Priming the immune system for heart disease: a perspective on group A streptococci.

Although immune responses against group A streptococci and the heart have been correlated with antibodies and T cell responses against cardiac myosin, there is no unifying hypothesis about carditis caused globally by many different serotypes. Our study identified disease-specific epitopes of human cardiac myosin in the development of rheumatic carditis in humans. We found that immune responses to cardiac myosin were similar in rheumatic carditis among a small sample of worldwide populations, in which immunoglobulin G targeted human cardiac myosin epitopes in the S2 subfragment hinge region within S2 peptides containing amino acid residues 842-992 and 1164-1272. An analysis of rheumatic carditis in a Pacific Islander family confirmed the presence of potential rheumatogenic epitopes in the S2 region of human cardiac myosin. Our report suggests that cardiac myosin epitopes in rheumatic carditis target the S2 region of cardiac myosin and are similar among populations with rheumatic carditis worldwide, regardless of the infecting group A streptococcal M serotype.

Comprehensive analysis of antibody responses to streptococcal and tissue antigens in patients with acute rheumatic fever.

Acute rheumatic fever (ARF) is an autoimmune disease occurring in individuals following untreated group A streptococcal infection believed to be triggered by antibodies to bacterial components that cross-react with human tissues. We developed a multiplexed immunoassay for the simultaneous quantitation of antibodies to nine streptococcal-related antigens including streptolysin O (SLO), DNase B, collagen I and IV, fibronectin, myosin, group A carbohydrate, M6 protein and streptococcal C5a peptidase. Utilizing this method, we examined serum from 49 ARF, 58 pharyngitis patients and age- and sex-matched controls in samples collected at initial disease onset, and at 4 weeks, 6 months and 1 year after diagnosis. Antibody responses were significantly higher for SLO, DNase B, M6 protein, group A carbohydrate and the cross-reactive antigens collagen I and myosin in ARF compared with pharyngitis patients (P

The logic for extending the use of echocardiography beyond childhood to detect subclinical rheumatic heart disease.

Rheumatic heart disease is the only residual morbidity, and the sole cause of mortality, from rheumatic fever. Echocardiography is ideally suited to confirm and follow the course of rheumatic heart disease. Additionally, both minimal valvar pathology in children, and extensive valvar pathology in adults, may not cause a murmur and can be detected only by echocardiography. Whenever possible, echocardiography should be routinely employed for management of patients with rheumatic fever or suspected rheumatic fever.

Rheumatic chorea: relationship to systemic manifestations and response to corticosteroids.

OBJECTIVE: To describe Sydenham chorea among children in a cohort of patients with rheumatic fever (RF). STUDY DESIGN: An existing database was used to identify demographic characteristics, clinical manifestations, and therapy in persons with RF identified in Salt Lake City, Utah, from 1985 through January 2002. RESULTS: Of 584 cases in the database, 537 (91%) were new-onset RF (median age of 10 years) and 177 (33%) had chorea. Patients with chorea were more often female (OR = 0.37, 95% CI = 0.25-0.55, P < .0001) and were less likely to have carditis or arthritis. Prednisone treatment may lead to a shortened course of chorea (4.0 weeks in prednisone-treated [n = 32] vs 9.0 weeks in untreated [n = 14]; P < .0001). Among 33 patients seen at a median of 10.3 years (range 6.3-14.9 years) after their initial bout of chorea, 20% reported residual tremor or mood swings. Ten of the 33 (30%) had one or more recurrences of chorea. CONCLUSIONS: Chorea affected one-third of the children with RF. Patients with chorea were less likely to have severe cardiac or rheumatologic complications of RF. Therapy with prednisone shortened the duration of rheumatic chorea; some reported recurrences of chorea and had minor neurologic sequelae.

Single ventricle palliation: greater risk of complications with the Fontan procedure than with the bidirectional Glenn procedure alone.

BACKGROUND: This study was performed to evaluate and compare the early, intermediate, and long-term outcomes of the bidirectional Glenn procedure and Fontan procedure in patients who live at moderately high altitude. METHODS: The outcome of each method of palliation for patients with a functionally single ventricle was retrospectively evaluated from a review of medical records. RESULTS: The bidirectional Glenn procedure was performed in 177 patients from October 1984 to June 2004. The Fontan procedure was performed in 149 patients from June 1978 to June 2004. Cardiovascular death or heart transplantation occurred in 8% of patients after the bidirectional Glenn procedure and 17% of patients after the Fontan procedure. Complications of systemic thromboembolic events, bleeding associated with anticoagulation therapy, protein losing enteropathy, and arrhythmias requiring implantation of a pacemaker, cardioversion, or radiofrequency ablation occurred in 7% of patients after the bidirectional Glenn procedure and 47% of patients after the Fontan procedure. Cardiovascular deaths and heart transplantation occurred less frequently when the Fontan procedure was performed in patients with a previous bidirectional Glenn procedure. However, the actuarial transplant-free survival and freedom from complications was not superior for a subgroup of patients who had a Fontan procedure after a bidirectional Glenn procedure in comparison to a subgroup of patients who had a bidirectional Glenn procedure alone. CONCLUSIONS: The bidirectional Glenn procedure can be used for long-term palliation of patients with a functionally single ventricle. Additional palliation with a Fontan procedure may increase the risk of stroke, protein losing enteropathy and arrhythmias without improving survival.

Molecular characterization of Streptococcus pyogenes isolates collected during periods of increased acute rheumatic fever activity in Utah.

BACKGROUND: Salt Lake City, Utah has seen a continuing resurgence of rheumatic fever (RF) since 1985. METHODS: emm genotyping and multilocus sequence typing of streptococcal isolates from periods of increased RF activity were performed. RESULTS: Multiple genotypes were present during 1985 and 1998, two peak years of RF activity, and in 1992, a year with reduced RF activity. emm3 and emm18.1 were present in 1985 and 1998, but not in 1992. Two other emm types, 12 and L28, were significantly elevated in 1998 (a peak RF year) over 1992 (a non-peak RF year). Allelic profiles for the emm3 and emm18.1 isolates exhibited clonality. CONCLUSIONS: During years of increased RF activity multiple emm types, including emm18.1 and emm3, were circulating in the community. During a year of decreased RF activity, emm3 and emm18.1 genotypes were absent. The clonality of the emm3 and emm18.1 types suggests that specific clones of both types are important in the resurgence of RF during these peak years. Two other genotypes, emm12 and emmL28, may also be associated with the persistence of RF in the Salt Lake City, UT area.

Current results with intraaortic balloon pumping in infants and children.

BACKGROUND: Intraaortic balloon pumping (IABP) is useful for support in patients with moderate left ventricular dysfunction. IABP is usually timed with the R wave of the electrocardiogram. We have utilized M-mode echocardiography timed IABP in children with left-side heart failure since 1994. Electrocardiogram timing seems inappropriate for children, who have much higher heart rates. We describe our experience with children who underwent IABP therapy before and after 1994, when echocardiographic timing was instituted. METHODS: We reviewed records of 29 children who underwent IABP for all indications at Primary Children's Medical Center since 1988. RESULTS: Overall survival was 62.1% (18 of 29) in this series. Survival was similar for infants (odds ratio = 2.0, 95% confidence interval = 0.29 to 14.31, p = 0.43) and older children. Survival was similar in the echocardiography era when compared with the electrocardiogram era (odds ratio = 2.4, 95% confidence interval = 0.56 to 10.4, p = 0.44). CONCLUSIONS: IABP is a useful means of support in children with left ventricular dysfunction. M-mode echocardiography is effective in triggering IABP. The sample size in this study is too small to detect a mortality rate difference.

Rheumatic fever in children younger than 5 years: is the presentation different?

OBJECTIVE: To review our experience with children who presented with rheumatic fever (RF) before 5 years of age and to compare their presentation with that of older children. METHODS: The cardiology database was reviewed to identify patients who were younger than 5 years and had a diagnosis RF using the Jones criteria from January 1985 through March 2000. Patient age, sex, date and age at presentation, and the major Jones criteria fulfilled were noted. When carditis was present, its severity was judged to be moderate to severe when there was radiographic cardiomegaly and/or clinical congestive heart failure. The clinical presentation of patients who presented in the first 5 years of life were compared with the presentation of those whose RF was diagnosed after 5 years of age. Clinical findings at follow-up evaluation and echocardiographic findings both at presentation and at follow-up were noted for the children who were younger than 5 years at presentation. RESULTS: Of 541 cases of RF seen from January 1985 through March 20000, 27 (5%) were in children who were younger than 5 years (median: 4.0 years; range: 1.9-4.9 years). Major Jones criteria at presentation were arthritis in 17, carditis in 14, chorea in 3, and erythema marginatum in 3. The carditis was mild in 4 and moderate to severe in 10 patients. Compared with older children, younger children were more likely to present with moderate to severe carditis, arthritis without carditis or chorea, or the rash of erythema marginatum and were less likely to have chorea. The incidence of carditis was similar in the 2 groups as was the ratio of boys to girls. At follow-up (9.6 +/- 5.6 years), 69% of younger children who presented with carditis have clinical rheumatic heart disease. Subclinical, echocardiographically detected valvular abnormalities were detected both at presentation (33% of all children with RF before 5 years of age) and at follow-up (55% of those who initially had carditis). CONCLUSIONS: Approximately 5% of children with RF were younger than 5 years at diagnosis. Compared with older patients, children who presented before 5 years of age were more likely to have moderate to severe carditis and to present with arthritis or the rash of erythema marginatum and were less likely to have chorea. Chronic rheumatic heart disease was common in young children who presented with carditis. Long-term follow-up is necessary to determine the outcome for young children with subclinical echocardiographic evidence of valvular disease.

Molecular analysis of group A Streptococcus type emm18 isolates temporally associated with acute rheumatic fever outbreaks in Salt Lake City, Utah.

Acute rheumatic fever (ARF) and subsequent rheumatic heart disease are rare but serious sequelae of group A Streptococcus (GAS) infections in most western countries. Salt Lake City (SLC), Utah, and the surrounding intermountain region experienced a resurgence of ARF in 1985 which has persisted. The largest numbers of cases were encountered in 1985-1986 and in 1997-1998. Organisms with a mucoid colony phenotype when grown on blood agar plates were temporally associated with the higher incidence of ARF. To develop an understanding of the molecular population genetic structure of GAS strains associated with ARF in the SLC region, 964 mucoid and nonmucoid pharyngeal isolates recovered in SLC from 1984 to 1999 were studied by sequencing the emm gene. Isolates with an emm18 allele were further characterized by sequencing the spa, covR, and covS genes. Peak periods of ARF were associated with GAS isolates possessing an emm18 allele encoding the protein found in serotype M18 isolates. Among the serotype M18 isolates, the difference in the number of C repeats produced three size variants. Variation was limited in spa, a gene that encodes a streptococcal protective antigen, and covR and covS, genes that encode a two-component regulatory system that, when inactivated, results in a mucoid phenotype and enhanced virulence in mouse infection models. Pulsed-field gel electrophoresis showed a single restriction profile for serotype M18 organisms isolated during both peak periods of ARF. In SLC, the incidence of ARF coresurged with the occurrence of GAS serotype M18 isolates that have very restricted genetic variation.

Evidence for lack of myocardial injury in children with acute rheumatic carditis.

Despite pathologic evidence of myocardial inflammation, the significance of myocarditis in children with acute rheumatic carditis remains controversial. Elevations in cardiac troponin I have been demonstrated in other forms of myocarditis. The purpose of our study was to determine if levels of cardiac troponin I are elevated, suggesting myocardial injury, in patients with acute rheumatic carditis. We identified all those patients with acute rheumatic fever, presenting between July 1998 and December 2000, who had clinical evidence of carditis, such as a new murmur of mitral or aortic regurgitation, and who had an echocardiogram, measurements of levels of cardiac troponin I, erythrocyte sedimentation rate, and/or C-reactive protein performed at the time of presentation. Their charts were reviewed for demographic and clinical data. Echocardiograms were reviewed for severity of aortic and mitral regurgitation, and measurements made of left ventricular ejection fraction, fractional shortening, and end-diastolic dimension. We found 16 patients with acute rheumatic carditis, ranging in age from 2.0 to 16.1 years, with just over one-third having symptoms of congestive heart failure. All patients had evidence of acute inflammation. There was a significant relationship between symptoms and severity of mitral regurgitation. No patient had elevated levels of cardiac troponin I level. The fact that levels of cardiac troponin I are not elevated in the serum of children with acute rheumatic carditis suggests that there is minimal myocytic necrosis in this setting. This supports the concept that acute valvar regurgitation is the major hemodynamic abnormality in these patients.

Temporal association of the appearance of mucoid strains of Streptococcus pyogenes with a continuing high incidence of rheumatic fever in Utah.

OBJECTIVE: Our objective was to confirm an observed temporal association of increased numbers of rheumatic fever cases concomitant with the appearance of an increased prevalence of mucoid strains of Streptococcus pyogenes. During the resurgence of rheumatic fever (RF) that has occurred in the Intermountain area surrounding Salt Lake City, Utah, since 1985, the largest number of cases occurred in 1985 and 1986 and 12 years later in 1997 and 1998. During the initial outbreak and the later exacerbation of the resurgence, an increased number of mucoid strains of S pyogenes were present in the community. METHODS: The referred cases of RF that fulfilled Jones criteria have been systematically reviewed by the medical staff at Primary Children's Medical Center yearly since 1985. Before the resurgence of RF, a program was initiated by the microbiology laboratory at Primary Children's Medical Center to store frozen isolates of S pyogenes. All frozen specimens were randomly selected and entered into a log; the coded entry allowed for comments regarding the origin of the isolate and whether the isolate had a mucoid appearance on the blood agar culture plate. This log was reviewed in October 2002 to determine whether the percentage of frozen mucoid isolates stored during the resurgence of RF would support the clinical and epidemiologic suspicion that mucoid isolates seemed to be present with a higher frequency during the 2 periods of high incidence of RF. The percentage of mucoid isolates was compared with the yearly number of cases of RF. A Pearson r correlation analysis was completed to determine whether there was a significant association between the percentage of mucoid isolates and the number of cases of RF. RESULTS: The highest number of cases of RF was temporally associated with the highest percentage of mucoid isolates. There was statistically significant correlation between percentage of mucoid strains and the number of RF cases. CONCLUSIONS: The Utah experience with the resurgence of RF in a civilian population during the last decade and a half of the 20th century confirmed the temporal association of mucoid strains of S pyogenes, primarily M-type 18, with a high incidence of RF.

Current status of surgery for rheumatic carditis in children.

BACKGROUND: The incidence of rheumatic heart disease (RHD) has increased recently in the western United States. We reviewed our 18-year surgical experience with RHD in children to examine current surgical techniques and results. METHODS: From 1985 until 2003, 596 children (<21 years) with rheumatic fever were seen at Primary Children's Medical Center. Rheumatic carditis was diagnosed in 366 patients (61.4%). Twenty-six with carditis (26/366, 7.1%) required operation for rheumatic valve disease including 8 for mitral regurgitation, 7 for mitral and aortic regurgitation, 4 for aortic regurgitation, 4 for mitral regurgitation and stenosis, 2 for combined mitral stenosis and regurgitation with aortic insufficiency, and 1 for mitral and tricuspid regurgitation. RESULTS: Mean age at operation was 13.5 +/- 4 years. Three patients required operation during the acute phase of rheumatic fever (< 6 weeks), 2 during the subacute phase (< 6 months), and 21 during the chronic phase after the episode of rheumatic fever (6.7 +/- 3 years). Mitral valve repair was possible in 19 of 22 patients who required mitral operation. Aortic valve repair was possible in 4 patients whereas replacement was necessary in 9, including 2 Ross procedures. No operative deaths were recorded and 2 late deaths occurred at 4.6 and 10 years. Actuarial survival was 94% at 5 years and 78% at 10 years. Six patients required reoperation; actuarial freedom from reoperation was 78% at 5 years, 65% at 10 years, and 49% at 15 years. All survivors are in New York Heart Association class I or II. CONCLUSIONS: Children with RHD in the United States uncommonly require valve operation. Mitral repair with a technique that allows annular growth is possible in most children with good long-term functional results. Long-term surveillance of children with RHD is necessary because of the possible need for late valve operation.

D8/17 and CD19 expression on lymphocytes of patients with acute rheumatic fever and Tourette's disorder.

D8/17, an alloantigen found on B lymphocytes, has been reported to be elevated in patients susceptible to rheumatic fever and may be associated with autoimmune types of neuropsychiatric disorders. The pediatric-autoimmune-neuropsychiatric-disorders-associated-with-streptococci model is a putative model of pathogenesis for a group of children whose symptoms of obsessive-compulsive disorder and Tourette's disorder (TD) are abrupt and may be triggered by an infection with group A streptococci. As a test of this model, we have examined D8/17 levels on the B cells of patients with TD and acute rheumatic fever (ARF) along with those on the B cells of normal controls by flow cytometry. We have utilized several different preparations of D8/17 antibody along with a variety of secondary antibodies but have been unable to show an association with an elevated percentage of D8/17-positive, CD19-positive B cells in either ARF or TD. We did find, however, that the percentages of CD19-positive B cells in ARF and TD patients were significantly elevated compared to those in normal controls. Group A streptococcal pharyngitis patients also had an elevated percentage of CD19 B cells, however. These studies failed to confirm the utility of determining the percentage of B cells expressing the D8/17 alloantigen in ARF patients or our sample of TD patients. In contrast, the percentage of CD19-positive B cells was significantly elevated in ARF and TD patients, as well as group A streptococcal pharyngitis patients, suggesting a role for inflammation and/or autoimmunity in the pathogenesis of these disorders.

Characterization of two novel pyrogenic toxin superantigens made by an acute rheumatic fever clone of Streptococcus pyogenes associated with multiple disease outbreaks.

The pathogenesis of acute rheumatic fever (ARF) is poorly understood. We identified two contiguous bacteriophage genes, designated speL and speM, encoding novel inferred superantigens in the genome sequence of an ARF strain of serotype M18 group A streptococcus (GAS). speL and speM were located at the same genomic site in 33 serotype M18 isolates, and no nucleotide sequence diversity was observed in the 33 strains analyzed. Furthermore, the genes were absent in 13 non-M18 strains tested. These data indicate a recent acquisition event by a distinct clone of serotype M18 GAS. speL and speM were transcribed in vitro and upregulated in the exponential phase of growth. Purified SpeL and SpeM were pyrogenic and mitogenic for rabbit splenocytes and human peripheral blood mononuclear cells in picogram amounts. SpeL preferentially expanded human T cells expressing T-cell receptors Vbeta1, Vbeta5.1, and Vbeta23, and SpeM had specificity for Vbeta1 and Vbeta23 subsets, indicating that both proteins had superantigen activity. SpeL was lethal in two animal models of streptococcal toxic shock, and SpeM was lethal in one model. Serologic studies indicated that ARF patients were exposed to serotype M18 GAS, SpeL, and SpeM. The data demonstrate that SpeL and SpeM are pyrogenic toxin superantigens and suggest that they may participate in the host-pathogen interactions in some ARF patients.

Genome sequence and comparative microarray analysis of serotype M18 group A Streptococcus strains associated with acute rheumatic fever outbreaks.

Acute rheumatic fever (ARF), a sequelae of group A Streptococcus (GAS) infection, is the most common cause of preventable childhood heart disease worldwide. The molecular basis of ARF and the subsequent rheumatic heart disease are poorly understood. Serotype M18 GAS strains have been associated for decades with ARF outbreaks in the U.S. As a first step toward gaining new insight into ARF pathogenesis, we sequenced the genome of strain MGAS8232, a serotype M18 organism isolated from a patient with ARF. The genome is a circular chromosome of 1,895,017 bp, and it shares 1.7 Mb of closely related genetic material with strain SF370 (a sequenced serotype M1 strain). Strain MGAS8232 has 178 ORFs absent in SF370. Phages, phage-like elements, and insertion sequences are the major sources of variation between the genomes. The genomes of strain MGAS8232 and SF370 encode many of the same proven or putative virulence factors. Importantly, strain MGAS8232 has genes encoding many additional secreted proteins involved in human-GAS interactions, including streptococcal pyrogenic exotoxin A (scarlet fever toxin) and two uncharacterized pyrogenic exotoxin homologues, all phage-associated. DNA microarray analysis of 36 serotype M18 strains from diverse localities showed that most regions of variation were phages or phage-like elements. Two epidemics of ARF occurring 12 years apart in Salt Lake City, UT, were caused by serotype M18 strains that were genetically identical, or nearly so. Our analysis provides a critical foundation for accelerated research into ARF pathogenesis and a molecular framework to study the plasticity of GAS genomes.