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Title: Rheumatic fever and rheumatic heart disease : prevalence among Yemeni school children and studies of the immunopathogenesis of the disease
Author: Ba-Saddik, Iman Ali Mahmoud
ISNI:       0000 0004 2733 5513
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2012
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Background: The epidemiological, genetic and host immunogenetic association between Group A P haemolytic Streptococcal (GAS) pharyngotonsillitis and the subsequent development of Acute Rheumatic Fever (ARF) and Rheumatic Heart Disease (RHD) is an area of major interest. RHD still remains an important contributor to cardiovascular disease in children and adults in Yemen. Aims: The purpose of this study was to determine: (i) the prevalence ofRHD among primary school children in Aden City, Yemen, (ii) the prevalence of GAS and Non Group A β haemolytic Streptococcal (SNA) pharyngotonsillitis among patients attending primary health care centres, (iii) the distribution of emm genotypes and selected superantigen prophage exotoxin anasofgenes among GAS and SNA , (iv) the antimicrobial susceptibility pattern of GAS and SNA in patients with a history of ARF and RHD, (v) comparision of a profile of selected cytokines and chemokines between ARF and recurrent rheumatic fever (RRF) patients. Methods: A cross-sectional case-finding survey of RHD was conducted in 6000 school children aged 5 - 16 years in Aden City to determine the prevalence of RHD. A cross- sectional descriptive survey was undertaken in 730 children aged 1- 16 years with acute pharyngotonsillitis to determine the prevalence of GAS and SNA infections. Thirty four throat culture isolates from patients with GAS and SNA pharyngotonsillitis with history of ARF and echo-proven cases of RHD were analyzed by a multiplex PCR method to determine the emm genotypes, presence of superantigen prophage-associated virulence genes and so! genes. Antibiotic sensitivity tests were conducted on 24 GAS and SNA throat culture isolates using the BSAC disc diffusison method. Fourteen serum cytokine and chemokine concentrations including interleukin-Iβ (IL-lβ), interleukin-6 (IL-6), interleukin-7 (IL-7), interleukin-8 (IL-8), interleukin-9 (IL-9), interleukin-10 0 (IL-I0), interleukin-12p70 (IL-12p70), tumor necrosis factor (TNF-α), interferon gamma (IFN- γ), chemokines monocyte chemotactic protein-I (MCP-1), macrophage inflammatory protein-I a (MIP-1 a), macrophage inflammatory protein-I P (MIP-I P), human interferon inducable protein-I 0 (IP-IO) and regulated upon activation, normal T-cell expressed and secreted (RANTES) protein levels from children with ARF and RRF were analyzed by the BD F ACS Array Bioanalyzer using FCAP Array Software. Results: The prevalence of RHD was 36.5/1000 school children which is one of the highest reported among school echo cardiography surveys in the world. RHD had a high preponderance in 10-16 years old students. 49.8% had mitral regurgitation (MR) lesions, 26.6% had MR with mitral valve prolapse (MVP) and 17.8% with combined MR and aortic regurgitation (AR) lesions. RI--ID was diagnosed in more than one family member in 53 (24.2%) of the children. A high prevalence of GAS pharyngotonsillitis (41.5%) was noticed in children of 11 - 15 years of age. A red erythematous uvula and petechie on the soft palate were observed significantly more commoinlyin GAS pharyngotonsillitis. Group B (GBS), Group C (GCS) and Group Gβ haemolytic streptococci (GGS) were isolated from pharyngotonsillitis in 4.3% patients with history of ARF/RHD. The most frequent GAS isolates among ARF and RI-ID patients with pharyngotonsillitis were emm87, emm12, emm28 and emm5. This is the first report of emm87 and emm28 genotypes to be potentially rheumatogenic. The 11 emm87 GAS isolates shared a common PFGE pattern and profile of five exotoxin prophage genes spec, spdl, sdn, sUC and silD with the sof 87 sequence. emm12 and emm28 GAS strains were positive for gene sof , spec and spd1. This is the first report to describe the pattern of exotoxin prophage genes of spec, spd1, sdn, silC and silD among emm87,-emm12, emm28 and emm5 GAS and SNA (GBS, GCS and GGS) isolates with history of ARF and RHD. The genotypic characteristics of GBS, GCS and GGS isolates confirmed seven new emm sequence types first detected among children with acute pharyngotonsillitis. GAS and SNA isolates were susceptible to the β-lactam antimicrobials, penicillin and amoxicillin. Erythromycin resistance was detected in so! positive emm 12 and emm28 in 50% and 33% of isolates respectively. Chemokine MCP-l was significantly correlated with cytokines, IL-lβ, IL-6, IL-l0, IL- 12p70, TNF-α, IFN-γ and RANTES in patients with RRF. This suggests that MCP-l could serve as a potential inflammatorybiomarker for patients with RRF having underlying RHD. MIP-1~ had significant correlations with IL-8, IL-lO, IL-12p70, IP- 10, TNF-α and IFN-γ in patients with ARF. MIP-l~ may serve as a potential inflammatory biomarker in patients with ARF without RHD. Conclusions: The high prevalence of RHD is an alarming public health problem in Yemen. Urgent screening surveys and a preventive RHD prophylactic program with appropriate management of GAS pharyngotonsillitis are required. Future studies are needed to confirm the rheumatogenic GAS and SNA strains with their exotoxin prohage genes and the role of the chemokines and cytokines as biomarkers for ARF within the complex network of auto immune reactions in RF/RHD. This study hopes to provide a further small step in elucidating the pathogenesis of this complex immunological disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral