Joaquim Norões

Pathogenesis of Lymphatic Disease in Bancroftian Filariasis:: A Clinical Perspective

The pathogenesis of lymphatic filariasis has been a matter of debate for many decades. Here, Gerusa Dreyer and colleagues propose a dynamic model of bancroftian filariasis, integrating clinical, parasitological, surgical, therapeutic, ultrasonographic and histopathological data. This model has profound implications for filariasis control programs and the management of the individual patient.

The silent burden of sexual disability associated with lymphatic filariasis

Lymphatic filariasis is a mosquito-borne parasitic disease that affects approximately 100 million persons worldwide. It is estimated that 40 million people suffer from the chronic disfiguring manifestations of this disease including 27 million men with testicular hydrocele lymph scrotum or elephantiasis of the scrotum. An estimated 13 million people the majority of whom are women have filaria-associated lymphedema or elephantiasis of the leg arm or breast. Although lymphatic filariasis is ranked as the second leading known cause of disability worldwide little attention has focused on an important but hidden disability associated with the genital manifestations of this disease that of sexual disability. In our clinic in Recife Brazil where the trust of patients has been gained through long-term caring relationships we have begun to discover the magnitude depth and profound implications of this disability both for men and women. (excerpt)

Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in bancroftian filariasis.

Since diethylcarbamazine, the drug recommended for treatment of lymphatic filariasis, seems only partially effective against the adult worm, intense interest persists in identifying a macrofilaricidal drug for this infection. To evaluate directly in vivo the macrofilaricidal activity of repeat high‐dose ivermectin, 15 men who had living adult Wucbereria bancrofti detected in the scrotal area by ultrasound were treated with 400 μg/kg of ivermectin at 2‐week intervals for 6 months (total dose, 4.8 mg/kg). Serial ultrasound examinations were performed before, during, and for 6 months after treatment. Profound suppression of microfilaraemia followed the first dose of ivermectin, but movements characteristic of the adult worm on ultrasound remained unchanged both in location and pattern. Even when given in total doses of 4.8 mg/kg, ivermectin appears to have no observable activity against adult W. bancrofti, although its ability to suppress microfilaraemia makes it potentially useful for the control of lymphatic filariasis.

Treatment of bancroftian filariasis in Recife, Brazil: a two-year comparative study of the efficacy of single treatments with ivermectin or diethylcarbamazine

The effectiveness of single oral doses of ivermectin (200 or 400 micrograms/kg) and diethylcarbamazine (DEC, 6 mg/kg), preceded 4 d earlier by either placebo or very small doses of these drugs, was compared, over a 2-year period, in a double-blind trial in 67 microfilaraemic Brazilian men with bancroftian filariasis. Regimens containing ivermectin alone decreased the number of microfilariae significantly faster and more effectively for the first month after treatment than regimens containing DEC alone, but the latter were significantly more effective throughout the second year after treatment (1.7-8.2% of pretreatment levels with DEC vs. 12.6-30.8% with ivermectin during that period); the higher ivermectin dose showed a tendency towards more effectiveness than the lower dose. Most effective was the combination of ivermectin (20 micrograms/kg) followed 4 d later by DEC (6 mg/kg), with reduction of microfilaraemia to 2.4% of pretreatment levels at 2 years. Adverse reactions were well tolerated with all regimens, the reactions being significantly more generalized (i.e., fever) following ivermectin and localized (i.e., scrotal inflammatory nodules around dying adult worms) following DEC. Further trials of single-dose combination therapy vs. single high doses of ivermectin or DEC should determine the ideal regimen for treatment and control of bancroftian filariasis.

Bancroftian filariasis in a paediatric population : an ultrasonographic study

Little is known about lymphatic filariasis or the anatomical location of adult Wuchereria bancrofti in children. Seventy-eight children from Greater Recife, 23 microfilaria-positive and 55 microfilaria-negative in approximately 60 microL blood, underwent ultrasound examinations of the major superficial lymphatic vessels of the limbs, scrotal area (boys), and breast area (girls). The characteristic movements of adult worms, known as the filaria dance sign (FDS), were detected in 11 (14.1%) children. In 9 boys, the FDS was detected in lymphatic vessels of the scrotal area (8, ages 14-16) and the inguinal cord (1, age 11). In girls, the FDS was detected in a crural lymphatic vessel and an axillary lymph node. FDS detection was more common in boys (P = 0.06), older children (P = 0.001), and children with microfilaraemia (P = 0.05). Diffuse lymphangiectasia was visualized in 4 boys (ages 14-16) and 2 children had clinical signs of filariasis. These ultrasonographic findings associate W. bancrofti with both infection and disease in children.

Tolerance of diethylcarbamazine by microfilaraemic and amicrofilaraemic individuals in an endemic area of Bancroftian filariasis, Recife, Brazil.

To determine the tolerance to diethylcarbamazine (DEC) treatment of patients with Bancroftian filariasis, 193 individuals (138 asymptomatic microfilaraemic, 30 amicrofilaraemic diseased patients and 25 asymptomatic amicrofilaraemic endemic residents) were enrolled in a prospective trial with different dose schedules, in a hospital and outpatient clinic setting in Brazil. Systemic adverse reactions, localized adverse reactions, and side effects, related to microfilariae, adult worms and the drug itself, were evaluated. Systemic reactions occurred irrespective of the DEC dose and schedule in about 40% of the microfilariae carriers, but not in amicrofilaraemic diseased patients or residents; they usually consisted of microscopic haematuria, followed by fever and malaise. Localized reactions were manifested by the appearance of inflammatory reactions, mainly in the scrotal area. Nodules containing degenerating adult worms developed mainly in the scrotal lymphatics of microfilaraemic patients, diseased amicrofilaraemic patients, and residents. Drowsiness, which increased with higher doses of DEC, was the most common side effect in both microfilaraemic and amicrofilaraemic individuals, followed by nausea and gastric upset. The results indicate that the occurrence of systemic and local adverse reactions was unrelated to either the dose of DEC or the pretreatment microfilarial density. The severity of systemic reactions was proportional to the microfilarial density. Side effects were dependent on the drug dosage irrespective of infection status.

Progression of lymphatic vessel dilatation in the presence of living adult Wuchereria bancrofti

Bancroftian filariasis, a mosquito-transmitted disease commonly known as elephantiasis, is caused by infection with the parasite Wuchereria bancrofti. Infection with this parasite can induce a broad array of chronic debilitating and socially stigmatizing conditions, but the pathogenesis of this morbidity remains obscure. Recent evidence indicates that in filariasis-endemic areas the primary lesion is not lymphatic vessel obstruction but, rather, dilatation. To determine the extent to which lymphatic dilatation occurs in the presence of living adult W. bancrofti, we performed longitudinal ultrasonographic measurements in 80 men (mean age 24 years) in Brazil who had a total of 107 W. bancrofti nests detectable by ultrasound. Initial mean lymphatic vessel diameter at the site of the worms was 3.4 mm (range, 0.7-11.3), and was greater in men with 2 or more nests (3.9 mm) than in those with only one nest (3.0 mm, P = 0.003). During the study period (2-35 months, mean, 13.7), lymphatic vessel diameter increased at the site of 92 (86.0%) adult worm nests. Mean rate of increase of lymphatic vessel diameter was 1.2 mm per person-year (range, 0-0.93 mm per month). In a general linear model, no factors, including treatment with antifilarial drugs, were significantly associated with rate of vessel diameter increase. Thus, lymphatic vessel dilatation progress in the presence of living adult W. bancrofti; the rate of this progression is heterogeneous. These data suggest that lymphatic dilatation will continue to progress in most infected persons even after mass treatment with currently recommended antifilarial drugs. In addition to interrupting transmission, the global programme for elimination of lymphatic filariasis should address the potential for disease progression in persons who remain infected with adult W. bancrofti.

Histological evidence for adulticidal effect of low doses of diethylcarbamazine in bancroftian filariasis

The ability of diethylcarbamazine (DEC) to kill adult Wuchereria bancrofti worms was evaluated by examining lymphatic nodules formed after treatment with 4 different treatment schedules of 193 males living in the endemic area of Greater Recife, Brazil. Lymphatic nodules appeared in the spermatic cord or upper extremities in 43 of 138 microfilaraemic individuals, in 3 of 30 amicrofilaraemic patients with filarial disease manifestations, and in 1 of 25 asymptomatic amicrofilaraemic residents of the endemic area treated with DEC. Fourteen of these nodules were surgically removed 10-150 d after the start of treatment. Regardless of the DEC dosage and schedule used, all nodules contained damaged and degenerating adult worms. An exuberant granulomatous process with large numbers of eosinophils and progressive fibrosis gradually developed around the dead parasites. The mechanism(s) by which DEC killed adult W. bancrofti could not be determined.

Proposed panel of diagnostic criteria, including the use of ultrasound, to refine the concept of 'endemic normals' in lymphatic filariasis.

Summary Although living adult Wuchereria bancrofti worms can be detected by ultrasound examination of the scrotal area in approximately 80% of men infected with this filarial parasite, the location of the adult worms in the remaining 20% remains unclear. To determine this, 32 individuals who had W. bancrofti microfilaraemia but no adult worms detectable on ultrasound were treated with diethylcarbarmazine (DEC), either with a single 6 mg/kg dose (n = 13) or with a 12‐day course of 6 mg/kg per day (n = 19). They were then monitored with serial physical and ultrasound examinations. Thirteen (41%) subjects developed small, single scrotal nodules 12 h to 7 days after treatment; this rate was unaffected by the dose of DEC. No nodules were detected outside the scrotal area. All 5 men with lymphangiectasia suspected on ultrasound before treatment developed scrotal nodules, compared to 8 (29.6%) of 27 men without ultrasonographic evidence (P = 0.006). Thus, using both ultrasound and ‘provocative’ treatment with DEC, adult W. bancrofti can be detected in the scrotal area of an estimated 88% of infected men. Because no single diagnostic test for W. bancrofti infection is completely sensitive, a panel of tests, including ultrasound, is proposed to identify with greater accuracy ‘endemic normals’ for immunological and epidemiological studies.

A Mechanism for Chronic Filarial Hydrocele with Implications for Its Surgical Repair

Background Chronic hydrocele is the most common manifestation of bancroftian filariasis, an endemic disease in 80 countries. In a prospective study, we evaluated the occurrence of intrascrotal lymphangiectasia, gross appearance/consistency of the testis, and the efficacy of complete excision of hydrocele sac in patients living in a bancroftian filariasis endemic area who underwent hydrocelectomy at the Center for Teaching, Research and Tertiary Referral for Bancroftian Filariasis (NEPAF). Methodology/Principal Findings A total of 968 patients with uni- or bilateral filarial hydrocele (Group-1) and a Comparison Group (CG) of 218 patients from the same area who already had undergone hydrocele-sac-sparing hydrocelectomy elsewhere were enrolled at NEPAF. Twenty-eight patients from the Comparison Group with hydrocele recurrence were re-operated on at NEPAF and constitute Group-2. In Group-1 a total of 1,128 hydrocelectomies were performed (mean patient age of 30.3yr and mean follow-up of 8.6yr [range 5.3–12]). The hydrocele recurrence rates in Group-1 and in the Comparison Group (mean age of 31.5 yr) were 0.3%, and 19.3%, respectively (p<0,001). There was no hydrocele recurrence in Group-2 (mean patient age of 25.1yr and mean follow-up of 6yr [range 5–6.9]). Per surgically leaking or leak-prone dilated lymphatic vessels were seen in the inner or outer surface of the hydrocele sac wall or in surrounding tissue, particularly in the retrotesticular area, in 30.9% and in 46.3% of patients in Group-1 and Group-2, respectively (p = 0.081). The testicles were abnormal in shape, volume, and consistency in 203/1,128 (18%) and 10/28 (35.7%) of patients from Group-1 and Group-2, respectively (p = 0,025). Conclusions/Significance Lymph fluid from ruptured dilated lymphatic vessels is an important component of chronic filarial hydrocele fluid that threatens the integrity of the testis in an adult population living in bancroftian filariasis endemic areas. To avoid hydrocele recurrence the authors advise complete excision of hydrocele sac and when identified, leaking or leak-prone dilated lymphatic vessels should be sutured or excised.