Am. J. Trop. Med. Hyg., 90(1), 2014, pp. 80–88
Copyright © 2014 by The American Society of Tropical Medicine and Hygiene
A Longitudinal Analysis of the Effect of Mass Drug Administration on Acute Inflammatory
Episodes and Disease Progression in Lymphedema Patients in Le ´ogane, Haiti
Brittany A. Eddy, Anna J. Blackstock, John M. Williamson, David G. Addiss, Thomas G. Streit,
Valery M. Beau de Rochars, and LeAnne M. Fox*
Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia; Division of Parasitic Diseases and Malaria,
Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia; Atlanta Research and Education Foundation, Decatur,
Georgia; Children Without Worms, Task Force for Global Health, Decatur, Georgia; Center for Tropical Disease Research and Training, University
of Notre Dame, Notre Dame, Indiana; and Lymphatic Filariasis Program, Ho ˆpital Sainte Croix, Le ´ogane, Haiti
during 1995–2008. No difference in lymphedema progression between those who received or did not receive mass drug
administration (MDA) was found on measures of foot (P = 0.24), ankle (P = 0.87), or leg (P = 0.46) circumference; leg
volume displacement (P = 0.09), lymphedema stage (P = 0.93), or frequency of adenolymphangitis (ADL) episodes (P =
0.57). Rates of ADL per year were greater after initiation of MDA among both groups (P < 0.01). Nevertheless, patients
who received MDA reported improvement in four areas of lymphedema-related quality of life (P £ 0.01). Decreases in
foot and ankle circumference and ADL episodes were observed during the 1995-1998 lymphedema management study
(P £ 0.01). This study represents the first longitudinal, quantitative, leg-specific analysis examining the clinical effect of
diethylcarbamazine on lymphedema progression and ADL episodes.
We conducted a longitudinal analysis of 117 lymphedema patients in a filariasis-endemic area of Haiti
Lymphatic filariasis (LF) is a chronic disabling and debili-
tating parasitic infection that is one of the major causes of
long-term disability worldwide.1After acquisition of infec-
tion, there is evidence of subclinical changes that later pro-
gress to overt clinical disease, including lymphedema and
adenolymphangitis, and chyluria.2,3Persons with lymphatic
gioadenitis (ADL) episodes, which are characterized by swell-
ing, fever, pain, and inflammation of the affected extremity.4,5
Skin lesions, including interdigital lesions, serve as an entry
point for bacteria believed to initiate the ADL episode.6Epi-
sodes of ADL can increase the pace with which lymphedema
progresses to elephantiasis.4Repeated episodes of ADL
accelerate damage to superficial lymphatic vessels in the skin,
which results in worsened lymphatic dysfunction, fibrosis, and
increased risk for future episodes of ADL.5,7–10
The Global Programme to Eliminate Lymphatic Filariasis
has two components: primary prevention, which uses massdrug
administration (MDA) with diethylcarbamazine (DEC) and
albendazole or ivermectin and albendazole to interrupt LF
transmission and secondary or tertiary prevention, which
focuses on preventing and managing disability for affected
persons.11Disability prevention for patients with filarial mor-
bidity includes basic lymphedema management for those with
lymphedema and hydrocelectomy for men with hydrocele.
Lymphedema management involves leg hygiene, early treat-
ment of bacterial and fungal infections, elevation, and exer-
cises.12Clinical and histopathologic studies suggest that
lymphedema management can decrease the number of ADL
episodes9,13–19and halt or, in some cases, partially reverse
Although there are several studies demonstrating improve-
ment in lymphedema in patients who adhere to a lymphedema
management regimen, the literature exploring the effect of
mass drug administration with DEC, either alone or in combi-
nation with albendazole, on filarial morbidity is inconclusive.
Recent clinical research using ultrasonography and lympho-
scintigraphy has documented the reversal of early lymph-vessel
damage in Brugia malayi–infected children after MDA with
DEC in India.21However, earlier studies in Brazil have failed
to find a decrease in lymphatic vessel dilation after treatment
with DEC in adults infected with Wuchereria bancrofti.22,23Of
the 13 published studies assessing the effect of DEC on lymph-
edema-specific filarial morbidity, nine found a beneficial effect
of DEC on lymphedema20,24–31and the other studies demon-
strated no effect.32–35In addition, seven of eight studies dem-
onstrated that DEC decreased the incidence of ADL episodes
in patients with lymphedema14,20,24–26,32,36and one study
showed no effect.33It is important to note that these studies
differ with regard to study design, evaluation criteria, fre-
quency and dosage of drug treatment, case definitions, and
clinical follow-up, thus making direct comparisons difficult.
For most of these studies, the primary outcome was micro-
filaremia as opposed to clinical morbidity (i.e., lymphedema
and ADL episodes), and many had small sample sizes. In addi-
tion, none of the studies were conducted in a filariasis-endemic
area in the Western Hemisphere.
Le ´ogane, Haiti has long been endemic for W. bancrofti
infection with antigen prevalence documented as high as
50% in some communities.37Yearly MDA with DEC began
in Le ´ogane in October 2000 for persons more than two years
of age. Because of concerns of toxicity, women of childbear-
ing age were not administered albendazole until 2002. Drugs
have been distributed yearly, with the exception of 2006, in
which MDA was suspended because of a gap in funding.38,39
The major health facility for Le ´ogane Commune is Sainte
Croix Hospital.40In 1995, a lymphedema management study
was initiated at the outpatient clinic at Sainte Croix Hospital
to help lymphedema patients manage their symptoms and
prevent further acceleration of the disease.
The objective of this study was to assess the impact of mass
drug administration with DEC on clinical measures of filarial
morbidity, including lymphedema progression and the num-
ber of ADL episodes per year, as well as on quality of life
*Address correspondence to LeAnne M. Fox, Centers for Disease
Control and Prevention, 1600 Clifton Road NE, Mailstop A-06,
Atlanta, GA 30333. E-mail: email@example.com
indicators in a cohort of Haitian lymphedema patients living
in a filariasis-endemic area. A secondary objective involved
assessing the impact of lymphedema management on these
same clinical measures of filarial morbidity.
Study population. A cohort of 175 lymphedema patients
was enrolled in a prospective lymphedema management study
that was conducted during 1995–1998 at the outpatient clinic
of Sainte Croix Hospital in the Le ´ogane Commune. Patients
visited the clinic regularly during 1995–1998, and some per-
sons from this original cohort were also involved with other
clinical studies conducted at Sainte Croix Hospital outpatient
lymphedema clinic in 2000, 2001, and 2002. The original
cohort of 175 patients was subsequently targeted for long-
term follow-up in 2008. Databases for the 1995–1998 prospec-
tive cohort study and the long-term follow-up in 2008 were
combined with additional data from a cross-sectional study
conducted in 2000 and a prospective cohort study conducted
during 2001–2002 that contained pertinent data on this study
cohort.41,42The study protocols and consent forms were
approved by the Ethics Committee at Sainte Croix Hospital
and the Institutional Review Board at the Centers for Disease
Control and Prevention. Written informed consent was
obtained from patients for their involvement in all studies.
Clinical history and physical examination. During study
years spanning 1995 to 2008, patients were evaluated at the
clinic or were seen at home if they were either unwilling or
unable to come to the clinic. Patients underwent physical
examinations specific to their lymphedema, which included
measurements of lower limb volume and circumference,
lymphedema stage, and an assessment of the presence of
Circumference measurements were taken (in cm) at three
fixed points: the foot 10 cm proximal to the tip of the first toe,
the ankle 10 cm from the floor, and the leg 25 cm from the
floor. The volume of each leg (in mL) was determined by
measuring the displacement of a standard volume of water
into a calibrated cylinder.43Severity of lymphedema was
staged on a seven-stage classification system developed by
Dreyer and others.12Questionnaires were administered at
enrollment of each study with information about patient
demographics, history of lymphedema, quality of life, compli-
ance with lymphedema management, and ADL episode
history in the previous 12 months. The EuroQol-5D ques-
tionnaire was used for quality of life questions. For the pur-
poses of this study, an ADL episode was defined as a
combination of two or more of the following symptoms: swell-
ing, redness, and pain in a lower extremity with or without
systemic manifestations of fever, and chills. Data were
obtained on both legs for all patients, regardless of whether
lymphedema was visualized.
Study exposure. Mass drug administration is conducted
through distribution posts in Haiti where the drugs are pro-
vided with water to help participants swallow the pills. The
drug distributors insist on direct observation of treatment.
The main exposure evaluated was a self-reported dichoto-
mous variable collected in 2008, which indicated whether a
person had ever ingested DEC during MDA. If a patient
reported ever having taken DEC during MDA, they were
considered as having received MDA. If a patient reported
never receiving DEC during MDA, they were considered as
never having received MDA. Pre-intervention refers to the
period before initiation of MDA (before 2000), whereas
post-intervention refers to the year 2000 and beyond, which
was after the initiation of MDA. A secondary exposure eval-
uated was the impact of the lymphedema management study
that was conducted during 1995–1998.
Study outcomes. We investigated six primary outcomes of
interest: foot circumference, ankle circumference, leg circum-
ference, leg volume (assessed by water displacement), stage of
lymphedema, and number of ADL episodes per year. For
measurement outcomes (i.e., foot, ankle, and leg circumfer-
ence, and volume displacement of leg) for prospective cohort
studies, the median values were calculated for each year to
mirror the data available in the cross-sectional studies. The
number of ADL episodes in the previous 12-month period
was self-reported upon enrollment in cross-sectional and pro-
spective cohort studies. For prospective cohort studies after
enrollment, the number of ADL episodes per year was calcu-
lated by summing the number of ADL episodes reported
since the last visit during a 12-month period. Stage of lymph-
edema was recorded after a thorough physical examination of
the patient’s legs.
In addition to the six quantitative outcomes, a qualitative
outcome, quality of life, was investigated. During the 2008
study, patients who received MDA retrospectively self-
reported perceptions of quality of life before taking DEC
and reported current perspectives on quality of life. Differ-
ences in four areas of quality of life directly related to the
patient’s lymphedema were compared pre- and post-interven-
tion: experience of pain or discomfort, suffering from anxiety
or depression, problems with mobility, and difficulties per-
forming usual activities.
Study covariates. Demographic variables collected across
all studies included sex, age, education level, literacy, and
wealth quintile (Table 1). A principal components analysis
was applied to assets, which were included in the Haitian
Demographic and Health Survey, to create a household socio-
economic index. Ownership of a bicycle, phone, car, refriger-
ator, radio, and television were included in the principal
components analysis. Patients were then assigned to wealth
quintiles based on the value of the index. The LF transmission
level was estimated for each patient by the section of the
Le ´ogane Commune in which the patient’s home was located
and rated as low, intermediate, or high level transmission
based on antigenemia data obtained from sentinel site surveys
included self-reported number of years with lymphedema and
physical examination findings of number of interdigital lesions
at each visit. Compliance with lymphedema management was
assessed by using a hygiene composite score, which was created
for each person at every time point where information was
available. The composite score was comprised of three compo-
nents: washing, elevation, and exercise. Patients were grouped
into three categories: highly compliant (participating in wash-
ing, elevation, and exercise activities several times per week to
every day), moderately compliant (participating in these activ-
ities two times per month to once a week), and rarely or never
compliant (participating in these activities never to once per
month). Similarly, the extent to which a person self-bandaged
his or her leg was categorized as highly compliant for those
who bandaged several days a week to everyday, moderately
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EDDY AND OTHERS