Children and adolescents infected with <i>wuchereria bancrofti</i> in greater recife, brazil: a randomized, year-long clinical trial of single treatments with diethylcarbamazine or diethylcarbamazineÂŒalbendazole

Annals of Tropical Medicine & Parasitology, Vol. 101, No. 5, 423–433 (2007) Children and adolescents infected with Wuchereriabancrofti in Greater Recife, Brazil: a randomized,year-long clinical trial of single treatments withdiethylcarbamazine or diethylcarbamazine–albendazole ˆ . RIZZO*,{, C. BELO{, R. LINS{ and G. DREYER{,1 *Rua do Sossego 715, CEP 50100-150, Recife, PE, Brazil{Centro de Pesquisas em Alergia e Imunologia Clı´nica, Ambulato´rio de Alergia, Hospital dasClı´nicas, Universidade Federal de Pernambuco, Avenida Moraes Rego s/n, Cidade Universita´ria,CEP 50740-900, Recife, PE, Brazil{Nu´cleo de Ensino, Pesquisa e Assisteˆncia em Filariose (NEPAF), Centro de Cieˆncias da Sau´de,Hospital das Clı´nicas, Universidade Federal de Pernambuco, Avenida Professor Moraes Rego s/n,Cidade Universita´ria, CEP 50740-900, Recife, PE, Brazil1Centro de Pesquisas Aggeu Magalha˜es – Fiocruz, Avenida Moraes Rego s/n, CidadeUniversita´ria, CEP 50670-420, Recife, PE, Brazil Received 10 May 2006, Revised 20 November 2006,Accepted 23 November 2006 In filariasis-endemic areas beyond sub-Saharan Africa, the World Health Organization’s recommended strategy forinterrupting transmission of the causative parasites is annual, single-dose, mass treatment with a combination ofdiethylcarbamazine (DEC; given at 6 mg/kg) and albendazole (ALB; given at 400 mg) for 4–6 years (the minimumestimated life-span of the adult parasites). In an open, hospital-based, randomized and controlled trial, with ablinded evaluation of outcome, 82 children and adolescents from Recife, all with Wuchereria bancroftimicrofilaraemias, were given either DEC alone (6 mg/kg) or the same dose of DEC combined with ALB (at400 mg/patient). Every 90 days for 1 year after the single treatment, each patient was checked for microfilaraemiaby the filtration of up to 5 ml of venous blood collected at night. One year post-treatment, 16 (39%) of the 41patients given DEC alone and 20 (49%) of the 41 given DEC–ALB were found microfilaraemic (relative risk50.8,with a 95% confidence interval of 0.49–1.31) and the corresponding geometric mean levels of microfilaraemia were2.0% and 1.8% of the levels recorded immediately pre-treatment, respectively (P.0.05). In terms of theprevalences and intensities of microfilaraemia, therefore, the addition of ALB to the DEC appeared to offer nosignificant benefit.
In humans, lymphatic filariasis (LF) is a South and Central America. It is considered major cause of clinical morbidity, affecting of permanent disability (WHO, 2003).
Wuchereria bancrofti is the most wide-spread of the species of filariae that cause LF andone that infects approximately 100 millionpeople in tropical and sub-tropical areas, Pesquisa e Assisteˆncia em Filariose (NEPAF), Centrode Professor Moraes Rego s/n, Cidade Universita´ria, tions occur years after initial infection, LF is CEP 50740-900, Recife, PE, Brazil. E-mail; fax: z55 81 3426 4348.
frequently viewed as an adult disease. The # 2007 The Liverpool School of Tropical Medicine earlier notion that LF is not a paediatric (2001) found that many children in endemic Most clinical and field trials investigating the efficacy and tolerance of such DEC– filaraemic, even when the detection method ALB combinations, in bancroftian filariasis, have used adult subjects (Ismail et al., 1998, technique traditionally used for diagnosis: 2001; Pani et al., 2002; El Setouhy et al., 2004; Kshirsagar et al., 2004; Fox et al., 2005), and not all of them have included a diagnostic tools, such as assays to detect filarial antigens and ultrasound to visualize living adult worms in their natural habitat, even in the absence of microfilaraemia, has included 24 children under 14 years of age added further evidence of childhood infec- in their study group of 54 individuals but tion. In a cohort of Haitian children, for did not give separate efficacy results for their example, the prevalence of microfilaraemia recent, community-based study, Fox et al.
1.3% between the ages of 2 and 4 years but relatively short follow-up (6 months) and a relatively insensitive method (the microsco- pical examination of a 20-ml thick smear) to (14%) of the 78 children they investigated.
appear to have been no randomized trials, Living adult worms were detected, in nine boys, in the intrascrotal lymphatic vessels effects on microfilaraemia of single treat- and those of the inguinal cord, demonstrat- the present study, which was triggered partly tasia) without overt clinical disease (Dreyer lymphatic damage of infected children sets Kumaraswami, 2004), was to fill this gap, the stage for the pathological changes and using, as subjects, children and adolescents disability seen in adults. By treating the possible to prevent many, if not all, ofthe chronic and often irreversible manifesta-tions of lymphatic dysfunction seen later inlife.
The research protocol was approved by the Federal University of Pernambuco, Brazil, and written informed consent was obtained either from the subjects (if aged >16 years) or their parents/guardians (for subjects aged ,16 years). The travel costs of the patients DEC OR DEC–ALBENDAZOLE TREATMENT OF CHILDREN and their parents were paid by the research microfilaraemia clearance previously observed 1 year after a single treatment with DEC(40%; Andrade et al. 1995), and thecorresponding frequencies, of about 70%, observed or predicted for ALB–ivermectin (Bockarie et al., 1998) and DEC–ivermec- tin (Ismail et al., 1998). In order to give a (microfilaraemia prevalence and intensity), using stratified, parallel groups of micro- in the prevalence of microfilaraemia, it was estimated that 42 patients would be needed aim was to compare the effects on outcome, up to 1 year post-treatment, of a single dose study, the patients were stratified into four groups according to the intensities of their microfilaraemias (1–100, 101–250, 251–1000 and .1000 microfilarae/ml blood). A restricted block-randomization list for each To be enrolled, a patient had to be aged 9– stratum was then generated (by an indivi- 19 years and to have been found microfilar- dual who was not otherwise connected with aemic (by the microscopical examination of the research). At the Nu´cleo de Ensino, a thick bloodsmear), by staff working for the Pesquisa e Assisteˆncia em Filariose (NEPAF), governmental programme for filariasis con- trol, during screening in the city of Jaboata˜o metropolitan area. Greater Recife lies in an area of north–eastern Brazil where bancrof- their baseline levels of microfilaraemia.
Patients were excluded if they: (1) had a They were then sent to the paediatric ward history of any previous treatment with DEC, in the Hospital das Clı´nicas, for medical ivermectin or any other anti-helminthic drug history of severe asthma or seizures, cardio- patient for microfilaraemia, and estimated vascular, hepatic or renal disease, or other conditions for which antifilarial drugs might be contra-indicated; (3) were female and of reproductive age and either refused to be tested for pregnancy or gave a positive resultin a pregnancy (human chorionic gonado- tropin) test; (4) reported personal or par- All patients underwent an initial assessment for inclusion and exclusion criteria, quanti- fication of microfilaraemia at night, and amedical evaluation that included the taking of a clinical history, a complete physical examination, and a social interview. All the females of reproductive age had a blood test ,0.05 was considered indicative of a statis- supervision, between 08.30 and 09.30 hours.
Doses of DEC (Farmanguinhos, Rio deJaneiro, Brazil) were calculated as 6 mg/kgbody weight, rounded upwards to the nearest 25 mg (i.e. half of a 50-mg tablet).
Albendazole Overall, 84 microfilaraemic patients aged 9– single dose, irrespective of bodyweight. A 5-ml sample of venous ‘night’ blood was the other 41 patients to the DEC–ALB arm.
At baseline, the patients in the two treat- filtration of 1-ml aliquots of these blood ment arms appeared similar (see Table).
membranes (Nuclepore, Pleasanton, CA).
days of follow-up. The two other patients (who had pre-treatment microfilaraemias of Giemsa’s stain so that the trapped micro- five and 222 mff/ml) accepted their sched- Kean, 1971). If a 1-ml aliquot of ‘night’ negative for microfilariae (mff), the remain- ing sample (4 ml) was also checked for mff by membrane filtration. (Sera isolated from the blood samples collected are currently arm significantly different from those in the being checked for circulating filarial antigen DEC–ALB arm. Patients in both treatment arms showed statistically significant declinesin microfilaraemia intensity up to day 270 post-treatment but then a much less steep and non-significant reduction between day unpaired t-tests or x2 tests. Intensities of 270 and the final follow-up on day 360. At the end of follow-up, prevalences of micro- means (i.e. using the ‘nz1’ convention to were 2.0% and 1.8% of their pre-treatment transformed before comparison in unpaired levels, respectively (P.0.05; Fig. 1).
intensities of microfilaraemia at different Bonferroni’s correction. The prevalences of interval of 34%–64%) of the 41 patients in microfilaraemia in the two treatment arms were compared using x2 tests. Within each aemic (giving a relative risk of 0.8, with a 95% confidence interval of 0.49–1.31). The was used to investigate the significance of the temporal differences seen in the pre- DEC OR DEC–ALBENDAZOLE TREATMENT OF CHILDREN lence of microfilaraemia decreased steadily, although this decrease was only statistically recorded in the DEC arm were similar, both in frequency and type, to those observed in and not throughout the entire follow-up, as function [as measured by forced expiratory stratum for microfilaraemia intensity were arms still appeared similar in terms of the prevalence of microfilaraemia on day 360.
than the patients who had the lowest levels mild dyspnoea but only one of them showed a corresponding fall in FEV1. A localized AE — an uncomfortable scrotal nodule — was observed in three patients (two given was observed in 81% of the patients. All of the systemic AE observed began within 24 h of treatment and, in all but one patient,had disappeared within 48 h of treatment.
Almost all (85%) of these events were mild, and only one patient was considered to havesuffered a severe AE and that was a cough The present study appears to represent the that disturbed the patient’s sleep until trolled trial to evaluate and compare the Descriptive data for the subjects in the two treatment groups, on enrolment INTENSITY OF MICROFILARAEMIA (microfilariae/ml blood) FIG. 1. The geometric mean intensities of microfilaraemia recorded, immediately pre-treatment (‘time 0’) andduring the post-treatment follow-up, among the patients given a single dose of diethylcarbamazine only (&) andthose given a single dose of diethylcarbamazine–albendazole (%).
year-long efficacies of single treatments with microfilaraemia, only one of the 15 patients children and adolescents with W. bancrofti their microfilaraemias by day 360 (data not intensities of microfilariaemia declined with time in both treatment arms and were lowest study was the lack of an adequate placebo treatment. There were, in fact, no signifi- tablets. All the checks for microfilaraemia patients who had low baseline intensities of DEC OR DEC–ALBENDAZOLE TREATMENT OF CHILDREN FIG. 2. The prevalences of microfilaraemia recorded, immediately pre-treatment (‘time 0’) and during the post-treatment follow-up, among the patients given a single dose of diethylcarbamazine only (&) and those given asingle dose of diethylcarbamazine–albendazole (%).
attending physicians were always unaware of the intensity of microfilaraemia (if any) in each patient. The present study, with fewer their blood was filtered, was tested again, than 50 patients in each treatment arm, may using a 4-ml sample of blood. On day 360, also have failed to reveal between-treatment however, only three more microfilaraemics differences that, although relatively small, (one in the DEC arm and two in the DEC– may still be important in the context of mass ALB) were detected as the result of testing the 4-ml blood samples (data not shown).
results may indicate levels of efficacy that of DEC–ALB to each of 11 adult patients 956 mff/ml and, after testing a 1-ml blood (73%) of the patients still microfilaraemic treatment on the prevalence of microfilar- aemia observed 1 year post-treatment have similar treatment to another 14 adults, with varied between the published studies. One difficulty in comparing the results of such long-term follow-up, even from randomized microfilaraemic 1 year later (Ismail et al., and controlled trials, is the between-study 2001). The prevalences of microfilaraemia variation in the baseline intensities of micro- recorded, by Ismail et al. (1998, 2001), 1 Simonsen et al., 2004). Another problem is the between-study variation in the sensitivity study among the patients with similar base- of the method used to detect microfilarae- line intensities of microfilaraemia (data mias. Sensitivity may be affected, for exam- ple, by the volume of blood tested/subject, collected, and the way in which the samples are checked for mff (Dreyer et al., 1996b).
In their three-arm trials, Pani et al. (2002) studied the effects of single treatments with over the following 12 months. It is a pity who had relatively mild microfilaraemias at that this study did not include a DEC-only 79.4 mff/ml, respectively). One year post- benefit of adding albendazole to DEC, both for a single treatment and for daily treat- appeared similar in terms of the prevalence and intensity of microfilaraemia, although, study (Fig. 2), the prevalences of microfilar- aemia recorded at the 1-year follow-up were 5–11 years, they found the combination to relatively high (82.4% for DEC, 73.9% for reducing the intensities (but not the pre- valences) of microfilaraemia 6 months post- reductions in the prevalences of microfilar- treatment. Their evaluations were, however, aemia, in all three treatment arms, during based on the examinations of relatively small the second year post-treatment (Pani et al., (20-ml) samples of fingerprick blood col- 2004). Unfortunately, Pani et al. (2002) did lected early at night. As in the present study, of W. bancrofti in Brazil, in their study of subject, did not describe the method they used to evaluate the prevalence or intensity their efficacy results by age-group.
single, annual doses — as DEC–ALB (or that 67% of 21 patients given a single dose In a recent review, Gyapong et al. (2005) of DEC and 59% of 22 patients given DEC– cited five trials in which DEC and DEC– microfilaraemia clearance are slightly higher [including one, among adults from Recife, than the corresponding values (of 61% and which has since appeared in the scientific 51%, respectively) seen in the present study, literature (Dreyer et al., 2006)]. Although Kshirsagar et al. (2004) only used micro- the authors of this review concluded that blood/patient (at each follow-up) and prob- ior to DEC alone, their analysis was flawed meta-analysis. The effect of this error was to increase the total patient number artificially, doses as used singly in the present study) was much more effective, in clearing blood between-treatment difference where actually microfilariae after 1 year, than a single dose there was none (Critchley et al., 2005).
patients in the multi-dose group were given a single dose of the combination, 1 year after lished randomized trials in which the effi- their week of treatment, and all but one was found amicrofilaraemic a year later. In the single-dose group, this single dose at 1 year DEC OR DEC–ALBENDAZOLE TREATMENT OF CHILDREN and pooling the prevalences and intensities low levels over the year post-treatment. The of microfilaraemia reported in the trials, the treatment of microfilaraemic children and adolescents from the metropolitan area of improve effectiveness, and that, to date, the Recife, Brazil, did not show any benefit in most efficacious combination is DEC–iver- terms of further reducing the prevalence or intensity of microfilaraemia at 1 year post- ever, that the relative efficacies of the treatment. Clearly, considerable collateral helminthiases may be realised if any anti- large, conclusive studies on this topic. In their Cochrane review, Critchley et al.
effects on intestinal helminths, regular treat- the lack of consistent information on the effects of ALB when used to treat LF.
regardless of whether LF is endemic in those treatments for bancroftian filariasis, it is very benefits of ALB do not, however, diminish baseline intensities of microfilaraemia and the need to elucidate the real effects on the sensitivity of the detection method, as the apparent efficacy of a treatment is very dependent on both of these factors. This isadvisable even for population-based studies,since individuals with intense microfilarae- the patients and their guardians for their mias are unlikely to become amicrofilarae- trust and co-operation, the Amaury Coutinho mic, even after five or six annual treatment financial support, and Dr E. Meireles, for referring patients. They are also grateful to et al., 1998; Ramaiah et al., 2002).
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