**PNM system for classification of human alveolar echinococcosis**

#### **Classification of findings**

#### **P: Hepatic localisation of the parasite**

PX: Primary lesion cannot be assessed

P0: No detectable lesion in the liver

P1: Peripheral lesions without proximal vascular and/or biliar involvement

P2: Central lesions with proximal vascular and/or biliar involvement of one lobe (a)

P3: Central lesions with hilar vascular and biliar involvement of both lobes and/or with involvement of two hepatic veins

P4: Any liver lesion with extension along the vessels (b) and the biliary tree

### **N: Extrahepatic involvement of neighbouring organs**

Diaphragm, lung, pleura, pericardium, heart, gastric and duodenal wall, adrenal glands, peritoneum, retroperitoneum, parietal wall (muscles, skin, bone), pancreas, regional lymph nodes, liver ligaments, kidney

NX: Not evaluable

N0: No regional involvement (see above)

N1: Regional involvement of contiguous organs or tissues

### **M: Absence or presence of distant metastases**

Lung, distant lymph nodes, spleen, CNS, orbital, bone, skin, muscle, distant peritoneum and retroperitoneum]

MX: Not completely evaluated

M0: No metastasis(c)

M1: Metastasis

312 Current Topics in Tropical Medicine

with the potential to induce serious disease with a high fatality rate. Metacestodes develop primarily almost exclusively in the liver varying from small foci of a few millimetres in size to large areas of infiltration (15-20 cm.). From the liver, the metacestode tends to spread to both the adjacent and distant organs by infiltration or metastasis formation (Eckert, 1998). Cases of AE are characterized by an initial asymptomatic incubation period of 5-15 years duration and a subsequent chronic course. Fatality rate in untreated or inadequately treated

High burden of AE is known to be common in certain rural communities in China whilst it is generally rare and sporadic elsewhere. Recently, a study was carried out to estimate the global incidence of this disease by country (Torgerson, 2010). They undertook a detailed review of published literature and data from other sources suggesting that there are approximately 18,235 (CI 11,900–28,200) new cases of AE per annum globally with 16,629 (91%) occurring in China and 1,606 outside China. Most of these cases are in regions where there is little treatment available and therefore will be fatal cases. They were able to calculate

Age at the time of diagnosis of AE is significantly higher than for CE. The primary site of metacestode development is almost exclusively in the liver. The right lobe is predominantly infected, but the liver hilus together with one or two lobes may also be involved. Extra hepatic primarily locations are rare. During the infection, secondary echinococcosis may occur in variety of adjacent or distant organs. Symptoms of AE are primarily cholestatic jaundice (1/3 of cases) and/or epigastric pain (1/3 of the cases). In the remaining third of patients, AE is detected incidentally during medical examination for symptoms such as

that AE results in a median of 666,434 DALYs per annum (CI 331,000-1.3 million).

fatigue, weight loss, hepatomegaly, or abnormal routine laboratory findings.

P1: Peripheral lesions without proximal vascular and/or biliar involvement

P4: Any liver lesion with extension along the vessels (b) and the biliary tree

**N: Extrahepatic involvement of neighbouring organs** 

N1: Regional involvement of contiguous organs or tissues

P2: Central lesions with proximal vascular and/or biliar involvement of one lobe (a)

P3: Central lesions with hilar vascular and biliar involvement of both lobes and/or with

Diaphragm, lung, pleura, pericardium, heart, gastric and duodenal wall, adrenal glands, peritoneum, retroperitoneum, parietal wall (muscles, skin, bone), pancreas, regional lymph

Lung, distant lymph nodes, spleen, CNS, orbital, bone, skin, muscle, distant peritoneum and

**PNM system for classification of human alveolar echinococcosis** 

persons is high.

**2.2.2.1 Clinical presentation of AE** 

**2.2.2.2 Classification and staging of AE** 

**P: Hepatic localisation of the parasite**  PX: Primary lesion cannot be assessed P0: No detectable lesion in the liver

involvement of two hepatic veins

nodes, liver ligaments, kidney

N0: No regional involvement (see above)

**M: Absence or presence of distant metastases** 

NX: Not evaluable

retroperitoneum]

**Classification of findings** 


*Source*: European Network for Concerted Surveillance of AE: PNM system for the classification of human cases of AE.


*Source*: European Network for Concerted Surveillance of Alveolar Echinococcosis: PNM system for the classification of human cases of alveolar echinococcosis.

#### **2.2.2.3 Diagnosis of AE**

Diagnosis of AE is based on similar findings and criteria as in CE.

Hepatic lesions are characterised in US and CT by heterogenous hypodense masses, often associated with necrotic cavities. The lesion contours are irregular and there is lack of a welldefined wall. Calcifications are often found and exhibit a typical pattern in regard to shape and distribution: clusters of microcalcifications or irregular plaque-like calcified foci are located in the central or peripheral parts of the lesions. Discrepancies between US and CT patterns can be found. Hyperechoic haemangioma-like nodules could represent early forms of AE lesions. Quite frequently an extension of the lesions beyond the liver is found toward diaphragm, lungs, pericardium, retroperitoneum, hepatoduodenal ligament and pancreas.

Magnetic resonance imaging is used to observe compression or obstruction of inferior vena cava, the hepatic veins or the portal branches. Pathognomonic aspects are represented by multicystic honeycomb-like images.

#### **2.2.2.4 Laboratory findings of AE**

The routine laboratory tests do not yield specific findings. The blood sedimentation rate is elevated in most of the cases. The numbers of leucocytes and platelets may be depressed in patients with splenomegaly. Lymphopaenia is frequent in advanced cases, and eosinophilia is usually absent. Cholestasis with or without jaundice is observed in patients with intrahepatic bile duct compression or obstruction. Cholangitis and/or liver abscesses, which usually result from bile duct obstruction, are associated with typical alterations of the laboratory parameters. Hypergammaglobulinaemia is present in most of the patients and reflects the specific and polyclonal antibody response. In about one-half of the patients, the presence of specific anti-*E. multilocularis* – IgE can be demonstrated.

Echinococcosis/Hydatidosis 315

There are a variety of options to select the adequate treatment for each individual patient. Clinical experience is crucial for AE; therefore patients should be referred to a recognised national or regional reference centre. Early diagnosis of AE is of special importance for successful treatment because the lesion is acting as a malignant tumour. Screening programmes in Japan and Europe have shown that early diagnosis reduces mortality and morbidity due to AE. Some considerations for treatment of AE are generally accepted: the first choice treatment in all operable cases is radical surgical resection of the entire parasitic lesion from the liver and other affected organs, chemotherapy is indicated after radical surgery for a limited period of time, and long-term chemotherapy is mandatory after incomplete resection of the lesions, in inoperable patients and in AE patients after liver

 Applicable for limited period of time after radical surgery. Since residual parasite tissue may remain undetected at radical surgery, post-operative chemotherapy for at least 2 years should be carried out and patients should be monitored for a minimum of 10

 Long-term chemotherapy for several years is mandatory in inoperable AE patients, in cases following incomplete surgical resection of the parasite lesions and after liver

 Pre-surgical chemotherapy is not indicated in cases of AE. However, in rare cases that surgery was contraindicated at the time of diagnosis of AE, surgery can be carried out

Mebendazole (MBZ) is given as 500-mg tablets in daily doses of 40-50 mg/kg bw in three divided doses postprandially. After an initial continuous treatment of 4 weeks, it is advisable to adjust the oral doses in order to obtain plasma drug levels of >250 nmol/l (= 74 ng/ml). The duration of treatment is at least 2 years after radical surgery or continuously for many years in inoperable cases, as well as for patients who have undergone incomplete

Albendazole (ABZ) is given as 400-mg tablet or as a 4% suspension at daily doses of 10 -15 mg/kg bw (in two divided doses). In practice, a daily dose of 800 mg is given to adults, divided into two doses of 400 mg. Repeated cycles of 28 days treatment should be followed by a 'wash out' phase without chemotherapy of 14 days. However, data from the People's Republic of China (Liu, 1997) and Italy indicate that a continuous ABZ treatment of AE is at least equally or more effective and well tolerated. The duration of necessary chemotherapy has not yet been determined but might well be life-long for most of the patients without

Adverse effects of the chemotherapy with benzimidazoles are neutropaenia, alopecia and liver dysfunction. They are contraindicated in pregnancy due to its potential embryotoxicity and teratogenicity. Monitoring of the AE patients is similar to that in CE patients. A long-

Interventional procedures are indicated for AE patients for whom surgery is contraindicated. Some of them are dilation and stent implantation in vessels or bile ducts,

**2.2.2.7 Treatment of AE** 

transplantation.

Chemotherapy has several indications, as follows:

after a prolonged course of chemotherapy. Benzimidazoles are preferentially used for AE:

years for possible recurrence

resection or liver transplantation.

complete resection of the AE lesions.

term follow-up of more than 10 years is recommended.

and endoscopic sclerosing of oesophageal varices.

transplantation


#### **2.2.2.5 Immunodiagnosis of AE (table 3)**

Table 3. Approaches for immunodiagnosis of AE

#### **2.2.2.6 Pathological and histological examination of AE**

Metacestode of *E. multilocularis* typically exhibits an alveolar structure composed of numerous irregular cysts with diameters between less than 1 mm and 30 mm. when is examined in a macroscopic section of the liver. Due to necrosis of the lesion, cavities filled with liquid and necrotic material may be formed in the central parts of the parasite (Eckert, 1998). Microscopically, the cysts consist of a relatively thin PAS-positive laminated layer and a delicate germinal layer often with only a few nuclei. Brood capsules and protoscoleces are rarely formed in the human host (Eckert, 1998). The cysts are surrounded by an inner zone of necrotic tissue and outer layers of histiocytes and lymphocytes. In later phases, tissue reactions of chronic inflammation, often with giant cell foreign body reaction, fibrous tissue and calcifications are seen around cysts.

**Fisrt step: Primary antibody test**  Tests with high sensitivity and less specific value **Subsequent steps** 

> **Seropositive samples + With or without suggestive images for AE**

**Asymptomatic and symptomatic cases**  Secondary antibody test: Em2Plus-ELISA (Gottstein et al., 1993) Em alkaline phosphatiseantigen-ELISA (Sarciron et al., 1997) Immunoblot for specific bands or similar test Serological differential diagnosis

**Seronegative samples + Suggestive images for AE** 

**Asymptomatic cases**  Extended and/or advanced imaging and repeated serological examinations. Fine needle biopsy for PCR or immunohistology may be considered in rare cases. If lesions are fully calcified, serological and imaging follow-up after 6 months to confirm parasite abortion.

Consideration of surgical intervention and/or chemotherapy without further serological examinations

Metacestode of *E. multilocularis* typically exhibits an alveolar structure composed of numerous irregular cysts with diameters between less than 1 mm and 30 mm. when is examined in a macroscopic section of the liver. Due to necrosis of the lesion, cavities filled with liquid and necrotic material may be formed in the central parts of the parasite (Eckert, 1998). Microscopically, the cysts consist of a relatively thin PAS-positive laminated layer and a delicate germinal layer often with only a few nuclei. Brood capsules and protoscoleces are rarely formed in the human host (Eckert, 1998). The cysts are surrounded by an inner zone of necrotic tissue and outer layers of histiocytes and lymphocytes. In later phases, tissue reactions of chronic inflammation, often with giant cell foreign body reaction, fibrous tissue

for CE **Symptomatic cases** 

**2.2.2.5 Immunodiagnosis of AE (table 3)** 

**Seronegative samples + No suggestive images for AE** 

No further serological follow-up. Persons with suspected infection risk may require repeated serological examinations after 3-6 months, and US imaging.

Table 3. Approaches for immunodiagnosis of AE

and calcifications are seen around cysts.

**2.2.2.6 Pathological and histological examination of AE** 

#### **2.2.2.7 Treatment of AE**

There are a variety of options to select the adequate treatment for each individual patient. Clinical experience is crucial for AE; therefore patients should be referred to a recognised national or regional reference centre. Early diagnosis of AE is of special importance for successful treatment because the lesion is acting as a malignant tumour. Screening programmes in Japan and Europe have shown that early diagnosis reduces mortality and morbidity due to AE. Some considerations for treatment of AE are generally accepted: the first choice treatment in all operable cases is radical surgical resection of the entire parasitic lesion from the liver and other affected organs, chemotherapy is indicated after radical surgery for a limited period of time, and long-term chemotherapy is mandatory after incomplete resection of the lesions, in inoperable patients and in AE patients after liver transplantation.

Chemotherapy has several indications, as follows:


Benzimidazoles are preferentially used for AE:

Mebendazole (MBZ) is given as 500-mg tablets in daily doses of 40-50 mg/kg bw in three divided doses postprandially. After an initial continuous treatment of 4 weeks, it is advisable to adjust the oral doses in order to obtain plasma drug levels of >250 nmol/l (= 74 ng/ml). The duration of treatment is at least 2 years after radical surgery or continuously for many years in inoperable cases, as well as for patients who have undergone incomplete resection or liver transplantation.

Albendazole (ABZ) is given as 400-mg tablet or as a 4% suspension at daily doses of 10 -15 mg/kg bw (in two divided doses). In practice, a daily dose of 800 mg is given to adults, divided into two doses of 400 mg. Repeated cycles of 28 days treatment should be followed by a 'wash out' phase without chemotherapy of 14 days. However, data from the People's Republic of China (Liu, 1997) and Italy indicate that a continuous ABZ treatment of AE is at least equally or more effective and well tolerated. The duration of necessary chemotherapy has not yet been determined but might well be life-long for most of the patients without complete resection of the AE lesions.

Adverse effects of the chemotherapy with benzimidazoles are neutropaenia, alopecia and liver dysfunction. They are contraindicated in pregnancy due to its potential embryotoxicity and teratogenicity. Monitoring of the AE patients is similar to that in CE patients. A longterm follow-up of more than 10 years is recommended.

Interventional procedures are indicated for AE patients for whom surgery is contraindicated. Some of them are dilation and stent implantation in vessels or bile ducts, and endoscopic sclerosing of oesophageal varices.

Echinococcosis/Hydatidosis 317

Echinococcosis is therefore a neglected disease which is under-reported and requires urgent attention in common with a number of other zoonoses in order to reduce morbidity and to help alleviate poverty in poor pastoral areas of the sub-tropics and temperate zones. It's also difficult to formulate interventions and to apply cost-effective

Human behaviour is crucial in facilitating transmission of this infection between domestic animal hosts as a result of traditional pastoral and husbandry practices (Mcpherson, 2005; Craig, 2007). Dogs are also susceptible to infection with *E. multilocularis* and *E. vogeli* (whose intermediate hosts are principally rodents) and therefore dogs may constitute a greater zoonotic reservoir of infection compared to natural wild canid hosts. Peri-domestic transmission may occur and could for example sustain a level of transmission of *E. multilocularis* in highly endemic communities (Li, 2005), but is probably not responsible for long-term maintenance of these Echinococcus species adapted to small mammals. Therefore, echinococcosis is a disease where humans may acquire infection from wild or domestic animal hosts but the parasite cannot be directly transmitted between humans (Wolfe, 2007), and due to all of these concepts treatment of human echinococcosis cases will have no effect on pathogen transmission. We will need to apply interventions to reduce human exposure or break transmission cycles in order to control the disease. This places echinococcosis in a 'difficult-to-deal-with' category; firstly, unlike the other neglected parasitic diseases humans can not act as a definitive host, and secondly, echinococcosis in livestock (or dogs) is not

Clinical symptoms and subsequent diagnosis occur in adults (20-60 years) but infections in children may also become symptomatic (Soriano Arandes et al., 2010), and imaging techniques are the basis for diagnosis preferably accompanied by a specific serological test (Craig et al., 2003). Surgical removal of cysts/cystic masses, cyst drainage or organ resection, are the main form of treatment, often supported by high dose albendazole cover; the latter

The key factors of echinococcosis as a neglected disease are best described in a recent paper

 Human echinococcosis is a zoonosis, non vector-borne zoonosis, that is not transmitted between humans. Therefore, it's a disease that is not amenable to vector-based control

 Human CE and AE are chronic diseases with very long asymptomatic periods so that endemic communities and health authorities fail to properly recognise the negative health impacts. Prevalence values represent infection events some years previously. CE remains an important health problem in many regions of the world, both where no control measures have been implemented, and where control programs have been incompletely successful with ensuing re-emergence of the disease. In Spain, official data on CE show an increase in the proportion of intermediate hosts with CE during the last few years, and autochthonous pediatric patients have been reported, a sign of active local transmission of disease. However, several crucial aspects related to CE that would help better understand and control the disease have not been tackled appropriately, in particular the emergence of infection in specific geographical areas. The introduction of national registries for CE with online data entry, following the example set by the European Registry for Alveolar Echinococcosis, would help streamline data collection on CE by eliminating the need for evaluating and

control programmes in this disease.

perceived as an animal health problem.

(Craig et al., 2007):

also has a benefit in medically-only treated cases (WHO, 2001).

nor to direct human-treatment-approaches for case prevention.

Liver transplantation should only be considered in patients with very severe hilar extension, leading to uncontrolled biliary infections, symptomatic secondary biliary cirrhosis with ascites or severe variceal bleeding owing to portal hypertension (Bresson-Hadni, 1997). It requires long-term and continuous postoperative chemotherapy.
