Cystic Echinococcosis

Rogelio López-Vélez MD, DTM&H, PhD National Referral Unit for Tropical Diseases Infectious Diseases Department ESCMIDRamón y Cajal University eLibraryHospital. Madrid. Spain © by author National Referral Unit for Tropical Diseases. Infectious Diseases

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ESCMID eLibrary © by author Echinococcosis (Echinococcus spp.)

Echinococcosis Helminth, Cestod (tapeworm), genus Echinococcus – E. granulosus: Cystic Echinococcosis (CE) – E. multilocularis: Alveolar Echinococcosis (AE) – E. vogeli; E. oligarthus: Policystic Echinococcosis (PCE) – E. felidis, E. shiquicus

Cystic Echinococcosis (CE) – E.granulosus s.l. consists of five geno-species: • E. granulosus s.s. (G1,G2,G3) • E.equinus (G4) • E.ortleppi (G5) • E.canadensis (G6,G7,G8,G10) •ESCMIDE.felidis eLibrary © by author Cystic echinococcosis: Epidemiology

• CE is globally distributed and found in every continent except Antarctica. • More than 1 million people are affected with echinococcosis at any one time • In endemic regions, human incidence rates for CE can reach >50/100 000 person-years, and prevalence levels as high as 5%–10% may occur in parts of Argentina, Chile, Uruguay, Peru, East Africa, Central Asia, Western China and Mediterranean region • In slaughtered animals in some areas of South America varies from 20%–95%

• NTD, chronic and complex disease • Is associated with poor hygiene in areas contiguous to sheep farming and dogs. • Childhood acquisition is usual; ESCMID eLibraryhowever, clinical disease may become manifest only after many years. © by author Echinococcosis: Epidemiology in EU

≈800 cases/year Rate: 0.2/100.000 ESCMID eLibrary © by author LIFE CYCLE of Echinococcus granulosus

Dog/canid is the definitive hosts (the adult form lives in the small bowel)

The eggs can remain infective for months

Human-to-human transmission does not occur

Sheep, goat, swine, cattle, horses, camel… is the intermediate host (the larval The liver and lungs are form/cyst or metacestode primarily affected, but any lives in the tissues (mainly organ can be infected liver, lungs…any viscera)

The adult E granulosus (3-6 mm long) resides in the small bowel of the definitive hosts, dogs or other canids. Gravid proglottids release eggs thatESCMIDare passed in the feces. After ingestion by a suitable intermediateeLibraryhost (sheep, goat, swine, cattle, horses , camel), the egg hatches in the small bowel and releases an oncosphere that penetrates the intestinal wall and migrates through the circulatory system into various organs, especially the liver and lungs. In these organs, the oncosphere develops into a cyst that enlarges gradually, producing protoscolices and daughter cysts that fill the cyst interior. The definitive host becomes infected by ingesting the cyst-containing organs of the infected intermediate host. After ingestion , the protoscolices evaginate ©, attach to thebyintestinal mucosa, authorand develop into adult stages in 32 to 80 days. Hydatid cyst morphology

Cysts (with the exception of bone) are composed of

-PERICYST (host reactive tissue) -ENDOCYST (larva) -outer, acellular laminated layer -inner, germinal layer that gives rise to brood capsules >> protoscolices = pre adult -free daughter cysts (+/- laminar layer) in some stages -hydatid fluid, clear -hydatid sand with abundant free-ﬂoating hooklets (when are degenerating)

ESCMID eLibrary © by author PATHOLOGY of Echinococcus granulosus

• After ingestion of the eggs, the oncosphere hatches, penetrates the intestinal mucosa, and migrates through the bloodstream to internal organs (liver, lung, etc.) where a the cyst grows. The minimum time for development of protoscolices is ≈1 year.

• Each protoscolex is capable of generate into a new cyst (secondary echinococcosis) if the cystic ﬂuid is spilled in a cavity such as the peritoneum

• The growth rate per year of the cyst is variable: 50%= 6-15 mm, 30%= 1-5 mm, 15%= no growth. Cysts range in size from few centimetres up to many litres (size can be related to the genotype)

• The majority of CE cases historically were attributed to G1. However, recent molecular studies of CE cases have revealed that G1 genotype is responsible for ~ 75% of human cases. Natural evolution: ACTIVE > INACTIVE ESCMID eLibrary © by author E.granulosus s.l. geno-species distribution

May have different clinical manifestations, pathogenesis ESCMIDand drug sensitivity: G8 is predominantly pulmonary, eLibrary grows slowly and few complications © by author Cystic echinococcosis: CLINICAL SYMPTOMS

• Incubation period is highly variable (up to >10 years) • Clinical presentation depends of the organ involved, the location inside the organ, the surrounding structures, the size and integrity of the cyst • It is not uncommon to be discovered incidentally • Usually asymptomatic unless complications

LOCATION • Single cyst in a single organ 40-80%. Also multiple sites • Liver (right lobe) 70% – abdominal pain, nausea and vomiting • Lung 20% (lower lobes) – chronic cough, chest pain and shortness of breath • Other ESCMIDviscera 10% eLibrary – bones, kidneys, spleen, muscles, heart, mediastinum, brain, eyes… © by author DIAGNOSIS of Cystic Echinococcosis: imaging

• Classification is based on ultrasonography on liver cysts but can be applied to any organ

• MRI>>CT: T2-sequences best detect liquid content, but miss wall calcifications

• CLASIFICATION – Active: CE1, CE2 [CE3b] – Transitional: CE3a, CE3b. – Inactive: CE4, CE5

• Long-term follow-up with imaging is required to evaluate the efﬁcacy ofESCMIDtreatment (recommended for eLibrary5 years) © by author Sonographic features of CE cysts WHO-IWGE, 2003. International classification of ultrasound images in cystic echinococcosis for application in clinical and field epidemiological settings. Acta Trop 85: 253–261

• Double wall of the cyst, especially evident in fluid-filled CE1 cysts. • “Water lily sign” of CE3a cysts, which reflects the detached endocyst fluctuating in the cyst fluid content. • “Honeycomb appearance” of multivesiculated cysts (CE2 and CE3b), in which the impression of “septa” is formed by the adjacent walls of daughter vesicles (CE2) or in which daughter vesicles have formed in pseudo- solid, hyperechoic, and nonhomogeneous cyst content (CE3b). • The “ball-of-wool” sign of CE4 cysts, characterized by the appearance of hypoechoic, degenerating cyst membranes ESCMIDfolded inside pseudo-solid cyst content eLibrary. • The wall calcification of cysts with pseudo-solid content (CE5). © by author ESCMID eLibrary © by author DIAGNOSIS of Cystic Echinococcosis: serology

• Limited sensitivity (depend on the integrity of the wall and the stage of the cyst: false negative in early and late cysts) • liver: 80-90% • lung: 60-85% • tests with recombinant antigens > sensitivity

• Xreactions: cysticercosis, fascioliasis, filariasis…

• Sequential testing: 1st test (IHA, ELISA: Eg hydatid fluid antigen) followed by immunoblot with specific IgG subclases (Immunoblotting: 8KDa/12KDa subunits Eg antigen B)

• There is no test of cure, as serology results may remain positive for years even after successful treatment ESCMID. eLibrary © by author DIAGNOSIS of Cystic Echinococcosis: cytology

• Biopsies and punctures may also be performed for differential diagnosis of cysts from tumours and abscesses – acellular laminated layer – germinal layer Activity of the cysts is measured by: -integrity and motility of protoscolices – protoescolices -intact architecture of the germinal layer – free hooklets

ESCMID eLibrary © by author CE in the liver: giant cysts

ESCMID eLibrary © by author CE in the liver: multiple cysts

ESCMID eLibrary © by authorDr. Carmen-Michaela Cretu CE in the liver: rupture into the biliary tree

ESCMID eLibrary © by author CE in the liver: haemorrhage

ESCMID eLibrary © by author CE in the liver: transdiafragmatic fistula

ESCMID eLibrary © by author CE in the liver and in the lung

ESCMID eLibrary © by author CE in the lungs

ESCMID eLibrary © by authorDr. Carmen-Michaela Cretu Giant CE in the lung

ESCMID eLibrary © by author CE in the lungs: rupture to pleural space

ESCMID eLibrary © by author CE in the lungs: lung abscess

ESCMID eLibrary © by author Concomittant CE + TB

ESCMID eLibrary © by author CE in the spleen

ESCMID eLibrary © by author CE in the kidneys

ESCMID eLibrary © by author CE in the psoas

ESCMID eLibrary © by author Dissemniated CE: lungs + liver + peritoneal cavity

ESCMID eLibrary © by author CE in the spine

ESCMID eLibrary CMA © by author CE in the spine

ESCMID eLibrary © by author CE in the spine: overinfected

ESCMID eLibrary © by author ESCMID eLibrary © by author CE in the pelvic gride

ESCMID eLibrary © by author CE in the pelvic gride

ESCMID eLibrary © by author CE in the shoulder

ESCMID eLibrary © by author CE in the thoracic wall

ESCMID eLibrary © by author CE in the leg muscles

ESCMID eLibrary © by author Cardiac and endovascular CE

ESCMID eLibrary © by author Pulmonary embolisms

Liver

Cava vein ESCMID eLibraryR auricula © by author Cardiac and endovascular CE

ESCMID eLibrary © by author endovascular CE: portal vein thrombosis

ESCMID eLibrary © by author CE in the brain

ESCMID eLibraryNeurol Med Chir (Tokyo). 2006 Aug;46(8):415 -7. © by author Cystic echinococcosis: TREATMENT

There are 4 options for the treatment

1. Anti-infective drug treatment (albendazole) 2. Percutaneous puncture (PAIR) Percutaneous Puncture, Aspiration, Injection and Re-aspiration (PEVAC) Percutaneous Puncture large-bore needle and EVACuation

3. Surgery: Partial / total cystectomy 4. “Watch and wait”

The choice must primarily be based on the ultrasound images of the cyst, following a stage-specific approach, presence of complications and also on the medical infrastructureESCMIDand human resources availableeLibrary. © by author Cystic echinococcosis: Albendazole treatment (1)

• Benzimidazole family

• Dose: 10–15 mg/kg/day divided into 2 doses

• Take with fat-rich-meal (absorption increases 2-5 fold due to high lipid solubility)

• Entirely metabolized in the liver to albendazole sulfoxide

• Peak serum level at 2-5 hours; elimination half-life is 8-12 hours

• The overall efficacy of benzimidazoles has been overstated in the past.

• Works better in small (<6 cm) young active cysts: CE1, CE2 overall efficacy of 40-60%

• CE3b cysts respond initially (convert to CE4) but frequently relapse after treatment • Repeated ESCMIDcourses can be given eLibrary © by author Cystic echinococcosis: Albendazole treatment (2)

• Length of treatment: 3-6 months, but In some cases with extensive/bone disease indefinite

• The process of cyst involution continues up to one year after termination of treatment

• Failure after initial response observed up to one year after termination of treatment

• For prevention of secondary CE after intervention: start 4 h before and up to 1 month after

• Praziquantel can be associated to prevent secondary CE based on its protoscolicidal activity

• The efficacy of adjunct nitazoxanide treatment remains to be defined

• Do not give when cysts are at risk of rupture (albendazole soften the pericystic tissue)

• Do not give in pregnancy

• Toxicity: >>liver enzymes (stop when go above 4 times NV); rare bone marrow suppression • Follow ESCMIDup for a minimum of 5 years after eLibrarytreatment © by author Cystic echinococcosis Benznidazole treatment

CE2 ESCMID membrane detachment after albendazole eLibrarytreatment © by author Cystic echinococcosis Benznidazole treatment

CE2 large cyst relapse after albendazole treatment ESCMID eLibrary © by author Cystic echinococcosis: PERCUTANEOUS TREATMENT

(PAIR) percutaneous Puncture, Aspiration, Injection and Re-aspiration • Indicated for CE1, CE3a cysts of 5 to <10 cm • Albendazole (4 h before until 1 month after). • Puncture under US guidance. Aspiration (only hydatid fluid is removed). Cysto-biliary fistulas must be excluded (aspect of the fluid, test-strip for bilirrubine, injection of contrast). Aspiration of the contrast. Injection of 20% NaCl. Wait for 15-20 min. Reaspiration. • Follow-up for 5 years

(PEVAC) Percutaneous Puncture large-bore needle and EVACuation • Indicated for CE2, CE3b cysts • Albendazole • Cysto-biliary fistulas must be excluded ESCMID eLibrary © by author Cystic echinococcosis PEVAC treatment

– 20% hypertonic saline – alcohol 96% and polidocanol 1% – povidone iodine – ethacrine lactate (rivanol) – hydrogen peroxide – silver nitrate – cetrimideESCMID eLibrary – formalin © by author Cystic echinococcosis: surgery

Risk of complications ≤5-6 cm >5-6 cm <10 cm ≥10 cm

CE1

CE3a

CE2

CE3b

Benzimidazoles (possibly higher efficacy) Benzimidazoles (possibly lower efficacy) CE4 PAIR Surgery / (continuous catheter drainage [CE1, CE3a], large-bore catheter [CE3a, CE3b, CE2 ]) Stojkovic, Gottstein, Junghanss CE5 Watch & wait in: Manson‘s TropicalESCMID Diseases eLibrary 2014 © by author TREATMENT OF COMPLICATED Cystic Echinococcosis

• Fistulas – Cysto-biliary fistula: endoscopic retrograde cholangiopancreatography (ERCP) + ALBZ – Cysto-bronchial fistula: surgery + ALBZ + antibiotics • Bacterial infections – Abscess: (blood-borne or retrograde via fistulas): drainage + antibiotics, followed by ALBZ (infection can sterilize the cyst) • Compression – Surgery • Rupture – Allergic reaction/anaphylactic shock: specific treatment . – Prevention of secondary CE: ALBZ +/- PZQ followed by surgery • Embolism – ALBZ +/- PZQ + surgery • Rare locations – Bone: ALBZ for life time? – ESCMIDCardiac and endovascular (cava vein): surgery,eLibrarydo not give ALBZ (may precipitate rupture) © by author Cystic echinococcosis in the cava vein: surgery

• Regular dog deworming with praziquantel

• Controlled slaughtering with meat inspection and appropriate disposal of infected organs (do not feed dogs with infected viscera)

• Vaccination of sheep with an E. granulosus recombinant antigen (EG95)

• Early detection of human cases (active screening campaigns with US)