• View in gallery

    (A and B) The intra-operative appearance of intrascrotal nodules seen in patients from an area edemic for bancroftian filariasis. (A) Filarial granuloma (arrow) not related to antifilarial treatment (Group 2) located in the parietal tunica vaginalis measuring 0.7 cm in greatest diameter. (B) Ectopic adrenal (arrow) on the anterior aspect of the spermatic cord with 0.5 cm. Note the similarities in shape and size of both nodules. (C and D) Typical bancroftian nodule, 0.5 cm in greatest diameter excised from the spermatic cord in a diethylcarbamazine (DEC)-treated patient. (C ) Fresh gross appearance. (D ) Low magnification (40×) of a histologic cross section of a bancroftian nodule seen in (C) showing a granulomatous reaction in a moderately dilated lymphatic vessel harboring degenerating W. bancrofti adult worms (arrows), surrounded by necrotic acidophilic material (*). A peripheral ring of mild fibrosis is observed (in blue). Masson’s trichome.

  • 1

    Santiago-Stevenson D, Oliver-González J, Hewitt RI, 1947. Treatment of filariasis bancrofti with 1-diethylcarbamyl-4-methylpiperazine hydrochoride (“Hetrazan”). JAMA 135 :708–712.

    • Search Google Scholar
    • Export Citation
  • 2

    Galliard H, 1971. Effects of diethyl-carbamazine on lymphatic filariosis at the beginning of the prophylactic campaign in Tahiti. Bull Soc Pathol Exot Filiales 64 :340–343.

    • Search Google Scholar
    • Export Citation
  • 3

    Galliard H, Mille R, 1949. Essais de traitement de la filariose à Wuchereria bancrofti var. pacifica par le 1-diéthyl-carbamyl-4-méthyl pipérazine, à Tahiti. Bull Soc Pathol Exot 42 :304–313.

    • Search Google Scholar
    • Export Citation
  • 4

    Ch’en T-T, 1964. Demonstration of macrofilaricidal action of hetrazan, antimony and arsenic preparations in man. Chinese Med J 83 :625–640.

    • Search Google Scholar
    • Export Citation
  • 5

    Ch’en T-T, Ch’en C-T, Hsü F-Y, Hsü C-K, Lo H-M, Hsü H-C, Yang C-L, Hu M-T, Shih H-L, 1959. Preliminary observations on intensive Hetrazan treatment of filariasis. Chin Med J 78 :174.

    • Search Google Scholar
    • Export Citation
  • 6

    Jungmann P, Figueredo-Silva J, Dreyer G, 1992. Bancroftian lymphangitis in northeastern Brazil: a histopathological study of 17 cases. J Trop Med Hyg 95 :114–118.

    • Search Google Scholar
    • Export Citation
  • 7

    Dreyer G, Pires ML, Andrade LD, Lopes E, Medeiros Z, Tenorio J, Coutinho A, Norões J, Figueredo-Silva J, 1994. Tolerance of diethylcarbamazine by microfilaraemic and amicrofilaraemic individuals in an endemic area of bancroftian filariasis, Recife, Brazil. Trans R Soc Trop Med Hyg 88 :232–236.

    • Search Google Scholar
    • Export Citation
  • 8

    Dreyer G, Coutinho A, Miranda D, Norões J, Rizzo JA, Galdino E, Rocha A, Medeiros Z, Andrade LD, Santos A, Figueredo-Silva J, Ottesen EA, 1995. Treatment of bancroftian filariasis in Recife, Brazil: a two year comparative study of the efficacy of single treatments with ivermectin or diethylcarbamazine. Trans R Soc Trop Med Hyg 89 :98–102.

    • Search Google Scholar
    • Export Citation
  • 9

    Figueredo-Silva J, Jungmann P, Norões J, Piessens WF, Coutinho A, Brito C, Rocha A, Dreyer G, 1996. Histological evidence for the adulticidal effect of low doses of diethycarbamazine in bancroftian filariasis. Trans R Soc Trop Med Hyg 90 :192–194.

    • Search Google Scholar
    • Export Citation
  • 10

    Rocha A, Addiss D, Ribeiro ME, Norões J, Baliza M, Medeiros Z, Dreyer G, 1996. Evaluation of the Og4C3 ELISA in Wuchereria bancrofti infection: infected persons with undetectable or ultra-low microfilarial densities. Trop Med Int Health 1 :859–864.

    • Search Google Scholar
    • Export Citation
  • 11

    Norões J, Dreyer G, Santos A, Mendes VG, Medeiros Z, Addiss D, 1997. Assessment of the efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo. Trans R Soc Trop Med Hyg 91 :78–81.

    • Search Google Scholar
    • Export Citation
  • 12

    Dreyer G, Addiss D, Santos A, Figueredo-Silva J, Norões J, 1998. Direct assessment in vivo of the efficacy of combined single-dose ivermectin and diethylcarbamazine against adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 92 :219–222.

    • Search Google Scholar
    • Export Citation
  • 13

    Dreyer G, Medeiros Z, Netto MJ, Leal NC, De Castro LG, Piessens WF, 1999. Acute attacks in the extremities of persons living in an area endemic for bancroftian filariasis: differentiation of two syndromes. Trans R Soc Trop Med Hyg 93 :413–417.

    • Search Google Scholar
    • Export Citation
  • 14

    Dreyer G, Santos A, Norões J, Addiss D, 1999. Proposed panel of diagnostic criteria, including the use of ultrasound, to refine the concept of “endemic normals” in lymphatic filariasis. Trop Med Int Health 4 :575–579.

    • Search Google Scholar
    • Export Citation
  • 15

    Figueredo-Silva J, Norões J, Cedenho A, Dreyer G, 2002. The histopathology of bancroftian filariasis revisited: the role of the adult worm in the lymphatic-vessel disease. Ann Trop Med Parasitol 96 :531–541.

    • Search Google Scholar
    • Export Citation
  • 16

    Norões J, Addiss D, Cedenho A, Figueredo-Silva J, Lima G, Dreyer G, 2003. Pathogenesis of filarial hydrocele: risk associated with intrascrotal nodules caused by death of adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 97 :561–566.

    • Search Google Scholar
    • Export Citation
  • 17

    Figueredo-Silva J, Dreyer G, 2005. Bancroftian filariasis in children and adolescents: clinical-pathological observations in 22 cases from an endemic area. Ann Trop Med Parasitol 99 :759–769.

    • Search Google Scholar
    • Export Citation
  • 18

    Figueredo-Silva J, Norões J, Addiss D, Dreyer G, 2008. Sex ratio of Wuchereria bancrofti in surgical specimens from an endemic area of Brazil. Ann Trop Med Parasitol 102 :229–238.

    • Search Google Scholar
    • Export Citation
  • 19

    Dreyer G, Lins R, Norões J, Rizzo JA, Figueredo-Silva J, 2008. Sensitivity of the ICT test relative to detection of adult Wuchereria bancrofti worms by ultrasound. Am J Trop Med Hyg 78 :28–34.

    • Search Google Scholar
    • Export Citation
  • 20

    Norões J, Addiss D, Amaral F, Coutinho A, Medeiros Z, Dreyer G, 1996. Occurrence of living adult Wuchereria bancrofti in the scrotal area of men with microfilaremia. Trans R Soc Trop Med Hyg 90 :55–56.

    • Search Google Scholar
    • Export Citation
  • 21

    Norões J, Addiss D, Santos A, Medeiros Z, Coutinho A, Dreyer G, 1996. Ultrasonographic evidence of abnormal lymphatic vessels in young men with adult Wuchereria bancrofti infection in the scrotal area. J Urol 156 :409–412.

    • Search Google Scholar
    • Export Citation
  • 22

    Reddy GS, Das LK, Pani SP, 2004. The preferential site of adult Wuchereria bancrofti: an ultrasound study of male asymptomatic microfilaria carriers in Pondicherry, India. Natl Med J India 17 :195–196.

    • Search Google Scholar
    • Export Citation
  • 23

    Michael E, Bundy DAP, Grenfell BT, 1996. Re-assessing the global prevalence and distribution of lymphatic filariasis. Parasitology 112 :409–428.

    • Search Google Scholar
    • Export Citation
  • 24

    Dreyer G, Norões J, Figueredo-Silva J, Piessens WF, 2000. Pathogenesis of lymphatic disease in bancroftian filariasis: a clinical perspective. Parasitol Today 16 :544–548.

    • Search Google Scholar
    • Export Citation
  • 25

    Dreyer G, Addiss D, Norões J, Amaral F, Rocha A, Coutinho A, 1996. Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in bancroftian filariasis. Trop Med Int Health 1 :427–432.

    • Search Google Scholar
    • Export Citation
  • 26

    Dreyer G, Norões J, Amaral F, Nen A, Medeiros Z, Coutinho A, Addiss D, 1995. Direct assessment of the adulticidal efficacy of single dose ivermectin in bancroftian filariasis. Trans R Soc Trop Med Hyg 89 :441–443.

    • Search Google Scholar
    • Export Citation
  • 27

    Dreyer G, Addiss D, Williamson J, Norões J, 2006. Efficacy of co-administered diethylcarbamazine and albendazole against adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 100 :1118–1125.

    • Search Google Scholar
    • Export Citation
  • 28

    Ottesen EA, 1985. Efficacy of diethylcarbamazine in eradicating infection with lymphatic-dwelling filariae in humans. Rev Infect Dis 7 :341–356.

    • Search Google Scholar
    • Export Citation
  • 29

    Amaral F, Dreyer G, Figueredo-Silva J, Norões J, Cavalcanti A, Samico SF, Santos A, Coutinho A, 1994. Live adult worms detected by ultrasonography in human bancroftian filariasis. Am J Trop Med Hyg 50 :753–757.

    • Search Google Scholar
    • Export Citation
  • 30

    Kar SK, 1986. Atypical features in lymphatic filariasis. Indian J Med Res 84 :270–274.

  • 31

    Kar SK, Mania J, Kar PK, 1993. Prevalence of lymphatic nodule in a bancroftian endemic population. Acta Trop 55 :53–60.

  • 32

    Thooris GC, Heuls J, Kessel JF, L’hoiry, Bambridge B, 1956. Research on methods of diagnosis and treatment of filariosis due to Wuchereria bancrofti in French Oceania. Bull Soc Pathol Exot Filiales 49 :1138–1157.

    • Search Google Scholar
    • Export Citation
  • 33

    Dreyer G, Santos A, Norões J, Rocha A, Addiss D, 1996. Amicrofilaraemic carriers of adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 90 :288–289.

    • Search Google Scholar
    • Export Citation
  • 34

    Dreyer G, Figueredo-Silva J, Carvalho K, Amaral F, Ottesen EA, 2001. Lymphatic filariasis in children: adenopathy and its evolution in two young girls. Am J Trop Med Hyg 65 :204–207.

    • Search Google Scholar
    • Export Citation
  • 35

    Dreyer G, Norões J, Addiss D, Santos A, Medeiros Z, Figueredo-Silva J, 1999. Bancroftian filariasis in a paediatric population: an ultrasonographic study. Trans R Soc Trop Med Hyg 93 :633–636.

    • Search Google Scholar
    • Export Citation
  • 36

    Ottesen EA, Ismail MM, Horton J, 1999. The role of albendazole in programmes to eliminate lymphatic filariasis. Parasitol Today 15 :382–386.

    • Search Google Scholar
    • Export Citation
  • 37

    Araújo AC, Figueredo-Silva J, Souto-Padron T, Dreyer G, Norões J, De Souza W, 1995. Scanning electron microscopy of adult Wuchereria bancrofti (nematoda: filarioidea). J Parasitol 81 :468–474.

    • Search Google Scholar
    • Export Citation
  • 38

    Ramzy RM, Helmy H, el-Lethy AS, Kandil AM, Ahmed ES, Weil GJ, Faris R, 1999. Field evaluation of a rapid-format kit for the diagnosis of bancroftian filariasis in Egypt. East Mediterr Health J 5 :880–887.

    • Search Google Scholar
    • Export Citation
  • 39

    Hussein O, El Setouhy M, Ahmed ES, Kandil AM, Ramzy RMR, Helmy H, Weil GJ, 2004. Duplex doppler sonographic assessment of the effects of diethylcarbamazine and albendazole therapy on adult filarial worms and adjacent host tissues in bancroftian filariasis. Am J Trop Med Hyg 71 :471–477.

    • Search Google Scholar
    • Export Citation
  • 40

    Debrah AY, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Larbi J, Lawson B, Taylor M, Adjei O, Hoerauf A, 2006. Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog 2 :e92.

    • Search Google Scholar
    • Export Citation
  • 41

    Mand S, Supali T, Djuardi J, Kar S, Ravindran B, Hoerauf A, 2006. Detection of adult Brugia malayi filariae by ultrasonography in humans in India and Indonesia. Trop Med Int Health 11 :1375–1381.

    • Search Google Scholar
    • Export Citation
  • 42

    Delmas V, Dauge MC, 1986. Accessory adrenals in the spermatic cord. Apropos of 2 cases. Ann Urol (Paris) 20 :261–264 (Paris).

  • 43

    Gualtieri T, Segal AD, 1949. Report of case of adrenal-type tumor of spermatic cord; A review of aberrant adrenal tissues. J Urol 61 :949–955.

    • Search Google Scholar
    • Export Citation
  • 44

    Roca Suarez A, Alvarez Ossorio JL, Del Toro Bacerra JA, Maximiano Vasquez R, Gordon Laporte R, 1993. Adrenal ectopia in the spermatic cord. Actas Urol Esp 17 :584–587.

    • Search Google Scholar
    • Export Citation
  • 45

    Mares AJ, Shkolnik A, Sacks M, Feuchtwanger MM, 1980. Aberrant (ectopic) adrenocortical tissue along the spermatic cord. J Pediatr Surg 15 :289–292.

    • Search Google Scholar
    • Export Citation
  • 46

    Savas C, Candir O, Bezir M, Cakmak M, 2001. Ectopic adrenocortical nodules along the spermatic cord of children. Int Urol Nephrol 32 :681–685.

    • Search Google Scholar
    • Export Citation

 

 

 

 

Intrascrotal Nodules in Adult Men as a Marker for Filarial Granuloma in a Bancroftian Filariasis-Endemic Area

View More View Less
  • 1 Departamento de Cirurgia, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil; Organização Não governamental Amaury Coutinho para Doenças Endêmicas e Tropicais, Recife, Pernambuco, Brazil; Núcleo de Ensino e Pesquisa em Patologia, Faculdade de Ciências Médicas, Universidade Estadual do Piauí, Centro-Sul, Teresina, Piauí, Brazil; Núcleo de Ensino Pesquisa e Assistência em Filariose (NEPAF), Hospital das Clínicas, Universidade Federal de Pernambuco, Recife, Pernambuco, Brazil; Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, (FIOCRUZ), Recife, Pernambuco, Brazil

A retrospective study was undertaken in Recife, Brazil to evaluate the specificity of intrascrotal nodules detected by physical examination as a marker of dead or degenerating adult Wuchereria bancrofti worms (filarial granuloma). A total of 372 nodules from 340 adult male patients (mean age 23.1 years) were studied. Of those, 253 (68%) nodules were from 226 patients treated with antifilarial drugs (Group 1) and 119 (32%) nodules were considered non-drug related and were obtained from 114 patients (Group 2). On histologic examination, all nodules from Group 1 and all but one (99.1%) from Group 2 contained degenerated or dead adult worms. In the one case without filarial granuloma, ectopic cortical adrenal tissue was found in the spermatic cord. These findings emphasize the high specificity of intrascrotal nodules for bancroftian granuloma and draw attention to the importance of examining the scrotal contents of young men in studies of antifilarial drug efficacy. These findings also have potential implications for bancroftian filariasis control programs.

INTRODUCTION

An association between treatment with diethylcarbamazine (DEC), a microfilaridal drug that can also kill adult worms (AWs) of Wuchereria bancrofti, and the formation of inflammatory nodules along the lymphatic vessels, so-called filarial granulomas, has been recognized since 1947.1 Many reports of DEC treatment do not mention the incidence/occurrence of nodule formation, whereas others describe their occurrence but do not specify their location. 2,3 The largest case series that analyze the pathology of nodules after DEC treatment have been accumulated by Chinese 4,5 and, more recently, by Brazilian workers.619 Most commonly, the nodules were reported in the scrotal contents.

In contrast with brugian filariasis, in which no clinical disease is found in the urogenital area, the high frequency of urogenital disease in men with bancroftian filariasis is almost certainly related to the apparent preference of adult W. bancrofti for that anatomic site. In fact, there is a growing body of evidence indicating that intrascrotal lymphatic vessels are the preferential site for adult W. bancrofti in adult men. 11,16,2022 This could explain why hydrocele is the most common manifestation of bancroftian filariasis in endemic areas. 23 This peculiar anatomic location of W. bancrofti adult worms in the male population has provided a unique opportunity to study host-parasite interplay, both before and after antifilarial treatment. 15,16,18,24 In this regard, access to the AW habitat—the intrascrotal lymphatic vessels—through physical examination, ultrasonography, and biopsy has facilitated studies of the effect of macrofilacidal effect of old and new drugs, alone or in combination, 9,11,12,14,16,2527 and the performance of antigen tests. 10,19

According to Ottesen, 28 in a classic paper that described five criteria for assessing the efficacy of DEC in killing the AWs of lymphatic filariasis, only one criterion is direct—the histologic examination of nodules. Accordingly, this study was conducted in an endemic area in Brazil to evaluate the specificity of intrascrotal nodules detected on physical examination, both in the absence of, and, after atifilarial drug treatment, when compared with the “gold standard” of histologically confirmed dead or degenerating W. bancrofti AWs.

MATERIALS AND METHODS

This retrospective study was conducted in the Center for Teaching, Research and Tertiary Referral Hospital for Bancroftian Filariasis (NEPAF) and the Laboratory of Immunopathology Keizo Asami (LIKA), Federal University of Pernambuco in Recife, Brazil and had the approval of the Ethical Committee of the Hospital das Clinicas at Federal University of Pernambuco. Information extracted from the medical charts included patient age, symptoms, and signs, including the detection of intrascrotal nodules and reports of nodule biopsy and histopathology. All subjects who underwent DEC treatment were examined before and after treatment. Male patients were selected from various drug trials711,1419 and from a routine protocol used at NEPAF for patients seeking medical attention. To be included in the study, the patient had to have 1) lived his entire life in Greater Recife, 2) denied previous antifilarial treatment before the first consultation, and 3) provided written informed consent. Patients were excluded if they had any condition that interfered with the physical examination of intrascrotal contents, e.g., ipsilateral tense or large hydrocele, previous inguino-scrotal surgery, lymphedema of the scrotal wall, past or current intrascrotal inflammation from trauma or bacterial infection. An intrascrotal nodule was defined as a palpable cord-like, spherical, or egg-shaped mass in the intrascrotal lymphatic vessels (surrounding the testicles, epididymis, or spermatic cord), and varying from hard to rubbery in consistency, whether tender or not. 11 All surgical specimens had been fixed in 10% buffered formalin and routinely processed, as previously described.9

RESULTS

A total of 340 male patients met the case definition. On examination, 372 nodules were detected (Table 1); 253 nodules were from men under observation as part of drug trials (Group 1), and the remaining 119 were considered spontaneous or not drug related (Group 2). In Group 1 all nodules were detected by physical examination within 7 days after DEC intake. No signs or symptoms of intrascrotal disease in Group 1 were detected before treatment; thus, the findings reported here for these subjects were post-treatment. The nodules detected by physical examination and the symptoms related to them (varying from none to tenderness on palpation to mild pain) were similar in both groups. 16 Intra-operative findings were also similar (Figure 1A and 1B); no edema or inflammatory reaction was observed outside the nodule. The gross appearance (Figure 1A, 1B, and 1C) of all nodules was similar in both groups, regardless of nodule diameter, with the exception of one patient from Group 2. In this case (Figure 1B), the nodule was yellowish in color, although distinguishable from intrascrotal fat, it contrasted with the usual white-grayish intra-operative appearance of filarial granuloma (Figure 1A). Histologic examination showed that all nodules (100%) from Group 1, and all but one (99.1%) from Group 2 contained degenerated or dead adult worms with a granulomatous inflammatory response (Figure 1D). It was impossible to differentiate histologically between the two groups. The tissue alterations associated with degenerating/dead adult worms were previously described in detail. 6,8,9,15 The Group 2 patient without filarial granuloma was a microfilaremic 20-year-old man sent for antifilarial treatment. On physical examination he had a flaccid testicular hydrocele. A painless nodule ~4 mm in diameter was palpated along the right spermatic cord. In the right infratesticular area, a nest of adult W. bancrofti was seen by ultrasound, exhibiting the movement characteristic of living AWs known as the filaria dance sign (FDS). 29 On the left side, the intrascrotal contents were normal by physical and ultrasound examinations. The patient was treated with a single 6 mg/kg dose of DEC and no new nodules were palpated up to 3 months after drug intake. The FDS remained unchanged, as did the nodule palpated before treatment in the right spermatic cord. The patient underwent hydrocele repair and both the spermatic cord nodule and the non-sensitive DEC parasite nest 11 were removed at the time of surgery. Histologic examination of the nodule showed ectopic cortical adrenal tissue.

DISCUSSION

There are several reports of post-chemotherapeutic lymphatic nodules with confirmatory biopsy in bancroftian filariasis, 4,79,11,12,1416 but only a few studies describe nodular reactions in endemic patients without a recent history of antifilarial drug intake. 6,16,30,31 Although the appearance of a nodule immediately after antifilarial therapy is considered strong evidence of AW death, post-DEC biopsies of anatomic sites other than the intrascrotal lymphatics have not always revealed adult worms. 4,32 This is also the case for non-drug-related nodules. 30 The current study was limited to nodules in the intrascrotal lymphatic vessels.

Among 226 men who developed intrascrotal nodules within 7 days after DEC treatment, all 253 nodules were confirmed as filarial granuloma. Thus, in our study population, the specificity of post-DEC intrascrotal nodules was 100% for filarial granuloma. These findings are in accordance with a Chinese study of 27 cases where 100% of intrascrotal nodules also were shown to be filarial granuloma.4 Therefore, past and the present experience indicates that the development of scrotal nodules constitutes a major tool for assessing the macrofilaricidal efficacy of drugs in bancroftian filariasis.79,11,12,1416

Even in the absence of antifilarial drug treatment, the specificity of intrascrotal nodules was remarkably high for filarial granuloma in our study population. Among 119 spontaneous nodules derived from Group 2 patients, only one was not confirmed on histologic examination as filarial granuloma, for a specificity of 99.1%. In his case, ectopic adrenal tissue could not be distinguished from a filarial nodule by physical examination. A specificity of less than 100% has been reported previously for non-drug-associated nodules from sites other than the intrascrotal area. 30 The remarkably high specificity of intrascrotal nodules as an indicator for AW death in this study was influenced, in part, by the strict inclusion criteria, which would have tended to exclude men with intrascrotal conditions that could interfere with the physical examination. However, such criteria are standard for clinical drug trials in Recife, Brazil, a bancroftian filariasis-endemic area.712,14,16,17,21,2527 In our experience, many young men undergoing routine medical examination in filariasis-endemic areas will meet the inclusion criteria for this study.

In contrast to specificity, the sensitivity of intrascrotal nodules as an indicator of AW is more difficult to assess. Sensitivity will vary by geographic area, among different examiners, and in different clinical settings. Unfortunately, no gold standard exists to determine with absolute certainty that an endemic individual is not infected with W. bancrofti adult worms, although several tests have been evaluated, including the absence of microfilaria by the membrane filtration technique, lack of circulating antigen (ICT and Og4C3), and the detection of FDS by ultrasound. These tests seem to compliment each other, but not in all cases. 10,17,19,3337 The detection of intrascrotal nodules developed after a DEC therapeutic test might help to rule out so-called “endemic normals” 14 and can be used to better interpret the antigen tests. 10,19 The DEC therapeutic test, however, is not recommended in areas where Loa loa and Onchocerca volvulus co-exist with W. bancrofti.36

In vivo, the most direct, non-invasive indicator of the presence of living W. bancrofti is the FDS, the characteristic random movement of AWs localized in nests within lymphatic vessels seen by ultrasound. 29,37 After antifilarial treatment, disappearance of the FDS at a site where it was previously observed is highly indicative of AW death, if it is followed by the appearance of nodules at those sites. Some authors claim that the simple disappearance of FDS, without nodule formation, is adequate evidence of AW death. 3840 This position, however, does not seem to apply to brugian filariasis, in which a migratory pattern AWs has been observed 41 making it more difficult to assess worm mortality. Although the stability of W. bancrofti nests provides greater assurance that the loss of FDS indicates AW death 11,12,14,16,19,27 our experience leads us to regard the presence of FDS as a clear indication for living worms, and nodule formation as a marker for AW death. Therefore, the best way to monitor the effectiveness of anti-filarial drugs in bancroftian filariasis is the combined use of ultrasound and physical examination.912,14,16,19,26,27

After treatment, three outcomes are possible for each bancroftian AW nest: 1) a sensitive reaction, in which drugs kill all the worms, a nodule, which may be tender, develops and the FDS ceases; 2) a non-sensitive reaction, where the adult worms are unaffected, no nodule develops and the FDS persists; and 3) a mixed reaction, when some but not all AWs are killed. In this case, a nodule develops, but the FDS persists, usually in a pattern that differs from that of previously recorded images, including changes in the largest lymphatic diameter of the nest. 11 These three possible outcomes, based on ultrasound and physical examination findings, have been validated by both surgery and histopathology. 11,12,1416,18,19,27,29 Interestingly enough, these reactions might occur alone or in combination in patients with more than one nest. Unfortunately, it is still impossible to determine whether the death of a single worm (male or female, gravid or not) always results in a scrotal nodule perceptible by physical examination. This is due in part, to the limitation of ultrasound and all other available non-invasive tests to determine the number and gender of worms in a given nest.

Other benign nodular lesions of the spermatic cord can also occur in filariasis-endemic areas, and may be similar to filarial granuloma by physical examination. Ectopic adrenal cortical tissue (EACT) is one such example. The EACT is generally found in the upper abdomen or along the descending path of the gonads. 4244 Usually, adrenal nests are found incidentally during inguinal operations, especially in children, where they appear macroscopically as bright, yellow, small nodules (1–5 mm in diameter), and microscopically as lipid-rich cortical cells without a medullar component. 45,46

In conclusion, intrascrotal nodules are highly specific for filarial granuloma in Recife, Brazil, a bancroftian filariasis-endemic area. This high degree of specificity highlights the importance of physical examination of the scrotal contents as part of any protocol to study the macrofilaricidal activity drugs and drug combinations, as well as in studies of the immunologic and clinical features of W. bancrofti infection in Recife and elsewhere. To our knowledge, this is the largest study of lymphatic filarial granuloma that involves assessments before and after antifilarial treatment and the first report of EACT in a patient infected with W. bancrofti. Similar studies in other filariasis-endemic settings are encouraged to investigate the specificity of pre- and post-treatment nodule formation as a marker of bancroftian granuloma and its potential implications for monitoring control programs.

Table 1

Characteristics of study participants in Group 1 (treated with DEC*) and Group 2 (where nodules were considered non-drug related)

Table 1
Figure 1.
Figure 1.

(A and B) The intra-operative appearance of intrascrotal nodules seen in patients from an area edemic for bancroftian filariasis. (A) Filarial granuloma (arrow) not related to antifilarial treatment (Group 2) located in the parietal tunica vaginalis measuring 0.7 cm in greatest diameter. (B) Ectopic adrenal (arrow) on the anterior aspect of the spermatic cord with 0.5 cm. Note the similarities in shape and size of both nodules. (C and D) Typical bancroftian nodule, 0.5 cm in greatest diameter excised from the spermatic cord in a diethylcarbamazine (DEC)-treated patient. (C ) Fresh gross appearance. (D ) Low magnification (40×) of a histologic cross section of a bancroftian nodule seen in (C) showing a granulomatous reaction in a moderately dilated lymphatic vessel harboring degenerating W. bancrofti adult worms (arrows), surrounded by necrotic acidophilic material (*). A peripheral ring of mild fibrosis is observed (in blue). Masson’s trichome.

Citation: The American Journal of Tropical Medicine and Hygiene Am J Trop Med Hyg 81, 2; 10.4269/ajtmh.2009.81.317

*

Address correspondence to Gerusa Dreyer, Organização Não Governamental Amaury Coutinho para Doenças Endêmicas e Tropicais, Rua Conselheiro Portela, 665, Sala 120, Graças, Recife, Pernambuco, Brazil, CEP 52020-030. E-mail: dreyer-g@uol.com.br

Authors’ addresses: Joaquim Norões, Departamento de Cirurgia, Centro de Ciências da Saúde, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego s/n, Cidade Universitária, Recife-PE, Brazil, CEP 50670-900; Organização Não governamental Amaury Coutinho para Doenças Endêmicas e Tropicais, Rua Conselheiro Portela, 665, Sala 120, Graças, Recife-PE, Brazil, CEP 52020-030, Tel: 55 81 34264348, Fax: 55 81 34426195, E-mail: jnoroes@hotmail.com. José Figueredo-Silva, Núcleo de Ensino e Pesquisa em Patologia, Faculdade de Ciências Médicas, Universidade Estadual do Piauí, Rua Olavo Bilac, 2335 - Centro-Sul, Teresina-PI, Brazil, CEP 64001-280; Organização Não governamental Amaury Coutinho para Doenças Endêmicas e Tropicais, Rua Conselheiro Portela, 665, Sala 120, Graças, Recife-PE, Brazil, CEP 52020-030; Tel/Fax: 55 86 3221 4749, E-mail: figueredo_silva@hotmail.com. Gerusa Dreyer, Núcleo de Ensino Pesquisa e Assistência em Filariose (NEPAF), Hospital das Clínicas, Universidade Federal de Pernambuco, Av. Prof. Moraes Rego s/n, Cidade Universitária, Recife-PE, Brazil, CEP 50670-900, Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, (FIOCRUZ), Av. Prof. Moraes Rego s/n, Cidade Universitária, Recife-PE, Brazil, CEP 50670-420; Organização Não governamental Amaury Coutinho para Doenças Endêmicas e Tropicais, Rua Conselheiro Portela, 665, Sala 120, Graças, Recife-PE, Brazil, CEP 52020-030, Tel: 55 81 34264348, Fax: 55 81 34426195, E-mail: dreyer-g@uol.com.br.

Acknowledgments: We thank David Addiss for critically reading and making valuable suggestions on the original manuscript; Hospital das Clínicas (NEPAF) at the Federal University of Pernambuco, where all biopsies were performed; Carmelita Cavalcanti for technical assistance and Wendilynn W. McAfee for invaluable help with literature retrieval.

Finacial support: The study was supported by NGO Amaury Coutinho, Recife, Brazil.

Disclaimers: None of the authors have conflicts of interest to declare.

REFERENCES

  • 1

    Santiago-Stevenson D, Oliver-González J, Hewitt RI, 1947. Treatment of filariasis bancrofti with 1-diethylcarbamyl-4-methylpiperazine hydrochoride (“Hetrazan”). JAMA 135 :708–712.

    • Search Google Scholar
    • Export Citation
  • 2

    Galliard H, 1971. Effects of diethyl-carbamazine on lymphatic filariosis at the beginning of the prophylactic campaign in Tahiti. Bull Soc Pathol Exot Filiales 64 :340–343.

    • Search Google Scholar
    • Export Citation
  • 3

    Galliard H, Mille R, 1949. Essais de traitement de la filariose à Wuchereria bancrofti var. pacifica par le 1-diéthyl-carbamyl-4-méthyl pipérazine, à Tahiti. Bull Soc Pathol Exot 42 :304–313.

    • Search Google Scholar
    • Export Citation
  • 4

    Ch’en T-T, 1964. Demonstration of macrofilaricidal action of hetrazan, antimony and arsenic preparations in man. Chinese Med J 83 :625–640.

    • Search Google Scholar
    • Export Citation
  • 5

    Ch’en T-T, Ch’en C-T, Hsü F-Y, Hsü C-K, Lo H-M, Hsü H-C, Yang C-L, Hu M-T, Shih H-L, 1959. Preliminary observations on intensive Hetrazan treatment of filariasis. Chin Med J 78 :174.

    • Search Google Scholar
    • Export Citation
  • 6

    Jungmann P, Figueredo-Silva J, Dreyer G, 1992. Bancroftian lymphangitis in northeastern Brazil: a histopathological study of 17 cases. J Trop Med Hyg 95 :114–118.

    • Search Google Scholar
    • Export Citation
  • 7

    Dreyer G, Pires ML, Andrade LD, Lopes E, Medeiros Z, Tenorio J, Coutinho A, Norões J, Figueredo-Silva J, 1994. Tolerance of diethylcarbamazine by microfilaraemic and amicrofilaraemic individuals in an endemic area of bancroftian filariasis, Recife, Brazil. Trans R Soc Trop Med Hyg 88 :232–236.

    • Search Google Scholar
    • Export Citation
  • 8

    Dreyer G, Coutinho A, Miranda D, Norões J, Rizzo JA, Galdino E, Rocha A, Medeiros Z, Andrade LD, Santos A, Figueredo-Silva J, Ottesen EA, 1995. Treatment of bancroftian filariasis in Recife, Brazil: a two year comparative study of the efficacy of single treatments with ivermectin or diethylcarbamazine. Trans R Soc Trop Med Hyg 89 :98–102.

    • Search Google Scholar
    • Export Citation
  • 9

    Figueredo-Silva J, Jungmann P, Norões J, Piessens WF, Coutinho A, Brito C, Rocha A, Dreyer G, 1996. Histological evidence for the adulticidal effect of low doses of diethycarbamazine in bancroftian filariasis. Trans R Soc Trop Med Hyg 90 :192–194.

    • Search Google Scholar
    • Export Citation
  • 10

    Rocha A, Addiss D, Ribeiro ME, Norões J, Baliza M, Medeiros Z, Dreyer G, 1996. Evaluation of the Og4C3 ELISA in Wuchereria bancrofti infection: infected persons with undetectable or ultra-low microfilarial densities. Trop Med Int Health 1 :859–864.

    • Search Google Scholar
    • Export Citation
  • 11

    Norões J, Dreyer G, Santos A, Mendes VG, Medeiros Z, Addiss D, 1997. Assessment of the efficacy of diethylcarbamazine on adult Wuchereria bancrofti in vivo. Trans R Soc Trop Med Hyg 91 :78–81.

    • Search Google Scholar
    • Export Citation
  • 12

    Dreyer G, Addiss D, Santos A, Figueredo-Silva J, Norões J, 1998. Direct assessment in vivo of the efficacy of combined single-dose ivermectin and diethylcarbamazine against adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 92 :219–222.

    • Search Google Scholar
    • Export Citation
  • 13

    Dreyer G, Medeiros Z, Netto MJ, Leal NC, De Castro LG, Piessens WF, 1999. Acute attacks in the extremities of persons living in an area endemic for bancroftian filariasis: differentiation of two syndromes. Trans R Soc Trop Med Hyg 93 :413–417.

    • Search Google Scholar
    • Export Citation
  • 14

    Dreyer G, Santos A, Norões J, Addiss D, 1999. Proposed panel of diagnostic criteria, including the use of ultrasound, to refine the concept of “endemic normals” in lymphatic filariasis. Trop Med Int Health 4 :575–579.

    • Search Google Scholar
    • Export Citation
  • 15

    Figueredo-Silva J, Norões J, Cedenho A, Dreyer G, 2002. The histopathology of bancroftian filariasis revisited: the role of the adult worm in the lymphatic-vessel disease. Ann Trop Med Parasitol 96 :531–541.

    • Search Google Scholar
    • Export Citation
  • 16

    Norões J, Addiss D, Cedenho A, Figueredo-Silva J, Lima G, Dreyer G, 2003. Pathogenesis of filarial hydrocele: risk associated with intrascrotal nodules caused by death of adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 97 :561–566.

    • Search Google Scholar
    • Export Citation
  • 17

    Figueredo-Silva J, Dreyer G, 2005. Bancroftian filariasis in children and adolescents: clinical-pathological observations in 22 cases from an endemic area. Ann Trop Med Parasitol 99 :759–769.

    • Search Google Scholar
    • Export Citation
  • 18

    Figueredo-Silva J, Norões J, Addiss D, Dreyer G, 2008. Sex ratio of Wuchereria bancrofti in surgical specimens from an endemic area of Brazil. Ann Trop Med Parasitol 102 :229–238.

    • Search Google Scholar
    • Export Citation
  • 19

    Dreyer G, Lins R, Norões J, Rizzo JA, Figueredo-Silva J, 2008. Sensitivity of the ICT test relative to detection of adult Wuchereria bancrofti worms by ultrasound. Am J Trop Med Hyg 78 :28–34.

    • Search Google Scholar
    • Export Citation
  • 20

    Norões J, Addiss D, Amaral F, Coutinho A, Medeiros Z, Dreyer G, 1996. Occurrence of living adult Wuchereria bancrofti in the scrotal area of men with microfilaremia. Trans R Soc Trop Med Hyg 90 :55–56.

    • Search Google Scholar
    • Export Citation
  • 21

    Norões J, Addiss D, Santos A, Medeiros Z, Coutinho A, Dreyer G, 1996. Ultrasonographic evidence of abnormal lymphatic vessels in young men with adult Wuchereria bancrofti infection in the scrotal area. J Urol 156 :409–412.

    • Search Google Scholar
    • Export Citation
  • 22

    Reddy GS, Das LK, Pani SP, 2004. The preferential site of adult Wuchereria bancrofti: an ultrasound study of male asymptomatic microfilaria carriers in Pondicherry, India. Natl Med J India 17 :195–196.

    • Search Google Scholar
    • Export Citation
  • 23

    Michael E, Bundy DAP, Grenfell BT, 1996. Re-assessing the global prevalence and distribution of lymphatic filariasis. Parasitology 112 :409–428.

    • Search Google Scholar
    • Export Citation
  • 24

    Dreyer G, Norões J, Figueredo-Silva J, Piessens WF, 2000. Pathogenesis of lymphatic disease in bancroftian filariasis: a clinical perspective. Parasitol Today 16 :544–548.

    • Search Google Scholar
    • Export Citation
  • 25

    Dreyer G, Addiss D, Norões J, Amaral F, Rocha A, Coutinho A, 1996. Ultrasonographic assessment of the adulticidal efficacy of repeat high-dose ivermectin in bancroftian filariasis. Trop Med Int Health 1 :427–432.

    • Search Google Scholar
    • Export Citation
  • 26

    Dreyer G, Norões J, Amaral F, Nen A, Medeiros Z, Coutinho A, Addiss D, 1995. Direct assessment of the adulticidal efficacy of single dose ivermectin in bancroftian filariasis. Trans R Soc Trop Med Hyg 89 :441–443.

    • Search Google Scholar
    • Export Citation
  • 27

    Dreyer G, Addiss D, Williamson J, Norões J, 2006. Efficacy of co-administered diethylcarbamazine and albendazole against adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 100 :1118–1125.

    • Search Google Scholar
    • Export Citation
  • 28

    Ottesen EA, 1985. Efficacy of diethylcarbamazine in eradicating infection with lymphatic-dwelling filariae in humans. Rev Infect Dis 7 :341–356.

    • Search Google Scholar
    • Export Citation
  • 29

    Amaral F, Dreyer G, Figueredo-Silva J, Norões J, Cavalcanti A, Samico SF, Santos A, Coutinho A, 1994. Live adult worms detected by ultrasonography in human bancroftian filariasis. Am J Trop Med Hyg 50 :753–757.

    • Search Google Scholar
    • Export Citation
  • 30

    Kar SK, 1986. Atypical features in lymphatic filariasis. Indian J Med Res 84 :270–274.

  • 31

    Kar SK, Mania J, Kar PK, 1993. Prevalence of lymphatic nodule in a bancroftian endemic population. Acta Trop 55 :53–60.

  • 32

    Thooris GC, Heuls J, Kessel JF, L’hoiry, Bambridge B, 1956. Research on methods of diagnosis and treatment of filariosis due to Wuchereria bancrofti in French Oceania. Bull Soc Pathol Exot Filiales 49 :1138–1157.

    • Search Google Scholar
    • Export Citation
  • 33

    Dreyer G, Santos A, Norões J, Rocha A, Addiss D, 1996. Amicrofilaraemic carriers of adult Wuchereria bancrofti. Trans R Soc Trop Med Hyg 90 :288–289.

    • Search Google Scholar
    • Export Citation
  • 34

    Dreyer G, Figueredo-Silva J, Carvalho K, Amaral F, Ottesen EA, 2001. Lymphatic filariasis in children: adenopathy and its evolution in two young girls. Am J Trop Med Hyg 65 :204–207.

    • Search Google Scholar
    • Export Citation
  • 35

    Dreyer G, Norões J, Addiss D, Santos A, Medeiros Z, Figueredo-Silva J, 1999. Bancroftian filariasis in a paediatric population: an ultrasonographic study. Trans R Soc Trop Med Hyg 93 :633–636.

    • Search Google Scholar
    • Export Citation
  • 36

    Ottesen EA, Ismail MM, Horton J, 1999. The role of albendazole in programmes to eliminate lymphatic filariasis. Parasitol Today 15 :382–386.

    • Search Google Scholar
    • Export Citation
  • 37

    Araújo AC, Figueredo-Silva J, Souto-Padron T, Dreyer G, Norões J, De Souza W, 1995. Scanning electron microscopy of adult Wuchereria bancrofti (nematoda: filarioidea). J Parasitol 81 :468–474.

    • Search Google Scholar
    • Export Citation
  • 38

    Ramzy RM, Helmy H, el-Lethy AS, Kandil AM, Ahmed ES, Weil GJ, Faris R, 1999. Field evaluation of a rapid-format kit for the diagnosis of bancroftian filariasis in Egypt. East Mediterr Health J 5 :880–887.

    • Search Google Scholar
    • Export Citation
  • 39

    Hussein O, El Setouhy M, Ahmed ES, Kandil AM, Ramzy RMR, Helmy H, Weil GJ, 2004. Duplex doppler sonographic assessment of the effects of diethylcarbamazine and albendazole therapy on adult filarial worms and adjacent host tissues in bancroftian filariasis. Am J Trop Med Hyg 71 :471–477.

    • Search Google Scholar
    • Export Citation
  • 40

    Debrah AY, Mand S, Specht S, Marfo-Debrekyei Y, Batsa L, Pfarr K, Larbi J, Lawson B, Taylor M, Adjei O, Hoerauf A, 2006. Doxycycline reduces plasma VEGF-C/sVEGFR-3 and improves pathology in lymphatic filariasis. PLoS Pathog 2 :e92.

    • Search Google Scholar
    • Export Citation
  • 41

    Mand S, Supali T, Djuardi J, Kar S, Ravindran B, Hoerauf A, 2006. Detection of adult Brugia malayi filariae by ultrasonography in humans in India and Indonesia. Trop Med Int Health 11 :1375–1381.

    • Search Google Scholar
    • Export Citation
  • 42

    Delmas V, Dauge MC, 1986. Accessory adrenals in the spermatic cord. Apropos of 2 cases. Ann Urol (Paris) 20 :261–264 (Paris).

  • 43

    Gualtieri T, Segal AD, 1949. Report of case of adrenal-type tumor of spermatic cord; A review of aberrant adrenal tissues. J Urol 61 :949–955.

    • Search Google Scholar
    • Export Citation
  • 44

    Roca Suarez A, Alvarez Ossorio JL, Del Toro Bacerra JA, Maximiano Vasquez R, Gordon Laporte R, 1993. Adrenal ectopia in the spermatic cord. Actas Urol Esp 17 :584–587.

    • Search Google Scholar
    • Export Citation
  • 45

    Mares AJ, Shkolnik A, Sacks M, Feuchtwanger MM, 1980. Aberrant (ectopic) adrenocortical tissue along the spermatic cord. J Pediatr Surg 15 :289–292.

    • Search Google Scholar
    • Export Citation
  • 46

    Savas C, Candir O, Bezir M, Cakmak M, 2001. Ectopic adrenocortical nodules along the spermatic cord of children. Int Urol Nephrol 32 :681–685.

    • Search Google Scholar
    • Export Citation

Author Notes

Reprint requests: Gerusa Dreyer, Organização Não Governamental Amaury Coutinho para Doenças Endêmicas e Tropicais, Rua Conselheiro Portela, 665, Sala 120, Graças, Recife, Pernambuco, Brazil, CEP 52020-030, E-mail: dreyer-g@uol.com.br.
Save