Sore Throat in Primary Care Project

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Family Practice, 2015, Vol. 32, No. 3, 263–268 doi:10.1093/fampra/cmv015 Advance Access publication 25 March 2015

Epidemiology Sore throat in primary care project: a clinical score to diagnose viral sore throat Selcuk Mistika,*, Selma Gokahmetoglub, Elcin Balcic, and Fahri A Onukd Downloaded from https://academic.oup.com/fampra/article-abstract/32/3/263/695324 by guest on 31 July 2019 aDepartment of Family Medicine, bDepartment of Microbiology, cDepartment of Public Health, Erciyes University Medical Faculty, Kayseri, Turkey, and dBunyamin Somyurek Family Medicine Centre, Kayseri, Turkey.

*Correspondence to Prof. S. Mistik, Department of Family Medicine, Erciyes University Medical Faculty, Kayseri 38039, Turkey; E-mail: [email protected]

Abstract Objective. Viral agents cause the majority of sore throats. However, there is not currently a score to diagnose viral sore throat. The aims of this study were (i) to find the rate of bacterial and viral causes, (ii) to show the seasonal variations and (iii) to form a new scoring system to diagnose viral sore throat. Methods. A throat culture for group A beta haemolytic streptococci (GABHS) and a nasopharyngeal swab to detect 16 respiratory viruses were obtained from each patient. Over a period of 52 weeks, a total of 624 throat cultures and polymerase chain reaction analyses were performed. Logistic regression analysis was performed to find the clinical score. Results. Viral infection was found in 277 patients (44.3%), and GABHS infection was found in 116 patients (18.5%). An infectious cause was found in 356 patients (57.1%). Rhinovirus was the most commonly detected infectious agent overall (highest in November, 34.5%), and the highest GABHS rate was in November (32.7%). Analysis of data provided a scoring system, called the Mistik Score, to diagnose viral sore throat. The predictive model for positive viral analysis included the following variables: absence of headache, stuffy nose, sneezing, temperature of ≥37.5°C on physical examination, and the absence of tonsillar exudate and/or swelling. The probability of a positive viral analysis for a score of 5 was 82.1%. Conclusion. The Mistik Score may be useful to diagnose viral sore throat. We suggest its use either alone or in combination with the Modified Centor Score.

Key words: Diagnose, sore throat, primary care, viral, score.

Introduction in an antibiotic prescription rate that is much higher than the actual GABHS infection rate. In a survey of antibiotic prescribing in UK Sore throat is a very common problem seen in general practice. general practice, half of all patients presenting with coughs, colds and Documented group A beta haemolytic streptococci (GABHS) is viral sore throats were prescribed an antibiotic (4). Shallcross and found in 15%–30% of children and in 10% of adults (1). Viral Davies (5) reported that innovative ways must be found to reduce agents cause the majority of sore throats (2). Many scores have the level of antimicrobial prescribing in primary care. The problem focused on the diagnosis of GABHS in patients with a sore throat; in using antibiotics for a sore throat which is presumed to be viral is this is important because GABHS requires treatment with antibiot- the emergence of bacteria which are resistant to antibiotics. ics. However, at present there is not a score to directly diagnose viral There are 4 derived and 12 validated clinical decision rules to sore throat for a physician who suspects that the aetiology is viral. diagnose streptococcal pharyngitis in children (6). The problem in The aim of treatment for a sore throat is to prevent complica- using these decision rules is their low positive predictive values, tions, such as acute rheumatic fever (3). However, this has resulted which makes them less used in clinical practice. Throat culture is still

© The Author 2015. Published by Oxford University Press. All rights reserved. 263 For permissions, please e-mail: [email protected]. 264 Family Practice, 2015, Vol. 32, No. 3 used as a gold standard laboratory test. New generation rapid anti- Statistical analysis gen tests are better. However, they cannot be used alone or instead Univariate and multivariate binary logistic regression analyses were of throat culture (7). The clinical manifestations of GABHS and performed to find the factors predicting viral infection. Every factor nonstreptococcal pharyngitis overlap broadly (8). The Centor Score in the history of the patient and physical examination was evaluated is used for the diagnosis of GABHS sore throat (9). The Modified one by one. The statistically significant factors in univariate binary Centor Score, which includes the evaluation of the age of patients logistic regression analysis were included in the model by using mul- with a sore throat, was described by McIsaac et al. (2). Although tivariate binary logistic regression with the backward Wald method. these two scores and many others are used for the diagnosis of In the logistic regression analysis, there was a statistically significant GABHS sore throat, there is need to improve the criteria, in order difference only in the analysis of viruses compared with bacteria, to prevent the unnecessary use of antibiotics throughout the world. bacteria plus virus and no microbiological cause. There was no sta- The aims of this study were (i) to find the rate of bacterial and tistically significant difference when the no microbiological cause viral causes of sore throats, (ii) to show the seasonal variations and group was added to the virus group as presumed viral infection. The (iii) to form a new scoring system to diagnose viral sore throat which model was formed according to the equation below (9). may reduce overuse of antibiotics. Downloaded from https://academic.oup.com/fampra/article-abstract/32/3/263/695324 by guest on 31 July 2019 eββ01++XX1 +βkk P = , Methods 1+ eββ01++XX1 +βkk Study population where ‘P’ stands for probability. One point was given for the pres- Patients with a sore throat, who had applied to Bunyamin Somyurek ence of each variable in the model (9). The probability of the pres- Family Medicine Centre which is located in the centre of Kayseri ence of viral infection was calculated for each score. If the score is province, were included in the study. Patients of any age or gen- 0, 1 or 2 there is no virus, and if it is 4 or 5 a virus is present. When der may apply to their family physicians for any medical problems. the score is 3, a decision is made by putting the score in the logistic A family physician examines approximately 600 sore throat patients regression model. When the coefficients are placed, P < 0.5 means in a year. The family physicians were asked to include one sore there is no virus and P ≥ 0.5 means a virus is present. The probabil- throat patient for every week in the study. Sore throat patients with ity changes depending on the presence of different types of variable a history suggesting infectious causes who were between the ages combinations. of 3 and over and agreed to participate in the study were included. Receiver operating characteristic (ROC) curve analysis was per- The patients with non-infectious causes such as postnasal drip, low formed between the scores and the PCR analysis results. The sensi- humidity in the environment, irritant exposure to cigarettes or smog tivity, specificity, positive predictive value, negative predictive value, and malignant disease were not included in the study. Informed con- positive likelihood and negative likelihood ratio were calculated sents were obtained from adults and the parents of the children. for the scores and the signs and symptoms, which were statistically significant. Throat culture and PCR analysis were used as reference Questionnaire standards for the Modified Centor Score and the score to diagnose The patients’ histories and clinical findings were recorded in detail. A ques- viral sore throat, respectively. The level of significance was consid- tionnaire consisting of demographic data questions and complaints was ered at 5%. given to the patients and the physical examination findings were also recorded. In order to minimise observer variations or discrepancies, training was given to the family physicians by an ear, nose and throat specialist. Results Patients’ characteristics Setting and procedure Over a period of 52 weeks, 624 patients were included in the study. The study was conducted in a Family Medicine Centre, in which 12 The mean age of the patients was 25.50 ± 17.71 (range 3–85, median family physicians work. A throat culture for GABHS and a naso- 21). Of the patients, 42.0% were male, and 58.0% were female. pharyngeal swab to detect 16 respiratory viruses were obtained from Sixty-four patients (10.3%) were preschool children, 268 (42.9%) each patient. The study was started in the first week of June 2013 were students, 152 (24.4%) were housewives, 32 (5.1%) were and samples were taken for 52 weeks. Throat swab cultures were retired and the remaining 108 (17.3%) were government employ- collected from the patients and swab specimens were inoculated ees and those working in the private sector. In our study, age was to 5% sheep blood agar. After overnight incubation of the plates not statistically significant in the logistic regression analysis for at 37°C, the plates were evaluated for the presence of GABHS. the Modified Centor Score and the Mistik Score. The distribution Nasopharyngeal swab specimens were collected from the patients of viral infection versus GABHS according to age group is given in and placed in viral transport media (Copan, Italy). The specimens Supplementary Figure s1. were sent to the virology laboratory for respiratory virus testing. A total of 624 throat cultures and polymerase chain reaction (PCR) analyses were performed. An Anyplex II RV16 Detection Viral analysis and throat culture kit (Seegene, Korea) was used to detect 14 RNA viruses and two Of the 624 sore throat patients included in the study in the period DNA viruses including human adenovirus (ADV), influenza A and June 2013–June 2014, viral infection was found in 277 patients B viruses (FluA, FluB), human parainfluenza viruses 1/2/3/4 (44.3%), and GABHS infection was found in 116 patients (18.5%). (PIV1/2/3/4), human rhinovirus A/B/C (HRV A/B/C), human respira- An infectious cause was found in 356 patients (57.1%), whereas no tory syncytial viruses A and B (RSV-A, RSV-B), human bocaviruses infectious cause was found in 268 patients (42.9%). Thirty-seven 1/2/3/4 (BoV1/2/3/4), human coronaviruses 229E, NL63 and OC43 patients (5.9%) had both GABHS and viral infections. Viral infec- (CoV-229E, CoV-NL63, CoV-OC43), human metapneumovirus tion only was found in 240 (38.4%) of the patients, and GABHS (MPV) and human enterovirus (EV) (coxsackievirus). infection only was found in 79 patients (12.6%) (Table 1). Sore throat in primary care 265

Detected viruses their symptoms and the physical examination findings. In case of a The detected viruses are shown in Table 2. The coronavirus types GABHS positive throat culture result, the prescription of the patient were: OC43 (21), NL63 (8) and 229E (10). The parainfluenza types was rapidly evaluated for the presence of an antibiotic. In this study, were: PIV1 (15), PIV 2 (1), PIV3 (11) and PIV4 (5). Four viruses 489 (78.4%) patients were prescribed an antibiotic by their general were detected in one patient (rhinovirus, parainfluenza 4, bocavirus practitioners. and enterovirus). In another patient, three viruses were detected (rhi- Infection type and the Modified Centor Scores are given in novirus, coronavirus OC43 and coronavirus 229E). Sixteen patients Table 3. Viruses caused a Modified Centor Score of 4 or 5 on many had two virus infections including rhinovirus [six with enterovirus, occasions (HRV 23, PIV 3, coronavirus 3, FLUB 2, HEV 2, MPV 2, three with parainflenza (two PIV1, one PIV3), three with influenza RSV 1, ADV 1, and two virus infections seven times). A, two with coronavirus (OC43 and NL63), one with ADV, and one with RSV A]. There were two virus combinations of influenza Score to diagnose viral sore throat A (three with influenza B, two with coronavirus 229E). Two other The predictive model for positive viral analysis included the fol- two-virus combinations (PIV1 plus PIV3, and coronavirus 229E plus lowing variables: absence of headache, stuffy nose, sneezing, tem- RSV B) were also found. perature of ≥37.5°C on physical examination and the absence of Downloaded from https://academic.oup.com/fampra/article-abstract/32/3/263/695324 by guest on 31 July 2019 Twenty-three patients had rhinovirus with GABHS. Five patients tonsillar exudate and/or swelling (Table 4). The logistic regression had influenza A and GABHS. Three patients had parainfluenza model is given in Supplementary Figure s3. (PIV1) and GABHS. Two patients had RSV and GABHS (one RSV The probability of a positive viral analysis for scores of 0 to 5 A and one RSV B). Three other patients had coronavirus (OC43), was 8.3%, 14.7%–20.4%, 25.2%–36.3%, 42.2%–55.3%, 61.9%– ADV, and metapneumovirus in combination with GABHS infection. 70.7% and 82.1%, respectively. No GABHS was present in patients One patient had rhinovirus plus enterovirus plus GABHS. with a score of 5. Rhinovirus was the most commonly detected infectious agent In order to generalise the results, we randomly split our data as overall (highest in November at 34.5%, lowest in March at 70% (training data) for ROC model building and 30% (validation 16.6%) (Supplementary Figure s2). The highest GABHS rate was in data) for validation. We defined cut-off values for each variable in November (32.7%) and the lowest in June (6.5%). the training data and assessed the performances in the validation data. The performance results of each factor are given in Table 5. Evaluation with the Modified Centor Score The sensitivity of this score, called the ‘Mistik Score’, was 60.2% Of the patients, 170 (27.2%) had Modified Centor Scores of zero and the specificity was 72.5%. The positive predictive value was or less, 359 (57.5%) had scores between 1 and 3, and 95 (15.2%) 62.5% and the negative predictive value was 70.5%. The positive had scores of 4 or more. It has been stated that empiric antibiotic likelihood ratio was 2.19 and the negative likelihood ratio was 0.55. treatment may be considered in patients with a score of 4 or more The Mistik Score was compared with the Modified Centor Score as (10). There were 35 (5.6%) patients with a Centor Score of 4 and a clinical decision rule, which is used for the diagnosis of GABHS, 95 (15.2%) patients with a Modified Centor Score of 4 or more in Table 2. Results of viral analysis our study. The throat culture results were sent to the general practitioners by e-mail in approximately 48 hours. However, the design Virus Frequency Percent of this study did not include an intervention to reduce the antibiotic prescription rates. In general, the patients were treated based on Rhinovirus 153 24.5 Coronavirus 39 6.2 Parainfluenza 32 5.1 Table 1. Distribution of viral and GABHS infections Influenza A 29 4.6 Enterovirus 15 2.4 Infection Frequency Percent RSVa 14 2.2 Influenza B 10 1.6 Virus 240 38.4 Adenovirus 6 0.9 a GABHS 79 12.6 MPVb 6 0.9 GABHS and virus 37 5.9 Bocavirus 2 0.3 None 268 42.9 None 347 55.6 Total 624 100.0

aRespiratory syncytial virus. a Group a beta haemolytic streptococci. bMetapneumovirus.

Table 3. Infection type and Modified Centor Scores

Infection Modified Centor Score

−1 0 1 2 3 4 5 Total

Virus 19 60 62 47 21 24 7 240 GABHSa 2 4 7 13 24 18 11 79 GABHS and virus 0 4 8 5 8 10 2 37 None 27 54 76 54 34 15 8 268 Total 48 122 153 119 87 67 28 624

aGroup a beta haemolytic streptococci. 266 Family Practice, 2015, Vol. 32, No. 3

Table 4. Score to diagnose viral sore throat

Variables Points ORa 95% CIb

Lower Upper

Absence of headache 1 1.975 1.285 3.035 Stuffy nose 1 2.081 1.330 3.257 Sneezing 1 2.811 1.799 4.393 Temperature (≥37.5°C) 1 1.765 1.094 2.845 Absence of tonsillar exudate and/or swelling 1 1.823 1.181 2.815 Total score 5 – – –

aOR = odds ratio. bCI = confidence interval. Downloaded from https://academic.oup.com/fampra/article-abstract/32/3/263/695324 by guest on 31 July 2019 Table 5. Comparison of ‘Mistik Score’ and Modified Centor Score

Sensitivity (%) Specificity (%) PPVa (%) NPVb (%) LR+c LR−

Mistik Score variables Absence of headache 45.8 62.4 48.1 60.2 1.22 0.87 Stuffy nose 71.1 56.0 55.1 71.8 1.61 0.52 Sneezing 55.4 74.3 62.2 68.6 2.16 0.60 Temperature (≥37.5°C) 30.1 68.5 35.1 63.4 0.95 1.02 Absence of tonsillar exudate and/or swelling 63.9 51.4 50.0 65.1 1.31 0.70 Mistik Score 60.2 72.5 62.5 70.5 2.19 0.55 Modified Centor Score variables Absence of cough 77.5. 56.4 20.7 94.5 1.77 0.39 Tonsillar exudate and/or swelling 82.5 57.2 22.1 95.7 1.92 0.30 Fever (>38.0°C) 16.3 92.3 23.6 88.2 2.11 0.90 Anterior cervical lymphadenopathy 66.3 69.5 24.2 93.3 2.17 0.48 Ages 3–14 46.4 69.0 47.0 68.5 1.50 0.78 Modified Centor Score 62.9 78.5 40.1 90.3 2.93 0.47

aPPV = positive predictive value. bNPV = negative predictive value. cLR = likelihood ratio. as there is no other score at present for the diagnosis of viral sore 5. We have described herein a score to diagnose viral sore throat with throat. the following variables: absence of headache, stuffy nose, sneezing, In our study, the sensitivity of the Modified Centor Score was temperature of ≥37.5°C on physical examination and the absence of 62.9%, the specificity was 78.5%, the positive predictive value was tonsillar exudates and/or swelling. 40.1%, and the negative predictive value was 90.3%. The positive likelihood ratio was 2.93 and the negative likelihood ratio was 0.47. Strengths and limitations The positive predictive values of the Mistik Score and the Modified The strength of our study was that we worked on laboratory proven Centor Score were found for each month, and varied between viral infections, instead of presumed viral infections, and showed 47.8%–65.2% and 31.0%–62.5%, respectively. The diagnostic the clinical association of signs and symptoms with a score which accuracy of the Mistik Score was 68%, and that of the Modified could make a major difference in the clinical approach of many fam- Centor Score was 75%. There was a negative correlation between the ily physicians and other doctors. The first variable of the score is Modified Centor Score and the Mistik Score (r = −0.357, P < 0.001). absence of headache. It has been reported that although headache is not one of the Centor criteria, it is a commonly looked for symptom Discussion of strep throat and is associated with GABHS infection in both children and adults (11). Stuffy nose and sneezing are the most common Statement of principal findings symptoms caused by respiratory viruses. Although rhinovirus, the This study demonstrated to us, by means of laboratory findings, that most common virus, is not thought to cause fever, Bellei et al. (12) viral infection was found in 44.3% of the patients and GABHS infec- reported a 50.5% incidence of fever in rhinovirus related cases in tion was found in 18.5%. An infectious cause was found in 57.1% their study. This is in agreement with the Mistik Score’s fever crite- of the patients, whereas no infectious cause was found in 42.9%. rion. The presence of the fever variable in both bacterial and viral Thirty-seven (5.9%) patients had both GABHS and viral infections. scores is possible because fever is observed in both kinds of infec- Viral infection only was found in 240 (38.4%) of the patients and tions. Also, the difference in the temperature levels may explain how GABHS infection only was found in 79 patients (12.6%). Rhinovirus fever may be present in both scores. Exudative tonsillitis is commonly was the most commonly detected infectious agent overall (highest in associated with ADV, EBV, and GABHS infection, although influ- November, 34.5%), and the highest GABHS rate was in November enza virus, parainfluenza virus or enteroviruses have been reported (32.7%). Viral sore throat can have a Modified Centor Score of 4 or (13–15). We had few cases of ADV and enterovirus infections or Sore throat in primary care 267 influenza and parainfluenza infections in our study. However, the sensitivity was reported as 49%, and the specificity as 82% (19). In absence of tonsillar exudates is a criterion of the Mistik Score. our study we used the Modified Centor Score because of the pres- The limitation of this study was that we did not ask the doctors ence of children. The Modified Centor Score had a sensitivity of in the study to change their routine practice and only prescribe anti- 62.9% and a specificity of 78.5% in our study. The Mistik Score’s biotics according to culture results. This resulted in a high antibiotic sensitivity was higher than that of the Centor Score and similar to prescription rate of 74.8% in the presence of an 18.5% GABHS that of the Modified Centor Score. The specificity of the Centor infection rate. Another limitation of this study was that it was Score was higher than those of the Modified Centor Score and the designed to identify only GABHS and 16 respiratory viruses. Certain Mistik Score. Smeesters et al. suggested a new clinical score with a bacteria that are sometimes found in sore throat, such as group B, sensitivity of 41%, a specificity of 84% and a positive likelihood C and G streptococci (Streptococcus dysgalactiae spp. equisimilis, ratio of 2.6 for low-resource settings. They used a cut-off value and Streptococcus anginosus group), fusobacterium (F. necrophorum) stated that the use of this score would prevent 41%–55% of unnec- and also some other viral causes like herpes simplex virus, Epstein- essary antibiotic use (20). The same calculation was performed for Barr virus and cytomegalovirus were not identified in our study (16). patients with a Mistik Score of 3–5. According to this calculation, These might have been the cause of sore throat in cases in which the use of the Mistik Score could have prevented 30.7% of unneces- no germs were identified. However, it has been stated that in 20% sary antibiotic use. Downloaded from https://academic.oup.com/fampra/article-abstract/32/3/263/695324 by guest on 31 July 2019 to 65% (average 30%) of patients with pharyngitis, no infectious The positive predictive value when using a Modified Centor pathogen can be found (16).This suggests to us that examining these Score of 4 was reported as 48% by Mazur et al. (21). In our study, a microorganisms may only provide an increase of approximately Modified Centor Score of 4 had a positive predictive value of 46.4%. 10%, or no increase in the identification rate in clinical practice. However, the best cut-off point was with a score of 3, which had a Therefore, identification of these aetiologic agents will probably not positive predictive value of 40.1%. Our score had a positive pre- change the variables of the Mistik Score. dictive value of 62.5%, which seems to be better than that of the Modified Centor Score. The importance of a negative likelihood Comparison with existing literature ratio has been stated as an important factor for use as a clinical cri- The aetiology of sore throat has been described in many textbooks terion (6,21). A negative likelihood ratio of under 0.2 is considered and studies. Primary bacterial pathogens were stated as 30% in chil- useful. In our study, the negative likelihood ratios of the Modified dren aged 5- to 11-years old, 15% in adolescents and 5% in adults Centor Score and the Mistik Score were 0.47 and 0.55, which were with pharyngitis. Viruses were identified in 15%–40% of children both higher than the desired level. The diagnostic accuracy of the and in 30%–80% of adults. Rhinovirus has been stated as the most Modified Centor Score (75%) in our study was a little higher than common viral agent (16). The overall GABHS rate of 18.5% and that of the Mistik Score (68%). This suggests to us that the Mistik virus rate of 44.3% are in agreement with these findings. In addi- Score may be used as well as the Modified Centor Score. tion, rhinovirus was the most common aetiologic agent in our study. The spectrum of respiratory viruses stated as the causative agent Implications in sore throat, and the rate of GABHS differ from study to study. Chi The use of the Mistik Score may be analysed with an example. et al. reported a virus rate of 29.6% and a GABHS rate of 1.7%. A 5-year-old child may present to his/her general practitioner with Viruses mixed with bacteria were found in 11.1% of cases. They sug- the complaints of sore throat, runny nose and cough. The history gested that routine throat cultures and antibiotics are not indicated and physical examination of the patient reveal absence of headache, in children with acute pharyngitis (15). In our study, the bacterial stuffy nose, sneezing, cough and the absence of tonsillar exudates and viral rates are higher, and mixed infection is lower. We cannot and/or swelling. This patient has a Centor Score of zero, and a suggest not using antibiotics considering the high rates of GABHS Modified Centor Score of one. A Modified Centor Score of one indi- in our study. Hashigucci and Matsunobu reported a 10.7% GABHS cates a 5%–10% risk of GABHS infection, and no further testing or rate, a 33.9% rate for viruses, and no etiological pathogens in 28.6% antibiotics are suggested for this patient (7,22). In this patient, the of cases. ADV was the most common virus (19.6%). The rate of Modified Centor Score may only suggest presumed viral infection. 42.9% for no aetiologic agent in our study is higher when compared However, the Mistik Score has proven viral infection with PCR anal- with their study, but in agreement with other results (6,17). Laguna- ysis results (61.9%–70.7%, with a score of four). If this patient had Torres et al. (18) reported that the influenza A was the most common a fever of >38.0°C, this would make the Modified Centor Score two, virus in influenza-like illness patients (25.1%). Our study shows that and the Mistik Score would be five. It is possible to determine that the rhinovirus was the most common virus, and this seems to be the infection is 82.1% viral by using the Mistik Score. The use of the more reasonable when the ailment is a sore throat. Modified Centor Score alone with a score of two will make further Many studies have been conducted in an attempt to find a score testing necessary in the case of a viral (rhinovirus) infection (7). to diagnose bacterial sore throat, so that the unnecessary use of anti- The presence of a low Modified Centor Score may suggest probable biotics can be prevented. In the first study by Centor et al. it was viral sore throat, but this score is not valid for showing viral infection. reported that knowing that a patient has a 56% chance of having In addition, a low Mistik Score is not valid for showing bacterial infec- GABHS on culture may be very helpful in decision making (9). In tion. A physician may choose to use one of these scores to decide on the our study, we found that the chance of having a viral sore throat on aetiology of sore throat. However, knowing the probabilities of both PCR analysis was 82.1% by using the Mistik Score. The variables of bacterial and viral sore throats may result in a better evaluation. absence of headache, stuffy nose, sneezing, temperature of ≥37.5°C on physical examination, and the absence of tonsillar exudates and/ or swelling were already symptoms and signs known to be indicators Conclusions of viral infection. The analysis of our data allowed us to produce a scoring system to The increase in the diagnostic test accuracy of a score may diagnose viral sore throat. Our score for diagnosing viral sore throat enable its use by a large number of physicians. The Centor Score’s has slightly lower sensitivity and specificity, a higher positive predictive 268 Family Practice, 2015, Vol. 32, No. 3 value and a lower negative predictive value when compared with the 7. McIsaac WJ, Kellner JD, Aufricht P, Vanjaka A, Low DE. Empirical vali- Modified Centor Score. The ‘Mistik Score’ may be useful to diagnose dation of guidelines for the management of pharyngitis in children and viral sore throat either alone or in combination with the Modified adults. JAMA 2004; 291: 1587–95. Centor Score, which is used for the diagnosis of GABHS in sore throats. 8. Bisno AL, Peter GS, Kaplan EL. Diagnosis of strep throat in adults: are clinical criteria really good enough? Clin Infect Dis 2002; 35: 126–9. 9. Centor RM, Witherspoon JM, Dalton HP, Brody CE, Link K. The diag- Funding: this study was funded by the Scientific Research Council of Erciyes nosis of strep throat in adults in the emergency room. Med Decis Making University (ERUBAP, Project No. TOA-2012–4148). 1981; 1: 239–46. Ethical approval: Erciyes University Ethics Committee approved this study 10. Choby BA. Diagnosis and treatment of streptococcal pharyngitis. Am Fam (Date: 07.08.2012, No. 2012/464). Physician 2009; 79: 383–90. Conflict of interest: the authors have no financial or proprietary interest in any 11. Tiemstra J, Miranda RL. Role of non-group a streptococci in acute phar- of the instruments or products used in this study. yngitis. J Am Board Fam Med 2009; 22: 663–9. 12. Bellei N, Carraro E, Perosa A, Watanabe A, Arruda E, Granato C. Acute Supplementary material respiratory infection and influenza-like illness viral etiologies in Brazilian adults. J Med Virol 2008; 80: 1824–7.

Supplementary material is available at Family Practice online. 13. Hsieh TH, Chen PY, Huang FL, et al. Are empiric antibiotics for acute Downloaded from https://academic.oup.com/fampra/article-abstract/32/3/263/695324 by guest on 31 July 2019 exudative tonsillitis needed in children? J Microbiol Immunol Infect 2011; 44: 328–32. Acknowledgements 14. Putto A. Febrile exudative tonsillitis: viral or streptococcal? Pediatrics We presented this study as a poster at the Royal College of General 1987; 80: 6–12. Practitioners, Annual Primary Care Conference 2013, 3–5 October 2013, 15. Chi H, Chiu NC, Li WC, Huang FY. Etiology of acute pharyngitis in chil- Harrogate, UK. The authors would like to thank Assistant Professor Ferhan dren: is antibiotic therapy needed? J Microbiol Immunol Infect 2003; 36: Elmali for his assistance in statistical analysis, and Isabel Steel for her com- 26–30. ments and Erciyes University Editing Office for help in editing. 16. Evans P, Miser WF. Sinusitis and pharyngitis. In: Family Medicine: Princi- ples and Practice. 6th edn. New York: Springer-Verlag, 2003. 17. Hashigucci K, Matsunobu T. Etiology of acute pharyngitis in adults: the References presence of viruses and bacteria. Nihon Jibiinkoka Gakkai Kaiho 2003; 1. Smith JL. Pharyngitis. In: Paulman PM, Paulman AA, Harrison JD (eds). 106: 532–9. Taylor’s Manual of Family Medicine. Philadelphia, PA: Lippincot Williams 18. Laguna-Torres VA, Gómez J, Ocaña V, et al. Influenza-like illness sentinel & Wilkins, 2007, pp. 274–276. surveillance in Peru. PloS One 2009; 4: e6118. 2. McIsaac WJ, White D, Tannenbaum D, Low DE. A clinical score to reduce 19. Aalbers J, O’Brien KK, Chan WS, et al. Predicting streptococcal pharyngi- unnecessary antibiotic use in patients with sore throat. CMAJ 1998; 158: tis in adults in primary care: a systematic review of the diagnostic accuracy 75–83. of symptoms and signs and validation of the Centor score. BMC Med 3. Matthys J, De Meyere M, van Driel ML, De Sutter A. Differences among 2011; 9: 67. international pharyngitis guidelines: not just academic. Ann Fam Med 20. Smeesters PR, Campos D Jr, Van Melderen L, de Aguiar E, Vanderpas 2007; 5: 436–43. J, Vergison A. Pharyngitis in low-resources settings: a pragmatic clini- 4. Hawker JI, Smith S, Smith GE, et al. Trends in antibiotic prescribing in pri- cal approach to reduce unnecessary antibiotic use. Pediatrics 2006; 118: mary care for clinical syndromes subject to national recommendations to e1607–11. reduce antibiotic resistance, UK 1995–2011: analysis of a large database 21. Mazur E, Bochyńska E, Juda M, Kozioł-Montewka M. Empirical vali- of primary care consultations. J Antimicrob Chemoter 2014; 69: 3423–30. dation of Polish guidelines for the management of acute streptococ- 5. Shallcross LJ, Davies DS. Antibiotic overuse: a key driver of antimicrobial cal pharyngitis in children. Int J Pediatr Otorhinolaryngol 2014; 78: resistance. Br J Gen Pract 2014; 64: 604–5. 102–6. 6. Le Marechal F, Martinot A, Duhamel A, Pruvost I, Dubos F. Streptococcal 22. Pelucchi C, Grigoryan L, Galeone C, et al. ESCMID Guideline for the pharyngitis in children: a meta-analysis of clinical decision rules and their management of acute sore throat. Clin Microbiol Infect 2012; 18 (Suppl clinical variables. BMJ Open 2013; 3:1–10. 1): 1–28. Journal name: International Journal of General Medicine Article Designation: Original Research Year: 2018 Volume: 11 International Journal of General Medicine Dovepress Running head verso: Matthews et al Running head recto: Bactericidal action of AMC/DCBA lozenges in pharyngitis open access to scientific and medical research DOI: http://dx.doi.org/10.2147/IJGM.S184406

Open Access Full Text Article Original Research Spectrum of bactericidal action of amylmetacresol/2,4-dichlorobenzyl alcohol lozenges against oropharyngeal organisms implicated in pharyngitis

Derek Matthews Purpose: Pharyngitis is commonly caused by a self-limiting upper respiratory tract infection Robert Atkinson (URTI) and symptoms typically include sore throat. Antibiotics are often inappropriately used Adrian Shephard for the treatment of pharyngitis, which can contribute to antimicrobial resistance, therefore non- antibiotic treatments which have broad antiseptic effects may be more appropriate. Amylmetacresol Reckitt Benckiser Healthcare International Ltd, Slough, Berkshire, (AMC) and 2,4-dichlorobenzyl alcohol (DCBA) are present in some antiseptic lozenges and have UK established benefits in providing symptomatic relief and some in vitro antiviral action. Methods: Seven bacterial species associated with pharyngitis, namely Streptococcus pyogenes,

For personal use only. Fusobacterium necrophorum, Streptococcus dysgalactiae subspecies equisimilis, Moraxella catarrhalis, Haemophilus influenza, Arcanobacterium haemolyticum and Staphylococcus aureus, were exposed to an AMC/DCBA lozenge dissolved in artificial saliva. In vitro bactericidal activity was measured as a log reduction in colony-forming units (CFUs). Results: Bactericidal activity was recorded against all organisms after 1 minute. Greater than 3

log10 reductions in CFUs were observed at 1 minute for S. pyogenes (log10 reduction CFU/mL ± SD, 5.7±0.1), H. influenza (6.1±0.1), A. haemolyticum (6.5±0.0) and F. necrophorum (6.5±0.0), at 5 minutes for S. dysgalactiae (6.3±0.0) and M. catarrhalis (5.0±0.9) and at 10 minutes for S. aureus (3.5±0.1). Conclusion: An AMC/DCBA lozenge demonstrated a greater than 99.9% reduction in CFUs against all tested species within 10 minutes, which is consistent with the time a lozenge remains in the mouth. Patients with uncomplicated bacterial pharyngitis may benefit from the antibacterial action of antiseptic AMC/DCBA lozenges. Furthermore, AMC/DCBA lozenges may be International Journal of General Medicine downloaded from https://www.dovepress.com/ by 197.83.196.4 on 01-Aug-2019 more relevant and appropriate than antibiotics for pharyngitis associated with a self-limiting viral URTI. Keywords: pharyngitis, bacterial infections, antibacterial agents, Streptococcus, sore throat

Plain language summary Pharyngitis is a common condition. It can last several days and is usually the result of self-limiting viral infections, such as the common cold, although occasionally, pharyngitis can be caused by a bacterial infection. The most commonly reported symptom is sore throat. Antibiotics do not Correspondence: Robert Atkinson work against the viruses that in most cases cause pharyngitis but are often prescribed anyway. Reckitt Benckiser Healthcare International Ltd, 103–105 Bath Road, This contributes to antimicrobial resistance, where bacteria become immune to antibiotics and Slough, Berkshire SL1 3UH, UK treatment for infections becomes difficult. Alternative treatments could help reduce inappropriate Tel +44 148 258 3969 Fax +44 175 321 7899 prescriptions of antibiotics for pharyngitis, and previous studies have demonstrated the antiviral Email [email protected] and pain-relieving qualities of some antiseptic lozenges. The authors conducted a laboratory-

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based study to assess the ability of antiseptic lozenges to kill a in a recent study as a true pathogen rather than a colonizer broad range of bacteria known to cause pharyngitis. They found of the oropharynx,22 and the Streptococcus dysgalactiae that, when lozenges containing two antiseptic ingredients were subspecies equisimilis, which can cause severe or recurrent dissolved in a solution similar to human saliva, the mixture killed pharyngitis,3,17,23 although there is insufficient evidence of a 99.9% of all pharyngitis-associated bacteria that were tested within role for S. dysgalactiae in other adverse outcomes.3 Moraxella 10 minutes. These results suggest that patients with uncomplicated catarrhalis has been frequently isolated from patients bacterial pharyngitis may benefit from the antibacterial and pain- with pharyngitis in combination with S. pyogenes,24 which relieving action of antiseptic lozenges, including those taking may be significant considering that separate studies have antibiotics. Additionally, antiseptic lozenges may be more relevant and appropriate than antibiotics for pharyngitis of a viral origin. demonstrated that M. catarrhalis potentiates the adhesion of S. pyogenes to the nasopharyngeal epithelium.25,26 Other bacteria Introduction cultured from patients with pharyngitis include Haemophilus 27 28 Pharyngitis is associated with inflammation of the pharynx1 influenza, Arcanobacterium haemolyticum and the and is one of the most common reasons patients seek health opportunistic pathogen, Staphylococcus aureus, although the 19 care professional advice.2 Acute pharyngitis is predomi- clinical significance of S. aureus association is not known. nantly caused by a viral upper respiratory tract infection In patients diagnosed with tonsillitis, F. necrophorum, such as the common cold3,4 and is usually self-limiting with appears to be a clinically important species, with a prevalence symptoms, such as sore throat, lasting ~3–7 days.5 Despite significantly higher in subjects with clinical tonsillitis 29 this, antibiotics are still frequently inappropriately used for compared to subjects without tonsillitis. S. aureus has also 30,31 the treatment of pharyngitis even though patients consult- been identified as a common cause of tonsillitis and was ing their doctor are often primarily seeking reassurance and the most common pathogen isolated from patients undergoing 30 symptomatic relief.6,7 Antibiotics are ineffective against the tonsillectomy due to recurrent tonsillitis. H. influenza viruses that cause ~90% of cases, do not offer symptomatic has similarly been recovered from patients with tonsillitis, although the clinical significance is currently unknown.27 For personal use only. relief and inappropriate antibiotic prescription can contribute to antimicrobial resistance, which is a serious threat to global Non-antibiotic antimicrobial treatments could potentially public health.8 Consequently, there is a need for non-antibiotic benefit patients with bacterial pharyngitis by offering not treatments,9,10 which have broad anti-infective effects while only antimicrobial activity but also symptomatic relief. The meeting patient needs for relief of symptoms. in vitro activity of 10 lozenge formulations has previously 32 Antiseptics are a class of antimicrobial agent which kill via been investigated against S. pyogenes and S. aureus. In a physical action on the bacteria.11 In addition to bactericidal this study, the in vitro bactericidal activity of AMC/DCBA activity, some antiseptics – such as amylmetacresol (AMC) lozenges against a broader range of potentially pathogenic and 2,4-dichlorobenzyl alcohol (DCBA) – have been shown oropharyngeal bacteria was assessed to evaluate the potential to have antiviral effects in vitro12,13 and anesthetic-like in vivo action of these lozenges against organisms associated effects14 with established benefits in providing symptomatic with pharyngitis. relief of pain.15,16

International Journal of General Medicine downloaded from https://www.dovepress.com/ by 197.83.196.4 on 01-Aug-2019 Bacterial infections contribute to 5%–15% of pharyngitis Methods and materials cases in adults.4,17,18 The most common bacterial cause of Test samples acute pharyngitis, and the reason for legitimate antibiotic For the bactericidal assay, AMC 0.6 mg, DCBA 1.2 mg prescribing to prevent complications, is group A β-hemolytic lozenges (Strepsils Honey and Lemon, Reckitt Benckiser Streptococcus (GABHS or Streptococcus pyogenes).3,19 It Healthcare Ltd, Slough, UK) were dissolved into 5 mL is responsible for ~30% of cases in children20 and is less of artificial saliva medium (0.1% meat extract [VWR frequent in adults at ~10% of cases,17 but rarely results in International, Lutterworth, UK], 0.2% yeast extract complications.3 A number of other bacteria have also been [VWR International], 0.5% protease peptone [Oxoid, implicated in infections of the throat, which may present Basingstoke, UK], 0.02% potassium chloride [Fisher with a more complicated pathology or represent either Scientific, Loughborough, UK], 0.02% sodium chloride opportunistic infection or an underlying medical condition. [Fisher Scientific], 0.03% calcium carbonate [Fisher Less common species recovered from patients presenting Scientific], 0.2% glucose [VWR International], 0.2% mucin with symptoms of pharyngitis or with a clinical diagnosis of from porcine stomach Type II [Sigma Aldrich, Gillingham, pharyngitis include Fusobacterium necrophorum,21 described Dorset, UK], pH 6.7±0.3) at 44°C±1°C.

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Test organisms and incubations Results S. aureus (NCTC7445, Public Health England, Salisbury, In vitro bactericidal activity of AMC/ UK) were cultured on tryptone soya agar (SGL, Corby, UK) DCBA lozenges at 32°C±2°C; S. pyogenes (NCTC12696, Public Health For all test organisms, evidence of bactericidal activity was England) were cultured on Columbia blood agar with 5% recorded at the 1-minute time point (Table 1, Figure 1), defibrinated sheep blood (SGL) at 36°C±2°C; M. catarrha- and test control counts demonstrated that the test method lis (NCTC3622, Public Health England) were cultured on and media did not affect the survival of the organisms. Columbia blood agar (SGL) at 32°C±2°C; H. influenza For S. pyogenes, H. influenza, A. haemolyticum and F. nec- (NCTC4842, Public Health England) were cultured on rophorum, the decrease in CFU/mL at 1 minute exceeded 3 chocolate blood agar (SGL) at 32°C±2°C; F. necrophorum log10 (99.9% decrease), whereas greater than 3 log10 reduc- (NCTC12238, Public Health England) were cultured on tions were recorded at 5 minutes for S. dysgalactiae and anaerobic blood agar (FAA) with 5% horse blood (SGL) at M. catarrhalis and at 10 minutes for S. aureus. Additionally, 37°C±2°C anaerobically; A. haemolyticum (NCIMB702294, at all time points, the SD (Table 1) of the replicates was small NCIMB, Aberdeen, UK) were cultured on Columbia blood (≤0.9 log10 CFU/mL), indicating consistent and reproducible agar with 5% defibrinated sheep blood at 36°C±2°C; S. observations. dysgalactiae (ATCC12388, LGC, Teddington, UK) were cultured on Columbia blood agar with 5% defibrinated sheep Discussion blood at 36°C±2°C. This study examined the bactericidal action of an antiseptic lozenge containing AMC and DCBA. The organisms tested Bactericidal assay included gram-positive cocci (S. pyogenes, S. aureus, S. dys- The bactericidal assay was performed following a protocol galactiae) and bacilli (A. haemolyticum), as well as gram- similar to the Clinical and Laboratory Standards Institute negative cocci (M. catarrhalis) and bacilli (H. influenza, 33 For personal use only. approved guideline. Specifically, inoculum cultures were F. necrophorum), representing a broad range of bacterial cell prepared for each challenge organism to give an approximate structures and sensitivities. population of 108 colony-forming unit (CFU)/mL in saline The results demonstrated that the AMC/DCBA lozenge (0.9% sodium chloride [Fisher Scientific]). One inoculum exhibits broad bactericidal activity against a range of organ- suspension was prepared for each replicate tested. Test sample isms implicated in pharyngitis and the rapid activity observed (4.9 mL) was prepared as above and inoculated with 0.1 is consistent with the time taken for a lozenge to dissolve mL of the inoculum suspension. The solution was vortexed in the mouth.16 thoroughly to mix and then tested after 1-, 5- and 10-minute For all test organisms, evidence of bactericidal activity for contact times, consistent with the time a lozenge takes to the AMC/DCBA lozenge was recorded at the 1-minute time dissolve in the mouth,16 by removing 1 mL of sample/inocula point. Of particular interest is the robust bactericidal activ- mixture and transferring into 9 mL of neutralizing diluent ity against S. pyogenes, the most frequent cause of bacterial (0.1% peptone water [VWR International], 0.9% sodium pharyngitis.4 Reductions exceeding 99.9% were achieved

International Journal of General Medicine downloaded from https://www.dovepress.com/ by 197.83.196.4 on 01-Aug-2019 chloride [Fisher Scientific], 0.3% lecithin [MP Biomedicals, by 1 minute for S. pyogenes, H. influenza, A. haemolyticum Illkirch-Graffenstaden, France], 1% polysorbate 80 [Univar, and F. necrophorum, by 5 minutes for S. dysgalactiae and Bradford, UK], pH 6.6±0.2). Neutralization validation was M. catarrhalis and by 10 minutes for S. aureus. The bacteri- carried out against all test organisms. Solutions were seri- cidal activity of an AMC/DCBA lozenge within a 10-minute ally diluted to 10−5, plated onto the appropriate agar medium period is important as it is consistent with the duration that and incubated for a minimum of 3 days. A positive control a lozenge remains in the mouth; furthermore, the active sample of 4.9 mL artificial saliva medium and 0.1 mL of the ingredients were also tested at the expected concentration test inoculum for each organism was also prepared without achieved when a lozenge is dissolved in the mouth, assuming exposure to test samples and assayed at a 30-minute time a volume of 5 mL of saliva. point. Test control counts were performed to confirm the A previous in vitro evaluation of the bactericidal activity of total population of the culture suspensions used for each antiseptic lozenges ([DCBA 1.2 mg, menthol 8 mg, AMC 0.6 test replicate. The test controls were used to calculate the log mg] and [DCBA 1.2 mg, AMC 0.6 mg]) against S. pyogenes reduction on exposure to test samples. Mean log reduction in and S. aureus demonstrated antibacterial effectiveness.32 Both CFUs per milliliter was calculated from three test replicates. AMC and DCBA formulations were highly active against the

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Time (mintues) 0 5 10 0 Streptococcus pyogenes

–1 Staphylococcus aureus

–2 Moraxella catarrhalis CFU/mL) 10 Haemophilus influenza –3 Fusobacterium necrophorum

–4 Streptococcus dysgalactiae

–5 Arcanobacterium haemolyticum Average* log reduction (log –6

–7

Figure 1 Bactericidal activity of an AMC/DCBA lozenge. Notes: Bactericidal activity was measured against seven common oropharyngeal organisms over a 10-minute period. Bactericidal activity was defined as a decrease in bacterial count (CFUs per mL), using the average of three test replicates. *Average of the three test replicates. Abbreviations: AMC, amylmetacresol; CFUs, colony-forming units; DCBA, 2,4-dichlorobenzyl alcohol.

For personal use only. Table 1 Control and test counts of challenge organisms

Challenge organism Test control count Log reduction (mean log10 CFUs/mL ± SD) (mean log CFUs/mL ± SD) 10 1 minute 5 minutes 10 minutes Staphylococcus aureus 6.5±0.1 0.5±0.2 2.2±0.1 3.5±0.1 Streptococcus pyogenes 6.7±0.1 5.7±0.1 5.7±0.1 5.7±0.1 Moraxella catarrhalis 7.2±0.1 0.5±0.1 5.0±0.9 6.2±0.1 Haemophilus influenza 7.1±0.1 6.1±0.1 6.0±0.1 6.2±0.1 Fusobacterium necrophorum 6.3±0.0 5.3±0.0 5.3±0.0 5.3±0.0 Arcanobacterium haemolyticum 7.5±0.0 6.5±0.0 6.5±0.0 6.5±0.0 Streptococcus dysgalactiae 7.3±0.0 1.5±0.2 6.3±0.0 6.3±0.0 Abbreviation: CFU, colony-forming unit. International Journal of General Medicine downloaded from https://www.dovepress.com/ by 197.83.196.4 on 01-Aug-2019 bacteria tested within 5 minutes of exposure, in contrast to the A and severe acute respiratory syndrome coronavirus.12,13 slow and weak action of the local antibiotic tyrothricin.33 The In addition to antimicrobial activity, AMC and DCBA are data generated in this study support and expand upon these proven to provide relief from the symptoms of pharyngitis, previously published observations, providing further evidence particularly sore throat, likely through their demonstrated of effectiveness against a broader range of bacterial species local anesthetic-like action against voltage-gated neuronal under in vitro conditions, including those where knowledge sodium channels,14,34 and therefore may benefit patients of their clinical pathology in pharyngitis is continuing to presenting with either bacterial or viral pharyngitis. evolve or those that represent either an opportunistic infection Furthermore, by relieving symptoms and managing patient or an underlying medical condition. These data likewise expectations, the number of instances of inappropriate complement recent studies showing the in vitro viricidal antibiotic prescribing for viral pharyngitis may be reduced. effects of lozenges containing AMC/DCBA (and the active A limitation of this study is that these observations ingredients as free substances) against parainfluenza virus were performed in vitro and therefore do not fully reflect type 3, cytomegalovirus, respirator y syncytial virus, influenza the environment of the throat. For example, the throat may

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contain multiple microorganisms whereas this study tested the Disclosure bactericidal activity against organisms in isolation. The role Derek Matthews, Robert Atkinson and Adrian Shephard are of the patient’s immune system and swallowing action on the employees of Reckitt Benckiser Healthcare Ltd, UK. The antimicrobial activity of the lozenge or active ingredients can authors report no other conflicts of interest in this work. also not be determined using in vitro methodology. However, the incidence of these bacteria is relevantly low in the general References population; therefore, studying the bactericidal activity of . 1 Renner B, Mueller CA, Shephard A. Environmental and non-infectious factors in the aetiology of pharyngitis (sore throat). Inflamm Res. AMC/DCBA in vivo can be challenging. Consequently, an in 2012;61(10):1041–1052. vitro approach is advantageous allowing the rapid generation 2. Vincent MT, Celestin N, Hussain AN. Pharyngitis. Am Fam Physician. of robust data, for multiple organisms simultaneously, that can 2004;69(6):1465–1470. 3. ESCMID Sore Throat Guideline Group; Pelucchi C, Grigoryan L, et be used to evaluate the potential of AMC/DCBA for efficacy al. Guideline for the management of acute sore throat. Clin Microbiol in vivo. Infect. 2012;18(Suppl 1):1–28. 4. Worrall GJ. Acute sore throat. Can Fam Physician. 2007;53(11): 1961–1962. Conclusion 5. Spinks A, Glasziou PP, Del Mar CB. Antibiotics for sore throat. These data show that an AMC/DCBA lozenge demonstrates Cochrane Database Syst Rev. 2013;(11):CD000023. 6. van Driel ML, De Sutter A, Deveugele M, et al. Are sore throat patients bactericidal activity against all test organisms, representing who hope for antibiotics actually asking for pain relief? Ann Fam Med. a broad range of bacterial cell structures, from 1 minute 2006;4(6):494–499. 7. Linder JA, Singer DE. Desire for antibiotics and antibiotic prescribing and achieves greater than 99.9% kill for all test organisms for adults with upper respiratory tract infections. J Gen Intern Med. within 10 minutes, which is consistent with the duration that 2003;18(10):795–801. a lozenge remains in the mouth. 8. World Health Organization. Antimicrobial Resistance Fact Sheet. Available from: http://www.who.int/en/news-room/fact-sheets/detail/antimicrobial- Therefore, patients with uncomplicated bacterial phar- resistance. Published February 15, 2018. Accessed July 07, 2018. yngitis, including those taking antibiotics, from low-risk 9. Dekker AR, Verheij TJ, van der Velden AW. Inappropriate antibiotic prescription for respiratory tract indications: most prominent in adult populations and without additional risk factors, may benefit For personal use only. patients. Fam Pract. 2015;32(4):401–407. from the antiseptic action of AMC/DCBA against a range 10. Gulliford MC, Dregan A, Moore MV, et al. Continued high rates of of bacterial species associated with pharyngitis. Most cases antibiotic prescribing to adults with respiratory tract infection: survey of 568 UK general practices. BMJ Open. 2014;4(10):e006245. of pharyngitis should not require antibiotics as they are 11. Sheldon AT Jr. Antiseptic “resistance”: real or perceived threat? Clin typically self-limiting and often viral in origin. Therefore, Infect Dis. 2005;40(11):1650–1656. 12. Oxford JS, Lambkin R, Gibb I, Balasingam S, Chan C, Catchpole A. A over-the-counter antiseptics like AMC/DCBA may be more throat lozenge containing amyl meta cresol and dichlorobenzyl alcohol appropriate, unless the condition deteriorates or a streptococ- has a direct virucidal effect on respiratory syncytial virus, influenza A cal infection is diagnosed. and SARS-CoV. Antivir Chem Chemother. 2005;16(2):129–134. 13. Shephard A, Zybeshari S. Virucidal action of sore throat lozenges against respiratory viruses parainfluenza type 3 and cytomegalovirus. Antiviral Res. 2015;123:158–162. Data sharing statement 14. Foadi N, de Oliveira RC, Buchholz V, et al. A combination of topi- All data generated or analyzed during this study are included cal antiseptics for the treatment of sore throat blocks voltage-gated in this manuscript. neuronal sodium channels. Naunyn Schmiedebergs Arch Pharmacol. 2014;387(10):991–1000. International Journal of General Medicine downloaded from https://www.dovepress.com/ by 197.83.196.4 on 01-Aug-2019 15. McNally D, Simpson M, Morris C, Shephard A, Goulder M. Rapid Acknowledgments relief of acute sore throat with AMC/DCBA throat lozenges: randomised The authors would like to thank Aisat Fatade Ogunpola controlled trial. Int J Clin Pract. 2010;64(2):194–207. 16. Wade AG, Morris C, Shephard A, Crawford GM, Goulder MA. A (a former employee of Reckitt Benckiser Healthcare Ltd, multicentre, randomised, double-blind, single-dose study assessing the UK) for laboratory support. Medical writing assistance efficacy of AMC/DCBA Warm lozenge or AMC/DCBA Cool lozenge in the relief of acute sore throat. BMC Fam Pract. 2011;12(1):6. was provided by Daniel East at Elements Communications 17. Shephard A, Smith G, Aspley S, Schachtel BP. Randomised, double- Ltd, Westerham, UK and was funded by Reckitt Benckiser blind, placebo-controlled studies on flurbiprofen 8.75 mg lozenges in Healthcare Ltd, UK. This work was supported by Reckitt patients with/without group A or C streptococcal throat infection, with an assessment of clinicians’ prediction of “strep throat”. Int J Clin Pract. Benckiser Healthcare Ltd, UK. 2015;69(1):59–71. 18. Radkova E, Burova N, Bychkova V, Devito R. Efficacy of flurbiprofen 8.75 mg delivered as a spray or lozenge in patients with sore throat due Author contributions to upper respiratory tract infection: a randomized, non-inferiority trial All authors contributed to data analysis, drafting or revising in the Russian Federation. J Pain Res. 2017;10:1591–1600. 19. Dagnelie CF, Touw-Otten FW, Kuyvenhoven MM, Rozenberg-Arska the article, gave final approval of the version to be published, MR, de Melker RA. Bacterial flora in patients presenting with sore and agree to be accountable for all aspects of the work. throat in Dutch general practice. Fam Pract. 1993;10(4):371–377.

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20. Shaikh N, Leonard E, Martin JM. Prevalence of streptococcal pharyn- 27. Mihancea N. Frequency and distribution per species, biotypes, resistance gitis and streptococcal carriage in children: a meta-analysis. Pediatrics. to antibiotics and beta-lactamase production of the hemophils isolated 2010;126(3):e557–e564. from patients with respiratory diseases. Roum Arch Microbiol Immunol. 21. Batty A, Wren MW. Prevalence of Fusobacterium necrophorum and 1998;57(2):125–137. other upper respiratory tract pathogens isolated from throat swabs. Br 28. Carlson P, Renkonen OV, Kontiainen S. Arcanobacterium haemolyticum J Biomed Sci. 2005;62(2):66–70. and streptococcal pharyngitis. Scand J Infect Dis. 1994;26(3):283–287. 22. Eaton C, Swindells J. The significance and epidemiology of 29. Jensen A, Hansen TM, Bank S, Kristensen LH, Prag J. Fusobacterium Fusobacterium necrophorum in sore throats. J Infect. 2014;69(2): necrophorum tonsillitis: an important cause of tonsillitis in adolescents 194–196. and young adults. Clin Microbiol Infect. 2015;21(3):266.e1–e3. 23. Harrington AT, Clarridge JE 3rd. Impact of identification of Streptococ- 30. Katkowska M, Garbacz K, Stromkowski J. Staphylococcus aureus cus dysgalactiae subspecies equisimilis from throat cultures in an adult isolated from tonsillectomized adult patients with recurrent tonsillitis. population. Diagn Microbiol Infect Dis. 2013;76(1):20–23. APMIS. 2017;125(1):46–51. 24. Gergova RT, Petrova G, Gergov S, Minchev P, Mitov I, Strateva T. 31. Zautner AE, Krause M, Stropahl G, et al. Intracellular persisting Microbiological features of upper respiratory tract infections in Bul- Staphylococcus aureus is the major pathogen in recurrent tonsillitis. garian children for the period 1998–2014. Balkan Med J. 2016;33(6): PLoS One. 2010;5(3):e9452. 675–680. 32. Richards RM, Xing DK. In vitro evaluation of the antimicrobial activi- 25. Lafontaine ER, Wall D, Vanlerberg SL, Donabedian H, Sledjeski DD. ties of selected lozenges. J Pharm Sci. 1993;82(12):1218–1220. Moraxella catarrhalis coaggregates with Streptococcus pyogenes and 33. CLSI. Methods for Determining Bactericidal Activity of Antimicrobial modulates interactions of S. pyogenes with human epithelial cells. Infect Agents. Approved Guideline, CLSI Document M26-A. Wayne, PA: Immun. 2004;72(11):6689–6693. Clinical and Laboratory Standards Institute (CLSI); 1999. 26. Verhaegh SJ, Flores AR, van Belkum A, Musser JM, Hays JP. Dif- 34. Buchholz V, Leuwer M, Ahrens J, Foadi N, Krampfl K, Haeseler G. ferential virulence gene expression of group A Streptococcus serotype Topical antiseptics for the treatment of sore throat block voltage-gated M3 in response to co-culture with Moraxella catarrhalis. PLoS One. neuronal sodium channels in a local anaesthetic-like manner. Naunyn 2013;8(4):e62549. Schmiedebergs Arch Pharmacol. 2009;380(2):161–168. For personal use only. International Journal of General Medicine downloaded from https://www.dovepress.com/ by 197.83.196.4 on 01-Aug-2019

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Received: 2 February 2017 | Accepted: 8 August 2017 DOI: 10.1111/ijcp.13002

META-ANALYSIS

Efficacy of AMC/DCBA lozenges for sore throat: A systematic review and meta-analysis

Gesine Weckmann1 | Anke Hauptmann-Voß1 | Sebastian E. Baumeister2,3 | Christine Klötzer1 | Jean-François Chenot1

1Department of General Practice, Institute for Community Medicine, University Medicine Summary Greifswald, Germany Background: Lozenges containing Amylmetacresol and 2,4-Dichlorobenzylalcohol 2 Division of Epidemiology, Department (AMC/DCBA, eg Strepsils®) are marketed as a remedy for acute sore throat. This over- of Sport and Health Sciences, Technical University of Munich, Germany the-counter formulation has antiseptic and local anaesthetic qualities. 3Institute for Community Medicine, SHIP/KEF Objectives: The objective of this systematic review and meta-analysis is to evaluate Clinical-Epidemiological Research, University the efficacy and safety of AMC/DCBA for the relief of pain associated with acute un- Medicine Greifswald, Germany complicated sore throat. Correspondence Methods: A systematic review of Literature was conducted using databases Medline, Gesine Weckmann, Department of General Practice and Family Medicine, Institute for Embase and Cochrane to identify randomised controlled trials comparing AMC/DCBA Community Medicine, University Medicine against placebo or alternative local treatment options for acute uncomplicated sore Greifswald, Greifswald, Germany. Email: [email protected] throat. An additional hand search was performed. Two reviewers independently assessed citations for relevance, inclusion criteria and risk of bias. Meta-analysis was

performed on included trials and standardised mean differences (SMD; dCohen) with 95% confidence intervals (CIs) were calculated. Results: The literature search yielded 77 citations, 3 of which met the inclusion criteria. AMC/DCBA lozenges (0.6 mg Amylmetacresol, 1.2 mg 2, 4-Dichlorobenzylalcohol) were compared with unflavoured, non-medicated lozenges. The AMC/DCBA formulation additionally contained lidocaine in one and flavouring additives in another trial. A total of 660 adults participated in the included trials. Primary outcome was reduction in pain intensity against baseline, 2 hours after intervention compared with placebo group. Fixed effects meta-analysis resulted in a standardised mean difference in pain intensity of −0.6 (−0.75; −0.45) on an 11-point ordinal rating scale, favouring the AMC/DCBA lozenges. Secondary outcomes were sore throat relief, difficulty swallowing and throat numbness. No serious side effects were reported, whereas mild side effects like headache, cough, nasal congestion and irritation of the oral cavity, were reported in up to 16% of subjects in both groups. All included trials were sponsored by a manufacturer of AMC/DCBA containing lozenges. Conclusions: Lozenges with AMC/DCBA can be a safe treatment option to relieve pain in patients with uncomplicated sore throat looking for local treatment options and valuing the modest additional effect compared with non-medicated lozenges. Registration: PROSPERO CRD42015008826.

Gesine Weckmann and Anke Hauptmann-Voß contributed equally to this work.

1 | INTRODUCTION

What’s known Over the course of one year, approximately 30% of the general Non medicated Lozenges are a popular home remedy for population will experience at least one episode of sore throat mostly sore throat. The emollient effects of lozenges are probably caused by viral infection. The majority of affected individuals do not mediated by increased salivation. Various lozenges with 1 seek medical attention and the natural course is usually self-limiting. pharmaceutically active substances with local anaesthetic Although treatment with antibiotics may shorten the duration of effects or vitro antimicrobials and antiviral effects are mar- symptoms in the small subgroup of patients with bacterial infections keted for symptom relief in sore throat. antibiotic stewardship and the relatively high prevalence of side effects warrant careful consideration.2,3 Patient history, clinical exami- What’s new nation, and the use of scoring systems to predict bacterial infections, This is the first quantitative summary of evidence from ran- have a limited reliability in identifying the small proportion of patients domised clinical trials for effectiveness of local treatment of 4 who will develop complications. Because of decrease in the incidence acute uncomplicated sore throat with AMC/DCBA lozenges. of complications like rheumatic fever or post-streptococcal glomeru- AMC/DCBA provided a modest additional effect compared lonephritis, most industrialised countries do not recommend preven- with non- medicated lozenges and can be a safe treatment op- 4-6 tive antibiotics. tion to relieve pain in patients with uncomplicated sore throat. Perceived patient pressure is an important factor for antibiotic prescriptions.7 Physicians tend to overestimate patients’ preferences for treatment with antibiotics and patients desire antibiotics mainly because they expect pain relief.8,9 Gargling with emollient fluids, 2.1 | Data sources drinking warm liquids and analgesic medications, are commonly used symptomatic treatment options.10 Lozenges containing a combination We searched three electronic bibliographic databases for rel- of Amylmetacresol and 2, 4-Dichlorobenzylalcohol (AMC/DCBA) are evant publications: MEDLINE (PubMed), EMBASE and Cochrane marketed worldwide as over-the counter drug (OTC) for pain relief for (CENTRAL). We included studies published between 1966 and 20 sore throat.11 Proposed mechanisms of action of AMC/DCBA are an- September 2016. The search algorithm contained the following key- tiseptic (virucidal) as well as anaesthetic qualities, which have been words and MeSH-terms: (Dichlorobenzylalcohol* OR AMC DCBA OR demonstrated in in vitro studies.12-14 Therefore, AMC/DCBA lozenges cresol* OR Neo Angin OR Strepsils) AND (pharyngitis OR tonsillitis might be a useful option for symptom relief in patients with sore throat OR rhinopharyngitis OR tonsillopharyngitis OR pharyngotonsillitis OR and might contribute to the reduction in antibiotic prescription for sore throat) NOT (tonsillectomy OR intubation OR postoperative OR sore throat. autoimmune). Additionally, we performed a manual search in the ref- We have performed a systematic review and meta-analysis of ran- erence lists of eligible papers and searched for unpublished trials in domised controlled trials (RCTs) to assess the efficacy and safety of trial registries www.clinicaltrials.gov, ISRCTN and EURACT.18-20 AMC/DCBA lozenges vs placebo lozenges for the treatment of acute If necessary, investigators of included or unpublished trials were uncomplicated sore throat pain in ambulatory patients. We will discuss contacted by telephone or by e-mail to obtain additional information. the implications of our findings for current treatment practice in this group of patients. 2.2 | Study selection

1.1 | Review questions Our search strategy included all relevant published randomised controlled trials and reviews about the treatment of acute sore • Are AMC/DCBA lozenges more effective than placebo in reducing throat. We excluded articles that focused on sore throat caused by throat pain in patients consulting for acute sore throat in ambula- intubation or autoimmune diseases, pregnancy or chronic sore throat. tory settings? Inclusion criteria were: • How frequent and severe are side effects of AMC/DCBA lozenges? • randomised controlled trials • patients with acute sore throat • topical treatment with AMC/DCBA • ambulatory setting 2 | METHODS • sore throat probably caused by upper respiratory tract infection (URTI)

This systematic review has been conducted according to the guide- Exclusion criteria were: lines of the PRISMA statement(S1) and AMSTAR.15,16 The review has been prospectively registered with the international prospective reg- • non-randomised, observational study designs ister of systematic reviews (PROSPERO) CRD42015008826.17 • postoperative patients WECKMANN et al. | 3 of 11

• probable causes of sore throat other than URTI • Intervention characteristics: description of intervention, duration of • allergy treatment. • chronic respiratory diseases like asthma • Outcomes: Primary outcome sore throat pain intensity and sec- • malignant disease ondary outcomes: sore throat pain relief, difficulty swallowing and • pregnancy throat numbness were recorded, including assessment methods and measurement characteristics. We collected quantitative data We did not place restrictions on duration of application, duration of for each of the outcomes, details of their definitions and cut-offs for follow-up, publication language, year of publication, or study population categorisations. We extracted data on any reported adverse events. characteristics. Two independent reviewers (AHV, GW) screened titles and ab- Standardised mean differences with confidence intervals were stracts of publications using a standardised form. We excluded titles calculated, assuming fixed effects. All confidence intervals reported and abstracts that clearly did not meet the inclusion criteria. For those in this paper are 95% confidence intervals unless stated otherwise. titles fulfilling inclusion criteria full-text articles were obtained. The re- Heterogeneity was quantified by calculating the I2 statistic.21 Risk of se- viewers resolved disagreements by consensus. lection, performance, detection, attrition, reporting and other bias of all included trials was assessed with the Cochrane bias assessment tool.22 Publication bias was assessed by calculating funnel plots and identifica- 2.3 | Data extraction and analysis tion of unpublished trials. Rigor of reporting was assessed according to We extracted information from the original reports into standardised the CONSORT statement for reporting randomised controlled trials.23 forms. We did not have access to individual data and used summary Quality of evidence was appraised with GRADE.24 All data were entered data provided in the included publications. For all trials, the following in and analysed with Review manager (RevMan) version 5.3. data were extracted:

3 | RESULTS • Study characteristics: first author; year of publication; country of origin; funding source; study design and setting; duration of fol- 3.1 | Search results and study selection low-up; number of randomised patients; number of patients analysed for each outcome; number of drop-outs with reason for We identified 84 potentially relevant publications through database discontinuation, registration in a public clinical trial registry. and hand search. A list of all citations is available on request. After • Population characteristics: inclusion and exclusion criteria; patient screening of titles and abstracts, 8 publications were evaluated ac- characteristics (eg, age, gender, race) underlying disease or condi- cording to the eligibility criteria and included in our final analysis tion; co-morbidities (eg, sleep apnea). (Figure 1).25-27 All included trials were financed by Reckitt Benckiser

DatabasesManual search Trial registries 61 citations16citations 9citations

86 citations Title and abstract review (excluded: 78 ) Duplicate records n = 35 Did not meet in– and exclusion criteria n = 24 (e.g. in vitro study, pregnancy) No abstract or article available n = 11 Missing data or information n = 7 Comment or letter n = 1

8full text articles full text review (excluded: 5)

Informative publication (no RCT) n = 3 Consumer survey n = 1 Flavor testing trial n = 1

FIGURE 1 Flow diagram - Literature 3RCTs included search results and study selection 4 of 11 | WECKMANN et al.

Healthcare International (RB), manufacturer of AMC/DCBA containing scale (TSS).30 Main exclusion criteria were known allergy to the study lozenges.25-27 The search and selection process is displayed in Figure 1. medication, chronic respiratory diseases and recent use of analgesics. We conducted a separate search of trial registries, using the key The Wade 2011 trial did not describe exclusion criteria. words “Amylmetacresol AND adults” or “Dichlorobenzylacohol AND The reporting did not fully adhere to stipulations of the CONSORT adults.” We identified 6 RCTs from the EURACT and 1 RCT from the statement.23 Setting, study population, data allowing assessment of ISRCTN clinical trial registry.19,20 The trial identified from the ISRCTN selection bias and limitations of the trials were not sufficiently re- registry, was explicitly labelled as published by Wade 2011. Of the ported.23,25-27 Patients were recruited in ambulatory care settings and remaining 6 trials, 3 trials were probably identical with McNally 2010, by advertisements in the United Kingdom, but it remains unclear if Wade 2011 and McNally 2012, which suggests that Wade 2011 was these “primary care investigational sites” were general practice surger- registered in both the ISRCTN and EURACT registries(S2). ies, or linked to a commercial clinical trials company. Additionally, it is 3 trials were unpublished and no results of these trials were docu- not reported whether patients received an incentive for participation mented in the registries26: One of these 3 unpublished trials was con- and completion of the study. Limitations of the trials were not dis- ducted between 2012 and 2015 sponsored by Cassella-med GmbH cussed at all or only incompletely in 2 of the 3 included trials. A patient & Co. KG (Gereonsmühlengasse, Cologne, Germany), of Klosterfrau flow chart as stipulated by the CONSORT statement was available for Healthcare Group, a German pharmaceutical manufacturer and mar- 2 of the 3 trials (McNally 2010, Wade 2011).23,25,26 In 2 of the trials keting partner of RB until 2014.28 We contacted the trial contact per- (Wade 2011, McNally 2012) no screening failures were reported, but son in January 2015 to inquire if the trial had been published and to a several patients who did not meet the inclusion criteria were ran- ask for detailed information to include the trial in out meta-analysis. domised and included in the intention-to-tr eat analysis of these trials We received information that the results of the trial were being anal- (Table 1).26,27 As McNally 2010 only reported treatment effects calcu- ysed and publication was expected in 2016.29 No further information lated with per-pr otocol data, we asked for additional information, but on the results of the trial was provided, so that we could not include this request remained unanswered. All included trials reported patient this unpublished trial in out meta-analysis. characteristics (age, sex) of eligible patients, but not of drop-outs.25-27 We have no information on the results of the other 2 unpublished Patient characteristics including throat soreness at baseline and med- trials.All unpublished randomised controlled trials were sponsored by ical history were similar in intervention and control groups of the tri- RB except for the aforementioned trial sponsored by Cassella. als, but Wade 2011 did not report on baseline symptom severity for any symptom or group and the other two trials reported incompletely. There was some imbalance of male trial participants in the McNally 3.2 | Study characteristics and assessment of 2012 trial, with 33% males in the intervention vs 58% in the control reporting group.27 Concomitant disease was not reported by Wade 2011 and The characteristics of the included trials are summarised in Table 1. A McNally 2012.26,27 total of 661 patients were included in the 3 eligible RCTs. In all RCTs, McNally 2010 reported concomitant medication in 52% of the lozenges containing 0.6 mg AMC and 1.2 mg DCBA were applied in treatment and 60% of the placebo group, including anti-histamines and the intervention group, whereas the control group was treated with 1 patient (0.6%) in each group taking systemic antibiotics.25 McNally placebo lozenges without AMC/DCBA or other active substances. In 2012 reported that 56% of the treatment group vs 42% placebo group one of the trials (Wade 2011) cooling or warming flavours were added used concomitant non-analgesic medication, including included one to the treatment lozenges, while no flavour was added to the placebo patient in the treatment group taking the NSAID etodolac for rheuma- lozenges.26 The study medication in the intervention group of one of toid arthritis.27 Acetaminophen was allowed as rescue medication in the trials (McNally 2012), contained lidocaine in addition to AMC/ one of the trials (McNally 2010). The average consumption of rescue DCBA while the placebo lozenges contained neither AMC/DCBA nor medication was 2 doses within 24 hours after the start of intervention Lidocaine.27 This McNally 2012 study had a smaller number of sub- and 5 doses within 96 hours after treatment begin and no significant jects than the other studies, while the results of this study tended difference in consumption was found between intervention and pla- to be similar in magnitude and direction to the results of the other cebo groups. Wade 2011 provided no information on rescue or con- included studies (Figures 2C and A, TableS3, TableS4a, S4b, S4c, S4d). comitant medication.26 We conducted a sensitivity analysis by calculating the results of Risk of bias of all included trials was assessed with the Cochrane the meta-analysis without inclusion of the McNally 2012 study with bias assessment tool and is reported in Table 2.22 Risk of bias was lidocaine-containing intervention medication. This sensitivity analysis generally low in all trials, but an unclear risk of bias was found for indicated no significant differences in magnitude or direction of the allocation concealment in the McNally 2010 and 2012 trials and meta-analysis results when omitting the results of this trial (TableS4a, for blinding of participants in all trials. Incomplete outcome data S4b, S4c, S4d). and selective reporting bias were high in the Wade 2011 trial and All studies included had similar in- and exclusion criteria.25-27 Main unclear in McNally 2012. An unclear risk of “other bias” was found inclusion criteria were sore throat with confirmed tonsillopharyngitis in all included trials because of possible publication bias based on with duration of ≤ 4 days before inclusion, probably caused by URTI funding by the manufacturer of AMC/DCBA lozenges in combina- and with sore throat pain intensity ≥ 6 on the 11-point throat soreness tion with the unpublished trials identified through literature search. WECKMANN et al. | 5 of 11

= at

(VAS100)

2):

10) 1) 1) =

= = = mm

2) (VAS100) 8) 10) 1)

3): 1) 4) 0)

50 =

= = =

= = = =

≤

mm (n (n =

(n (n 2): 10) 0)

6 6

= = = 1) 33

< < <6 <6

= ≤ 6) 5)

up (n

1) 5)

= =

reported:

swallowing

throat

soreness soreness soreness soreness

outs 16):

Intervention group (n mouth ulcer (n Placebo group (n throat pain increase(n lost to follow- withdreew, lack of time after 1h (n vomiting (n throat throat intervention group cool (n throat Missing assessment (n intervention group warm (n wrong assessment time (n placebo group (n Excluded from per protocol analysis (n swollen Drop- intervention group (n placebo group (n no differentiation between intervention and placebo groups: throat no URTI (n difficulty screening screening (n wrong assessment time (n d

h,3

3 min Excluded from per protocol analysis:

h,24 h,1-

2 120 2 sugar based lozenge sugar based lozenge sugar based lozenge Comparison Follow up Dropouts unflavored unflavoured unflavoured

lidocaine

mg/DCBA mg/DCBA mg/DCBA

0.6 0.6 0.6

mg lozenge mg cool(1) or mg mg lozenge

1.2 1.2 warm (2) lozenge 1.2 10 AMC AMC AMC United Kingdom United Kingdom United Kingdom ground(% Ethnic back- caucasian)98% Setting(Country) Treatment 97% Sex(% male) 32% 76) 75) 42% 75) 41% 98% (18- (16- (18-

36 Age mean (inclusion criteria) 32 32 Number of Participants 126 1 Characteristics of included trials

McNally 2010 310 References Wade 2011 225 McNally 2012 TABLE 6 of 11 | WECKMANN et al.

(A)

(B)

(C)

FIGURE 2 Forest plots for primary and secondary outcomes (A) sore throat pain intensity as measured with the 11-pt Throat Soreness Scale (TSS); (B) sore throat pain relief on the 7-pt sore throat relief scale; (C) difficulty swallowing on a 100 mm visual analogue scale (VAS)

TABLE 2 Risk of bias of included trials

adequate blinding of blinding of incomplete sequence allocation participants and outcome outcome selective Reference generation con-cealment personnel assessment data reporting other bias

McNally et al 2010 low unclear unclear low low low Unclear Wade et al 2011 low low low unclear high high unclear McNally et al 2012 low unclear unclear low unclear unclear high WECKMANN et al. | 7 of 11

No indication for publication bias was detected in the funnel plot for change in difficulty swallowing is represented in Figure 2C. The (TableS5). heterogeneity was high for this outcome (I2 87%), but needs to be interpreted with caution.

4 | META-ANALYSIS 4.2.3 | Throat numbness 4.1 | Primary outcome Wade 2011 and McNally 2012 reported on throat numbness, meas- All included trials included sore throat pain intensity as a primary ured with a 5-pt. categorical scale from 1 representing none to 5 outcome. We pooled the results of the included trials for the primary representing complete numbness. Baseline throat numbness was not outcome of sore throat after 2 hours as measured with the 11-point reported in both publications, so that only relative improvement could ordinal TSS, with 0 meaning no sore throat and 10 meaning maximum be evaluated. Mean increase in throat numbness was 2.05 in the treat- sore throat. One of the trials (Wade 2011) did not report baseline val- ment and 1.59 in the placebo group at 2 hours after start of treatment. ues of the outcomes. The reported mean sore throat pain intensity Standardised mean difference was 0.59 (0.39, 0.78; P < .00001) in calculated from the other trials was 7.15 points before the start of favour of AMC/DCBA at 2 hours after the start of treatment (Table treatment.25-27,30 120 minutes after start of treatment, the weighted S3). A summary of findings table for the meta-analysis is available in mean sore throat pain reduction on this scale was −1.92 (−1.78 to Table S6. −2.06) in the treatment group and −0.95 (−0.85 to −1.03) in the placebo group respectively. Meta-analysis showed a standardised mean 4.2.4 | Other reported outcomes difference of −0.60 (−0.75 to −0.45) in the treatment group compared with the placebo group and this difference was statistically significant 2 trials reported on onset of anaesthesia with a median onset after (P < .00001) (Figure 2A). We did not find indication of heterogeneity 45 minutes (15 to 780 ns) in McNally 2010 and 30 minutes in McNally in effect estimates (I²=0%). 2012. Meta-analysis was not possible because of incomplete reporting. For the outcomes throat numbness and sore throat relief, McNally 2012 reports maximum results at 15 minutes after treatment begin. All trials 4.2 | Secondary outcomes reported on significant subjective improvement of the general condition in patients in the treatment group compared with the placebo group 4.2.1 | Sore throat relief on different dimensions of consumer questionnaires.25,26 Aggregation All included trials reported about sore throat relief after 2 hours. of these data for these outcomes was not attempted, because of lack Sore throat relief was measured with a 7-point categorical sore of comparable measurement methods and incomplete reporting of throat relief scale,30 where 0 signifies no sore throat relief and 6 data where there was overlap (Wade 2011).25-27 In the McNally 2010 complete sore throat relief. By default, the initial measurement was trial, the subjects were questioned for freedom of symptoms after 24, deemed 0. Mean absolute sore throat relief scores were 1.90 and 48 and 72 hours. After 24 hours, the difference between placebo and 0.87 in treatment and placebo groups, respectively. This is equiva- treatment groups was not significant. After 48 and 96 hours, 16% and lent with mild relief on the scale in the treatment group and slight 35% of subjects in the treatment group vs 6% and 10% in the placebo relief in the placebo group. group were free from symptoms and these differences were statistically Standardised mean difference in sore throat pain relief at 120 min- significant.25 McNally (2012) found a significant improvement of throat utes was with 0.89 (1.04, 0.73; P < .00001) points significantly higher swelling of −8.8 (−15.3 to −2.2; P < .0001) on a VAS 100 swollen throat in the treatment group compared with the placebo group, as depicted scale, with 0 meaning not swollen and 100 very swollen.27 Additionally, in Figure 2B. Calculated heterogeneity was low. McNally (2010) found a significant improvement in eating and speaking in the treatment vs placebo group.25 Wade reported on the emotional benefit as reported in a questionnaire with of 52 and 58% of subjects in 4.2.2 | Difficulty swallowing cold and warm treatment groups reporting benefit compared with 19% Difficulty swallowing after 2 hours was measured with a visual ana- in the placebo group (p < .00001).26 logue scale (VAS 100) in all included trials with 0 representing swallowing not difficult and 100 very difficult. Baseline characteristics were not reported in one of the publications (Wade 2011). Before 5 | ADVERSE EFFECTS treatment, difficulty swallowing was measured as 67.1 and 66.0 at baseline in intervention and control groups, respectively as calculated All included trials reported adverse events, which varied from 2%- from the other trials. 120 minutes after the start of treatment, mean 16%, and did not differ significantly between intervention and control difficulty swallowing in the treatment and placebo group had de- group in any of these trials. Most reported side effects were mild and creased with −16.2 and −6.1, respectively on the VAS 100 scale with a could be attributed to the URTI.31 Examples are headache, earache, standardised mean difference of −0.90 (−1.06, −0.75; P < .00001), fa- cough, chills, pyrexia and nasal congestion.25-27 However, 3 events of vouring the treatment group. A forest plot with comparison of results mouth ulceration were reported in the treatment group by McNally 8 of 11 | WECKMANN et al.

(2010), one of which severe and probably related to the study medi- from symptoms at 24, 48 and 72 hours after treatment begin and cation, one mild and possibly related25 and a possibly related case of found a significant difference between treatment and placebo groups tongue ulceration in the control group.25 Apart from this, no clinically at 48 and 72 hours with 16 and 35% of the treatment vs 6 and 10% of significant related side effects or serious adverse events were re- the placebo group reporting no symptoms.25 ported in the intervention group of any of the trials.25-27 The included trials reported 2-16% mostly mild adverse effects. The incidence of adverse effects did not differ significantly between intervention and control groups. No clinically significant related side 6 | DISCUSSION effects or serious adverse effects were reported. Several other topical treatment options for sore throat are available 6.1 | Summary of main results and have similar effect on pain reduction. Ambroxol is a substance with This meta-analysis summarises 3 RCTs with 660 subjects, comparing local anaesthetic properties, available as lozenge. A meta-analysis on AMC/DCBA with non-medicated lozenges for treatment of sore throat. the efficacy of ambroxol as a topical treatment of sore throat vs placebo A standardised mean difference on the main outcome of reduction in lozenges showed a difference in pain reduction in SMD −0.11 (CI −0.15; sore throat pain on an 11-pt. pain scale after two hours of −0.60 (−0.75 −0.07) for 20 mg ambroxol after 3 hours.38 tA the end of the first day to −0.45; P < .00001) was observed. For the secondary outcomes sore 69% in the ambroxol group and 53% in the Placebo group reported a throat relief on a 7-pt. scale SMDs of 0.89 (1.04, 0.73; P < .00001) and good or very good efficacy.38 Another option for local treatment of sore difficulty swallowing on an 11-pt. scale a SMD of −0.90 (−1.06, −0.75; throat is flurbiprofen, a non-steroidal anti-inflammatory drug, available P < .00001) was observed after 2 hours. In both groups 2-16% of sub- as spray or lozenge. A trial on the efficacy of lozenges containing the jects reported adverse events, which were mostly mild and could be at- local anaesthetic lidocaine, found a significant difference in sore throat tributed to the underlying URTI, but in 2 patients with mouth ulcers a pain relief compared with placebo with 38% in the treatment group relation with the study medication could not be ruled out.25-27 against 12% in the placebo group showing a ≥50% improvement in pain relief.39 One study assessing the effectiveness of a flurbiprofen spray compared with non-medicated spray, reported a statistically significant 6.2 | Meaning of the results and comparison with average pain reduction (intervention −1.82, control −1.13 points on the other topical treatments STIS) in a similar range as in our review of AMC/DCBA in both groups.40 The reported SMD of 0.60 for throat soreness corresponds to an av- 5 other trials reported statistically significant benefit for flurbiprofen erage pain reduction in 1.9 pt. on the 11-pt. pain scale in the interven- lozenges compared with placebo lozenges. The reported efficacy on tion group after 2 hours. This is slightly below the estimated minimum the 11-pt- ordinal sore throat scale, was −1.01 and −2.14 for flurbipro- value considered as clinically important pain reduction in acute pain fen vs −0.45 and −1.65 for placebo lozenges.41-43 of ≥ 2 pt. on an 11-pt. pain scale.32,33 The control group also showed All these RCTs of different topical treatments report a statis- an average reduction in 0.95 pt. on the 11-pt. pain scale. Albeit this tically significant small effect size of pain relief compared with pla- is statistically significant lower than in the intervention group this is cebo. Consistently, a significant proportion of patients in the placebo less than the 2 pt. considered clinically important. The difference in group also reported improvement. The non-medicated lozenges serv- pain reduction between AMC/DCBA and non-medicated lozenges ing as comparisons for lozenges containing a pharmaceutically active might be imperceptible for most people suffering from sore throat. substance cannot be regarded as an inert placebo intervention. The The effect sizes of the favourable effects of AMC/DCBA compared emollient effects of lozenges are probably mediated by increased with placebo for the other outcomes were 1.90 and 0.87 (SMD 0.89) salivation.44 There sucking lozenges in general might be beneficial on the 7-pt throat pain relief scale and−11% reduction in difficulty to sooth sore throat and the benefits of medicated lozenges are swallowing on the VAS100. This is lower, than the threshold of 33% or underestimated. ca. 30 mm considered significant in postoperative pain.34-36 Although no studies on the threshold of clinically significant pain reduction pain 6.3 | Strengths and limitations in acute sore throat have been conducted, it is unlikely that the effect size in acute sore throat is smaller than for other kinds of acute pain. 6.3.1 | Limitations of the trials For some of the other reported outcomes not evaluated in all studies, a significant subjective benefit was reported compared with Recruitment setting was described incompletely and some of the pa- placebo.26 Since this is not a standard outcome in trials evaluating the tients were recruited via advertisements, so that selection bias cannot effectiveness of sore throat relief, the meaning of this finding remains be ruled out. This is a possible limitation for generalising the finding unclear given the small benefit observed with established outcomes. to patients seen in general practice which might be sicker than those Additionally, the single question assessing betterment is not validated included in the trials. A patient flowchart was missing in McNally 2012 and could be interpreted as suggestive (“At 2 hours post dose, do you and not all trials report on number of patients screened for inclusion feel any better than before you took the throat lozenge?”)37 and on drop-outs. One trial (Wade 2011) did not report absolute Alld include trials measured pain relief for up to 2 hours after treat- baseline values for any of the outcomes and only reported relative ment begin. Only McNally 2010 reported about subjective freedom changes to the unreported baseline values. The control group in this WECKMANN et al. | 9 of 11 trial had less smokers, than the treatment group, with 15% and 26%, successful. The treatment lozenge in one trial contained lidocaine and respectively but this is unlikely to have changed the direction of the indirect comparison or correction for this effect was not attempted.27 results. Additionally, the mean duration of sore throat in the control Although the funnel plot is not suggestive for publication bias, this group was reported to be 3.6 ± 7.1 days, which is implausible, since result should be interpreted with caution because of the small number one of the inclusion criteria was sore throat with duration of less than of trials included in the analysis. We identified 3 unpublished trials in four days. Reporting on disease severity was incomplete and Wade public study registries from which we have no information on the re- 2011 and McNally 2012 included patients who did not meet inclu- sults. All identified published and unpublished randomised controlled sion criteria in their ITT analyses. Exclusion of patients using antibi- trials have been sponsored by manufacturers of AMC/DCBA contain- otic or antihistaminic co-medication was incomplete. In one of the ing lozenges. trials acetaminophen was allowed as rescue medication, but failed to report on the differences in use of this rescue medication in both treatment and placebo groups.24 It is therefore possible that analgesic 7 | CONCLUSIONS co-medication might have influenced results. In one of the trials AMC/DCBA was combined with lidocaine in Lozenges with AMC/DCBA can be a safe treatment option to relieve the treatment lozenges, whereas the placebo lozenge contained no pain in patients with uncomplicated sore throat valuing the modest active ingredient.27 The positive effects of the intervention treatment additional effect compared with non-medicated lozenges. were not as strong as in the other 2 trials, where no co-medication was included in the AMC/DCBA lozenge. Inhibition of the effects of AMC/ DCBA by concurrent application of lidocaine cannot be ruled out, es- 8 | IMPLICATIONS FOR RESEARCH pecially as the analgesic effect of AMC/DCBA is at least partly mediated by blockage of voltage gated sodium channels, which parallels Because of the small, but robust effects found in the meta-analysis the mechanism of action of lidocaine, which also targets these chan- and because of several completed, yet unpublished RCTs, we do not nels.12,45 fAll o the included trials used non-medica ted unflavoured expect further research on short term effectiveness of AMC/DCBA lozenges were used in the control group, while the lozenges in the to yield significantly different results with major relevance for treat- some of the treatment groups (Wade 2011) were flavoured.26 AMC/ ment of patients with uncomplicated sore throat. Future trials on the DCBA has a distinct taste, so that blinding was impaired in this respect effectiveness of topical treatments for sore throat should avoid the and it cannot be ruled out that the taste difference had an influence uncontrolled addition of pharmaceutically active ingredients in the on patients’ evaluation of the treatment effect.26,46-48 This is especially study medication. In planning follow-up time, the average duration of important as subjective measures were used for the evaluation of the the underlying condition should be taken into account. Future trials treatment effect. Furthermore, all included RCTs were sponsored by should adhere better to standards of reporting. the manufacturer of AMC/DCBA. The included trials focused on pain relief after 2 hours and two of the trials extended their follow-up to AUTHOR CONTRIBUTION 72 hours, whereas the average duration of acute sore throat is 6 to 8 days.49 The effect of local treatment with lozenges is expected to AHV, GW and JFC were responsible for the study design. Literature wear off after a few hours, so that repeated sucking of lozenges is search and data extraction have been performed by AHV, GW and CK. needed for sustained pain relief. Interestingly, McNally 2012 reported Statistical analysis was done by SB, AHV and GW. All authors drafted maximum throat numbness and sore throat relief at 15 minutes post- and reviewed the manuscript. dose and the median onset of anaesthesia was reported at 30 minutes in this trial. Therefore, treatment with oral analgesics might be a better DISCLOSURES option for patients with systemic symptoms like fever and headache, because of the longer lasting analgesic effect and systemic symptom The authors declare that they have no proprietary, financial, profes- relief.38 tI is noteworthy that the package insert limits the use of AMC/ sional or other personal interest of any nature or kind in any product, DCBA to 3 days without consulting a physician.11 service and/or company that could be construed as influencing the position presented in this paper.

6.3.2 | Limitations of the review ACKNOWLEDGEMENTS The results of our analysis are limited by several factors. We had to rely on published aggregated data and had no access to individual pa- The authors thank Ms Annekathrin Haase for reviewing the tient data for the analysis. For one of the trials (McNally 2010), only manuscript. treatment effects calculated with per-protocol data were reported. Intention-to-treat analysis base on the reported data resulted in a ORCID slightly less favourable difference for the treatment group, but the result was still statistically significant. Our request for more data was not Gesine Weckmann http://orcid.org/0000-0003-2117-2154 10 of 11 | WECKMANN et al.

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