Clinical and epidemiologic features of group a streptococcal pneumonia in Ontario,Canada

BACKGROUND: Since the 1960s, group A streptococcus (GAS) has accounted for less than 1% of cases of community-acquired pneumonia. During the past 2 decades there has been a resurgence of invasive GAS infection, but no large study of GAS pneumonia has been performed. METHODS: To determine the clinical and epidemiologic features of GAS pneumonia, we conducted prospective, population-based surveillance of all invasive GAS infection in residents of Ontario from January 1, 1992, through December 31, 1999. RESULTS: Of 2079 cases of invasive GAS infection, 222 (11%) represented GAS pneumonia. The incidence of GAS pneumonia ranged from 0.16 per 100 000 in 1992 to 0.35 per 100 000 in 1999. Most cases were community acquired (81%). Forty-four percent of nursing home-acquired cases occurred during outbreaks. The case fatality rate was 38% for GAS pneumonia, compared with 12% for the entire cohort with invasive GAS infection and 26% for patients with necrotizing fasciitis. The presence of streptococcal toxic shock syndrome (odds ratio, 19; 95% confidence interval, 8.4-42; P =.001) and increasing age (odds ratio per decade, 1.45; 95% confidence interval, 1.2-1.7; P<.001) were associated with fatal outcome. Time to death was rapid, with a median of 2 days despite antimicrobial therapy and supportive measures. CONCLUSIONS: Group A streptococcal pneumonia is a common form of invasive GAS disease but remains an uncommon cause of community-acquired pneumonia. Progression is rapid despite appropriate therapy. The incidence is similar to, and the case fatality rate higher than, that of necrotizing fasciitis.     

Immunogenicity of a divalent group A streptococcal vaccine

We designed and recombined the polypeptide based on the M protein of group A streptococci (GAS)—the causative pathogen of rheumatic fever and rheumatic heart disease, which would be a divalent vaccine to prevent and defend the diseases in relation to the different GAS strains. A divalent vaccine comprising three different peptide epitopes of the antiphagocytic M protein of GAS—an aminoterminal specific sequences, respectively, from the M1 and M12 proteins and J14 peptide (ASREAKKQVEKALE) within the highly conserved C-terminal repeat region of the M1 and M12 proteins—was subcutaneously delivered to mice with the adjuvant. Furthermore, the antisera titers of mice inoculated with the divalent vaccine were assayed by ELISA, and then opsonization and percentage killing against two different GAS serotypes were completed. Our data demonstrated that antisera raised against the divalent vaccine containing amino acids and M-protein-conserved C repeat region are able to kill several GAS strains isolated from the Guangzhou population. Therefore, the divalent vaccine can be used to prevent those diseases caused by GAS in an endemic area. We successfully construct the M-protein-based divalent vaccine that can bring out a high-level antisera titer of mice vaccinated with it. So, the vaccine has the potential to be used to prevent diseases caused by GAS in our country.     

Intranasal vaccination with a lipopeptide containing a conformationally constrained conserved minimal peptide, a universal T cell epitope, and a self-adjuvanting lipid protects mice from group A streptococcus challenge and reduces throat colonization

Infection with group A streptococcus (GAS) may result in a number of human diseases, including potentially life-threatening postinfectious sequelae. In the present study, J14, a conformationally constrained conserved minimal peptide from the M protein, was incorporated into a lipopeptide construct to which a universal T cell epitope and a self-adjuvanting lipid moiety, Pam(2)Cys, were also attached. We demonstrate that this lipopeptide construct, when administered intranasally (inl) without additional adjuvants, protects outbred mice from lethal respiratory GAS challenge. In addition, the lipopeptide was capable of inducing J14-specific mucosal immunoglobulin A, which coincided with reduced throat colonization after respiratory GAS challenge. These preclinical experiments show that this lipopeptide could form the basis of an antidisease and transmission-blocking inl GAS vaccine.     

Toward the development of an antidisease, transmission-blocking intranasal vaccine for group a streptococcus

Infection with group A streptococcus (GAS) may result in a number of clinical conditions, including the potentially life-threatening postinfectious sequelae of rheumatic fever and rheumatic heart disease. As part of the search for a vaccine to prevent GAS infection, a conformationally constrained and minimally conserved peptide, J14, from the M protein of GAS has been defined. In the present study, J14 was formulated with bacterial outer membrane proteins (proteosomes) and then intranasally administered to outbred mice without additional adjuvant. Such immunization led to high titers of J14-specific serum immunoglobulin (Ig) G and mucosal IgA. After upper respiratory tract GAS challenge, immunized mice demonstrated increased survival and reduced GAS colonization of the throat.     

Type-specific opsonophagocytosis of group A Streptococcus by use of a rapid chemiluminescence assay

A whole-blood chemiluminescence (CL) assay was developed to determine the presence of type-specific opsonic antibodies against group A streptococcus (GAS). Convalescent sera with high bactericidal activities against an M-1 serotype were used to opsonize different M-types of GAS. CL responses were monitored for 20 min, and results were expressed as integral counts/minute per phagocyte. CL responses of phagocytes incubated with M-1 GAS opsonized with homologous (M-1) serum were significantly higher than responses of phagocytes incubated with heterologous (M-3) GAS. Adsorption of convalescent serum against the homologous, but not the heterologous, strain markedly reduced the CL response, demonstrating type specificity. The CL assay showed a high correlation with the indirect bactericidal test (r=0.90). In conclusion, this CL assay is a rapid, highly sensitive, specific, and reproducible method for quantifying type-specific opsonic antibodies against GAS and will be a useful tool for future clinical, basic science, and epidemiological studies.     

Immunization with a tetraepitopic lipid core peptide vaccine construct induces broadly protective immune responses against group A streptococcus

BACKGROUND: The development of a vaccine to prevent infection with group A streptococcus (GAS) is hampered by the widespread diversity of circulating GAS strains and M protein types, and it is widely believed that a multivalent vaccine would provide better protective immunity. METHODS: We investigated the efficacy of incorporating 3 M protein serotypic amino-terminal epitopes from GAS isolates that are common in Australian Aboriginal communities and a conformational epitope from the conserved carboxy-terminal C-repeat region into a single synthetic lipid core peptide (LCP) vaccine construct in inducing broadly protective immune responses against GAS after parenteral delivery to mice. RESULTS: Immunization with the tetraepitopic LCP vaccine construct led to high titers of systemic, antigen-specific IgG responses and the induction of broadly protective immune responses, as was demonstrated by the ability of immune serum to opsonize multiple GAS strains. Systemic challenge of mice with a lethal dose of GAS given 60 or 300 days after primary immunization showed that, compared with the control mice, the vaccinated mice were significantly protected against GAS infection, demonstrating that the vaccination stimulated long-lasting protective immunity. CONCLUSIONS: These data support the efficacy of the LCP vaccine delivery system in the development of a synthetic, multiepitopic vaccine for the prevention of GAS infection.     

Cluster of deaths from group A streptococcus in a long-term care facility--Georgia, 2001

BACKGROUND: Invasive group A streptococcus (GAS) affects approximately 10,500 persons annually; 1 in 5 patients >/=65 years die. In August 2001, CDC investigated a cluster of GAS deaths in a Georgia long-term care facility (LTCF). METHODS: We screened LTCF residents and staff for GAS carriage and conducted a retrospective cohort study among residents. We defined a case as GAS isolation associated with clinical infection. RESULTS: Eight cases were identified (median age: 79 years); 6 (75%) patients died. Carriage was similar in residents (10%) and staff (9%). All isolates among residents and 63% among staff were type emm 77. Risk factors for GAS disease or carriage among residents were receiving skin treatment (relative risk [RR] = 4.0, 95% confidence interval [CI] = 1.9-11.0) and having an infected or colonized roommate (RR = 2.0, 95% CI = 1.10-5.0). No wound care nurse carried GAS. Interventions included education about standardized infection control guidelines and appropriate hand hygiene; carriers were treated with antibiotics. No subsequent GAS cases were identified in the following year. CONCLUSIONS: Transmission of GAS in this outbreak likely occurred during wound care and ended with improved hand hygiene. This investigation highlights additional research and policy needs for control of severe GAS infections among the high-risk LTCF population.     

Induction of group A Streptococcus virulence by a human antimicrobial peptide

Group A streptococci (Streptococcus pyogenes or GAS) freshly isolated from individuals with streptococcal sore throat or invasive ("flesh-eating") infection often grow as mucoid colonies on primary culture but lose this colony appearance after laboratory passage. The mucoid phenotype is due to abundant production of the hyaluronic acid capsular polysaccharide, a key virulence determinant associated with severe GAS infections. These observations suggest that signal(s) from the human host trigger increased production of capsule and perhaps other virulence factors during infection. Here we show that subinhibitory concentrations of the human antimicrobial cathelicidin peptide LL-37 stimulate expression of the GAS capsule synthesis operon (hasABC). Up-regulation is mediated by the CsrRS 2-component regulatory system: it requires a functional CsrS sensor protein and can be antagonized by increased extracellular Mg(2+), the other identified environmental signal for CsrS. Up-regulation was also evident for other CsrRS-regulated virulence genes, including the IL-8 protease PrtS/ScpC and the integrin-like/IgG protease Mac/IdeS, findings that suggest a coordinated GAS virulence response elicited by this antimicrobial immune effector peptide. LL-37 signaling through CsrRS led to a marked increase in GAS resistance to opsonophagocytic killing by human leukocytes, an in vitro measure of enhanced GAS virulence, consistent with increased expression of the antiphagocytic capsular polysaccharide and Mac/IdeS. We propose that the human cathelicidin LL-37 has the paradoxical effect of stimulating CsrRS-regulated virulence gene expression, thereby enhancing GAS pathogenicity during infection. The ability of GAS to sense and respond to LL-37 may explain, at least in part, the unique susceptibility of the human species to streptococcal infection.     

Primary peritonitis due to group A Streptococcus in a previously healthy pediatric patient

Primary peritonitis remains a rare disease in otherwise healthy children, with group A Streptococcus (GAS) being a particularly unusual cause. A case involving a 14-year-old girl, who presented with an ‘acute abdomen’ and was taken to the operating room for urgent laparoscopy, is reported. Abdominal and pelvic structures were only minimally inflamed, as was the appendix. Peritoneal fluid and blood cultures both grew pure cultures of GAS. The patient’s course was complicated by streptococcal toxic shock syndrome. She fortunately made a full recovery. The present report highlights the diagnostic and treatment dilemmas associated with GAS primary peritonitis.     

A族链球菌表面蛋白Fba的原核表达及免疫原性分析

目的 研究A族链球菌(GAS)表面新型纤连蛋白Fba的免疫原性,探讨GAS感染机体的免疫应答机制.方法 PCR扩增fba基因,测序正确后克隆至原核表达质粒pGEX4T-2,并在E.coli BL21中表达,应用ELISA和Western印迹法鉴定目的 蛋白表达,以该蛋白作为抗原,包被酶联板,检测GAS全菌免疫鼠血清、33份抗链球菌"O"阳性患者血清.同时,将该蛋白免疫Balb/C小鼠,3次免疫后收集皿清,检测IgG效价.结果 ELISA和Western印迹证实,表达的Fba重组蛋白可与已知兔抗Fba阳性血清产生特异性反应;且Fba蛋白可与GAS全菌免疫鼠血清、抗链球菌"O"阳性患者血清发生特异性结合.Fba蛋白免疫小鼠后抗血清IgG效价达1:4800.结论 GAS感染或Fba蛋白免疫动物后均可诱导动物体产生Fba抗体,该抗体与Fba重组蛋白可产生特异性反应,提示Fba蛋白具有良好的免疫原性和抗原性.Fba蛋白可作为GAS的候选疫苗及检测GAS感染患者血清效价的重要工具.     

A 7-month outbreak of relapsing postpartum group A streptococcal infections linked to a nurse with atopic dermatitis.

A 7-month outbreak of 15 cases of postpartum sepsis with group A haemolytic Streptococci (GAS) was stopped when a carrier was identified. Comparing delivery dates with duty rotas revealed that the carrier had been present during delivery in 13 of the 15 cases. The epidemic GAS type, T3-13-B3264, was found in a carbuncle in her groin and in atopic dermatitis lesions behind her ears and on her eyelids. Thus, it was not the microbiological screening of staff that helped detect the carrier. The outbreak went unnoticed for 6 months, as no 2 cases were diagnosed by the same physician and 5 cases were diagnosed by different general practitioners. The main risk factors for infection were presence of the carrier relative risk (relative risk RR 47.8, 95% confidence interval (CI) 10.9-209.5) and suturing of episiotomy (RR 11.0; 95% CI 2.6-47.9). We recommend that a thorough epidemiological investigation should be carried out in every single case of GAS postpartum infection. Despite initial intravenous treatment with penicillin, 8 patients experienced > 15 recurring postpartum GAS infections, such as endometritis, wound infection, tonsillitis, erysipelas and Brodie's abscess. Eradication of GAS should be confirmed after completion of treatment.     

Successful management of severe group A streptococcal soft tissue infections using an aggressive medical regimen including intravenous polyspecific immunoglobulin together with a conservative surgical approach

Intravenous polyspecific immunoglobulin G (IVIG) has been reported to be efficacious as adjunctive therapy in patients with toxic shock syndrome caused by a group A streptococci (GAS). GAS is also an important cause of necrotizing fasciitis, for which an early and extensive surgical intervention is currently advocated. Here we report on the use of an aggressive medical regimen including high-dose IVIG together with a conservative surgical approach in severe GAS soft tissue infection. We describe 7 patients with severe soft tissue infection caused by GAS, who all were treated with effective antimicrobials and high-dose IVIG. Surgery was either not performed or only limited exploration was carried out. Six of the patients had toxic shock syndrome. All patients survived. Immunostaining of tissue biopsies from 2 of the patients revealed high levels of GAS, superantigen and pro-inflammatory cytokines initially, which were dramatically reduced in a repeat biopsy of the initial operative site collected from 1 of the patients 66 h post-IVIG administration. The study suggests that the use of a medical regimen including IVIG in patients with severe GAS soft tissue infections may allow an initial non-operative or minimally invasive approach, which can limit the need to perform immediate wide debridements and amputations in unstable patients.     

Streptococcal Toxic Shock Syndrome in Two Patients Infected by a Colonized Surgeon

Summary The incidence of severe invasive infections caused by Streptococcus pyogenes, a group A streptococcus (GAS), has increased in the past 10 years. Most cases occur outside of the hospital setting. We report on two patients with nosocomial streptococcal toxic shock syndrome (StrepTSS). In patient 1 the syndrome was associated with the development of necrotizing fasciitis following inguinal hernia repair. Patient 2 suffered from StrepTSS shortly after receiving a tetanus vaccine in her left deltoid. Epidemiologic investigations of these cases, which were noted within 48 hours of each other, showed that the same surgeon performed the vaccination on patient 2 after assisting a colleague during the hernia repair procedure on patient 1. He was found to be a nasal carrier of GAS. All GAS isolates from the patients and the surgeon were indistinguishable by pulsed field gel electrophoresis. PCR analysis demonstrated the presence of streptococcal pyogenic exotoxins A and F. All strains were of the T-1 serotype and possessed the gene for M-protein 1. This report demonstrates that a virulent strain of GAS may be spread by asymptomatically colonized medical personnel via the air route. Received: February 26, 1999 · Revision accepted: May 26, 1999     

Antibody to streptococcal cysteine proteinase as a seromarker of group A Streptococcal (Streptococcus pyogenes) infections

Serological tests are commonly employed to aid the diagnosis of Streptococcus pyogenes infections, particularly when non-suppurative sequelae are suspected. Conventional laboratory practice is to measure antibody levels to various combinations of the extracellular group A Streptococcus (GAS) antigens streptolysin O (SLO), DNase B, streptokinase and hyaluronidase. Antibody to the extracellular cysteine proteinase streptococcal pyrogenic exotoxin B (SPE B) and its precursor zymogen is also produced in response to GAS infections. An indirect hemagglutination test for antibody to zymogen/SPE B was established and evaluated in serum samples from 168 patients with proven (n = 27) or suspected GAS (n = 141) infections, which were also screened for antibodies using the 4 conventional tests. For comparison, sera from 56 patients infected with a variety of other pathogens, as well as sera from 16 patients infected with either S. agalactiae or S. pneumoniae and 34 sera from healthy subjects, were tested. Statistical analysis confirmed that antibody to zymogen/SPE B is a serological marker that can discriminate GAS infections. It can be ranked with the anti-SLO titer, currently the most widely used test, as a marker of an antecedent GAS infection.     

Etiology and management of acute and recurrent group a Streptococcal tonsillitis

Tonsillitis is one of the most prevalent infections in children and adolescents. The etiologic agents might be viral or bacterial. About 30% of cases are reported to be of bacterial origin, mainly due to group A Streptococcus (GAS). Although in most instances GAS tonsillitis is a self-limited disease, antibiotic treatment is recommended, mainly to prevent the suppurative and nonsuppurative poststreptococcal sequelae of acute rheumatic fever and to prevent glomerulonephritis. In this paper we review the current knowledge of the etiology of acute and recurrent GAS tonsillitis, with special emphasis on a recent hypothesis regarding the etiology of bacterial eradication failure. While penicillin V remains the drug of choice for acute tonsillitis, other antibiotics are being approved and recommended for particular indications in both Europe and the United States.     

Interpersonal relationships and group A streptococcus spread in a Mexican day-care center

OBJECTIVE: To study the effect of different degrees of centrality on the carrying of identical group A streptococcus (GAS) clones in the nasopharynx of children from a Mexican public day-care center. MATERIAL AND METHODS: Nasopharyngeal cultures were performed in children from rooms B (RB) (n = 35) and C (RC) (n = 37). The Restriction Fragment Length Polymorphism (RFLP) patterns were compared among GAS isolates. A social networks questionnaire was filled out for each child and 10 classmates. Structure coefficients were compared among children with and without GAS. RESULTS: Four GAS clones were identified; clone I in five children from RC; clone II in two from RC and one from RB; clone III in one from RB and one from RC; and clone IV in one from RC. Social network structure: Density of RB and RC = 0.40 (+/- 0.87) and 0.35 (+/- 0.80), respectively. In RB, the homophily pattern of interaction was different in carriers (0.00), non-carriers (0.47) and both (0.47) p = 0.35. In RC, the homophily pattern was also different in carriers (0.46), non-carriers (0.68) and mixed (0.19), p = .001. In 4/5 with clone I, the values of degree, closeness and betweenness were above the group mean. In 3/3 with clone II, the values of degree and betweenness were also above the mean. In contrast, in those with clone III and IV, the values of degree, closeness and betweenness were below the group mean. CONCLUSION: The spread of specific GAS clones was associated with groups of children having a high proportion of ties and a high centrality level. This is evidence that spread of GAS strains among children attending day-care centers is not random but dependent on the degree of communication and physical contact between pairs.     

Progress toward characterization of the group A Streptococcus metagenome: complete genome sequence of a macrolide-resistant serotype M6 strain

We describe the genome sequence of a macrolide-resistant strain (MGAS10394) of serotype M6 group A Streptococcus (GAS). The genome is 1,900,156 bp in length, and 8 prophage-like elements or remnants compose 12.4% of the chromosome. A 8.3-kb prophage remnant encodes the SpeA4 variant of streptococcal pyrogenic exotoxin A. The genome of strain MGAS10394 contains a chimeric genetic element composed of prophage genes and a transposon encoding the mefA gene conferring macrolide resistance. This chimeric element also has a gene encoding a novel surface-exposed protein (designated "R6 protein"), with an LPKTG cell-anchor motif located at the carboxyterminus. Surface expression of this protein was confirmed by flow cytometry. Humans with GAS pharyngitis caused by serotype M6 strains had antibody against the R6 protein present in convalescent, but not acute, serum samples. Our studies add to the theme that GAS prophage-encoded extracellular proteins contribute to host-pathogen interactions in a strain-specific fashion.     

Cytocidal effect of Streptococcus pyogenes on mouse neutrophils in vivo and the critical role of streptolysin S

We analyzed the in vivo dynamics of peritoneal exudate cells (PECs) in mice injected with group A streptococcus (GAS). A live low-virulence strain, as well as heat-killed low- and high-virulence strains, significantly increased the number of PECs (primarily neutrophils), whereas a live high-virulence strain did not. When coinjected with thioglycollate, the live high-virulence strain, as well as most other GAS strains, suppressed the ability of thioglycollate to induce neutrophil exudation. This suppression was due to a cytocidal effect of GAS on exuded neutrophils rather than an inhibition of neutrophil migration. In addition, GAS enhanced the apoptosis of neutrophils. These cytocidal effects were significantly reduced by the deletion of functional streptolysin S from GAS. Our findings suggest that, in addition to the production of antiphagocytic factors and survival inside phagocytes, GAS uses a more aggressive method--the elimination of neutrophils--to evade the host's innate immune system.     

Invasive group A streptococcal infections in a large tertiary center: epidemiology,characteristics and outcome

Background: Invasive group A streptococcal (GAS) infections are increasing alarmingly worldwide. Patients and Methods: To determine the clinical and epidemiologic characteristics of invasive GAS in a large tertiary medical center, we retrospectively surveyed microbiology and medical records of patients with invasive GAS infections (isolation of Group A Streptococcus from a normally sterile site) treated in our hospital from January 1995 to December 1997. Results: 70 patients with a median age of 48 years (range 2 months–88 years) were identified. Of the 70 identified, 53 (76%) were adults (age ≥ 19 years). The most common co-morbid diseases for invasive GAS in adults were diabetes mellitus, congestive heart failure (CHF), malignancy and immunosuppression. A probable port of entry was identified in 31 (44%) of the cases. In children, varicella lesions were the major port of entry. Overall mortality rate was 17%: The difference in mortality between pediatric and adult cases was significant (0/17 vs 12/53, respectively; p = 0.03). Toxic shock syndrome (TSS) and necrotizing fasciitis were identified in 8.6% and 5.7% of the cases, respectively, with mortalities of 83.3% and 25%. Hyponatremia and hypocalcemia were more frequently observed among the severely ill. Conclusion: Invasive GAS infections tend to have an unexpected course and a broad clinical spectrum, ranging from local skin or pharyngeal involvement to deeply invasive fasciitis with TSS and high mortality. The elderly and those with underlying medical conditions are at utmost risk for invasive GAS. Clear-cut guidelines for early therapeutic strategy, i. e. antibiotic administration and preemptive hospital admission are needed for community-based physicians. Received: December 21, 2000 · Revision accepted: January 9, 2002