Pediatrician's approach to diagnosis and management of group A streptococcal pharyngitis.

Group A streptococcal (GAS) pharyngitis is responsible for 20-30% of pharyngitis cases in children (Shulman et al. Clin Infect Dis 55(10):e86-e102, 2012). Recommendations for the diagnosis and treatment of GAS pharyngitis have been published by the Italian National Institute of Health guidelines in 2012 (ESCMID Sore Throat Guideline Group et al. Clin Microbiol Infect 18(Suppl 1):1-28, 2012). Adherence to such guidance is relevant for primary prevention of complications of GAS pharyngitis, above all rheumatic fever (RF). The aim of our study was to evaluate the application of Italian guidelines by the family pediatricians from the Abruzzo region. A validated questionnaire was completed by the family pediatricians and used for data collection. The 154 family pediatricians from Abruzzo (88% of the total number of family pediatricians) participated in the study. Out of the 1232 answers, 455 (37%) were wrong. Only 8% of the participants answered correctly all the questions, whereas 0.6% missed all the questions. Through the Spearman's correlation, our study found an inverse significant correlation between the questions regarding primary prophylaxis (Score B) and the work experience of pediatricians (Rho = - 0.276, p = 0.048). The majority of the family pediatricians from the Abruzzo region, in line with studies from other countries, have significant knowledge gaps about the diagnosis and treatment of GAS pharyngitis. Therefore, strategies to increase the pediatricians' awareness of the guidelines are needed, in order to reduce the RF incidence.

A population pharmacokinetic study of benzathine benzylpenicillin G administration in children and adolescents with rheumatic heart disease: new insights for improved secondary prophylaxis strategies.

BACKGROUND: Benzathine benzylpenicillin G (BPG) is recommended as secondary prophylaxis to prevent recurrence of acute rheumatic fever and subsequent rheumatic heart disease (RHD). Following intramuscular injection, BPG is hydrolysed to benzylpenicillin. Little is known of the pharmacokinetics of benzylpenicillin following BPG in populations at risk of RHD. METHODS: We conducted a longitudinal pharmacokinetic study of children and adolescents receiving secondary prophylaxis throughout six monthly cycles of BPG. Dried blood spot samples were assayed with LC-MS/MS. Benzylpenicillin concentrations were analysed using non-linear mixed-effects modelling with subsequent simulations based on published BMI-for-age and weight-for-age data. RESULTS: Eighteen participants contributed 256 concentrations for analysis. None had benzylpenicillin concentrations >0.02 mg/L for the full time between doses. The median duration above this target was 9.8 days for those with a lower BMI (<25 kg/m2), who also had lower weights, and 0 days for those with a higher BMI (≥25 kg/m2). Although fat-free mass was a key determinant of benzylpenicillin exposure after a standard dose of BPG, having a higher BMI influenced absorption and almost doubled (increase of 86%) the observed t½. CONCLUSIONS: Few children and adolescents receiving BPG as secondary prophylaxis will achieve concentrations >0.02 mg/L for the majority of the time between injections. The discordance of this observation with reported efficacy of BPG to prevent rheumatic fever implies a major knowledge gap relating to pharmacokinetic/pharmacodynamic relationships between benzylpenicillin exposure and clinical outcomes.

Sydenham's Chorea.

BACKGROUND: Sydenham's chorea is the most common acquired movement disorder of adolescence. This clinical manifestation of acute rheumatic fever has a clear and documented relationship with Group A streptococcal infections. The symptoms are involuntary choreiform movements that can affect the face and all extremities. The pathophysiology remains unclear. CASE REPORT: A 12-year-old female was brought to the emergency department with a 2-week history of involuntary muscle spasms of her right arm and leg. Her parents reported intermittent slurred speech and difficulty grasping utensils. Physical examination revealed an awake, alert, age-appropriate female with normal cranial nerves. Patient was found to have choreoathetoid movements on the right extremities with dystonia of right leg with ambulation. Neurology consultation, computed tomography of the head, and magnetic resonance imaging of the brain did not show any acute pathology. Echocardiogram did show mild tricuspid regurgitation, suggestive of rheumatic fever. Anti-streptolysin O titer was markedly elevated, along with DNAse-B antibodies. The patient had marked improvement of movement disorder at just over 1 week later. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Sydenham's chorea is a rare but important movement disorder often related to Group A streptococcus and rheumatic fever. The incidence of rheumatic fever has been decreasing in North America but continues to be much more prevalent in developing countries as well as immigrant populations. This diagnosis is rare and can occasionally be misdiagnosed as a "fidgety" child or as a psychiatric manifestation. Sydenham's chorea is important to diagnose because acute treatment and prophylactic antibiotics can help improve symptoms and minimize cardiac damage.

Using preceding hospital admissions to identify children at risk of developing acute rheumatic fever.

AIMS: New Zealand (NZ) Maori and Pacific children have high rates of acute rheumatic fever (ARF). Around 150 new cases arise each year. As part of the national ARF prevention programme, funding is available to improve housing. To obtain maximum benefit from interventions, an effective tool is needed for targeting high-risk children. This study aimed to assess the effectiveness of using hospitalisations for identifying children at risk of subsequent ARF. METHODS: Three potentially avoidable hospitalisation (PAH) groups were investigated, including diseases thought to be influenced by housing. All were developed using expert opinion or systematic reviews. These were: (i) the PAH conditions associated with the housing environment (PAHHE) group; (ii) the Crowding group; and (iii) the Ministry of Health (MoH) group. We analysed NZ public hospital discharge data (2000-2014). The prevalence of ARF among patients hospitalised in each group was calculated to estimate sensitivity and potential effectiveness. The number needed to screen (NNS) to identify one ARF case was estimated as a measure of efficiency. RESULTS: Nearly one-third of ARF patients experienced a PAH as children (before developing ARF). Sensitivity for detecting future ARF ranged from <5% (MoH group) to 27% (PAHHE group). NNS ranged from 502.4 (PAHHE) to 707.5 (MoH). CONCLUSIONS: Because ARF is relatively rare, observing hospitalisations is not particularly efficient for targeting prevention activities for this condition alone. However, housing interventions are likely to improve multiple outcomes; thus, the hospital setting is still useful for identifying at-risk children who could benefit from such programmes.

Poststreptococcal Illness: Recognition and Management.

Group A beta-hemolytic streptococcus can cause several postinfectious, nonsuppurative immune- mediated diseases including acute rheumatic fever, poststreptococcal reactive arthritis, pediatric autoimmune neuropsychiatric disorders, and poststreptococcal glomerulonephritis. Except for sporadic outbreaks, poststreptococcal autoimmune syndromes occur most commonly in sub-Saharan Africa, India, Australia, and New Zealand. Children younger than three years are rarely affected by group A streptococcus pharyngitis or rheumatic fever, and usually do not require testing. Rheumatic fever is a rare condition that presents as a febrile illness characterized by arthritis, carditis or valvulitis, and neurologic and cutaneous disease, followed many years later by acquired valvular disease. Recurrence rates are high. In addition to evidence of recent streptococcal infection, two major or one major and two minor Jones criteria are required for diagnosis. Electrocardiography, chest radiography, erythrocyte sedimentation rate, and an antistreptolysin O titer are the most useful initial tests. Echocardiography is recommended to identify patients with subclinical carditis. The arthritis usually responds within three days to nonsteroidal anti-inflammatory drugs. Poststreptococcal reactive arthritis is nonmigratory, can affect any joint, and typically does not respond to aspirin. Pediatric autoimmune neuropsychiatric disorders affect the basal ganglia and are manifested by obsessive-compulsive and tic disorders. The presentation of poststreptococcal glomerulonephritis ranges from asymptomatic microscopic hematuria to gross hematuria, edema, hypertension, proteinuria, and elevated serum creatinine levels.

Epidemiology of pharyngitis as reported by Zambian school children and their families: implications for demand-side interventions to prevent rheumatic heart disease.

BACKGROUND: Prompt and appropriate treatment of streptococcal pharyngitis decreases the risk of acute rheumatic fever and rheumatic heart disease (RHD). Understanding public perceptions and behaviors related to sore throat is fundamental to inform health programs aimed at eliminating new cases of RHD in endemic regions. We sought to describe the epidemiology of pediatric pharyngitis and its treatment, as reported by children and their parents or guardians in Lusaka, Zambia. METHODS: This was a cross-sectional investigation using interviews and written surveys, nested in a school-based RHD prevalence study. Students and their parents were asked to report number of sore throats in the previous 12 months, treatment received, and type and place of treatment. A focused history and physical examination to detect pharyngitis was conducted and children were referred for follow-up as indicated. RESULTS: A total of 3462 students from 47 schools participated in the study, along with their parents or guardians. Six hundred and fifty eight (19%) parents/guardians reported their child had at least one sore throat in the previous year, and 835 (24%) of students reported at least one sore throat in the same time period. Girls were reported to have pharyngitis 50% more often than boys, and also made up two-thirds of the total students treated. Approximately two-thirds of children who had at least one episode of pharyngitis during the previous year were also reported to have received some form of treatment. The majority of treatments were received in government clinics (36.6%) and at home (26.3%). Half of treatments included an antibiotic. Nineteen students (0.5%) had clinically-apparent pharyngitis at screening. CONCLUSION: Pharyngitis is common among school-aged children and adolescents in Zambia, with females reporting significantly more sore throat episodes than males. Parents/guardians have variable knowledge about the frequency of sore throat in their children, and management of pharyngitis may be suboptimal for many children since more than a quarter were reported to have received treatment without skilled assessment. These results provide insight into current perceptions and practices related to sore throat in Zambia and will be used to design public awareness activities aimed at reducing RHD.

A retrospective study: Acute rheumatic fever and post-streptococcal reactive arthritis in Japan.

BACKGROUND: Acute rheumatic fever (ARF) and post-streptococcal reactive arthritis (PSRA) are immune-mediated consequences of group A streptococcal pharyngitis. ARF has declined in developed nations. No prevalence survey of PSRA has been conducted. This study evaluated the incidence and characteristics of ARF and PSRA in Japanese children. METHODS: From 2010 to 2015, ARF and PSRA were evaluated using clinical data retrospectively collected by chart review from 528 hospitals. RESULTS: From 323 hospitals (61% response rate), 44 cases of ARF and 21 cases of PSRA were reported. Patients with ARF and/or PSRA were mainly from large cities in Japan. The mean age of ARF occurrence was 8.5 years, and the ratio of female/male patients was 16:28. Major manifestations in the acute phase included carditis, 27 cases (61.4%); polyarthritis, 22 cases (50%); erythema marginatum, 7 cases (15.9%); Sydenham chorea, 3 cases (6.8%); and subcutaneous nodules, 1 case (2.3%). Twenty-one (58.3%) patients had migratory arthritis. During the follow-up period, 6 patients (13.6%) showed mild carditis. For PRSA, the mean age was 8.2 years, and the ratio of female/male patients was 12:9. Six (28.6%) patients had monoarthritis, and 4 (19%) patients had migratory arthritis. No patient had carditis. CONCLUSIONS: Although ARF and PSRA are rare in the Japanese pediatric population, substantial numbers of patients with both conditions were identified in this study. We observed a high incidence of arthritis and carditis in ARF patients. No PSRA case was complicated with carditis. General pediatricians need to have updated information about ARF and PSRA, even in industrialized countries.

Snippets From the Past: Imaginative Designs--Separating Hereditary From Environmental Effects in pre-DNA Times.

In an attempt to reproduce the results of an inconclusive 1927 report by the British Medical Research Council on the hereditary versus social origins of rheumatic fever, Read, Ciocco, and Taussig, from Johns Hopkins University, with the support of Frost, conducted a case-control study in 1935 and 1936. Their study, which appeared in the American Journal of Hygiene in 1938, was outstanding for its clear and tidy rationale for separating hereditary from environmental causes. The authors compared the prevalence of rheumatic fever among the relatives of 33 children admitted for "incident" rheumatic fever and 33 control children admitted in a tuberculosis clinic for reasons other than rheumatic fever. Both rheumatic fever (cases) and tuberculosis (controls) were diseases of the poor. All family members of both cases and controls, including uncles, aunts, and grandparents, were eligible for interview and physical examination. The results were compatible with the presence of an "inherited predisposition" to rheumatic fever because the disease was more prevalent among the uncles, aunts, and grandparents of case patients than among those of control patients. Methodologically, the paper by Read, Ciocco, and Taussig is an important but almost completely forgotten milestone in the evolution of case-control studies and of genetic epidemiology.

The national incidence and clinical picture of SLE in children in Australia - a report from the Australian Paediatric Surveillance Unit.

OBJECTIVES: The objectives of this paper are to prospectively determine the incidence of paediatric systemic lupus erythematosus (pSLE) in Australia as well as describe the demographics, clinical presentation and one-year outcome. STUDY DESIGN: Newly diagnosed cases of pSLE were ascertained prospectively from October 2009 to October 2011 through the Australian Paediatric Surveillance Unit (a national monthly surveillance scheme for notification of childhood rare diseases) as well as national subspecialty groups. Questionnaires were sent to notifying physicians at presentation and at one year. RESULTS: The annual incidence rate was 0.32 per 10(5) children aged less than 16 years. The incidence was significantly higher in children of Asian or Australian Aboriginal and Torres Strait Islander parents. Approximately one-third of children underwent a renal biopsy at presentation and 7% required dialysis initially although only one child had end-stage kidney disease (ESKD) at one-year follow-up. CONCLUSION: The incidence of pSLE in Australia is comparable to that worldwide with a significantly higher incidence seen in children of Asian and Australian Aboriginal and Torres Strait Islander backgrounds. Renal involvement is common but progression to ESKD, at least in the short term, is rare.

Brain human monoclonal autoantibody from sydenham chorea targets dopaminergic neurons in transgenic mice and signals dopamine D2 receptor: implications in human disease.

How autoantibodies target the brain and lead to disease in disorders such as Sydenham chorea (SC) is not known. SC is characterized by autoantibodies against the brain and is the main neurologic manifestation of streptococcal-induced rheumatic fever. Previously, our novel SC-derived mAb 24.3.1 was found to recognize streptococcal and brain Ags. To investigate in vivo targets of human mAb 24.3.1, VH/VL genes were expressed in B cells of transgenic (Tg) mice as functional chimeric human VH 24.3.1-mouse C-region IgG1(a) autoantibody. Chimeric human-mouse IgG1(a) autoantibody colocalized with tyrosine hydroxylase in the basal ganglia within dopaminergic neurons in vivo in VH 24.3.1 Tg mice. Both human mAb 24.3.1 and IgG1(a) in Tg sera were found to react with human dopamine D2 receptor (D2R). Reactivity of chorea-derived mAb 24.3.1 or SC IgG with D2R was confirmed by dose-dependent inhibitory signaling of D2R as a potential consequence of targeting dopaminergic neurons, reaction with surface-exposed FLAG epitope-tagged D2R, and blocking of Ab reactivity by an extracellular D2R peptide. IgG from SC and a related subset of streptococcal-associated behavioral disorders called "pediatric autoimmune neuropsychiatric disorder associated with streptococci" (PANDAS) with small choreiform movements reacted in ELISA with D2R. Reaction with FLAG-tagged D2R distinguished SC from PANDAS, whereas sera from both SC and PANDAS induced inhibitory signaling of D2R on transfected cells comparably to dopamine. In this study, we define a mechanism by which the brain may be altered by Ab in movement and behavioral disorders.

How many patients with post-chikungunya chronic inflammatory rheumatism can we expect in the new endemic areas of Latin America?

Post-chikungunya chronic inflammatory rheumatism (pCHIK-CIR) is one of the consequences that are impacting new endemic countries, such as those in the Americas. The relative frequency of pCHIK-CIR is highly variable, ranging from 14.4 % to 87.2 % (including variable number of patients and follow-up times). Based on those non-weighted values, it is difficult to estimate which would be the expected number of patients with CHIK who will develop CIR. For these reasons, we modeled weighted estimations based on pooled data extracted from those eight representative studies in order to provide cumulative proportion of pCHIK-CIR over time and median time of it, but also estimations of the number of patients with CHIK reported in Latin American countries (within a 95 % CI). This model estimated a prevalence of 47.57 % for pCHIK-CIR (95 % CI 45.08-50.13), with a median time to 50 % of pCHIK-CIR in 20.12 months. Given the reported number of patients with acute CHIK during 2014 in the Americas, our estimates suggest that from those patients, 385,835-429,058 patients will develop pCHIK-CIR. Despite the limitations of these estimates, the provided figures of pCHIK-CIR presented here are preliminary approximations of what the future burden of related rheumatic disease in the region as a consequence of CHIK infection for 2015-2016 could be, given the timeframe of median time of occurrence.

[Acute rheumatic fever and infectious-inflammatory diseases of the pharynx: the relationship, treatment, and prophylaxis].

The relationship between pharyngeal infections, such as tonsillitis and pharyngitis, caused by group A beta-hemolytic streptococci (BHSA) and acute rheumatic fever (ARF) is a well-established fact confirmed by numerous studies carried out along the following lines: epidemiological, immunological, therapeutic, and prophylactic. The currently available data provide an opportunity to discuss the existence of «rheumatogenic¼ BHSA strains exhibiting a number of characteristic clinical and morphological properties. According to the current recommendations penicillins remain the means of first-line therapy for the treatment of acute forms of BHSA-induced tonsillitis and pharyngitis, whereas the macrolides should be applied only as the alternative medications in the patients with intolerance to beta-lactam antibiotics. This article contains characteristics of BHSA-carrier state and the principal indications for the prescription of antibiotics to the patients with these conditions. The key principle of secondary medicamental prophylaxis of acute respiratory infections are expounded along with the main fines of future research on the problems associated with BHSA-induced pharyngeal infections.

Host-pathogen interactions in streptococcal immune sequelae.

Otherwise uncomplicated infections with Streptococcus pyogenes can cause two insidious immune sequelae known as post-streptococcal glomerulonephritis (PSGN) and acute rheumatic fever (ARF). These diseases follow with a latency of a few weeks or months after primary infection and are responsible for high mortality and morbidity. PSGN has also been linked to infections with group C streptococci of the species S. equi ssp. zooepidemicus (SESZ). Moreover, there are some indications that infection with group C and G streptococci (GCGS) of the subspecies Streptococcus dysgalactiae ssp. equisimilis (SDSE) leads to ARF. Despite decades of research, the picture of the molecular pathogenesis of streptococcal immune sequelae resembles a jigsaw puzzle. Herein we try to put some of the puzzle bits together that have been collected till date.

[Rheumatic fever].

This lecture-style paper highlights all major problems pertinent to rheumatic fever Definition of acute RF and chronic rheumatic heart disease is proposed and desirability of the use of these terms in clinical practice is explained. Present-day epidemiology of RF is described with reference to marked differences in its prevalence in developed and developing countries. Modern classification of acute RF is described as adopted by the Russian Association of Rheumatologists and recommended for the use in Russian medical facilities. Discussion of etiological issues is focused on such virulence factors as beta-hemolytic streptococcus A and genetic predisposition confirming hereditary nature of RE Its clinical features are described along with laboratory and instrumental methods applied for its diagnostics. Large and small diagnostic criteria of RF are considered. Special attention is given to the treatment of RF and its complications (antibiotic, pathogenetic, and drug therapy). Its primary and secondary prophylaxis is discussed in detail, preparations for the purpose are listed (with doses and duration of application). In conclusion, criteria for the efficacy of therapy are presented along with indications for hospitalization and emergency treatment.

Rheumatic fever - identification, management and secondary prevention.

BACKGROUND: Acute rheumatic fever is a rare multisystem disease caused by an immunological response to Group A streptococcus infection. Acute rheumatic fever usually has onset in childhood and is most prevalent in Aboriginal and Maori populations and other disadvantaged groups. OBJECTIVE: In this article we outline the clinical features of acute rheumatic fever and describe the important role of primary healthcare providers in its identification, management and secondary prevention. DISCUSSION: Recurrent episodes of acute rheumatic fever may lead to rheumatic heart disease. Early detection of acute rheumatic fever and provision of secondary prophylaxis with antibiotics is paramount to the prevention of rheumatic heart disease. Primary healthcare providers can play an important role in identifying acute rheumatic fever and ensuring adherence to treatment within the context of a complex interplay of cultural and socioeconomic factors. The recent establishment of RHD Australia will support the development of appropriate educational resources and their dissemination among health professionals and vulnerable communities.

Group A Streptococcus virulence factors genes in north India & their association with emm type in pharyngitis.

BACKGROUND & OBJECTIVES: Group A streptococcal (GAS) pharyngitis, especially among children, leads to high prevalence of rheumatic fever (RF)/rheumatic heart disease (RHD) in India, as compared to the western world where invasive diseases are common. GAS encodes numerous virulence factors that cause diseases by exhibiting extraordinary biological diversity. Hence, we studied the virulence factors genes of GAS isolated from the throat of children with pharyngitis and also asymptomatic carriers. METHODS: Fifty GAS isolates cultured from throats of north Indian children aged 5-15 yr with mild pharyngitis (20), severe pharyngitis (24) and asymptomatic pharyngeal carriers (6), during 2000-2003 along with reference M1 strain were emm typed and characterized for virulence factors genes by PCR. The presence of virulence factors was also checked for their association with emm type in pharyngitis. RESULTS: Twenty emm types, six sequence types, and one non-typeable strain were found circulating in north India. The five most prevalent types were emm 74 (12%), 11 & StI129 (8% each) and emm 68 and NS292 (6% each). The spe B gene was found to be significantly higher (P=0.0007) in opacity factor (OF) negative isolates. emm 3, 11, 77, 86, 87, 109 and StI129 showed maximum virulence factors genes. INTERPRETATION & CONCLUSIONS: GAS isolates collected from throats of children from north India possess highly virulent antigens. This study also supports concept of isolate-associated virulence rather than type relatedness.

Ficolin-3 in rheumatic fever and rheumatic heart disease.

Rheumatic fever (RF) and chronic rheumatic heart disease (RHD) are complications of oropharyngeal infection caused by Streptococcus pyogenes. Despite the importance of the complement system against infections and autoimmunity diseases, studies on the role of the lectin pathway in RF and RHD are scarce. Thus, our aim was to evaluate the association of ficolin-3 serum levels, FCN3 polymorphisms and haplotypes with the susceptibility to RF and RHD. We investigated 179 patients with a history of RF (126 RHD and 53 RF only) and 170 healthy blood donors as control group. Ficolin-3 serum concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Three FCN3 single nucleotide polymorphisms (SNPs rs532781899, rs28362807 and rs4494157) were genotyped through the sequence-specific PCR method. Lower ficolin-3 serum levels were observed in RF patients when compared to controls (12.81 µg/mL vs. 18.14 µg/mL respectively, p < 0.0001, OR 1.22 [1.12-1.34]), and in RHD in comparison to RF only (RFo) (12.72 µg/mL vs. 14.29 µg/mL respectively, p = 0.016, OR 1.38 [1.06-1.80]). Low ficolin-3 levels (<10.7 µg/mL) were more common in patients (39.5 %, 30/76) than controls (20.6 %, 13/63, p = 0.018, OR = 2.51 [1.14-5.31]), and in RHD (44.4 %, 28/63) than RFo (15.4 %, 2/13, p = 0.007, OR = 3.08 [1.43-6.79]). On the other hand, FCN3 polymorphism/haplotypes were not associated with ficolin-3 serum levels or the disease. Low ficolin-3 levels might be associated with RF, being a potential marker of disease progression.

Studies of the relationship between the production of bacteriocines by group A streptococci and acute glomerulonephritis.

The previously reported relationship between nephritogenicity and bacteriocine production among Group A streptococci has been examined. Using techniques comparable to the earlier study, the present study did not reveal any such relationship. Among 73 strains tested, 53% produced bacteriocines; no significant difference was noted between bacteriocines from strains isolated from cases of nephritis and those from a group of strains recovered from patients with other conditions. In addition, no correlation between type and bacteriocine production was observed.

Difference in the structural features of streptococcal M proteins from nephritogenic and rheumatogenic serotypes.

The association of only certain M protein serotypes of group A streptococci with acute glomerulonephritis is very well recognized. Structural information on the M protein, a dimeric alpha-helical coiled-coil molecule, has come so far from three rheumatogenic serotypes, 5, 6, and 24. However, M proteins from the nephritogenic serotypes have not been well characterized. In the present study, we have isolated a biologically active 20,000 Mr pepsin fragment of type 49 M protein (PepM49), a nephritogenic serotype, and purified it to homogeneity using DEAE-Sephadex and gel filtration. The amino acid composition of PepM49 is similar to those of the rheumatogenic M protein serotypes PepM5, PepM6, and PepM24. However, the sequence of the NH2-terminal 60 residues of PepM49 shows little homology to any of these M protein serotypes, although the latter have significant homology among themselves. Nevertheless, PepM49 exhibits a strong heptad periodicity in its nonpolar residues, suggesting its overall conformational similarity with the other M molecules. During the course of the present studies, Moravek et al. (17) reported the NH2-terminal sequence of another M protein serotype, PepM1, which also does not exhibit much homology with the PepM5, PepM6, and PepM24 proteins. Our analysis of this sequence revealed that the PepM1 protein also exhibits a heptad periodicity of the nonpolar amino acids. A closer examination has revealed that the pattern of heptad periodicity in PepM49 and PepM1 proteins is more regular and more similar to each other than has been previously seen for the PepM5, PepM6, and PepM24 proteins. PepM1 is also a nephritogenic serotype. Taken together, these findings indicate an underlying conservation of the tertiary structure of the various M protein serotypes, despite the complexity in their antigenic variation and suggest that the nephritogenic M protein serotypes M1 and M49 may be further apart evolutionarily from the rheumatogenic serotypes 5, 6, and 24. The distinct differences in the structural features of the PepM1 and PepM49 proteins relative to the PepM5, PepM6, and PepM24 proteins are also suggestive of a correlation with the earlier broader classification of the group A streptococci into rheumatogenic and nephritogenic serotypes.