Nonsuppurative Sequelae Research Articles

Adult and pediatric pharyngitis: A review

Acute pharyngitis is frequently encountered in the ambulatory care setting. Although usually of viral etiology, streptococcal disease is the focus of diagnostic efforts, in light of significant suppurative and nonsuppurative sequelae. The traditional symptoms of fever, adenopathy, and pharyngeal exudate are suggestive, but not diagnostic of streptococcal pharyngitis. Thus, the importance of diagnostic testing, including Group A beta hemolytic strep antigen screen and culture, is emphasized. Recent innovations in therapy include modification of antibiotic dosing regimens and use of cephalosporins to improve patient compliance.

INVASIVE GROUP A STREPTOCOCCAL INFECTIONS

Beginning in the mid-1980s and continuing to the present, there has been an apparent increase in the number of severe group A streptococcal infections and their suppurative and nonsuppurative sequelae. The reasons for this epidemiologic change remain incompletely explained. At present, the data seem to suggest that this change is related to the reappearance in the population of not only "new" serotypes, but most likely virulent strains of these serotypes. This has been suggested by available epidemiologic surveys. The pathogenetic mechanism by which these virulent strains cause an increased severity of disease is also incompletely understood. It has been suggested that certain of the streptococcal pyrogenic exotoxins (pyrogenic exotoxin A or B) are associated with strains isolated from severe cases of systemic group A streptococcal infections, but the data conflict in many instances. Clinically, this is an extraordinarily virulent syndrome often leading to the death of the patient within a matter of hours or days. This is despite what would seem to be adequate and appropriate antimicrobial therapy with agents which are effective in vitro against the offending group A streptococcus. Therapy therefore is still based on appropriate antibiotic therapy and support of other systemic manifestations with appropriate medical therapy. At present, prevention of these suppurative and nonsuppurative sequelae is impractical simply because the initial streptococcal infection or colonization is rarely recognized. These events of the last half decade strongly support the need for additional understanding of the epidemiology, pathogenesis, treatment, and prevention of serious group A beta-hemolytic streptococcal infections.

Induction of antigen‐specific CD8+ cytolytic T cells by the exogenous bacterial antigen streptolysin O in rhesus monkeys

We have characterized the T cell responses induced by streptolysin O (SLO), a sulfhydryl-activated hemolysin secreted by streptococci, by applying long-term in vitro culture and cloning rhesus monkey (Macaca mulatta) T cells. T cell lines specific for SLO were obtained from three rhesus monkeys. These T cell lines required autologous antigen-presenting cells (APC) to proliferate in response to SLO and did not respond to purified protein derivative. Phenotypic analysis showed that the cells from two of three SLO-specific T cell lines were more than 85% CD3+CD4-CD8+ after prolonged in vitro culture. The rh 1842 CD8+ T cell line proliferative response to SLO was inhibited by the addition of anti-major histocompatibility complex (MHC) class I and anti-CD8 but not of anti-MHC class II and anti-CD4 monoclonal antibody (mAb). This cell line was able to lyse P815 target cells in the presence of anti-CD3 mAb and did not show natural killer activity. Moreover, specific lysis of autologous but not allogeneic non-rosetting E- cell targets pulsed with SLO was observed. Such lysis was inhibited by the addition of anti-MHC class I mAb. In the attempt to identify the restriction elements involved in SLO presentation APC from six unrelated rhesus monkeys and three humans were used. A CD4+ rh 1842 T cell clone responded when SLO was presented by one of six, and a CD8+ rh 1842 T cell clone by four of six rhesus monkeys APC. Both CD4+ and CD8+ T cell clones did not respond when SLO was presented by human APC. However, both clones responded when APC from all donors were used in conjunction with anti-CD3 mb. Furthermore, SLO required active processing to be presented to CD4+ and CD8+ T cell clones as glutaraldehyde fixation of APC before but not after antigen pulsing inhibited T cell proliferation. The SLO-specific CD8+ cytolytic T cells described here could play a role in the regulation of the immune response occurring during streptococcal infections and/or could participate in the pathogenesis of poststreptococcal nonsuppurative sequelae.

Human heart sarcolemmal sheath antibodies in children with non-suppurative sequelae of group A streptococcal infections: a follow up study.

The kinetics of the human heart sarcolemmal sheath antibody were studied in children with acute rheumatic fever who had no carditis, children with acute rheumatic fever who had carditis and developed rheumatic heart disease, and in children with acute poststreptococcal glomerulonephritis. The children with rheumatic fever and those who developed valvular heart disease were given continuous secondary antistreptococcal prophylaxis. The titre of antibody at onset was significantly higher than that of the controls in children with acute rheumatic fever and carditis and in children with acute poststreptococcal nephritis. The difference in the antibody titre between children with rheumatic fever who had no carditis and controls was not statistically significant. After a mean follow up of three years, however, a high titre was only maintained in children with rheumatic fever who developed valvular heart disease.

Polyclonal B-cell activation by bacteria that induce nonsuppurative sequelae.

The polyclonal B cell activation (PBA) process induced by Klebsiella pneumoniae K34 (klebs) and Yersinia enterocolitica 03 (yers) was investigated. Both heat-inactivated bacteria and their cell wall biostructures (klebsM, muriene, protein I etc.) stimulate human blood B cells to differentiate into immunoglobulin-secreting cells without prior proliferation and without T cells. Klebs-activated B cells secrete mainly IgM and to a lesser degree IgG (mainly IgG2). The PBA process was regulated by CD4+ cells and monocytes, but not by CD8+ cells. While interleukin 2 is able both to induce proliferation and to enhance differentiation in klebs-activated B cell cultures, the low-molecular-weight B cell growth factor (BCGF) did not lead to a significant amount of 3H-thymidine uptake. In addition, in klebs-activated B cell cultures various anti-polynucleotide autoantibodies and the 16/6 idiotype were detectable. Thus, bacteria that induce nonsuppurative sequelae (e.g. klebs, yers) can use several mechanisms to overcome tolerance in their host.

Diagnosis and management of children with streptococcal pharyngitis.

Physicians must be aware that rheumatic fever can no longer be considered a disease of the past and be prepared to diagnose and treat promptly children with streptococcal pharyngitis. Although the rapid diagnostic kits for detecting Group A streptococci in pharyngeal swabs are not perfect, they can be useful to the practitioner if positive because the specificity of the test is excellent. Thus, a child with pharyngitis who has a positive rapid test should be treated immediately to shorten the period of morbidity and to reduce the risk of nonsuppurative sequelae. Upon completion of a 10-day treatment course there is usually no reason to reculture the pharynx if the child is asymptomatic. Recurrence of symptoms is an indication to perform another culture and to retreat with either benzathine penicillin G or erythromycin depending on compliance of the patient and the agent used initially for therapy. Eradication of Group A streptococci from the pharynx of children who are carriers is usually a difficult and unnecessary task. When eradication is indicated, such as when the carrier has had contact with a person who had rheumatic fever, rifampin should be added to the penicillin regimen (Table 4).

Streptococcal Group A polysaccharide Antibodies Assayed by an ELISA Determination of Antibodies in Rabbit Hyperimmune Sera; Normal levels in Man and Comparison with Levels in Patients with Rheumatic Fever and with Poststreptococcal Glomerulonephritis

An enzyme-linked immunosorbent assay (ELISA) was adapted to measure antibodies to streptococcal group A polysaccharide. The components of the reaction were studied, including the concentration of the polysaccharide antigen, the suppression of non-specific reactions, optimal conjugate binding conditions and the most suitable plates. The specificity of this test was documented by studies using immune sera and polysaccharide antigens of various groups of beta-hemolytic streptococci. In addition dynamics of the antibody response in animals as well as in man were investigated. The upper limit of normal level of this antibody in normal healthy persons was determined by this technique. We found that 80% of patients with rheumatic fever and acute glomerulonephritis showed an elevation of the group A polysaccharide antibody titer. Determination of this antibody response by the ELISA technique is clinically useful in evaluation patients with the nonsuppurative sequelae of group A streptococcal infections.

Prevention of Streptococcal Neurosis

Despite the decrease in the incidence and severity of rheumatic fever and rheumatic heart disease in the United States, overzealous emphasis on proper diagnosis and treatment of group A streptococcal pharyngitis in order to prevent these illnesses may often result in a frustrating, anxiety-provoking condition known as "streptococcal neurosis." Physicians, parents, and patients may all suffer from this condition, which often occurs even after all possible and appropriate treatment has been used to eradicate the group A streptococci. "Streptococcal neurosis" and the perplexing problem of treatment failure can be avoided or alleviated by utilizing knowledge of the interrelationship of the human host, the group A streptococcus, and nonsuppurative sequelae.

An evaluation of penicillin prophylaxis during an outbreak of foodborne streptococcal pharyngitis.

Between August 16 and 21, 1974, an outbreak of beta-hemolytic group A M-9 T-9 streptococcal pharyngitis affected 49% of a randomly selected group of inmates at a jail in southern Florida. Food-specific attack rates incriminated improperly stored egg salad served at lunch on August 16 as the vehicle of transmission. By August 20, 290 symptomatic inmates had been placed on penicillin or erythromycin; on that day fewer than 5% of throat cultures from 400 allegedly non-penicillin-allergic largely asymptomatic inmates, cultured just before penicillin prophylaxis, were positive for the epidemic strain. At the time prophylaxis was given, secondary transmission had accounted for only 3% of cases. No non-suppurative sequelae were observed but 5% of inmates who received penicillin prophylaxis experienced an adverse reaction to the drug. Although widespread penicillin prophylaxis during outbreaks of group A beta-hemolytic streptococcal pharyngitis will likely prevent transmission of these organisms, prompt treatment of all symptomatic cases may be equally as effective in controlling adult institutional foodborne outbreaks of streptococcal pharyngitis and will likely minimize the number of adverse reactions to penicillin which may be seen.

Specificity and Sensitivity of the Streptozyme Test for the Detection of Streptococcal Antibodies

A comparison between the results of the streptozyme hemagglutination test and serological titers for anti-streptolysin O (ASO), anti-hyaluronidase (AH), anti-deoxyribonuclease B (ADN-B), and anti-nicotinamide adenine dinucleotidase (ANAD) was made in two groups of human sera. In one group, serological titers for all the four antibodies were lower than the threshold of sensitization reported by the producing firm. In the second group, the titer of at least one of the four antibodies was equal to or higher than the threshold. False-positive and false-negative reactions occur with those sera when one or more antibody titer is at or near the threshold of the test as described by the manufacturer. The test was positive for all sera where either the ASO was greater than 166 or the ANAD was greater than 270, and for 98% of the sera with ADN-B greater than 360. It is, therefore, concluded that the streptozyme test can be used as an adjunct to the clinical diagnosis of streptococcal infections and their nonsuppurative sequelae. It is less useful to assess the levels of antibodies in sera from general population surveys. For such sera, the relative specificity and sensitivity of the test might yield misleading results. Until more experience is gained with the test, caution should be used in its application to infant and older adult age groups, where significant streptococcal antibody titers are frequently near the threshold of the test.

IMMUNOLOGY OF STREPTOCOCCAL INFECTION

Summary.— The antigenic properties of clinically important β‐haemolytic streptococci and the immunological response to infection with these organisms are described. The relevance of streptococcal antigens in the production of nonsuppurative sequelae to infection such as rheumatic fever, acute post‐streptococcal glomerulonephritis and certain skin diseases is discussed in relation to possible immunopathological mechanisms. It is concluded that although striking immunological phenomena have been demonstrated in several of these diseases their exact relation to tissue damage and to the production of lesions remains to be clarified.

AN EFFECTIVE PROGRAM FOR REDUCING GROUP A STREPTOCOCCAL PREVALENCE

A relatively simple and inexpensive streptococcal control program was applied to two school populations located in an area of high endemicity in Colorado. Throat cultures were obtained from children admitting sore throat and from a small, continuously rotating random sample of the student body. This method of surveillance provided a reliable index of total streptococcal incidence in the two schools. Children with Group A positive cultures sought consultation with private physicians on a voluntary basis. The application of these sampling procedures resulted in a reduction of prevalence rates to less than 5%. Comparable endemic prevalence rates observed in school children in three other Colorado communities averaged 21.9%. The program described is practical and effective in substantially lowering the incidence of Group A infections and reducing risk to development of nonsuppurative sequelae.

Food-borne epidemic of streptococcal pharyngitis at the United States Air Force Academy.

Abstract An explosive epidemic of pharyngitis due to Group A streptococci occurred among the cadets at the United States Air Force Academy during a seven-day period in the spring of 1968. Symptoms of streptococcal pharyngitis developed in over 1000 cadets during the course of the epidemic. Prompt institution of control measures probably confined the outbreak to the cadet wing and prevented extensive secondary spread. The epidemic strain was identified as a Group A, T-Type 12 streptococcus that could not be M-typed with available typing serums and may represent a new M-Type. An epidemiologic investigation incriminated a single food item as the vehicle of transmission. Nonsuppurative sequelae were not detected despite intensive surveillance.

Mimetic Relationships Between Group A Streptococci And Mammalian Tissues

This chapter discusses the role of structural similarities between parasite and host in initiating pathological events, primarily through immunological reactions to the parasite affecting the host. It is a particularly promising approach to the study of rheumatic fever and the various connective tissue disorders and is summarized well by a pioneer in this field. In this connection, special emphasis is placed on the nature of the role this biological mimicry play in streptococcal infections and their nonsuppurative sequelae. Evidence for cross-reactions between host and parasite in other biological organisms is discussed primarily as they relate to similar observations in the Group A streptococcus and its host. Orientation to specific details of biological mimicry among bacteria or helminthes and the blood group substances, heterophile antigens, and tissue-specific antigens is obtained. The long association of this organism to the pathogenic infections of man and its relationship to the nonsuppurative sequelae following a streptococcal infection makes it an ideal model for the study of biological mimicry between host and parasite.

A streptococcal epidemic in an isolated civilian population with institution of mass prophylaxis

A virulent streptococcal epidemic involving two strains concurrently occurred in Eagle Butte, South Dakota, in the spring of 1965. Index cases of acute rheumatic fever and acute glomerulonephritis occurred in this isolated civilian population. Certain criteria, previously proposed, confirm streptococcal epidemicity and offer guidelines in the consideration of mass prophylaxis. A mass prophylaxis regimen was applied to this population. The epidemic was interrupted and additional cases of nonsuppurative sequelae may have been prevented.

THE DETERMINATION OF ANTIBODY TO GROUP A STREPTOCOCCAL POLYSACCHARIDE IN HUMAN SERA BY HEMAGGLUTINATION.

A hemagglutination method employing tanned human O erythrocytes sensitized with purified Group A streptococcal polysaccharide has been developed to measure A polysaccharide antibody in antistreptococcal rabbit and human sera. The reaction of sensitized RBC with known Group A streptococcal rabbit antisera, inhibition of hemagglutination with A polysaccharide, and abolition of hemagglutination and hemagglutination-inhibition by exposure of polysaccharide antigen to A enzyme, which destroys the specific immunologic determinant of A carbohydrate, were utilized to demonstrate the specificity of this hemagglutinating system. The results of A polysaccharide antibody determinations on sera from normal persons, patients convalescent from streptococcal infection, and patients with non-suppurative streptococcal sequelae are presented.

IMMUNOLOGIC RELATION OF STREPTOCOCCAL AND TISSUE ANTIGENS. III. PRESENCE IN HUMAN SERA OF STREPTOCOCCAL ANTIBODY CROSS-REACTIVE WITH HEART TISSUE. ASSOCIATION WITH STREPTOCOCCAL INFECTION, RHEUMATIC FEVER, AND GLOMERULONEPHRITIS.

Sera from patients with recent streptococcal infection or non-suppurative sequelae exhibit with variable frequency a precipitin reaction in agar gel with a partially purified streptococcal antigen which has been shown previously to be immunologically related to human heart tissue. This precipitin could be absorbed from sera with normal human heart tissue homogenates but not with homogenates of other organs. Demonstration of this cross-reaction by heart absorption was found dependent both upon the serologic properties of individual sera and the nature or state of purification of the streptococcal product employed as test antigen. Evidence was obtained of a close association of heart-related and non-heart-related antigenic determinants in partially purified preparations of the streptococcal antigen by both gel diffusion and immunoelectrophoresis. On immunoelectrophoretic analysis, cross-reactive antigen exhibited a more rapid mobility toward the anode than M protein. It was destroyed by digestion with trypsin, pepsin, and chymotrypsin. Based on specific absorption tests with a Type 5 and Type 19 strain, the antigen was localized to cell walls and to a lesser extent to cell membranes of these strains. Precipitating activity related to cross-reactive antibody was localized to the immunoglobulin zone in immunoelectrophoresis. Reactive sera showed diminution or loss of serological activity following heat inactivation at 56 degrees C or after prolonged storage at 4 degrees C. Sera containing cross-reactive precipitating antibody exhibited an immunofluorescent reaction with sarcolemma of cardiac myofibers, which was inhibited by streptococcal cross-reactive antigen. By this inhibition test, the immunofluorescent reaction related to cross-reactive antibody could be distinguished from that due to other heart-reactive factors. Antibody to streptococcal cross-reactive antigen defined by precipitation-absorption tests was observed in 24 per cent of patients with recent history of uncomplicated streptococcal infection and in the majority of patients with acute rheumatic fever, rheumatic heart disease, or acute glomerulonephritis. It was observed rarely in patients with non-streptococcal related disease. These data provide evidence that induction of cross-reactive autoantibody to heart in certain individuals is associated with streptococcal infection.

Attack Rates of Streptococcal Pharyngitis, Rheumatic Fever and Glomerulonephritis in the General Population

SINCE the attack rate of rheumatic fever and of acute hemorrhagic glomerulonephritis after untreated infection due to Group A streptococci has been estimated at between 1.5 and 5 per cent1 2 3 4 5 penicillin treatment has been widely recommended for the control of these late nonsuppurative sequelae. The attack rate of glomerulonephritis is even higher when related to Type 12 infections.6 The attack rate of both diseases has been determined primarily from epidemic studies conducted in more or less closed communities living under epidemiologic conditions not prevalent in the general population.Several recent reports7 8 9 10 11 12 13 14 have suggested that rheumatic fever and glomerulonephritis occur less . . .

Streptococcal sore throat and throat culture.

In view of the availability of laboratory aids applicable in modern medical practice, it is difficult indeed for the general practitioner to cite inconvenience, delay or inaccessibility as a reason for failure to employ these technics to determine whether or not a case of pharyngitis or tonsillitis is due to streptococci. As the general practitioner employs these aids, benefits will accrue in terms of more accurate diagnosis, applied specific therapy, and decreased opportunity for drug sensitivity and development of resistant strains of staphylococci, as well as possible clarification of the epidemiology of nonsuppurative sequelae of streptococcal sore throat.

Immunological studies on a C polysaccharide complex of group A streptococci having a direct toxic effect on connective tissue.

A macromolecular complex of C polysaccharide and peptide derived from Group A streptococcal cells produces a multinodular, remittent, and intermittent lesion of dermal connective tissue following a single intradermal injection. This lesion is greatly modified, both in the gross and microscopically, in rabbits hyperimmunized with a Group A streptococcal vaccine. The immune serum, absorbed to yield only antibodies against C polysaccharide as indicated by agar diffusion techniques, will precipitate and neutralize the toxic material. This neutralization and in vitro precipitation can be inhibited with formamide-isolated C polysaccharide hapten and with N-acetylglucosamine, the primary directive group of this antigen. This clearly demonstrates that antibodies against the group-specific C polysaccharide are responsible for resistance to this toxic material. The immunological and other properties of the toxic C polysaccharide complex, the fact that it is a product of Group A streptococci, the gross and microscopic features of the experimental lesion produced with this substance, and the observations on the chronic course of the experimental lesion, indicate that this toxic material should be investigated as a possible factor in the pathogenesis of the non-suppurative sequelae associated with Group A streptococci.