culture. (i) It can be negative for all potential bacterial agents of pharyngitis. (ii) It can be positive for GAS with a clinical score supporting the GAS diagnosis. The physician will need to decide whether to treat or not. (iii) It can be positive for GAS but represent asymptomatic carriage. During the winter and early spring months, when GAS pharyngitis is most common, carriage rates of between 10 and 20% may be present in children. Antimicrobial treatment in this group is controversial but may be done if recurrent GAS infections are being seen in other family members. (iv) It can be positive for other bacterial agents associated with pharyngitis, including groups C and G streptococci or Arcanobacterium haemolyticum. There is no evidence that these agents cause nonsuppurative poststreptococcal sequelae. Nor is there good evidence that antimicrobials will reduce the length of their disease course. Given the limited benefit, there is no evidence that culture should be used to support treatment of pharyngitis.
3. The patient was at risk for two nonsuppurative poststreptococcal sequelae, rheumatic fever and glomerulonephritis. Because he received antimicrobial therapy, his risk of rheumatic fever was essentially zero. The likelihood of an untreated, infected person developing either one of these complications is low in the industrialized world but is dependent on the serotype of the organism with which he is infected. Typing of GAS, called emm typing, is based on sequence analysis of the gene encoding the M protein, a surface protein that is anchored in the organism’s cell wall. There are >150 different emm types of this antiphagocytic protein. Certain M types, such as M1 and M3, are associated with rheumatic fever and are said to be “rheumatogenic.” Other strains, such as M12 and M49, are considered “nephritogenic” and are associated with glomerulonephritis. Glomerulonephritis is seen following both pharyngitis and skin infections (pyoderma or impetigo), whereas rheumatic fever is believed to occur only following pharyngitis.
These noninfectious poststreptococcal sequelae occur after an acute GAS infection. Rheumatic fever occurs 1 to 5 weeks after infection, while glomerulonephritis following pharyngitis occurs at 1 to 2 weeks and 3 to 6 weeks following pyoderma. Both sequelae are believed to be immune-mediated diseases whereby antibodies made in response to GAS react with tissues in the target organ.
In rheumatic fever, antibodies directed against the M protein are believed to cross-react with a variety of tissue components in the heart, including myosin, laminin, and tropomyosin. This can result in damage to heart valves and muscle and produce the carditis and heart murmurs that are manifestations of this syndrome.
In glomerulonephritis, streptococcal antibodies that cross-react with the glomerular basement membrane are believed to be important in the disease process as well as the deposition in the glomeruli of circulating immune complexes containing streptococcal antigens. Clinically, individuals present with edema, hypertension, and hematuria.
4. Despite the use of penicillin to treat GAS infections for more than 50 years, this organism continues to be uniformly sensitive to this antimicrobial. In penicillin-allergic patients, erythromycin and the newer macrolide antimicrobials clarithromycin and azithromycin are recommended therapeutic agents for GAS pharyngitis. A study in Finland showed that GAS resistance to erythromycin was associated with increasing use of this antimicrobial. In 1993, almost 20% of GAS isolates were resistant to erythromycin. Following a national education effort, use of erythromycin and related antimicrobials declined. By 1996, the percentage of erythromycin-resistant strains of GAS declined to 8.6%, a level still much higher than that seen in the United States. The important lesson here is that once resistance is present in an organism, reducing specific antimicrobial pressure will only result in a reduction in the number of resistant strains, not an elimination of them. A 2011-2012 survey at a U.S. university teaching hospital of GAS isolates from patients with pharyngitis indicated that resistance is still modest, with 5% of isolates resistant to both erythromycin and clindamycin.
5. Streptococcal pyogenic exotoxins (Spe) A through C were once referred to as erythrogenic or scarlet fever toxins. Scarlet fever is considered to be a benign complication of pharyngitis caused by a pyrogenic exotoxin-producing strain of GAS. The skin rash seen in scarlet fever is believed to be superantigen mediated.
6. Given the frequency and the potential seriousness of GAS infections, they would seem a logical candidate for the development of a vaccine. Vaccine development strategies for GAS are targeting the M protein and a variety of other virulence factors, including the C5 peptidase (important in the organism evading phagocytes), cysteine protease, and hyaluronic acid capsule. The molecule that has been the most attractive target for the development of a GAS vaccine is the M protein. This protein is known to play an important role in evasion of the immune system; it is located on the cell surface, and with modern biochemical techniques it is fairly easy to purify. However, epitopes of M protein have been shown to share antigenic properties with several human tissue components, including myosin and sarcolemmal membrane proteins. Therefore, vaccines against M proteins have the potential to induce antibodies that could bind and damage a variety of tissues.
The challenge of making a vaccine against the M protein component of GAS is to identify epitopes that will induce the production of protective antibodies against as many different M types as possible while at the same time ensuring that the antibodies raised against these epitopes will not react with human tissues. It is also important to have a vaccine strategy that will elicit mucosal immunity, as that is likely to be important in protecting against this respiratory tract pathogen. The most advanced GAS candidate vaccine is 26-valent, targeting small N-terminal peptides on the M protein. Based on an epidemiologic survey of invasive GAS disease, it should cover ~80% of those isolates. In phase 1 and 2 trials, the vaccine was found to be safe and to have good immunogenicity. A phase 3 trial is needed to judge efficacy. However, with the ever expanding repertoire of emm types in GAS, the individual M protein approach is likely flawed. Identification of antigens that are shared across emm types and can induce protective immunity without producing molecular mimicry is the holy grail of GAS vaccinology.
REFERENCES
1. Ebell MH, Smith MA, Barry HC, Ives K, Carey M. 2000. The rational clinical examination. Does this patient have strep throat? JAMA 284:2912–2918.
2. ESCMID Sore Throat Guideline Group, Pelucchi C, Grigoryan L, Galeone C, Esposito S, Huovinen P, Little P, Verheij T. 2012. Guideline for the management of acute sore throat. Clin Microbiol Infect 18(Suppl 1):1–28.
3. O’Loughlin RE, Roberson A, Cieslak PR, Lynfield R, Gershman K, Craig A, Albanese BA, Farley MM, Barrett NL, Spina NL, Beall B, Harrison LH, Reingold A, Van Beneden C; Active Bacterial Core Surveillance Team. 2007. The epidemiology of invasive group A streptococcal infection and potential vaccine implications: United States, 2000–2004. Clin Infect Dis 45:853–862.
4. Seppälä H, Klaukka T, Vuopio-Varkila J, Muotiala A, Helenius H, Lager K, Huovinen P; Finnish Study Group for Antimicrobial Resistance. 1997. The effect of changes in the consumption of macrolide antibiotics on erythromycin resistance in group A streptococci in Finland. N Engl J Med 337:441–446.
5. Steer AC, Batzloff MR, Mulholland K, Carapetis JR. 2009. Group A streptococcal vaccines: facts versus fantasy. Curr Opin Infect Dis 22:544–552.
6. Wessels MR. 2011. Clinical practice. Streptococcal pharyngitis. N Engl J Med 364:648–655.
CASE 8
The patient was a 64-year-old retired postal worker with a medical history of extensive facial reconstruction for squamous cell carcinoma of the head and neck. He had a 30-year history of smoking. The patient presented with progressive shortness of breath, a persistent, productive cough, purulent sputum, and fever to 39.0°C 2 days prior to admission.
On physical examination he had a temperature of 37.3°C, respiratory rate of