Lewis W. Wannamaker

The Chain that Links the Heart to the Throat

N OWHERE HAVE THE POWER-and the limitations-of antimicrobial agents been more clearly revealed than in the control of rheumatic heart disease. On the one hand, we have an organism which in the test tube is exquisitely and uniformly sensitive to penicillin. And we can point with pride to the remarkable prophylactic record of antimicrobials in reducing the frequency of rheumatic recurrences. On the other hand, we must be cautious in attributing our currently favorable position exclusively or even primarily to the use of antimicrobials. A close examination of the statistics reveals that the rheumatic fever problem was declining before these agents were available.1 The reasons for the beginning decline before the antibiotic era are obscure-possibly due to socioeconomic improvements such as changes in housing or even in nutrition. Since the reasons for this are obscure we must be guarded in our optimism that this trend will continue forever downward. Above all, we must not become mesmerized into believing that antibiotics are the final answer to the rheumatic fever problem, that all we have to do is improve our delivery of health care-spread enough penicillin widely and judiciously-and the disease will disappear completely and permanently. We still have problems. Even with throat

Comparison of the antibody response to streptococcal cellular and extracellular antigens in acute pharyngitis

The antibody response to the group A carbohydrate moiety of the streptococcal cell wall is of special interest because of its postulated role in the pathogenesis of rheumatic valvulitis. The immune response to this somatic antigen was measured in 159 children with culture-proved group A streptococcal pharyngitis and was compared with that to two extracellular antigens of the Group A streptococcus: streptolysin O and streptococcal DNase B. The data suggest that the maximum anti-A-carbohydrate rise occurs soon after the onset of streptococcal pharyngitis in a fashion similar to the response to some streptococcal extracellular antigens. However, the anti-A-carbohydrate antibody response appeared to be a less sensitive indicator of streptococcal upper respiratory tract infection.

The serum opacity reaction of Streptococcus pyogenes : frequency of production of streptococcal lipoproteinase by strains of different serological types and the relationship to M protein production

The serum opacity reaction of Streptococcus pyoyenes (Ward & Rudd, 1938) has been found to be associated with a lipoproteinase which acts upon the ocl lipoprotein of the serum of various species to produce opa.lescence (Krumwiede, 1954; Rowen & Martin, 1963). Some observations on the general properties of the streptococcal factor and on the nature of the reaction in aged serum are recorded in an accompanying paper (Hill & Wannamaker, 1968). Although the nature of the reaction is not fully defined and other factors may possibly produce opalescence in serum, the terms serum opacity reaction (SOR) and lipoproteinase will be used interchangeably in this communication. Data presented by Ward & Rudd (1938), Gooder (1961), and Kohler (1963) suggested to us that production of the serum opacity reaction was rather closely associated with serotype a.s determined by M and T antigens. Burthermore, both Gooder and Kohler concluded that strains which were difficult to type by the Mprecipitin method generally produced a, SOR but that M-typable strains rarely produced this reaction. If an inverse relationship between M-antigen and SOR could be substantiated, the serum opacity reaction might be useful as a preliminary test to characterize group A strains as M-positive or M-negative. Further investigation of the production of this enzyme in individuaWl strains in relationship both to serotype and to production of an M-antigen and an investigation of the consistency of production of lipoproteinase by individual strains were therefore undertaken.

Benzathine penicillin in the prophylaxis of streptococcal skin infections: A pilot study*

The value of intramuscular benzathine penicillin (Bicillin) for the prophylaxis of streptococcal skin infections was examined in a population in which this problem has been endemic for a number of years. Seventy-eight children from 18 families were enrolled in this controlled pilot study and received in a double-blind fashion a single intramuscular injection of either Bicillin or placebo followed in 6 weeks by the opposite of the first injection. Dosage of Bicillin was 600,000 units in children 6 years of age or younger and 1.2 million units in those 7 years or older. During the immediate weeks after injection the prevalence and incidence of skin lesions were reduced in children who had received Bicillin when compared to those who had received a placebo injection. In the 6 week follow-up period after each injection, the overall frequency of lesions was reduced 38 per cent after Bicillin administration, and the duration of protection in individual children ranged from 3 to 6 weeks (mean interval of 4 weeks). However, 18 per cent of children experienced a breakthrough within 5 weeks; the majority of these were 6 years of age or younger. Less protection in younger children may have reflected an influence of age or inadequacy of dosage of the Bicillin.

The serum opacity reaction of Streptococcus pyogenes: general properties of the streptococcal factor and of the reaction in aged serum.

The capacity of certain strains of Streptococcus pyogenes to produce opacity in aged horse serum has been studied. Cells from all stages of the growth cycle are able to produce opacity. Maximal activity is reached towards the end of the exponential phase of growth. Examination of cell fractions obtained by mechanical breakage and differential centrifugation suggested that the cell-bound activity is predominantly associated with the membrane fraction. Extraction with sodium deoxycholate yields a soluble fraction of high activity. There is considerable strain variation in heat stability of the serum opacity factor. Cell-bound activity is often quite resistant to heat, whereas extracted activity is less stable. Low concentrations of divalent cations have an activating effect, whereas high concentrations inhibit the serum opacity reaction. High concentrations of uni-valent cations are without effect on the cell-free enzyme but have an activating effect on the cell-bound enzyme. For both the cell-bound and the cell-free enzyme the pH optimum was 5·8. Although sensitive to trypsin and pepsin, the serum opacity factor appears to be resistant to streptococcal proteinase. Its activity is destroyed by formaldehyde and by periodate but is unaffected by a number of reducing agents. Pre-heating of the serum or the addition of iodoacetate did not affect the serum opacity reaction. The enhanced cholesterol esterification previously described with fresh serum appears to be a secondary reaction. Even when isolated by relatively gentle methods, α-lipoprotein serves as a substrate only in the presence of crystalline serum albumin.

Type 49 Streptococcus pyogenes: phage subtypes as epidemiological markers in isolates from skin sepsis and acute glomerulonephritis.

Studies of group A, M type 49 streptococci from England, Trinidad and Alaska indicate that isolates of this serotype often differ with respect to phage subtype from one geographical area to another, but are generally homogeneous in one place at one time. The findings support the conclusion that acute glomerulonephritis can be associated with a variety of phage subtypes of M type 49 streptococci. In outbreaks of skin sepsis without nephritis in England, the phage subtypes of M type 49 streptococci isolated from skin lesions of meat handlers were the same as those recovered from skin lesions of non-meat handlers in the same community. The findings on the Trinidad isolates suggest that M type 49 streptococci of one phage subtype may persist in a population for 9 years and may result in a second outbreak of acute glomerulonephritis. In an Alaska Eskimo population in whom acute glomerulonephritis was occurring, most of the M type 49 isolates available for testing were of a single phage subtype. Equally prevalent in this population were group A streptococci that exhibited the same T antigen as the type 49 isolates but differed in their serum opacity reaction and phage subtype. This apparently related strain was not typable with available M antisera but showed functional evidence of M protein and is probably a new M type.

Cholesterol Inhibition of Streptolysin O Toxicity for Myocardial Cells in Tissue Culture

Abstract Cholesterol has been shown to inhibit the hemolytic activity and the immunogenicity of streptolysin O. It has been found that in tissue culture, cholesterol also protects spontaneously contracting rat myocardial cells from the cytotoxic injury caused by streptolysin O.

Streptolysin O: Suppression of Its Antigenicity by Lipids Extracted from Skin

Summary Chloroform: methanol extractable lipid(s) from rabbit dermis and epidermis has the ability to prevent hemolysis of erythrocytes by streptolysin O, an extracellular antigen of Group A streptococci. The data from this study also indicate that these same lipid preparations are able to suppress the immune response to this streptococcal antigen. These experimental data appear to provide a logical explanation for the epidemiologic finding that the antistreptolysin O response is feeble following streptococcal impetigo. They may also bear on the clinical observation that rheumatic fever fails to develop after Group A streptococcal infections of the skin. The authors acknowledge the valuable technical assistance of Mrs. Lois Helland and Miss Karen Tanaka in these studies. This work was monitored by the Commission on Streptococcal and Staphylococcal Diseases of the Armed Forces Epidemiological Board, and was supported in part by the United States Army Medical Research and Development Command (DADA17-70-C-0081). This work was also supported in part by a grant from the U. S. Public Health Service (AI 09527). Dr. Wannamaker is a Career Investigator of the American Heart Association.

The immunologic response to group A streptococcal upper respiratory tract infections in very young children

The immunologic responses to streptolysin O and streptococcal deoxyribonuclease B were evaluated in children with group A streptococci recovered from the upper respiratory tract to re-examine the hypothesis that a limited capacity to respond to group A streptococcal infection may explain the rare occurrence of acute rheumatic fever in very young children. ASO and anti-DNase B titers were determined on serial bleedings from a total of 301 individuals (52 less than or equal to 3 years; 249 older than 3 years). Very young children with group A streptococcal upper respiratory tract infections had an immunologic response to SO greater than the response in older children as reflected by the magnitude of the antibody rise, and comparable to the ASO response in older children as measured by the percentage showing a significant titer rise. Similar analyses of the anti-DNase B responses showed the response in young children to be comparable to those of the older group. Clinical manifestations of group A streptococcal upper respiratory tract infection in very young children differ from those observed in older children and have not changed significantly in the past several decades. These data suggest that the infrequent occurrence of acute rheumatic fever in very young children is not due to a difference in antibody response to streptolysin O or streptococcal DNase B.

Immunology of Streptococci

The wealth of antigens and of immune responses associated with streptococci has provided a wide choice of antibodies for clinical diagnosis of streptococcal infections, abundant materials and models for experimental immunologists and immunogeneticists, and a diversity of hypotheses about the pathogenesis of the nonsuppurative complications of streptococcal infections, acute nephritis and acute rheumatic fever.