YJINF3509_proof ■ 30 April 2015 ■ 1/5 Journal of Infection (2015) xx, 1e5
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www.elsevierhealth.com/journals/jinf
Q5
Sore throat: Is it such a big deal anymore?
Q4
Verangi C.K. Herath a,d, Jonathan Carapetis b,c,* a
Department of Paediatrics, Royal Darwin Hospital, 105 Rockland Drive, Tiwi, Northern Territory 0810, Australia b Telethon Kids Institute, University of Western Australia, West Perth, Western Australia 6872, Australia c Princess Margaret Hospital for Children, Subiaco, Perth, Western Australia 6008, Australia Accepted 21 April 2015 Available online - - -
KEYWORDS Sore throat; Pharyngitis; Diagnosis; Treatment; Bacterial; Antibiotic; Child
Summary Sore throat remains a common disease of childhood, and a major cost and cause for antibiotic prescriptions. The management of sore throat remains controversial in affluent countries with various guidelines available and overall poor adherence to those guidelines. Group A streptococcus is the commonest bacterial cause with important sequelae including acute rheumatic fever (ARF). The driver for diagnosis and treatment is still questionable. In most affluent populations it is difficult to justify antibiotic treatment on the basis of preventing ARF, whereas this remains the major driver for sore throat management in populations at higher risk of ARF. Reduction in severity and duration of symptoms may be a reasonable basis to consider antibiotic treatment, and thus accurate diagnosis of GAS pharyngitis, particularly in those with more severe symptoms. The potential role of rapid tests in diagnosis appears to be increasing. ª 2015 Published by Elsevier Ltd on behalf of The British Infection Association.
Introduction The management of sore throat is controversial in affluent countries with varying diagnostic criteria and guidelines for management in existence. The role of antibiotic treatment has been questioned in an era when many no longer perceive ‘Strep throat’ to be a significant problem.1 As group A streptococcus (GAS) pharyngitis is usually selflimiting, the drivers for early diagnosis and appropriate
treatment are reducing transmission, symptom severity and duration and the risk of developing acute rheumatic fever (ARF).2 ARF is a post-infectious auto-immune sequelae of GAS.1 The incidence of ARF is low in industrialised countries, although ARF continues to cause hundreds of thousands of cases and deaths each year in developing countries.1 The use of a single dose of intramuscular Penicillin has been shown to be effective at reducing ARF incidence after
* Corresponding author. Telethon Kids Institute, University of Western Australia, West Perth, Western Australia 6872, Australia. Tel.: þ61 894897777. E-mail addresses: [email protected] (V.C.K. Herath), [email protected] (J. Carapetis). d Tel.: þ61 889228888. http://dx.doi.org/10.1016/j.jinf.2015.04.010 0163-4453/ª 2015 Published by Elsevier Ltd on behalf of The British Infection Association. Please cite this article in press as: Herath VCK, Carapetis J, Sore throat: Is it such a big deal anymore?, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.010
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a suspected GAS pharyngitis episode; a meta-analysis found an overall 80% protective effect with the use of penicillin for GAS pharyngitis, with number needed to treat of 60 and overall absolute risk reduction of 1.67% with any antibiotic use.3
Epidemiology There are many causes of sore throat which range from bacteria such as GAS and Neisseria gonorrhoea to multiple respiratory viruses including Influenza, Parainfluenza and Adenovirus.4 The probability of a patient having GAS is only second to a viral cause at 5e36% versus 50e80%. GAS is the most common bacterial cause for acute pharyngitis and the major reason for which antibiotic therapy may be indicated.5 Therefore, in a patient with acute pharyngitis, the clinical decision that usually needs to be made is whether or not the pharyngitis is attributable to GAS. In Australia, about 6% of presentations to primary care by children are with tonsillitis.6 There are an estimated 7.3 million primary care visits per year annually with sore throat in the United States for children aged between 3 and 17 years of age.7 The estimated cost for sore throat consultation visits per year in the United Kingdom is 60 million pounds excluding any costs of further investigation or management.8 There is a paucity of studies that estimate the incidence of GAS pharyngitis and most are from the mid-20th Century. The most extensive studies of incidence were the Dingle family studies in the 1950s based on a group of Cleveland families. They noted an incidence of sore throat at 0.20 per person-year in children.9 More recent studies done between 1988 and 1998 in populations with high rates of ARF, were in New Zealand, Kuwait and India. They noted an incidence of a GAS culture-positive sore throat once every one to two years in each child. However serology was not done in any of these studies so incidence will have been overestimated because of the inclusion of GAS carriers.10 The most comprehensive population-based study in recent times was a prospective, family based cohort study over a 16 month period from August 2001 in Melbourne, Australia. A total of 853 people were included from 202 families, randomly selected from 3 primary care practices in diverse geographic and socioeconomic regions of suburban Melbourne. The incidence in school-aged children aged between 5 and 12 years for acute sore throat, GAS swabpositive pharyngitis and serologically confirmed GAS pharyngitis was 33, 13 and 8 per 100 child-years respectively. The overall GAS carriage rate was 8e16% with the lowest rate in summer and highest rate in winter.11 While the Melbourne study demonstrated that the incidence of sore throat and GAS pharyngitis has remained remarkably stable over at least half a century in affluent, temperate-climate regions, studies from tropical regions tend to show more diversity in incidence rates. A prospective surveillance study of 685 children in Fiji showed a high incidence of 1.6 episodes of sore throat per child-year of which 14.7 cases per 100 child-years (95% CI, 11.2e18.8) were GAS culture-positive (serological confirmation was not performed). Group C and group G streptococci were frequently isolated with an incidence of 28.8 cases per
V.C.K. Herath, J. Carapetis 100 child-years (95% CI, 23.9e34.5), although their contribution to pharyngeal infection is not clear. The overall GAS carriage rate was 6%.12 By contrast, the Aboriginal population of northern Australia seems to have a remarkably low incidence of both sore throat and GAS culture-positive pharyngitis. A study from August 2003 to June 2005 in the Top End of the Northern Territory of Australia was conducted in three remote Aboriginal communities. There were a total of 531 household visits which included 4842 consultations. Based on two reported episodes of sore throat in children, the incidence density was 8 episodes per 100 person-years (95% CI, 4e15 episodes per 100 person-years). There were no cases of symptomatic GAS pharyngitis. The median point prevalence of throat carriage of GAS was 3.7%, group C was 0.7% and 5.1% for group G. There was no correlation with season or overcrowding.13 Knowing risk factors for transmission is important when considering control measures. The highest rates of GAS infection are in school-aged children and usually secondary cases occur within 2 weeks of index case. The 2001 study in Melbourne noted that 18/42 (43%) families with a primary case of GAS culture-positive sore throat had at least one secondary case. Of those 18 families, more than half (11/ 18) had more than 2 secondary cases. Of those at risk, 13% (95% CI: 9e18) contracted a secondary case. They were able to determine emm type in 26/32 (81%) of secondary culture positive cases, of which 25/26 (96%) were the same as the primary case.11
Clinical features GAS sore throat is most common in children aged between 5 and 15 years of age and usually presents in winter or early spring. There is often a history of exposure to someone with sore throat. There are two distinctive groups of clinical features that have previously been described in an attempt to differentiate between likely viral and GAS pharyngitis. Features most indicative of GAS pharyngitis are a sudden onset of sore throat, fever, headache, nausea, vomiting and abdominal pain. On examination, features may include tonsillopharyngeal inflammation with patchy exudates, palatal petechiae, anterior cervical adenitis and/or a scarlatiniform rash. Viral pharyngitis tends to be accompanied by symptoms of conjunctivitis, coryza, cough, diarrhoea and hoarseness. Additionally, discrete ulcerative stomatitis and a viral exanthem may be present.4 Of course, most individuals with sore throat have only some of these features, which makes differentiation between viral and bacterial causes fraught if based on clinical features alone. A systematic review and meta-analysis published in 2012 reviewed the best clinical decision rules (CDRs) published between 1975 and 2010 to diagnosis GAS pharyngitis in children. Some CDRs were found to have equal performance to some rapid diagnostic tests (RADTs) for excluding diagnosis. The suggestion from this review was that the CDRs should be used to aid reduction of antibiotic use only in those children with high risk of GAS pharyngitis.14 The most common CDRs used to date are the Centor and McIsaac (which is a modified version of Centor and accounts for patient age) criteria, which determines
Please cite this article in press as: Herath VCK, Carapetis J, Sore throat: Is it such a big deal anymore?, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.010
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a likelihood ratio based on the number of specific symptoms or signs present. In some cases, these CDRs have improved the sensitivity of diagnosis to as high as 97% in children. However, specificity has been shown uniformly to be low at 67% in children.2 This further reinforces that attempting to distinguish between non-streptococcocal and GAS pharyngitis based on clinical grounds alone is difficult.
Diagnostic tools (Table 1) Culturing GAS on throat swab has been a simple method of confirmation in the past. However, a recent comparative cost-effectiveness study of diagnostic methods and treatment of pharyngitis in children in South Africa found that a throat swab added no benefit and increased cost compared to CDRs alone.15 RADTs have been in existence since the early 1980s with different methodologies utilised to provide a quick turnaround time for results.16 The first RADTs developed, such as latex agglutination methods, were not sensitive and had unclear end-points.4 Subsequent techniques developed included lateral flow and immunochromatographic assays, enzyme-linked immunosorbent assays (ELISAs) and optical immunoassays which have offered increased sensitivity and more defined end points.4,16 Molecular-based techniques have been developed more recently and utilise DNA probes, fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) methods. A metaanalysis published in 2014 compared RADTs for GAS pharyngitis. The results from 48 studies noted overall sensitivity of 0.86 (95% CI 0.83e0.88) and specificity of 0.96 (95% CI 0.94e0.97). The suggestion was that RADTs could be used for accurate GAS pharyngitis diagnosis. The newer molecular techniques were found to perform the best with a sensitivity of 0.95 or above. In Australia, it is more cost effective Table 1
to utilise RADTs in direct comparison to culture at approximately AUD$5 to $10 per RADT versus AUD$30 per culture. In contrast, the cost in the United States and Europe is difficult to compare as there are a range of prices across different companies that produce these tests. The use of culture to confirm RADTs results increases costs dramatically; this strategy would lead to a cost of $8 million for every additional case of rheumatic heart disease (RHD) prevented in the United States.16
Treatment A Cochrane review published in 2006 reviewed the use of antibiotics in sore throat. The numbers need to treat (NNT) to prevent one sore throat by day 3 was 3.7 if GAS positive versus 6.5 if GAS negative. If no swab was done, NNT was 14.4. A reduction was also shown in other illnesses whereby for every 100 patients treated with antibiotics, there was one fewer case of ARF and three fewer cases of quinsy. The absolute benefit of antibiotics was modest, with an estimated mean absolute reduction of duration of symptoms of about 1 day at around day 3 of illness. It is not clear to what extent included studies of antibiotics in sore throat may have excluded cases with the most severe symptoms, who may stand to benefit the most from the symptom-reduction benefits of antibiotics. Given that, overall, 90% of patients were symptom free by one week, regardless of treatment with antibiotics, the authors concluded that, in populations at low risk of ARF, the choice as to whether to use antibiotics may need to be a clinician-led decision based on the individual case. The notable exclusion is in populations at high risk of ARF, where treatment of GAS pharyngitis remains a critical approach to primary prevention.17 There are various guidelines available for treatment of sore throat (refer to Table 1), with all of them
Summary of recommendations for diagnosis and treatment of sore throat by guideline.
Routine throat culture or RADT RADT only in some cases (e.g. more Centor criteria) Throat culture after negative RADT Use clinical score to target RADTs and antibiotics Anti-inflammatories for pain Steroids Antibiotics to prevent complications Antibiotics to reduce symptoms First line antibiotic Tonsillectomy
IDSA4 (USA)
ESCMID20 (Europe)
SIGN19 (Scotland)
NICE18 (UK)
Yes (unless clearly viral) No
No
No
No
Yes (physician discretion) No
No
No
N/A
N/A
Yes (antibiotics only) Yes No
Yes (antibiotics only) Yes No
No
No
No
No
Pen V
Pen V
Severe (criteria)
Selected children
No No (unless clearly viral) Yes No Yes Not clear Pen V, Amox or BPG Rarely
Yes Yes Adults with severe presentations Not in low risk populations Only severe cases (no. of Centor criteria) Pen V N/A
Key: RADT Z Rapid diagnostic tests, Pen V Z Penicillin V (Phenoxymethylpenicillin), Amox Z Amoxycillin, BPG Z Benzathine Penicillin G, IDSA Z Infectious Diseases Society of America, ESCMID Z European Society of Clinical Microbiology and Infectious Diseases, SIGN Z Scottish Intercollegiate Guidelines Network, NICE Z National Institute for Health and Care Excellence.
Please cite this article in press as: Herath VCK, Carapetis J, Sore throat: Is it such a big deal anymore?, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.010
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recommending anti-inflammatories for pain. In the clinical practice guideline update by the Infectious Diseases Society of America (IDSA), antibiotics are only routinely recommended if there is a clinical or epidemiological high level of suspicion of GAS while awaiting confirmation on diagnostic tests. None of the other guidelines routinely recommend antibiotics for reduction of symptoms or prevention of complications from sore throat, though there is a caveat for severe cases in the European guidelines. In all guidelines, Penicillin V is the first line choice of antibiotic treatment, if treatment is to be used.8,18e20 For people allergic to penicillins, the alternatives include a Cephalosporin or Azithromycin. For those who are chronic carriers, additional recommendations include the use of Clindamycin, Rifampicin or Amoxycillin/Clavulanic acid.8 Regardless of the approach recommended in guidelines, there is good evidence from a number of settings that guidelines are often not followed in primary care, with many practitioners opting for antibiotic treatment. In Australia, 89% of patients with sore throat were noted to have received antibiotics during 1999 to 2001.21 Antibiotic prescriptions rates were lower in the USA at 73% (CI, 70e76%) in 1989 to 1999.7 Another study in the USA in 1992 noted similar rates of antibiotic prescriptions at 71% (5246/7435) of all sore throat presentations.22 A retrospective review of over 5 million primary clinic consultations for respiratory symptoms in Hong Kong from 2005 to 2010 noted that though overall antibiotic prescriptions use declined, the use for GAS pharyngitis increased from 89.2% to 97.8%.23 Overall these studies suggested higher rates of prescription than recommended by the guidelines. A review of adherence to acute pharyngitis treatment guidelines in Israel noted that only about 50% of physicians followed the strategies suggested. The factors noted to be associated with more antibiotic prescriptions were physicians who were male, younger, family medicine practitioners, worked in rural areas or prescriptions just before the weekend.24
Prevention There is currently no vaccine for GAS. A recent study compared the use of bacteriocin-producing Streptococcus salivarius K12 oral probiotic with a control as prophylaxis in children with proven recurrent GAS pharyngitis. There was a considerable reduction in episodes of GAS infections from 3.1 to 0.1 average cases compared to the preceding year versus 3.0 to 2.8 for the control group. Additional benefits included reduction in overall viral infection, other medication use, including antibiotics and antipyretics, as well as absenteeism from work or school. It was felt that the bacteriocin-producing S. salivarius was protective against recurrent GAS pharyngitis.25 Further studies of this intervention are currently underway, including in children not already diagnosed with recurrent pharyngitis.
Role of tonsillectomy Guidelines for tonsillectomy often cite the Paradise criteria as essential for identifying individuals with more severe disease that may be appropriate for tonsillectomy.26 The
V.C.K. Herath, J. Carapetis Paradise criteria are defined as: ‘(1) seven or more episodes in the preceding year, or five or more in each of the preceding two years, or three or more in each of the preceding three years comprising (2) characteristic clinical features, having been (3) treated with antibiotics when streptococcal infection was proven or suspected, and (4) each episode had to have been documented in a clinical record.’ The criteria are less strictly followed these days with more emphasis on the number of episodes than on assessing ‘certainty’ of each episode.27 A Cochrane review published in 2009 reviewed the effects of tonsillectomy in children (and/or adenoidectomy) on reduction and severity of tonsillitis and sore throat in the first postoperative year. Tonsillectomy in “more severely affected children” defined as children who fulfil the Paradise criteria, resulted in avoidance of three episodes of sore throat including one moderate or severe episode in the following year. On the other hand, less severely affected children avoided an average of one sore throat (two versus three) in the first post-operative year. The number of sore throat days was noted to reduce from 22 to 17 (although 5e7 of these were in the immediate post-operative period). This highlights the cost of postoperative pain and potential complications following a tonsillectomy. The reviewers concluded that the effectiveness of adeno-/tonsillectomy is most seen in those severely affected, with a moderate benefit via reduction of duration and number of episodes of sore throat. Some children are noted to improve without surgery. The impact on reduction of sore throats secondary to pharyngitis is less predictable.27 A multicentre, randomised controlled trial done over three years from March 2000 in the Netherlands reviewed the cost-effectiveness of adenotonsillectomy versus watchful waiting. They found that surgery because of mild to moderate symptoms alone resulted in higher costs without the relevant clinical benefit.28 The American stance does not recommend tonsillectomy solely to reduce the frequency of GAS pharyngitis, rather it is only recommended in rare cases with patients with recurrent pharyngitis and no alternative explanation.8 The UK Guidelines note poor evidence and suggested potential benefit in select cases of persistent recurrence.18 The Scottish Guidelines advise that for mild recurrent sore throats, ‘watchful waiting’ is more appropriate. They provide clear criteria for referral for tonsillectomy which include the Paradise criteria for recurrence, sore throats due to acute tonsillitis, and episodes that prevent normal functioning and are disabling.19 There were no recommendations for tonsillectomy in the European guidelines (refer to Table 1).20
Conclusions Sore throat is just as common as ever. It is still a major cost and cause for antibiotic prescriptions. Guidelines are divided between North America and Europe. Despite these guidelines, many children receive antibiotics. The driver for diagnosis and treatment is still questionable, but in most affluent populations it is difficult to justify antibiotic treatment on the basis of preventing ARF, whereas this
Please cite this article in press as: Herath VCK, Carapetis J, Sore throat: Is it such a big deal anymore?, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.010
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remains the major driver for sore throat management in populations at higher risk of ARF. Reduction in severity and duration of symptoms may be a reasonable basis to consider antibiotic treatment, and thus accurate diagnosis, of GAS pharyngitis particularly in those with more severe symptoms. The potential role of rapid tests in diagnosis appears to be increasing.
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Conflict of interest There are no conflicts of interest to declare. Q2
References
1. Seckeler MD, Hoke TR. The worldwide epidemiology of acute rheumatic fever and rheumatic heart disease. Clin Epidemiol 2011;3:67e84. 2. Dunne EM, Marshall JL, Baker CA, Manning J, Gonis G, Danchin MH, et al. Detection of group a streptococcal pharyngitis by quantitative PCR. BMC Infect Dis 2013;13:312. 3. Robertson KA, Volmink JA, Mayosi BM. Antibiotics for the primary prevention of acute rheumatic fever: a meta-analysis. BMC Cardiovasc Disord 2005;5:11. 4. 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. Q3 cis629. 5. Ebell MH, Smith MA, Barry HC, Ives K, Carey M. Does this patient have Strep throat? JAMA 2000 Dec 13;284:22. 6. Charles J, Pan Y, Britt H. Trends in childhood illness and treatment in Australian general practice, 1971e2001. MJA 2004; 180:216e9. 7. Linder JA, Bates DW, Lee GM, Finkelstein JA. Antibiotic treatment of children with sore throat. JAMA 2005;294:2315e22. 8. Bisno AL, Gerber MA, Gwaltney JM, Kaplan EL, Schwartz RH. Practice guidelines for the diagnosis and management of Group A Streptococcal pharyngitis. Clin Infect Dis 2002;35:113e25. 9. James WES, Badger GF, Dingle JH. A study of illness of illness in a group of Cleveland families: XIX. The epidemiology of the acquisition of Group A Streptococci and of associated illnesses. NEJM 1960 April 7;262:14. 10. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal diseases. Lancet 2005 Nov;5: 685e94. 11. Danchin MH, Rogers S, Kelpie L, Selvaraj G, Curtis N, Carlin JB, et al. Burden of acute sore throat and Group A Streptococcal pharyngitis in school-aged children and their families in Australia. Pediatrics 2007:120e950. 12. Steer AC, Jenney AWJ, Kado J, Good MF, Batzloff M, Magor G, et al. Prospective surveillance of Streptococcal sore in a tropical country. Pediatr Infect Dis J 2009;28:477e82. 13. Mcdonald MI, Towers RJ, Andrews R, Benger N, Fagan P, Currie BJ, et al. The dynamic nature of group A Streptococcal
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epidemiology in tropical communities with high rates of rheumatic heart disease. Epidemiol Infect 2008;136:529e39. Le Marechal F, Martinot A, Duhamel A, Pruvost I, Dubos F. Streptococcal pharyngitis in children: a meta-analysis of clinical decision rules and their clinical variables. BMJ Open 2013;3:e001482. Irlam J, Mayosi BM, Engel M, Gaziano TA. Primary prevention of acute rheumatic fever and rheumatic heart disease with Penicillin in South African children with pharyngitis: a costeffective analysis. Circulation Cardiovasc Qual Outcome 2013;6:343e51. Lean WL, Arnup S, Danchin M, Steer AC. Rapid diagnostic tests for Group A Streptococcal pharyngitis: a meta-analysis. Pediatrics 2014 Oct;134:4. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat (review). The Cochrane Collaboration; 2006. Sore throat e acute [Internet] Natl Inst Health Care Excell 2012 October [updated 2014 February; cited 2014 October]. Available from:, http://cks.nice.org.uk/sore-throat-acute. Management of sore throat and indications for tonsillectomy: a national clinical guideline [Internet] Scott Intercoll Guidel Netw 2010 April [cited 2014 October]. Available from:, http://www.sign.ac.uk/guidelines/fulltext/117/index.html. Pelucchi C, Grigoryan L, Galeone C, Esposito S, Huovinen P, Little P, et alESCMID Sore Throat Guideline Group. Guideline for the management of acute sore throat. Clin Microbiol Infect 2012;18(1):1e27. Patterson CA, Mackson JM, Weekes LM. Antibiotic prescribing for upper respiratory-tract infections in primary care. Commun Dis Intell 2003 May:27. Nyquist AC, Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis. JAMA 1998;279:875e7. Kung K, Wong CK, Wong SY, Lam A, Chan CK, Griffiths S, et al. Patient presentation and physician management of upper respiratory tract infections: a retrospective review of over 5 million primary clinic consultations in Hong Kong. BMC Fam Pract 2014;15:95. Urkin J, Allenbogen M, Friger M, Vinker S, Reuveni H, Elahayani A. Acute pharyngitis: low adherence to guidelines highlights need for greater flexibility in managing paediatric cases. Acta Paediatr 2013;102:1075e80. Di Pierro F, Colombo M, Zanvit A, Risso P, Rottoli AS. Use of Streptococcus salivarius K12 in the prevention of streptococcal and viral pharyngotonsillitis in children. Drug, Healthc Patient Saf 2014;6:15e20. Randel A. AAO-HNS Guidelines for tonsillectomy in children and adolescents. Am Fam Physician 2011 Sept 1;84(5):566e73. Burton MJ, Glasziou PP. Tonsillectomy or adeno-tonsillectomy versus non-surgical treatment for chronic/recurrent acute tonsillitis (Review). The Cochrane Collaboration; 2009. Buskens E, van Staaij B, van den Akker J, Hoes AW, Schilder AGM. Adenotonsillectomy or watchful waiting in patients with mild to moderate symptoms of throat infections or adenotonsillar hypertrophy. Archives Otolaryngology e Q1 Head Neck Surg 2007;133(11):1083e8.
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www.elsevierhealth.com/journals/jinf
Q5
Sore throat: Is it such a big deal anymore?
Q4
Verangi C.K. Herath a,d, Jonathan Carapetis b,c,* a
Department of Paediatrics, Royal Darwin Hospital, 105 Rockland Drive, Tiwi, Northern Territory 0810, Australia b Telethon Kids Institute, University of Western Australia, West Perth, Western Australia 6872, Australia c Princess Margaret Hospital for Children, Subiaco, Perth, Western Australia 6008, Australia Accepted 21 April 2015 Available online - - -
KEYWORDS Sore throat; Pharyngitis; Diagnosis; Treatment; Bacterial; Antibiotic; Child
Summary Sore throat remains a common disease of childhood, and a major cost and cause for antibiotic prescriptions. The management of sore throat remains controversial in affluent countries with various guidelines available and overall poor adherence to those guidelines. Group A streptococcus is the commonest bacterial cause with important sequelae including acute rheumatic fever (ARF). The driver for diagnosis and treatment is still questionable. In most affluent populations it is difficult to justify antibiotic treatment on the basis of preventing ARF, whereas this remains the major driver for sore throat management in populations at higher risk of ARF. Reduction in severity and duration of symptoms may be a reasonable basis to consider antibiotic treatment, and thus accurate diagnosis of GAS pharyngitis, particularly in those with more severe symptoms. The potential role of rapid tests in diagnosis appears to be increasing. ª 2015 Published by Elsevier Ltd on behalf of The British Infection Association.
Introduction The management of sore throat is controversial in affluent countries with varying diagnostic criteria and guidelines for management in existence. The role of antibiotic treatment has been questioned in an era when many no longer perceive ‘Strep throat’ to be a significant problem.1 As group A streptococcus (GAS) pharyngitis is usually selflimiting, the drivers for early diagnosis and appropriate
treatment are reducing transmission, symptom severity and duration and the risk of developing acute rheumatic fever (ARF).2 ARF is a post-infectious auto-immune sequelae of GAS.1 The incidence of ARF is low in industrialised countries, although ARF continues to cause hundreds of thousands of cases and deaths each year in developing countries.1 The use of a single dose of intramuscular Penicillin has been shown to be effective at reducing ARF incidence after
* Corresponding author. Telethon Kids Institute, University of Western Australia, West Perth, Western Australia 6872, Australia. Tel.: þ61 894897777. E-mail addresses: [email protected] (V.C.K. Herath), [email protected] (J. Carapetis). d Tel.: þ61 889228888. http://dx.doi.org/10.1016/j.jinf.2015.04.010 0163-4453/ª 2015 Published by Elsevier Ltd on behalf of The British Infection Association. Please cite this article in press as: Herath VCK, Carapetis J, Sore throat: Is it such a big deal anymore?, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.010
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a suspected GAS pharyngitis episode; a meta-analysis found an overall 80% protective effect with the use of penicillin for GAS pharyngitis, with number needed to treat of 60 and overall absolute risk reduction of 1.67% with any antibiotic use.3
Epidemiology There are many causes of sore throat which range from bacteria such as GAS and Neisseria gonorrhoea to multiple respiratory viruses including Influenza, Parainfluenza and Adenovirus.4 The probability of a patient having GAS is only second to a viral cause at 5e36% versus 50e80%. GAS is the most common bacterial cause for acute pharyngitis and the major reason for which antibiotic therapy may be indicated.5 Therefore, in a patient with acute pharyngitis, the clinical decision that usually needs to be made is whether or not the pharyngitis is attributable to GAS. In Australia, about 6% of presentations to primary care by children are with tonsillitis.6 There are an estimated 7.3 million primary care visits per year annually with sore throat in the United States for children aged between 3 and 17 years of age.7 The estimated cost for sore throat consultation visits per year in the United Kingdom is 60 million pounds excluding any costs of further investigation or management.8 There is a paucity of studies that estimate the incidence of GAS pharyngitis and most are from the mid-20th Century. The most extensive studies of incidence were the Dingle family studies in the 1950s based on a group of Cleveland families. They noted an incidence of sore throat at 0.20 per person-year in children.9 More recent studies done between 1988 and 1998 in populations with high rates of ARF, were in New Zealand, Kuwait and India. They noted an incidence of a GAS culture-positive sore throat once every one to two years in each child. However serology was not done in any of these studies so incidence will have been overestimated because of the inclusion of GAS carriers.10 The most comprehensive population-based study in recent times was a prospective, family based cohort study over a 16 month period from August 2001 in Melbourne, Australia. A total of 853 people were included from 202 families, randomly selected from 3 primary care practices in diverse geographic and socioeconomic regions of suburban Melbourne. The incidence in school-aged children aged between 5 and 12 years for acute sore throat, GAS swabpositive pharyngitis and serologically confirmed GAS pharyngitis was 33, 13 and 8 per 100 child-years respectively. The overall GAS carriage rate was 8e16% with the lowest rate in summer and highest rate in winter.11 While the Melbourne study demonstrated that the incidence of sore throat and GAS pharyngitis has remained remarkably stable over at least half a century in affluent, temperate-climate regions, studies from tropical regions tend to show more diversity in incidence rates. A prospective surveillance study of 685 children in Fiji showed a high incidence of 1.6 episodes of sore throat per child-year of which 14.7 cases per 100 child-years (95% CI, 11.2e18.8) were GAS culture-positive (serological confirmation was not performed). Group C and group G streptococci were frequently isolated with an incidence of 28.8 cases per
V.C.K. Herath, J. Carapetis 100 child-years (95% CI, 23.9e34.5), although their contribution to pharyngeal infection is not clear. The overall GAS carriage rate was 6%.12 By contrast, the Aboriginal population of northern Australia seems to have a remarkably low incidence of both sore throat and GAS culture-positive pharyngitis. A study from August 2003 to June 2005 in the Top End of the Northern Territory of Australia was conducted in three remote Aboriginal communities. There were a total of 531 household visits which included 4842 consultations. Based on two reported episodes of sore throat in children, the incidence density was 8 episodes per 100 person-years (95% CI, 4e15 episodes per 100 person-years). There were no cases of symptomatic GAS pharyngitis. The median point prevalence of throat carriage of GAS was 3.7%, group C was 0.7% and 5.1% for group G. There was no correlation with season or overcrowding.13 Knowing risk factors for transmission is important when considering control measures. The highest rates of GAS infection are in school-aged children and usually secondary cases occur within 2 weeks of index case. The 2001 study in Melbourne noted that 18/42 (43%) families with a primary case of GAS culture-positive sore throat had at least one secondary case. Of those 18 families, more than half (11/ 18) had more than 2 secondary cases. Of those at risk, 13% (95% CI: 9e18) contracted a secondary case. They were able to determine emm type in 26/32 (81%) of secondary culture positive cases, of which 25/26 (96%) were the same as the primary case.11
Clinical features GAS sore throat is most common in children aged between 5 and 15 years of age and usually presents in winter or early spring. There is often a history of exposure to someone with sore throat. There are two distinctive groups of clinical features that have previously been described in an attempt to differentiate between likely viral and GAS pharyngitis. Features most indicative of GAS pharyngitis are a sudden onset of sore throat, fever, headache, nausea, vomiting and abdominal pain. On examination, features may include tonsillopharyngeal inflammation with patchy exudates, palatal petechiae, anterior cervical adenitis and/or a scarlatiniform rash. Viral pharyngitis tends to be accompanied by symptoms of conjunctivitis, coryza, cough, diarrhoea and hoarseness. Additionally, discrete ulcerative stomatitis and a viral exanthem may be present.4 Of course, most individuals with sore throat have only some of these features, which makes differentiation between viral and bacterial causes fraught if based on clinical features alone. A systematic review and meta-analysis published in 2012 reviewed the best clinical decision rules (CDRs) published between 1975 and 2010 to diagnosis GAS pharyngitis in children. Some CDRs were found to have equal performance to some rapid diagnostic tests (RADTs) for excluding diagnosis. The suggestion from this review was that the CDRs should be used to aid reduction of antibiotic use only in those children with high risk of GAS pharyngitis.14 The most common CDRs used to date are the Centor and McIsaac (which is a modified version of Centor and accounts for patient age) criteria, which determines
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a likelihood ratio based on the number of specific symptoms or signs present. In some cases, these CDRs have improved the sensitivity of diagnosis to as high as 97% in children. However, specificity has been shown uniformly to be low at 67% in children.2 This further reinforces that attempting to distinguish between non-streptococcocal and GAS pharyngitis based on clinical grounds alone is difficult.
Diagnostic tools (Table 1) Culturing GAS on throat swab has been a simple method of confirmation in the past. However, a recent comparative cost-effectiveness study of diagnostic methods and treatment of pharyngitis in children in South Africa found that a throat swab added no benefit and increased cost compared to CDRs alone.15 RADTs have been in existence since the early 1980s with different methodologies utilised to provide a quick turnaround time for results.16 The first RADTs developed, such as latex agglutination methods, were not sensitive and had unclear end-points.4 Subsequent techniques developed included lateral flow and immunochromatographic assays, enzyme-linked immunosorbent assays (ELISAs) and optical immunoassays which have offered increased sensitivity and more defined end points.4,16 Molecular-based techniques have been developed more recently and utilise DNA probes, fluorescence in situ hybridization (FISH) and polymerase chain reaction (PCR) methods. A metaanalysis published in 2014 compared RADTs for GAS pharyngitis. The results from 48 studies noted overall sensitivity of 0.86 (95% CI 0.83e0.88) and specificity of 0.96 (95% CI 0.94e0.97). The suggestion was that RADTs could be used for accurate GAS pharyngitis diagnosis. The newer molecular techniques were found to perform the best with a sensitivity of 0.95 or above. In Australia, it is more cost effective Table 1
to utilise RADTs in direct comparison to culture at approximately AUD$5 to $10 per RADT versus AUD$30 per culture. In contrast, the cost in the United States and Europe is difficult to compare as there are a range of prices across different companies that produce these tests. The use of culture to confirm RADTs results increases costs dramatically; this strategy would lead to a cost of $8 million for every additional case of rheumatic heart disease (RHD) prevented in the United States.16
Treatment A Cochrane review published in 2006 reviewed the use of antibiotics in sore throat. The numbers need to treat (NNT) to prevent one sore throat by day 3 was 3.7 if GAS positive versus 6.5 if GAS negative. If no swab was done, NNT was 14.4. A reduction was also shown in other illnesses whereby for every 100 patients treated with antibiotics, there was one fewer case of ARF and three fewer cases of quinsy. The absolute benefit of antibiotics was modest, with an estimated mean absolute reduction of duration of symptoms of about 1 day at around day 3 of illness. It is not clear to what extent included studies of antibiotics in sore throat may have excluded cases with the most severe symptoms, who may stand to benefit the most from the symptom-reduction benefits of antibiotics. Given that, overall, 90% of patients were symptom free by one week, regardless of treatment with antibiotics, the authors concluded that, in populations at low risk of ARF, the choice as to whether to use antibiotics may need to be a clinician-led decision based on the individual case. The notable exclusion is in populations at high risk of ARF, where treatment of GAS pharyngitis remains a critical approach to primary prevention.17 There are various guidelines available for treatment of sore throat (refer to Table 1), with all of them
Summary of recommendations for diagnosis and treatment of sore throat by guideline.
Routine throat culture or RADT RADT only in some cases (e.g. more Centor criteria) Throat culture after negative RADT Use clinical score to target RADTs and antibiotics Anti-inflammatories for pain Steroids Antibiotics to prevent complications Antibiotics to reduce symptoms First line antibiotic Tonsillectomy
IDSA4 (USA)
ESCMID20 (Europe)
SIGN19 (Scotland)
NICE18 (UK)
Yes (unless clearly viral) No
No
No
No
Yes (physician discretion) No
No
No
N/A
N/A
Yes (antibiotics only) Yes No
Yes (antibiotics only) Yes No
No
No
No
No
Pen V
Pen V
Severe (criteria)
Selected children
No No (unless clearly viral) Yes No Yes Not clear Pen V, Amox or BPG Rarely
Yes Yes Adults with severe presentations Not in low risk populations Only severe cases (no. of Centor criteria) Pen V N/A
Key: RADT Z Rapid diagnostic tests, Pen V Z Penicillin V (Phenoxymethylpenicillin), Amox Z Amoxycillin, BPG Z Benzathine Penicillin G, IDSA Z Infectious Diseases Society of America, ESCMID Z European Society of Clinical Microbiology and Infectious Diseases, SIGN Z Scottish Intercollegiate Guidelines Network, NICE Z National Institute for Health and Care Excellence.
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recommending anti-inflammatories for pain. In the clinical practice guideline update by the Infectious Diseases Society of America (IDSA), antibiotics are only routinely recommended if there is a clinical or epidemiological high level of suspicion of GAS while awaiting confirmation on diagnostic tests. None of the other guidelines routinely recommend antibiotics for reduction of symptoms or prevention of complications from sore throat, though there is a caveat for severe cases in the European guidelines. In all guidelines, Penicillin V is the first line choice of antibiotic treatment, if treatment is to be used.8,18e20 For people allergic to penicillins, the alternatives include a Cephalosporin or Azithromycin. For those who are chronic carriers, additional recommendations include the use of Clindamycin, Rifampicin or Amoxycillin/Clavulanic acid.8 Regardless of the approach recommended in guidelines, there is good evidence from a number of settings that guidelines are often not followed in primary care, with many practitioners opting for antibiotic treatment. In Australia, 89% of patients with sore throat were noted to have received antibiotics during 1999 to 2001.21 Antibiotic prescriptions rates were lower in the USA at 73% (CI, 70e76%) in 1989 to 1999.7 Another study in the USA in 1992 noted similar rates of antibiotic prescriptions at 71% (5246/7435) of all sore throat presentations.22 A retrospective review of over 5 million primary clinic consultations for respiratory symptoms in Hong Kong from 2005 to 2010 noted that though overall antibiotic prescriptions use declined, the use for GAS pharyngitis increased from 89.2% to 97.8%.23 Overall these studies suggested higher rates of prescription than recommended by the guidelines. A review of adherence to acute pharyngitis treatment guidelines in Israel noted that only about 50% of physicians followed the strategies suggested. The factors noted to be associated with more antibiotic prescriptions were physicians who were male, younger, family medicine practitioners, worked in rural areas or prescriptions just before the weekend.24
Prevention There is currently no vaccine for GAS. A recent study compared the use of bacteriocin-producing Streptococcus salivarius K12 oral probiotic with a control as prophylaxis in children with proven recurrent GAS pharyngitis. There was a considerable reduction in episodes of GAS infections from 3.1 to 0.1 average cases compared to the preceding year versus 3.0 to 2.8 for the control group. Additional benefits included reduction in overall viral infection, other medication use, including antibiotics and antipyretics, as well as absenteeism from work or school. It was felt that the bacteriocin-producing S. salivarius was protective against recurrent GAS pharyngitis.25 Further studies of this intervention are currently underway, including in children not already diagnosed with recurrent pharyngitis.
Role of tonsillectomy Guidelines for tonsillectomy often cite the Paradise criteria as essential for identifying individuals with more severe disease that may be appropriate for tonsillectomy.26 The
V.C.K. Herath, J. Carapetis Paradise criteria are defined as: ‘(1) seven or more episodes in the preceding year, or five or more in each of the preceding two years, or three or more in each of the preceding three years comprising (2) characteristic clinical features, having been (3) treated with antibiotics when streptococcal infection was proven or suspected, and (4) each episode had to have been documented in a clinical record.’ The criteria are less strictly followed these days with more emphasis on the number of episodes than on assessing ‘certainty’ of each episode.27 A Cochrane review published in 2009 reviewed the effects of tonsillectomy in children (and/or adenoidectomy) on reduction and severity of tonsillitis and sore throat in the first postoperative year. Tonsillectomy in “more severely affected children” defined as children who fulfil the Paradise criteria, resulted in avoidance of three episodes of sore throat including one moderate or severe episode in the following year. On the other hand, less severely affected children avoided an average of one sore throat (two versus three) in the first post-operative year. The number of sore throat days was noted to reduce from 22 to 17 (although 5e7 of these were in the immediate post-operative period). This highlights the cost of postoperative pain and potential complications following a tonsillectomy. The reviewers concluded that the effectiveness of adeno-/tonsillectomy is most seen in those severely affected, with a moderate benefit via reduction of duration and number of episodes of sore throat. Some children are noted to improve without surgery. The impact on reduction of sore throats secondary to pharyngitis is less predictable.27 A multicentre, randomised controlled trial done over three years from March 2000 in the Netherlands reviewed the cost-effectiveness of adenotonsillectomy versus watchful waiting. They found that surgery because of mild to moderate symptoms alone resulted in higher costs without the relevant clinical benefit.28 The American stance does not recommend tonsillectomy solely to reduce the frequency of GAS pharyngitis, rather it is only recommended in rare cases with patients with recurrent pharyngitis and no alternative explanation.8 The UK Guidelines note poor evidence and suggested potential benefit in select cases of persistent recurrence.18 The Scottish Guidelines advise that for mild recurrent sore throats, ‘watchful waiting’ is more appropriate. They provide clear criteria for referral for tonsillectomy which include the Paradise criteria for recurrence, sore throats due to acute tonsillitis, and episodes that prevent normal functioning and are disabling.19 There were no recommendations for tonsillectomy in the European guidelines (refer to Table 1).20
Conclusions Sore throat is just as common as ever. It is still a major cost and cause for antibiotic prescriptions. Guidelines are divided between North America and Europe. Despite these guidelines, many children receive antibiotics. The driver for diagnosis and treatment is still questionable, but in most affluent populations it is difficult to justify antibiotic treatment on the basis of preventing ARF, whereas this
Please cite this article in press as: Herath VCK, Carapetis J, Sore throat: Is it such a big deal anymore?, J Infect (2015), http://dx.doi.org/ 10.1016/j.jinf.2015.04.010
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remains the major driver for sore throat management in populations at higher risk of ARF. Reduction in severity and duration of symptoms may be a reasonable basis to consider antibiotic treatment, and thus accurate diagnosis, of GAS pharyngitis particularly in those with more severe symptoms. The potential role of rapid tests in diagnosis appears to be increasing.
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Conflict of interest There are no conflicts of interest to declare. Q2
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