Melina Lopez
3/9/12
Humbio 153: Parasites & Pestilence
Trachoma: Diagnosis, Treatment, and Prevention
Learning Objectives:
-Understand and differentiate the different stages of Trachoma in the context of the
WHO grading system
- Understand the faults of the WHO grading system and advocate development of
easy & accurate point-of-care tests
-Understand pros/cons of common treatments: azithromycin and tetracycline
-Understand possible surgical interventions and other solutions for trichiasis
-Understand importance of administering treatment as a from of prevention as well
as addressing environmental factors
-Understand the prominence of human transmission and stress hygiene
-Understand the importance of surveying communities and implementing the SAFE
strategy
-Understand ability to eliminate Trachoma with continued efforts and SAFE
implementation
DIAGNOSIS AND CLINICAL MANIFESTATION (Slides 3-11)
As part of the World Health Organization’s guidelines to treat and prevent
complications of Trachoma, a grading system for clinical presentation is employed.
Based upon prevalence of certain stages of trachoma in a given community, public
health workers choose different courses of action. For this reason, understanding
the clinical manifestations of Trachoma is crucial in order for rapid management to
commence in hopes of interrupting the transmission of Trachoma. Later in this
presentation the WHO Trachoma Grading System will be discussed. First, however,
it is necessary to review and recognize the different stages of Trachoma
progression.
In examining clinical effects of Trachoma, the conjunctiva is the focal point.
Looking at the anatomy of the eye, we are most concerned in examining the tarsal
conjunctiva on the inner surface of the eyelid and the bulbar conjunctiva over the
sclera, (See slide 3). The conjunctiva is essentially a thin mucous membrane
covering the outer surface of the eye that becomes inflamed with repeated infection.
The disease progresses over years as repeated infections cause scarring on
the inside of the eyelid, earning it the name of the “quiet diseasei” Those living in
endemic areas for a significant amount of time are most prone to Trachoma due to
continual repeated infections that ultimately lead to later cicatricial disease
progression.
It is important to note that Trachoma is a chronic infection that begins with
Active Trachoma and later develops into Cicatricial Disease. Active Trachoma is
generally present in the at risk population of children <10 years oldii. Continual reinfection then leads to Cicatrical, or “scarring” disease, present in late childhood and
adulthood. It follows that adult bacterial loads are usually lower than those of
children, and the duration of infection and disease also declines with age,
presumably as the result of an acquired immune responseiii,iv. This is in contrast to
the scarring features of trachoma, the prevalence of which increase with age,
reflecting the cumulative nature of the damagev.
The principal signs and symptoms in the early stages of trachoma include
mild itching and irritation of the eyes and eyelids, and discharge from the eyes
containing mucus or pusvi, in addition to TF (Trachomatous inflammation follicular)
and TI (Trachomatous inflammation intense), which will be discussed later. As the
disease progresses, later trachoma symptoms include: marked light sensitivity
(photophobia), blurred vision, and eye pain, in addition to complications caused by
scarring6.
Specifically, the WHO grading system calls for clinical diagnosis of active
trachoma by everting the upper eyelid to look for the presence of 5 or more
lymphoid follicles within the grading region, (see slide 6). Lymphoid follicles
present as yellow-white colored dots/sacs on the conjunctiva of the everted upper
eyelid. Follicles are sub epithelial collections of lymphoid cells5. Also, one can
discern the presence of “Herbert’s pits,” which are circular depressions at the
limbus (the conjunctiva-cornea junction) and are (due to) earlier follicles that
resolved with scarringvii. Initial follicle inflammation will turn to more intense
inflammation, called TI (Trachomatous inflammation intense), resulting in the
appearance of intense velvety thickeningviii. This thickening makes it very hard to
see blood vessels underneath mass inflammation.
Then, the severity and duration of active trachoma infection predicts the
likelihood of progression to Cicatricial disease in adulthood1. This leads specifically
to presence of TS (Trachomatous conjunctival scarring) and TT (Trachomatous
Trichiasis). Scarring initially appears as thin discrete white lines that transverse the
conjunctiva. Then, as scarring progresses, conjunctival tissue coalesces, forming a
thick white band near the lid margin known as Arlt's line, (see slide 8)1.
Eventually, eyelid scar tissue contracts and can distort the lid margin leading
to entropion (inward rolling of the eyelid) and subsequent trichiasis (ingrown
eyelashes)1. Trichiasis is staged as minor (one to five eyelashes touching the globe)
or major (more than five eyelashes touching the globe). Inwardly turned eyelashes
scratch the corneal surface and cause repeated mechanical irritation to the eye. This
presents a huge risk to developing blindness and the finding of trichiasis should
prompt surgical intervention.
Trichiasis can result in pannus then corneal opacification (CO). Pannus is the
growth of vascular tissue over the cornea as a result of edema and ulceration due to
eyelash abrasion on the cornea. It is a hallmark of trachoma but is not actually
assessed in the current grading system. Later development of CO is classified by
evidence of corneal opacity blurring part of the pupil margin1.
Overall the gradual progression of Trachoma can be depicted in the
simplified flow below:
Follicle InflammationScarred eyelidseyes turn inward trichiasiseyelashes
scratch surface of cornea inflammation and scarring of corneablindness
Follow the WHO grading system as shown on slide 11 to classify clinical
presentation of the patient’s stage of Trachoma. Later guidelines will advise what
steps should be taken based upon measuring community prevalence of trachoma.
WHO GRADING SYSTEM AND OTHER METHODS OF DIAGNOSIS (12-14)
The current reliance on clinical signs of Trachoma can present some
problems. For one, the system is very susceptible to error by medical officials who
may over- or under- diagnosis Trachoma. Also, the kinetics of the disease, with a
short latent phase (infection before clinical signs with the incubation period for
disease), a patent phase (infection and clinical signs) and a recovery phase
(infection cleared but clinical signs persist, which can last for many months) may
result in misdiagnosesix,x.
Moreover, Dr. Keenan of UCSF stresses the point that it is hard to
differentiate active trachoma present in an individual before treatment and after
treatment. Many articles confirm this difficulty in clinical diagnosis in those
communities that have already received mass treatment. One may still see a few
follicles and not realize that treatment has been administered already and that the
patient’s condition is actually steadily improving. Instead they may call for more
treatment, which could lead to a great waste of antibiotics and potentially other
bacterial infections’ resistance to azithromycin (even though C. trachomatis hasn’t
proven resistance to azithromycin yet). Overall, the difficulties with clinical
diagnosis give inaccurate percentages of the community prevalence and affects
decisions for subsequent public health implementation strategies.
Perhaps some of the bigger issues, however, have to do with the fact that C.
trachomatis cannot be detected in all cases of active disease, even in those cases
where laboratory testing use nucleic acid amplification tests (NAAT) and PCR in
addition to clinical diagnosis. Again, much of this is due to “kinetics” of the disease.
Due to the various issues that a solely clinical diagnosis presents, other forms
of testing Trachoma have been implemented. For example, laboratory assays are
used for research studies and areas with low prevalence. Specifically, Nucleic Acid
Amplification Tests (NAAT) have been implemented in research studies conducted
by UCSF. NAATs are highly specific and are generally used in areas with low
prevalence to give a more accurate measure of Trachoma presence. However, they
are not necessary in areas with higher prevalence because of higher correlation
between disease and infectionxi. The benefits of NAAT tests have been praised and it
has been noted that as the positive predictive value of clinical diagnosis for
trachoma falls with decreasing prevalence, microbiologic diagnosis may become a
more important tool1.
At the same time, resources required for most laboratory tests are incredibly
expensive including PCR machines generally used with NAATs. As a result, clinical
grading has remained the most common form of diagnosis.
There is one promising area of development for another way to diagnosis
Trachoma, however: easy point-of-care tests2. A simple point of care test for C.
trachomatis showed promise when evaluated in trachoma-endemic communities in
Tanzaniaxii but it is not yet commercially available. This test is overall based on the
same principle of tests used for Chlamydia urogenital infections. In their study, the
University of Cambridge research team explained that the (point of care) assay is a
dipstick immunoassay that detects chlamydial lipopolysaccharidexiii By initially
taking swab samples then performing the dipstick immunoassay this test eliminates
the need for expensive machinery including PCR that NAAT tests require. Also, the
test is very easy to use and does not take long to train local community health
workers on how to administer it. Unfortunately, later research studies have
concluded that the sensitivity and specificity of this test were lower when evaluated
in subsequent, larger studies in The Gambia and Senegal5. Overall, however, the
research into point-of-care tests has still made great strides and can be further
developed. Use of such a test is easy and accurate and can significantly help measure
trachoma prevalence.
TREATMENT (15-17)
WHO recommends azithromycin (single oral dose) or topical tetracycline (1
percent eye ointment twice a day for six weeks) for community-wide distribution.
Azithromycin is preferred because it is given as a single oral dose, although it is
expensive. Pfizer has donated 135 million doses to control programs through the
International Trachoma Initiative. Overall, it has been shown that a single dose of
oral azithromycin is as effective as a long course of topical tetracycline for the
treatment of active trachomaxiv.
The call for mass treatment of azithromycin specifically has brought up
questions of antibiotic resistance. However, Chlamydial resistance to azithromycin
has not been documented, (although it is possible that this may be due to difficulties
associated with culturing the bacterium)1. The main worry of mass treatment with
azithromycin is development of resistance from other bacterial infections that
azithromycin is also meant to treat. For example, strains of streptococcus have
shown resistance to azithromycin2 as well as S. pneumonia, which was observed
following mass azithromycin treatment for trachoma in Nepal and in an Australian
Aboriginal community1.
Overall, however, proven benefits of Azithromycin may outweigh potential
risks. For instance, Azithromycin has proven to reduce mortality in children due to
other infections, (including respiratory infections, diarrhea, and malaria). This was
illustrated in a cohort including 5507 children in Ethiopia aged one to five years of
age who received azithromycin for mass treatment of trachoma1.
Finally, other treatments of Trachoma may target later progression of the
disease, specifically at the onset of trichiasis. The aim of surgery for trichiasis is to
reduce the progression to corneal opacity and blindness as a result of lashes
abrading the cornea. Specifically, bilamellar tarsal rotation is used to direct the
lashes away from the eye. For these surgical interventions to be employed, the WHO
recommends regular surgical sessions at fixed sites once a week, with periodic
outreach stations held in trachoma-endemic communities5.
For areas without a surgical intervention program, epilation (eyelash
removal) has been used to treat trichiasis. This may limit development of corneal
opacity in patients who present with moderate to severe entropion1. Similarly,
eyelid taping has been proposed as a non-surgical intervention, but this is generally
a short-term measure prior to surgery5.
IDENTIFYING NEED FOR INTERVENTION (slides 18-20)
Currently, the WHO recommends Population-based prevalence surveys
(PBPS), which provide comprehensive prevalence data and are considered the gold
standard for trachoma surveys5. This method includes collecting previous surveys,
written reports, hospital eye surgery records and interviewing people with local
experience. Also, identification of water access and latrines in the community must
be performed, in addition to other tasks outlined by WHO guidelines. PBPS can be
time consuming and costly so other methods of assessing communities are being
employed: TRA and ASTRA. In the mean time, population based prevalence surveys
are still considered the (most) reliable source of prevalence data for trachoma, and
have generally been used to prepare national control plans, and to forecast ultimate
intervention goals for surgery and antibiotic treatment5 .
An important component of theses surveys is clinical screening for TF
(Trachomatous follicular inflammation) in children 1-9 years old. WHO criteria for
mass antibiotic treatment distribution depending on prevalence rates is depicted in
the table on slide 20. When mass treatment is declared necessary, the WHO
recommends that treatment coverage should be between 80% and 90%xv.
Mathematical modeling assuming 80% treatment coverage and 3 years of annual
treatment demonstrated elimination of infection in 95% of communities5. It is
imperative to note that several years of annual mass treatment is considered
necessary to eliminate trachoma as noted by WHO protocol to continue annual
treatment for 3 years.
INTERVENTION (slides 21-24)
When considering intervention and treatment, it is important to always
consider the most “at-risk” group, children <10 years old. Indeed, it has been noted
that frequent mass antibiotic treatment of children may confer “herd protection” to
the entire community. This was illustrated in a cluster-randomized trial of over
10,000 children in Ethiopia. Results after 12 months proved the mean prevalence of
infection among treated children less than 10 years old went from 48%-->3% and
among individuals older than 10 in communities where the children received
treatment, the mean prevalence was reduced 47% from baseline2.
Furthermore, in addition to intervention in Trachoma-endemic areas by
treating infection, one must also consider environmental risk factors that
perpetuate infection. Specifically, one must recall the 6 D’s and the 5 F’sxvi.
6 D’s: Dryness, dust, dirt, dung, discharge, density (overcrowding)
5 F’s: flies, feces, faces, fingers, and fomites.
In addition to considering environmental factors, many debate about control
of humans’ transmission and control of the mechanical fly vector. Some locations
have seen reduction in active trachoma by targeting the fly population. However, in
other locations, the density of eye-seeking flies is insignificant and does not appear
to contribute towards transmission5. Increasingly, physicians and researchers have
been calling for more attention to the human transmission factor in Trachoma
infection. With that, facial cleanliness, especially of children, is extremely important.
In an interview with Dr. Keenan of UCSF, sanitation was stressed above targeting
the fly vector.
PREVENTION IN HUMANITARIAN CRISES (SLIDE 25)
In terms of humanitarian crises where individuals are in close contact with
each other, human-human transmission poses a huge risk factor. At the same time,
women and children who may stay at refugee camps while men go to fight or to seek
work are immediately at a higher risk for getting Trachoma. General sanitation is
crucial for these situations so building makeshift latrines to separate human feces
and to contain mechanical fly vectors is beneficial.
Similarly, advocating and raising funds for a “medical cocktail” with
azithromycin can help prevent many infections including Trachoma2. As noted
previously, azithromycin can easily help prevent other bacterial infections. For this
reason, including this antibiotic in a medical regimen administered in humanitarian
crises situations with many people in close contact could prove extremely beneficial.
THE SAFE STRATEGY (Slide 26)
This strategy is currently the number one comprehensive recommended
strategy that the WHO recommends to combat Trachoma in communities.
OUTLINED FROM HOTEZ, CHAPTER 5 (source 2 in references)
S: simple surgery to create a slit in the eyelid and peel back a portion to prevent
further corneal scarring. This is a relatively simple procedure for which health
professionals and nurses can be trained.
A: antibiotics. Single dose of generic drug, azithromycin, marketed under the title,
Zithromax. Zithromax can also be replaced by tetracycline, which requires topical
administration for 4-6 weeks. However, the ability of just one dose of azithromycin
to penetrate inside infected human cells so efficiently makes this the more attractive
option. In 1998, Pfizer donated $60 million of Zithromax.
F: facial hygiene. Face washing, especially among children who may be outdoors
playing with many other kids, is a great step in interrupting transmission.
E: environmental empowerment. Improve access to clean water, improve sanitation
and latrines to reduce fly populations. Educational empowerment for community
members also lends them the ability to prevent human-human transmission by
better hygiene.
MOROCCO 1999: Management and Prevention Success Story!
Multifaceted approach to stop the infliction and impact of Trachoma
-5 government ministries partnered, including health and education, local NGOs and
international organizations such as UNICEF and WHO
-Mobile surgery units
-Administer Zithromax
-Build wells and latrines
-Provide education
The widespread implementation of the SAFE strategy and single dose Zithromax
administration made Morocco, in 2005, the first developing country to successfully
interrupt the transmission of Trachoma!
ITI: (International Trachoma Initiative) is sponsoring Trachoma control programs in
11 other countries including:
9 African nations (Tanzania, Ghana, Niger, Mali, Ethiopia, Kenya, Sudan, Mauritania,
and Senegal)
2 Asian nations (Nepal and Vietnam)
TRACHOMA ELIMINATION
There is currently a lot of work and research surrounding Trachoma and there is a
great possibly that the WHO goal to eliminate endemic Trachoma by 2020 may be
reached if we continue:
-SAFE implementation
-Including mass drug administration (Evidence that this works is seen in the
effectiveness of the Tanzanian study: “high coverage single-dose azithromycin
treatment reduced the prevalence of PCR positivity among clinically active people
from 58 (33%) of 174 before antibiotics to one (2%) of 49 people 2 years later,”
(Solomon et al., 2004).
-Develop Point of care tests for better diagnosis and regulation
-Continue education to improve sanitation
References:
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of Trachoma. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA, 2012.
i
ii
Keenan, J. Telephone interview. 6 Mar. 2012.
Bailey R, Duong T, Carpenter R, Whittle H & Mabey D (1999) The duration of
human ocular Chlamydia trachomatis infection is age dependent. Epidemiology and
Infection 123, 479–486.
iii
Grassly NC, Ward ME, Ferris S, Mabey DC & Bailey RL (2008). The natural history
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iv
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v
vi
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vii
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viii
ix
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xvi