Burden of lymphatic filariasis morbidity in an area of low endemicity in Brazil

Accepted Manuscript Title: Burden of lymphatic filariasis morbidity in an area of low endemicity in Brazil Author: Maria Jos´e Netto Cristine Bonfim Eduardo Brand˜ao Ana Maria Aguiar Santos Zulma Medeiros PII: DOI: Reference:

S0001-706X(16)30494-6 http://dx.doi.org/doi:10.1016/j.actatropica.2016.07.006 ACTROP 3984

To appear in:

Acta Tropica

Received date: Revised date: Accepted date:

2-3-2016 8-7-2016 13-7-2016

Please cite this article as: Netto, Maria Jos´e, Bonfim, Cristine, Brand˜ao, Eduardo, Santos, Ana Maria Aguiar, Medeiros, Zulma, Burden of lymphatic filariasis morbidity in an area of low endemicity in Brazil.Acta Tropica http://dx.doi.org/10.1016/j.actatropica.2016.07.006 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Burden of lymphatic filariasis morbidity in an area of low endemicity in Brazil

Maria José Nettoa, Cristine Bonfimb,c, Eduardo Brandãoa, Ana Maria Aguiar Santosa, Zulma Medeirosa,d *

a

Lymphatic Filariasis National Center, Parasitology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, PE, Brazil.

b

Social Research Department, Joaquim Nabuco Foundation, PE, Brazil.

c

Postgraduate Integrated Public Health Program, Federal University of Pernambuco, PE, Brazil.

d

Pathology Department, Institute of Biological Sciences, University of Pernambuco, PE, Brazil.

* Corresponding author: Medeiros Zulma, Transmissible Disease Laboratory, Parasitology Department, Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Recife, Pernambuco, Brazil. Tel.: +55 81 2101-2662, Fax: +55 81 21012671; E-mail: [email protected]

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GRAPHICAL ABSTRACT Describe the prevalence of morbidity and its correlation with filarial infection, thereby filling a gap that existed regarding the data on morbidity in Brazil.

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HIGHLIGHTS  Among the 23,673 individuals examined, 741 cases of complaints relating to LF were identified (3.13%).  The prevalence of microfilaremia was found to be 1.36% (323/23,673).  Positive associations with complaints of ADLA, hydrocele and cloudy urine were observed, and the association was most notable with hydrocele.

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ABSTRACT The Global Programme to Eliminate Lymphatic Filariasis has two main components: interrupting transmission of lymphatic filariasis (LF) and managing morbidity and preventing disability. However, interventions to prevent and manage LF-related disabilities in endemic communities have been of limited extent. The aim of this study was to describe the prevalence of morbidity and its correlation with filarial infection, thereby filling a gap that existed regarding the data on morbidity in Brazil. Presence of Wuchereria bancrofti microfilaria was investigated using the thick smear technique. Information on parasitosis-related clinical manifestations was obtained using a questionnaire applied by community health agents with previous training and capacitation to know about and identify the disease. To analyze correlations, Pearson’s correlation coefficient was used with the corresponding statistical significance test. 23,673 individuals were investigated: 323 presented microfilaremia (1.36%) and 741 (3.13%)

had

clinical

complaints

that

were

attributable

to

LF.

Acute

dermatolymphangioadenitis (ADLA) was the most prevalent condition (2.2%). Lymphedema, ADLA and chyluria were more commonly reported among female patients. There were positive associations between all the clinical complaints reported and filarial infection. Hydrocele presented the most strongly positive association (r = 0.699; p < 0.001). The present study showed that there is an association between clinical condition reported and the rate of infection among people living in an area of low endemicity for LF. It contributes data that might provide support for healthcare systems and thus optimize disease management, through incorporating surveillance measures directed towards preventing disability and reducing the psychosocial and economic impact of the disease on poor populations living in areas endemic for LF. Keywords: neglected tropical diseases; lymphatic filariasis; Wuchereria bancrofti; morbidity; hydrocele; lymphedema; control; elimination.

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1. Introduction Lymphatic filariasis (LF) is a parasitic infection that stands out as a serious public health problem worldwide, both because of its wide geographical distribution and because of its clinical expression, with lymphatic damage and sequelae that are often irreversible (WHO, 2013). The disease occurs predominantly in areas of low socioeconomic level and it has been estimated that 15 to 20% of asymptomatic infected individuals may evolve to filarial disease (Bonfim et al., 2009a; Bonfim et al., 2009b; Omundo and Ochoga, 2011; WHO, 1992). The prevalence of infection and intensity of transmission present a close relationship with occurrences of clinical manifestations in the population (Dreyer et al., 1998). The World Health Organization (WHO) has estimated that 120 million people are infected, of whom 40 million show the disease. The importance of the clinical manifestations, especially urogenital forms, have made LF the biggest cause of morbidity worldwide and the second biggest cause of definitive incapacity, with complications that limit occupational and educational activities, employment opportunities and mobility (Ichimori et al., 2014; WHO, 2014). The Global Programme to Eliminate Lymphatic Filariasis (GPELF) was created with the objective of eliminating LF by 2020. This program is based on two pillars: interruption of transmission and prevention and relief of incapacities associated with LF (Addis, 2005; Ottesen et al., 1997; Ottesen and Molyneux, 2006). In 2014, 73 countries were considered to be endemic, among which 18 countries were at the surveillance stage and 55 were continuing to apply mass treatment (mass drug administration, MDA) (WHO, 2015). It is believed that on a worldwide scale, the number of cases of filarial disease has been underestimated (Dreyer and Norões, 2001; Tobian et al., 2003), because of difficulties both in making the etiological diagnosis and in providing access for these individuals to healthcare services. Studies using ultrasonography as a diagnostic aid have demonstrated the existence of adult worms located in lymphatic vessels of the scrotal sac in individuals presenting microfilaremia and in asymptomatic individuals without microfilaremia, thus showing that the disease gives rise to subclinical alterations (Amaral et al., 1994; Mand et al., 2003).

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In Brazil, LF is a public health problem only in the state of Pernambuco, in the urban areas of four adjacent municipalities: Recife (the state capital), Olinda, Paulista and Jaboatão dos Guararapes (Simonsen and Mwakitalu, 2013). Among these, the municipality of Jaboatão dos Guararapes has presented the highest prevalence rates for microfilaremia and vector infectivity (Medeiros et al., 1992; Medeiros et al., 2008). MDA was the main strategy developed for eliminating this parasitosis in Brazil, and this started in 2003 (Lima et al., 2012). Recently, a transmission assessment survey was conducted in seven evaluation units in Recife, Jaboatão do Guararapes and Olinda (WHO, 2015). Information on the burden of filarial morbidity remains scarce and consists only of isolated reports on occurrences of manifestations of the disease (Aguiar-Santos et al., 2009; Albuquerque et al., 1995; Marchetti et al., 1998). Knowledge of the prevalence and distribution of filarial infection and/or disease is a critically important step, not only for ensuring the success of GPELF, but also for optimizing healthcare service provision and delivery, with appropriate resource management. The aim of this study was to describe the burden of morbidity and its correlation with filarial infection in an area of low endemicity, where the MDA had not yet been started, thereby filling a gap that existed regarding the data on filarial morbidity in Brazil.

2. Material and Methods 2.1 Study area The municipality of Jaboatão dos Guararapes is located 18 km from the city of Recife (the capital of the state of Pernambuco), in northeastern Brazil, with a total area of 256 km². According to the 2000 census, the municipality has 644,620 inhabitants, distributed across 27 districts and 492 census tracts (IBGE, 2010). Three districts and eight census tracts were excluded because they covered rural areas, given that in Brazil LF exclusively presents distribution in urban areas (Simonsen and Mwakitalu, 2013). 2.2 Survey To determine the sample size, the total number of permanent private households was taken to be 111,666, distributed across 484 census tracts. It was estimated that 6% of the households would be positive for LF (i.e. prevalence of 6%), with an acceptable error of 5% for each 95% confidence interval (CI). Thus the minimum sample size was estimated to be 5,915 households.

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Households were registered in each of the 484 census tracts. Although it was only necessary to evaluate 12 households per census tract, 14 were registered, considering that some residents in these households might refuse to participate in the survey. Households in each census tract were selected by consulting a map produced by the Brazilian Institute for Geography and Statistics (Instituto Brasileiro de Geografia e Estatística, IBGE). This map was manipulated to define quadrants. A straight line was applied to the diagonal (2nd and 3rd quadrants), thus joining opposite quadrants. After locating the midpoint of each quadrant (2nd and 3rd), Two street addresses were chosen: one at each midpoint of the quadrant. Seven households were then investigated on each street, thus totaling 14 in each census tract. Individuals of both sexes were examined, of ages ranging from one to 99 years. The morbidity survey was conducted by a team composed of health agents, medical students and nursing students, who were supervised by physicians. Information on the clinical condition reported was gathered at the time of registering the families. For this, a panel containing images of the clinical manifestations was used (Figure 1). The questions were objective and used popular expressions to refer to the disease. Individuals presenting any complaint of lymphedema, acute dermatolymphangioadenitis (ADLA), hydrocele or chyluria were considered to be symptomatic. If these individuals presented any complaints, they then underwent a clinical examination conducted by physicians. Fingerprick blood sampling, taking samples of around 50 µl, was performed between 23:00 h and 01:00 h. Thick blood smears from these samples were stained with eosin and counterstained with Giemsa. The slides were read at the Aggeu Magalhães Research Center, Fiocruz. 2.3 Data handling and analysis The data obtained through the study were stored and analyzed using Epi Info, version 6.04.d. To compare the quantitative variables, the chi-square test (χ2) was applied. Odds ratios were used as a measurement for associations. Pearson’s correlation coefficient was used to analyze correlations (r = simple linear regression). P values < 0.05 were considered indicative of a statistically significant difference. The spatial distribution of the prevalence of microfilaremia and filarial morbidity was ascertained using

the

TerraView

software,

(http://www.dpi.inpe.br/terraview/index.php). 2.4 Ethical considerations 7

version

4.2.2

The study was approved by the Research Ethics Committee of the Aggeu Magalhães Research Center, Oswaldo Cruz Foundation, Pernambuco, Brazil (CAEE 0033.0.095.000-07). All the data were collected only after the informed consent statement had been signed. For all children and adolescents, consent was given by a parent/guardian. All adult participants have their own consent. All individuals presenting microfilaremia were treated with diethylcarbamazine citrate (6 mg/kg/12 days) and cases with clinical complaints were followed up by the municipal healthcare services.

3. Results Among the 23,673 individuals examined, 741 cases of complaints relating to LF were identified (3.13%) and the prevalence of microfilaremia was found to be 1.36% (323/23,673), as shown in Table 1. The prevalence rate of acute ADLA was 2.29%, with cases present in all the districts investigated. The prevalence of hydrocele was 1.82%, with cases distributed in 21 districts, and the prevalence of lymphedema was 0.07%. It is clear that the areas with the highest prevalence of microfilaremia (> 0.2%) overlap with those identified where the highest rates of ADLA, hydrocele, milky urine and lymphedema (Figure 2). In relation to the distribution of reported complaints according to age group, it was found that lymphedema was most prevalent in the population aged 50 to 59 years. Reports of ADLA became progressively greater in number starting from the age of 10 years and reached their greatest occurrence in the age group from 60 to 99 years, while complaints of hydrocele were most prevalent in the age group from 30 to 39 years and complaints of chyluria in the age group from 60 to 99 years (Table 2). Table 3 presents the results from the microfilaremia tests and examinations on reported morbidity, according to sex. The rates of presence of filarial infection among the individuals with ADLA among men and women were 1.06% and 1.39%, respectively. Among the men who reported complaints of hydrocele, 3.19% presented microfilaremia. All the individuals who reported having lymphedema and chyluria were free from microfilaremia. Figure 3 presents a correlation between the prevalence of microfilaremia and reports of filarial morbidity. Positive associations with complaints of ADLA, hydrocele and chyluria were observed, and the association was most notable with hydrocele (p = 0.001; r = 0.699). 8

4. Discussion A significant proportion of the public health problem represented by LF is due to impairment and disability relating to lymphedema and hydrocele (Addis, 2013; WHO, 2013). Data from WHO demonstrate that in 2014 only 18 countries that are endemic for LF reported having morbidity management activities (WHO, 2015). This shows that there is a mismatch between the two components of GPELF. There are deficiencies in national programs with regard to morbidity control (Kumari, Yuvaraj and Das, 2012). The present survey found that the prevalence of clinical complaints attributable to filariasis was 3.13%. Thus, taking into account the population of the municipality, it is possible to estimate that there are 18,000 individuals with filarial disease, which indicates that all healthcare levels within the municipality need to be structured to meet this demand. Acute dermatolymphangioadenitis was the clinical complaint most mentioned and this was seen in people living in all districts, in all the age groups. The occurrence rate increased progressively with age and was higher among females. The frequency of ADLA in the population was greater among people with chronic diseases, particularly lymphedema, and its recurrence resulted in disability over a short period, which was a greater cause for concern than the lymphedema per se. The epidemiological association between the frequency of ADLA and the stage of the lymphedema, along with extensive clinical experience both in areas endemic for filariasis and in areas that are not endemic, strongly suggests that episodes of ADLA are the largest or most important factors regarding the progression of lymphedema, particularly in areas that are endemic for filariasis (Addis and Moll, 2007; Babar and Terence, 2003). Advanced lymphedema is clinical conditions with poor prognoses. However, simple intervention programs based on prophylactic actions against secondary infection have been implemented as the current GPELF strategy in many countries and have resulted in better quality of life for these patients (Addis, 2005; Suzanne et al., 2004). In the state of Orissa, India, a community-based program for lymphedema management was developed with the aim of reducing the morbidity associated with lymphedema, and the results from this showed that there were reductions in incapacity and in the number of days of work lost (Budge et al., 2013). It has been proven that W. bancrofti is not directly involved in establishing these clinical manifestations, as had previously been reported (Dreyer, Dreyer and Piessens, 9

1999; Olszewski et al., 1997; McPherson et al., 2006; Shenoy et al., 1995). Taylor and Hoerauf (2001) reported that the endosymbiotic bacterium Wolbachia has essential mutualistic action with the filarial parasite, thereby mediating the acute inflammatory pathogenesis associated with acute filarial lymphangitis and adverse reactions to chemotherapy treatment. Repeated episodes of acute inflammatory disease and chronic exposure to inflammatory mediators released by Wolbachia lead to lymphatic dysfunction and desensitization of the innate immune response. This may lead to increased susceptibility to infection and establishment of opportunistic microorganisms associated with ADLA in cases of lymphedema. In relation to hydrocele, it was observed that its prevalence increases with age, until stabilizing beyond the age group of 30-39 years. These findings add to the discussion on the appearance of morbidity consequent to lymphatic damage, even if no adult worm is present, which results both from the longevity of the parasite, and from the treatment (Dreyer, Addis and Norões, 2005). In this study, information of hydrocele through reported complaints may be subject to information bias, given that the use of ultrasound in the investigation of LF has revealed the presence of lymphatic dysfunction in cases with subclinical changes such as in cases of mild hydrocele. These observations confirm the information that the hydrocele in endemic areas of LF, is a clinical condition certainly underestimated (Dreyer and Norões, 2001; Norões, Figueredo-Silva and Dreyer, 2009; Tobian et al., 2003). Hydrocele has been found to be the predominant clinical manifestation of bancroftian filariasis (Pani, Das and Vanamail, 2005). Although it is only rarely fatal and is usually painless, it gives rise to severe social and economic harm and has a significant negative impact on work activities, sexual performance and social interaction (Ahorly et al., 2001; Christiana, Olajumoke and Oyetunde, 2014). Identification of Bancroftian filariasis, done by trained individuals within the community, has been a useful instrument for rapid assessment of an area. The prevalence of its manifestations can be used as a means of epidemiological mapping of the prevalence of filarial disease (Christiana, Olajumoke and Oyetunde, 2014; Srividya et al., 2000). Although the area studied here presented low endemicity (1.4%), the reports of hydrocele and chyluria presented good predictive value for the risk of filariasis. However, it was observed that hydrocele was reported complaint with the strongest association with filariasis, thus providing reliability in the use of this clinical

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manifestation as a rapid diagnostic index for LF to assess endemic areas and corroborating the findings of Gyapong et al. (1998). The chyluria is one of the rare and late manifestation of LF. However, the characteristics of spontaneous remission and the intermittent pattern of chyluria (Peng, et al., 1997) and the low rate of occurrence of reports of chyluria (17 cases) limits the use of this finding as a marker, even though it showed a positive association with filarial infection. In this survey, most of the individuals presenting microfilaremia were asymptomatic. From an epidemiological point of view, identification of these individuals is necessary for GPELF because this group plays an important role in maintaining transmission of W. bancrofti, since these individuals are the main source of infection for the vector (Medeiros, 1998); and also because of the risk of development of filarial disease, given that they already present lymphatic alterations (Norões et al., 1996; Nutman, 2013). Despite the advances achieved through GPELF, the pillar of morbidity management has not advanced as much as the pillar of preventive chemotherapy (Mathieu et al., 2013). Nonetheless, strengthening of such actions is essential for reaching the objectives proposed by WHO. Thus, the present study contributes data that might provide support for healthcare systems and thus optimize the management of filarial disease, through incorporating surveillance measures directed towards reducing the psychosocial and economic impact on poor populations living in areas endemic for this parasitosis.

Acknowledgements We are grateful to the Health Department of Jaboatão dos Guararapes, Pernambuco, for its cooperation and logistical support for the parasitological survey. Also, we are grateful to the data-gathering team.

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LYMPHATIC FILARIASIS MORBIDITY Figure 1. Panel containing images of the clinical manifestations used in the morbidity survey.

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Figure 2. Distribution of prevalence of microfilaremia (A), Hydrocele (B), ADLA (C), Chyluria (D) and Lymphedema (E) according to district, Jaboatão dos Guararapes, Pernambuco, Brazil.

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Figure 2. Distribution of prevalence of microfilaremia (A), Hydrocele (B), ADLA (C), Chyluria (D) and Lymphedema (E) according to district, Jaboatão dos Guararapes, Pernambuco, Brazil.

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% Positive Microfilaremia Results

% Positive Microfilaremia Results

r=0.002

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

(0.992)

0.0

0.2

0.4

0.6

0.8

r=0.435

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

(0.055)

0.0

1.0

2.0

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5

r=0.699 (0.001)

0.0

0.5

1.0 % Hydrocele

4.0

5.0

% Erysipelas

% Positive Microfilaremia Results

% Positive Microfilaremia Results

% Elephantiasis

3.0

1.5

2.0

4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0

r=0.468 (0.037)

0.0

0.1

0.1

0.2

0.2

0.3

% Chyluria

Figure 3. Dispersion of prevalence of microfilaremia and prevalence of reported morbidity according to district in Jaboatão dos Guararapes, Brazil.

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0.3

Table 1. Relationship between reported morbidity and microfilaremia in Jaboatão dos Guararapes, Pernambuco, Brazil. Microfilaremia Positive Negative Total

Positive for disease

Negative for disease 309 (1.30%) 22,623 (95.57%) 22,932 (96.87%)

14 (0.06%) 727 (3.07%) 741 (3.13%)

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Total 323 (1.36%) 23,350 (98.64%) 23,673 (100%)

Table 2. Prevalence of reported filarial morbidity according to age group, in Jaboatão dos Guararapes, Pernambuco, Brazil. Age Group 1-9 10-19 20 - 29 30 - 39 40 - 49 50 - 59 60 - 99 Unknown Total

Lymphedema N 1 2 2 1 7 4 17

% 5.8 11.8 11.8 5.8 41.2 23.6 100

ADLA N 6 34 35 68 91 108 177 519

% 1.1 6.5 6.6 13.1 17.5 20.8 34.1 100

Hydrocele N 3 9 21 42 39 35 38 1 188

% 1.6 4.8 11.2 22.3 20.7 18.6 20.2 0.5 100

Chyluria N 1 3 3 3 2 1 4 17

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% 5.9 17.6 17.6 17.6 11.8 5.9 23.5 100

No sign N 3,622 5,458 4,113 3,485 2,733 1,656 1,638 45 22,750

Unknown

% N 15.9 28 24.0 36 18.1 37 15.3 32 12 23 7.3 14 7.2 6 0.2 6 100 182

Total

% N 15.9 3,660 24.0 5,541 18.1 4,211 15.3 3,632 12 2,889 7.3 1,821 7.2 1,867 0.2 52 100 23,673

% 15.5 23.4 17.8 15.3 12.2 7.7 7.9 0.2 100

Table 3. Population with reported filarial morbidity according to sex and results from microfilaremia tests, in Jaboatão dos Guararapes, Pernambuco, Brazil. Morbidity/ Result from microfilaremia tests Lymphedema

ADLA

Female

No Sign Unknown Total

Total

OR

95% CI

p value

Positive

Negative

Positive

Negative

Positive

Negative

N

%

N

%

N

%

N

%

N

%

N

%

-

-

11

100.0

-

-

6

100.0

-

-

17

100.0

-

4

1.1

372

98.9

2

1.4

141

98.6

6

1.2

513

98.8

0.86

0.34-1.99

0.706

6

3.2

182

96.8

6

3.2

188

96.8

6

0.96-5.67

0.045

-

-

2

100.0

-

-

17

100.0

-

0.00-21.84 1.000

9,659

98.0

98.6

-

-

-

91

98.9

98.9

-

-

-

Hydrocele Chyluria

Male

NA -

NA -

15

112 0.9 12,782 1

1.1

89

117 0.9 13,269

100.0 99.1 98.9 99.1

197 2.0 1

1.1

206 2.0 10,081

NA = not applicable

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98.0

309 1.4 22,441 2

1.1

180

323 1.4 23,350

98.6

0.00-21.84 1.000