59 Angiostrongylus cantonensis and Human angiostrongylosis

Angiostrongylus cantonensis was first discovered in rats in Guangzhou (Canton), China in 1935 (Chen 1935). A. cantonensis is a zoonotic pathogen, which causes human angiostrongylosis with the main clinical manifestation of eosinophilic meningitis. The first case of human angiostrongylosis was reported in Taiwan in 1945. Subsequently several outbreaks of this disease occurred in Pacific Islands (Rosen et al. 1961; Kliks and Palumbo 1992). In the past decade, a number of outbreaks of human angiostrongylosis have emerged in some endemic regions, especially in China (Wang et al. 2008). Additionally, increasing numbers of travellers are diagnosed with eosinophilic meningitis caused by A. cantonensis after returning from endemic regions (Lo et al. 2001; Slom et al. 2002; Bartschi et al. 2004; Podwall et al. 2004; Kumar et al. 2005; Leone et al. 2007; Ali et al. 2008). The parasite continues to threaten human beings, especially people living in the Pacific Islands and Asia. So far, at least 2,825 cases have been recorded; of them, 1,337 were reported in Thailand, 769 in China (Hong Kong and Taiwan), 256 in Tahiti, 116 in the USA (Hawaii and Samoa) and 114 cases in Cuba (Wang et al. 2008).

The life cycle of A. cantonensis includes the rat definitive hosts and mollusk intermediate hosts (Fig. 59.1). Human A. cantonensis infections occur after eating mollusks or paratenic hosts such as prawns, frogs and monitor lizards, or vegetables, which contain or are contaminated by the infective larvae (the third stage) of the worm (Fig. 59.1). The larvae invade via intestine and enter bloodstream, and eventually reach the central nervous system (CNS) in about two weeks, causing eosinophilic meningitis. The external surface of brain and spinal cord are frequently normal without gross haemorrhage (Sonakul 1978; Chotmongkol and Sawanyawisuth 2002; Eamsobhana and Tungtrongchitr 2005). But physical lesions of tracks and microcavities caused by migrating parasites can be observed in the brain, and even the spinal cord. Infiltrations of lymphocytes, plasma cells and eosinophils are commonly revealed in the meninges and around intracerebral vessels (Sonakul 1978; Eamsobhana and Tungtrongchitr 2005). Cellular infiltration around living worms is not prominent, but dead worms are usually surrounded by a granuloma, increased eosinophils and sometimes Charcot-Leyden crystals (Eamsobhana and Tungtrongchitr 2005). The larvae occasionally move to the eyes and cause ocular angiostrongylosis with visual disturbance such as diplopia or strabismus (Punyagupta et al. 1978; Sawanyawisuth et al. 2006).

The incubation of human angiostrongylosis is highly variable ranging from one day to several months (usually two weeks), depending on the number of parasites involved (Wang et al. 2008). Fig. 59.2 summarizes the clinical symptoms in 778 adult patients and 114 pediatric patients reported with eosinophilic meningitis caused by A. cantonensis (Wang et al. 2008  ). In adult patients, the common symptoms were headache (95%), stiff neck (46%), paresthesia (44%), vomiting (38%) and nausea (28%). Headache was frequently intermittent and can be relieved by repeated lumbar punctures (Punyagupta et al. 1975; Yii 1978). Neck stiffness usually was mild but nuchal rigidity has been observed in severe cases (Slom et al. 2002; Chau et al. 2003). Paresthesia occurred in a great variety of anatomical locations, usually in the extremities, and was expressed as pain, numbness, itching, or a sensation of worms crawling under the skin (Yii 1978). Vomiting and nausea probably were related to increased intracranial pressure and usually disappeared after the first lumbar puncture. Although a few adult patients suffering from visual disturbance or diplopia have been reported in China, this symptom was noted in 38% of patients in Thailand and 92% of patients in the USA (Punyagupta et al. 1978; Slom et al. 2002).

In children, stiff neck and paresthesia have been reported in 39% and 28% of cases. It was reported that 82% of pediatric patients had nausea and vomiting with 56% of the vomiting being projectile. The symptoms disappeared within one week in the most cases (Yii 1978). In addition, the incidence of fever (up to 80%), somnolence (82%), constipation (76%) and abdominal pain (34.2%) were relatively higher in children than among adults.

Patients may also develop additional clinical symptoms, including weakness of extremities, muscle weakness, muscle twitching, muscle pain, fatigue, diarrhoea, convulsions, and hyperesthesia. In heavy infections, coma and death may occur (Punyagupta et al. 1978; Chotmongkol and Sawanyawisuth 2002).

The recovery of A. cantonensis from patients confirms human angiostrongylosis. However, the frequency of the recovery is very low from clinical cases (2–11%) (Punyagupta et al. 1975; Yii 1978). For most cases, diagnoses of human angiostrongylosis are based on the clinical symptoms, medical history, laboratory findings in blood and cerebrospinal fluid (CSF), brain images and serological tests. The common clinical symptoms include headache, nausea and vomiting, neck stiffness, paresthesia and diplopia. However, a history of having eaten intermediate or paratenic hosts is very important for the diagnosis of this disease. In laboratory findings, eosinophils dominates in white cell counts in CSF (>10%) and peripheral blood (7–36%) (Yii 1978; Kuberski and Wallace 1979; Tsai et al. 2001; Slom et al. 2002). CNS images using MRI and CT can reveal lesions and are useful for differential diagnosis of angiostrongylosis from other parasitic diseases, such as cysticercosis, paragonimiasis, gnathostomiasis and schistosomiasis (Punyagupta et al. 1975, 1990; Ogawa et al. 1998; Kanpittaya et al. 2000; Hasbun et al. 2001; Chau et al. 2003; Lo 2003; Jin et al. 2005).

Various enzyme-linked immunosorbant assay (ELISA) methods have been developed to detect antigens of, or antibodies against A. cantonensis, although none of them are commercially available (Cross and Chi 1982; Chen 1986; Eamsobhana et al. 1997, 2003). Antigens such as 29 kD, 31 kD and 32 kD have been found useful for development of ELISA detect (Nuamtanong 1996; Maleewong 2001; Li et al. 2005). The 29 kD antigen from female worms has showed potentiality to be a good marker for diagnosis with sensitivity and specificity 75% and 95%, respectively (Intapan et al. 2003). A dot-blot ELISA with 100% of sensitivity and specificity in laboratory tests has been developed to handle field samples for epidemiological surveys (Eamsobhana et al. 2003). A. cantonensis antigens can also be detected in serum by immuno-PCR (Chye et al. 2004).

Most patients with A. cantonensis infection are mild and self-limited, but death may occur in severe cases without prompt and appropriate treatment (Punyagupta et al. 1978; Chotmongkol and Sawanyawisuth 2002). Table 59.1 summarizes the treatment of  A. cantonesis infections in humans. Lumbar puncture was usually used to relieve headache caused by increasing intracranial pressure (Punyagupta et al. 1975; Yii 1978). Corticosteroids, anti-inflammatory agents are frequently effective in treating angiostrongylosis (Slom et al. 2002; Chotmongkol et al. 2006). However, anthelminthics, such as albendazole and mebendazole, usually are not recommended for treatment because of the theoretical possibility of exacerbating neurological symptoms (Hidelaratchi 2005). However these compounds have been used to treat this disease in Mainland China, Taiwan and Thailand where they appeared to relieve symptoms and reduce the duration of the disease (Chotmongkol et al. 2000, 2004). Sometimes, surgery is required to remove worms from eyes of patient with ocular angiostrongylosis (Kumar 2005; Sawanyawisuth et al. 2005).

Angiostrongylus cantonensis is mainly endemic in the Pacific Islands and Asia where it has been found as a main cause of eosinophilic meningitis. Many outbreaks of human A. cantonensis infections with cases from several to hundreds have been reported in these regions during the past decades. Over 2,800 cases of human angiostrongylosis have been reported in approximately 30 countries: Thailand, China (including Taiwan, Hong Kong), Tahiti, The USA (Hawaiian Islands, American Samoa), Cuba, Australia, Japan (Okinawa, Ryukyu Islands), New Caledonia, Vanuatu Republic (New Hebrides), India, Vietnam, Malaysia, Reunion Island, Egypt, Mayotte, Sri Lanka, Cambodia, Western Samoa, Costa Rica, Fiji, Indonesia, Ivory Coast, New Zealand, Papua New Guinea (New Britain), Germany, Italy, Belgium, Switzerland and the UK (Fig. 59.3, in the colour plate section; Table 59.2).

So far, at least 1, 337 cases of human angiostrongylosis have been reported in Thailand. The main cause of this disease is the popular dietary habit of eating raw or undercooked snails (Pila spp.) with among young adult males: seventy percent were 20–40 years old (Punyagupta et al. 1978; Schmutzhard 1988; Cross and Chen 2007).

In Mainland China, A. cantonensis is endemic in at least seven provinces (Wang et al. 2007). The first case of human angiostrongylosis was documented in 1984. However, many outbreaks of A. cantonensis infections have emerged during the past decade. Nine outbreaks with a total of 319 cases have been reported since 1997 (Wang et al. 2008). Most of patients in these outbreaks were caused by eating raw or undercooked meat of an invasive freshwater snail Pomacea canaliculata. The snail, as a major infectious source in Taiwan, has also caused two outbreaks with a total of 17 human infections in 1998 and 2001 (Tsai et al. 2001; Tsai et al. 2004). Notably, an outbreak with 5 cases in Taiwan due to drinking vegetable juices was also reported (Tsai et al. 2004).

In pacific islands, most cases of human angiostrongylosis appeared in Tahiti, Samoa, New Caledonia, and Hawaii (Wang et al. 2008). The largest outbreak, with 202 cases, occurred in Tahiti in 1962 (Rosen et al. 1962). A further outbreak with 16 cases occurred in Samoa in 1982 (Kilks et al. 1982). Over 65 cases and 72 cases have been recorded in Hawaii and New Caledonia respectively (Hochberg et al. 2007; Wang et al. 2008).

Caribbean Islands and North American have become new endemic regions. The first case of human angiostrongylosis in the Caribbean Islands was reported in Cuba in 1973 (Pascual-Gispert et al. 1981), with a total of 114 cases recorded in this country since (Wang et al. 2008). Subsequently, many cases were reported in Costa Rica, and Jamaica (Vazquez et al. 1993; Lindo et al. 2004). Also, sporadic cases have been described in western travellers diagnosed with A. cantonensis after returning from Caribbean islands. The first case of human angiostrongylosis in North American was reported in New Orleans, Louisiana in 1985 (New et al. 1985).

The sources of human A. cantonensis infection are snails and slugs, crustaceans including freshwater shrimps and land crabs, and predacious land planarians such as flatworms in the genus Platydemus. Most species of mollusks are susceptible to and are capable of transmitting A. cantonensis. Terrestrial and some aquatic snails are the primary intermediate hosts (Cross and Chen 2007; Lv et al. 2008). However, in certain places, one or two species of snails are the main intermediate hosts and the intensity of infection in these hosts usually is very high. The giant African snail, Achatina fulica, is the major source of infection worldwide. The dispersal of A. cantonensis is associated with the spread of this snail from its native origin in Africa throughout the Pacific Islands and South Asia (Kliks and Palumbo 1992). The golden apple snail, P. canaliculata, a very successfully invasive snail from South American, has a very wide distribution in Asia and has caused great damage to local agricultural systems (Hollingsworth and Cowie 2006). Unfortunately, this snail is also very susceptible to A. cantonensis and has replaced the African giant snail, A. fulica, as the major intermediate host of A. cantonensis and has become the main source of human infection in these regions (Wang et al. 2007). The infection rate in this snail is very high, 21% in Taiwan, 42–69.4% in Mainland China, and 10–39% in Okinawa.

There is little knowledge regarding the prevalence of A. cantonensis in reported paratenic hosts such as crustaceans (prawns and land crabs), predacious land planarians (flatworms in the genus Platydemus), fish, frogs or monitor lizards (Radomyos et al. 1994; Panackel et al. 2004; Hidelaratchi et al. 2005). Small planarians may represent a very important but overlooked source for human infection, when they are consumed along with contaminated uncooked vegetables. Four outbreaks of human angiostrongylosis have been caused by eating contaminated vegetables or vegetable juice (Bowden 1981; Slom et al. 2002; Tsai et al. 2004). Frogs, monitor lizards and toads are also important reservoirs for A. cantonensis. In New Caledonia, 53.4% of frogs (Hyla aurea) were infected with the infective larvae (Ash et al. 1968). Eating raw frogs has been implicated in human infections in Taiwan, Mainland China and the USA. In Thailand, 95.5% of monitor lizards have been found infected with A. cantonensis and more than 18 cases of human angiostrongylosis in Thailand, Sri Lanka and India were attributed to consumption of monitor lizard (Radomyos et al. 1994; Panackel et al. 2004; Hidelaratchi et al. 2005).

Rattus rattus and R. norvegicus have been considered the most common definitive hosts for A. cantonensis, but other species of rats found in rural and forested areas are also reported to be natural hosts (Cross and Chen 2007; Wu 2006). Rats are very necessary for the establishment of A. cantonensis foci in a local area. Table 59.3 summarizes the prevalence of A. cantonensis in definitive hosts R. rattus, R. norvegicus and R. exulans in some regions, where human infections or outbreaks have occurred.

Human beings and non-human primates can be accidental hosts for this parasite. It is unable to complete its development in either human or non-human primates and usually dies in the central nervous system of these hosts, causing eosinophilic meningitis or even death of the hosts. The worms have been reported as the cause of death of captive primates in the Bahamas, in Australia and in the USA (Gardiner et al. 1990; Prociv et al. 2000; Prociv et al. 2004).

Because of the worldwide distribution of large numbers of rats and mollusks that are highly susceptible to this parasite, it would be very difficult to eliminate A. cantonensis from the environment. However, it is relatively easy to block the transmission pathway of this parasite to humans by educating susceptible populations not to eat raw or undercooked intermediate and paratenic hosts or potentially contaminated vegetables, particularly in endemic regions. Programs educating public health workers and physicians in endemic areas to be aware of this parasite, its hosts, and the dangers to the health of populations, and campaigns to warn against eating uncooked mollusks and paratenic hosts, are very useful, practical and achievable interventions for control of human A. cantonensis infection. The habit of eating raw snails and paratenic hosts should be strongly discouraged, although it is very difficult for people to abandon these customs that have existed for generations in some endemic regions, especially Thailand and China. Eating raw or undercooked snails with seasonings, such as pepper and pericarpium, is very popular, particularly in some Chinese restaurants. Several outbreaks of human A. cantonensis infections in China have been attributed to this method of preparing snails. So far, recommended measures for prevention in these endemic regions include:

Washing hands frequently, particularly after gardening, is also strongly recommended especially in endemic regions. For physicians in both non-endemic and endemic regions, it is very important to have good knowledge of the parasite in order to diagnose A. cantonensis infection in humans promptly.

Zhao-Rong Lun’s laboratory was supported by grants from National Basic Research Program (973 project, #2010CB530000) and the National Nature and Science Foundation of China (30670275).