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Keywords:

  • Brugia timori;
  • Wuchereria bancrofti;
  • diethylcarbamazine;
  • albendazole

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Filariasis caused by Brugia timori and Wuchereria bancrofti is an important public health problem on Alor island, East Nusa Tenggara, Indonesia. To implement a control programme, adverse reactions and short-term effects on the microfilaria (mf) density were studied following a divided dose of diethylcarbamazine (DEC, 6 mg/kg body weight – 100 mg on day 1 and the rest on day 3) or a single dose of DEC (6 mg/kg body weight on day 3) and albendazole (Alb, 400 mg). In order to define the most appropriate regimen, 30 persons infected with B. timori were treated in the hospital and results were compared with those obtained from the treatment of 27 persons infected with W. bancrofti. Adverse reactions consisted of systemic reactions such as fever, headache, myalgia, itching and local reactions such as adenolymphangitis. Fever experienced by a number of patients in both treatment groups generally occurred 12–24 h after drug administration and lasted up to 2 days. Adenolymphangitis tended to occur later and was resolved within 4 days. The number of W. bancrofti patients suffering from adverse reactions was lower and the reactions were milder than those of the B. timori patients. There was no difference in adverse reactions between DEC alone and DEC–Alb treatment for either infection. The geometric mean mf count decreased on day 7 in the B. timori infected patients from 234 mf/ml in the DEC group and from 257 mf/ml in the DEC–Alb group to 7 and 8 mf/ml, respectively. The mf densities of the W. bancrofti infected patients decreased on day 7 from 214 mf/ml in the DEC group and from 559 mf/ml in the DEC–Alb group to 15 and 14 mf/ml, respectively. Our data indicate that the microfilaricidal effect of the drugs is achieved more rapidly for B. timori, which is associated with more adverse reactions than W. bancrofti. In addition, 111 B. timori infected persons were treated in the community with DEC–Alb in one selected village. The adverse reactions and the reduction of mf density was similar to the findings of the hospital-based study. In this group, there was a strong correlation of mf density with the frequency and severity of adverse reactions. The addition of Alb resulted in no additional adverse reactions compared with DEC treatment alone and can also be used for the treatment of B. timori infection. In Indonesia, where the prevalence of intestinal helminths is high, the use of a combination of DEC and Alb to control lymphatic filariasis may also have impact on the control of intestinal helminths.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Lymphatic filariasis has been targeted by the World Health Organization for elimination as a public health problem by the year 2020 (Bebehani 1998). In Indonesia, control programmes for lymphatic filariasis have been underway since 1970. Such programmes have relied on low dosage diethylcarbamazine (DEC), 100 mg per week for 40 weeks (Partono 1984). While some success has been observed, filariasis remains a public health problem in many parts of Indonesia. The efficacy of control programmes using the DEC regimen outlined above has been limited by the long duration of the treatment which eventually leads to a decrease in compliance.

The filarial parasite Brugia timori is endemic in eastern Indonesia and is locally of great public health importance (Partono et al. 1978). However, information about epidemiology and control of this parasite is scarce. On Alor island in the province of Nusa Tenggara Timur, B. timori infection is highly prevalent in rice-growing areas, with a prevalence ranging from 5% to 25%, while Wuchereria bancrofti infection can be found in the coastal areas, with a prevalence of up to 20% (Supali et al. 2002).

For the control of W. bancrofti infection, treatment using DEC or ivermectin or a combination of both or of DEC and albendazole (Alb) or ivermectin and Alb, all given in single dose yearly or on two consecutive days, has been shown to be highly effective (Addiss et al. 1993; Kazura et al. 1993; Moulia-Pelat et al. 1994; Addiss et al. 1997). These treatment strategies are recommended for community-based control for the elimination of lymphatic filariasis (Ottesen et al. 1997). However, there is little information available reporting the efficacy of either single dose therapy, or combination therapy for Brugia malayi infection (Mak et al. 1993; Hakim et al. 1995; Shenoy et al. 1998, 2000; Horton et al. 2000). One study shows that ivermectin causes a significant but transient reduction of microfilaremia (Mak et al. 1993), but the manufacturer does not donate ivermectin for use in Asia. Another study shows that a single dose of 6 mg/kg body weight of DEC may be as effective as a standard dose regimen given over a period of 2 weeks (Hakim et al. 1995). The combination of a single dose of DEC with Alb was shown to be most effective for the control of B. malayi infection (Shenoy et al. 1998, 2000). In contrast to B. malayi, no data exist documenting the efficacy of such single dose treatment regimens for the control of B. timori infection.

We compared the efficacy of the new treatment strategies using a single dose of DEC or a combination of DEC and Alb for the treatment of lymphatic filariasis because of B. timori and W. bancrofti on Alor island. Both regimens are highly effective for the rapid elimination of microfilariae (mf) and may be used for community-based treatment on Alor, but more adverse reactions occur in B. timori.

Study area and patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

The study was conducted on the island of Alor, East Nusa Tenggara, Indonesia. Patients were selected from two different villages. Mainang village was highly endemic for B. timori and located in the rice-growing highland area, whereas Wolwal was endemic for W. bancrofti in the coastal area. A previous survey showed that no mixed infections with both filarial parasites occurred in either village (Supali et al. 2002). A total of 57 asymptomatic microfilaremic individuals participated in the hospital-based study. The participants were divided into two groups, the B. timori group and the W. bancrofti group and then stratified by mf densities. Each group contained an equal number of persons with low (1–100 mf/ml night blood), moderate (101–500 mf/ml) and high (> 500 mf/ml) mf densities (Brito et al. 1998). As no experience in single dose DEC or DEC–Alb treatment existed for B. timori, only men were selected for the hospital-based trial. However, two non-pregnant women aged 15 and 20 years insisted to be treated and were therefore included in the study. In total, 30 persons infected with B. timori were treated (average age 30 years, range 11–52 years; average weight 49 kg, range 25–63 kg). For comparison, 27 individuals infected with W. bancrofti were included in the study. This group included 10 non-pregnant women. Three more microfilaremic women had been selected for treatment, but were excluded because of pregnancy. The age and weight distribution in the W. bancrofti group was similar to the B. timori group (average age 30 years, range 13–52 years; average weight 49 kg, range 27–73 kg). There was no significant difference in age, weight and mf density in both treated groups (P > 0.05). With regard to age and weight, individuals were allocated at random to the DEC or the DEC–Alb group. All participants appeared healthy and without acute disease (e.g. malaria).

Hospital-based treatment

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Ethical clearance was received from the Ethical Committee of the Medical Faculty, University of Indonesia, Jakarta. After purpose and methods of the trial had been explained to the participants, informed consent was obtained. Persons were hospitalized for a period of 7 days to monitor adverse reactions and the short-term effects on mf more accurately. The medical history was recorded on a questionnaire by a physician previously trained in filariasis. This was followed by a physical examination. In addition to the general findings, the patients were examined for clinical signs of filariasis (i.e. evaluation of the skin, extremities, lymph nodes and scrotum). All patients were weighed to calculate the appropriate drug dosage.

The patients were then divided into two groups

  • Group DEC:  Day 1: one tablet of DEC (100 mg)

  •  Day 3: rest of DEC up to a total dose of  6 mg/kg body weight

    • Group DEC–Alb: Day 1: placebo

  •  Day 3: DEC (6 mg/kg body weight) and Alb  (400 mg)

Each group consisted of 15 individuals infected with B. timori and 14 or 13 persons infected with W. bancrofti. The DEC–Alb group served as the control group for days 1–2. The patients were instructed to take the tablets after breakfast under the supervision of a doctor.

Assessment of microfilaria densities

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Microfilaria densities were assessed by filtration of 1 ml venous night blood collected between 9.00 and 11.00 p.m. The blood was filtered using a polycarbonate membrane with a pore size of 5 μm (Millipore, Eschborn, Germany). The slides containing the membrane were fixed with methanol, stained with Giemsa and microscopically examined using 100-fold magnification. The microfilarial density was monitored before treatment (day 0) and after treatment on days 1, 3, 5 and 7. The blood collection on day 1 was performed 12 h after drug administration and subsequent collections were started at 9.00 p.m. at the hospital, whereas the blood collection on day 7 was performed after the patients had returned to their villages. The mf counts were log-transferred, and the geometric mean mf counts calculated from the absolute value +1 including those with no mf.

Evaluation of adverse reactions

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Adverse reactions accompanying treatment were systemic ones such as fever, headache, myalgia, itching, or localized like adenolymphangitis. An experienced physician monitored all participants by questioning and through physical examination two times a day, on days 1–5. Body temperature was measured in the armpits at least in the morning and in the evening. Fever was graded as 0 (< 37.8 °C), 1 (37.8–38.5 °C), 2 (38.6–39.5 °C), or 3 (> 39.5 °C). Some patients received symptomatic treatment for adverse reactions with antipyretics and antihistamines.

Community treatment

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

In addition to the hospital-based study, selective treatment was offered to microfilaremic patients in the village endemic for B. timori infection using 6 mg/kg body weight DEC and 400 mg Alb. Children younger than 2 years, pregnant women, breast-feeding women and individuals with cachexia or coexisting major illness were excluded from the treatment. Two local physicians and one physician from the team monitored adverse reactions for 7 days at the primary health centre of Mainang. The local physicians have been trained to recognize them. The medical personnel were also assisted by people who had the experience of treatment in the hospital and had been taught how to explain to their community about the adverse reactions and the benefit of the treatment. To assess the short-term effects on mf densities, night blood was examined on days 1 and 7.

Data analysis

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Statistical analysis was performed using standard software. Patient's data, adverse reactions and microfilaricidal effects were documented and analysed using SPSS Version 10. The geometric mean of mf density before (day 0) and after treatment (days 1, 3, 5, 7) was analysed using one-way anova, and then further analysed by Tukey test if the one-way anova result was significant. The correlation between mf density and fever was analysed by Spearman, as well as the correlation between mf density and adverse reactions. The difference of the adverse reactions observed in both treatment groups was compared by chi-square.

Treatment of B. timori infection

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Thirty B. timori infected patients participated in the hospital-based trial and were monitored for possible adverse reactions as well as for their mf count. In the DEC treated group, fever was observed in seven patients, but only one of them had 39.2 °C, whereas the others had < 38.5 °C. Fever lasted no longer than 2 days. In the DEC–Alb treated group, only five patients had fever occurring 12–24 h after drug administration (four patients 37.8–38.5 °C, one patient 38.6–39.5 °C). There was no significant difference in the number of patients who experienced fever in both groups (P = 0.456). In both treatment groups, no significant correlation was detected between mf density and the frequency and severity of fever in persons who received DEC (r = −0.224, P = 0.423), as well as in those who received DEC–Alb (r = 0.217, P = 0.438).

No difference in the frequency of other adverse reactions was found in the two treatment groups (P = 0.107). Headache was the most frequent (15 patients) followed by myalgia (13 patients), itching (eight patients) and adenolymphangitis (eight patients). All 30 patients reported at least one kind of side-effect. In this small sample, no association between the number of adverse reactions and mf density could be found (r = 0.449, P = 0.093 in DEC group and r = 0.610, P = 0.056 in DEC–Alb). Nobody experienced severe or life-threatening adverse reactions. Systemic adverse reactions occurred 6–24 h after treatment, lasted up to 48 h and could be easily resolved by antipyretics and antihistamines. Localized adverse reactions tended to occur slightly later, 12 h after treatment, and lasted 4 days.

On day 1 following DEC treatment, the geometric mean mf count decreased significantly (P < 0.0001) as much as 93% from the pre-treatment level and reached the highest reduction (98%) on day 3. One patient with mf count of 77 mf/ml was amicrofilaremic on day 1 and continued to be so until day 7, whereas three patients with mf counts of 49, 116 and 768 mf/ml before treatment became amicrofilaremic on day 7. The geometric mean mf count of the DEC–Alb treatment group decreased sharply by 95% 12 h after drug administration. One patient with a mf density of 62 mf/ml became amicrofilaremic on day 7. The decrease of the mf density before (day 0) and after treatment (day 1, 3, 5, 7) was significant (P < 0.0001) (Figure 1).

image

Figure 1. The geometric mean of microfilaria (mf) density of Brugia timori infected individuals before treatment and following treatment with either DEC (6 mg/kg body weight, 100 mg on day 1 and the rest on day 3) or a combination of DEC (6 mg/kg body weight, on day 3) and albendazole (400 mg, on day 3).

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In both groups, the mf count slightly increased after reaching lowest peak. However, the geometric mean mf count on days 5 and 7 was not significantly higher compared with the lowest level of mf count (day 3) (P = 0.056). By comparing the decrease of geometric mean mf count between both treatment groups, there was no significant difference on day 3 (P = 0.607) as well as the slight increase of geometric mf count on days 5 and 7, P = 0.894 and P = 0.927, respectively.

Comparison of treatment of W. bancrofti and B. timori infection

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Twenty-seven patients infected with W. bancrofti participated in the hospital-based treatment. Fever between 37.8 and 38.5 °C was observed in one patient treated with DEC as well as in one patient treated with DEC–Alb and no correlation of the occurrence of fever with mf density was found (r = −0.201, P = 0.278). Only systemic adverse reactions were recorded in the treated patients and no adenolymphangitis was observed. A total of 16 (59%) patients reported at least one sign of side-effects. The number of adverse reactions showed no significant correlation with mf density in either treatment group (DEC group: r = 0.05, P = 0.870, DEC–Alb: r = 0.107, P = 0.716), and there was no significant difference in adverse reactions between DEC alone and DEC–Alb treatments (P = 0.527).

In the DEC treated patients, as well as in DEC–Alb treated patients, the geometric mean mf count declined progressively beginning from day 1 to day 5, reaching a minimum of 98% and 99% of the pre-treatment counts. After reaching the lowest peak, the geometric mf count rose slightly on day 7. On day 1, no patients of the DEC treated group became amicrofilaremic, but until day 7, two patients with pre-treatment mf densities of 5 and 74 mf/ml, respectively, were mf negative. In the DEC–Alb group, one patient with a pre-treatment mf density of 8 mf/ml became amicrofilaremic on day 7. The pattern of the microfilaricidal effect in both groups of treatment showed that the mf count decreased sharply in 2 days after the administration of the total dose, then followed by a slight increase. However, this increase was not significant compared with the lowest level of mf density (P = 0.22) (Figure 2).

image

Figure 2. The geometric mean of microfilaria (mf) density in the treatment of Wuchereria bancrofti infected persons before treatment and following treatment with either DEC (6 mg/kg body weight, 100 mg on day 1 and the rest on day 3) or a combination of DEC (6 mg/kg body weight, on day 3) and albendazole (400 mg, on day 3).

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In both B. timori and W. bancrofti infection, the signs, number and severity of adverse reactions were similar in the DEC and in the DEC–Alb treatment group. But fever after treatment occurred in 40% of the B. timori patients and only in 7% of the W. bancrofti patients. This difference is statistically significant (P = 0.004). In addition, all of the B. timori patients suffered at least one adverse reaction, while 41% of the W. bancrofti patients had no complaints. A significantly higher number of adverse reactions was found in B. timori patients (P < 0.0001). The decline of mf count in the W. bancrofti group was slower. The mf density in both groups was slightly increased on day 7 but not significantly different compared with the lowest level of mf density. Although short-term efficacy of DEC and DEC–Alb was similar in W. bancrofti and B. timori, more adverse reactions were encountered in the patients infected with the latter species.

Community treatment of B. timori

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Of 158 microfilaremic patients identified in one B. timori endemic village, 30 patients were treated in the hospital and 111 persons were treated in the village. In the hospital-based trial, there was no difference between DEC and DEC–Alb with regard to adverse reactions and short-term reduction mf density. Because of the helminthicidal effect of Alb on intestinal helminths, DEC–Alb was chosen for treatment in the community. Infected individuals were called to the primary health centre and received a single oral dose of DEC–Alb. Seventy-three treated patients came to the health centre for monitoring of adverse reactions. The rest of the treated patients, who were mostly children, did not come to the health centre as they had no complaints. About 10% of the treated patients experienced unpleasant adverse reactions that interfered with their daily activities and five reported that they could not leave their beds. They stayed in bed only 1 day until the symptomatic drugs could alleviate the adverse reactions. Most of the treated people reported fever and myalgia, followed by adenolymphangitis, headache and itching. The number of adverse reactions correlated positively with mf density (r = 0.413 and P < 0.0001) (Figure 3).

image

Figure 3. Adverse reactions of 73 individuals infected with B. timori following treatment in Mainang village using a single dose combination of DEC (6 mg/kg body weight) and albendazole (400 mg) in relation to microfilaria (mf) density. Low mf density was defined as 1–100 mf/ml, moderate mf density as 101–500 mf/ml and high mf density as above 500 mf/ml.

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Fifty-four patients came to the primary health centre for night blood collection on day 1 after treatment. Twenty-three (43%) of these 54 patients became mf negative and 31 were still mf positive with the highest mf density of 389 mf/ml. On day 7, 38 patients participated in night blood collection, seven patients were still mf negative, while 31 were microfilaremic. The mf densities 1 week following treatment were usually low, 48% had less than 100 mf/ml, 42% between 101 and 500 mf/ml and only 10% more than 500 mf/ml (Figure 4).

image

Figure 4. The geometric mean of microfilaria (mf) density in B. timori infected individuals treated in the community of Mainang village before treatment and following treatment with a combination of DEC (6 mg/kg body weight) and albendazole (400 mg).

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

Indonesia is the only country in the world endemic for all three lymphatic filarial parasites, W. bancrofti, B. malayi and B. timori. Before a national filariasis control programme using a combination of DEC and Alb as recommended by WHO can be started in Indonesia, it is necessary to evaluate safety and efficacy of the treatment for all of these parasites. Most of the published treatment studies of lymphatic filariasis in humans were carried out with W. bancrofti. Less information is available on the treatment of brugian filariasis and there is a need to collect further data on a single dose treatment strategy to predict the outcome of elimination programmes targeting brugian filariasis (Horton et al. 2000). Only very few drug studies, especially with low dosage of DEC, were performed in B. timori endemic areas (Partono et al. 1981, 1984).

We used two regimens, DEC 6 mg/kg given on 2 days (100 mg on day 1 and the rest on day 3) and single oral dose of DEC 6 mg/kg and Alb 400 mg, to treat B. timori and W. bancrofti infected patients in a hospital-based trial. The types of adverse reactions were generally similar in both regimens. No evidence was found that the addition of Alb resulted in additional adverse reactions compared with DEC treatment alone. In this sample, no correlation between adverse reactions and mf density was found. However, this may be caused by the relatively small sample size. Adverse reactions were usually mild and could be treated symptomatically using antipyretics and antihistamines. In the treated B. timori infected individuals, the percentage of fever as well as the number of adverse reactions was higher than in W. bancrofti patients. Adenolymphangitis observed in patients treated with both regimens showed that DEC has prominent macrofilaricidal activity that induces local inflammatory responses around dying parasites (Partono et al. 1984).

The mf killing effect of the drug on the low, moderate and high mf densities of B. timori infected patients gave a characteristic pattern similar to that in the W. bancrofti infected patients. However, there was a significant difference between both filarial parasites in reaching the minimum level of mf count. In the B. timori patients, the mf count decreased dramatically on day 3 and slightly increased on days 5 and 7. On the other hand, in W. bancrofti patients, the mf count went down gradually and reached minimum level on day 5. Our data indicate that the microfilaricidal effect 1 week after drug administration is more potent in B. timori infections, which is associated with more severe adverse reactions compared with W. bancrofti. There was no significant difference in decreasing mf count between both treatment regimens in B. timori and W. bancrofti patients. In W. bancrofti infection, Alb also has moderate microfilaricidal effect (Ismail et al. 1998). However, our data from the hospital-based treatment of B. timori or W. bancrofti patients could not show that the addition of Alb to DEC does significantly increase the microfilaricidal effect. The decline in mf counts may be indicative of the initial direct microfilaricidal effect of DEC being followed by DEC–Alb action on the adult parasites. Therefore, further studies on the micro- and macrofilaricidal effects of the treatment are needed and in our project blood sample collection will be continued every 6 months for 2 years.

Resurgence of mf count was also observed in DEC treatment alone in B. malayi filariasis carried out in India. The mf level increased marginally from day 2 to peak on day 30 and then falling again to give 97% clearance by 1 year (Shenoy et al. 1993). The marked clearance of mf on the first day following treatment with DEC is probably attributable to rapid killing of mf by DEC.

Our data indicate that the addition of Alb may not induce more adverse reactions. However, more attention should be paid in treating the B. timori infected population, because of its higher number of adverse reactions. In a country such as Indonesia, where the prevalence of intestinal helminths is also high, the use of the combination drugs, DEC–Alb, in the lymphatic filariasis control programme will give additional impact in the control programme of intestinal helminths.

Taken together, adverse reactions after treatment of B. timori infection were more frequently observed than following treatment of W. bancrofti infection. However, the adverse reactions observed following treatment of B. timori appear to be similar to those observed in the treatment of B. malayi infections. In the treatment of B. timori infections, mf densities are rapidly reduced and there was no evidence that treatment of B. timori infection differs from the treatment of B. malayi. The adverse reactions accompanying treatment in most patients are usually tolerable and our results indicate that a combination of DEC and Alb may be suitable for the community-based treatment of B. timori infection in Indonesia.

In the community treatment, there was correlation between mf density and adverse reactions. This result confirms earlier findings on therapy in B. malayi filariasis patients (‘endemic normals’, microfilaremics and elephantiasis patients) carried out in South Sulawesi, Indonesia; that the increase in severity of adverse reactions correlated with mf density in the blood. It was suggested that the adverse reactions were associated with the presence of mf and not with the adult worms in the lymphatics or with developing worms in any tissue as a proportion of the ‘endemic normals’ and mf-negative elephantiasis patients who had elevated antifilarial IgG4 experienced no or only mild adverse reactions (Haarbrink et al. 1999a). The adverse reactions to DEC treatment are due to host inflammatory mediators released in response to antigens from the direct effect of the drug in killing the mf. The dead parasites, mf and adult worms, induce the release of high levels of antigen, which results in local and systemic inflammatory reactions. Some studies showed a correlation between the increase of cytokine level in the plasma after treatment of microfilaremics with the adverse reactions (Yazdanbakhsh et al. 1992; Turner et al. 1994). The level of IL-6, which is known to play a central role in the induction of acute phase proteins during inflammation, increased early after the initiation of the treatment. The increase of IL-6 level is strongly correlated to the increase of body temperature. The increase of IL-6 was followed by an increase in LBP and TNF-R75 indicating a strong association between the immunological markers and systemic reaction to DEC (Haarbrink et al. 1999b).

We showed that B. timori can be treated using a single dose of DEC–Alb as recommended by WHO in the global programme for the elimination of lymphatic filariasis. Although more side-effects were observed in the treatment of B. timori infection, they were neither severe nor life-threatening. The strong reduction of mf density after 1 week does not indicate that the efficacy of a single dose of DEC–Alb is lower in B. timori than in W. bancrofti infection or as reported for B. malayi infection. Further studies have to evaluate the long-term reduction of B. timori mf load after DEC–Alb treatment.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References

We would like to thank Dr Yenny Djuardi, Dr Heri Wibowo and Sudirman from the Department of Parasitology, Faculty of Medicine, University of Indonesia and Dr Paul Manoempil, Head of Health District Administration, Alor Regency. We also appreciate the help of the district health workers during the survey and all participants of the study. This study received financial support from the German Agency for Technical Co-operation GTZ/SISKES.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Study area and patients
  6. Hospital-based treatment
  7. Assessment of microfilaria densities
  8. Evaluation of adverse reactions
  9. Community treatment
  10. Data analysis
  11. Results
  12. Treatment of B. timori infection
  13. Comparison of treatment of W. bancrofti and B. timori infection
  14. Community treatment of B. timori
  15. Discussion
  16. Acknowledgements
  17. References
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