Trachoma Clinical Trial
Official title:
A Within-subject Laboratory and Field Trial to Test the Use of Commercially Available Insect Repellents Against Contact From Musca Sorbens, the Putative Vector of Trachoma
Musca sorbens, a fly that feeds from ocular and nasal discharge on humans, is thought to be the vector of trachoma. We are developing methods of fly control that specifically target this species, in the hope of interrupting Ct transmission. To our knowledge, the use of commercially available insect repellents has never been tested for prevention of Musca sorbens fly-eye contact (i.e. nuisance and landing in the peri-ocular area). Given the likely necessity for prolonged and/or high frequency fly-eye contact for Ct transmission, the reduction of these contacts through the use of fly repellents presents an exciting opportunity for disease control. Here we propose a within-subject, non-masked, trial of the use of commercially available insect repellents against Musca sorbens, with two consecutive participant groups in the laboratory and in the field, and a primary endpoint of measuring the protective efficacy of each repellent product. Repellent products will be chosen from: DEET (N,N-diethyl-3-methylbenzamide), IR3535 (3-[N-butyl-N-acetyl]-aminopropionic acid ethyl ester), Picaridin (2-(2-hydroxyethyl)-1-piperidinecarboxylic acid 1-methylpropyl ester); PMD (para-Menthane-3,8-diol) or permethrin (m-Phenoxybenzyl)-cis,trans-3-(2,2-dichlorovinyl)-2,2-dimethylcyclopropanecarboxylate). Products tested will be either (1) topical repellents, or (2) in long-lasting, plastic formulations of repellents that can be worn on the body (wearable repellent technologies). The insect repellent synergist Vanillin (4-Hydroxy-3-methoxybenzaldehyde) may be added to the long-lasting plastic formulations, to improve the duration of protection.
Introduction
Trachoma
Trachoma, a Neglected Tropical Disease (NTD), is the commonest infectious cause of blindness
globally, affecting some of the world's poorest communities. Trachoma is caused by repeated
ocular infection with the bacterium Chlamydia trachomatis (Ct). Active trachoma begins in
childhood with recurrent episodes of follicular conjunctivitis (TF). Chronic inflammation
results in immunologically mediated conjunctival scarring and in-turned eyelashes scratching
the eye: trichiasis. Eventually sight is lost from irreversible corneal opacification.
Trachoma is currently endemic in 42 countries. The latest estimates from the Global Trachoma
Mapping Programme (GTMP) suggest that 180 million people live in trachoma endemic areas and
3.2 million people have trachomatous trichiasis. Around 2.2 million people are visually
impaired, of whom 1.2 million are blind. More than 80% of the burden of active trachoma is
concentrated in 14 countries, mainly in the Sahel of West Africa and savannahs of East and
Central Africa, where water supplies are often scarce.
Trachoma in Ethiopia
Ethiopia is working towards eliminating trachoma by 2020 and began implementing the SAFE
strategy as part of national policy in 2003. This has focused on the provision of improved
trichiasis surgery, mass drug administration (MDA) and the distribution of public health
messages by radio, video, and printed material. From 2001-2015 more than one million
trichiasis surgeries were performed, over 170 million doses of azithromycin were given
through MDA and more than 24 million latrines were built. Despite these encouraging efforts,
trachoma remains a public health problem in many regions of the country, and the burden of
disease is far above the elimination targets set by the World Health Organisation (WHO). In
many of these communities, despite seven years of annual or biannual high-coverage MDA, the
prevalence of TF remains well above threshold for continuing MDA. Data on Ct prevalence after
repeated rounds of MDA in hyperendemic settings such as Ethiopia, indicate that reliable
long-term control is not consistently achieved, with gradual re-emergence of infection being
typical.
Flies and Trachoma
Flies are likely to contribute to Ct transmission in some locations. The three members of the
species complex Musca sorbens live in close association with humans across the Old World
tropics and sub-tropics, Asia, the Pacific Islands and Australasian regions. The African
species, M. sorbens and Musca biseta, are collectively known as The Bazaar fly, but all are
also known as 'face flies', because of their habit of aggressively visiting the face to
obtain the protein and liquid found in ocular and nasal secretions. When M. sorbens flies
visit the face to feed, they can pick up Ct and transfer it on their bodies to another
person. This is called mechanical transmission. Sometimes the house fly, Musca domestica,
will also display eye-seeking behaviour, but across most trachoma-endemic regions, the vast
majority of fly-eye contacts are made by M. sorbens. As well as transmitting trachoma, M.
sorbens has been found to harbour enteric pathogens. In communities without adequate
sanitation such as pit latrines, filth flies including M. sorbens have direct access to
faecal breeding sites in the form of open defection. Here, they contact diarrhoea-causing
pathogens, and subsequent contact to children's faces, or contamination of eating surfaces,
can lead to pathogen transmission.
Ct can be cultured from guts and limbs of M. domestica fed on Ct-infected egg yolk. Using a
tightly controlled guinea pig trachoma model, Chlamydia psittaci was transmitted by flies
from infected to uninfected eyes. Infection was established consistently if the time between
flies feeding on infected guinea pig ocular secretions and being exposed to uninfected guinea
pigs was under one hour. Other, circumstantial, evidence suggests that flies contribute to
the transmission of trachoma. In randomised controlled trials, significantly decreasing the
M. sorbens population through long-term insecticide spraying led to decreases in the
prevalence of clinical signs of active trachoma (infection not tested). However, azithromycin
MDA combined with intensive insecticide spraying in other regions had no effect. Multiple
transmission routes complicate trachoma epidemiology, and the extent to which flies
contribute to transmission must also be dependent on local factors such as fly seasonality,
abundance and local environmental factors that influence fly population dynamics. Two studies
tested M. sorbens caught leaving faces of Ethiopian children for Ct by polymerase chain
reaction (PCR); 15-23% of flies were positive. In The Gambia, Ct positive flies were also
caught from children's faces. These data strongly suggest M. sorbens is a vector of trachoma,
however, its relative importance probably varies by setting. Although it is probable that
flies are involved in transmission, this pathway is poorly understood.
Olfactory cues have been exploited for monitoring and control of vector populations for many
years, through the deployment of odour-baited traps. However, in recent years the use of such
traps for population suppression of disease vectors has received increased attention, and
recently the potential of these methods for malaria control was empirically demonstrated for
the first time. One of the most long-standing and established examples of the use of
odour-baited traps is the control of tsetse flies and Human African Trypanosomiasis in East
Africa.
The investigators have recently conducted field studies in Oromia, Ethiopia, during Phase 1
and Phase 2 of the Stronger SAFE programme, designing a trap from locally sourced and cheaply
available materials. The performance of this trap was tested, baited with a commercial lure,
relative to several other commercially available fly traps and found to be superior. A major
advantage of odour-baited trapping for fly control is that it is not associated with
environmental impact concerns. This is in contrast to widespread insecticide spraying, which
although has been shown to suppress fly populations very successfully, can be damaging to the
environment.
Insect repellents are used world-wide to prevent nuisance biting by non-vector species, and
to prevent disease transmission by vectors in disease-endemic regions. Although the use of
plants with repellent qualities, either by burning leaves or presenting fresh foliage, is
prevalent in many regions, commercially available topical repellents are rarely used by
people in low-income and disease-endemic countries. This is because of cost, availability,
and the impracticality of a product that requires repeat application. However, when use of
insect repellents has been successfully adopted by communities, they have been found to be
protective against malaria. Repellents have also been successfully used to control other
arthropods of public health significance, including lice and the chigoe flea. A recent review
of the evidence that topical insect repellents can be used to protect against clinical
malaria or malaria infection found insufficient evidence, and called for better designed
trials to generate higher-certainty evidence.
There is growing interest in the use of repellents as personal protection from disease
transmission, particularly around the use of insecticide-treated clothing, which can repel
biting insects. In these instances, the insecticide used has spatially repellent properties
or is a contact irritant, which protects the individual user and the insecticides are not
sprayed into the environment. Insecticide-treated clothing has been shown to provide
protection from both malaria and leishmaniasis. Another study looked at the use of
permethrin-treated headscarves for Afghan women in a Pakistani refugee camp, and found a
reduction in the incidence of malaria in people under 20 years old. There is better evidence
for the use of insecticide-treated clothing against malaria transmission, particularly
advocated in areas where more evidence-based vector control strategies such as long-lasting
insecticide-treated bed nets are not appropriate. Again, however, further high-quality
studies are required to improve the efficacy evidence base.
Using the M. sorbens colony that the investigators have established at LSHTM, preliminary
studies have been conducted that demonstrate M. sorbens are susceptible to most commercially
available repellents. The investigators have found evidence that the insecticide permethrin
has some spatial repellency to M. sorbens, if impregnated at safe doses into fabric scarves.
In areas of high fly density, it is expected that the nuisance caused by these flies may
allow such an intervention to be successful, as the immediate benefit of reduced face contact
would encourage continued uptake of this intervention. Attractant (odour-baited trap) and
repellent (commercially available repellents) technologies will be combined to create a
"push-pull" strategy to reduce vector-host contact and attract flies to lethal odour-baited
traps that will supress populations.
Research hypothesis
Commercially available insect repellent products can be used to decrease contact to the face,
particularly the eyes, nose and mouth, by the eye-seeking fly Musca sorbens. The protection
afforded by insect repellents will prevent transmission of Chlamydia trachomatis by infected
flies, as well as reducing the nuisance caused by this species.
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