EDITORIAL
Annals of Internal Medicine
Sore Throat: Avoid Overcomplicating the Uncomplicated
M
anagement of most patients with a sore throat is not complicated. Respiratory viruses cause most sore throat cases. In the United States, sore throat and pharyngitis guidelines focus on separating patients with respiratory viruses from patients likely to have group A streptococcus (1). Antibiotic treatment of group A streptococcus decreases symptoms, prevents suppurative complications, and decreases contagion. Patients with a Centor score of 0 or 1 (1 point each for history of fever, absence of cough, tender anterior cervical lymphadenopathy, and tonsillar exudates) are unlikely to have group A streptococcus; therefore, further testing is not useful. For patients with a Centor score of 2 or greater, widely available rapid antigendetection tests identify patients with a high enough probability of group A streptococcus to justify antibiotic treatment. The antibiotic of choice for adults with group A streptococcal pharyngitis is penicillin, which is inexpensive and well-tolerated and to which group A streptococcus is universally susceptible. Although management of adults with a sore throat is simple, clinicians often overcomplicate it. Approximately one half of adults who seek care for a sore throat will have a Centor score of 0 or 1, but many clinics indiscriminately test all patients who present with a sore throat (2, 3). Indiscriminant testing may improve patient flow, but it exposes patients to inconvenience, discomfort, expense, false-positive test results, and unnecessary antibiotics. Better triage before visits, whether by online symptom checkers, phone, video, or asynchronous e-visits, could reduce unnecessary visits for a self-limited illness (4). Beyond overtesting, physicians overprescribe antibiotics. Roughly 10% of adults who seek care for a sore throat have group A streptococcus. However, between 1997 and 2010, physicians in the United States prescribed antibiotics during 60% of sore throat visits (5). During that time, they increasingly prescribed the wrong antibiotics. They prescribed penicillin (again, group A streptococcus is never resistant to penicillin) during only 9% of visits. Physicians prescribed azithromycin, to which group A streptococcus is sometimes resistant, during as many as 15% of visits. Physicians also prescribed other nonrecommended antibiotics (such as second- and third-generation cephalosporins, penicillin–-lactamase inhibitor combinations, and fluoroquinolones) at 15% of visits. Respiratory viruses and group A streptococcus should dominate decision making, but physicians need to be open to the possibility that some cases of pharyngitis are more complicated. The differential diagnosis of adult pharyngitis includes Epstein–Barr virus, human immunodeficiency virus, Corynebacterium diphtheriae, Neisseria gonorrhoeae, and possibly Fusobacterium necrophorum. Fusobacterium necrophorum, an anaerobic gramnegative rod, is a normal part of the oropharyngeal, genitourinary, and gastrointestinal microflora. How-
ever, it can be pathogenic and can cause sinusitis, appendicitis, abscesses, and endocarditis (6). Fusobacterium necrophorum is also associated with the Lemierre syndrome, which is septic thrombophlebitis of the internal jugular vein accompanied by metastatic infections. Metastatic infections almost always involve the lungs but can also affect the joints, bones, liver, meninges, and brain. The syndrome primarily affects adolescents and young adults and possibly has a male predominance. Centor (7) estimated that 1 in 400 cases of adolescent F. necrophorum pharyngitis results in the Lemierre syndrome and argued for a change in pharyngitis guidelines for adolescents and young adults to include consideration of F. necrophorum and the Lemierre syndrome. In this issue, Centor and colleagues (8) report a cross-sectional comparison of 312 patients at a university health clinic presenting with a sore throat and 180 healthy students—likely mostly medical students— without a sore throat. All of the participants were aged 15 to 30 years. The investigators assessed the Centor score, collected throat swabs, and performed polymerase chain reaction testing to detect F. necrophorum, group A streptococcus, group C/G streptococcus, and Mycoplasma pneumoniae. In patients with an acute sore throat, the rate of detection of F. necrophorum was 21%, group A streptococcus was 10%, group C/G streptococcus was 9%, and M. pneumoniae was 2%. The respective rates in asymptomatic students were 9%, 1%, 4%, and 0%. These new data are interesting but do not warrant reconsideration of pharyngitis guidelines. First, some results from this study differed notably from previous studies. The 1% asymptomatic carrier rate of group A streptococcus was low. The rate of asymptomatic carriage of group A streptococcus in schoolchildren can be as high as 20%; in adolescents and young adults, it has been reported to be approximately 5% (9). In addition, the distribution of Centor scores for patients with group A streptococcus detected was unusually low, although the numbers were quite small. In the present study, the rates of group A streptococcus detection by polymerase chain reaction for patients with Centor scores of 0, 1, 2, 3, and 4 were 5%, 5%, 6%, 14%, and 11%, respectively. By comparison, in a retail clinic study with greater than 140 000 patients, the respective rates of rapid antigen-detection test results that were positive were 7%, 12%, 21%, 38%, and 57% (2). Second, detection of an organism by polymerase chain reaction or even culture is not definitive evidence of infection. Although not clinically useful, the gold standard for pharyngeal infection, even for group A streptococcus, is paired acute and convalescent serologies. In the study by Centor and colleagues, viral pharyngitis may have led to changes in the pharyngeal microflora and increased F. necrophorum detection. Third, from a practical standpoint, a test for F. necrophorum is not commercially available. It is not cur© 2015 American College of Physicians 311
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EDITORIAL rently possible to operationalize a routine search for F. necrophorum. Fourth, there is no direct correlation between F. necrophorum pharyngitis and the Lemierre syndrome. One widely used textbook of infectious diseases states that although the Lemierre syndrome “begins with infection in the throat, pharyngitis is not a prominent early syndrome” (10). The Lemierre syndrome can also complicate mastoiditis, otitis, peritonsillar abscesses, and dental infections. Even its cause can vary. Fusobacterium necrophorum is most common, but it can also be caused by Bacteroides, Eikenella, Streptococcus, Peptostreptococcus, Porphyromonas, Prevotella, Proteus, and Staphylococcus. Finally, empirical evidence is lacking to document that treating Fusobacterium necrophorum pharyngitis with antibiotics decreases symptoms or prevents the Lemierre syndrome. Clearly, the Lemierre syndrome can be catastrophic. F. necrophorum, the Lemierre syndrome, and other causes of pharyngitis demand attention, and physicians need to avoid undercomplicating complicated pharyngitis. In particular, physicians should broaden their differential diagnosis and consider additional testing for patients who have a Centor score of 3 or 4, have a negative rapid test result for group A streptococcus, and do not improve, as well as patients who do not improve within 24 to 36 hours of antibiotic treatment. However, the major quality problem in the management of a sore throat is that physicians and the settings in which they practice overcomplicate uncomplicated pharyngitis. Physicians should remember that the prevalence of group A streptococcus in adults with a sore throat is approximately 10%; use the Centor scoring criteria; selectively use rapid antigen-detection testing; limit antibiotic treatment to patients most likely to have group A streptococcus; and most of the time when prescribing antibiotics, use penicillin. Jeffrey A. Linder, MD, MPH Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts Grant Support: Dr. Linder has been supported by grants from
the National Institutes of Health (RC4 AG039115), the National Institute of Allergy and Infectious Diseases (R21 AI097759), and the Agency for Healthcare Research and Quality (R18 HS018419).
Sore Throat: Avoid Overcomplicating the Uncomplicated
Disclosures: Disclosures can be viewed at www.acponline
.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14 -2899. Requests for Single Reprints: Jeffrey A. Linder, MD, MPH, Division of General Medicine and Primary Care, Brigham and Women's Hospital, 1620 Tremont Street, BC-3-2X, Boston, MA 02120; e-mail, [email protected].
Ann Intern Med. 2015;162:311-312. doi:10.7326/M14-2899
References 1. Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55:1279-82. [PMID: 23091044] doi:10.1093/cid/cis847 2. Fine AM, Nizet V, Mandl KD. Large-scale validation of the Centor and McIsaac scores to predict group A streptococcal pharyngitis. Arch Intern Med. 2012;172:847-52. [PMID: 22566485] doi:10.1001 /archinternmed.2012.950 3. Linder JA, Chan JC, Bates DW. Evaluation and treatment of pharyngitis in primary care practice: the difference between guidelines is largely academic. Arch Intern Med. 2006;166:1374-9. [PMID: 16832002] 4. Fine AM, Nizet V, Mandl KD. Participatory medicine: A home score for streptococcal pharyngitis enabled by real-time biosurveillance: a cohort study. Ann Intern Med. 2013;159:577-83. [PMID: 24189592] doi:10.7326/0003-4819-159-9-201311050-00003 5. Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. JAMA Intern Med. 2014; 174:138-40. [PMID: 24091806] doi:10.1001/jamainternmed.2013 .11673 6. Kuppalli K, Livorsi D, Talati NJ, Osborn M. Lemierre's syndrome due to Fusobacterium necrophorum. Lancet Infect Dis. 2012;12:808-15. [PMID: 22633566] doi:10.1016/S14733099(12)70089-0 7. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009;151:812-5. [PMID: 19949147] doi:10.7326/0003-4819-151-11-200912010-00011 8. Centor RM, Atkinson TP, Ratliff AE, Xiao L, Crabb DM, Estrada CA, et al. The clinical presentation of Fusobacterium–positive pharyngitis and streptococcal–positive pharyngitis in a university health clinic. A cross-sectional study. Ann Intern Med. 2015;162:241-7. doi: 10.7326/M14-1305 9. Gunnarsson RK, Holm SE, So¨derstro¨m M. The prevalence of betahaemolytic streptococci in throat specimens from healthy children and adults. Implications for the clinical value of throat cultures. Scand J Prim Health Care. 1997;15:149-55. [PMID: 9323783] 10. Garrett WS, Onderdonk AB. Bacteroides, Prevotella, Porphyromonas, and Fusobacterium species (and other medically important anaerobic gram-negative bacilli). In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. Philadelphia: Elsevier Saunders; 2015: 2773-80.
312 Annals of Internal Medicine • Vol. 162 No. 4 • 17 February 2015
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www.annals.org
Annals of Internal Medicine
Sore Throat: Avoid Overcomplicating the Uncomplicated
M
anagement of most patients with a sore throat is not complicated. Respiratory viruses cause most sore throat cases. In the United States, sore throat and pharyngitis guidelines focus on separating patients with respiratory viruses from patients likely to have group A streptococcus (1). Antibiotic treatment of group A streptococcus decreases symptoms, prevents suppurative complications, and decreases contagion. Patients with a Centor score of 0 or 1 (1 point each for history of fever, absence of cough, tender anterior cervical lymphadenopathy, and tonsillar exudates) are unlikely to have group A streptococcus; therefore, further testing is not useful. For patients with a Centor score of 2 or greater, widely available rapid antigendetection tests identify patients with a high enough probability of group A streptococcus to justify antibiotic treatment. The antibiotic of choice for adults with group A streptococcal pharyngitis is penicillin, which is inexpensive and well-tolerated and to which group A streptococcus is universally susceptible. Although management of adults with a sore throat is simple, clinicians often overcomplicate it. Approximately one half of adults who seek care for a sore throat will have a Centor score of 0 or 1, but many clinics indiscriminately test all patients who present with a sore throat (2, 3). Indiscriminant testing may improve patient flow, but it exposes patients to inconvenience, discomfort, expense, false-positive test results, and unnecessary antibiotics. Better triage before visits, whether by online symptom checkers, phone, video, or asynchronous e-visits, could reduce unnecessary visits for a self-limited illness (4). Beyond overtesting, physicians overprescribe antibiotics. Roughly 10% of adults who seek care for a sore throat have group A streptococcus. However, between 1997 and 2010, physicians in the United States prescribed antibiotics during 60% of sore throat visits (5). During that time, they increasingly prescribed the wrong antibiotics. They prescribed penicillin (again, group A streptococcus is never resistant to penicillin) during only 9% of visits. Physicians prescribed azithromycin, to which group A streptococcus is sometimes resistant, during as many as 15% of visits. Physicians also prescribed other nonrecommended antibiotics (such as second- and third-generation cephalosporins, penicillin–-lactamase inhibitor combinations, and fluoroquinolones) at 15% of visits. Respiratory viruses and group A streptococcus should dominate decision making, but physicians need to be open to the possibility that some cases of pharyngitis are more complicated. The differential diagnosis of adult pharyngitis includes Epstein–Barr virus, human immunodeficiency virus, Corynebacterium diphtheriae, Neisseria gonorrhoeae, and possibly Fusobacterium necrophorum. Fusobacterium necrophorum, an anaerobic gramnegative rod, is a normal part of the oropharyngeal, genitourinary, and gastrointestinal microflora. How-
ever, it can be pathogenic and can cause sinusitis, appendicitis, abscesses, and endocarditis (6). Fusobacterium necrophorum is also associated with the Lemierre syndrome, which is septic thrombophlebitis of the internal jugular vein accompanied by metastatic infections. Metastatic infections almost always involve the lungs but can also affect the joints, bones, liver, meninges, and brain. The syndrome primarily affects adolescents and young adults and possibly has a male predominance. Centor (7) estimated that 1 in 400 cases of adolescent F. necrophorum pharyngitis results in the Lemierre syndrome and argued for a change in pharyngitis guidelines for adolescents and young adults to include consideration of F. necrophorum and the Lemierre syndrome. In this issue, Centor and colleagues (8) report a cross-sectional comparison of 312 patients at a university health clinic presenting with a sore throat and 180 healthy students—likely mostly medical students— without a sore throat. All of the participants were aged 15 to 30 years. The investigators assessed the Centor score, collected throat swabs, and performed polymerase chain reaction testing to detect F. necrophorum, group A streptococcus, group C/G streptococcus, and Mycoplasma pneumoniae. In patients with an acute sore throat, the rate of detection of F. necrophorum was 21%, group A streptococcus was 10%, group C/G streptococcus was 9%, and M. pneumoniae was 2%. The respective rates in asymptomatic students were 9%, 1%, 4%, and 0%. These new data are interesting but do not warrant reconsideration of pharyngitis guidelines. First, some results from this study differed notably from previous studies. The 1% asymptomatic carrier rate of group A streptococcus was low. The rate of asymptomatic carriage of group A streptococcus in schoolchildren can be as high as 20%; in adolescents and young adults, it has been reported to be approximately 5% (9). In addition, the distribution of Centor scores for patients with group A streptococcus detected was unusually low, although the numbers were quite small. In the present study, the rates of group A streptococcus detection by polymerase chain reaction for patients with Centor scores of 0, 1, 2, 3, and 4 were 5%, 5%, 6%, 14%, and 11%, respectively. By comparison, in a retail clinic study with greater than 140 000 patients, the respective rates of rapid antigen-detection test results that were positive were 7%, 12%, 21%, 38%, and 57% (2). Second, detection of an organism by polymerase chain reaction or even culture is not definitive evidence of infection. Although not clinically useful, the gold standard for pharyngeal infection, even for group A streptococcus, is paired acute and convalescent serologies. In the study by Centor and colleagues, viral pharyngitis may have led to changes in the pharyngeal microflora and increased F. necrophorum detection. Third, from a practical standpoint, a test for F. necrophorum is not commercially available. It is not cur© 2015 American College of Physicians 311
Downloaded From: http://annals.org/ by a Dalhousie University-Dal-11762 User on 05/18/2015
EDITORIAL rently possible to operationalize a routine search for F. necrophorum. Fourth, there is no direct correlation between F. necrophorum pharyngitis and the Lemierre syndrome. One widely used textbook of infectious diseases states that although the Lemierre syndrome “begins with infection in the throat, pharyngitis is not a prominent early syndrome” (10). The Lemierre syndrome can also complicate mastoiditis, otitis, peritonsillar abscesses, and dental infections. Even its cause can vary. Fusobacterium necrophorum is most common, but it can also be caused by Bacteroides, Eikenella, Streptococcus, Peptostreptococcus, Porphyromonas, Prevotella, Proteus, and Staphylococcus. Finally, empirical evidence is lacking to document that treating Fusobacterium necrophorum pharyngitis with antibiotics decreases symptoms or prevents the Lemierre syndrome. Clearly, the Lemierre syndrome can be catastrophic. F. necrophorum, the Lemierre syndrome, and other causes of pharyngitis demand attention, and physicians need to avoid undercomplicating complicated pharyngitis. In particular, physicians should broaden their differential diagnosis and consider additional testing for patients who have a Centor score of 3 or 4, have a negative rapid test result for group A streptococcus, and do not improve, as well as patients who do not improve within 24 to 36 hours of antibiotic treatment. However, the major quality problem in the management of a sore throat is that physicians and the settings in which they practice overcomplicate uncomplicated pharyngitis. Physicians should remember that the prevalence of group A streptococcus in adults with a sore throat is approximately 10%; use the Centor scoring criteria; selectively use rapid antigen-detection testing; limit antibiotic treatment to patients most likely to have group A streptococcus; and most of the time when prescribing antibiotics, use penicillin. Jeffrey A. Linder, MD, MPH Brigham and Women's Hospital and Harvard Medical School Boston, Massachusetts Grant Support: Dr. Linder has been supported by grants from
the National Institutes of Health (RC4 AG039115), the National Institute of Allergy and Infectious Diseases (R21 AI097759), and the Agency for Healthcare Research and Quality (R18 HS018419).
Sore Throat: Avoid Overcomplicating the Uncomplicated
Disclosures: Disclosures can be viewed at www.acponline
.org/authors/icmje/ConflictOfInterestForms.do?msNum=M14 -2899. Requests for Single Reprints: Jeffrey A. Linder, MD, MPH, Division of General Medicine and Primary Care, Brigham and Women's Hospital, 1620 Tremont Street, BC-3-2X, Boston, MA 02120; e-mail, [email protected].
Ann Intern Med. 2015;162:311-312. doi:10.7326/M14-2899
References 1. Shulman ST, Bisno AL, Clegg HW, Gerber MA, Kaplan EL, Lee G, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55:1279-82. [PMID: 23091044] doi:10.1093/cid/cis847 2. Fine AM, Nizet V, Mandl KD. Large-scale validation of the Centor and McIsaac scores to predict group A streptococcal pharyngitis. Arch Intern Med. 2012;172:847-52. [PMID: 22566485] doi:10.1001 /archinternmed.2012.950 3. Linder JA, Chan JC, Bates DW. Evaluation and treatment of pharyngitis in primary care practice: the difference between guidelines is largely academic. Arch Intern Med. 2006;166:1374-9. [PMID: 16832002] 4. Fine AM, Nizet V, Mandl KD. Participatory medicine: A home score for streptococcal pharyngitis enabled by real-time biosurveillance: a cohort study. Ann Intern Med. 2013;159:577-83. [PMID: 24189592] doi:10.7326/0003-4819-159-9-201311050-00003 5. Barnett ML, Linder JA. Antibiotic prescribing to adults with sore throat in the United States, 1997-2010. JAMA Intern Med. 2014; 174:138-40. [PMID: 24091806] doi:10.1001/jamainternmed.2013 .11673 6. Kuppalli K, Livorsi D, Talati NJ, Osborn M. Lemierre's syndrome due to Fusobacterium necrophorum. Lancet Infect Dis. 2012;12:808-15. [PMID: 22633566] doi:10.1016/S14733099(12)70089-0 7. Centor RM. Expand the pharyngitis paradigm for adolescents and young adults. Ann Intern Med. 2009;151:812-5. [PMID: 19949147] doi:10.7326/0003-4819-151-11-200912010-00011 8. Centor RM, Atkinson TP, Ratliff AE, Xiao L, Crabb DM, Estrada CA, et al. The clinical presentation of Fusobacterium–positive pharyngitis and streptococcal–positive pharyngitis in a university health clinic. A cross-sectional study. Ann Intern Med. 2015;162:241-7. doi: 10.7326/M14-1305 9. Gunnarsson RK, Holm SE, So¨derstro¨m M. The prevalence of betahaemolytic streptococci in throat specimens from healthy children and adults. Implications for the clinical value of throat cultures. Scand J Prim Health Care. 1997;15:149-55. [PMID: 9323783] 10. Garrett WS, Onderdonk AB. Bacteroides, Prevotella, Porphyromonas, and Fusobacterium species (and other medically important anaerobic gram-negative bacilli). In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 8th ed. Philadelphia: Elsevier Saunders; 2015: 2773-80.
312 Annals of Internal Medicine • Vol. 162 No. 4 • 17 February 2015
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