| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
 |
ABSTRACT |
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
0.0001). FDS and lymphangiectasia were detected in the intrascrotal (N = 3) and inguinal (N = 1) lymphatic vessels of three postpubescent boys. This study demonstrates clinical and subclinical findings of LF in FDS-positive children. |
INTRODUCTION |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Unlike other helminth infections, LF is generally considered a disease of adults and late adolescence with a higher prevalence in males.4 In Leogane, Haiti, about 5% of women suffer from lymphedema and up to 30% of adult males have hydrocele, both of which are clinical manifestations of filarial disease.5 In addition, approximately 25–30% of the adult population is microfilaremic (MF+) and 50% have evidence of circulating filarial antigen (CFA), an indicator of adult worm infection.6 As the chronic manifestations of disease traditionally occur after puberty or early adulthood, most clinical and epidemiologic investigations have focused on adult populations, and little is known about the pathogenesis of filarial disease in children.
Only recently has it been demonstrated that infection and disease are more common in children than previously thought. Analysis of circulating filarial antigen levels in young children in Leogane, Haiti, demonstrated that filarial infections are acquired early in life with filarial antigen prevalence greater than 30% among 4-year-old children.7 In addition, the finding of unexplained chronic adenopathy has been shown, both histopathologically and clinically, to be an important presentation of LF in children.8,9
The application of ultrasonography has been a useful tool for understanding filariasis in both symptomatic and asymptomatic adults and children.10–12 It has been successfully used to assess, in vivo, the efficacy of antifilarial drugs, describe preclinical abnormalities in the lymphatic vessels of males, identify living adult worms in amicrofilaremic (MF–) males, and localize living adult worms in the lymphatics of the female breast.13–18 Nevertheless, there have been few published studies where ultrasound has been used in children.9,12
The objectives of this study were to assess the feasibility of using ultrasound as a diagnostic tool for filariasis in children, to determine factors associated with a positive ultrasound finding, and finally, to longitudinally assess, both clinically and ultrasonographically, a subpopulation of infected children.
|
MATERIALS AND METHODS |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
One hundred eighty-six schoolchildren were selected from the enrollees in the drug study for clinical and ultrasono-graphic assessment. These included all 116 microfilaremic (MF+) children and a representative sample of 70 amicrofilaremic (MF–) children. The 186 children underwent laboratory, clinical, and ultrasonographic assessments in November 1998 as detailed in Table 1
. All 28 FDS-positive children underwent serial laboratory, clinical, and ultrasonographic examinations in March and May 1999, 3 and 6 months posttreatment, respectively.
|
Laboratory evaluation.
Microfilaria status was determined by microscopic examination of a Giemsa-stained 20 µL blood smear obtained by finger prick between 1900 and 2130 hours.20 An additional 100 µL of blood was collected in capillary tubes at the same time and serum samples were separated and frozen for later testing. The Og4C3 assay (JCU Tropical Biotechnology Pty Ltd., Queensland, Australia) for circulating filarial antigen was performed.6 Antigen levels were quantified against a standard curve and were highly reproducible between assays. Quantitative antigen assay results of 250 units or greater were considered positive and specimens with a response of 
32,000 antigen units were assigned a fixed value of 32,000. Laboratory personnel were blinded to the infection status of the children.
Clinical evaluation. Medical history was collected in a single interview with children and their parents. Questions were asked regarding pain, redness, swelling, and warmth of the lower extremities and lymph nodes (axillary, crural, epitrochlear, inguinal, and popliteal) and past surgical procedures. Crural lymph nodes are located in the medial thigh area below the superficial inguinal lymph nodes.21,22
Physical examinations were also performed on each of the children concentrating on sexual maturity and lymphadenopathy of the axillary, crural, epitrochlear, inguinal, and popliteal lymph nodes. Lymphadenopathy was defined as tenderness, induration, or palpable irregularity of the lymp node on physical examination. The sexual maturity ratings (SMRs) of Marshall and Tanner were used to assess the secondary sexual characteristics of pubertal maturation. These SMRs comprise five stages for each sex and are based on breast and pubic hair development in girls and genital and pubic hair development in boys.23 The presence of hydrocele or spermatic cord thickening, both of which can be indicators of filarial disease in men, was also documented for boys. A single examiner (B. F.) performed physical examinations during the first 1.5 years. In 2002, two examiners (B. F. and L. F.) performed the physical examinations. Personnel performing the physical examinations were blinded to the infection status of the children on the 1998 exams.
Ultrasound (US) examinations (Acuson Computer Sonogram 128XP/10C, 5.0 MHz transducer; Mountain View, CA) were performed to detect evidence of adult worm infections including adult worm nests and lymphangiectasia (lymphatic dilatation) in the lymph node areas (axillary, crural, and inguinal), the breast in postpubescent females, and the scrotum for boys. Exams were conducted for 20–30 minutes with children resting in the supine position. As with the laboratory and physical examinations, personnel performing the ultrasonographic examinations were blinded to the infection status of the children. Adult worm nests were identified based on the characteristic motility of the adult worm (filaria dance sign; FDS). Every worm nest was confirmed in B-mode, M-mode, and pulse wave Doppler-mode.
Statistical methods.
For the purposes of data analysis, participants were allocated to one of two groups based on ultrasonographic findings; those children who had evidence of living adult worms on ultrasonographic examination (FDS-positive) and those children who had no evidence of adult worms on ultrasound (FDS-negative). Data were analyzed using Epi-Info version 6.04 (CDC, Stone Mountain, GA) and SAS version 8 (SAS Institute, Cary, NC). In univariate analyses, 
2 and two-sided Fisher’s exact tests were used to compare categorical variables; continuous variables were compared using the nonparametric Wilcoxon rank sum tests.
|
RESULTS |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
250 units). All 186 children had data collected on medical history. Only 4 (2%) children reported a history of lower extremity problems, as defined by pain, redness, swelling, or warmth of the lower extremity. In contrast, 122 (66%) reported a history of lymph node pain, redness, swelling, or warmth. All of these children reported lymph node swelling, 119 (98%) with lymph node involvement of the inguinal area. No children complained of popliteal lymphadenopathy. Only one child reported any past surgical procedures. This 11-year-old child had a cystectomy of her left breast and axillary area 7 years earlier. Medical history of lymph node or lower extremity problems did not differ significantly by sex, microfilaria status, or antigen status.
All 186 children had physical examinations performed. Of these, 179 (96%) had a SMR stage of 1 or 2, indicating early sexual development. On physical exam, 158 (85%) children had inguinal lymphadenopathy, 44 (24%) had axillary lymphadenopathy, and 11 (6%) had crural lymphadenopathy. No epitrochlear or popliteal lymphadenopathy was detected. In males, no hydrocele or spermatic cord thickening was noted. Of children with inguinal lymphadenopathy on physical examination, 89 (56%) were boys. Physical findings did not differ significantly among SMR stages or by antigenemia or microfilaremia status.
All 186 children had an US examination. Of these, 28 (15%) had ultrasonographic evidence of adult Wuchereria bancrofti nests; that is, the filaria dance sign (FDS) was detected. These children ranged in age from 8 to 11 years (Table 2). Detection of adult W. bancrofti nests was associated with microfilaremia (P = 0.02), a higher geometric mean microfilarial density (P = 0.004), a higher geometric mean filarial antigen level (P = 0.03), and a greater mean age (P = 0.003). In the FDS-positive children, a total of 32 living adult worm nests were visualized, with a range of one to two nests per child. All of these nests were located in the inguinal (88%) or crural (12%) lymphatic vessels. The mean lymphatic diameter at the site of living adult worm nests was 4.5 mm (range 3–7 mm); a value that indicated lymphangiectasia given previous work demonstrating normal lymphatic vessel diameters of 0.5 to 1 mm in the intrascrotal lymphatic vessels of adult men.24
|
Posttreatment assessment.
The 28 FDS-positive children, who were randomized to four treatment groups in November 1998 (Figure 1, Treatment no. 1), underwent follow-up ultrasonographic examinations in March and May 1999, 3 and 6 months posttreatment. Twelve living adult worm nests were detected in March 1999 and eight adult worm nests were detected in May 1999; both of which were statistically fewer from the initial number of adult worm nests detected (P 10–5). The proportion of FDS-positive children belonging to each of the treatment groups is noted in Figure 1. Seventeen (71%) children demonstrated a decrease in circulating filarial antigen level from November 1998 through May 1999 and the mean percent reduction in circulating filarial antigen level among these children was 44% (range, 2–100%).
|
). Of these, 18 (72%) had filarial antigen detected; 7 (28%) had lost circulating filarial antigen. Although the geometric mean filarial antigen level was lower (1017.6 versus 3113.0) than that seen in the same population in 1998, this difference was not statistically significant. Even so, 15 (63%) children demonstrated a decrease in circulating filarial antigen level from 1998 to 2002 and the mean percent reduction in circulating filarial antigen level among these children was 78% (range, 39–100%). Only 12% (3/25) of children were still considered prepubescent (SMR stage 1 or 2). The majority of children (84%) reported having had prior lymph node problems (pain, redness, swelling or warmth) and inguinal lymph node problems (80%), respectively. Compared with their physical exam findings in 1998, children were less likely to have inguinal lymphadenopathy on physical exam in 2002 (RR = 0.25, 95% CI = 0.1 to 0.5). Of note, 14 (61%) children reported having participated in all three rounds of MDA.
|
), all but one in the intrascrotal lymphatics. One child (Patient no. 3), with high circulating filarial antigen levels in both 1998 and 2002, had two worm nests visualized, one in the left inguinal region and the other in the intrascrotal lymphatic vessels. The nest in the left inguinal region was 9 mm in diameter in 2002 compared with 5 mm in 1998. All three children reported participation in three rounds of MDA in their community. All three children were postpubescent with SMR ratings of 3 or higher as assessed on the 2002 physical exam. Additionally, a small right-sided hydrocele was detected by ultrasound and thickening of the spermatic cord was detected by physical exam in Patient no. 2 in 2002.
|
|
DISCUSSION |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
In this study, key history and physical exam findings were associated with the detection of living adult worms on ultrasonographic examination. FDS-positive children reported lymph node pain, redness, swelling, or warmth, specifically in the inguinal region, and inguinal and crural lymphadenopathies were found on physical exam. As adult worms in pre-pubescent children localize to the lymph nodes, they can cause lymph node hypertrophy. The presence of crural lymphadenopathy and, to a lesser extent, inguinal lymphadenopathy might indicate early filarial disease, particularly in prepubescent children. After puberty, the children in this cohort were less likely to have either inguinal or crural adenopathy; whether this is due to the older age of these children and fewer non-parasitic causes of adenopathy, localization of adult worms to other sites, or antifilarial drug treatment is unknown. Additionally, the clinical findings of lymphadenopathy have been seen in human experimental infections with Brugia malayi as well as in early clinical observations of filariasis in American troops returning from the Pacific islands.25,26 Although the specificity of lymphadenopathy for LF may be low, these results support the consideration of filarial disease in the differential diagnosis for lymphadenopathy in children from LF-endemic countries.8
The ultrasonographic findings in this study demonstrating lymphangiectasia provide further evidence for subclinical filarial disease in infected children. In this cohort, lymphatic dilatation (lymphangiectasia) at the site of living adult worm nests ranged from 2 to 9 mm. Detection of living adult worms in children was associated with older age as well as both higher microfilarial density and a higher circulating filarial antigen level suggesting that the probability of a positive ultrasound examination is associated with these measures of infection intensity. This is similar to previous work by Dreyer and others from Recife, Brazil, where FDS detection was more common in older children, in boys and in children with microfilaremia.12
Ultrasonographic exam findings in this population confirm the different location of adult worms in children associated with puberty. In 1998, all 16 boys who had a positive ultrasonographic examination were prepubescent (SMR 1–2) and had worms localized to either the crural or inguinal areas. There were no nests located in the intrascrotal lymphatic vessels and no hydrocele on ultrasonographic examination. Similarly, neither hydrocele nor spermatic cord thickening was noted on physical examination. In contrast, 4 years later, three postpubescent not consistent with earlier writing of postpubescent boys (SMR 3–4) all demonstrated adult worms in the intrascrotal lymphatics, as has been reported previously for adult males and adolescent boys.11,16 In addition, one of the three FDS-positive boys had both hydrocele and spermatic cord thickening on ultrasonographic and physical exam, respectively. These results imply that worms tend to localize to different sites before and after puberty, at least in males. It is unknown why there is an apparent difference in adult worm tropism with advancing age in boys. Perhaps the hormonal changes that occur around puberty signal differing localization of worms, especially as at least 80% of W. bancrofti worms nests in adult men that are detectable by ultrasound are found in the intrascrotal area.17 In the animal literature, changes in the localization of worms have been seen at the onset of puberty.27 Alternatively, hormonal changes may stimulate development of lymphatic vessels, which allows the worm movement to be visualized.
The proportion of children with adult worm nests detected by ultrasound was similar for prepubescent boys and girls (16.7% versus 13.3%), but in postpubescent children, only males were found to be FDS-positive. Although other investigators have localized living adult worms in postpubescent females and adult women, no worm nests were found on our 2002 assessment of a relatively small number of adolescent females (N = 11), suggesting that adult worms are more easily detected in boys, particularly once they reach puberty.12,18
Although adult worms were detected by ultrasound in amicrofilaremic and filarial antigen negative individuals (N = 2), only 20% (23/116) of MF+ children and 18% (26/142) of CFA+ children had adult worms detected by ultrasound. This is similar to a previous report by Dreyer and others where 14.1% of children in her pediatric population demonstrated the characteristic movements of adult worms.12 The sensitivity of adult worm detection appears to be much lower than that reported in adult men, where adult W. bancrofti worms can be visualized in 80% of microfilaremic men and 37% of amicrofilaremic men.15,17 This may be due, in part, to the lack of a single preferred location of adult worms in prepubescent children, making ultrasound examinations more difficult and time-consuming and suggests that ultrasound may not be the primary diagnostic tool in children.
Longitudinal assessment of this cohort of FDS-positive children demonstrates a decrease in the number of detectable living adult worm nests over time (Figure 1
). This decrease is greater in the group of children who received DEC alone or DEC and ALB in the randomized placebo-controlled study. In these children, the number of living adult worm nests decreased within 6 months from seven to zero and nine to three, respectively; whereas the ALB only and placebo groups demonstrated a decrease from five to three and four to two nests, respectively, during the same period of time. Ultrasonographic follow-up of these children demonstrated a continued decrease in total living adult worm burden; with 12 worm nests detected in March 1999, 8 detected in May 1999 and 3 detected in November 2002. The decreased ability to find FDS-positive children by ultrasound on follow-up suggests that mass drug administration may have killed some adult worms and, by decreasing transmission, prevented the establishment of new worms in these children. Nevertheless, it is intriguing to note that of the four worm nests visualized on ultrasound in November 2002, three nests, all located in the intrascrotal lymphatics of adolescent boys, were not detected on previous ultrasound exams. This finding suggests that new infections occurred in these boys during the 3-year period. Another possibility is that these worms were already present, but below the limit of detection by ultrasound. Alternatively, it is conceivable that existing adult worms migrated to the scrotal area, but this seems less likely given the remarkable stability of adult worm nest location.28
Of the 32 worm nests initially noted on ultrasonographic examination in November of 1999, only one, a worm nest in the left inguinal area, was found in the same location 4 years later. This boy reported having participated in three rounds of MDA with DEC and ALB but continued to have high levels of circulating filarial antigen and inguinal and crural lymphadenopathy both in 1998 and 2002. He also had a second worm nest in the left infratesticular location. The lymphatic vessel dilatation seen at the site of the living adult worm continued to progress, increasing in diameter by 4 mm in 4 years, which is consistent with previously published data on the rate of lymphatic vessel dilatation over time in adult men.29 This finding suggests the continuous presence of adult worms at this site.
This study has several limitations. First, due to the fact that participation in mass drug administration was self-reported, we are unable to assess whether any individual child actually participated in the MDAs. Overall drug coverage during the Leogane MDA was 72%, 55%, and 78%, in 2000, 2001, and 2002, respectively (Mathieu E. and others, unpublished observations).30 Second, the small number of FDS-positive children who were longitudinally evaluated made it difficult to distinguish between the effects of age and other factors such as drug treatment on physical and ultrasonographic findings.
This is one of the first studies to longitudinally evaluate a cohort of FDS-positive children using a combination of past medical history, physical examination findings, laboratory assay results, and ultrasound examination findings. These ultrasonographic data demonstrate the change in location of adult worms that occurs around puberty in males and confirm the utility of ultrasound in better understanding the natural history of bancroftian filariasis in the pediatric population. They suggest a role for pertinent physical exam findings, specifically crural and inguinal lymphadenopathy, as signs of FDS-positivity in young children. Further longitudinal and population-based studies that delineate LF pathogenesis and evaluate macrofilaricidal efficacy of antifilarial drugs in children are needed to determine the optimal management and prevention of filarial disease in the pediatric population.
Received May 28, 2004. Accepted for publication August 22, 2004.
Acknowledgments: We would like to thank Amanda Freeman, Marie-Denise Milord, Jack Lafontant, and the Hôpital Sainte Croix Filariasis Team for their assistance with the project. We are especially indebted to the children of Leogane who participated in this study, their parents, and the headmasters and staff of the participating schools.
Authors’ addresses: LeAnne M. Fox, Center for International Health and Development, Boston University School of Public Health, Boston, MA 02118, Telephone: 617-414-1209, Fax: 617-414-1261. Bruce W. Furness, STD Control Program, Washington, DC, 20005, Telephone: 202-727-9066, Fax: 202-727-3345. Jennifer K. Haser, Oregon Health & Science University (OHSU), Portland, OR 97239, Telephone: 503-494-8428, Fax, 503-494-8120. Jean-Marc Brissau, Filariasis Program, Hôpital Sainte Croix, Leogane, Haiti, Telephone, 509-557-6424, Fax, 509-235-1845. Jacky Louis-Charles, Filariasis Program, Hôpital Sainte Croix, Leogane, Haiti, Telephone, 509-512-1868, Fax: 509-235-1845. Susan F. Wilson, New Jersey Medical School, Newark, NJ 07101, Telephone, 973-220-8547. David G. Addiss, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30341-3724, Telephone 770-488-7760, Fax: 770-488-7761. Patrick J. Lammie, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30341-3724, Telephone: 770-488-4054, Fax: 770-488-4108. Michael J. Beach, Division of Parasitic Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30341-3724, Telephone, 770-488-7760, Fax, 770-488-7761.
Reprint requests: LeAnne M. Fox, Center for International Health and Development, Boston University School of Public Health, 85 East Concord Street, Boston, MA 02118, Telephone: 617-414-1209, Fax: 617-414-1261, E-mail: lfox{at}bu.edu.
|
REFERENCES |
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  L. M. FOX, S. F. WILSON, D. G. ADDISS, J. LOUIS-CHARLES, M. V. B. DE ROCHARS, and P. J. LAMMIE CLINICAL CORRELATES OF FILARIAL INFECTION IN HAITIAN CHILDREN: AN ASSOCIATION WITH INTERDIGITAL LESIONS Am J Trop Med Hyg, October 1, 2005; 73(4): 759 - 765. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. M. FOX, B. W. FURNESS, J. K. HASER, D. DESIRE, J.-M. BRISSAU, M.-D. MILORD, J. LAFONTANT, P. J. LAMMIE, and M. J. BEACH TOLERANCE AND EFFICACY OF COMBINED DIETHYLCARBAMAZINE AND ALBENDAZOLE FOR TREATMENT OF WUCHERERIA BANCROFTI AND INTESTINAL HELMINTH INFECTIONS IN HAITIAN CHILDREN Am J Trop Med Hyg, July 1, 2005; 73(1): 115 - 121. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
