Treatment of acute rhinosinusitis diagnosed by clinical criteria or ultrasound in primary care A placebo-controlled randomised trial

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1 ORIGINAL PAPER Treatment of acute rhinosinusitis diagnosed by clinical criteria or ultrasound in primary care A placebo-controlled randomised trial Helena Varonen 1, Ilkka Kunnamo 2, Seppo Savolainen 3, Marjukka Mäkelä 4, Matti Revonta 5, Jarkko Ruotsalainen 6 and Henrik Malmberg 1 1 Department of Otorhinolaryngology, University of Helsinki, Finland, 2 Karstula Health Centre, Karstula, Finland, 3 Department of Otolaryngology, Central Military Hospital, Helsinki, Finland, 4 Stakes, Finnish Office for Health Technology Assessment, Helsinki, Finland, 5 Department of Otolaryngology, Central Hospital, Hämeenlinna, 6 Juuka Pharmacy, Juuka, Finland. Scand J Prim Health Care 2003;21: ISSN Results A total of 146 patients completed the 2-week follow-up. Patients receiving antibiotics achieved a slightly higher rate of Objecti es To compare antibiotics and placebo in patients with clinical success than patients receiving placebo (80% vs 66%; p= clinically diagnosed acute maxillary sinusitis (AMS). To study 0.068). whether sinus ultrasound examination would help to detect those Conclusions Antibiotics hasten symptom relief in AMS. Yet many patients who benefit from antibiotic therapy. patients recover in 2 weeks without antimicrobial treatment. Only Design A double-blind, randomised, placebo-controlled multicentre half of patients with a clinical diagnosis of AMS have sinusitis in trial. ultrasound examination. Setting Nine primary care sites in Finland. Subjects 150 adult patients (mean age 39.7 years) with a clinical Key words: maxillary sinusitis, randomised controlled trial, sinusitis, diagnosis of sinusitis. ultrasound. Inter ention Antibiotics (amoxicillin 750 mg 2, doxycycline 100 mg 2 or penicillin V 1500 mg 2) or placebo twice daily for 7 days; Helena Varonen, Kuninkaantie 4, FIN Kirkkonummi, Fin- all patients were examined with sinus ultrasound after randomisation. land. helena. aronen@duodecim.fi Main outcome measure Clinical success (patients report of recovery) in telephone interview at 2 weeks. Acute maxillary sinusitis (AMS) is a common infectious disease and by no means a settled question. In a Finnish survey, 12% of patients consulting for infectious diseases were diagnosed as having sinusitis (1). Rhinoviruses are common in the sinus epithelium of AMS patients (2,3), and may cause AMS in up to 50% of cases (4). Symptoms and signs are unspecific (5 7), and if AMS is diagnosed solely by clinical criteria, antibiotics are prescribed unnecessarily to many patients with viral infections (8). In a previous primary care study, antibiotic treatment did not improve the clinical course of AMS (9). Despite limited research evidence on the effectiveness of antibiotics for AMS, this disease nevertheless is most often treated with antibiotics (10,11). Fluid retention is usually regarded as indicating bacterial infection in sinusitis (12). In studies of AMS therapy, the diagnosis is most often based on radiography or aspiration (13). However, these diagnostic methods are impractical in the primary care setting and not recommended in recent guidelines (8,14). Ultrasound examination has been suggested as a means to detect fluid in sinuses and to improve AMS diagnosis (15,16). In this diagnostic therapeutic trial we compared the effect of antibiotics to that of placebo in clinically diagnosed AMS in adults, and studied whether sinus ultrasound examination would help to detect patients who would benefit from antibiotic therapy. PATIENTS AND METHODS Setting and patients The study took place in nine health centres in Finland from November 1998 to October 1999 Although antibiotics are widely used for maxillary sinusitis, research evidence on their effectiveness is still limited. Antibiotics hasten symptom relief in acute maxillary sinusitis. However, many patients recover in two weeks without antimicrobial treatment. Only about 50% of patients with a clinical diagnosis of acute maxillary sinusitis have sinusitis confirmed by ultrasound. DOI /

2 122 H. Varonen et al. (Karstula, Saarijärvi, Halikko, Salo, Katriina, Simo, Kuivaniemi, Heinävesi and Tikkurila). Ear, nose and throat (ENT) specialists (SS and MR) gave a small group tutorial of 1.5 h on sinus ultrasound to 60 physicians in participating health centres. Our inclusion criteria covered adult patients (over 18 years of age) with a clinical diagnosis of AMS. Reasons for exclusion were AMS symptoms lasting over 30 days, antibiotics during the previous month, allergy to study medications, pregnancy or breastfeeding, exacerbation of a diagnosed chronic maxillary sinusitis, previous paranasal sinus surgery, and clinical suspicion of dental or frontal sinusitis or pansinusitis or suspicion of a severe complication, and previous sinus surgery. Data collection Nurse receptionists at health centres screened patients with upper respiratory tract infections to find study patients. Nurses gave written information of the study to possible rhinosinusitis patients and asked them to fill in the patient information form while waiting for the physician s consultation. Data were collected on 12 symptoms related to AMS (nasal obstruction, nasal discharge, headache, postnasal drip, cough, sinus pain, unilateral facial pain, maxillary toothache, hyposmia, anosmia, malaise and fever), and three clinical signs (purulent secretion in the nasal cavity, discharge in the pharynx and tenderness in sinus tapping). Patients assessed the symptoms on a 3-step scale (1=no, 2=little, 3=much). A symptom score of the 12 symptoms was counted by giving 2 points for much answers and 1 point for little answers. The points for the three most important symptoms (maxillary pain, postnasal drip and cough) were doubled. The maximum symptom score was thus 30. We also asked the patients whether they had had symptoms for more than 5 days before the visit and whether they had experienced 2 phases in the disease (double sickening). The physicians discussed the study with the patients, recorded history and clinical findings, and delivered the study medication if the patient had AMS on clinical grounds. The minimum criterion for clinical diagnosis of AMS was the presence of at least three symptoms and one clinical sign. After the treatment decision was made, the ultrasound examination was performed by using a technique described in detail earlier (12,15). The ultrasound device used was Sinuscan 102 (Oriola, Espoo, Finland) with a frequency of 3 MHz and a transducer with an 8-mm diameter. The criterion for AMS was a back wall echo on the screen of the device at a distance of 3.5 cm or more, indicating fluid in the maxillary sinus. None of the other findings were considered sinusitis. To avoid bias, the result was not disclosed to the patient because the ultrasound-negative cases also received treatment. To control the severity of AMS at the Karstula health centre, also nasal samples for bacteriological culture were taken and sinus radiography (occipitomental, Waters view) was examined between 15 min and 1 h after the ultrasound examination. Criteria for AMS were total opacification or an air fluid level or mucosal thickening of 6 mm or more. Bacterial culture was performed according to common bacteriological methods. Randomisation and treatments The patients were randomised to 1 of 4 treatment options, all for 7 days: amoxicillin 750 mg 2, penicillin V 1500 IU 2, doxycyclin 100 mg 2 or placebo 1 2. The placebo group was doubled: two patients out of five received placebo. The treatments were previously randomised in blocks of 20 consecutive patients at the Military Pharmacy in Helsinki and distributed in identical sealed bottles. The study medications were coded with six-number individual codes and physicians, patients and the main researcher (HV) remained blind to the treatments until the recruitment was ended. During the trial, the senior researcher (SS) kept the code and was the primary contact in the case of adverse effects or severe complications. All study centres also had the code in a closed envelope to be opened only if SS could not be reached. Symptomatic treatments with xylometazoline, paracetamol or anti-inflammatory agents were possible if the physician considered them necessary, and their use was recorded. Follow-up The patients received diaries for recording their symptoms daily over 2 weeks. The same list of 12 symptoms with a 3-step scale as in the initial patient form was used. Possible self-medication and side effects were recorded daily in the diary as well as the patients overall estimate of whether they thought they continued to have sinusitis. Two weeks (14 16 days) after the initial consultation, the researcher (HV) interviewed the patients by telephone, asking about subjective symptoms, their severity, possible side effects and the patient s estimate of recovery or recurrence. The interviewer did not know the patient s history, treatment or the result of the ultrasound examination. After 1 year the researcher (HV) checked the patient records to register recurrent or chronic sinusitis in the study patients. Recurrent sinusitis was defined as another episode of sinusitis diagnosed by a primary care physician. Chronic sinusitis was defined as sinusitis with symptoms lasting for more than 3 months.

3 Outcome measures Our main outcome measure was frequency of recovery at the 2-week follow-up (according to the telephone interview). Other outcome measures included subjective symptom scores on days 3 and 10 in patient diaries, frequency of side effects, duration of sinusitis, use of additional medication and the frequency of chronic or recurrent sinusitis and number of physician consultations during the 1-year followup. Study size and statistical analysis Previous studies have shown that approximately 75 80% of patients with AMS treated with placebo recover in 2 weeks (9,17). To find a 15% treatment difference from 75% to 90% at the significance level of =0.05 and =0.20 (power=0.80), a sample size of 98 patients in each treatment arm was needed. We analysed the data by intention-to-treat in main outcomes. Differences in proportions in study groups were tested with the chi-squared or Fisher exact test. Duration of sinusitis was analysed only in patients who recovered fully during the 2-week follow-up. We investigated differences in symptom scores between the group using descriptive statistics, unpaired t-tests and the Mann-Whitney U-test. All reported p-values are two-sided. We analysed all data with StatView software (SAS Institute Inc.). Ethical aspects The ethics committee of the National Research and Development Centre for Welfare and Health and the local ethics committees at study centres accepted the study protocol. The patients received written information on the study and its possible harmful effects. Because the study was placebo-controlled, study centres were provided with a second medication, doxycycline for the amoxicillin group and amoxicillin for the others. The second medication was given if the patient reconsulted with worsened symptoms and the physician considered antibiotics necessary. Patients and physicians stayed blind also to the second medication, knowing only that it contained an active agent. Physicians ensured that the patients had sufficient information and understood the process of the study. The patients gave their written informed consent. Treatment of acute rhinosinusitis 123 RESULTS Patients The trial profile is presented in Fig. 1. Thirty-five primary care physicians in nine health centres participated in patient recruitment. Of 187 patients with suspected AMS considered for study, 150 were eligible and randomised; 105 females (70%) and 45 males (30%). Reasons for exclusion are presented in Fig. 1. Patients were aged between 18 and 75 years (mean 39.7 years). The baseline characteristics of the study patients are presented in Table I. Ultrasound examination was performed on 148 patients, and 74 (50%) tested positive for AMS. At Karstula health centre, 32 patients had sinus radiographies taken, and 13 (41%) had a radiologically diagnosed AMS. Nasal bacterial cultures were obtained from 28 patients in Karstula, and in the culture of 8 cases (29%) grew pathogens for acute maxillary sinusitis. Main outcome The main outcome, recovery at the 2-week follow-up, was slightly better in patients receiving active treatment, antibiotics (70/88, 80%), than in the placebo group (39/59 patients, 66%, chi-squared=3.33, d.f. =1, p=0.068). There were no differences between antibiotics (clinical success rates 18/23, 78% for amoxicillin, 26/33, 79% for doxycycline and 26/32, 81% for penicillin V). Other outcomes Patients receiving antibiotics recovered faster than those receiving placebo. On day 3, the difference in symptom scores was 2.1 (p=0.048, Table II). By day 10, the difference had disappeared. Mean disease duration of AMS was 6.4 days in the placebo group and 6.0 days in the antibiotics group (Table II). Patients receiving placebo used additional medication, especially analgesics, more often than those receiving antibiotics (Table II). Patients in the placebo group started other antibiotics more often (10/58, 17%) than patients in the active treatment group (6/88, 7%, p=0.09 Table II). Subgroups of ultrasound positi e and negati e patients Ultrasound positive and negative patients had similar symptom scores at the beginning of study (15.3, SD 4.3 and 15.4, SD 4.3, respectively). At the 2-week follow-up, patients with sinusitis on ultrasound examination had recovered better (symptom score 2.8, SD 3.2) than those without findings (symptom score 4.1, SD 3.8, p=0.03). In the placebo group, patients who had sinusitis on ultrasound started other antibiotics and withdrew from the study more often than those with no sinusitis on ultrasound (7/32, 22% versus 3/25, 12%, p=0.33). Side effects We analysed side effects in the 130 patients who completed the 2-week follow-up in the initial treat-

4 124 H. Varonen et al. Fig. 1. Flow chart of the study population. Table I. Baseline characteristics of study patients (n=148). Antibiotic Placebo (n=88) (n=60) Patient characteristics Mean age (SD) in years 40.6 (14.1) 38.1 (12.3) Male/female 24 (27%)/ 20 (33%)/ 64 (73%) 40(67%) History Previous sinusitis 74 (84%) 49 (82%) Allergic rhinitis 24 (28%) 10 (17%) Vasomotor rhinitis 6 (7%) 5 (8%) Asthma 8 (9%) 2 (3%) Symptoms and signs Mean initial symptom score (SD) 15.3 (4.6) 15.3 (4.1) Symptoms for more than 5 days 63 (72%) 45 (75%) Double sickening 45 (51%) 35 (58%) ment arm. In the telephone interview at 2 weeks, 13 out of 48 (27%) patients in the placebo group and 32 out of the 82 (39%) receiving antibiotics reported side effects (Table III). Stomach pain, diarrhoea and fatigue were the most common side effects (Table III). Two patients receiving penicillin V withdrew: one got nausea and the other stomach pain and skin rash. One patient receiving amoxicillin stopped treatment because of diarrhoea, and one in the placebo group discontinued treatment because of stomach pain and headache. Follow-up One-year follow-up data were available for 144 patients (60 in the placebo arm and 84 in the antibiotics group). Two patients in the placebo group developed chronic sinusitis in follow-up, and both

5 Treatment of acute rhinosinusitis 125 Table II. Other outcome measures. Outcome measure Antibiotics Placebo Difference (95% CI) p-value Mean symptom score (SD) on day (4.7) 11.5 (5.2) Mean symptom score (SD) on day (4.9) 5.4 (4.7) Mean duration of sinusitis (days) Percentage of patients using additional medication 37/88 (42%) 32/58 (55%) 13% ( 3% to 29%) Analgesics 26% 43% 17% (1% to 32%) Vasoconstrictors and antihistamines 10% 12% 2% ( 8% to 14%) Antibiotics 7% 17% 10% ( 1% to 21%) Mean number (SD) of physician consultations during 3.9 (3.5) 5.1 (6.1) year follow-up Percentage of patients having recurrent sinusitis during 26% 24% 2% ( 16% to 13%) year follow-up Percentage of patients consulting because of respiratory 32% 26% 6% ( 21% to 9%) tract infections during 1-year follow-up 1 Mann-Whitney U-test. 2 T-test. 3 Chi-squared test. lem is that our study lacks power and the ultrasound subgroups are too small for definite conclusions to be drawn. For the same reason, we cannot draw conclusions about the different antibiotics in the study. This randomised study in primary care has several strengths: we combined diagnosis and treatment, the study was conducted in a real-life situation and the length of follow-up was adequate. The slow rate of patient recruitment was a disappointment to us, and we tried to find out what the barriers had been. The barrier first mentioned was work pressure. Sinusitis is mostly treated during busy on-call hours, when filling study forms may be too much of a burden for the physician. Another problem was the placebo arm. Giving placebo to patients who normally would be treated with antibiotics was such a radical change of practice that the physicians might have needed better support from the researchers. Also, financial support was lacking: we did not remunerate the participating physicians for their work. Overall, most patients with clinically diagnosed AMS recovered well without antibiotics. Also patients with AMS diagnosed by radiography and with pathogens in nasal culture improved sometimes well when treated with placebo. Our study confirms previous findings (13,18): up to two-thirds of patients with sinusitis recover well in 2 weeks with or without antibiotics. However, from the patients point of view, clinical success at the 2-week follow-up point may not be the primary outcome. Patients with suspected AMS seek faster relief for their symptoms. A recent study showed that adding fluticasone to xylometazoline and antimicrobial therapy improves clinical success in acute rhinosinusitis (19). We designed this study after the findings of van Buchem et al. (9) were published: a primary carehad AMS in ultrasound examination. There were no differences in the number of cases with recurrent sinusitis in the study groups, but the patients who received antibiotics consulted slightly more often because of respiratory tract infections during the follow-up year (32% vs 26%, p=0.42). DISCUSSION In our study, antibiotics were slightly more effective than placebo for patients with sinusitis diagnosed by clinical criteria. Recovery was similar at 2 weeks, however, patients who received antibiotics recovered faster, having lower symptom scores on day 3. Half of the study patients had AMS on ultrasound examination, and two of them developed chronic sinusitis, both in the placebo group. No complications were seen in the ultrasound-negative patients. It seems that the ultrasound-positive patients in our study had a more severe pattern of disease and, if given placebo, they withdrew from the study and started antibiotics during the 2-week follow-up more often than the ultrasound-negative patients. A prob- Table III. Side effects in patients who completed the 2-week follow-up in the initial treatment arm. Side effect Antibiotics Placebo p-value (n=82) (n=48) ( 2 -test) Diarrhoea 6 (7%) 3 (6%) 0.81 Stomach pain 18 (22%) 6 (12%) 0.18 Headache 3 (6%) 3 (4%) 0.50 Rash 2 (2%) Vaginal discharge 3 (4%) Fatigue 5 (6%) 3 (6%) 0.73 All 32 (39%) 13 (27%) 0.17

6 126 H. Varonen et al. based study found no benefit in antibiotic therapy for AMS diagnosed by radiography. At that point, we considered that another placebo-controlled study comparing the first-line antibiotics would be ethical and justified. Concentrating on one active treatment instead of three might have been a better strategy. A Cochrane review (13) and another meta-analysis (18) on the therapy of AMS have later shown that there is a small treatment effect and that different antibiotics have similar efficacy. More research is needed to compare feasible strategies of AMS diagnosis in primary care to bridge the gap between current practice and the evidence. Ultrasound seems accurate and practical and has no adverse effects. Its use warrants further studies in primary care. CONCLUSIONS Antibiotics hasten symptom relief in AMS. However, many patients recover in 2 weeks without antimicrobial treatment. Only half of patients with a clinical diagnosis of AMS have sinusitis in ultrasound examination. ACKNOWLEDGEMENTS We thank all the patients and physicians who participated in this study as well as the nurses at the study centres for their assistance. Stakes, the National Research and Development Centre for Welfare and Health covered the administrative and travel costs of this study. Leiras-Schering and SmithKline Beecham provided the study medication. REFERENCES 1. Rautakorpi UM, Klaukka T, Honkanen P, Makela M, Nikkarinen T, Palva E, et al. Antibiotic use by indication: a basis for active antibiotic policy in the community. Scand J Infect Dis 2001;33: Pitkaranta A, Starck M, Savolainen S, Poyry T, Suomalainen I, Hyypia T, et al. Rhinovirus RNA in the maxillary sinus epithelium of adult patients with acute sinusitis. Clin Infect Dis 2001;33: Gwaltney Jr JM, Scheld WM, Sande MA, Sydnor A. The microbial etiology and antimicrobial therapy of adults with acute community-acquired sinusitis: a fifteen-year experience at the University of Virginia and review of other selected studies. J Allergy Clin Immunol 1992;90: Pitkaranta A, Arruda E, Malmberg H, Hayden FG. Detection of rhinovirus in sinus brushings of patients with acute community-acquired sinusitis by reverse transcription PCR. J Clin Microbiol 1997;35: Hansen JG, Schmidt H, Rosborg J, Lund E. Predicting acute maxillary sinusitis in general practice population. BMJ 1995;311: Williams Jr JW, Simel DL, Roberts L, Samsa GP. Clinical evaluation for sinusitis. Making the diagnosis by history and physical examination. Ann Intern Med 1992;117: Varonen H, Makela M, Savolainen S, Laara E, Hilden J. Comparison of ultrasound, radiography, and clinical examination in the diagnosis of acute maxillary sinusitis: a systematic review. J Clin Epidemiol 2000;53: Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann Emerg Med 2001;37: Van Buchem FL, Knottnerus JA, Schrijnemaekers VJ, Peeters MF. Primary-care-based randomised placebo-controlled trial of antibiotic treatment in acute maxillary sinusitis. Lancet 1997;349: Piccirillo JF, Mager DE, Frisse ME, Brophy RH, Goggin A. Impact of first-line vs second-line antibiotics for the treatment of acute uncomplicated sinusitis. JAMA 2001;286: Poole MD. A focus on acute sinusitis in adults: changes in disease management. Am J Med 1999;106: Savolainen S, Pietola M, Kiukaanniemi H, Lappalainen E, Salminen M, Mikkonen P. An ultrasound device in the diagnosis of acute maxillary sinusitis. Acta Otolaryngol Suppl 1997;529: Williams Jr JW, Aguilar C, Makela M, Cornell J, Holleman DR, Chiquette E, et al. Antibiotics for acute maxillary sinusitis. Cochrane Database Syst Rev 2000;2:CD Brooks I, Gooch WM, Jenkins SG, Pichichero ME, Reiner SA, Sher L, et al. Medical management of acute bacterial sinusitis. Recommendations of a clinical advisory committee on pediatric and adult sinusitis. Ann Otol Rhinol Laryngol Suppl 2000;182: Revonta M. Ultrasound in the diagnosis of maxillary and frontal sinusitis. Acta Otolaryngol Suppl 1980;370: Puhakka T, Heikkinen T, Makela MJ, Alanen A, Kallio T, Korsoff L, et al. Validity of ultrasonography in diagnosis of acute maxillary sinusitis. Arch Otolaryngol Head Neck Surg 2000;126: Stalman W, van Essen GA, van der Graaf Y, de Melker RA. Maxillary sinusitis in adults: an evaluation of placebocontrolled double-blind trials. Fam Pract 1997;14: de Ferranti SD, Ioannidis JP, Lau J, Anninger WV, Barza M. Are amoxycillin and folate inhibitors as effective as other antibiotics for acute sinusitis? A meta-analysis. BMJ 1998;317: Dolor RJ, Witsell DL, Hellkamp AS, Williams Jr JW, Califf RM, Simel DL. Comparison of cefuroxime with or without intranasal fluticasone for the treatment of rhinosinusitis. The CAFFS Trial: a randomized controlled trial. JAMA 2001;286: