by

Eisaku Kimura, M.D., D.M.Sc., Aichi Medical University

Atsuhide Takesue, M.D., Aichi Medical University

Hiroshi Ohmae, M.D., Ph.D., National Institute of Infectious Diseases

　

　

　東チモール国におけるリンパ管フィラリア症と腸管内寄生虫病を制圧するため、2004年、現地厚生省とWHOは、笹川記念保健協力財団などの支援のもと、全住民の集団治療（MDA）を根幹とする全国規模のプロジェクトを開始した。MDAは、原則としてフィラリア症には年1回、腸管内寄生虫病には年2回実施される。治療薬はジエチルカルバマジンとアルベンダゾールである。

　東チモール国は13の地区（district）より成るが、フィラリア症の調査が十分行われていないため、MDAに先立って全国規模の有病率地図の作成が急がれた。インフラに不備の多い東チモールでは、一般に行われている夜間採血による有病率調査は困難と判断されたため、尿を検体とする免疫診断法（尿ELISA）が導入されることとなった。この診断法はフィラリア特異的IgG4を検出する。尿採取は極めて容易なため、住民の協力が得られやすく、調査は短時間で終了すると期待された。

　有病率調査は、2006年の2−5月、11月−2007年2月の2回実施され、全国13地区より選ばれた34の中学校の5715人の生徒が対象となった。現在まで、20校3,461人のIgG4測定が終了している。その結果、平均有病率は2.6%で、高い有病率（10.9%、8.2%）がCovalima地区の2校で得られた。一般に、北部海岸沿いの有病率は、南部海岸沿いの貧困地帯の有病率よりも低いようである。また中央に位置する山間部において有病率が低いことが示された。媒介蚊が水田地帯に発生することと関係があると思われる。残りの14校、2,254人の生徒については、現在解析が進行中である（但し、チモールフィラリアに対する尿ELISAの感度が確立していないため、現時点におけるデータである）。

　2006年5月に起きた首都での動乱等、本プロジェクト進行の遅延を招く不安定要因は尚あるが、フィラリア症の有病率は予想外に低く、MDAが今後軌道に乗れば、その制圧は十分可能であると考える。

　

 Lymphatic filariasis is a mosquito-borne disease caused by 3 species of filarial parasite, Wuchereria bancrofti, Brugia malayi and Brugia timori. Filariasis affects 120 million people worldwide, and causes disfiguring symptoms like elephantiasis and hydrocele. The Global Programme to Eliminate Lymphatic Filariasis was adopted at the 50^th World Health Assembly in 1997, with the goal to eliminate the disease by the year 2020 from the whole world.

 The cooperative activities to eliminate lymphatic filariasis in Timor-Leste started in 2004 with participation of the Ministry of Health, WHO/Dili and Sasakawa Memorial Health Foundation. The Foundation provides, among others, technical assistance to obtain essential information required for the elimination program: the data on distribution, prevalence and intensity of filariasis before elimination measures are taken. Such data are necessary to monitor the progress/effect of drug treatments, and eventually to confirm the 'complete' elimination of filariasis in Timor-Leste.

 A large-scale pre-treatment prevalence survey started in 2006 at 35 schools selected country-wide from 13 Districts. The survey is based on immunodiagnosis using urine samples instead of serum. This method was developed at Aichi Medical University, Japan, and employed successfully in several Asian countries. As urine collection is much easier than sampling blood, field work has been facilitated remarkably.

　

 The global program formulated by WHO requires the following 5 steps. The technical cooperation by Sasakawa Foundation, as far as this report is concerned, is in relation to steps (1) and (3).

 Pre-treatment surveys are carried out, in most endemic countries, by means of blood smear method using finger-prick blood. As microfilariae appear in the peripheral blood only at night, we must sample blood at night, and this is the biggest disadvantage of this method. In Timor-Leste, where basic infrastructure such as accessibility to villages, electricity, etc. are still underdeveloped, and health manpower is not sufficient, it will be difficult to employ routine night blood surveys. Immunodiagnosis can be performed with daytime blood and is sufficiently accurate. Unfortunately, presently available test kits are expensive and therefore not widely used in developing countries. In the present cooperative activities, we employ enzyme-linked immunosorbent assay to detect filaria-specific IgG4 in urine (urine ELISA). A urine test is more acceptable to people because collecting urine samples is not painful and very easy. Thus, it is expected that the urine-based diagnosis will facilitate field studies greatly.

 For monitoring the effect of MDAs, WHO recommends to carry out prevalence surveys at pre-fixed 'sentinel' sites, and spot-check sites selected for each surveillance. The sentinel sites should have high prevalence, so that the gradual reduction of prevalence can be followed up in several succeeding years. As a matter of course, the sites have to be identified during our pre-treatment survey.

　

 The new immunodiagnosis, detecting specific IgG4 in urine (urine ELISA) was developed by Itoh et al. (2001). It showed high sensitivity (95.6%) and specificity (99.0%), when tested with Wuchereria bancrofti infection and non-endemic controls. The prevalence of filariasis increases as ages get older. Therefore, with urine ELISA, recent filarial infections/transmissions can be detected and assessed by targeting children, that is, in a high endemic area, a 1-year-old baby could be IgG4 positive with a high titer (Weerasooriya et al., 2003), while in a low endemic area, the youngest positive case may be > 10 years old and with a low IgG4 titer. Urine ELISA can be used to monitor the effects of MDAs. With Sri Lankan schoolchildren, it was observed that several rounds of MDA with DEC and albendazole significantly reduced the number of the IgG4 positives and their antibody titers.

 The sensitivity of urine ELISA for B. timori has not been established. Judging from the result obtained in Korea with B. malayi infection (not published), and the fact that urine ELISA uses Brugia antigens to detect IgG4 antibodies, it is most likely that the ELISA is also useful to detect B. timori infection. However, the exact sensitivity must be determined. This can be done by comparing results obtained by urine ELISA and 'Brugia Rapid' blood tests, the latter being reported to have a very high sensitivity with B. timori (Supali et al., 2004).

　

 It has been reported that all 3 species of lymphatic filarial parasite are endemic in Timor-Leste. According to a WHO/Dili document (2003), brugian filariasis was widely endemic with the average prevalence of 9.8%. Unfortunately, the data did not distinguish B. timori and B. malayi infections. (B. timori is believed to be the main species in Timor-Leste.) The distribution of W. bancrofti was reported sporadic with a low prevalence rate (0.8%). These data obtained from a total of 419 military recruits can not be a good representative of the whole country, but are the only information we have in recent years. Therefore, it is prerequisite to have reliable pre-treatment baseline data for Timor-Leste before starting MDAs.

 The presence of 3 species of filariae with unknown distribution and prevalence may pose difficulties in conducting the pre-treatment surveys and monitoring, because no one test (except the blood smear method) can make an accurate diagnosis for all species at the same time. Brugia Rapid test may miss 10 to < 50% of W. bancrofti infections (Rahmah N. et al., 2003), antigen tests like ICT tests and Og4C3 ELISA are useful only for W. bancrofti, and our urine ELISA has not been verified for B. timori infection. Therefore, we will have to analyze obtained data carefully, and employ several different diagnostic tests whenever needed.

　

 Communicable diseases are a part of the major problems of Timor-Leste. As the health services system has become developed, emphasis is given to prevent and control the major communicable diseases such as HIV/AIDS, tuberculosis, and malaria by the Ministry of Health, together with other development partners. However, there are still other infectious diseases including lymphatic filariasis (LF) and intestinal parasitic infection (IPI) which also have priorities. These diseases are highly prevalent in different age groups, and are a serious public health problem in Timor-Leste. The Ministry of Health and WHO therefore made a proposal for funding the establishment of the national LF elimination and IPI control programs.

 Timor-Leste belongs to SEARO of WHO, but its filariasis elimination program is placed under an inter-regional scheme named 'Mekong Plus', which includes 12 countries such as Thailand, Myanmar, and Indonesia of SEARO, or the Philippines and Vietnam of WPRO. Timor-Leste, a new member of WHO, joined the scheme as the last country, and the anti-filariasis campaign started in 2004.

　

 In the beginning of national LF elimination and IPI control programs, WHO office of Timor-Leste and SEARO asked the Sasakawa Memorial Health Foundation to collaborate in these control programs. In order to investigate the factual situation of the control programs the Foundation decided to dispatch a survey team. In March 2004, Dr. Hiroshi Ohmae and Mr. Genji Matsumoto visited Timor-Leste for a preliminary study. They reported that priority of integrated control programs of LF elimination and IPI control was high, but that human and financial resources were insufficient in Timor-Leste. Based on their reports, the Foundation decided to provide financial support for launching the control programs. The suggestions given by the team were instrumental during the process of national strategy formulation.

 The anti-filariasis campaign started in 2004, with financial support by Sasakawa Memorial Health Foundation and Australian Government. WHO organized many meetings with NGOs and provided technical justification to use integrated approach for LF elimination and IPI control since May 2004. Training courses for the tutors started in September 2004. The first MDA campaign was conducted in February 2005 in Oecussi district.

 In order to evaluate achievement of the control programs, the Sasakawa Foundation dispatched Drs. Hiroshi Ohmae and Eisaku Kimura in March 2005. Based on their reports, the Foundation decided to continue its financial support for the programs of LF elimination and IPI control, and to start the technical assistance for monitoring the epidemiological changes of filariasis. The experiences gained from the first MDA in Oecussi district were analyzed and documented, and based on them, the control program was modified and then extended into other districts in Timor-Leste. Despite delays in start, Timor Lesto conducted the very successful first MDA in 2005 in 4 districts, Oecussi, Dili, Liquica and Manatuto (Table 1). The reported treatment coverage of 92-100% was a remarkable achievement.

 The MDA program was extended to 2 districts, Manufahi and Viqueque in January, 2006. Unfortunately, due to the political disturbance, MDAs in other districts had to be postponed. After the crisis settled, in August, 2006, MDAs were carried out in 2 other districts, Baucau and Lautem (Table 1). The treatment coverage rates in these 4 districts were 96-100%, again very high percentages. It is likely that infection rates in these districts reduced considerably.