical therapy is generally effective for bone, especially spinal, echinococcosis. Surgery to treat cardiac cysts can be risky, and there is very little experience with the use of albendazole in this site.
Sometimes after removal of a cyst, one or more new cysts may develop at a different site. A hypothesis for this is that the growth of some cysts may be inhibited by the presence of the cyst that has been removed.
Months or years may pass before an individual exhibits any signs or symptoms of infection with the cystic larval stages.
During the natural course of infection, the fate of E granulosus cysts is variable. Some cysts may grow to a certain size and then persist without noticeable change for many years. Other cysts may rupture spontaneously or collapse and completely disappear.
Spontaneous or traumatic cyst rupture and spillage of viable parasitic tissue during interventional procedures may result in secondary echinococcosis. Cysts may rupture into the peritoneal or pleural cavity, the pericardium, the bile ducts, the gastrointestinal tract, or even blood vessels, leading to extraordinary manifestations and severe complications.
Spontaneous cure of cystic echinococcosis is possible.
After a variable incubation period, infections may become symptomatic if cysts are growing and exerting pressure on adjacent tissue and inducing other pathologic findings.
Sudden symptomatology is usually due to spontaneous or traumatic cyst rupture.
Usually, cysts do not induce clinical symptoms before they have reached a size sufficient to exert pressure on adjacent organs.
The presentation of human echinococcosis is protean. Patients come to the clinician's attention for different reasons, such as when a large cyst has some mechanical effect on organ function or rupture of a cyst causes acute hypersensitivity reactions. The cyst may also be discovered accidentally during radiographic examination, body scanning, surgery, or for other clinical reasons.[11]
Common chief symptoms are upper abdominal discomfort and pain, poor appetite, and a self-diagnosed mass in the abdomen. Physical findings are hepatomegaly, a palpable mass if on the surface of the liver or other organs, and abdominal distention. If cysts in the lung rupture into the bronchi, intense cough may develop, followed by vomiting of hydatid material and cystic membranes.[12]
Liver findings may include the following:
Lung findings may include the following:
Heart findings may include the following:
Breast masses may be found (must be differentiated from neoplasms).[11]
Spine masses with neurologic symptoms may be found.
Brain masses with neurologic symptoms may be found.
See Background for a brief discussion of infection routes.
Susceptibility of humans to infection varies, presumably because of individual differences in nutritional, immunologic, and genetic factors.
The cysts may rupture, and the cyst content may be released into biliary or bronchial systems. This may cause infection of the cyst and an obstruction of the biliary or bronchial tree with severe clinical consequences (eg, pneumonitis, pleural effusion, pneumothorax, secondary echinococcosis of the pleural and peritoneal cavity).
Generally, routine laboratory tests do not show specific results. In patients with rupture of the cyst in the biliary tree, marked and transient elevation of cholestatic enzyme levels occurs, often in association with hyperamylasemia and eosinophilia (up to 60%). In most cases, eosinophilia is limited (< 15%) or absent.
Cystic echinococcosis is one of the few parasitic infections in which the basis for laboratory diagnosis is primarily serology.[13]
Indirect hemagglutination test and enzyme-linked immunosorbent assay are the most widely used methods for detection of anti-Echinococcus antibodies (immunoglobulin G [IgG]).
Depending on the test system used and other parameters, approximately 10% of patients with hepatic cysts and 40% with pulmonary cysts do not produce detectable serum IgG antibodies and exhibit false-negative results.
Cysts of the brain or eye and calcified cysts often induce no or low antibody titers.
Children aged 3-15 years may produce minimal serologic reactions.
No standard, highly sensitive, and specific serologic test exists for cystic echinococcosis antibody detection. In specialized laboratories, the arc 5 test or detection of cestode-specific antibodies can be used to exclude cross-reactions caused by noncestode parasites.
For liver cysts, seropositivity is a function of cyst viability, with early CE1 cysts sometimes being seronegative until nonsurgical treatments disrupt the integrity of the cyst (eg, endocyst detachment). Inactive cysts may be seropositive for reasons that are still unknown, generating confusion as to whether treatment is needed.
Endoscopic retrograde cholangiopancreatography may be indicated in patients with cholestatic jaundice. This technique may also be a therapeutic intervention when cysts communicating with the biliary tree can be basketed out.
Fine-needle aspiration biopsy of the cyst performed under ultrasonographic guidance, by the transhepatic approach, and under anthelmintic coverage is generally safe and diagnostically useful for differentiation of cystic echinococcosis, malignancy, and abscesses.[14] It may be particularly helpful in cases with no detectable anti-Echinococcus serum antibodies and inconclusive imaging appearance. The hooks are usually numerous and can be found even in bacteriologically infected and/or degenerating cysts. Rostellar hooklets are seen in the image below.
View Image | Viable scolices (note rostellar hooklets). |
Radiographic examination is useful for cysts in the lungs, bone, and muscle and for detecting calcified cysts.
Ultrasonography is the procedure of choice when making the diagnosis of asymptomatic cystic echinococcosis because it is safe, noninvasive, and relatively inexpensive. Ultrasonography is an imaging technique that uses the reflection of ultrasound waves emitted by a probe on the bodily organs to build images of the organs explored.
Any abnormality can be viewed using ultrasonography from an infinite number of angles and positions. Cysts in every part of the abdomen and in muscles can be imaged with ultrasonography.
Ultrasonography is useful in longitudinal studies, such as monitoring the response of cysts to treatment and recording cyst growth rate.[15]
Ultrasonography has also been used extensively in endemic areas for mass screening, often using portable machines that can work without an electrical distribution system by running on batteries or on a generator.
Many authors consider ultrasonographic mass surveys to be the best way to assess prevalence.
Various classifications exist of the ultrasonographic picture in cystic echinococcosis, the most widely used still being the one proposed by Gharbi in the early 1980s.[16] In 2003, the World Health Organization Informal Working Group on Echinococcosis (WHO-IWGE) proposed a standardized ultrasound classification based on the active-transitional-inactive status of the cyst as suggested by its sonographic appearance.[17]
The standardized classification scheme is intended to promote uniform standards of diagnosis and treatment and may be applied to the clinical treatment of patients as well as to field diagnostic surveys. This classification has important implications for clinical decision-making ad prognosis.[18, 19, 13] CE1 and CE2 are active cysts containing viable protoscolices. CE3 has been subdivided into CE3a (detached endocyst) and CE3b (predominantly solid with daughter cysts). This subdivision is supported by a recent work that used high-field 1 H magnetic resonance spectroscopy to evaluate ex vivo the metabolic profiles of cyst contents.[20] Another paper has shown that, contrary to what previously assumed, calcifications are not limited to CE5 cysts, but are present to a various extent in all cystic stages.[21]
Whatever the classification used, general consensus exists about the following:
CT scanning has the advantage of inspecting any organ (lungs cannot be explored with ultrasonography), detecting smaller cysts when located outside the liver, locating cysts precisely, and sometimes differentiating parasitic from nonparasitic cysts. Measurement of cyst density appears to be an additional tool to differentiate parasitic from nonparasitic cysts and for follow-up studies during chemotherapy. However, the cost of CT scanning is prohibitive in several endemic countries.
MRI may have some advantages over CT scanning in the evaluation of postsurgical residual lesions, recurrences, and selected extrahepatic infections, such as cardiac infections.[22] It is also superior in identifying changes of the intrahepatic and extrahepatic venous system and in identifying cysto-biliary fistulas.[23]
A 2012 study found that MRI reproduces the ultrasound-defined features of CE better than CT. If ultrasonography cannot be performed owing to cyst location or patient-specific reasons, MRI with heavily T2-weighted series is preferable to CT.[24]
For liver cysts, a stage-specific approach should be taken, in which CE1 and CE3a cysts should be treated with either albendazole alone (if < 5 cm in diameter) or percutaneous treatment in association with medical therapy (if cysts are 5-10 cm in diameter). For cysts larger than 10 cm, continuous catheterization may be a viable option. Inactive uncomplicated cysts can be safely managed expectantly, especially if they became spontaneously inactive (ie, as opposed to treatment-induced inactivity).[25, 26, 27, 28, 29]
Two benzimidazolic drugs, mebendazole and albendazole, are the only anthelmintics effective against cystic echinococcosis. Albendazole and mebendazole are well tolerated but show different efficacy.
Albendazole is significantly more effective than mebendazole in the treatment of liver cysts. Benzimidazole treatment alone requires prolonged administration over many weeks, with an unpredictable outcome in terms of response rates in individuals.[30]
Treatment with albendazole in E granulosus infection can result in an apparent cure in as many as 30% of patients, with a further 40-50% of patients showing objective evidence of response when observed short term. Patients who do not show obvious initial evidence of response may be found to be cured when observed over several years.
Duration of therapy and doses are also important. Albendazole efficacy increases with courses of up to 3 months in the more common cyst sites.
Patients once received these drugs in cycles of 4 weeks separated by 1-2 weeks without drugs. This regimen is no longer advocated given the parasitostatic activity of benzimidazoles and their safety as shown by cumulative data from several retrospective studies. Continuous treatment is preferred and has been administered for periods of up to 2 years without significant side effects.[31, 13] The safety profile shows that liver function abnormalities are common, although they rarely limit treatment, while occasional hematologic changes affecting white cells may be more serious. The safety data supply the rationale for monitoring patients during treatment.
Overall, albendazole has been demonstrated to be a useful advance in the management of cystic echinococcosis when used as sole treatment or as an adjunct to surgery or other treatments.
Praziquantel has recently been suggested, administered additionally once per week in a dose of 40 mg/kg during treatment with albendazole. However, available data are limited.[32]
A 2013 case report described a patient with sternal CE that was successfully treated with radiation therapy after multiple surgical procedures and medical treatment had failed.[33] However, a recent editorial on the subject concluded that “in light of existing data, radiotherapy cannot be advocated as an alternative to surgery in osseous echinococcosis where complete excision of the affected bone is possible, and thus potentially curative. In fact, radiotherapy has to be regarded as contraindicated in such cases.”[34]
Surgery was the only treatment available before the introduction of anthelmintic drugs. It is considered the first choice of treatment for echinococcosis but is associated with considerable mortality (up to 2% in some series, increasing with second and further operations), morbidity,[35] and recurrence rates (2-25%). Given the more frequent detection of early and asymptomatic E granulosus liver lesions, a widened indication for chemotherapy exists.
Several procedures have been described for the treatment of hepatic echinococcal cysts, ranging from simple puncture to liver resection and transplantation, although the most commonly used technique is total or partial cystopericystectomy.
Usually, radical surgery (total pericystectomy or partial hepatectomy) is indicated for liver cysts. Conservative surgery (open endocystectomy with or without omentoplasty) or palliative surgery (simple tube drainage of infected cysts or communicating cysts) is also an option. More radical interventions have higher intraoperative risks but less numerous relapses. With the inclusion of chemotherapy prior to or after surgery, less-aggressive surgery may be possible.
Surgery for pulmonary cysts includes extrusion of cysts using Barrett technique (intact endocystectomy without preliminary aspiration), pericystectomy, and lobectomy.[36]
Peripheral and unilobar echinococcal cysts, regardless of how complicated they are, can also be treated with laparoscopic surgery using partial cystopericystectomy and drainage. When surgery cannot be avoided, presurgical use of albendazole reduces risk of recurrence and facilitates surgery by reducing intracystic pressure.
Surgery is the treatment of choice for spinal echinococcosis, with decompression of a compromised spinal cord and stabilization of a compromised spinal column being the two primary tasks. However, the existing data on follow-up of spinal CE cases is largely insufficient to judge the long-term outcome of surgery.[37]
Minimally invasive treatment is discussed below.
The puncture of echinococcal cysts has long been discouraged because of risks of anaphylactic shock and spillage of the fluid; however, as experience with ultrasonography-guided interventional techniques has increased since the early 1980s, an increasing number of articles have reported its effectiveness and safety in treating abdominal, especially liver, echinococcal cysts. A recent systematic review of the literature found that the overall fatality rate due to lethal anaphylaxis from puncture of echinococcal cysts is 0.03% (2 in 5943 procedures) for procedures and 0.04% (2 in 5517 cysts) for cysts, respectively.[14]
One study of 446 patients who were treated surgically for cystic echinococcosis (CE) found an increased incidence in anaphylatic shock in younger patients (P< 0.001) and in patients with pulmonary cysts. The authors suggest taking precautions such as reducing intracystic pressure, preventing antigen from contacting other tissues where it might trigger anaphylaxis, and resecting the cyst completely when feasible.[38]
Under albendazole coverage, cysts are punctured under ultrasonographic or CT guidance either with a needle or with a catheter according to their size. The presence of an anesthesiologist who intervenes in case of allergic manifestations or anaphylactic shock is mandatory. Usually, a small quantity of fluid is first aspirated and examined by light microscope to observe for the presence of viable protoscolices. If they are present, the cyst is aspirated completely.
At this point, exclude possible connections of the cyst with the biliary tree by means of injection of contrast medium in the cavity. If no connections are evident, a scolecoidal agent, usually hypertonic sodium chloride solution or ethanol, is injected and left for a variable period (usually 5-30 min) and then reaspirated. The destruction of protoscolices can be observed in fluid sample aspirated after the injection of a scolecoidal agent. This sequence is termed PAIR (puncture, aspiration, injection, reaspiration). As happens with drug therapy, positive responses include both a decrease in cyst size and a progressive change in echo pattern (generally solidification).[39, 40, 41]
From a diagnostic standpoint, PAIR is the only method that helps provide a direct diagnosis of the parasitic nature of the cysts. Neither imaging modalities nor serology is sufficient to exclude the diagnosis. PAIR is also an effective alternative to chemotherapy alone because it has a higher efficacy and avoids the problem of drug resistance. It also shortens the time of treatment and final recovery. PAIR is a valuable alternative to surgery in terms of cost containment and hospitalization time.[42, 43, 44, 45, 46, 47] In types I and II (Gharbi classification), CE1 and CE3a (WHO-IWGE classification) echinococcal cysts with no or incomplete response to therapy, PAIR is an effective therapeutic tool in the management of human cystic echinococcosis.
Increasing evidence shows that CE2 cysts (multivesiculated, type I in Gharbi classification) and CE3b (predominantly solid with daughter vesicles)[13] tend to relapse after PAIR,[48] so other percutaneous treatments should be adopted, if indicated, for this type of cyst.
Reserve PAIR for use in highly specialized centers where teams are well prepared to deal with possible complications.
Some authors have treated CE2 and CE3b cysts with large-bore catheters, but studies on larger cohorts of patients are needed to conclude that this method is efficacious.[49, 50]
A 2017 retrospective study showed that percutaneous aspiration without injection of scolicidal agents but in combination with long-term albendazole administration is probably as effective as, simpler than, and safer than percutaneous treatments with injection of scolicidal agents.[51]
Consult a surgeon to discuss the opportunity of surgical intervention.
Consult a radiologist for injection of contrast medium in the cyst after fluid aspiration if PAIR is scheduled. Contrast injection in the cyst allows the physician to exclude connections of the cyst with the biliary tree. Contact of scolecoidal agents, such as alcohol and hypertonic sodium chloride solution, with the biliary epithelium may lead to cholangitis. Attempts to inject albendazole directly into the cysts have yielded interesting results in animal studies but are still methodologically weak in human studies. Most recently, a glucose solution as a scolecoidal agent has been used with good results in vitro.[52] Studies in vivo should confirm the safety of this approach before it can be applied to humans.
Consult an anesthesiologist for assistance in case of anaphylactic shock or anaphylactoid reactions if PAIR is scheduled.
In endemic areas, distribution of educational material in elementary schools regarding modes of transmission of the disease is helpful to increase knowledge about the nature and transmissibility of cystic echinococcosis.
Educational material should include information about proper disposal of sheep viscera in abattoirs and proximity to dogs and sources of transmission.
During treatment of patients discharged on benzimidazoles, monitor aminotransferases, WBC, RBC, and hemoglobin monthly.
Evaluate patients for ultrasonographic appearance modifications and changes in serology titers after 3 months of treatment and then for several years (at least 5).
Reevaluate patients for symptom resolution and determination of cure.
Albendazole and mebendazole are the only anthelmintics effective against cystic echinococcosis. Albendazole is the drug of choice against this disease because its degree of systemic absorption and penetration into hydatid cysts is superior to that of mebendazole. Albendazole in combination with percutaneous aspiration or PAIR therapy can lead to a reduction in cyst size, and, in one study, it improved efficacy over albendazole alone against hepatic hydatid cysts.[42] When surgery cannot be avoided, presurgical use of albendazole in echinococcus infestations reduced risk of recurrence and/or facilitated surgery by reducing intracystic pressure.
Treatment of echinococcosis for patients weighing more than 60 kg is albendazole administered PO with meals in a dose of 400 mg twice daily for 28 days. A dose of 15 mg/kg of body weight daily in 2 divided doses (not to exceed total daily dose of 800 mg) has been suggested for patients weighing less than 60 kg. For cystic echinococcosis, the 28-day course may be repeated after 14 days without treatment to a total of 3 treatment cycles.
Clinical Context: Decreases ATP production in worm, causing energy depletion, immobilization, and, finally, death. To avoid inflammatory response in CNS, patient must also take anticonvulsants and high-dose glucocorticoids.
Clinical Context: Causes worm death by selectively and irreversibly blocking uptake of glucose and other nutrients in susceptible adult intestine where helminths dwell.
Parasite biochemical pathways are sufficiently different from the human host to allow selective interference by chemotherapeutic agents in relatively small doses.