Streptococcal superantigens and the return of scarlet fever.

Streptococcus pyogenes (group A Streptococcus) is a globally disseminated and human-adapted bacterial pathogen that causes a wide range of infections, including scarlet fever. Scarlet fever is a toxin-mediated disease characterized by the formation of an erythematous, sandpaper-like rash that typically occurs in children aged 5 to 15. This infectious disease is caused by toxins called superantigens, a family of highly potent immunomodulators. Although scarlet fever had largely declined in both prevalence and severity since the late 19th century, outbreaks have now reemerged in multiple geographical regions over the past decade. Here, we review recent findings that address the role of superantigens in promoting a fitness advantage for S. pyogenes within human populations and discuss how superantigens may be suitable targets for vaccination strategies.

Hallazgos clínicos inusuales en un brote de escarlatina / Unusual clinical findings in an outbreak of scarlet fever

Introducción: la escarlatina es una enfermedad infecciosa producida por Streptococcus pyogenes que produce un cuadro característico de faringoamigdalitis y exantema. Su diagnóstico suele ser fácil, pero los casos atípicos pueden pasar desapercibidos o ser confundidos con otros cuadros. Pacientes y método: estudio descriptivo retrospectivo de los casos de escarlatina en la población pediátrica adscrita a un centro de salud en la temporada 2013/2014. Describimos la epidemiología, las características clínicas, las pruebas microbiológicas, el tratamiento y la presencia de recidivas. Resultados: se obtuvieron 91 casos, resultando una incidencia de 3,2%, de los que 76 fueron confirmados microbiológicamente con test rápido o cultivo. La edad media fue 4,15 años. Los principales motivos de consulta fueron 'fiebre y dolor de garganta' y 'fiebre y erupción cutánea'. Las alteraciones faríngeas más frecuentes fueron la hiperemia y petequias en paladar, y en pocos pacientes se encontró exudado amigdalar. Casi un 40% de pacientes tenían síntomas catarrales, 71 pacientes presentaban un exantema típico, y 20 uno atípico. La mayoría se trató con amoxicilina o penicilina durante diez días; 15 pacientes tuvieron recidivas. Conclusiones: de los datos obtenidos destacan el gran número de casos, la presencia de síntomas catarrales y la poca frecuencia de exudado amigdalar. Fue llamativa la variabilidad de los exantemas con hallazgos como eritrodermia extensa, urticaria, exantema macular, petequias en localizaciones atípicas y edema facial y de miembros. El test rápido en Atención Primaria permite, por su utilidad, el diagnóstico de casos dudosos (AU)

Introduction: scarlet fever is an infectious disease caused by Streptococcus pyogenes that manifests as a typical pharyngoamigdalitis and exanthema. Its diagnosis is usually easy, but atypical cases may go unnoticed. Patients and methodology: retrospective descriptive study of pediatric population assigned to a Primary Care center a health centre between 2013/2014. We define the epidemiology, clinical characteristics, microbiological tests, treat­ment and appearance of relapses. Results: 91 cases, resulting in an incidence of 3.2% of which 76 were confirmed microbiologically with a rapid test or culture. The average age was 4,15 years. The main reasons for consultation were 'fever and sore throat' and 'fever and rash'. The most common alterations were pharyingeal hyper­emia and petechiae on the palate and in a few patients we found tonsillar exudate. Almost 40% of patients had catarrhal symptoms. 71 patients showed a typical exanthema and 20 of them an atypical one. Most of them were treated with amoxicillin or penicillin for 10 days. 15 patients had recurrence. Conclusions: from the data obtained it is important to highlight the large amount of cases, the presence of catarrhal symptoms and the infrequency of tonsillar exudates. It was remarkable the variability of recurrences with findings such as extensive erythroderma, urticaria, macular rashes, atypically placed petechiae and facial and member edema. The rapid test on primary care units allows diagnosis on doubtful cases (AU)

Scarlet Fever Upsurge in England and Molecular-Genetic Analysis in North-West London, 2014.

Scarlet fever notifications surged across the United Kingdom in spring 2014. Molecular epidemiologic investigation of Streptococcus pyogenes infections in North-West London highlighted increased emm4 and emm3 infections coincident with the upsurge. Unlike outbreaks in other countries, antimicrobial resistance was uncommon, highlighting an urgent need to better understand the drivers of scarlet fever activity.

[Scarlet fever with multisystem organ failure and hypertrophic gastritis]. / Scarlatine compliquée d'une défaillance multiviscérale avec gastrite hypertrophique.

Scarlet fever is a rare disease in adult patients. We report a patient in whom scarlet fever was associated with hypertrophic gastritis and multiple organ failure. A 62-year-old woman presented with septic shock and multiple organ failure. Bacteriological survey was negative. Abdominal tomodensitometry showed an hypertrophic gastritis. Histological analysis demonstrated a non specific gastritis without any tumoral sign. Cefotaxime and amoxicillin led to improvement and hypertrophic gastritis progressively resolved. A sandpaper rash over the body with finger desquamation, elevation of antistreptolysin O and a recent contact with an infected grandson led to the diagnosis of scarlet fever. Due to antibiotic prescription, scarlet fever is now uncommon. Although classical, ENT or gastroenteritis presentations may be puzzling for the diagnosis of scarlet fever. As 150 years ago, diagnosis of scarlet fever is still a clinical challenge.

An SEIQR model for childhood diseases.

It has been shown that the inclusion of an isolated class in the classical SIR model for childhood diseases can be responsible for self-sustained oscillations. Hence, the recurrent outbreaks of such diseases can be caused by autonomous, deterministic factors. We extend the model to include a latent class (i.e. individuals who are infected with the disease, but are not yet able to pass the disease to others) and study the resulting dynamics. The existence of Hopf bifurcations is shown for the model, as well as a homoclinic bifurcation for a perturbation to the model. For historical data on scarlet fever in England, our model agrees with the epidemiological data much more closely than the model without the latent class. For other childhood diseases, our model suggests that isolation is unlikely to be a major factor in sustained oscillations.

Pathogenesis of poststreptococcal glomerulonephritis a century after Clemens von Pirquet.

Considerable insight has been gained into the etiopathogenesis of poststreptococcal glomerulonephritis since the landmark theoretical construct of Clemens von Pirquet postulated that disease-causing immune complexes were responsible for the nephritis that followed scarlet fever. Over the years, molecular mimicry between streptococcal products and renal components, autoimmune reactivity and several streptococcal antigens have been extensively studied. Recent investigations assign a critical role to both in situ formation and deposition of circulating immune complexes that would trigger a variety of effector mechanisms. Glomerular plasmin-binding activity of streptococcal glyceraldehyde-3-phosphate-dehydrogenase may play a role in nephritogenicity and streptococcal pyrogenic exotoxin B and its zymogen precursor may be the long-sought nephritogenic antigen.

Escarlatina recurrente por reinfección reciente causada por cepas no relacionadas de Streptococcus pyogenes / Recurrent scarlet fever due to recent reinfection caused by strains unrelated to Streptococcus pyogenes

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Reactivity of rheumatic fever and scarlet fever patients' sera with group A streptococcal M protein, cardiac myosin, and cardiac tropomyosin: a retrospective study.

Archived sera (collected in 1946) from acute rheumatic fever (ARF) and untreated scarlet fever and/or pharyngitis patients were reacted with streptococcal M protein, cardiac myosin, and cardiac tropomyosin. Except for very low levels to tropomyosin, antibodies to other antigens were not elevated in the sera of ARF patients relative to those of non-ARF patients, even though there was roughly equivalent exposure to group A streptococci. This suggests that antibodies to these molecules may not play a central role in the induction of ARF.

Increased level of circulating gamma/delta T cells in a patient with eosinophilic granuloma.

A patient with eosinophilic granuloma, histologically confirmed from open lung biopsy specimen, had a history of scarlet fever and a prominently high level of circulating gamma/delta T cells (25 percent) in comparison with normal levels (< 10 percent). Despite steroid therapy, the levels were persistently high. To our knowledge, this is the first report of an increased level of circulating gamma/delta T cells in a patient with eosinophilic granuloma.

Stimulation of human T cells by streptococcal "superantigen" erythrogenic toxins (scarlet fever toxins).

The pyrogenic (erythrogenic) exotoxins A and C (SPEA and SPEC) of Streptococcus pyogenes belong to the family of mitogenic toxins of which the staphylococcal enterotoxins are the prototypes. The erythrogenic toxin B (SPEB) is a proteinase precursor. All SPE have been reported to be superantigens. Here we have analyzed the human T cell response to these toxins. We used highly purified preparations of SPEA, SPEB, and SPEC from different S. pyogenes strains. These toxins were apparently homogenous in SDS-PAGE, IEF, and HPLC. In addition, recombinant SPEA and SPEC were produced in Escherichia coli. In cultures of PBMC, all three toxins expanded preferentially a fraction of T cells. Using mAb against V beta 2, -5, -6, -8, and -12, we investigated the phenotype of the stimulated cells. Natural SPEA, SPEB, and SPEC strongly stimulated V beta 8+ T cells, whereas recombinant SPEA and SPEC did not. Both natural and recombinant SPEA stimulated V beta 12+ cells and both natural and recombinant SPEC stimulated V beta 2+ cells. In accordance with these findings, a human V beta 8+ line responded to all three toxins derived from S. pyogenes but not to the recombinant proteins. An antiserum against natural SPEC neutralized specifically the V beta 2-stimulating activity of SPEC and the V beta 8-stimulating activity of all three toxins, but had no effect on the response to other superantigens. This shows that trace amounts of a potent novel V beta 8-stimulating activity not identical to SPEA and SPEC are responsible for the stimulation of V beta 8+ T cells by natural SPEA and SPEC reported previously. In a preliminary screening of S. pyogenes strains from patients, we found that this novel superantigen appears to be more widely distributed than SPEA and SPEC. Furthermore, we present evidence that also the superantigenic properties of SPEB are due to contaminations with this V beta 8 stimulator. The response to SPEB usually required 1000 times higher concentrations than to SPEA or SPEC. Antisera to SPEC but not to SPEB inhibited the response of PBMC and V beta 8+ Jurkat cells to SPEB. Furthermore, more stringent purification of SPEB yielded SPEB preparations devoid of mitogenic activity. These results indicate that the mitogenicity that is commonly attributed to SPEB is due to minute contaminations of the V beta 8 stimulator. These results raise two important caveats for the work with these highly potent T cell mitogens.(ABSTRACT TRUNCATED AT 400 WORDS)

Development and evaluation of capture enzyme-linked immunosorbent assays for detection of immunoglobulin G and M antibodies to group A streptococcal antigens.

Capture enzyme-linked immunosorbent assays (ELISAs) were developed to detect immunoglobulin G and M antibodies to group A streptococcal (GAS) antigens, streptolysin O, streptokinase, and group A carbohydrate. The sensitivities and the specificities of the IgM capture ELISAs to each GAS antigen were high enough to distinguish the patients with GAS infections (diagnosed as GAS pharyngitis or scarlet fever) from the control groups (healthy people and patients with pharyngitis from whom GAS could not be isolated). On the other hand, the specificities of the IgG capture ELISAs were not very effective in diagnosis of GAS infections. When the capture ELISA and an indirect ELISA detecting IgM antibodies to group A carbohydrate were compared, false-positive reactions due to rheumatoid factor occurred in the indirect ELISA, but did not occur in the capture ELISA. These results indicate that the capture ELISA works better than the indirect ELISA in detecting the IgM antibody, and that the IgM capture ELISA to GAS antigen provides a rapid and highly reliable serodiagnosis for GAS infections employing only a single serum.

Outbreaks of group A beta-hemolytic streptococcal pharyngitis in children: correlation of serotype T4 with scarlet fever.

We evaluated the clinical features of 121 children who had group A beta-hemolytic streptococcal (GABHS) pharyngitis during 2 outbreaks in the Chikuhou district, Fukuoka, Japan, with respect to T types. During the first outbreak (November 1989-February 1990), T12 (50%) and T22 (27%) were the dominant T types isolated. During the second outbreak (January-April 1991), 64% of the typable strains were T4. Pus on the tonsils was less common and strawberry tongue more common in patients with eruptions than in those without. Skin eruptions were much more common in the patients infected with T4 than with other T types (p < 0.001). Despite a 10-day regimen of amoxicillin, 12/69 patients (17.4%) had evidence of GABHS on repeat cultures. The results suggest that T4 may be associated with a high incidence of scarlet fever. Serotyping should be performed to identify disease carriers and patterns of GABHS infection.

[The OF characteristics of streptococci group A and immunity to streptococcal infection based on the results of OF and anti-OF tests]. / OF-kharakteristika streptokokkov gruppy A i immunitet k streptokokkovoi infektsii po rezul'tatam OF- i anti-OF-testov.

The influence of the OF activity of group A streptococci on their specific pathogenic properties has been shown, which is manifested by increased virulence of these streptococci for children of younger age groups and by a two times higher isolation rate of OF+ strains in tonsillitis than in scarlet fever. The possibility of the indirect evaluation of the content of anti-M-antibodies by the results of the anti-OF test has been revealed, which permits using this test instead of the bactericidal test, more complicated, in the study of immunity to infection induced by group A OF+ streptococci. Among the main methods of laboratory support of epidemiological surveillance on streptococcal infection, the introduction of the highly discriminating OF typing and the anti-OF test into practical use is recommended.

Hypothesis--the natural selection of psoriasis.

The high genetic frequency of some inherited disorders may in part be related to a survival advantage conferred against an environmental hazard. Psoriasis is an inherited disorder which is common amongst populations of northern latitudes. Cutaneous delayed-type hypersensitivity response to streptococcal antigen is altered in such patients with a decrease in induration and erythema. Scarlet fever has until recently been associated with a high childhood mortality, the pathogenesis of which is related to interdependent primary toxicity and secondary toxicity (including delayed-type hypersensitivity) to streptococcal antigen (erythrogenic toxin), leading to cellular damage and potentially lethal shock. Streptococcal infection, usually presenting as pharyngitis, is a classical trigger for both scarlet fever and psoriasis. Individual susceptibility to scarlet fever has been clinically assessed in the past by the Dick test--an intradermal injection of the filtrate of a broth culture of scarlatina-producing strains of Streptococcus giving an erythematous reaction at 24-48 h (Dick-positive). The degree of reaction is directly related to susceptibility to scarlet fever. The severity of and mortality from scarlet fever may be ameliorated by immunological mechanisms also found in psoriatic patients. The high prevalence of psoriasis amongst some populations today may be related to such a protective factor.

Anti-streptopolysaccharide antibody in children with rheumatic fever and scarlet fever.

As the serological test of streptococcal infection, the measurement of anti-exotoxin antibodies such as ASO is widely practiced. M protein of the cell wall of group A streptococcus has type specificity. To detect the anti M protein antibody is very significant, but it is not easy to apply this to clinical practice because there are many types and because of the difficulty of purifying M protein. C polypeptide has group specificity, so the measurement of the antibody to C polypeptide is very important as the serological test of group A streptococcus.

A comparative study of alteration in lymphocyte subsets among varicella, hand-foot-and-mouth disease, scarlet fever, measles, and Kawasaki disease.

Changes in the lymphocyte subsets of 13 patients with varicella, 5 with hand-foot-and-mouth disease, 4 with scarlet fever, 10 with measles and 20 with Kawasaki disease were examined by immunofluorescent flow cytometric analysis using monoclonal antibodies against lymphocyte cell surface antigens. The results were compared with those of age-matched normal controls. A significant increase in the percentage of Leu-2a positive (Leu-2a+) cells was shown during the early convalescence of varicella, scarlet fever and measles. A significant decrease in the percentage of Leu-3a+ cells during the acute phase was common to all the diseases examined, and a significant decrease of Leu-4+ cells was observed except in measles. As a result, a significant decrease in the Leu-3a+/Leu-2a+ ratio was common to all the diseases examined during the acute and/or early convalescent phases. Leu-M3+ cells increased significantly in varicella, scarlet fever, and Kawasaki disease. HLA-DR+ cells increased significantly in varicella and Kawasaki disease. No significant changes in the proportions of Leu-7+, Leu-10+, and 2H7+ cells were found throughout the course of all the diseases examined.