Pathophysiology

• There are 4 known species of Echinococcus but only 3 are of medical importance to humans:
  • Echinococcus granulosus, causing cystic echinococcosis (CE) - the most common of the three
  • Echinococcus multilocularis, causing alveolar echinococcosis (AE) - rare but it is the most virulent
  • Echinococcus vogeli, causing polycystic echinococcosis - very rare
• The life cycle of the Echinococcus helps to explain how the disease is transmitted and develops:^[4],
  • The Echinoccoccus adult tapeworms are about 5 mm long and live in the small intestines of dogs (and other canid species such as coyotes, wolves and foxes)
  • The cyst stages occur in intermediate hosts, typically sheep (but also cattle, horses, camels, pigs and goats, to name a few)
  • Tapeworm eggs are passed in the faeces of infected dogs and then are ingested by grazing sheep. These eggs hatch into embryos in the intestine and then penetrate the intestine to be carried by the blood to major organs such as the liver and lungs. This larval stage of the parasite is called an oncosphere
  • The larval stage spreads via the bloodstream to target organs in other parts of the body (liver, lungs, brain, and muscles, for example) where they develop by expansion into a hydatid or echinococcal cyst (called a metacestode)
  • Within the larval echinococcal cysts, protosolices (multiple tiny tapeworm heads) are produced by asexual reproduction
  • To complete the cycle these are then ingested by dogs feeding on the viscera of the infected intermediate host and, about 6 weeks later, adult egg-producing tapeworms develop in the dog intestines
  The practice of feeding the viscera of slaughtered animals to dogs in endemic countries is responsible for the high incidence and spread of infection. Humans are effectively intermediate hosts and become infected by handling infected dogs (or other carnivore hosts).
  
  
• Hydatid disease or echinococcosis can be either primary (spread by ingestion) or secondary (larval tissue proliferates after spread from the primary site - usually from trauma). In primary echinococcosis larval cysts develop in a single organ in most cases (about 80% of cases). About 70% of cases involve the liver.The cysts have a wall made from both host tissue (pericyst) and larval origin (endocyst) The cysts are fluid-filled and grow very slowly (about 1 cm in diameter every year). Clinical features are varied and depend on:
  • The size of cysts
  • The organs involved
  • Complications caused by, for example, the effects on structures adjacent to and within the organs, rupturing of cysts, infection and immunological reactions (asthma, membranous nephropathy, anaphylactic reactions)

Epidemiology

It is found in sheep-farming areas, mainly in developing countries. There are endemic areas in every continent, ranging from South America, Africa, parts of Europe (notably Greece and Turkey), Australasia, Russia, China and the Middle East.

• E. multilocularis occurs in the northern hemisphere, including central Europe and the northern parts of Europe, Asia, and North America. E. vogeli and E. oligarthrus occur in Central and South America.^[4]
• E. granulosus, which causes cystic echinococcosis (CE), is the only species of the tapeworm found in the UK.
  • In the UK there are well-documented 'hotspots' of infection in Wales and the Western Isles of Scotland.
  • Approximately 10-20 human cases are reported in the UK each year (most have arisen following exposure abroad).
  • Current evidence suggests that the main areas for hydatid disease in Wales are Powys, Monmouthshire and farms on the southern slopes of the Brecon Beacons and the Black Mountains. A pocket of disease is also present in the part of South Herefordshire adjacent to South Powys.

Risk factors

It is very important that the risk, particularly in endemic areas, be properly understood and appropriate measures taken. Risk factors include:

• Feeding dogs with raw offal.
• Allowing dogs to roam.
• Poor hygiene (both animal and personal).
• Regular close contact with dogs.

Presentation

The cysts of E. granulosus may take many years to produce clinical symptoms. In the UK E. granulosus only is found and this leads to cystic echinococcosis (CE) and not the complications of alveolar echinococcosis.
In theory, echinococcosis can involve any organ. However, in practice, the liver is the most common organ affected, followed by the lungs. These account for 90% of cases.

Cystic echinococcosis

• Symptoms can be produced by mass effect or complications of the cyst.
• Pressure symptoms can take a long time to become evident, except when they involve the brain or eyes. Most cysts causing symptoms are larger than 5 cm in diameter. Symptoms can include vague pains, cough, low-grade pyrexia and abdominal fullness. Later, as the mass presses on surrounding organs, symptoms become more specific.
• In the liver, symptoms of obstructive jaundice and abdominal pain can develop. Pressure of the cyst on the biliary tract can cause biliary colic, jaundice, and urticaria. Vomiting of hydatid membranes (hydatid emesia) and passage of membranes in the stools (hydatid enterica) occur rarely.
• Involvement of the lungs may result in chronic cough, dyspnoea, pleuritic chest pain or haemoptysis. Expectoration of cyst membranes and fluid may be observed with intrabronchial rupture.
• Secondary complications may occur as a result of infection of the cyst or leakage of the cyst. Minor leaks can cause increased pain, flushing and urticaria. Major rupture can result in severe anaphylactic reaction, which may be fatal if not treated quickly. Rupture into the biliary tree can lead to obstruction by daughter cysts, resulting in cholangitis. Rupture into bronchi can cause expectoration of cyst fluid.
• Infection of the cyst results in a range of symptoms from mild fever to full-blown sepsis.

Alveolar echinococcosis

• The liver is the primary site of infection, and the symptoms may closely mimic those of cirrhosis or carcinoma.
• The clinical picture is one of progressive liver dysfunction leading to liver failure. This can occur over weeks, months or years.
• Distant metastases are possible, and involvement of other organs (for example, in the lung, brain, and bone) can occur in as many as 13% of the patients.
• Disease in the liver produces hepatomegaly, occasionally obstructive jaundice, mild upper gastrointestinal symptoms.
• Disease in the lung causes cough, haemoptysis, dyspnoea and pyrexia.
• Disease in the brain causes raised intracranial pressure and can cause epilepsy.
• Disease in the vertebrae can lead to compression of the spinal cord, causing paraplegia. In the long bones it may cause fractures and deformity.

Differential diagnosis

• Liver abscess.
• Pyonephrosis.
• Epidermoid cyst.
• Simple cysts.
• Neoplasia.

Investigations

Diagnosis is made by a combination of clinical, imaging, serological and molecular techniques. For example:

• Ultrasound for abdominal cysts with fine-needle aspiration.^[5]
• Chest X-ray or CT scan for those in the lung.
• Serological diagnosis is, unusually for parasitic infections, the basis for laboratory diagnosis. Western blot assay for antigens is highly specific. Indirect haemagglutination tests and enzyme-linked immunosorbent assays are widely used. However:
  • Serological diagnosis can be difficult from brain and eye cyst fluid samples
  • Young children produce minimal serological reactions
  • No standard sensitive and specific test exists for cystic echinococcus (CE) antibody detection

Management

In general, human disease is treated by surgical removal of the cyst with supplementary chemotherapy (mebendazole or albendazole). Surgical removal may not prevent other cysts growing and causing further problems.

• Treatment differs for cystic echinococcosis (CE) and alveolar echinococcosis (AE).
• Surgery remains the mainstay of treatment. Less invasive methods and combinations with chemotherapy are being developed.
• In CE, risks vs benefits, indications, and contra-indications for each individual must be considered before deciding on type and timing of surgery.
• In AE, more radical surgical excision is coupled with chemotherapy in operable cases but, if the cyst can only be partially resected, or is inoperable, long-term aggressive chemotherapy is employed.

Cystic echinococcosis

Chemotherapy^[6][7]

• This is indicated as an adjunct to surgery in patients with inoperable lung or liver cysts (due to the site of cysts or patients being too ill for surgery), for patients with cysts in two or more organs, and for peritoneal cysts.
• Two drugs are available, both from the benzimidazole group, albendazole and mebendazole.
  • Albendazole appears to have better absorption and better clinical results than mebendazole. It is taken together with a fat-containing meal twice-daily (manufacturer's recommendation, 10-15 mg/kg/day). The drug is licensed for cyclical treatment only (ie 28 days of treatment followed by 14 days of interruption), but trials using continuous long-term treatment do not show any adverse effects
  • Mebendazole is taken with a fat-containing meal three times daily (recommended daily dosage 40-50 mg/kg/day). If used alone, chemotherapy is usually required for months or years
• Contra-indications:
  • Early pregnancy
  • Bone marrow suppression
  • Chronic hepatic disease
  • Large cysts with the risk of rupture
  • Inactive or calcified cysts
  • A relative contra-indication is bone cysts because of the significantly decreased response
• Most frequent adverse effects of benzimadoles:
  • Gastrointestinal disturbances
  • Reversible alopecia
  • Elevation of serum transaminases
  • Proteinuria
  • Neurological symptoms
  • Neutropenia
• Significant interactions:
  • Carbamazepine (may decrease efficacy)
  • Dexamethasone and cimetidine (may increase toxicity)
• Monitoring:
  • Full blood count and liver function tests should be performed every 2 weeks
  • The patient should be advised to report adverse effects
  • Drug level monitoring is ideal, but few laboratories provide this service
  • Imaging of the cyst is required to follow up morphological resolution
• Newer drugs such as praziquantel are being evaluated. Trials suggest that a combination of praziquantel with albendazole is more effective than albendazole alone.
• Outcome - one study of 1,000 patients showed 30% cure rate (as measured by disappearance of cyst), 3-50% had decrease in size of cyst, and 20-40% had no change. The younger the patient, the better the outcome.

Interventional procedures^[6][8][9]

P uncture, A spiration, I njection, R e-aspiration (PAIR) is an effective and safe treatment.

• Indications:
  • Cysts not suitable for conventional surgery
  • Multiple cysts in segments I, II, and III of the liver (as described in the Couinaud liver classification)^[10]
  • Cysts should be larger than 5 cm in diameter and either Gharbi type I or II, or type III if not a honeycomb cyst
  • Gharbi classification:
    • Type I - purely cystic
    • Type II- purely cystic plus hydatid sand
    • Type III - membrane undulating in the cystic cavity
    • Type IV - peripheral or diffuse distribution of coarse echoes in a complex and heterogeneous mass
  • Patients refusing conventional surgery
  • Relapse after surgery or chemotherapy
• Aspiration and re-aspiration are repeated until the aspirate is clear, and the cyst is then filled with isotonic sodium chloride.
• Cover with a benzimidazole is imperative (4 days prior to, and 1-3 months after, the procedure).
• The technique can be performed on liver, bone, and kidney cysts but should not be performed on lung and brain cysts.
• Transhepatic puncture is recommended for superficially located cysts.
• Contra-indications:
  • Early pregnancy
  • Lung cysts
  • Inaccessible cysts
  • Superficially located cysts (risk of spillage)
  • Type II honeycomb cysts
  • Type IV cysts, and cysts communicating with the biliary tree (risk of sclerosing cholangitis from the scolecidal agent)
• Complications
  • Spillage of cyst contents
  • Anaphylactic reactions
  • Sclerosing cholangitis (chemical)
  • Biliary fistulas
• Outcome:
  • One meta-analysis demonstrated greater clinical and parasitological efficacy in patients treated with PAIR plus chemotherapy than those undergoing radical surgery such as cystectomy or partial organ resection
  • The PAIR group also had lower rates of morbidity, mortality, disease recurrence, and shorter hospital stays

Conventional surgery

• Indications:
  • Large liver cysts with numerous daughter cysts
  • Liver cysts with communication to biliary tree or pressing on surrounding structures
  • Superficially located single liver cysts
  • Likely to rupture infected cysts
  • Cysts in the lungs, brain, kidneys, eyes, and bones
• Contra-indications:
  • Pregnancy
  • Medically unsuitable for surgery
  • Multiple cysts in multiple organs
  • Inaccessible cysts
  • Cysts that are inactive, calcified or very small
• Choice of technique - must be individualised for each patient. Options include:
  • Radical surgery (total pericystectomy or partial affected organ resection, if possible)
  • Conservative surgery (open cystectomy)
  • Simple tube drainage for infected and communicating cysts
• The more radical the procedure, the lower the risk of relapses but the higher the risk of complications.
• Basic steps:
  • Protection of surrounding tissue with cetrimide-soaked pads
  • Suction evacuation of the cyst
  • Sterilisation of the cyst cavity by injection of a scolecidal agent
  • Avoiding spillage which might cause seeding and secondary infestation
  • Hepatic cysts: evidence sought for bile duct communication - if present, it should be sutured
• Concomitant treatment with benzimidazoles reduces risk of secondary echinococcosis (start 4 days preoperatively, and continue for one month).

Alveolar echinococcosis

Chemotherapy^[6][7][11]

• Treatment with benzimadoles is indicated for:
  • 2 years perioperatively for patients considered for radical resection in order to combat undetected infected tissue
  • Long-term therapy (3-10 years) for patients who have partial resection
  • Inoperable conditions
  • Liver transplants
• Contra-indications - if chemotherapy is the only available option, the risks outweigh the benefits for all but early pregnancy and severe leukopenia.
• Drug choices and monitoring are as for cystic echinococcosis (CE), but the duration of treatment is different (see above).
• Outcome - a significant increase in 10-year survival rates exists in patients receiving chemotherapy compared with patients who are not (85-90% vs 10%, respectively).

Interventional procedures^[6][8][9]

Minimally Invasive

• Indications: this is useful when radical resective surgery is not possible, for example:
  • Hyperbilirubinaemia
  • Vena cava thrombosis
  • Portal vein thrombosis
  • Necrotic collections
  • Bleeding oesophageal varices
• Examples of minimally invasive procedures done under ultrasound or CT guidance include:
  • Dilatation
  • Stenting
  • Drainage
  • Sclerosis of oesophageal varices
• Contra-indicated if postinterventional chemotherapy is not possible, as the risk of spreading the parasite is high.

Conventional surgery

• Indications - resectable liver lesion as assessed by imaging.
• Contra-indications - inoperable lesions, extensive lesions, lesions involving other organs.
• Options:
  • The only curative procedure is radical surgery with complete excision of the lesion
  • Total hepatectomy with transplantation is warranted in some cases if no extra hepatic disease is present
• Re-emergence of the parasite in the transplanted liver, and distant metastasis, may occur under immunosuppression.
• Partial resections of unresectable masses decrease the parasite load and may aid chemotherapy.

Prevention

The infected organs of animals must be condemned and destroyed. However, there are no specific signs of hydatid disease in farm animals. Hydatid infection in food animals is, in nearly all cases, confined to the lungs and the liver. A summary of preventative measures is outlined in the box below.