Читать книгу Cases in Medical Microbiology and Infectious Diseases - Melissa B. Miller - Страница 57

1. Based on a GAS clinical prediction scoring system developed at the University of Virginia and validated in both adults and children, this patient scored positive for all the criteria: temperature of >38°C, no cough, tender anterior cervical lymphadenopathy, tonsillar swelling and exudates, and age 3 to 14 years. Patients with this score are estimated to have a risk of ~50% of having GAS pharyngitis. Although not part of the prediction rule, abdominal pain, nausea, and vomiting are frequently seen in patients with GAS pharyngitis, though only abdominal pain was seen in this patient. What if the patient had presented with low-grade fever (<38°C), cough, sore throat without exudates, conjunctivitis, and coryza? Such a patient would have a score of 1 (positive only by virtue of age). Patients with a score of 1 have only a 5 to 10% risk of GAS pharyngitis. Viruses including rhinovirus, coronavirus, adenovirus, and influenza virus can all cause a syndrome of sore throat, cough, coryza, and conjunctivitis. This constellation of symptoms by and large is self-limited. Viral pharyngitis should be treated only symptomatically with analgesics and warm saltwater gargles.

A decision was made to confirm the clinical impression by determining if GAS was present. There are two ways to detect GAS: by direct detection of group A polysaccharide antigen in throat swabs, as was done in this case (Fig. 7.1), and by culture using a blood-containing agar plate. Direct antigen detection is accomplished by extracting the group A polysaccharide antigen from the throat swab and then performing an immunoassay on the extract. The test is very rapid, taking 10 to 15 minutes, and is highly specific (>95%), but when compared with culture it has a sensitivity of 80 to 90%, meaning that GAS will not be detected by this test in 10 to 20% of patients with GAS in their throats. The advantage of the “rapid strep test,” as it is called, is that a swab can be obtained in the office or clinic and a result can be obtained while the patient waits, i.e., a “real-time” microbiology test. For patients with a high pretest probability of disease, such as this patient, and a positive rapid GAS antigen test, antibiotics can be prescribed on the spot if that is the clinical decision that is reached. See answer 2 for further discussion of this issue.

Most guidelines no longer recommend performing culture in patients with negative rapid GAS antigen tests. For further explanation of why, see answer 2.

2. There are several benefits of antibiotics in the treatment of GAS pharyngitis. Of greatest significance is that treatment prevents nonsuppurative poststreptococcal sequelae (see answer to question 3 for further explanation). Further, if given early in the disease course (first 24 to 48 hours), they may also shorten the length of time the patient is symptomatic. Additionally, antibiotic therapy will prevent suppurative complications of GAS pharyngitis, such as peritonsillar and retropharyngeal abscesses, and decrease the infectivity of the infected individual. In school-age children, this is important so that they are less likely to infect their classmates and siblings, both at-risk populations. Because both suppurative and nonsuppurative poststreptococcal sequelae are now rare in the industrialized world, the importance of antimicrobial therapy in treatment of GAS is limited to the benefits of shortening disease course and decreasing transmissibility. This must be balanced with the risks of antimicrobial therapy. These include allergic reactions, especially since this infection is treated with penicillin; changes in the microbiota that may put the patient at risk for other infections; and increasing antimicrobial resistance among respiratory pathogens such as Streptococcus pneumoniae.

The problem is even more complex with patients who have a negative rapid GAS antigen test. Often, physician practice, especially in pediatrics, is to “back up” negative rapid GAS antigen tests with culture. There are at least four possible outcomes of bacterial 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.