The organism group A beta-hemolytic streptococcus (streptococcus pyogenes), attach the epithelial cells of the upper respiratory tract and produce battery of enzymes, allowing them to damage and invade human tissues. Only infections of the pharynx have been shown to initiate or reactivate rheumatic fever in 0.3% - 3% of cases. However, epidemiological association in certain population have shown that group A streptococcus impetigo could predispose to or cause rheumatic fever as well [18] . Streptococcal proteins display molecular mimicry recognized by the immune system, especially bacterial M-proteins and human cardiac antigens such as myosin [19] and valvular endothelium. Currently emm typing is felt to be more discriminating than M typing [20] . Antimyosin antibody recognizes laminin, an extracellular matrix alpha-helix coiled protein, which is part of the valve basement membrane structure. T-cells that are responsive to the streptococcal M-protein infiltrate the valve through the valvular endothelium, activated by the binding of anti-streptococcal carbohydrate with the release of tumor necrosis factor (TNF) and interleukins [21] . Thus, cross-reactive antibodies bind to cardiac tissue, facilitate infiltration of streptococcal-primed CD4+T cells, which then triggers an autoimmune reaction and releasing inflammatory cytokines (TNF-α and IFN-gamma). Because few IL-4 producing cells are present in valvular tissue, inflammation persists, leading to valvular lesion. A study reported that the increased expression of Th 17 cell-associated cytokines might play an important role in the pathogenesis and development of rheumatic heart disease [22] . In chronic disease, there is thickening and fibrosis of the valve resulting in stenosis, or less commonly regurgitation.

In utero precursors predisposing to rheumatic heart disease have also been proposed [23] [24] . Eriksson et al. suggest increased spiraling of the umbilical cord may increase the risk of rheumatic heart disease secondary to presumed changes in hemodynamic conditions during the formation of the mitral valve [25] .

Familial studies of rheumatic heart disease suggest a vulnerable population with increased risk of having relationship between the development of rheumatic fever and human leukocyte antigens (HLA)-DR subtypes have been found [26] . HL-DR3 was present more frequently in rheumatic fever patients in India, DR-1 in South Africa, DR-2 in African-American population, DR-4 in Cauccasian and DQW2 in Asian Patients.

To find a solution to outbreaks of group A streptococcal (GAS) sore throat, a probiotic treatment was developed at Otago University. The BLIS K 12 probiotic specific to the throat and mouth, sold as “BLIS throat guard” was trialled in selected primary schools in Whakatane and Kawerau where the rheumatic fever has been an increasing problem and a school sore throat rheumatic fever programme has been running since 2010. The term antibiotics points to treatments which kill the microbes and the term probiotic refers to being “in support of life” as the mechanism supports the re-setting of the microbial biome, through growing beneficial microbes. BLIS K 12 populate the mouth and throat with a beneficial strains of streptococcus salivarius. When antibiotics were followed by taking the BLIS K 12 probiotic lozenges daily for 30 days, encouraging results were seen in school children with clearance of streptococcal infection from the throat up to 3 months [27] .

Efforts to produce a vaccine against streptococcus pyogenes began several decades ago, and different models have been proposed as M-protein based vaccines (N-and C-terminal portion), the major antigen of streptococcus pyogenes, the non-M protein based vaccine and other potential GAS vaccines such as Spe (streptococcal pyrogenic exotoxin) A and C.

StreptAvax is a M-protein based, multivalent type-specific vaccine, consists of a sequence of short peptides from the N terminal region of multiple different emm type strains in tandem, linked together using unique restriction sites. It may not produce sufficient and long-lasting protection in countries with highly endemic GAS diseases.

Streptlncor, a vaccine candidate peptide, comprising 55 aminoacid residues of the C-terminal portion of the M protein and encompassing both the T-and B-cell protective epitopes. Streptlncor overlapping peptides induced cellular and humoral immune responses of individuals bearing different HLA class II molecules of the macrophage to T lymphocytes via the T-cell receptor (TCR) and it could be considered as an immunogenic and safe vaccine. The safety of this vaccine was assessed using DR2, DR4, DQ6 and DQ 8 HLA class II transgenic mice.

StreptAnova^(R) multivalent vaccine is composed of four recombinant proteins containing protective peptides from 30 streptococcal serotypes that account for the vast majority of infections in North America and Europe. Phase I trial is ongoing as 3 injections over 6 months, with a one-year follow-up to assess the immune response to the vaccine [28] .

It is universally accepted that the most cost-effective approach to RHD (Rheumatic heart disease) control is delivery of secondary prophylaxis and improved clinical care of patients, using register-based RHD control programs as in New Zealand and Australia. An implantable form of penicillin could be a major advance. Naltrexone penicillin implants provide a promising model, given that the equivalent daily dose is similar to what would be required for penicillin [29] . Genetic studies to identify the nature of host susceptibility to detect the vulnerable groups and development of vaccine, screening echocardiography to detect subclinical carditis and to implement secondary prophylaxis are the priority measures in endemic areas.

Early medical therapy with statins in patients with rheumatic heart disease showed a significantly slower progression of the disease as found in a recent study done in Europe on 315 patients with rheumatic mitral stenosis in 2010 [30] and reducing LDL-C (low-density lipoprotein cholesterol) may help to prevent aortic valve disease [31] as found by Smith et al. in 2014.