CSU 99/2010: TWO ON TRACHOMA
| Sunday, 3rd of October 2010 |
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CSU 99/2010: TWO ON TRACHOMA
1) OVERVIEWS OF TRACHOMA
International Centre for Eye Health, Department of Infectious and Tropical Disease, London School of Hygiene and Tropical Medicine, Keppel Street, London, UK
British Medical Bulletin 2007; 84: 99–116
*Correspondence to: Matthew J. Burton, International Centre for Eye Health, Department of Infectious and Tropical Disease, London School of
Hygiene and Tropical Medicine, Keppel Street, London, UK. E-mail: matthew.burton@lshtm.ac.uk
Trachoma is the most common infectious cause of blindness worldwide. It afflicts some of the poorest regions of the globe, predominantly in Africa and Asia. The disease is initiated in early childhood by repeated infection of the ocular surface
by Chlamydia trachomatis. This triggers recurrent chronic inflammatory episodes, leading to the development of conjunctival scarring. This scar tissue contracts, distorting the eyelids (entropion) causing contact between the eyelashes and the surface of the eye (trichiasis). This compromises the cornea and blinding opacification often ensues.
The World Health Organization is leading a global effort to eliminate Blinding Trachoma, through the implementation of the SAFE strategy. This involves
surgery for trichiasis, antibiotics for infection, facial cleanliness (hygiene promotion) and environmental improvements to reduce transmission of the organism. Where this programme has been fully implemented, it has met with some success. However, there are significant gaps in the evidence base and optimal management remains uncertain.
Keywords: trachoma/chlamydia trachomatis/pathogenesis/epidemiology/
treatment
Clinical features
Clinically, trachoma is sub-divided into active (early) and cicatricial
(late-stage) disease. Active disease is more commonly found in children
and is characterized by a chronic, recurrent follicular conjunctivitis,
most prominently of the upper tarsal conjunctiva. Follicles are collections
of lymphoid tissue subjacent to the tarsal conjunctival epithelium.
Intense cases are characterized by the presence of papillary hypertrophy—
engorgement of small vessels with surrounding oedema. In more severe
cases, there is a pronounced inflammatory thickening of the conjunctiva
that obscures the normal deep tarsal blood vessels. During an episode
of active disease, the cornea can be affected. There may be minimal
symptoms of ocular irritation and a slight watery discharge.
The scarring sequelae of trachoma develop in later life, usually from
around the third decade, but can present earlier in regions with more
severe disease. Recurrent chronic conjunctival inflammation promotes
conjunctival scarring, which ranges from a few linear or stellate scars
to thick distorting bands of fibrosis with fornix shortening and symblepheron
(bands between eyelid and globe). The scar tissue contracts
causing in-turning of the eyelids (entropion). Contact between the eyelashes
and the eye is called trichiasis. In trachoma, trichiasis commonly
results from entropion. However, trichiasis may also arise from misdirection
of lashes in a normal position (aberrant lashes) or lashes
growing from abnormal positions (metaplastic lashes). Ultimately,
blinding corneal opacification can develop. Individuals with entropion
and trichiasis frequently experience pain as the lashes scratch the
cornea.
The clinical features are usually classified using the Simplified WHO
Trachoma Grading System (Table 1).1 This is reliable and easy to use,
yielding useful information on the prevalence of active and cicatricial
disease. For research purposes, a more detailed system is sometimes
used.2
Differential diagnosis
Several conditions can produce a chronic follicular conjunctivitis with
a similar appearance to active trachoma, including conjunctivitis
caused by viruses (e.g. adenovirus) and bacteria (e.g. Staphylococcus
aureus and Moraxella). Adult inclusion conjunctivitis, infection with
genital strains of Chlamydia trachomatis, is characterized by large opalescent
follicles.
There are several causes of entropion and trichiasis that should be
considered in the differential diagnosis, although most of these are relatively
rare in trachoma endemic regions. Cicatricial conjunctivitis can
be caused by mucus membrane pemphigoid, Stevens–Johnson syndrome,
systemic sclerosis, chemical injuries and drugs. In nontrachomatous
areas, most cases of entropion are due to involutional
Table 1 The simplified WHO system for the assessment of trachoma1
Grade Description
TF Trachomatous inflammation—Follicular: The presence of five or more follicles (.0.5 mm) in the upper tarsal conjunctiva
TI Trachomatous inflammation—Intense: Pronounced inflammatory thickening of the tarsal conjunctiva that obscures more than half of the deep normal vessels
TS Trachomatous scarring: The presence of scarring in the tarsal conjunctiva
TT Trachomatous trichiasis: At least one lash rubs on the eyeball
CO Corneal opacity: Easily visible corneal opacity over the pupil
eye: epiblepharon (upward riding of skin and orbicularis over the
inferior tarsus) and distichiasis (additional row of lashes arising from
the meibomian gland orifices).
Epidemiology
Prevalence
Trachoma is probably the third most common cause of blindness
worldwide, after cataract and glaucoma.3 Current estimates indicate
that there are 8 million people who are blind or have severe visual
impairment from trachoma, 7.6 million unoperated trichiasis cases and
84 million with active trachoma. These figures were a significant
reduction from the previous estimates (1995) of 6 million blind,
10 million trichiasis cases and 146 million with active disease.4
Distribution
During the last two centuries, trachoma retreated from some formerly
endemic regions, such as Europe and North America. This change is
attributed to general improvements in living standards, rather than
specific interventions against the disease.5 Today trachoma is prevalent
in large parts of Africa, and in some regions of the Middle East, the
Indian Subcontinent, South-east Asia and South America.6 The highest
prevalence of trachoma is reported from countries such as Ethiopia and
Sudan where the prevalence of active trachoma in children is often
greater than 50% and trichiasis is found in up to 5% of adults.7 For
many trachoma endemic countries, the socio-economic developments
that might promote the disappearance of the disease are likely to be
very slow in arriving, which in the light demographic trends and in the
absence of effective control programmes could lead to an increase in
the amount of trachoma blindness.8
Clustering of trachoma
In common with other infectious diseases, trachoma is frequently
found to cluster within endemic regions.9–12 Clustering has been
demonstrated at the village, household and bedroom level. This supports
the hypothesis that transmission of C. trachomatis generally
occurs with prolonged close contact between individuals. From the trachoma
control perspective clustering is very significant, as it greatly
increases the sample size required to accurately estimate the prevalence
within a region.12
Transmission of infection
Chlamydia trachomatis, the causative agent in trachoma, is probably
transmitted from infected to uninfected individuals within an endemic
community by various mechanisms: direct spread from eye to eye
during close contact, spread on fingers, indirect spread on fomites (e.g.
face cloths) and transmission by eye-seeking flies.5 A combination of
these and other modes of transmission probably functions in most
environments, with their relative importance varying between different
communities and between members of a community. Therefore, a combination
of interventions will be necessary to interrupt transmission.
Age
The signs of trachoma are strongly related to age. The prevalence of
active disease peaks in pre-school children and declines to low levels in
adulthood.11,13 –15 However, this maybe in part be due to shorter infection/
disease episodes with increasing age.16 Where tests have been used
to confirm the presence of C. trachomatis, the findings have generally
paralleled the clinical observations with much of the infection occurring
in children.14,17 In contrast to the signs of active disease, the
prevalence of trachomatous conjunctival scarring increases with age,
reflecting the cumulative nature of the damage.11,15
Gender
Clinically active trachoma generally occurs with equal prevalence in
male and female children. However, in most areas women are more frequently
affected by the blinding complications than men.11,15 About
75% of trichiasis and corneal blindness cases are women, probably due
to their greater lifetime exposure to C. trachomatis infection through
contact with children.18
Risk factors for trachoma
Various individual and environmental risk factors have been identified,
which may facilitate the introduction and transmission of C. trachomatis
in endemic communities. Migration of people between communities
is probably important for maintaining trachoma endemicity through
the introduction of new strains of C. trachomatis.19 Transmission is
probably promoted by crowded living conditions.9 Children with active
trachoma frequently have infectious ocular and nasal secretions and
trachoma is often prevalent in regions where water is scarce, probably
because less can be used for face washing.20
Eye-seeking flies are a common feature of life in many trachoma
endemic communities and are frequently observed feeding on ocular
secretions. There is good evidence that they can act as vectors for
C. trachomatis transmission in some environments.21 The fly most
commonly found in contact with eyes is Musca sorbens, which preferentially
breeds in human faeces. Lack of latrines has often been associated
with increased risk of trachoma, probably due to a larger fly
population.10 No animal reservoir for C. trachomatis has been found
in trachoma endemic environments, although there is an association
with cattle, which may result in an abundance of flies.22
Chlamydia trachomatis
Chlamydia trachomatis is an obligate intracellular bacteria, with
19 different serovars. These are sub-divided into two biovars; the
trachoma biovar (serovars A–K) and the lymphogranuloma venereum
biovar (serovars L1, L2, L2a and L3). Endemic trachoma is caused
by serovars A, B, Ba and C.23 Genital chlamydial infection, which
causes pelvic inflammatory disease and infertility, is associated with
serovars D–K.
During the course of its developmental cycle, C. trachomatis exists in
two principle forms: reticulate bodies (RB) and elementary bodies
(EB).24 The reticulate body is the larger, metabolically active, intracellular
stage. EB are the small, hardy, metabolically inactive extracellular
form of the organism in which it transfers between host cells
and organisms. The chlamydial developmental cycle commences with
the attachment of the EB to the surface of epithelial cells which triggers
endocytosis of the bacteria. Inside the host cell, the EB transforms into
the RB form which replicates by binary fission. Cells infected with
chlamydia are characterized by the presence of a chlamydial inclusion
in the peri-nuclear region of the host cell. Eventually, the newly formed
RB transform into EB, with condensation of nuclear material and an
overall reduction in size. The newly formed EB are released either by
lysis of the host cell or by the fusion of the inclusion body with the
plasma membrane. In vitro, the chlamydial development cycle takes
between 36 and 70 h to complete.
The major outer membrane protein (MOMP) accounts for 60% of
the surface protein. Variations in MOMP epitopes define serovar specificity
and may be an important target for the immune response to
C. trachomatis. The organism has a single chromosome coding 875
genes and a variable numbers of small plasmids.25 Although originally
believed to lack the ability to generate energy-rich compounds, the
chlamydial genome was found to contain a surprising number of genes
related to energy metabolism and may be able to perform some limited
ATP synthesis for at least part of its life cycle.25
Detection of Chlamydia trachomatis infection
The detection of C. trachomatis infection is problematic. Operationally,
trachoma control programmes rely on the clinical signs of disease
for diagnosis. However, for research studies, it is often important
to know the individual infection status. Various diagnostic tests
have been used to detect C. trachomatis, but there is no ‘Gold
Standard’ test.26,27 The earliest method was Giemsa staining of
smears of conjunctival cells to demonstrate the chlamydial inclusion
body. This allows assessment of the adequacy of the specimen, it is
specific but lacks sensitivity.26,27 The sensitivity of microscopy can
be increased by direct immunofluorescence with monoclonal antibodies
to C. trachomatis antigens.26,27 Chlamydia trachomatis can be
grown in cell culture from clinical specimens and then detected by
microscopy. This approach confirms the viability of the organism;
however, it requires stringent conditions and also lacks sensitivity.
26,27 Enzyme-linked immunoassays are commercially produced
which detect chlamydial antigens; however, these have moderate sensitivity
and cross-reaction with other bacteria is reported, reducing
specificity.27
Nucleic acid amplification tests, such as polymerase chain reaction
(PCR), are the current favoured modality for C. trachomatis detection.
27 These tests are both highly specific and sensitive, identifying significantly
more individuals harbouring C. trachomatis in endemic
populations than previously recognized. However, they are not appropriate
for non-research use due to expense and complexity.
Considerable care needs to be taken in the collection and processing of
conjunctival swab specimens to avoid contamination leading to false
positive results. Recently quantitative real-time PCR has been used to
measure the load of C. trachomatis infection in members of trachoma
endemic communities to better define the major reservoirs of infection
and monitor response to treatment.10,17,19,28 Currently, a point-of-care
rapid diagnostic test is being developed which may be of use to trachoma
control programmes in the future.29
Relationship between clinical signs and infection
Chlamydia trachomatis is thought to be the major stimulant triggering
conjunctival inflammation in trachoma, although other bacterial infections
have more recently been implicated in individuals with established
scarring and trichiasis.30,31 Corneal opacification and blindness
probably develop as a result of traumatic damage by trichiasis and secondary
bacterial infection.30,31
There is a complex relationship between disease and infection in trachoma,
with a mismatch between clinical signs and detection of C. trachomatis:
active trachoma without detectable C. trachomatis and conversely C. trachomatis detected in clinically normal individuals.32
This is a significant problem for trachoma control programmes, which
rely on signs to guide antibiotic treatment. It also indicates the importance
of the host response in the disease process. There are several contributory
reasons for this mismatch. First, there may be an ‘incubation
period’ during which infection is present but disease has not yet developed.
Secondly, the resolution of signs of disease lags behind the resolution
of infection, often by many weeks.16 The duration of both
disease and infection episodes are modified by age, lasting longer in
children. Thirdly, it is possible that a sub-clinical persistent form of
infection may develop under certain conditions in which the organism
is not replicating but lies dormant and may not provoke the disease
phenotype 26. Fourthly, the signs of conjunctival inflammation are not
exclusive to trachoma and could be initiated by other pathogens.
Finally, the presence of detectable chlamydial antigen or DNA does
not necessarily equate to an established, replicating infection. Tests
may be positive as a result of a transient inoculation of the conjunctiva
with C. trachomatis following close contact with a heavily infected
individual or the activities of eye-seeking flies.
Quantitative PCR for omp1 (a single copy gene on the C. trachomatis
chromosome) has been used to determine the relative load of infection
in members of trachoma endemic communities.10,17,19,28 The distribution
of infection load is skewed; the majority of infected individuals
have relatively low infection loads, whereas a smaller number have
high loads. The highest infection loads are generally found in children,
especially those with intense conjunctival inflammation. Clinically
normal individuals with detectable C. trachomatis tend to have lower
infection loads and do not have detectable expression of chlamydial
16S rRNA, a marker for a metabolically active replicating infection.33
In contrast, the presence of 16S rRNA expression was associated with
high infection loads and clinical disease.
Histopathology
Active trachoma in children is characterized by hyperplastic conjunctival
epithelium and a widespread inflammatory infiltrate of T and B
lymphocytes, macrophages, plasma cells and neutrophils.34 In places
this is organized into B-cell follicles. Staining for collagen sub-types
reveals a generalized increase in the amounts of types I, III and IV (normally
found in the stroma) and deposition of new type V.35 In adults
with trachomatous scarring, the conjunctival epithelium is atrophic
and goblet cells are lost.36 The loose sub-epithelial stroma is replaced
with a thick scar of type V collagen. These new vertically orientated
fibres are firmly attached to the tarsal plate, causing distortion.36
Conjunctival inflammation in the presence of scarring and trichiasis is
often observed and is associated with a T-cell infiltrate.
Immunity and immunopathology in trachoma
The human immune response to C. trachomatis is poorly understood.
The resolution of infection is probably dependent on a cell-mediated
response; however, this may also play a major role in the pathogenesis
of trachomatous scarring. Chlamydial infection is usually confined to a
minority of epithelial cells, whereas the inflammatory cell infiltrate
extends deep into the substantia propria. It is likely that the scarring
and blinding complications of trachoma arise from persistent or
repeated inflammatory reactions to the infection.
Innate immune response
The initial response to C. trachomatis infection at the epithelial surface
is probably made by the innate immune system, with the release of
pro-inflammatory cytokines (IL-1, TNF-a) by epithelial cells. This promotes
rapid influx of neutrophils and macrophages, which may help to
limit the initial infection through phagocytosis.34 Ongoing activation
of these cells, even after infection has resolved, probably plays an
important part in the development of scarring.
Adaptive immune response
The initial innate immune response to C. trachomatis infection is followed
by the development of adaptive immune responses with both
antibody-meditated (humoral) and cell-mediated components.
Humoral immunity
The role of the humoral immune response appears to be limited in trachoma.
Anti-chlamydial antibodies have been found in the tears and
serum of patients with clinically active trachoma. Longitudinal studies
of tear anti-chlamydial IgG suggest that this is associated with
increased risk of active disease, possibly through facilitating the entry
of C. trachomatis into host cells and may reflect a TH2 weighted
response.37 An opposite trend was found with anti-chlamydial IgA,
which may interfere with attachment to host cells.
Cell-mediated immunity
Animal models of chlamydial infections suggest that effective cellmediated
immune (CMI) responses are necessary for the resolution of
chlamydial infection.38 Individuals who resolve clinically active trachoma
have greater lymphoproliferative responses to chlamydial antigens
compared with those who had persistent clinical disease.39 In
contrast, individuals with trachomatous conjunctival scarring had
weaker peripheral blood lymphocyte proliferation responses compared
with normal controls.40 Interferon-g (IFN-g) appears to be the pivotal
cytokine in the resolution of infection through a variety of
anti-chlamydial actions.41 It is primarily released by TH1 lymphocytes.
Individuals with chlamydial infection have increased expression of
IFN-g, IL-2 and IL-12 within the conjunctiva, consistent with this.42
CD8þ cytotoxic lymphocytes (CTL) are found in the conjunctiva of
individuals with active trachoma, but their importance is uncertain.34
Clinically active trachoma often persists long after chlamydial infection
becomes undetectable. Chronic severe conjunctival inflammation is
associated with progression to scarring complications probably through
the activation of fibrogenic pathways.43 Clinically active trachoma,
irrespective of the presence of infection, is associated with increased
expression of pro-inflammatory cytokines (IL-1b, TNF-a), particularly
by macrophages.34,42 TNF-a has been found more frequently in the
tears of individuals with trachomatous scarring.44 A single nucleotide
polymorphism (SNP) in the TNF-a promoter region, TNFA-308A,
which leads to increased levels of TNF-a has been associated with
increased risk of trachomatous scarring and trichiasis.45 The antiinflammatory
cytokine IL-10 also appears to influence the outcome of
trachoma. It is produced by various cells including Regulatory T-cells
and type 2 T-helper cells. It counteracts pro-inflammatory responses.
However, IL-10 also opposes the action of the TH1 response mediated
through IFN-g, so may impede the resolution of infection. IL-10 is
expressed at increased levels in the conjunctiva of individuals with
active trachoma and certain genetic polymorphisms have been associated
with increased scarring, although their functional significance is
uncertain.42,46
be elucidated. As with other fibrotic diseases, it is likely that TGF-b is
important. Other fibrogenic cytokines associated with a TH2 response,
such as IL-13, may also be important.47 Matrix metalloproteinases
(MMP) are a family of proteolytic enzymes which are central to the
regulation of the extracellular matrix (ECM) and have been implicated
in many scarring disorders. They degrade the ECM and facilitate scar
contraction. The expression of MMP-9 is elevated in the conjunctiva
with active trachoma, becoming more marked with increasing severity
of inflammatory disease.42 A SNP in the catalytic domain of MMP-9,
possibly resulting in reduced function, is associated with a reduced risk
of scarring complications in trachoma.48
Trachoma control
The World Health Assembly has resolved to eliminate blinding trachoma
by the year 2020.49 To this end, the Global Alliance for the
Elimination of Blinding Trachoma (GET2020) was formed in 1998,
including the WHO, trachoma endemic countries and organizations
working in the field. Control activities focus on the implementation of
the SAFE strategy, surgery for trichiasis, antibiotics for infection, facial
cleanliness (hygiene promotion) and environmental improvements, to
reduce transmission of the organism. Each of these components tackles
the pathway to blindness at different stages. In this section, the major
issues around the implementation of this strategy and some of the supporting
evidence will be reviewed.
Trichiasis surgery
There are about 10 million people with trachomatous trichiasis (TT)
worldwide who are at increased risk of developing irreversible blinding
corneal opacification (CO). Surgical correction of TT probably reduces
the risk of progressive CO and blindness. The indications for TT
surgery vary between control programmes. Some advocate early
surgery when one or more lashes touch the eye, whereas others practice
epilation until more severe TT develops. As the progression of TT can
be quite swift in some people, where access to ophthalmic services is
limited, surgery for mild disease is a logical approach.
Various surgical procedures are in use. Several of these were compared,
of which the bilamellar tarsal rotation (BLTR) was found to
have the lowest TT recurrence rate and was therefore endorsed by the
WHO.50 Many trachoma endemic countries have insufficient ophthalmologists
to perform the volume of surgery to deal with the backlog of
unoperated trichiasis. Therefore, many programmes train nurses and
other para-medical staff to perform lid surgery with comparable outcomes
to ophthalmologists.51 The uptake of surgery, which has been
low in many areas, is often greater when offered at community level.52
A major problem limiting the effectiveness of surgery is the recurrence
of trichiasis following surgery, which can be as high as 40–
60%.53 Various factors may contribute: the choice of procedure, suture
type, inter-surgeon variability, infection and the pre-operative disease
severity. Trials examining whether peri-operative antibiotic (azithromycin)
reduces the risk of recurrence found that for hyperendemic regions,
this adjunctive therapy reduced recurrence but this was not the case in
meso-endemic settings.31,54 There is a need for additional research to
develop approaches to improve the long-term surgical outcome.
Despite these disappointing results, there can be a small improvement
in vision following surgery of about a line of Snellen visual acuity.31,50
Antibiotic in trachoma control
Antibiotic therapy has been used for many decades to reduce burden of
infection at the individual and community level. It is hoped that this in
turn reduces the drive to progressive trachomatous scarring, although
there is currently little direct evidence to support this. There are several
key issues related to antibiotics which have bearing on how they should
be used.
Which antibiotic should be used against C. trachomatis?
A number of different antibiotics have anti-chlamydial activity and
have been used for treatment of trachoma. Currently, the most commonly
used options are tetracycline eye ointment applied twice a day
for 6 weeks or a single oral dose of azithromycin (20 mg/kg up to a
maximum dose of 1 g). Tetracycline has been in routine use for five
decades in trachoma control. There is limited placebo-controlled trial
data demonstrating limited efficacy of this antibiotic in the treatment
of active trachoma.55 These studies were conducted at a time when the
standard practice was to only treat individuals with signs of active
disease. This approach would have probably left a large pool of
untreated infected individuals within a community to subsequently
re-infect treated individuals, undermining the effectiveness of the
intervention.
several trials and found to be equally effective.56 In the largest of these
studies (ACT) conducted in three endemic countries, mass communitywide
treatment produced a marked reduction in the prevalence of chlamydial
infection, which was sustained for 12 months of the study.14
Similar responses have been observed in subsequent studies.19,28 In an
operational comparison of azithromycin and tetracycline, the former
was found to be significantly more effective in the case of severe
inflammatory trachoma.57 This probably reflects the poor compliance
with a 6 week course of tetracycline ointment, which is messy and
sometimes irritating. Currently 12 trachoma endemic countries are
receiving azithromycin as part of a philanthropic donation from the
manufacturer (Pfizer Inc.).
there is currently no evidence that it is harmful. Moreover, in a large
trial of the presumptive treatment of sexually transmitted infections
during pregnancy, the use of azithromycin in combination with other
antibiotics was associated with more favourable outcomes for both the
mother and the child.58 The Centre for Disease Control supports this
view and recommends azithromycin for treating C. trachomatis infection
during pregnancy.59 Azithromycin is not used in infants under the
age of 6 months. This group was recently demonstrated to be significant
reservoir of infection and therefore important to treat. The WHO
currently recommends that a 6 week course of topical tetracycline be
used for infants under 6 months.
Who should receive antibiotic treatment?
It is increasingly appreciated that there can be a major mismatch
between the signs of active trachoma and the detection of chlamydial
infection (Relationship between clinical signs and infection). This is a
particular problem for control programmes in determining who should
be offered antibiotic treatment; if only those with signs of trachoma are
given antibiotic, many infected individuals with significant loads of
infection would be left untreated.10 The WHO currently recommends
that mass community-wide treatment should be used (Box1).
Box 1 WHO recommendation for antibiotic treatment for trachoma
1. Determine the district-level prevalence of TF in 1–9-year-old children
(a) If this is 10% or more, conduct mass treatment with antibiotic throughout
the district
(b) If this is less than 10%, conduct assessment at the community level in areas
of known disease
2. If assessment at the community level is undertaken
(a) in communities in which the prevalence of TF in 1–9-year-old children is
10% or more, conduct mass treatment with antibiotic
(b) in communities in which the prevalence of TF in 1–9-year-old children is 5%
or more, but less than 10%, targeted treatment should be considered
(c) In communities in which the prevalence of TF in 1–9-year-old children is less
than 5%, antibiotic distribution is not recommended
Frequency and duration of treatment
It remains uncertain how often and for how long mass antibiotic
therapy needs to be given to endemic populations to achieve control of
the disease. Several studies have reported significant reductions in the
prevalence of disease and infection following a single dose of azithromycin.
14,19,28 However, the impact is not 100% and in some studies
there has been rapid re-emergence of infection.19,60 This is probably
due to a combination of inadequate treatment coverage, introduction
of new chlamydial infections and primary treatment failures. A mathematical
model antibiotic treatment for trachoma control suggests that
for hyperendemic regions (.50%), mass antibiotic treatment would
probably be needed twice a year and for regions with moderate prevalence
(,35%), annual treatment is possibly sufficient.61 There are no
long-term data to guide programmes as to how long mass antibiotic
treatment should be given and this remains a difficult area that requires
further research. The current recommendation from the WHO is that
three annual rounds of mass treatment should initially be given. After
this, the community should then be re-assessed to see whether the
prevalence of active disease has dropped sufficiently to discontinue
treatment.
Resistance and side effects
Repeated mass distribution of a broad spectrum antibiotic such as azithromycin
raises the possibility of driving the selection of antibiotic
resistance. For Chlamydia trachomatis, this does not seem to be a significant
issue. Of greater concern is the potential for non-chlamydial
bacteria, such as Streptococcus pneumoniae to develop resistance. This
question is being monitored, but to date shifts in resistance patterns
have been short term and not thought to be clinically significant.62,63
Azithromycin is a well-tolerated drug which has proven to be safe in
mass distribution programmes. In formal studies, Azithromycin-treated
individuals have 20% fewer fever and headache episodes and 40%
fewer diarrhoea and vomiting episodes compared with those receiving
topical tetracycline.64 There is also a beneficial effect on malaria, with
a reduction in parasite counts, splenomegaly and the prevalence of
febrile parasitaemia in azithromycin-treated individuals.65
Facial cleanliness and environmental improvements
The F&E components of the SAFE strategy are primarily targeting the
transmission of C. trachomatis between individuals. Numerous epidemiological studies have found an association between dirty faces and
active trachoma in children.20 It was suggested that by washing away
potentially infected ocular secretions, the transmission of C. trachomatis
to others might be interrupted. To test this hypothesis, a community
randomized trial of an intensive participatory face-washing strategy
was conducted in Tanzania and found a moderate reduction in severe
inflammatory trachoma (TI) in the intervention villages.66,67 On the
basis of this study, the promotion of face washing was incorporated
into the SAFE strategy.
communities and have long been considered a potential vector.
Chlamydia trachomatis was found (by PCR) on 15% of flies caught
leaving faces of children in a study from Ethiopia.68 A community randomized
trial was conducted in the Gambia to test the hypothesis that
controlling the fly population could suppress the transmission of C. trachomatis and reduce the prevalence of active trachoma.21 Communities
were randomized to one of the three arms: (1) insecticide spray,
(2) latrine provision and (3) control. Latrine provision removes faecal
material from the environment and breeding sites for flies. Both intervention
arms of this study resulted in a significant reduction in the
number of flies caught on children’s faces, although only in the spray
villages was this sufficient to significantly suppress the prevalence of
active trachoma. A community randomized controlled trial conducted
in Tanzania did not find that the addition of insecticide spraying to azithromycin
distribution improved trachoma control.69
improvements in water supply (for face washing) and sanitation (to
suppress fly populations). This drive has fortunately coincided with the
setting of the United Nations’ Millennium Development Goals (MDG).
The target for the seventh MDG is to halve the number of people
without safe water and basic sanitation by 2015. This means that
many more organizations and resources are being mobilized in this
endeavour than would have been the case for trachoma control alone.
In previously endemic countries in Europe and elsewhere, trachoma
declined in the face of general improvements in living conditions and
health. Such changes are beginning to happen in some parts of currently
endemic countries. However, for many communities it may take
many decades for general improvements in living standards to happen
and to have an impact on trachoma. Therefore, it is necessary to
pro-actively implement the SAFE strategy as the best validated
approach to control this blinding disease. The limited published data
on the impact of implementing the SAFE strategy indicate that even in
some of the most highly endemic regions, such as South Sudan, significant
reductions in the prevalence of active disease can be achieved.70
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2) TRACHOMA IN MALI
http://www.plosntds.org/article/info%3Adoi%2F10.1371%2Fjournal.pntd.0000734
Published in the July 2010 Issue of PLoS Neglected Tropical Diseases
Where Do We Go from Here? Prevalence of Trachoma Three Years after Sping Mass Distribution of Antibiotics in the Regions of Kayes and Koulikoro, Mali
Trachoma, a blinding bacterial disease, is targeted for elimination by 2020. To achieve the elimination target, the World Health Organization (WHO) recommends member states implement the SAFE strategy; surgery, mass administration of antibiotics, promotion of hygiene and facial cleanliness and water and sanitation as environmental improvements. We present results from evaluation surveys conducted in 2006 and 2009 from the regions of Kayes and Koulikoro, Mali. Prevalence of active trachoma in 2006 was below baseline intervention thresholds in all surveyed districts and the national program sped antibiotic distribution. The prevalence of trachoma in 2009 remained well below levels in 1998. However, in 8 of 13 districts compared, the prevalence of active trachoma was higher in 2009 than 2006. Three years of antibiotic intervention did not equate in all districts to a sustained reduction of active trachoma. No surveillance activities were implemented after sping interventions. Surgical interventions may have reduced the burden of blinding trachoma but there is an ongoing need for surgeries specifically targeting affected women. Four districts meet the WHO criteria for resuming district-wide mass antibiotic distribution. A community-by-community approach to elimination may be needed in other districts. The promotion of facial cleanliness and good hygiene behavior should be reintroduced.
Sanoussi Bamani1, Jonathan D. King2*, Mamadou Dembele1, Famolo Coulibaly1, Dieudonne Sankara3, Yaya Kamissoko4, Jim Ting4, Lisa A. Rotondo5, Paul M. Emerson2
1 Programme National de Lutte contre la Cécité du Mali, Bamako, Mali, 2 The Carter Center, Atlanta, Georgia, United States of America, 3 RTI International, Washington, District of Columbia, United States of America, 4 The Carter Center, Bamako, Mali, 5 International Trachoma Initiative, Decatur, Georgia, United States of America
Objectives
A national survey in 1997 demonstrated that trachoma was endemic in Mali. Interventions to control trachoma including mass drug administration (MDA) with azithromycin were launched in the regions of Kayes and Koulikoro in 2003. MDA was discontinued after three annual rounds in 2006, and an impact survey conducted. We resurveyed all districts in Kayes and Koulikoro in 2009 to reassess trachoma prevalence and determine intervention objectives for the future. In this paper we present findings from both the 2006 and 2009 surveys.
Methods
Population-based cluster surveys were conducted in each of the nine districts in Koulikoro in 2006 and 2009, whilst in Kayes, four of seven districts in 2006 and all seven districts in 2009 were surveyed. Household members present were examined for clinical signs of trachoma.
Results
Overall, 29,179 persons from 2,528 compounds, in 260 clusters were examined in 2006 and 32,918 from 7,533 households in 320 clusters in 2009. The prevalence of TF in children aged 1–9 years in Kayes and Koulikoro was 3.9% (95%CI 2.9–5.0%, range by district 1.2–5.4%) and 2.7% (95%CI 2.3–3.1%, range by district 0.1–5.0%) respectively in 2006. In 2009 TF prevalence was 7.26% (95%CI 6.2–8.2%, range by district 2.5–15.4%) in Kayes and 8.19% (95%CI 7.3–9.1%, range by district 1.7–17.2%) in Koulikoro among children of the same age group. TT in adults 15 years of age and older was 2.37% (95%CI 1.66–3.07%, range by district 0.30–3.54%) in 2006 and 1.37% (95%CI 1.02–1.72%, range by district 0.37–1.87%) in 2009 in Kayes and 1.75% (95%CI 1.31–2.23%, range by district 1.06–2.49%) in 2006 and 1.08% (95%CI 0.86–1.30%, range by district 0.34–1.78%) in 2009 in Koulikoro.
Conclusions
Using WHO guidelines for decision making, four districts, Bafoulabe in Kayes Region; and Banamba, Kolokani and Koulikoro in Koulikoro Region, still meet criteria for district-wide implementation of the full SAFE strategy as TF in children exceeds 10%. A community-by-community approach to trachoma control may now be required in the other twelve districts. Trichiasis surgery provision remains a need in all districts and should be enhanced in six districts in Kayes and five in Koulikoro where the prevalence exceeded 1.0% in adults. Since 1997 great progress has been observed in the fight against blinding trachoma; however, greater effort is required to meet the elimination target of 2015.
Trachoma, a blinding bacterial disease, is targeted for elimination by 2020. To achieve the elimination target, the World Health Organization (WHO) recommends member states implement the SAFE strategy; surgery, mass administration of antibiotics, promotion of hygiene and facial cleanliness and water and sanitation as environmental improvements. We present results from evaluation surveys conducted in 2006 and 2009 from the regions of Kayes and Koulikoro, Mali. Prevalence of active trachoma in 2006 was below baseline intervention thresholds in all surveyed districts and the national program sped antibiotic distribution. The prevalence of trachoma in 2009 remained well below levels in 1998. However, in 8 of 13 districts compared, the prevalence of active trachoma was higher in 2009 than 2006. Three years of antibiotic intervention did not equate in all districts to a sustained reduction of active trachoma. No surveillance activities were implemented after sping interventions. Surgical interventions may have reduced the burden of blinding trachoma but there is an ongoing need for surgeries specifically targeting affected women. Four districts meet the WHO criteria for resuming district-wide mass antibiotic distribution. A community-by-community approach to elimination may be needed in other districts. The promotion of facial cleanliness and good hygiene behavior should be reintroduced.
Citation: Bamani S, King JD, Dembele M, Coulibaly F, Sankara D, et al. (2010) Where Do We Go from Here? Prevalence of Trachoma Three Years after Sping Mass Distribution of Antibiotics in the Regions of Kayes and Koulikoro, Mali. PLoS Negl Trop Dis 4(7): e734. doi:10.1371/journal.pntd.0000734
Editor: Jeremiah M. Ngondi, University of Cambridge, United Kingdom
Received: January 20, 2010; Accepted: May 18, 2010; Published: July 6, 2010
Copyright: © 2010 Bamani et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Funding for the surveys in 2006 was provided by Sight Savers International (SSI) and the International Trachoma Initiative (ITI). Surveys in 2009 were funded by The Carter Center Atlanta through a generous grant from the Conrad N. Hilton Foundation. Implementation of trachoma control program interventions in Mali has been supported by: L'Organisation pour la Prévention de la Cécité (OPC), International Trachoma Initiative, Sight Savers International, Helen Keller International, Lions Club International Foundation, The Bouamatou Foundation, Americares, Research Triangle Institute International, Conrad N. Hilton Foundation, The Carter Center and the Mali Ministry of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: jonathan.king@emory.edu
Trachoma, a blinding bacterial disease of the conjunctiva, is targeted for elimination as a public health problem by the year 2020, yet an estimated 8.2 million people remain at immediate risk of blindness or visual impairment due to the disease [1]. To achieve the elimination target, the World Health Organization (WHO) recommends member states implement an integrated strategy of interventions known as SAFE: surgery to correct trachomatous trichiasis; mass administration of antibiotics to treat current trachoma infections and reduce the infectious reservoir; promotion of hygiene and facial cleanliness; and water and sanitation as environmental improvements aimed at interrupting transmission of the infection. Based on WHO guidelines, districts are categorized for intervention based on the prevalence of clinical signs of disease: trachomatous inflammation follicular (TF) in children aged 1–9 years and trachomatous trichiasis (TT) in adults aged 15 years and older [2], [3].
Following a national trachoma prevalence survey in 1997, The National Blindness Prevention Program in Mali initiated a trachoma control program. Mapping of trachoma in Mali identified trachoma to be of public health significance throughout the country, including the regions of Kayes and Koulikoro where the prevalence of TF in children less than 10 years of age was 42.5% and 33.5% respectively [4]. The highest levels of TT among women 15 years of age and older were observed in Kayes (3.3%) and Koulikoro (3.9%) [4]. From 2002 to 2006 all sixteen districts in Kayes and Koulikoro received SAFE interventions to control trachoma. The interventions implemented in each region are listed in Table 1. Interventions were conducted in several ways: trained ophthalmic nurses moved from village to village offering free trichiasis surgery; mass distribution of oral azithromycin and tetracycline ophthalmic ointment occurred in annual campaigns for three consecutive years in each district following pilot distributions in target areas; facial hygiene, latrine construction and use, and the utilization of water for hygiene were promoted over local and regional radio stations; and persons in each region were trained to deliver health education and promote behavior change. The number of doses distributed and population coverage with azithromycin by district and year is shown in Table 2. In 2006, after three years of intervention and in accordance with the WHO guidelines, an impact evaluation was conducted to assess the effect of the SAFE activities [2]. The Ministry of Health withdrew A, and support for F and E interventions from partner organizations was limited. The Ministry of Health concentrated efforts to scale up the SAFE strategy in other regions yet to initiate interventions. The purpose of this study was to re-evaluate the prevalence of trachoma three years after SAFE interventions were discontinued in Kayes and Koulikoro. Here we present the data from the first impact evaluation in 2006 and the recent 2009 evaluation. We also aimed to quantify any need for additional interventions.
Table 1. SAFE Interventions in Kayes and Koulikoro Regions of Mali 2002–2006+.
doi:10.1371/journal.pntd.0000734.t001
Table 2. District level antibiotic coverage of the total population in Kayes and Koulikoro Regions of Mali based on reported doses of azithromycin distributed† from 2002–2006.
doi:10.1371/journal.pntd.0000734.t002
Ethical considerations
These prevalence surveys were conducted in accordance with WHO guidelines as part of the ongoing effort of the Ministry of Health to eliminate blinding trachoma in Mali and were necessary to evaluate the impact of interventions. In addition to the Ministry of Health, the survey protocol was approved by the Emory University IRB under protocol 079-2006. Informed verbal consent and assent was received according to the principles of the Declaration of Helsinki. Written consent was not obtained in these surveys due to the low literacy rate, ranging from 3% in rural Mali to 38% in Bamako (Enquête Démographique et de Santé 2001). Emory University IRB approved the use of informed verbal consent. Oral informed consent was sought first from village chiefs before surveys were conducted in the randomly selected villages. Consent was then obtained from household heads of randomly selected households and finally oral consent was obtained from each adult examined and consent from a parent or caretaker was obtained to examine children. Verbal assent was obtained also from children 6–14 years of age. Survey participants were informed of the purpose of the trachoma examinations and their rights not to participate or to s the examination at any time. Choosing not to participate did not affect any decision in determining the need for interventions. Verbal consent was documented on a standard survey data collection tool. All children presenting signs of TF or trachomatous inflammation intense (TI) were offered free tetracycline eye ointment and instructed to apply it twice daily for 6 weeks. Persons identified with TT were recorded, counseled, and offered free consultation and surgery with a trained TT surgeon.
Survey setting
Kayes Region is located in the extreme west of Mali bordering Mauritania to the north, Senegal to the west, and Guinea to the southwest (Figure 1). The region is divided into seven health districts with an estimated combined population of 1,763,987 persons (Mali National Demographic and Statistical Institute 2009 population projection). The primary ethnic groups are the Sarakole (Soninke) and Bambara.
Figure 1. Regions of Kayes and Koulikoro, Mali.
doi:10.1371/journal.pntd.0000734.g001
Koulikoro Region is located in the western interior of Mali directly east of Kayes Region. It also borders Mauritania to the north and Guinea to the southwest. Koulikoro is divided into nine health districts with an estimated population of 2,072,185 persons (Mali National Demographic and Statistical Institute 2009 population projection). The primary ethnic groups are the Bambara and Malinke.
Design/sampling
In both 2006 and 2009, population-based cross-sectional household surveys were conducted at the district level. Each survey in 2006 was done at least 6 months after the last round of antibiotic distribution following the implementation plan of the national program. Thus some districts in Kayes and Koulikoro were surveyed during the period between March and May and some during November and December. In 2009, all districts were surveyed during the period between March and May. Twenty villages (clusters) were selected from each district with a probability of selection proportional to the total population of the village. All villages with less than 5,000 total population from each district were eligible for selection. In 2006, 4 of 7 districts in Kayes (Bafoulabe, Diema, Kita and Nioro du Sahel) and all 9 districts in Koulikoro were assessed. In each of these districts, concessions (household compounds) were systematically selected using the random direction method [5]. All residents aged 1–9 years of age and 15 years of age and older from all households within selected concessions were examined for clinical signs of trachoma until approximately 60 qualifying children had been examined. In 2009, all 16 districts in the two regions were surveyed for a total of 320 clusters. Households within a cluster were randomly selected following the method of sketch mapping and segmentation which aimed to survey 24 households per cluster [6]. With the assistance of village leaders, survey teams drafted a list of all households, dividing households into segments of four. Village chiefs selected segments via lottery. All households in a selected segment were surveyed and all consenting persons over six months of age in each household were examined for trachoma. From the sampling methodology used in both surveys we assumed that the data was self-weighted.
Clinical survey and questionnaire
Residents of selected households in 2009 were enumerated and designated as either present or absent. Absent was defined as not being physically present in the village on the day of the survey. Enumerated persons who were not at home, but in the village were found and recruited to the survey. Teams made at least one attempt on the same day to find residents marked absent during the first visit to the household. Absent residents in the 2006 survey were not enumerated. Clinical signs of trachoma were assessed using the WHO Simplified Grading System [3]. Examiners recorded the presence or absence of all trachoma grades in both eyes of survey participants using a ×2.5 binocular loupe and adequate light. The findings from the worst affected eye were reported. At examination in 2009, children were assessed for a clean face, defined as the absence of both ocular and nasal discharge. In 2009, each child 6–15 years of age was asked about their attendance in school, defined as public or private non-religious school. Attendance of Koranic schools or non-formal education was not assessed. Examined persons were asked about their participation in the most recent round of antibiotic distribution for trachoma control, defined as whether a person took oral azithromycin, applied tetracycline eye ointment, or did not participate. Estimates for participation in antibiotic distribution included only those persons present to give a response. Additionally in 2009, one adult respondent was interviewed in each household to determine the presence and use of a household latrine and the location of the main water source used by the household. The presence of a latrine was confirmed by direct observation and ‘use’ was defined as the observation of feces in the pit. The location of the water source was designated as within the household compound, within the village, or outside the geographical village boundaries as a proxy for distance and availability of water. Household interviews were not conducted in the 2006 surveys.
Quality control and data management
Prior to the surveys, ophthalmic nurses were trained to use the WHO Simplified Trachoma Grading System through repetitive grading of digital photographs in a classroom setting and assessment of individual patients in the field. In 2009, these exercises were followed by a formal inter-observer reliability test of trachoma grading against a standardized set of 50 slides presented on a computer and a field exam of 50 children in which SB, DS and JDK were considered the reference examiners. Reference grading was supplemented with digital photographs. Eight out of ten ophthalmic nurses met the criteria of achieving greater than 80% reliability and a kappa statistic of 0.6 and above for grade TF and were selected as examiners for the survey. Survey teams were trained to randomly select households within a cluster, conduct household interviews, and record findings on standardized forms. A survey team consisted of one data recorder and one ophthalmic nurse. Formal inter-observer reliability tests were not conducted for the examiners in 2006.
Data were double-entered, compared and corrected. Based on the survey design used, we adjusted confidence intervals for the prevalence estimates and odds ratios to account for correlation among the data due to clustering using SAS SURVEY procedures (SAS version 9.2, SAS Institute Inc) [7], [8]. Regional prevalence estimates accounted for population differences between districts. We calculated differences between prevalence estimates from 2006 and 2009 and tested the equality of the estimates using the Z statistic with α = 0.05.
Quantification of SAFE interventions
The ultimate intervention goal considered for achieving blinding trachoma elimination is the presence of less than 1 TT case per 1,000 population [9]. We calculated the total backlog of persons with TT in need of surgery by multiplying the 2009 point estimate and confidence limits of the population prevalence of TT by the estimated total population to give a point estimate and lower and upper bounds of the total number of people to be operated. According to WHO guidelines, where district-level prevalence of TF in 1–9 year-old children exceeds 10% at baseline, A, F and E activities are warranted district-wide and thus the total population living in these areas is targeted [2]. Where SAFE activities have been implemented, all areas that remain above 5% TF prevalence among children should continue antibiotic distribution [2]. The target prevalence by which mass antibiotic interventions to control trachoma is not needed is below 5% TF [2]. We calculated the number of household latrines required to achieve goal 7c of the United Nations Millennium Development Goals (MDGs); halve by 2015 the proportion of people who do not have access to improved sanitation [10].
Surveys in 2006
In 2006, a total of 29,179 persons were examined from 29,779 persons available in 2 528 selected concessions. The mean number of concessions per district was 194.5 with a range by district of 110 to 312 concessions. A mean of 9.7 concessions were surveyed per village (range by village 1–25). The mean number of households per concession was 1.9 (range by concession 1–17). In the four surveyed districts of Kayes, 4,168 adults over 14 years of age and 4,808 children 1–9 years of age were examined for clinical signs of trachoma. In Koulikoro, 9,679 adults and 10,524 children were examined. Among examined adults over 14 years of age, 68.9% were women and among examined children 1–9 years of age, 51.5% were girls.
Clinical observations
The prevalence estimates of clinical signs of trachoma in Kayes and Koulikoro in 2006 are presented in the first three columns by district in Table 3. Among adults 15 years of age and older, the prevalence of TT in Kayes was 2.37% (95%CI 1.66–3.07%, range by district 0.30–3.54%) and in Koulikoro, 1.75% (95%CI 1.31–2.23%, range by district 1.06–2.49%). The prevalence of trachomatous scaring (TS) among adults was 10.33% (95%CI 8.6–12.0%, range by district 3.0–18.4%) and 4.18% (95%CI 3.5–4.8%, range by district 0.6%–9.2%) in Kayes and Koulikoro respectively (data not shown). Prevalence of trachomatous corneal opacity (CO) in Kayes was 0.38% (95%CI 0.14–0.61, range by district 0.0–0.9%) and 0.31% (95%CI 0.12–0.51%, range by district 0.0–0.9%) in Koulikoro. Women were more likely than men to have TT (OR = 1.61, 95%CI 1.16–2.23, p = 0.004). Adults 50 years and older were more likely to have TT than adults aged 15–49 years (OR = 6.73, 95%CI 4.99–9.07, p = <0.0001).
Table 3. Prevalence of clinical signs of trachoma in Kayes and Koulikoro Regions, Mali 2006 and 2009.
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District-level prevalence of TF among children 1–9 years of age had reduced to below the 10% intervention threshold in all surveyed districts. Among children 1–9 years of age, the prevalence of TF was 3.9% (95%CI 2.9–5.0%, range by district 1.2–5.4%) in Kayes and 2.7% (95%CI 2.3–3.1%, range by district 0.1–5.6%) in Koulikoro. The prevalence of trachomatous inflammation intense (TI) among children aged 1–9 years of age was 1.0% (95% CI 0.6–1.5%, range by district 0.3–1.8%) in Kayes and 0.4% (95% CI 0.2–0.5%, range by district 0–2.0%) in Koulikoro. Active trachoma (TF and/or TI) prevalence was 4.53% (95%CI 3.3–5.7%, range by district 1.2–6.5%) in Kayes and 2.96% (95%CI 2.5–3.4%, range by district 0.2–5.6%) in Koulikoro.
Surveys in 2009
In 2009, from all districts in both regions a total of 42,128 persons were enumerated in 7,533 households and 32,918 were examined. In Kayes, a total of 13,576 persons were examined for signs of trachoma out of 17,127 persons enumerated from 3,287 households for a response rate of 79.3%. In Koulikoro, 19,342 persons were examined out of 25,001 persons enumerated from 4,246 households (a response rate of 77.4%). The response rate in women was 83.1% (17,771/21,386) and 73.0% (15,147/20,742) in men. The majority of adult men unable to be examined were absent from the home at the time of the household visit. Children 1–9 years of age composed 33.9% of the total enumerated population. Adults 15 years of age and older were 51.0% of the total population. The proportion of enumerated children 1–9 years of age who were examined was 88.2% and 77.1% of enumerated adults were examined. Among examined adults over 14 years of age, 58.1% were women and among examined children 1–9 years of age, 49.7% were girls. Among children 6–15 years of age the proportion that reported attending school was 42.6% in Kayes and 54.1% in Koulikoro.
Clinical observations
The prevalence estimates of clinical signs of trachoma in Kayes and Koulikoro for 2009 are presented by district in the last four columns of Table 3. The prevalence of TT in the total population of Kayes region was 0.69% (95%CI 0.53–0.85%, range by district 0.20–0.91%). In Koulikoro, TT prevalence in the total population was 0.56% (95%CI 0.43–0.69%, range by district 0.25–0.85%). Among adults 15 years of age and older, the prevalence of TT in Kayes was 1.45% (95%CI 1.10–1.79%, range by district 0.37–1.87%) and in Koulikoro, 1.10% (95%CI 0.84–1.35%, range by district 0.34–1.78%). The prevalence of trachomatous scaring (TS) among adults was 4.22% (95%CI 3.7–4.8%, range by district 0.3–5.3%) and 4.68% (95%CI 4.1–5.2%, range by district 1.4–8.1%) in Kayes and Koulikoro, respectively (data not shown). Prevalence of CO in Kayes was 0.11% (95%CI 0.03–0.19, range by district 0–0.42%) and 0.21% (95%CI 0.13–0.29%, range by district 0–0.73%) in Koulikoro. Odds of TT among adults 50 years of age and older were ten times higher than adults 15–49 years of age (OR = 10.61, 95%CI 7.62–14.78, p<0.0001). Women were nearly two times more likely to have TT than men (OR = 1.85, 95%CI 1.40–2.46, p<0.0001).
At the regional level, the prevalence of TF was 6.6% (95%CI 5.7–7.5%, range by district 2.5–15.4%) among children 1–9 years of age in Kayes and 8.7% (95%CI 7.5–9.9%, range by district 1.7–17.2%) in Koulikoro. The prevalence of TI among children aged 1–9 years of age was 1.5% (95% CI 1.1–1.8%, range by district 0.3–3.3%) in Kayes and 0.6% (95% CI 0.4–0.8%, range by district 0–1.9%) in Koulikoro. Active trachoma (TF and/or TI) prevalence was 7.34% (95%CI 6.4–8.3%, range by district 2.7–16.8%) in Kayes and 8.91% (95%CI 7.7–10.1%, range by district 2.0–17.9%) in Koulikoro.
Characteristics associated with uptake of SAFE strategy 2009
A total of 7,533 households were surveyed (range by district 423–480). The mean number of persons living in each household was 5.2 (SD = 2.7, range by district 4.5–5.9) in Kayes and 5.9 (SD = 3.0, range by district 4.9–6.9) in Koulikoro. Indicators of uptake of the A, F and E components of the SAFE strategy are listed by district in Table 4. The proportion of examined household residents reporting taking azithromycin or using tetracycline eye ointment in the most recent round of distribution was 86.1% (95%CI 84.2–88.0, range by district 54.6–99.8%) in Kayes and 83.9% (95%CI 81.6–86.3%, range by district 59.9–96.8%) in Koulikoro. Among children 1–9 years of age, 76.5% (95%CI 74.3–78.7%, range by district 46.7–95.2%) and 75.0% (95%CI 71.8–78.1%, range by district 52.1–86.8%) in Kayes and Koulikoro, respectively, had a clean face at examination. Basic sanitation (a household latrine) was evident in over 80% of the households in 12 out of the 16 districts. The presence of a latrine with evidence of use was observed in 88.1% (95% CI 85.2–91.1%, range by district 50.4–100%) of surveyed households in Kayes and 87.2% (95%CI 84.5–89.9%, range by district 37.4–99.8%) in Koulikoro. A water source inside the compound was observed in 9.7% (95%CI 5.5–13.9%, range by district 0.6–17.2%) of surveyed households in Kayes and 3.2% (95%CI 0.5–6.0%, range by district 0–11.8%) reported having to travel outside the geographical boundaries of the village to collect water. In Koulikoro, 19.8% (95%CI 15.6–24.0%, range by district 0–31.9%) of households had a source of water within the compound and 5.6% (95%CI 3.5–7.7%, range by district 0–17.2%) reported having to collect water from a source outside of village boundaries. Overall, there was no difference in the prevalence of clean faces between children living in households with water access inside the compound and children in households where the water source was outside the compound; 76.3% compared to 75.7%, Z = 0.48, p = 0.633.
Table 4. Indicators of A, F and E uptake in Kayes and Koulikoro Regions, Mali 2009.
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Difference between 2006 and 2009 estimates
The regional estimates of prevalence of TT and CO among women 15 years of age and older from 2006 and 2009 are plotted in Figure 2 with the same estimates reported in 1997 for a comparison to baseline prevalence. In this age group, the difference in prevalence of TT between 2006 and 2009 for Kayes (Z = −1.33, p = 0.1829) and Koulikoro (Z = −1.78, p = 0.0744) regions was not statistically significant. There was no statistically significant difference in regional estimates of CO among adult women from 2006 to 2009 (Kayes Z = −1.01, p = 0.3117; Koulikoro Z = −0.44, p = 0.6626). However, among adults of both genders, the prevalence of TT in 2009 was less than the estimate in 2006 for both Kayes (Z = −2.06, p = 0.0396) and Koulikoro (Z = −2.79, p = 0.0052). The prevalence of CO among all adults between 2006 and 2009 did not differ in Kayes (Z = −1.21, p = 0.2245) or Koulikoro (Z = −0.55, p = 0.5838).
Figure 2. Prevalence of blinding trachoma (TT and CO) among women 15 years and older in Kayes and Koulikoro 1997*, 2006 and 2009.
*regional estimate from Schémann et al 1998.
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The regional prevalence of TF in 2009 was statistically greater than that observed in 2006 for both regions (Kayes Z = 8.13, p<0.0001; Koulikoro Z = 16.20, p<0.0001). The prevalence of TF for the region in 1997 is plotted with the district level estimates of TF from 2006 and 2009 in Figure 3. The differences in district level estimates between 2009 and 2006 with confidence intervals are listed in Table 5 along with Z statistic and p-values. The prevalence of TF observed in 2009 was statistically greater than that observed in 2006 for Bafoulabe, Nioro du Sahel, Banamba, Dioila, Fana, Kati, Kolokani and Koulikoro districts. The prevalence of TF in 2009 was the same or less than that observed in 2006 in the districts of Diema, Kita, Kangaba, Nara and Ouelessebougou. Regional estimates of TI among children from 1997, 2006 and 2009 are shown in Figure 4. Also for both regions, the prevalence of TI in this study was greater than that observed in 2006 (Kayes Z = 2.06, p = 0.0198; Koulikoro Z = 1.86, p = 0.0316). The prevalence of TI observed in 2009 was statistically greater than that observed in 2006 for Bafoulabe, Banamba, Dioila and Fana districts.
Figure 3. Prevalence of TF among children less than 10 years of age in Kayes and Koulikoro, Mali 1997*, 2006 and 2009.
† estimate based on surveyed districts. *regional estimate from Schémann et al 1998. **districts not surveyed in 2006.
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Figure 4. Prevalence of trachomatous inflammation intense (TI) among children under 10 years of age in Kayes and Koulikoro 1997*, 2006 and 2009.
*regional estimate from Schémann et al 1998.
doi:10.1371/journal.pntd.0000734.g004
Table 5. Difference in district-level prevalence estimates of active trachoma signs among children 1–9 years of age in 2006 and 2009 in Kayes and Koulikoro Regions, Mali.
doi:10.1371/journal.pntd.0000734.t005
Estimation of targets for continued SAFE interventions
Based on 2009 estimates, the total number of persons with TT who remain in need of surgery in Kayes is 10 967 (lower and upper bounds: 7,144 to 14,123) and 10,726 (bounds: 9,932 to 16,487) in Koulikoro. TT prevalence among adults exceeded 1% in 11 of 16 districts warranting continued, enhanced efforts to provide surgery to affected patients. While TT surgery may not be a priority in Yelimane, Fana, Kangaba, Nara and Oulessebougou where TT among adults is less than 1%, eye care facilities with the capacity to operate presenting TT cases should exist.
Mass distribution of antibiotics should resume in Bafoulabe, Banamba, Kolokani and Koulikoro where the prevalence of TF exceeds 10% among children. Additionally, according to WHO guidelines, mass distribution of antibiotics should continue in areas where after three years of intervention, the prevalence of TF remains greater than 5% among children under 10 years of age [2]. This would include communities within all of the 12 other districts of Kayes and Koulikoro. If this WHO guideline is interpreted at the district level, 10 districts in Kayes and Koulikoro regions warrant ongoing mass distribution of antibiotics, targeting a total population of approximately 2,637,492 persons.
The promotion of facial hygiene and environmental improvements should resume in all districts. Access to water within village boundaries and household latrine coverage was not lacking in most districts. Fana, Dioila, Yelimane and Nara had the highest proportion of households reporting having to collect water outside village boundaries. An estimated 11,526 households in Kayes and 19,718 households in Koulikoro must collect water outside village boundaries. The construction and maintenance of water points could be targeted to communities where access to water is lacking. Kenieba in Kayes and Nara in Koulikoro had the lowest proportion of households with a latrine. To ensure that every household has access to basic improved sanitation, 41,712 latrines need to be built in Kayes and 33,928 in Koulikoro. Building half of these by 2015 would meet MDG 7c.
The national survey conducted in 1997 providing baseline regional prevalence estimates were very useful in establishing the widespread nature of trachoma in Mali. In response to results from the national survey, trachoma control interventions were initiated in Kayes and Koulikoro Regions. Interventions were focused mostly on the S and A components of SAFE. F and E interventions were implemented, but had less geographical coverage of the target population than S and A. Until 2006, monitoring of interventions was limited to program reports and did not include rigorous field evaluations. According to reports of azithromycin distributed, antibiotic coverage was not consistent between districts or years with reported district level coverage ranging from 20.9% to 108.6% after the pilot phase in 2002. Several districts failed to reach the desired minimum of 80% coverage of total population in any one year and only one averaged above 80% over three years. These inconsistencies in coverage were either due to problems with the distribution or estimates of the target population. For example, the total population registered prior to MDA may have exceeded the census estimate of total population where coverage was greater than 100%. An evaluation of antibiotic distribution in Southern Sudan demonstrated the limitations of using distribution reports alone to calculate population coverage, as population estimates and treatment records can lead to inaccurate coverage estimates [11]. In Kayes and Koulikoro, we have defined “distributed” as the total number of doses reported to have been given out to individuals during mass drug administration campaigns, and caution that they have not been validated with coverage surveys. The figures are those reported by the district to the national program.
The first impact assessment in 2006 found prevalence of TF among children to be below 5% in 9 of 13 districts and below 10% in all districts. The programmatic decision was made to focus the available resources to other endemic regions that had not initiated SAFE interventions. This resulted in sping mass antibiotic distribution and limited ongoing promotion of facial cleanliness and environmental improvements through schools and radio. Follow-up on the progress of latrine construction and new water points targeted for trachoma control sped. Surgical services to correct trichiasis were maintained. Between the surveys in 2006 and 2009, it appears as though clinical signs of active trachoma returned in eight out of the thirteen districts.
The current data have several possible interpretations. There may have been a true decline in active trachoma from baseline to the present and this decline is associated with interventions from 2003–2006. Although prevalence of active trachoma signs are higher in some districts now than observed in 2006, the prevalence remains well below the 34% and 42% TF reported in Koulikoro and Kayes respectively during the 1997 baseline survey. National programs do not have control groups and it is not possible to determine whether the decline is due to the intervention, or to a secular decline, as has been described elsewhere [12], [13], [14], [15]. Prevalence of active trachoma has been observed to decline in the absence of a trachoma control program in the dessert region of Kidal [16]. We may also consider that there has been an heterogeneous effect of the interventions with some districts showing a sustained reduction in the prevalence of TF (Diema, Kita, Fana, Kangaba, Nara and Oulessebougou) and others showing a rapid rebound after initial control (Bafoulabe, Nioro du Sahel, Banamba, Dioila, Kati, Kolokani and Koulikoro). Such random effects are assumed possible by chance at the community level according to a stochastic model of trachoma transmission [17]. Models also suggest that trachoma endemicity at baseline is predictive of return of infection after antibiotic intervention [18], yet we have no district-level estimates at baseline on which to make assumptions. Antibiotic coverage is an important factor in the return of infection after treatment and thus the elimination of trachoma [17], [18], [19]. It is possible that high-risk marginalized sections of the population are systematically missed in mass drug administration leaving them untreated and able to repeatedly reintroduce infection into treated communities. Coverage surveys performed immediately following the mass distribution campaigns at least once during the three years of intervention may have identified any such problem.
Alternatively, there may be no difference between prevalence estimates of active trachoma in 2006 and 2009 due to the differences between the survey methods used and season of assessment in some districts, although this is unlikely given the scale of the observed differences and that seasonality of trachoma in Mali has not been established. In the 2006 survey, household selection methods may have biased the samples in villages where only a few large concessions were selected. The starting points were markets or mosques, structures typically at the center of a community and often surrounded by more populated concessions. Some clusters in the 2006 survey were composed of persons examined from households within a few, very large concessions, rather than the randomly distributed sample of households obtained using the sketch mapping and segmentation in the 2009 surveys. The household sampling in 2009 was more similar to that used in 1997 where a systematic random sample was taken from a listing of households within clusters. Both evaluations began with training ophthalmic nurses in the WHO simplified trachoma grading system. However, in 2009, the grader's reliability to diagnose TF was assessed rigorously and nurses not meeting a certain criteria were excluded from serving as a grader. This type of field assessment should improve the validity and reliability of a grader's findings.
The observed reduction in the prevalence of TT may have been a direct effect of the ongoing surgical services provided to TT patients. The diagnosis of TT is straightforward and allows less room for subjectivity than TF since the grade is based on one or more lashes touching the eye, rather than 5 or more follicles greater than 0.5 mm in diameter in the central part of the tarsal conjunctiva [3]. The grader's ability to identify TT is assessed in the classroom using slides but not in the field reliability assessment [2]. It may have been possible that graders under diagnosed TT in the field, but the possibility of this type of misclassification should not have differed from 2006 and 2009. Additionally, a greater proportion of adult males were absent from the household than females. TT impairs vision and thus compromises mobility; therefore men with healthy eyes may be more likely to be absent and not examined. Only if the reverse is true, men present in the household are more likely to have unhealthy eyes, would any bias in the prevalence of TT in men have masked any gender difference in TT. In both impact evaluations, women were more likely to have TT than men, which is consistent with findings from a recent review on the association of gender and trichiasis [20]. The statistically significant difference observed between TT prevalence among adults of both genders, but not among adult females from 2006 to 2009, may suggest a gender disparity in benefit from ongoing surgical services with men being more likely than women to present for surgery. Eliminating the backlog of trichiasis patients needing surgery remains a priority in both regions. Surgical services may need modification to specifically target women.
The indicators for A, F and E uptake (Table 4) obtained from the household surveys have several limitations. Although antibiotic coverage obtained from personal reports from household residents appears high, these results should be interpreted with caution. Residents were asked whether they had taken azithromycin during the most recent mass distribution campaign, which was in 2006. It is unlikely that residents could recall specifically taking drugs for trachoma given that mass drug distribution campaigns for other NTDs had occurred in more recent years. Additionally, only responses from residents available to respond were taken. These residents may have been more likely to have been available to receive antibiotics during campaigns than those residents absent from the household at the time of the survey, potentially inflating the coverage estimate. Not surprisingly, these personal reports are higher than coverage estimated by district distribution reports (Table 2).
More than 75% of households surveyed in each district, except Nara and Keneiba, had access to a household latrine with evidence of use. The evidence of use was determined by the presence of feces in the pit, which may be incorrectly interpreted as latrine use by all persons within the household. A latrine will be categorized as ‘in use’ if only a proportion of the household is using it. The role of latrines in reducing trachoma transmission assumes that where latrines are used, no open human feces is available for flies to utilize as a medium for egg and larval development; reducing successive fly populations and reducing the number of fly to eye contact. However, if use of a latrine is limited to only certain groups or if certain groups choose not to use the latrine, open defecation will continue. Further evaluation may be needed to assess actual behavior and potentially explain conflicting outcomes of endemic trachoma in the presence of high sanitation coverage as seen in Bafoulabe and Banamba districts. Assessing behavior is also necessary in determining the influence of water on trachoma. In this survey, there was no association of a clean face and having access to a water source within the boundaries of the household compound or having access to a water source outside of village boundaries. Additionally, greater than 80% of children were observed to have a clean face in only four districts; indicating that the practice of face-washing has not been fully accepted and adopted among residents in the two regions. On the contrary, our findings may also indicate that the ability of F and E components to control trachoma may not be as effective as anticipated. However, a recent analysis of factors associated with active trachoma in Mali supports the utility of face washing and environmental improvements [21].
One of the criteria for the certification of the elimination of trachoma is to demonstrate the sustained reduction of prevalence of TF among children below 5% for a period of three years after interventions have ceased [8]. In only six districts did the point estimate of the prevalence of TF remain below 5% at the district level from 2006 to 2009. In the 2009 survey the prevalence of TF among children was above 10% in four districts and above 5% in another six districts. With the recent global expansion of mass distribution of antibiotics for trachoma elimination, national programs may soon face a need to prioritize a limited quantity of drug [22]. Given such circumstances, Mali is facing unique programmatic decisions. Currently, WHO guidelines suggest the district be the implementation unit, but for certification of elimination, no community must have more than 5% TF among children [2], [9]. This suggests a community-by-community approach to trachoma elimination even in districts where district-level estimates of TF prevalence are below 5%. There are no recommendations or guidelines as to how a country such as Mali should attempt to demonstrate each and every community throughout the vast landscape has reached the elimination target. An acceptable level of TF prevalence at which the risk of developing blinding trachoma has been eliminated is unknown if the acceptable level is not zero. TF is not closely correlated with the presence of Chlamydia trachomatis DNA on ocular swabs and is thought to linger in the absence of infection [23], [24], [25], [26]. However, TI is better associated with DNA positive ocular swabs and is also linked to increased likelihood of progression to scarring, so is considered a more severe form of the disease [23], [27]. Ocular Chlamydia infection may have been significantly reduced by the interventions as evidenced by prevalence of TI in 9 districts of less than 1 child per 100. TI is more closely correlated to current infection with Chlamydia trachomatis than residual TF and has been suggested as a potential marker of infection post treatment [28]. In this setting, microbiological supporting evidence of the presence of bacteria would be useful, yet no guidelines exist for the use of laboratory diagnostics on a programmatic scale and it is perceived that costs of adding such tests to impact evaluations are prohibitive. Using TI for a proxy of infection, the prevalence of TI in 5 of the 10 districts in Kayes and Koulikoro qualified to receive mass distribution of antibiotics based on TF, indicates that less than 1 per 100 children would receive trachoma-specific benefits from the antibiotic.
Achieving less than 5% TF at the district level is achievable and can be feasibly determined on a programmatic scale through the cluster random survey design as demonstrated in this study and in Ghana [29]. Not considering the differences in survey methodology, a district level prevalence of less than 5% TF after three continuous years of heavy antibiotic intervention did not equate in all districts to a sustained reduction of TF below 5%. No surveillance activities were implemented after sping AFE interventions in these districts. Doing so may have identified resurgence in districts with an apparent rebound in active trachoma and allowed immediate intervention. Results from these surveys provide evidence in the setting of a national program that antibiotics alone are not enough to eliminate trachoma. An analysis of associations between the components of the SAFE strategy demonstrates clearly that changes in hygiene behavior and improved sanitation can have protective effects against active trachoma [30], which argues for equal emphasis on hygiene and environmental improvements. Indicators used in the 2009 survey suggest very high access to sanitation in the two regions, but the indicators fail to capture actual behaviors. The promotion of facial cleanliness and good hygiene behavior should be reintroduced in all districts of Kayes and Koulikoro. Surgical services to correct trichiasis should also be continued, but where and for how long to continue mass distribution of antibiotics is not as clear. Currently, the 4 districts with TF above 10% among children are priority for mass distribution of antibiotics. More guidelines from the international community are urgently required to help prioritize the limited quantity of donated antibiotic in addition to recommending appropriate evaluation methodology for determining when certification targets have been achieved.
STROBE checklist
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We gratefully acknowledge the leadership role played by the National, Regional and District Ministries of Health in Mali. We thank the data entry staff, survey teams, village leaders, local volunteers and the people who gave freely of their time to participate in the surveys.
Conceived and designed the experiments: SB JDK MD FC DS YK JT LAR PME. Performed the experiments: SB JDK MD FC YK JT. Analyzed the data: JDK MD. Wrote the paper: SB JDK PME. Reviewed and edited the paper: MD FC DS YK JT LAR. Trained survey team: DS LAR. Assisted with interpretation of data: DS.
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