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Biomedical subjects

David C W Mabey

Publications and source records attributed to David C W Mabey.

At least 19 recordsLinked to original sources
PubMed2006

Field evaluation of a rapid point-of-care assay for targeting antibiotic treatment for trachoma control: a comparative study.

BACKGROUND: Trachoma results from repeated episodes of conjunctival infection with Chlamydia trachomatis and is the leading infectious cause of blindness. To eliminate trachoma, control programmes use the SAFE strategy (Surgery, Antibiotics, Face cleanliness, and Environmental improvement). The A component is designed to treat C trachomatis infection, and is initiated on the basis of the prevalence of the clinical sign trachomatous inflammation-follicular (TF). Unfortunately, TF correlates poorly with C trachomatis infection. We sought to assess a newly developed point-of-care (POC) assay compared with presence of TF for guiding the use of antibiotics for trachoma control. METHODS: We compared performance outcomes of the POC assay and presence of TF using commercial PCR as a comparator in 664 children aged 1-9 years in remote, trachoma-endemic villages in Tanzania. Signs of trachoma were graded according to the WHO simplified trachoma grading system. FINDINGS: Of 664 participants, 128 (19%) were positive for ocular C trachomatis infection by PCR. Presence of TF had a sensitivity of 64.1% (95% CI 55.8-72.4), specificity of 80.2% (76.8-83.6), and positive predictive value of 43.6% (36.5-50.7). By contrast, the POC assay had a sensitivity of 83.6% (77.2-90.0), specificity of 99.4% (98.8-100.0), and positive predictive value of 97.3% (94.2-100.3). Interagreements and intra-agreements between four novice operators were 0.988 (0.973-1.000) and 0.950 (0.894-1.000), respectively. INTERPRETATION: The POC assay is substantially more accurate than TF prevalence in identifying the presence or absence of infection. Additional studies should assess the use of the assay in the planning and monitoring of trachoma control activities.

Anti-Bacterial Agents↗
PubMed2006

A coding polymorphism in matrix metalloproteinase 9 reduces risk of scarring sequelae of ocular Chlamydia trachomatis infection.

BACKGROUND: Trachoma, an infectious disease of the conjunctiva caused by Chlamydia trachomatis, is an important global cause of blindness. A dysregulated extracellular matrix (ECM) proteolysis during the processes of tissue repair following infection and inflammation are thought to play a key role in the development of fibrotic sequelae of infection, which ultimately leads to blindness. Expression and activity of matrix metalloproteinase 9 (MMP-9), a major effector of ECM turnover, is up-regulated in the inflamed conjunctiva of trachoma subjects. Genetic variation within the MMP9 gene affects in vitro MMP9 expression levels, enzymatic activity and susceptibility to various inflammatory and fibrotic conditions. METHODS: We genotyped 651 case-control pairs from trachoma endemic villages in The Gambia for coding single nucleotide polymorphisms (SNPs) in the MMP9 gene using the high-throughput Sequenom system. Single marker and haplotype conditional logistic regression (CLR) analysis for disease association was performed. RESULTS: The Q279R mutation located in exon 6 of MMP9 was found to be associated with lower risk for severe disease sequelae of ocular Chlamydia trachomatis infection. This mutation, which leads to a nonsynonymous amino-acid change within the active site of the enzyme may reduce MMP-9-induced degradation of the structural components of the ECM during inflammatory episodes in trachoma and its associated fibrosis. CONCLUSION: This work supports the hypothesis that MMP-9 has a role in the pathogenesis of blinding trachoma.

Case-Control Studies↗
PubMed2006

Conjunctival chlamydial 16S ribosomal RNA expression in trachoma: is chlamydial metabolic activity required for disease to develop?

BACKGROUND: Nucleic acid amplification testing frequently detects conjunctival Chlamydia trachomatis infection in subjects without clinical signs of trachoma. It is unclear whether such subjects are actually infected. We measured chlamydial 16S ribosomal RNA (rRNA) expression, a marker of chlamydial metabolic activity, in comparison with the quantitation of a chlamydial DNA target in subjects exposed to trachoma. METHODS: Subjects from 2 Gambian villages where trachoma was endemic were examined. Conjunctival samples were tested for the presence of C. trachomatis DNA using a quantitative real-time polymerase chain reaction (PCR) assay for the omp1 gene and for the expression of C. trachomatis 16S rRNA using a 1-step, real-time reverse-transcriptase PCR assay. RESULTS: A total of 248 people were examined. The prevalence of clinically active trachoma was 16.9%. C. trachomatis was detected in 19.8% and 6.8% of subjects by the omp1 and 16S rRNA assays, respectively. For subjects with positive results for both tests, the number of copies of 16S rRNA was approximately 100-fold greater than the number of copies of the omp1 gene. In samples from subjects in whom the omp1 gene was detected in the absence of 16S rRNA, typically only a few copies of omp1 were present. The expression of 16S rRNA was strongly associated with the presence of clinical signs of active trachoma. CONCLUSIONS: The use of 16S rRNA expression for the detection of chlamydial metabolic activity appears to usefully discriminate established infections from the inoculation of the conjunctiva with dead or subviable organisms, which probably occurs frequently in settings in which trachoma is endemic. The data support conclusions from primate challenge studies that live Chlamydiae species or antigens derived from them are needed to provoke the clinical signs of disease.

Adolescent↗
PubMed2006

The frequency of Chlamydia trachomatis major outer membrane protein-specific CD8+ T lymphocytes in active trachoma is associated with current ocular infection.

Chlamydia-specific cytotoxic T lymphocytes are able to control model infections but may be implicated in disease pathogenesis. HLA-A2 peptide tetramers to Chlamydia trachomatis major outer membrane protein 258-266 (MOMP258-266) and MOMP260-268 were used to characterize HLA class I-restricted CD8+ T cells in Gambian children aged 4 to 15 years with clinical signs of active trachoma and/or infection with C. trachomatis. The frequencies of circulating HLA-A2 tetramer binding cells (TBC) were determined in whole blood samples by flow cytometric analysis. Initial screening of subjects with an anti-HLA-A2 antibody confirmed the presence of either HLA-A2 or HLA-A28. These were subsequently further divided by molecular subtyping. The C. trachomatis-specific HLA-A2 peptide tetramers were able to bind T cells with receptors from subjects which were restricted by either the HLA-A2 or the HLA-A28 restriction element. In this population, the median value of C. trachomatis-specific CD8+ T cells was 0.02%, with frequencies of up to 3.71% of CD8+ T cells reactive with a single tetramer in a minority of subjects. TBC were detected more often in subjects who were infected at the ocular surface, and their presence was associated with infection episodes of longer duration. Detection of C. trachomatis-specific TBC was not associated with the presence of disease or with the estimated load of ocular C. trachomatis infection at the time of sample collection. High frequencies of C. trachomatis-specific cells did not predict subsequent appearance or resolution of the clinical disease signs of active trachoma.

Adolescent↗
PubMed2006

The long-term natural history of trachomatous trichiasis in the Gambia.

PURPOSE: Trachoma is the leading infectious cause of blindness. However, there are few data on the natural history of trachomatous trichiasis to guide program planning or that investigate its pathogenesis. METHODS: A cohort of Gambians with trichiasis in one or both eyes who had declined surgery was observed. Clinical examinations were performed at baseline and 4 years later. Conjunctival swab samples were collected for Chlamydia trachomatis PCR and bacteriology. RESULTS: One hundred fifty-four people were examined at baseline and 4 years later (241 nonsurgical eyes). At baseline 124 (52%) eyes had major trichiasis (5+ lashes), 75 (31%) minor trichiasis (1-4 lashes), and 42 (17%) no trichiasis. By 4 years, trichiasis had developed in 12 (29%) of 42 previously unaffected eyes. Minor trichiasis progressed to major in 28 (37%) of 75 eyes. New corneal opacification more commonly developed in eyes that had major (10%) compared to minor (5%) trichiasis at baseline. Bacterial infection was common (23%), becoming more frequent with increasing trichiasis. C. trachomatis infection was rare (1%). Conjunctival inflammation was common (29%) and was associated with progressive trichiasis and corneal opacification. CONCLUSIONS: Trichiasis progressed in the long-term in this environment, despite a low prevalence of C. trachomatis. Blinding corneal opacification develops infrequently, unless major trichiasis is present. Epilation and early surgery need to be formally compared for the management of minor trichiasis. The pathologic correlates and promoters of conjunctival inflammation need to be investigated.

Aged↗
PubMed2006

Conjunctival FOXP3 expression in trachoma: do regulatory T cells have a role in human ocular Chlamydia trachomatis infection?

BACKGROUND: Trachoma, caused by ocular infection with Chlamydia trachomatis, remains the leading infectious cause of blindness and in 2002 was responsible for 3.6% of total global blindness. Although transmission can be successfully interrupted using antibiotics and improvements in public and personal hygiene, the long-term success of the control programmes advocated by the World Health Organization are still uncertain. For the complete control and prevention of trachoma, a vaccine would be highly desirable. Currently there are no licensed vaccines for trachoma, and no human vaccine trials have been conducted since the 1960s. A barrier to new attempts to design and introduce a vaccine is the identification of immunologic correlates of protective immunity or immunopathology. We studied important correlates of the immune response in a trachoma-endemic population in order to improve our knowledge of this disease. This is essential for the successful development of a vaccine against both ocular and genital C. trachomatis infection. METHODS AND FINDINGS: We used quantitative real-time PCR for C. trachomatis 16S rRNA to identify conjunctival infection. The expression of IFN-gamma, IDO, IL-10, and FOXP3 mRNA transcripts was measured. We evaluated the role of immune effector and regulatory responses in the control of chlamydial infection and in the resolution of clinical signs of trachoma in endemic communities in Gambia. All host transcripts examined were detectable even in normal conjunctiva. The levels of these transcripts were increased, compared to normal uninfected conjunctiva, when infection was detected, with or without clinical disease signs. Interestingly, when clinical disease signs were present in the absence of infection, the expression of a regulatory T cell transcription factor, FOXP3, remained elevated. CONCLUSIONS: There is evidence of an increase in the magnitude of the local anti-chlamydial cytokine immune responses with age. This increase is coupled to a decline in the prevalence of infection and active trachoma, suggesting that effective adaptive immunity is acquired over a number of years. The anti-chlamydial and inflammatory immune response at the conjunctival surface, which may control chlamydial replication, is closely matched by counter inflammatory or regulatory IL-10 expression. Differences in the level of FOXP3 expression in the conjunctiva may indicate a role for regulatory T cells in the resolution of the conjunctival immune response, which is important in protection from immunopathology. However, the expression of cytokines that control chlamydial replication and those that regulate the conjunctival immune response is not simply juxtaposed; the interaction between the infection and the clinical disease process is therefore more complex.

Adolescent↗
PubMed2006

Operational evaluation of the use of photographs for grading active trachoma.

We evaluated the reliability of photographs to verify field diagnoses of active trachoma. We examined 956 residents of a trachoma-endemic village for signs of trachoma using the World Health Organization simplified grading system. Two photographs of the right eye of 948 persons were independently graded (masked to field assessment) by the field examiner and two other experienced graders. There was only moderate agreement between field assessment and the subsequent photographic evaluations by the three graders. When we counted ungradable photographs as disagreements, mean kappa scores for the signs trachomatous inflammation (follicular [TF]) and trachomatous inflammation (intense [TI]) were 0.44 and 0.51, respectively. There was also only fair-to-moderate agreement between the three assessments (by different examiners) of the photographs. Either the signs TF and TI themselves are not as reliable as previously believed, or photographs should be used for their diagnosis only when reliability testing demonstrates better agreement than found here.

Adolescent↗
PubMed2005

Infection with Chlamydia trachomatis after mass treatment of a trachoma hyperendemic community in Tanzania: a longitudinal study.

BACKGROUND: Data from studies done in communities where trachoma is mesoendemic suggest that ocular infection with Chlamydia trachomatis can be eliminated after one mass treatment with antibiotics. However, there are no comparable long-term data from trachoma hyperendemic communities. Our aim, therefore, was two-fold: first, to ascertain the disease pattern of trachoma and ocular infection with C trachomatis in a trachoma hyperendemic community after mass treatment; and, second, to ascertain the risk factors for incident infection. METHODS: We did a longitudinal study of a trachoma hyperendemic community (n=1017) in Tanzania. We did surveys, including ocular swabs, at baseline, 2, 6, 12, and 18 months to identify the presence, and quantity, of C trachomatis after single mass treatment of all individuals aged 6 months or older with azithromycin 20 mg per kg; pregnant women without clinical disease received topical tetracycline. FINDINGS: Mass treatment (coverage 86%) significantly reduced the prevalence of infection from 57% (495 of 871) to 12% (85 of 705) at 2 months. Infection remained fairly constant to 12 months, with evidence of increasing numbers and load of infection by 18 months post-treatment. Incident infection at 6 months was 3.5-times more likely if another member of the household had more than 19 organisms per swab at 2 months. Travel outside the village, and visitors to the household, did not increase the risk of infection within households up to 12 months. INTERPRETATION: In this trachoma hyperendemic community, infection levels after high antibiotic coverage persisted at a low level to 18 months, with evidence for re-emergence after 1 year. Fairly light loads of infection were associated with household transmission. Yearly mass treatment over a few years could be sufficient to eliminate infection.

Administration, Oral↗
PubMed2005

Acceptability of azithromycin for the control of trachoma in Northern Tanzania.

Trachoma causes blindness; the prevention strategy includes mass antibiotic treatment. In a community in Northern Tanzania offered mass treatment with azithromycin for the control of trachoma, we used focus group discussions, individual interviews, questionnaires and direct observation to quantify, explore and contextualize reasons for acceptance or refusal of the drug. In the village studied, 76% of the population eligible to receive azithromycin were treated. Uptake was significantly higher among women (79% treated) than men (72%). Factors affecting acceptability included: local prevention norms (such as the belief that injections, rather than oral medicine, should be used for prevention); perceptions of drugs in general and azithromycin in particular; perceptions of the distribution team's expertise; witnessing adverse effects in others; and the timing, quality and quantity of information about azithromycin and its availability. Familiarity with trachoma as a blinding disease was significantly associated with uptake. Individuals who refused treatment seemed to be less altruistic than other respondents. Neither socio-economic status nor use of traditional healers was related to uptake. Pre-distribution community assessment and community education, advance notice of the distribution, standardized distribution guidelines and improved distributor training are recommended to maximize acceptance of azithromycin in future campaigns.

Adult↗
PubMed2005

Impact of mass distribution of azithromycin on the antibiotic susceptibilities of ocular Chlamydia trachomatis.

In a community of Tanzania where trachoma is endemic, we cultured conjunctival swabs from all residents who had active trachoma and were PCR positive for ocular Chlamydia trachomatis, both before (43 isolates) and 2 months after (9 isolates) mass antibiotic treatment. No clinically or programmatically significant increase in azithromycin or tetracycline resistance was observed.

Azithromycin↗
PubMed2004

Mass treatment with single-dose azithromycin for trachoma.

BACKGROUND: Trachoma, caused by repeated ocular infection with Chlamydia trachomatis, is an important cause of blindness. Current recommended dosing intervals for mass azithromycin treatment for trachoma are based on a mathematical model. METHODS: We collected conjunctival swabs for quantitative polymerase-chain-reaction assay of C. trachomatis before and 2, 6, 12, 18, and 24 months after mass treatment with azithromycin in a Tanzanian community in which trachoma was endemic. For ethical reasons, at 6, 12, and 18 months, we gave tetracycline eye ointment to residents who had clinically active trachoma. RESULTS: At baseline, 956 of 978 residents (97.8 percent) received either one oral dose of azithromycin or (if azithromycin was contraindicated) a course of tetracycline eye ointment. The prevalence of infection fell from 9.5 percent before mass treatment to 2.1 percent at 2 months and 0.1 percent at 24 months. The quantitative burden of ocular C. trachomatis infection in the community was 13.9 percent of the pretreatment level at 2 months and 0.8 percent at 24 months. At each time point after baseline, over 90 percent of the total community burden of C. trachomatis infection was found among subjects who had been positive the previous time they were tested. CONCLUSIONS: The prevalence and intensity of infection fell dramatically and remained low for two years after treatment. One round of very-high-coverage mass treatment with azithromycin, perhaps aided by subsequent periodic use of tetracycline eye ointment for persons with active disease, can interrupt the transmission of ocular C. trachomatis infection.

Adolescent↗
PubMed2004

Diagnosis and assessment of trachoma.

Trachoma is caused by Chlamydia trachomatis. Clinical grading with the WHO simplified system can be highly repeatable provided graders are adequately trained and standardized. At the community level, rapid assessments are useful for confirming the absence of trachoma but do not determine the magnitude of the problem in communities where trachoma is present. New rapid assessment protocols incorporating techniques for obtaining representative population samples (without census preparation) may give better estimates of the prevalence of clinical trachoma. Clinical findings do not necessarily indicate the presence or absence of C. trachomatis infection, particularly as disease prevalence falls. The prevalence of ocular C. trachomatis infection (at the community level) is important because it is infection that is targeted when antibiotics are distributed in trachoma control campaigns. Methods to estimate infection prevalence are required. While culture is a sensitive test for the presence of viable organisms and nucleic acid amplification tests are sensitive and specific tools for the presence of chlamydial nucleic acids, the commercial assays presently available are all too expensive, too complex, or too unreliable for use in national programs. There is an urgent need for a rapid, reliable test for C. trachomatis to assist in measuring progress towards the elimination of trachoma.

Chlamydia Infections↗
PubMed2004

Cytokine and fibrogenic gene expression in the conjunctivas of subjects from a Gambian community where trachoma is endemic.

The role of immunity in blinding trachoma is unclear. Conjunctival gene expression was measured in a population where trachoma is endemic. Proinflammatory (tumor necrosis factor alpha and interleukin-1beta [IL-1beta]), anti-inflammatory (IL-10), and fibrogenic (matrix metalloprotease 9) gene expression was increased in active trachoma. Markers indicative of T-cell response (gamma interferon, IL-4, IL-12p40, and perforin) were increased when chlamydial infection was present.

Child↗
PubMed2003

Strategies for control of trachoma: observational study with quantitative PCR.

BACKGROUND: Antibiotics are an important part of WHO's strategy to eliminate trachoma as a blinding disease by 2020. At present, who needs to be treated is unclear. We aimed to establish the burden of ocular Chlamydia trachomatis in three trachoma-endemic communities in Tanzania and The Gambia with real-time quantitative PCR. METHODS: Conjunctival swabs were obtained at examination from 3146 individuals. Swabs were first tested by the qualitative Amplicor PCR, which is known to be highly sensitive. In positive samples, the number of copies of omp1 (a single-copy C trachomatis gene) was measured by quantitative PCR. FINDINGS: Children had the highest ocular loads of C trachomatis, although the amount of pooling in young age groups was less striking at the site with the lowest trachoma frequency. Individuals with intense inflammatory trachoma had higher loads than did those with other conjunctival signs. At the site with the highest prevalence of trachoma, 48 of 93 (52%) individuals with conjunctival scarring but no sign of active disease were positive for ocular chlamydiae. INTERPRETATION: Children younger than 10 years old, and those with intense inflammatory trachoma, probably represent the major source of ocular C trachomatis infection in endemic communities. Success of antibiotic distribution programmes could depend on these groups receiving effective treatment.

Adolescent↗
PubMed2003

Trachoma.

Trachoma is the most common infectious cause of blindness. It is caused by ocular serovars of Chlamydia trachomatis. Transmission is favoured in poor communities, where crowding is common and access to water and sanitation inadequate. Repeated reinfection over many years causes dense scarring of the upper eyelid. The resultant inversion of the lashes abrades the eyeball, and the abrasion leads to corneal opacification and visual impairment. The host immune response is probably at least partly the cause of this process. The "SAFE" strategy is used for the control of trachoma: surgery for in-turned lashes, antibiotics for active disease, facial cleanliness, and environmental improvement. The demonstration that a single oral dose of the antibiotic azithromycin is as effective as 6 weeks of topical tetracycline was an important advance in trachoma control. By means of the SAFE strategy, WHO and its partners aim to eliminate trachoma as a public-health problem by the year 2020.

Chlamydia trachomatis↗
PubMed2003

Impact of azithromycin administration for trachoma control on the carriage of antibiotic-resistant Streptococcus pneumoniae.

Community distribution of azithromycin has an important role to play in trachoma control. Previous studies have suggested that this may increase the prevalence of macrolide-resistant Streptococcus pneumoniae. S. pneumoniae was isolated from children under 7 years of age in Rombo District, northern Tanzania, before and 2 and 6 months after community-wide administration of azithromycin. Overall carriage rates were 11, 12, and 7%, respectively. Only one macrolide-resistant isolate carrying the mef gene was obtained 6 months after azithromycin administration. This contrasted with cotrimoxazole and penicillin resistance, both of which were common (cotrimoxazole resistance, 42, 43, and 47%, and penicillin resistance, 21, 17, and 16% at baseline, 2 months, and 6 months, respectively). There was a significant association between cotrimoxazole and penicillin resistance (P < 0.0001, Fisher's exact). These data suggest that in communities where macrolide resistance is rare, azithromycin distribution for trachoma control is unlikely to increase the prevalence of resistant organisms.

Anti-Bacterial Agents↗