Discussion and conclusions
GAS, also known as
S. pyogenes, is best known for causing mild infections such as pharyngitis and impetigo, but it can also cause serious infections such as bacteremia, cellulitis, necrotizing fasciitis, and streptococcal toxic shock syndrome [
6]. Invasive GAS (iGAS) disease is defined as the entry of GAS into usually sterile sites of the body [
6]. The morbidity and mortality of iGAS infection can be high, and in 2005 the World Health Organization reported 663,000 new iGAS cases with 163,000 iGAS-related deaths that year [
7]. Risk factors for iGAS diseases among adults include human immunodeficiency virus infection, cancer, heart disease, diabetes, lung disease, alcohol abuse, injection drug use, and pregnancy- related factors. Among children, varicella is a prominent risk factor [
8]. Nelson et al. reported that from 2005 to 2012, in patients of all ages with iGAS infections, frequencies of bacteremia, skin and soft tissue infections, and endocarditis or pericarditis in the United States were 24.9, 40.7, and 1.4%, respectively [
9]. Additionally, Plainvert et al. reported that between 2006 and 2010, in patients aged ≥18 years in France, rates of bacteremia, skin and soft tissue infections, and endocarditis were 25.4, 43.7, and 0.6%, respectively [
10].
Host genetic factors, such as human fibrinolytic protease plasmin, and various invasive factors including M protein, have been documented as contributing to iGAS diseases [
11]. M protein is a major surface protein and a critical virulence determinant, and plays a crucial role in adherence and resistance to opsonophagocytosis [
6]. Historically, GAS isolates were typed using serotype-specific antiserum raised against M protein. GAS strains are now more commonly categorized based on the
emm gene encoding M protein [
6]. A remarkable difference in the geographical distribution of
emm types has been reported, and the isolation frequency for
emm types from different GAS diseases parallels their rate of asymptomatic carriage in the same population [
12,
13]. Moreover, there are significant associations between some
emm types and disease severity. Examples include the association of
emm types 2, 4, 6, and 12 with superficial disease and
emm types 1 and 3 with invasive disease [
14]. Little is known, however, about the relation between IE and GAS
emm types. In several case reports,
emm types 1 and 3 were most commonly linked to invasive disease, but M protein nontypeable strains can also cause iGAS diseases [
15‐
17].
The M protein mainly plays three roles in iGAS disease: 1) adherence to the host cell, 2) resistance to host immune defense systems, and 3) gene regulation in response to environmental stress conditions [
1,
6]. Initial bacterial attachment is hypothesized to be a two-stage process, first involving lipoteichoic acid and surface proteins such as pili, followed by more specific, high-affinity binding including M proteins [
6]. M6 protein binds directly to ligands present on host cells [
6]. Additionally, M1, M3, and M6 proteins may promote bacterial colonization by binding directly to components of the extracellular matrix [
4,
6]. In resistance to host immune defense systems, M protein plays a crucial role in resistance to opsonophagocytosis. Streptococcal inhibitors of complement (SIC) produced by M1 and M57 strains also inhibit the binding of C5b67 complexes to cell membranes [
18]. Fibronectin-binding protein FbaA is encoded in the genome of GAS serotypes 1, 2, 4, 9, 13, 22, 28, 44, 49, 60, 67, 75, 77, 79, 80, 82, 87, and 89, and it inhibits C3 deposition on bacterial cells to promote survival in human blood [
19,
20]. Control of the two-component regulatory system
covRS is required for GAS survival under general environmental stress conditions. Spontaneous and unidirectional mutations within
covRS affect the expression of numerous virulence factors important for the initiation and progression of iGAS disease. The frequency of
covRS mutations in non-M1 T1 serotypes is lower than that in the M1 T1 strain, which may explain why non-M1 T1 serotypes are less frequently isolated from human invasive infections [
6,
11].
GAS is considered to be one of the less common etiologic organisms of IE. In pediatric IE,
S. aureus, viridans group streptococci, coagulase-negative staphylococci, and GAS comprise 57, 20, 14, and 3% of all cases, respectively [
4]. Additionally, IE occurs less often in children than in adults, accounting for approximately 1 in every 1300–2000 pediatric admissions annually [
4]. Risk factors include congenital heart diseases (CHD) and central indwelling venous catheters [
3]. Risk factors for mortality among patients without preexisting heart disease include premature/neonatal age and
S. aureus as an etiologic agent [
4]. Our patients had
emm types 6 and 4, both generally considered to be associated with more superficial diseases. Patient 1 (Case M in Table
1) was previously healthy with no known risk factors. She was found to have T6 M6 proteins. Patient 2 (Case N in Table
1) had a history of spontaneous closure of a ventricular septal defect and he was found to have T4 M4 proteins. Subsequent to the 2007 AHA guidelines for prevention of IE, patients with native unrepaired cardiac lesions such as VSD have been considered to be at low risk for IE [
21].
Table 1
Streptococcus pyogenes endocarditis and serotypes/emm types
| 1992 | 3 y, Female | Arnold-Chiari malformation, ventriculoperitoneal shunt, developmental delay | 12 | | |
| 2000 | 2 y 9 m, Male | | 12 | nontypeable | |
| 2013 | 60 y, Male | smoking, nonalcoholic steatohepatitis, left iliofemoral bypass | | |
44
|
| 2015 | 63 y, Male | | | |
12
|
| 2015 | 9 y, Female | VSDa repair at 7 y | 13 | | 90.2 |
| 2001 | 73 y, Female | Predisposing condition for IE | | | 77 |
| 2005 | 64 y, Male | | | | 82 |
| 2006 | 33 y, Male | Intravenous drug user | | | 82 |
| 2008 | 68 y, Female | | | | 87 |
| 2011 | 24 y, Male | Intravenous drug user | | | 66 |
| 2013 | 39 y, Male | Intravenous drug user, Prosthetic valve | | | 22 |
| 2013 | 51 y, Male | Intravenous drug user | | | 75 |
M [Patient 1] | 2016 | 14 y, Female | | 6 | 6 |
6.104
|
N [Patient 2] | 2015 | 1y 5 m, Male | VSDa (spontaneous closure at 5 m) | 4 | 4 |
4
|
Review of the literature
We searched PubMed and J-STAGE databases by using search terms “infective endocarditis and group A streptococcus or
Streptococcus pyogenes”. We found twelve case reports that contained detailed information and serotypes or
emm types (Table
1) [
22].
None of the strains isolated in these seven cases had M1 protein which is associated with a higher frequency of
covRS mutations than the non-M1 T1 strains. These serotypes are less commonly associated with iGAS diseases. M6 (Case M, Patient 1) is known to more readily adhere to host cells, and M4 (Case N, Patient 2) inhibits complement deposition, which may have contributed to the development of IE. T12 (Cases A and B) is found in more than 13
emm types, thus, it is difficult to discuss invasiveness according to T types [
23]. Case D was noted to have
emm12 which is generally associated with mild infection, but it has also been significantly found in nephritis-associated GAS serotypes including M1, M55 (Case L), and M57. These
emm types produce highly antigenic secretory proteins called SIC [
6]. In case C,
emm 44 was noted, which is also associated with mild infection. As previously noted, M44 strains produce FbaA, which inhibits complement deposition [
6]. Emm serotypes of Cases F, G, H, I, and K are also known to produce FbaA. Furthermore, Oppegard et al. reported to detect FbaA in Case J. In case E,
emm90 was noted. Fiona et al. described two cases of GAS necrotizing fasciitis caused by
emm90 strains from 1990 to 1998 in Australia [
24]. Guliz et al. reported 1428 isolates from Hawaii between 2000 and 2005 representing 21 different
emm types that were never reported in the continental United States during or before surveillance studies, including
emm90 strains [
25]. Additionally, Chen et al. identified 20 cases of iGAS diseases caused by
emm90 between 2005 to 2007 in Hawaii [
26]. They described that
emm90 strains appeared to be common after 2006 among iGAS disease-causing isolates. Therefore, with this many cases of iGAS being caused by
emm90 strains, the mechanism by which
emm90 strains cause invasive disease should be further elucidated.
Some categories of preexisting heart disease serve as risk factors for IE. Congenital heart diseases account for 80% of these cases, while previous rheumatic heart disease, prosthetic valves, and cardiomyopathies account for the majority of the rest [
4]. Tetralogy of Fallot is the most common congenital heart disease associated with IE (19.8%), followed by VSD (18%) [
4]. Corrective surgery for children with VSD, atrial septal defects, or patent ductus arteriosus with no residual defect is said to eliminate the attributable risk for endocarditis 6 months after surgery [
3]. Cases E and N should therefore be considered not to have had added risk factors for developing IE since their VSD’s had either been surgically corrected or had resolved spontaneously. Although the 2007 AHA antibiotic prophylaxis guidelines for the prevention of IE no longer consider native unrepaired cardiac lesions to be a high or moderate risk for IE, IE is known to occur in these patients [
21]. Knirsch et al. contend that IE should be considered a lifetime risk for non-operated, repaired, and palliated CHD, including VSD [
27]. We suspect that the GAS capsule, which inhibits complement deposition, quite possibly played a role in the development of IE in Patient 2.
In conclusion, GAS is a rare etiologic organism of IE, and there are few reports of GAS endocarditis with specific information on serotypes/emm types. In general, most serotypes/emm types associated with GAS typically cause only mild infection, but as this case report shows, GAS can be associated with serious invasive disease such as IE. A greater accumulation of cases is necessary to elucidate the association between serotypes/emm types and GAS IE.