4 2. LITERATURE REVIEW 2.1 Lymphatic Filariasis Lymphatic
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2. LITERATURE REVIEW 2.1 Lymphatic filariasis Lymphatic filariasis is an inflammatory parasitic infection of lymphatic vessels caused by the filarial roundworms Wuchereria bancrofti, Brugia malayi, and Brugia timori, which results in massive lymphoedema (elephantiasis) of the affected tissues. The adult worms inhabit the lymphatics where they elicit an inflammatory response that causes acute lymphangitis and eventualy lymphatic obstruction leading to severe lymphoedema. 2.1.1 Epidemiology WHO (1995) reported that lymphatic filariasis is widespread throughout the tropical and subtropical areas of Asia, Africa, the Western Pacific and some parts of the America. More than 1.1 thousand million people (20% of the world’s population) now live in areas where they are at risk of infection with lymphatic filarial parasites and a minimum of 120 million people is currently infected (about 107 million with W. bancrofti and 13 million with B. malayi or B. timori). A total of 44 million persons currently suffer from one or more of the overt manifestations of the infection: lymphoedema and elephantiasis of the limbs or genitals, hydrocele, chyluria, pneumonitis, or recurrent infections associated with damaged lymphatic vessels. The remainder of the 120 million infected has “preclinical” hidden damage of their lymphatic and renal systems. 2.1.1.1. Geographical distribution Lymphatic filariasis is known to occur in 73 countries (Figure 1); 38 in the Africa region, 7 in the region of the America, 4 in the Eastern Mediterranean region, 8 in the South-East Asia region and 16 in the Western Pacific region. The condition has been previously reported, and might still 4 5 occur in another 40 countries. The highest numbers of infected persons live in the South-East Asia region with India alone accounting for 45.5 million. In Sub- Sahara Africa, the estimate of 41 million cases is less precise, and there is a particular need to determine more accurately the distribution of infection and disease in affected countries. Several countries in Asia have large numbers of infectious cases that are very prevalent in many of the pacific islands as well. Brugian filariasis is most highly endemic in India and China (32% and 20% respectively, of the global burdens). It is also prevalent in Indonesia, Thailand, Malaysia, the Philippines, Vietnam, and Republic of Korea (Ottesen et al., 1997). Endemic countries Figure 1 Distribution of lymphatic filariasis (From WHO, 1992) 6 2.1.1.2 Situation of lymphatic filariasis in Thailand Lymphatic filariasis is an important health problem in many Asian countries. The largest numbers of people both at risk and infected live in India, but disease is a severe problem in Indonesia, Malaysia, Sri Lanka, the Philippines and Thailand (WHO, 1992). In Thailand, lymphatic filariasis is found in the rural areas. Its spreading and abundance are different depending on character of areas. Among 76 provinces, only 10 of them have some foci of lymphatic filariasis transmission, namely Mae Hong Son, Lamphun, Tak, Kanchanaburi, Ratchaburi, Ranong, Surat Thani, Krabi, Nakhon Si Thammarat and Narathiwat (Figure 2). Mae Hong Son Lamphun Tak Kanchanaburi Ratchanaburi Ranong Surat Thani Nakhon Si Thammarat Krabi Endemic area Narathiwat Figure 2 Endemic areas of lymphatic filariasis by provinces in Thailand (Modified from Annual report of Filariasis Division, 2004) 7 It has been reported that there were 326 patients with lymphatic filariasis registered between October 2001 and September 2002 (Annual report of Filariasis Division, 2002). Most of them (194 cases; 59.51%) were asymptomatic, 110 cases (33.74%) were patients having antigen of microfilariae in blood. The rest were lymphadenitis stage (11 cases; 3.37%) and in elephantiasis stage (11 cases; 3.37%). The prevalence rate of lymphatic filariasis was highest in Narathiwat (21.79 per a hundred thousand) and Mae Hong Son (20.92 per a hundred thousand). The highest rate of patients, who were in elephantiasis stage, was found in Nakhon Si Thammarat province (0.46 per a hundred thousand) and Surat Thani province (0.22 per a hundred thousand). Overall, the prevalence rates of lymphatic filariasis during previous 10 financial years (from 1992 to 2002) have decreased from 11.16 per a hundred thousand in 1992 financial year to 0.53 per a hundred thousand in 2002 financial year (Figure 3) (Annual report of Filariasis Division, 2002). Prevalence rate/100,000 Prevalence 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 Financial years Figure 3 Prevalence rate of lymphatic filariasis in Thailand (Modified from Annual report of Filariasis Division, 2004) Iyengar (1953) examined lymphatic filariasis in the South of Thailand for the first time in four southern provinces, namely Nakhon Si Thammarat, Surat Thani, Patthalung and Pattani, and found that B. malayi was the cause of the 8 disease and spread equivalently among these provinces. When the territories of examinations were expanded, the disease also existed in the areas of Eastern South, namely Chumphon, Pattani, Nakhon Si Thammarat, Surat Thani, Patthalung,and Narathiwat (Harinasuta et al., 1970). At present, lymphatic filariasis in the South of Thailand is under control and is limited in only 4 provinces. Number of patients with lymphatic filariasis who are registered for treating is as follow; Ranong, 2 patients, 1.25 per a hundred thousand; Surat Thani, 18 patients, 2.01 per a hundred thousand; Nakhon Si Thammarat, 8 patients, 0.52 per a hundred thousand; and Narathiwat, 148 patients, 21.79 per a hundred thousand (Annual report of Filariasis Division, 2002). In addition, blood examination of population in these areas for identifying the microfilaraemia subjects was preceded. Number of microfilaraemia subjects only caused by B. malayi was 10 subjects (0.10% of total population) in Surat Thani and 88 subjects (0.66% of total population) in Narathiwat (Annual report of Filariasis Division, 2002). However, spreading of the disease was found only in rural villages. Migration of population and non- cooperation of communities and patients are at risk. 2.1.2 Pathogenesis Mosquito bites transmit infective larvae that migrate to lymphatic and lymph nodes. After maturing into adult forms over several months, the worms mate and the females release microfilariae into lymph nodes and the bloodstream. The manifestations of lymphatic filariasis result from the inflammatory response to degenerating adult worms in the lymph nodes. The initial inflammatory response is an acute lymphangitis, which resolves in 1 to 2 week. Repeated filarial infections are common in endemic regions and produce repeated bouts of lymphangitis (filarial fevers), which eventually (over years) may cause extensive scarring and obstruction of 9 lymphatic vessels. The lymphatic vessels obstruction causes localized dependent edema, most commonly affecting legs, arms, genitalia and breasts. In its most severe form, which occurs in less than 5% of the infected population, this edematous distortion of body parts is known as elephantiasis (Genta & Conner, 1998). 2.1.2.1. Life cycle of the parasites In Thailand, lymphatic filariasis is caused by B. malayi and W. bancrofti. Life cycles of both parasites are similar and divided into 2 stages as follows (Figure 4). A. Mosquito stages 1 A mosquito takes human blood containing microfilariae. 2 Microfilariae shed theirs sheaths, penetrate mosquito’s stomach wall and migrate to muscle of thorax. 3 Microfilariae shapes become short, thick and are called sausage- stage or L1 larvae. The L1 larvae molt and transform to the L2 larvae or pre- infective larvae, which has one or two papillae at the caudal end. 4 L2 larvae molt and transform to the L3 larvae or infective larvae. Their shapes are longer than that of L2 larvae. 5 The L3 larvae migrate to proboscis of the mosquito. The time interval between microfilariae ingestion of mosquito and transformation to the L3 larvae is approximately 7-14 days, which depend on the type of parasites and microfilarial body temperature. Generally, the microfilariae are rapidly developed at the optimal temperature. 10 6 5 4 7 3 8 1 2 Figure 4 Life cycles of filarial parasites (B. malayi) (Modified from Garcia, 2001) B. Human stages 6 During a blood meal, the L3 larvae from the proboscis of the mosquito penetrate human skin and enter in the lymphatic system. 7 The L3 larvae develop into L4 larvae and enter adult stage containing male and female worms. 8 After fertilization, the female worms produce sheathed microfilariae reaching the blood circulation. The period from the entering of L3 larvae into human body to appearing 11 to sheathed microfilariae is approximately 3 months. Generally, microfilariae age 6-12 months and adult worms age 5-10 years (WHO, 1987). 2.1.2.2. Periodicity of lymphatic filariasis In human, the microfilariae show circadian periodicity. They live mostly in pulmonary capillaries and enter blood circulation at certain intervals of time. Periodicity of microfilariae in the blood circulation relates to the time of blood meal and divides into 2 main types as follows. 1) Periodic types a) Nocturnal periodic type The microfilariae are found in the blood circulation during night-time. b) Diurnal periodic type The microfilariae are found in the blood circulation during day-time. 2) Subperiodic types a) Nocturnal subperiodic type The microfilariae are found in the blood circulation during night-time and day-time with greater in density during night-time. b) Diurnal subperiodic type The microfilariae are found in the blood circulation during night-time and day-time with greater in density during day-time. The periodicity of parasites in human host is similar to that in animals. For example, the periodicity of B. malayi in an infected cat is nocturnal subperiodic, so the periodicity of parasites in infected human is nocturnal subperiodic too (Edeson, 1959). In the South of Thailand, lymphatic filariasis is generally caused by B. malayi, which is mainly nocturnal subperiodic type (Kanjanopas et al., 2001).