History, Epidemiology and Control of Filariasis

1 History of filariasis

1.1 Scientific discovery

Early scientific milestones in filariasis history abroad include the following.

• 1863: Demarquay in Paris found microfilariae in hydrocele liquid of a Cuban.

• 1866: Wucherer found microfilariae in chyluria.

• 1872: Lewis found microfilariae in blood.

• 1877: Bancroft found a female adult filarial worm in the ulcer of lymph node of the arm.

• 1877: Manson found microfilariae in the stomach of bloodsucked mosquito, which was practically the “birth” of medical entomology.

• 1879: Manson found microfilarial nocturnal periodicity.

• 1888: Sibthorpe found male adult worms.

Those in Japan include the following.

• 1876: Erwin Von Baelz detected microfilariae in blood (in Tokyo).

• 1896: Yushitaro Matsuura found a female adult worm in an inguinal lymph node (in Kumamoto).

• 1903: Shichiro Hida found a male filaria in the left seminiferous hydrocele.

1.2 Ancient filariasis

About 600 B.C., a singular symptom of bancroftian filariasis (elephantiasis arabum) was described by ancient Hindus and Persian doctors. However, there is an indication that lymphatic filariasis existed as early as 1500 B.C. The funeral temple of Queen Hatshepsut (1501-1480 B.C.) is located at the foot of a mountain that commands a fine view in Thebes (now Luxor city), Egypt. To the back (north) of the mountain is the Valley of the Kings where the tomb of Tutankhamen was found. Replicas of illustrations possibly depicting elephantiasis can be seen on the right side second layer limestone wall of the funeral temple along the middle terrace (Fig. 1a). The original reliefs have been exhibited at the Egyptian Museum in Cairo (Fig. 1b), with the following explanation: ‘Very fine painted limestone reliefs from Terrace of Queen Hatshepsut’s temple at EL-Deir Bahari which record a trading expedition to Punt, a locality near the sea and South of Egypt. The center block depicts the prince of Punt and his wife, the latter obviously suffering from elephantiasis (Fig. 1d), followed by bearers of merchandise. On the left is the princess’ ass, above which is inscribed “the ass which carries his wife”’ (Fig. 1c).

Fig. 1.

The ancient Egyptian relief depicting elephantiasis at the Terrace of Queen Hatshepsut’s temple.

(a) Queen Hatshepsut’s temple at EL-Deir Bahari, (b) The Egyptian Museum in Cairo, (c) A relief (replica) depicting bearers of merchandise and the ass to carry the princess of Punt (d) The princess of Punt with elephantiasis.

In Japan, pictures of a female with elephantiasis-like lower extremities and a male with suspected hydrocele/elephantiasis of the scrotum, which date back to about A.D. 1100-1200, were found. One picture in the “Diseases Picture Scroll”, which is the property of Tokyo National Museum, depicts a female with possible elephantiasis of the legs (Fig. 2a, b, c, d). The pictures in the “Strange Diseases Picture Scroll”, which is the property of Kyoto National Museum, show leg elephantiasis and hydrocele/elephantiasis of the scrotum (Fig. 3a, b, c, d).

Fig. 2.

A millennium-old picture scroll depicting elephantiasis.

(a) Tokyo National Museum, (b) The “Diseases Picture Scroll” (left) and its wooden container (right), (c) & (d) A picture of a woman with elephantiasis on both legs.

Fig. 3.

A millennium-old picture scroll (“Strange Diseases Picture Scroll”) depicting elephantiasis and hydrocele.

(a) Kyoto National Museum, (b) A lady with elephantiasis, (c) & (d) Hydocele (or elephantiasis of the scrotum) cases.

Concerning a big scrotum, the “Unofficial History of Kuma” describes an episode of a young soldier named Yohyoe Kitazaki. During the war between the Satsuma (Kagoshima) and Sagara (Kumamoto) clans fought in 1555, Kitazaki showed his comrades a wrapped head of a Satsuma enemy, which indicated his war achievement. In fact, however, in the cloth wrapper was a hydrocele of human-head size cut off from a dead soldier. The story suggests that a huge hydrocele was not uncommon in Satsuma in those days. Hokusai Katsushika (1760-1849), a renowned Japanese artist, portrayed huge elephantiasis of the scrotum in paintings (Fig. 4).

Fig. 4.

“Big scrotum”(elephantiasis of the scrotum) drawn by Hokusai Katsushika in the Edo era.

2 Epidemiology and control of filariasis

2.1 Prevalence in Kagoshima prefecture

Between 1911 and 1961, a year before the government-sponsored National Filariasis Control Program was started, there were 176 published reports on filariasis. The reported endemicity in mainland Kagoshima and coastal islands is shown in Table 1a, b. The microfilaria positive rate among people living on coastal islands was 16.6% (4,337 positives out of 26,069 examined), and the rate was especially high in Amami Oshima Island at 19.6%. In mainland Kagoshima, the microfilaria positive rate was 11.3% (1,629 positives out of 14,359 examined), revealing that filariasis was widely spread in Kagoshima prefecture.

Table 1.

Prevalence of filariasis in Kagoshima prefecture (1912-1961)

(a) Results of examinations in the islands of Kagoshima
Districts	No. report	No. examined	No. positive	Positive rate (%)
Amami-Oshima	58	15,206	2,976	19.6
Mishima and Toshima	13	2,304	369	16.0
Tanegashima and Yakushima	21	5,933	597	10.1
Koshikijima	11	1,788	267	14.9
Nagashima	9	838	128	15.3
Total	112	26,069	4,337	16.6

(b) Results of examinations in the mainland of Kagoshima
Districts	No. report	Mo.examined	No. positive	Positive rate (%)
South Satsuma	30	9,084	1,025	11.3
Central	9	793	102	12.9
Northern	15	2,504	293	11.7
North Osumi	1	97	0	0.0
South Osumi	12	1,881	209	11.1
Total	67	14,359	1,629	11.3

2.2 Filariasis treatment with diethylcarbamazine

For filariasis treatment, antimonials or arsenicals had been used without satisfactory results. In 1947, Hewitt and his colleagues used one of the piperazine derivatives, 1-diethyl-carbamyl-4-methylpiperazine hydrochloride (Hetrazan), for the first time and reported that it showed remarkable effects in the treatment of Litomosoides carinii and Dirqfilaria immitis. Afterwards, Santiago-Stevenson et al. (1947), Hewitt et al. (1950), and others reported, one after another, the disappearance of microfilariae in blood by using the drug. In Japan, Suganuma (Department of Pharmacology, Tokyo University, 1950) synthesized 1-diethylcarbamyl-4-methyl-piperazine citrate (Supatonin). Notable anti-microfilarial effects of Supatonin were confirmed and reported by such famous researchers as Kitamura and Katamine (1951), Sasa and Hayashi (1951), and Hachiro Sato (1952).

The drug, Supatonin, came into our possession in 1950 for trial use, and was proven to exert remarkable effects in filariasis control programs.

Kiyohara district, Bonotsu, Kagoshima prefecture, was heavily affected with filariasis and there were many symptomatic cases. Different doses of diethylcarbamazine citrate (DEC) were tested in the district and anti-microfilarial effects were followed up for as long as 5 years (Fig. 5). The study revealed that DEC was most effective when administered at a total dose of 71 mg/kg of body weight (BW). As the efficacy persisted for 5 years, it was considered that the dose could affect not only microfilariae but also adult worms.

Fig. 5.

Change in microfilaria (Mf) counts after DEC treatment at different dosages (results of 5-year follow-up). Pre-treatment counts are regarded as 100%.

2.3 Basic issues considered in conducting filariasis surveys

In the early stage of filariasis studies when a large-scale treatment campaign was expected in the near future, it was necessary to answer several basic questions, such as i) suitable treatment scheme (optimal dose of DEC and treatment period), ii) occurrence of side reactions after treatment, iii) suitable time for blood sampling, iv) amount of blood to be used for microfilaria detection, v) capability of examiners to collect blood samples, and vi) how to secure people’s cooperation.

(1) Treatment scheme:

The same dose of 5 mg/kg BW was given in 3 different treatment schedules, that is, 5 mg/kg daily for 10 days, once a week for 10 weeks, and once a month for 10 months. The study revealed that there was no difference among the 3 schedules (microfilaria reduction 74-80% at 1 year). Results of a 10-year follow-up study on the effect of 10 weekly treatments at 5 mg/kg, followed by another treatment at 6 mg/kg x 5 times 1 year after the weekly treatments, are shown in Fig. 6.

Fig. 6.

Effects of 10 weekly treatments with DEC at 5 mg/kg, followed by 5 treatments at 6 mg/kg, on microfilaria (Mf) positive rate and the number of Mf (results of 10-year observation). Pre-treatment levels are regarded as 100%.

(2) Occurrence of side reactions after treatment:

A variety of side effects developed after DEC administration, especially in microfilaria positive persons (Table 2). The most problematic one was fever, which occurred in 25.9% of those treated. The fever appeared 1-3 days after the start of DEC administration in most cases, and became highest when microfilariae decreased rapidly in blood (Fig. 7). The fever lowered gradually even when the drug was taken continuously. It has been assumed that fever is the result of allergic or pyrogenic reaction caused by killed worms. In the case of Brugia malayi high fever is common, while in Wuchereria bancrofti it is around 37.0°C. People used to accept the explanation that they should continue taking DEC even when fever appeared, because the fever was a sign that the drug was killing parasites.

Table 2.

Side effects caused by Supatonin

Study site (No. examined)	A (81)	B (27)	C (21)	D (8)	E (44)	Total (181)	%
symptoms
fever	18	10	2	4	13	47	25.9
shivering	8	8	2	0	10	28	15.5
lymphnode swelling	5	3	2	0	1	11	6.1
scrotal swelling	2	1	1	0	1	5	2.8
malaise	27	14	9	7	25	82	45.3
headache	22	15	4	7	20	68	37.6
dizziness	9	4	1	2	2	18	9.9
headache dull	15	7	2	4	11	39	21.5
nausea	7	2	3	1	4	17	9.4
vomiting	2	1	1	0	0	4	2.2
anorexia	11	4	3	2	11	31	17.1
diarrhea	4	6	3	3	8	24	13.2
gurgle	21	11	3	2	11	48	26.5
abdomiral pain	10	2	1	0	7	20	11.0
no reactions	33	4	7	0	8	52	28.7

Fig. 7.

The number of side reactions experienced by 181 people.

(3) Suitable time for blood sampling:

Nocturnally periodic W. bancrofti was endemic in Japan. In order to decide the proper time for blood collection, 63 known microfilaria positives were examined at 18:00, 19:00, 20:00, 21:00, and 22:00 hours, and microfilaria rates and counts were compared (Table 3). At 21:00, the count was only about a half of that at 22:00. However microfilaria detection rate was 98.4% (100% at 22:00). It was concluded that sampling at 21:00 was acceptable as long as careful microscopical examination would be done. Another factor necessary to decide sampling time was the relationship with people. People were requested to gather at a public hall for blood collection, and expected to be examined as early as possible. Considering the fact that a usual sample collection needed 3 to 4 hours to complete, the start at 21:00 was considered reasonable.

Table 3.

Effects of time of blood collection on Mf detection rate and the number of Mf*

Hours of blood collection		18:00	19:00	20:00	21:00	22:00
A	No. Mf positives	19	44	53	62	63
B	Mf positive rate 100 x (A/63)	30.1%	70.0%	84.1%	98.4%	100.0%
C	Total no. of Mf	29	653	2437	3596	7410
D	Average no. of Mf (C/A)	1.5	14.8	46	58	117.6

* 63 known Mf positives were examined.

(4) Amount of blood to be used for microfilaria detection:

Different quantities of 10 µl (sample A), 20 µl (sample B), and 30 µl (sample C) were smeared on each slide glass to compare the efficiency of microfilaria detection (60 µl in total was collected from each person). With 76 microfilaria positive persons, the positive rates according to different blood quantity were 66/76 (86.8%) in (A), 72/76 (94.7%) in (B), 74/76 (97.4%) in (A+B, 30 µl of blood), 73/76 (96.1%) in (C), and 76/76 (100%) in (A+B+C, 60 µl of blood). The total number of microfilariae detected was 579, 982, 1561, 1277 and 2838, respectively, which are in the ratios of 1 : 1.7 : 2.7 : 2.2 : 4.9. Although collecting 60 µl of blood was ideal, it was decided to use 30 µl samples.

(5) Capability of examiners to collect blood samples:

After a few days of training, an examiner became efficient enough to process about 100 blood smears in 3 hours, from 21:00 to 24:00 hours.

(6) How to secure people’s cooperation:

It became apparent that the most important and effective strategy to control filariasis was to obtain the support of people. At the same time, it was understood, by a questionnaire-based survey, that people did not have sufficient knowledge on filariasis transmission and its control. The survey revealed that 87 (25.1%) of 346 people questioned gave the answer that filariasis was a hereditary disease. Only about a half (52.8%) of those questioned knew that filariasis was an infectious disease. As for the night blood survey, 72 people (20.8%) answered that the survey was conducted at night for the convenience for the people gathering, while 230 (66.4%) correctly related it to the nocturnal periodicity of microfilariae. Activities to enlighten people were then intensified both by academic institutions and administrative agencies. Circulars explaining the importance of mosquitoes as a vector, and the necessity of blood examinations and DEC treatment were distributed. In villages, live microfilariae were demonstrated using a microscope.

In conclusion, the following policies were proposed for filariasis surveys: i) 30 µl of blood is taken starting from 21:00 hours, ii) one examiner collects 100 blood samples per night, iii) DEC is given at 70 mg/kg BW in total, which can be administered continuously (daily) or intermittently (weekly or monthly), and iv) to secure people’s cooperation, publicity and education activities are essential. Thorough explanation is needed on side reactions, especially fever.

2.4 The National Filariasis Control Program

After the end of World War II, such leading researchers as Hachiro Sato (Kagoshima University), Daisuke Katamine (Nagasaki University) and Manabu Sasa (Tokyo University) clarified the situation of filariasis prevalence in Japan. The disease was spread widely, affecting many people. The researchers urged the government to establish a national project to control filariasis, and the National Filariasis Control Program was inaugurated in 1962. The program continued for 10 years until l971.

The filariasis control measures included two components: anti-vector mosquito activities (residual spraying of DDT) and treatment of microfilaria carriers. However, it became apparent that the two components could not be performed together particularly in remote areas and islands. Accordingly, an emphasis was put on detecting microfilaria positives by night blood survey and treating them with DEC. The standard treatment recommended by the Ministry of Health was as follows. Using a 50 mg DEC tablet, adults are given 2 tablets/day for 3 consecutive days, 6 tablets/day for the next 3 days, followed by weekly dose of 6 tablets/day for 8 weeks. Thus 9 weeks were needed to complete the treatment. For younger people, reduced dosages were used but with the same time schedule, that is, for junior high school students, 2 tablets/day in the first 3 days and 4 tablets/day thereafter, and for elementary school and younger children, 1 tablet/day first and then 3 tablets/day.

Nine local governments (Tokyo and 8 prefectures) participated in the National Filariasis Control Program for 10 years (1962-1971), during which time 2,039,728 people were examined and 27,450 (l.7%) microfilaria positives were found. Particularly in Kagoshima prefecture, as many as 27,450 (3.56%) positives were found among 771,924 people examined, and in Nagasaki prefecture, 6,214 (0.88%) out of 709,300 were positive. The known microfilaria positive persons were treated with DEC with remarkable success. Yearly changes in microfilaremia prevalence in Kagoshima prefecture are shown in Table 4.

Table 4.

Changes in microfilaria (Mf) positive rate in Kagoshima prefecture during the National Filariasis Control Program

Year	No. examined	No. Mf positive	Mf Positive rate (%)
1962	135,557	8,968	6.6
1963	167,604	6,597	3.9
1964	99,864	4,498	4.5
1965	81,503	2,918	3.6
1966	61,969	1,958	3.2
1967	68,446	1,186	1.7
1968	61,116	755	1.2
1969	66,102	345	0.5
1970	18,118	134	0.7
1971	11,645	91	0.8
Total	771,924	27,450	3.6

2.5 Follow-up studies by means of the nuclepore filtration method and skin test

(1) A study in Kiyohara district, Bonotsu:

In this district, all 802 people examined in 1970 were proven to be microfilaria negative as a result of past DEC treatments. In 1979, a follow-up study was conducted by means of 60 µl blood smears using earlobe blood and 1 ml nuclepore membrane filtration using venous blood. No microfilaria was detected by either method. Skin test using FPT antigen (Tada, 1964), which was extracted from Dirofilaria immitis, was also employed to obtain information on sensitization to filariae. Positive rates by skin test in different age groups were 0% for 0-9 years, 5.3% for 10-19 years, 11.1% for 20-29 years, 35.3% for 30-39 years, 40.0% for 40-49 years, 42.6% for 50-59 years, 40.4% for 60-69 years, 54.8% for 70-79 years and 42.9% for 80 years and over. The positive rates increased gradually by age and reached a plateau after 40 years. A remarkable finding was that 56 children of age 0-9 years, who were born after treatments had eliminated microfilaremia were all negative (Fig. 8a, b). The skin test results from various endemic and non-endemic areas are compared in Fig. 9. Endemic areas show very high positive rates already at age 10 years, while Bonotsu shows a similar pattern to Nishinoura a non-endemic area, suggesting that the transmission of filariasis had been interrupted.

Fig. 8.

Skin test results according to age group. (a) Age groups under 40 years, (b) Age groups of 40 years or more.

Fig. 9.

Skin test results from various endemic and non-endemic areas.

(2) A study in Kuroshima island Yaeyama arehipelago, Okinawa:

Kuroshima had a population of 570 in 1967, but this decreased to 176 in 1980 for social and/or economic reasons. The microfilaria rates in 1967 and 1968 were 13.2% and 12.5%, respectively.

DEC treatment (6 tablets/day for 12 days) was given in 1968. The microfilaria rate by blood smear was 0.3% in 1976, which decreased to 0% in 1980. The nuclepore filtration method also detected no positive case in 1980.

The skin test results showed that the positive rate in the age group of 0-9 years declined steadily from 55.3% in 1967 to 11.3% in 1973 and to 0% in 1980, while adults of 30 years and older maintained high positive rates of 65-70%. These results suggested that children born after 1970 were not sensitized by filarial antigen, or that there had been no new infection over the previous 10 years.

2.6 Change in prevalence of chyluria after treatment

Between 1961 and 1965, 32,397 out-patients visited the 2nd Department of Internal Medicine, Kagoshima University Hospital, of whom 147 (0.45%) were chyluria cases. In the period of 1975-1979, there were 25 (0.09%) chyluria cases out of 27,037 out-patients. At Kagoshima Prefectural Oshima Hospital in Amami Oshima Island, where filariasis was highly endemic, chyluria patients in the same periods decreased from 176 (0.86% of 20,514 outpatients) to 30 (0.13% of 22,951 outpatients), indicating that DEC treatments contributed to the reduction of chyluria (Table 5a, b). It is interesting to note that at the same Oshima Hospital, the number of chyluria patients did not decrease between 1981 and 1990 (Kimura E. This issue: 58-59)

Table 5.

Change in the number of chyluria patients among outpatients.

(a) The 2nd Department of Internal Medicine, Kagoshima University Hospital
Year	1961	1962	1963	1964	1965	Total	1975	1976	1977	1978	1979	Total
No. of outpatients	5,880	6,130	6,349	6,429	7,609	32,397	5,420	5,819	5,501	5,143	5,154	27,037
No. of chyluria	15	62	29	19	22	147	5	6	5	3	6	25
Rate (%)	0.26	1.01	0.46	0.30	0.29	0.45	0.09	0.10	0.09	0.06	0.12	0.09

(b) Kagoshima Prefectural Oshima Hospital
Year	1961	1962	1963	1964	1965	Total	1975	1976	1977	1978	1979	Total
No. of outpatients	3,459	3,655	3,823	4,680	4,897	20,514	5,210	5,137	4,330	4,142	4,132	22,951
No. of chyluria	28	51	22	40	35	176	8	6	8	3	5	30
Rate (%)	0.81	1.40	0.58	0.85	0.71	0.86	0.15	0.12	0.18	0.07	0.12	0.13