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Keywords:

  • children;
  • lymphoedema;
  • hydrocoele;
  • treatment;
  • lymphangiectasia;
  • epidemiology;
  • antigenaemia;
  • microfilaraemia;
  • filariasis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Quick reference finder
  9. References
  10. Appendix

Lymphatic filariasis (LF), already recognized as a widespread, seriously handicapping disease of adults, was generally thought to occur only sporadically in children. New, highly sensitive diagnostic tests (antigen detection, ultrasound examination) now reveal, however, that LF is first acquired in childhood, often with as many as one-third of children infected before age 5. Initial damage to the lymphatic system by the parasites generally remains subclinical for years or gives rise only to non-specific presentations of adenitis/adenopathy; however, especially after puberty the characteristic clinical features of the adult disease syndromes (lymphoedema, hydrocoele) manifest themselves. Recognizing that LF disease starts its development in childhood has immediate practical implications both for management and prevention of the disease in individual patients and for the broader public health efforts to overcome all childhood illnesses. For the new World Health Organization (WHO)-supported, public-/private-sector collaboration (Global Alliance) to eliminate LF through once-yearly drug treatment, this recognition means that children will be not only the principal beneficiaries of LF elimination but also a population particularly important to target in order for the programme to achieve its twin goals of interrupting transmission and preventing disease.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Quick reference finder
  9. References
  10. Appendix

Numerous community-based epidemiologic studies and individual case reports attest both to the existence of lymphatic filariasis (LF) infection in children and to the occurrence of clinically evident disease (e.g. lymphoedema/elephantiasis and hydrocoele). From these reports we have recognized that LF can be a disease of children as well as adults, but the true extent and nature of childhood LF has remained very much under-appreciated and incompletely documented.

This under-appreciation can be attributed both to the natural history of the disease itself and to the limitations of previously available diagnostic methods. In the past, most published surveys based their diagnosis of infection on detecting microfilaraemia (MF). It is now clear, however, that this diagnostic approach is not sensitive enough to identify many infections (Weil et al. 1997), especially those of low density, as are often found in very young children, and those where adult worms are present but produce no microfilariae. Furthermore, as the subclinical manifestations of early stage infection are difficult to recognize, and because the more pathognomonic clinical manifestations such as lymphoedema or hydrocoele tend to be associated with long-term infection and thus are relatively infrequent in children, many investigators previously chose to exclude children below the age of 5 in their prevalence surveys, and some even excluded children less than 10 years of age. These factors have led to under-representation of children in epidemiologic studies, underestimates of their infection rate, and to inappropriate paucity of documentation of the importance of LF in children.

Principally, it has been the development of improved diagnostic techniques that has led to our new appreciation of the extent and importance of LF infection and disease in children. The availability of filaria-specific antigen assays providing more sensitive diagnosis, especially in early or low-density infection, and the use of ultrasound and other methods to detect filariasis-specific subclinical pathology have permitted recent studies (Jungmann & Figueredo-Silva 1989; More & Copeman 1990; Amaral et al. 1994; Figueredo-Silva et al. 1994; Lammie et al. 1994; Weil et al. 1996, 1997; Nicolas 1997; Faris et al. 1998; Dreyer et al. 1999a, 2000) to challenge the earlier assumption that LF in children is not a significant public health problem. Indeed, this newly available information now demands a full, critical re-evaluation of the nature and extent of LF in children, in order both to improve our approach to the management of this childhood infection and, equally, to identify the full range of benefits that can be attained by the new programmes underway to eliminate LF as a public health problem globally.

The purpose of this review is to bring together in a comprehensive fashion much of the information already available on LF in children and to focus attention on those critical uncertainties that still need to be resolved.

Materials and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Quick reference finder
  9. References
  10. Appendix

Search strategy and sources of information

A Medline-based literature search covering the years 1966–2000 (September) was carried out by exploding the identifier ‘filariasis’ with the terms ‘child’, ‘children’, ‘paediatric’ and ‘adolescent’; retrieved articles were supplemented by bibliographic references from these articles and by World Health Organization (WHO)-published reports and documents. Of all the publications assessed, 83 were selected for inclusion in this review (Table 1, nos. 2–6, 12–86 and 131), because they met the following criteria: they were published either in peer-reviewed journals (nos. 2–6, 12, 13, 15–86, 131 in Table 1) or in official government documents (Table 1, no. 14); they described age-delineated populations endemic for either Wuchereria bancrofti or Brugia malayi infection which had not been subjected to anti-filarial measures during at least the previous 5 years; and they included a complete description of the relevant diagnostic methods used.

Table 1.   Studies included: indicating diagnostic methods, numbers of persons in each study and use of information for this review Thumbnail image of Thumbnail image of Thumbnail image of Thumbnail image of Thumbnail image of Thumbnail image of

In addition (1) for the analysis of prevalence or incidence, studies contained sufficient information to derive standardized age-stratified MF rates; (2) for comparing MF and antigenaemia prevalence rates, the same patients were used to determine both parameters; (3) for analysing gender as a risk factor for infection, studies provided information on the number or percentage of infected males and females in the respective age groups and in the total population; (4) for reviewing childhood disease manifestations, studies contained descriptions of investigator-observed adenopathy, lymphoedema or hydrocoele (graded according to standard scales (Kumaraswami 2000) and described clinical or subclinical lesions diagnosed as LF; (5) for analysing congenital predisposition to LF, studies contained parental and child MF or antigenaemia status; (6) for reviewing the immunological aspects of LF infection, studies contained information on filaria-specific antibody or lymphocyte responses and related them to MF, antigenaemia or clinical status of infection.

From all publications meeting the above criteria, the information presented was accepted as published; there was no independent assessment of quality and no direct contact with authors to try to improve data sets deemed inadequate for inclusion in the review. The goal of the review was to be comprehensive in terms of geographical, parasitological and clinical representation, not necessarily exhaustive in publications cited.

Organization of study findings

For some analyses, studies were grouped according to the endemicity level of microfilaraemia among the adults of a population (low endemicity populations considered for this review as < 10% MF prevalence; intermediate, 10–30%; and high, > 30%).

For other analyses, studies were categorized according to MF detection method used, with high sensitivity assays defined as those evaluating ≥ 100 μl of blood (either venous or capillary) for the presence of microfilariae, and low sensitivity assays evaluating ≤ 60 μl of capillary blood. Where studies used more than one MF detection method to determine infection rates, the method which produced the highest MF rate was selected to represent the study.

Study populations were divided into 5-year age groups (< 5, 5–9, 10–14 and 15–19 years of age) or 10-year age groups (< 10 and 10–19 years of age); adults were defined for this review as ≥ 20 years old. For studies reporting not precisely these age groupings, closest approximations were used.

Antigenaemia detection techniques (ELISA detection with AD12, Og4C3 or PC-Gib13) were considered to be essentially equivalent in sensitivity (Forsyth et al. 1985; Weil et al. 1987, 1997; More & Copeman 1990; Kumaraswami 2000).

Study exclusion criteria

Studies which met the above criteria but which described populations that had received therapeutic or vector control interventions during the previous 5 years were not included in this review. Publications presenting information as secondary sources and articles reporting ‘infection rates’ determined only through use of anti-filarial antibody assays were also excluded. Most publications only suggestive of an LF aetiology for the reported clinical sign or symptom were excluded from analysis but some are referenced as ‘other clinical presentations’.

Statistical analysis

Linear regression analysis, chi-square, Spearman regression, Pearson correlation, Wilcoxon rank sum, Cochran-Armitage, Student’s t and Fisher’s exact-t tests were used to analyse findings as appropriate.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Quick reference finder
  9. References
  10. Appendix

Studies used for assessment

Table 1 lists 83 studies meeting the criteria for inclusion in this review (the numbers below refer to individual studies listed in this table). All were published between 1949 and 2000, 80 in peer-reviewed scientific journals and three (Institute Against Parasitic Diseases 1998) in official government scientific meeting reports. Seventy-eight studies described W. bancrofti endemic populations and five, B. malayi.

Thirty-nine studies provided information useful for analysing childhood MF prevalence rates. Of these, nine reported on low endemicity populations [13, 14 (two studies), 22, 48, 50, 52, 60, 68], 21 on intermediate endemicity populations (14, 16, 21, 26, 31, 32, 34, 41, 44, 45, 51, 54–56, 61, 62, 67, 77, 78, 82, 85), and nine on high endemicity populations (27, 29, 57, 66, 69, 70, 74, 81, 84). Ten-year age stratifications were possible in 39 of the study populations [13, 14 (two studies), 16, 21, 22, 26, 27, 29, 31, 32, 34, 41, 44, 45, 48, 50–57, 60–62, 66–70, 74, 77, 78, 81, 82, 84, 85], and 5-year stratifications in 19 populations (5, 16, 21, 26, 27, 41, 45, 48, 54, 57, 60, 66–68, 72, 78, 82, 84, 85). As delineated in Table 1, varying numbers of studies were used, as appropriate, to analyse each of the different infection, diagnostic and disease parameters evaluated.

Epidemiology of LF in children

Earlier studies determined the prevalence of LF in children by MF rates. Perhaps not surprisingly, MF prevalence in children from different populations was found to be significantly related to the level of endemicity seen in their respective adult populations. This correlation held for both the < 10-year olds (Figure 1a; R2=0.63; P < 0.001) and the 10–19-year-olds (Figure 1b; R2=0.82; P < 0.001); findings were similar when the 5-year age groups were analysed (data not shown). Indeed, if childhood prevalence rates are expressed as a percentage of the adult rates, rather constant relationships were found for each of the two age groups [averaging 30% for < 10-year olds (95% confidence interval 24–36%) and 69% for 10–19-year olds (95% confidence interval 60–80%)], and they were independent of both population endemicity level and the specific MF detection technique used (data not shown).

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Figure 1.  Correlation of childhood LF prevalence with adult LF prevalence (both determined by MF rates) for two age groups [<10-year old (a) and 10–19-year olds (b)]. Closed boxes (▮) represent the childhood (y-axis) and adult (x-axis) prevalence rates from the reviewed studies (some ‘overlapping points’ cannot be visualized in the figure); the correlation coefficient was 0.80 for the <10-year age group (n=38 studies) and 0.91 for the 10–19-year age group (n=39 studies). The line is the least-squares fit for the data points, across all studies, with the strength of the correlations (R2) being 0.63 and 0.82 and the corresponding regression equations being Y=0.62x – 6.65 and Y=0.64x + 0.90 for the <10 and 10–19-year olds, respectively (in Table 1, nos. 13, 14, 16, 21, 22, 26, 27, 29, 31, 32, 34, 41, 44, 45, 48, 50–52, 54–57, 60–62, 66–70, 74, 77, 78, 81, 82, 84, 85).

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It is because of this link between adult and child MF prevalence rates that the different levels of endemicity found in different populations probably account for the wide variation seen in the earlier descriptive reports of MF prevalence in children (Figure 2). Such prevalence ranged between 0.3 and 71% in the 39 studies reporting on children stratified by 10-year age groupings, with the older children having significantly (P < 0.001) higher rates than the younger ones. Similarly, in the 19 studies grouped by 5-year intervals (10 with ‘complete’ data sets and nine missing data from one of the age groups), prevalence was also seen to increase progressively from the younger to the older age groups, but again with an appreciable variation in all age groups that is likely principally to be due to the different endemicity levels in the populations (Figure 2).

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Figure 2.  Microfilaraemia prevalence in children: (a) by 10-year age groups (in Table 1, nos. 13, 14, 16, 21, 22, 26, 27, 29, 31, 32, 34, 41, 44, 45, 48, 50–52, 54–57, 60–62, 66–70, 74, 77, 78, 81, 82, 84, 85); (b) by 5-year age groups (in Table 1, nos. 13, 16, 21, 26, 27, 41, 45, 48, 54, 57, 60, 66–68, 72, 78, 82, 84, 85). Each box is composed of three horizontal lines representing the 25th, 50th (median), and 75th percentiles of the prevalence rates. Vertical lines denote the 10th and 90th percentiles, and circles indicate prevalence values lying outside these percentiles (some ‘overlapping’ points cannot be visualized in the figure).

Thirty-eight studies were examined to ascertain what influence different MF detection methods might have on estimates of LF prevalence in children. Nine studies described the use of high blood volume assays (i.e. ≥ 100 μl) and 31, the use of low blood volume assays (i.e. ≤ 60 μl – usually 20 μl blood smears). As seen in Table 2, when high blood volume techniques were used, the correlations between the MF rates of adults and those of both the younger and older children were strong and statistically significant. Low blood volume techniques also produced a strong correlation between adult rates and those for the 10–19-year olds, but the correlation with the rates for the younger children, although still significant, was weaker. Furthermore, in the younger children (< 10-year old group) high-volume techniques could detect a prevalence of MF that was just over half that found in adults, but the low-volume techniques detected an MF prevalence in these children only about one-fourth of that found in adults.

Table 2.   Blood volume used in diagnostic assay as a factor affecting MF prevalence estimates Thumbnail image of

Determination of LF in children by antigen detection is much more effective than by microfilaria detection, as illustrated in Figure 3 and Table 3. The greater effectiveness of antigenaemia detection is seen for all ages, but it is proportionately more pronounced in < 5-year old children (ranging from 42 to 90% in the three studies with this age group described in Table 3). The tight correlation between prevalence detection by antigenaemia and MF in the < 10-year old age group is shown in Figure 4 (correlation coefficient=0.98; R2=0.96; P < 0.004), which also demonstrates that this under-diagnosis of infection by MF assays is independent of population endemicity level. Finally, as indicated in Table 3, at least one-third of all infections are ‘missed’ using only MF detection to diagnose infections, and as Figure 5 shows, the proportion of infections missed by MF assays is significantly greater (P < 0.001) in the younger age groups than in older children or adults.

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Figure 3.  Differences in LF prevalence estimates based on antigenaemia (Ag) and MF detection assays from one published study (Simonsen et al. 1996). Open boxes (□) depict prevalence results from the antigen assay, while closed boxes (▮) represent results from the MF assay (cf. Table 3).

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Table 3.   LF infections detected and missed by microfilaraemia (MF) and antigenaemia (Ag) assays Thumbnail image of
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Figure 4.  Correlation between antigenaemia (Ag) and MF prevalence rates in <10-year olds. Closed boxes (▮) represent the Ag and MF values determined in the five studies analysed (Turner et al. 1993; Lammie et al. 1994; Chanteau et al. 1995; Simonsen et al. 1996; Steel et al. 2001). The correlation coefficient for the Ag and MF prevalence pairs for all studies was 0.98 (R2=0.95; Y=1.10x + 19.6).

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Figure 5.  Percentage of LF infections missed if microfilaraemia detection was used as the diagnostic, instead of antigenaemia detection (see text). Closed boxes (▮) represent the geometric means of values from five studies (Lammie et al. 1994; Ramzy et al. 1994; Simonsen et al. 1996; Steel et al. 2001). Bars represent ±1 SEM. Strength of correlation: R2=0.68; regression equation: Y=–7.49x + 74.0.

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In the single study (Lammie et al. 1998) detailing the incidence of LF in very young children, a cohort of 39 children was examined for antigenaemia and MF first at age 2 (antigenaemia=6%; MF=0%) and then 2 years later at age 4. Living in an area with an overall MF prevalence of approximately 30%, these children were found to have a 2-year incidence between ages 2 and 4 years of only 2% for MF but 20% for antigenaemia. This emphasizes not only how early in life young children acquire LF infection, but also how much more sensitive diagnosis of infection is using the antigen assay. Other studies (cross-sectional in design) confirm both this early age positivity and a progressive increase of antigen positivity with age (Lammie et al. 1994; Ramzy et al. 1994; Simonsen et al. 1996; Steel et al. 2001) Furthermore, a similar longitudinal study found that among microfilaria-negative children, antigen positivity is the best predictor for the development of MF during the subsequent year (Weil et al. 1999).

An earlier comprehensive review of gender as a risk factor for LF prevalence in adult populations found a significant predominance of infection among males (Brabin 1990). Figure 6 shows the results from the analysis of 14 studies assessing gender as a potential risk factor for LF infection among children (in Table 1, nos. 16, 21, 22, 29, 34, 45, 48, 51, 55, 61, 62, 65, 78, 85) Among the adults in the 14 studies, the previously described male predominance was confirmed as statistically significant (P < 0.02). But for children no significant gender difference in MF prevalence was observed (< 10-year olds, P=0.08; 10–19-year olds, P=0.33). Furthermore, the level of LF endemicity in populations did not influence these gender relationships in either adults or children (data not shown).

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Figure 6.  Male–female ratio of MF prevalence by age group. Mean ratios (±SEM) are plotted for two childhood age groups and for adults. Only the adults show a significant gender imbalance (male predominance; P < 0.02). NS: not statistically significant.

The influence of parental LF infection status on childhood infection (defined by microfilaraemia or antigenaemia) was examined in eight studies (in Table 1, nos. 17, 25, 38, 40, 43, 53, 75, 83), two of which (Lammie et al. 1991; Hightower et al. 1993) described overlapping but not identical populations (Table 4). Although there was an appreciable lapse of time in most of these studies between the birth of the child and assessment of the MF or antigenaemia status in the children and the parents, still maternal MF was seen as a relative risk factor for childhood MF, ranging from 1.56 to 2.85 (statistically significant in four of six studies). The paternal relative risk ranged from 1.43 to 2.76, being statistically significant in three of four studies. The aggregated data yielded a relative risk for a child’s being microfilaraemic when the mother was microfilaraemic of 4.19 (P < 0.001); for the father it was 4.11 (P < 0.001).

Table 4.   Parental filarial infection status as a risk factor for childhood filarial infection Thumbnail image of

Two studies also provided similar information but were based on filarial antigenaemia, not MF status (Table 4). The relative risk of a child being antigen-positive if a parent was antigen-positive was at least twice that of a child with antigen-negative parents, the association with maternal status being more highly significant (P < 0.001) than that with paternal status (P < 0.05).

The potential for congenital LF infection was reviewed in three studies reporting the identification of microfilariae in placental tissues and in four reporting the presence of microfilariae in cord blood (Table 5). All microfilariae-positive placentas and cord blood specimens were derived from mothers who were microfilaraemic. Three of the seven infants with microfilaria-positive cord blood specimens were found to be amicrofilaraemic upon subsequent examination before 8 months of age (Rao et al. 1984; Eberhard et al. 1993) two were lost to follow-up (Rao et al. 1984), two did not have their follow-up reported (Bloomfield et al. 1978; Hitch et al. 1997).

Table 5.   Evaluation for congenital LF infection Thumbnail image of

Immunological evaluation of umbilical cord blood (foetal-origin) for antibodies and antigens revealed the presence of filaria-specific IgM and IgE (antibody classes that should not cross the placental barrier) in one-third to one-half of samples associated with MF+ mothers (Dissanayake et al. 1980; Weil et al. 1983; Sanjeevi & Narayanan 1989; Hitch et al. 1997), and filaria-specific antigen (Og4C3) was detected in six of 29 cord blood samples (Hitch et al. 1997). With regard to in vitro cord blood mononuclear cell (CBMC) proliferative responses to filarial antigens, nine of 61 samples examined had positive responses, but these were independent of maternal MF status and were not statistically different from responses in non-endemic (negative) controls (Hitch et al. 1997).

Such findings suggest that exposure to, or rarely even passive acquisition of, microfilariae during the prenatal or perinatal period does occur, but actual prenatal infection with adult worms is unlikely. They also suggest that prenatal sensitization to filarial antigens, or to maternal anti-filarial (idiotypic) antibodies, occurs much more commonly.

Clinical manifestations and pathology of LF in children

Table 6, listing 133 childhood cases of hydrocoele and 57 cases of lymphoedema or elephantiasis attributed to LF (in Table 1, nos. 5, 24, 27, 30, 32, 33, 52, 54, 55, 63, 66, 74, 78, 80, 86), shows clearly that the same chronic pathology seen in adults with LF is also found in children, although it is unusual in children < 10 years of age. Furthermore, the fact that the stage of morbidity most frequently reported was Grade II (Kumaraswami 2000) or higher suggests that the earlier stages of this chronic progressive disease – not only the subclinical stages but also the early overt clinical stages – frequently go undetected in young children.

Table 6.   Lymphatic morbidity reported with LF in children Thumbnail image of

Other clinical pathology associated with the presence of filarial worms, such as adenopathy and lymphangitis has been demonstrated principally through histopathologic examinations (Cooray 1960; Jungmann & Figueredo-Silva 1989; Amaral et al. 1994; Figueredo-Silva et al. 1994; Faris et al. 1998; Dreyer et al. 1999b). Excisional biopsy with histopathologic diagnosis of either acute or chronic LF was made in 56 children (including 16 who were < 10-year old) presenting with soft tissue masses, but whose clinical presentations were generally not recognized as being caused by LF, despite the children’s residence in LF-endemic areas (Cooray 1960; Jungmann & Figueredo-Silva 1989; Figueredo-Silva 1994). The most frequent presumptive clinical diagnoses were neoplasia, tuberculosis, or inguinal hernia; in only two of these cases was the diagnosis of LF entertained before biopsy (Jungmann & Figueredo-Silva 1989). Histologically, these biopsies reflected the spectrum of tissue and inflammatory reactions seen in LF infections, regardless of patient age. In the proximity of live worms, there were varying degrees of lymphangiectasia, generally without inflammatory changes or lymphatic obstruction; if present, the acute inflammatory response was a non-granulomatous eosinophilic, lymphocytic and plasmacytic parietal lymphangitis. In-situ worm death was associated with a progressive granulomatous reaction, at times including polypoid endothelial hyperplasia or granulomatous endolymphangitis with sub-endothelial connective tissue involvement and ultimate effacement of lymphatic architecture and fibrous hyalinized scarring. This severe damage was most commonly seen associated with worm calcification (Jungmann et al. 1991).

Subclinical, asymptomatic or minimally symptomatic lesions have been identified on ultrasound, principally associated with the presence of nests of living adults worms [Filarial Dance Sign (FDS)] and constituting lymphangiectasia both around and at a distance from these worm nests; this lymphatic dilatation was seen to increase with patient age (mean of 1.6 mm in < 10-year olds vs. 2.1 mm in > 10-year olds (Dreyer et al. 1999a). The scrotal area was the exclusive site for detecting FDS in boys > 14 years of age, but in younger pre-pubescent children (both male and female) the FDS was detected primarily in axillary, crural and inguinal locations (Dreyer et al. 1999a, 2001). Unfortunately, because of difficult technical challenges in visualizing these particular locations with ultrasound, there remains a gross under-detection of live worms in the younger, pre-pubescent children.

Other types of clinical presentation in children have been reported, but often without a specific diagnosis. These include the relatively common acute adenolymphangitis (ADL) and, less commonly, chyluria and tropical pulmonary eosinophilia (TPE). A total of 145 children < 10 years old, and 181 children aged 10–19 were reported as having ADL characterized by episodic attacks of nodular inflammation in the limbs, scrotum or other subcutaneous tissues, and with or without accompanying general malaise and fever (Bai et al. 1977; Raghupathy & Date 1982; Ramzy et al. 1994; Gyapong et al. 1996; Alexander et al. 1999). These attacks were associated with incapacitation, often lasting several days and often re-occurring (Gyapong et al. 1996; Alexander et al. 1999). LF-associated chyluria was described in four cases (10–12-year-old children), two with accompanying haematuria (Gupta et al. 1967; Bai et al. 1977; Raghupathy & Date 1982; Kohli et al. 1994). Three of these children were microfilaraemic and two of them had microfilariae in the urine. Finally, TPE is also described as occurring in children, with one reported case, an 11-year-old boy, presenting with recurrent bouts of cough and dyspnea that progressed to incapacitating restrictive and obstructive lung disease (Magnussen et al. 1995).

Immune responses to LF infection in children

Almost all studies of antibody levels in children, either with LF infection or exposure, agree that the pattern of humoral immune responsiveness does not differ appreciably from that described in adults (in Table 1, nos. 18, 28, 35, 36, 43, 58, 64, 71, 73, 82, 83; Wamae et al. 1995; Dimock et al. 1996; Steel et al. 1996; Nicolas et al. 1999), even including the hyper-responsiveness of the tropical pulmonary eosinophilia syndrome (Magnussen et al. 1995). However, while the pattern of responsiveness is similar, the levels of antibodies are generally lower in children and rise progressively to those of adulthood (Chanteau et al. 1995). Furthermore, as also recognized in adult populations, the level of antibody response is generally higher in high-prevalence populations than in low-prevalence populations (Chanteau et al. 1995; Haarbrink et al. 1995).

Particularly noteworthy is the finding that children with MF or antigenaemia (especially if accompanied by MF) have high anti-filarial IgG4 responses, even in the youngest age groups (in Table 1, nos. 21, 36, 43, 64, 82, 83). Also as in adults, antibodies of other IgG subclasses (IgG1, IgG2 and IgG3) and other isotypes (IgE and IgM) appear generally lower in microfilaraemic children compared with those in endemic populations who are amicrofilaraemic (in Table 1, nos. 18, 35, 36, 43, 64, 71, 82, 83). There is, however, some suggestive data (Table 7) that this generalization, might not extend to the youngest age group of children, in whom the Th-1-type responses (IgG1, IgG2 and IgG3) of infected children appear to be relatively greater than they are later in life. Such an observation, if substantiated by further research, would be of particular interest because of its potential direct relevance to a postulated Th-1[RIGHTWARDS ARROW]Th-2 shift in the pattern of immune response during the course of LF (and other helminth) infection (Maizels et al. 1995).

Table 7.   Relative levels of filaria-specific antibodies in ‘infected’* and ‘non-infected’ individuals† living in LF endemic areas Thumbnail image of

In a study of amicrofilaraemic teenage children who had grown up exposed to filariasis infection, those born to mothers who were microfilaraemic at the time that the children were born had greater levels of IgG4 antibody to filarial antigens than those born to amicrofilaraemic mothers, while IgE titres were greater in those born to amicrofilaraemic mothers; IgG1, IgG2 and IgG3 responses did not vary with maternal status (Steel et al. 1994). These findings imply a potential prenatal programming or influencing of subsequent immune responsiveness depending on the mother’s infection status.

Another potentially important finding relates to the issue of protective immunity; specifically, in contrast to adults, few infected children (i.e. defined by MF or antigenaemia) have antibodies to the surface of infective larvae (L3), whereas a large percentage of adults in the same populations have such antibodies (Day et al. 1991b). This difference has been postulated to reflect a state of ‘concomitant immunity’ (i.e. protection from additional infection in those already infected) in adults but not children.

Lymphocyte responses and their clinical correlations

Table 8 presents information from four studies on lymphocyte proliferative responses to filarial antigens in children (Ottesen et al. 1977; Hitch et al. 1991b, 1997; Steel et al. 1994). The following generalizations can be made:

Table 8.   Lymphocyte responsiveness to filarial antigens in children Thumbnail image of

• Amicrofilaraemic children in endemic populations have a consistently higher proliferative response to filarial antigens than those with MF, irrespective of age (Ottesen et al. 1977; Hitch et al. 1991b), and the same relationship holds for antigen-negativity or positivity (Hitch et al. 1991b).

• Responses in amicrofilaraemic children are stronger than those of amicrofilaraemic adults (Ottesen et al. 1977).

• Microfilaria-positive maternal status at the time of a child’s birth appears to diminish the peripheral blood mononuclear cells (PBMC) proliferative response to filarial antigen even in amicrofilaraemic children 17–19 years old (Steel et al. 1994).

• There is no significant difference in the level of CBMC proliferation response to filarial antigen between children with microfilaraemic mothers and those with amicrofilaraemic mothers (Hitch et al. 1997).

Children have comprised part of several studies of cytokine production in LF endemic populations (Dimock et al. 1996; Steel et al. 1996; Sartono et al. 1997), but comparative analyses between the responses of adults and children have not been presented. However, responses of uninfected adolescents living in an endemic area and distinguished by their having been born to microfilaraemic or non-microfilaraemic mothers have been described (Steel et al. 1994). Interestingly, those born of MF+ mothers mounted significantly lower cytokine responses (IL2, IL5, IL10, INF-γ and granulocyte macrophage colony stimulating factor (GMCSF)) to filarial antigens than did those born to MF– mothers (Table 8). While this significant difference in responsiveness was seen at the age of adolescence, a study of newborns, born to either MF+ or MF− mothers failed to find any difference in cytokine production when cord blood lymphocytes were examined (Hitch et al. 1997).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Quick reference finder
  9. References
  10. Appendix

Lymphatic filariasis is now recognized as a widespread, important disease affecting as many as 120 million people worldwide, with a billion people living in areas at risk of infection (Ottesen et al. 1997). What has not been well appreciated, however, is the fact that it is the children in these areas who are at greatest risk, because it is during childhood that infection is first acquired and in childhood that the early damage to the lymphatic system takes place – damage that subsequently leads to the same clinical consequences (mainly early lymphoedema and hydrocoele) later in childhood that progress to the more prominent expressions of LF disease in adults. While it is clear from this review that some LF in children has been recognized previously, the availability of new, more sensitive diagnostic techniques has now greatly expanded our ability to detect and understand just how widespread these LF infections of children in endemic areas really are.

As demonstrated in Figure 1, across all endemicity levels the prevalence of LF infection in children is proportional to that of the adults in each population; those under 10 have prevalence rates averaging 30% of the adult rate and 10–19-year olds have about 69% of the adult rate. Thus, much of the wide variation in childhood prevalence of LF recognized earlier and seen in the aggregated data of Figure 2 can be explained by the differences in the prevalence of infection among the adults of these reported populations.

Technical factors associated with blood sampling volume and techniques also contributed to the variability and relatively low estimates of prevalence of LF in children, but the greatest cause for misdiagnosis of LF infection in children has certainly been the relatively poor sensitivity of microfilaria detection techniques. Regardless of how much blood is examined for microfilariae, the detection of circulating antigen (now by simple finger-prick techniques) has proven to be a much more sensitive diagnostic for bancroftian filariasis than anything previously available. Indeed, as indicated in Table 3 and Figure 3, the enhanced effectiveness of antigen detection, vis-à-vis microfilaria detection, to diagnose LF infection is greatest in very young children, many of whose infections had been previously undiagnosed. Furthermore, the direct observations on the incidence of infection in very young children (Lammie et al. 1998; Weil et al. 1999) emphasize again the magnitude of the proportion of children acquiring their LF infections even before age 5 in endemic communities.

It is not clear what exactly determines which children in a population become infected and at what age, and whether there are specific risk factors for acquiring infection. Gender does not appear to affect the acquisition of infection in childhood (defined by MF [Figure 6] or by antigenaemia [Steel et al. 2001]), although it is well recognized that among the adults in endemic areas men have significantly higher infection rates (determined by MF [Fig. 6] [Brabin 1990] or antigenaemia [Steel et al. 2001]) than do women. Maternal infection (determined either by MF or antigenaemia) has been clearly shown to be a risk factor for childhood infection (Table 4), and there is convincing immunological evidence for prenatal exposure and sensitization to filarial antigens. However, many of the same studies showing maternal infection as a risk factor make the same conclusion about paternal infection (Table 4), so that the relative importance of biological, vis-à-vis environmental, risk factors still remains uncertain (Ottesen et al. 1981).

Perhaps most important in our analysis and growing understanding of LF infection in children are the questions of what disease is caused by these infections and how reversible it is with treatment. Interestingly, almost all of the overt clinical disease reported in children is in those >10 years of age (Table 6). Whether this observation reflects only the length of time it takes to damage lymphatic systems sufficiently to express overt clinical disease or whether there is something ‘special’ about post-pubertal individuals that facilitates the development of overt disease (lymphoedema or hydrocoele) in the presence of underlying lymphatic damage is not clear. What is clear, however, is that while these ‘classic’ consequences of lymphatic dysfunction are not normally seen – some would argue, never seen (Dreyer et al. 2000) in the pre-pubertal years – other clinical manifestations of LF are seen in younger-age children. Most well documented is adenopathy which can be chronic, painless and clinically indistinguishable from neoplasia, tuberculosis and other such diagnoses that have been frequently applied to this presentation of LF (Cooray 1960; Jungmann & Figueredo-Silva 1989; Amaral et al. 1994; Figueredo-Silva et al. 1994; Faris et al. 1998; Dreyer et al. 1999b, 2001). Similarly, acute episodes of adenitis or adenolymphangitis can be seen in children of all age groups, but specific diagnostic criteria for differentiating LF from other causes of this clinical presentation have not yet been established.

In addition to the overt clinical manifestations of LF in childhood recognized previously (Table 6), after the development of ultrasonographic techniques to detect intralymphatic live adult worms (Amaral et al. 1994), it has been possible to define distinct subclinical pathology in the lymphatics of infected children (Dreyer et al. 1999a). As it is this subclinical pathology that leads to the development of overt disease, understanding these early lesions and defining their response to treatment should be of highest priority for future research efforts.

Thus far little has been written specifically on the treatment of LF in children, especially the clinical manifestations. The new, recently codified approaches to managing filarial lymphoedema and hydrocoele in adults (Addiss & Dreyer 2000; Dreyer et al. 2000) have also been used successfully with children, although little description of this has yet been published. A recent account of two young girls (6 and 10 years of age) presenting with adenopathy shown on ultrasound to be caused by living adult filarial worms, recorded the regression of both overt and identifiable subclinical pathology after diethylcarbamazine (DEC) treatment in one child and after spontaneous death of the adult parasite in the other (Dreyer et al. 2001). Formal studies are needed to extend these case-report observations and determine how effective the treatment of such children can be, either individually in the clinic or as part of community-wide mass drug administration campaigns to eliminate LF (Ottesen 2000).

Indeed, although we now recognize that LF is a frequent and common infection of children in all LF-endemic areas and that it causes both subclinical lymphatic damage and eventual overt clinical disease, an enormous number of questions (both conceptual and practical) remains to be answered. The most immediate concern the optimal approach to treatment and prevention, both of overt clinical disease and of the subclinical lymphatic damage of early infections. It is critically important to learn how to reverse these early lesions and thereby prevent future development of lymphoedema and hydrocoele in older children and adults. Treatment studies may be sufficient to define the reversibility of such lesions, but studies on the pathogenesis of lymphatic dysfunction are also necessary in order to provide the necessary insight for continuing to optimize therapeutic strategies in the future. It will also be important to identify whether or not the same renal pathology seen in microfilaraemic adults (Dreyer et al. 1992) is also a part of the clinical disease induced by LF in children. Further, as LF-induced lymphadenopathy and lymphadenitis still cannot be distinguished from the much more common viral and bacterial causes of these presentations, guidelines for the differential diagnosis of this problem in children must be established. Also, as already described with other filarial infections (Cooper et al. 1998), LF in children might alter their immunological responses either to other concurrent infections or to vaccine immunizations. As such possibilities are of critical public health importance, further studies on the immune responses of infected children to LF and other immunogens are extremely important.

Protecting children from LF infection and disease should be a primary goal of programmes to eliminate LF (Ottesen 2000). Studies to look at the value of the treatment regimens being advocated for LF elimination programmes to provide effective prophylaxis to children need to be undertaken. Similarly, the role of maternal infection as a risk factor for childhood infection should be explored, because a positive finding would make imperative the treatment of women of childbearing age if appropriate drug regimens could be established. Further, the definition of those immune parameters that could protect children from LF infection might offer a long-term ancillary tool for global efforts to eliminate LF that are based primarily on mass-drug administration. Finally, as children may well form the sentinel populations needed to assess the effectiveness of efforts to interrupt transmission during LF elimination programmes, it is important that the limits and usefulness of antigen detection methods to assess the acquisition of infection by young children be clearly defined.

Certainly, many questions remain unanswered, but it is clear already that LF infection in childhood is an issue that can no longer be disregarded. The best ways to treat and prevent infection must be established immediately, so that optimal care for the children in endemic areas can be assured. Not only should this care come from specific LF elimination programmes, but it should also come as a result of inclusion of this important childhood infection in programmes aimed at other health needs of school-age and pre-school age children. As many such programmes are currently active, it should be possible to achieve very significant additional health benefits from a very small added cost to these programmes. Indeed, this opportunity to coordinate the efforts to respond effectively to a broad range of childhood infections, including LF, now provides an essential public health challenge to all of those with concern for the health of children throughout the world.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Quick reference finder
  9. References
  10. Appendix

We gratefully acknowledge the considerable organizational and secretarial contributions of Ms Tabinda Faizi and the statistical assistance of Drs Ravinder Arnand and Hans Remme.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Quick reference finder
  9. References
  10. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Quick reference finder
  9. References
  10. Appendix

This review was originally written in Vancouver format, i.e. with references cited as numbers in the text and with a bibliography ordered by ascending numbers. TM & IH uses Harvard format, but in the interest of better readability we retained the Vancouver system where the authors described single characteristics of large groups of papers analysed. For technical reasons those papers which are not referenced in the text in Harvard style must appear separately, in an appendix rather than being part of the References section.

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