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Evaluation and Treatment of the Patient with Acute Undifferentiated Respiratory Tract Infection
The term acute upper respiratory tract infection (ARTI) refers to an infection, almost always viral,1 predominantly involving the nasopharynx, sinuses, and large bronchi. It encompasses what is frequently referred to as the common cold, sinusitis, pharyngitis, bronchitis, and otitis media. This review will focus primarily on the common cold, or undifferentiated ARTI, but there will be considerable overlap with the other diagnoses. The rationale for grouping these traditionally separate diagnostic categories together is straightforward. ARTI almost always presents with some combination of nasal congestion, rhinnorrhea, sore throat, and cough. Sometimes one or another of these symptoms predominates, but there is good reason to suggest that the traditional diagnostic distinctions are arbitrary.2 The overlap between the clinical signs, symptoms, and x-ray findings is so extensive that these terms are not very useful diagnostically. This symptom complex is among the top 3 reasons for visits to primary care doctors3 and accounts for approximately 100 million office visits in the United States per year4 at an annual cost of considerably more than 1 billion dollars.5 Overuse of antibiotics adds more than $11 to the cost of each encounter for ARTI.5
This review will summarize the evidence that patients who present with undifferentiated ARTI usually have self-limited disease, that complications are rare, effective treatments for symptoms are available, and antibiotics are not often indicated. The evidence is based on only adults and children over age 2 who have normal immune systems and do not have chronic respiratory disease. (J Fam Pract; 50:1070-1077)
Pathophysiology
Patients with undifferentiated ARTI present with any or all of the following symptoms: rhinnorrhea (which may be either clear or colored), nasal congestion, cough, sore throat, facial pain, malaise, headache, or fever. The etiology is almost always viral, most commonly rhinovirus, but other viruses have been implicated as well, particularly corona-viruses, parainfluenza, and influenza.6 Bacterial infection is rare in undifferentiated ARTI, occurring in approximately 2% of patients.1 The most common bacteria implicated are group A Streptococcus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.7 Chlamydia pnuemoniae and Mycoplasma pnuemoniae have rarely been identified as well.6 Bordatella pertussis can occasionally be the cause of persistent cough in children and adults.8, 9
Diagnosis
The major diagnostic consideration in a patient who presents with ARTI symptoms is to rule out a more serious illness which would require aggressive treatment. These include pneumonia, pharyngitis caused by group A streptococci, and bacterial sinusitis. The traditional symptoms and signs that physicians use to distinguish viral from bacterial infection have not been determined helpful in making this distinction. Both a history of colored nasal discharge and maxillary sinus tenderness to palpation have a positive likelihood ratio (LR+) near 1 in predicting computed tomography–based diagnosis of acute bacterial sinusitis (a likelihood ratio of 1 indicates that the result does not change the likelihood of disease).10 Purulent sputum does not distinguish between viral ARTI and bacterial pneumonia.11 Combinations of symptoms, however, in the form of clinical decision rules, can be useful at ruling out more serious conditions.
Nasal Discharge
In patients who present primarily with nasal discharge, a study that correlated computed tomography (CT) scans with direct sinus puncture demonstrated that 90% of primary care patients with CT findings of total opacification or air fluid level in the maxillary sinuses have a bacterial etiology.12 Unfortunately, there is no combination of clinical signs or symptoms that reliably predicts opacification or air fluid levels.12 There have been 3 decision rules published based on clinical findings that may be useful, particularly in helping clinicians identify the most important symptoms on which they should focus during their examination. However, 2 of the rules require a sedimentation rate or C-reactive protein value,10,12 not typically available in a routine office visit. The only other rule based on clinical findings included adult men and used x-ray as the reference standard, making it less useful.13
The suspicion of sinusitis by a generalist is actually quite accurate diagnostically, since about 40% of patients with suspected sinusitis have the diagnosis confirmed by aspiration or CT imaging.14 One must therefore be guided by overall clinical judgment in these patients, but a practical approach to empiric treatment is presented in the section on treatment.
Sore Throat
In patients who present primarily with sore throat, the important consideration is to rule out group A streptococcus as the etiology. The prevalence of streptococcal pharyngitis varies markedly with age, season of the year, and presence or absence of an outbreak in the community. For children prevalences have been reported ranging from 12% to 35%. Prevalence seems to peak in the 5 years to 9 years age range, and in the autumn. Reported prevalences for adults range from 5% to 15%.15-20
A recent systematic review noted nine published decision rules for diagnosis of streptococcal pharyngitis,21 but the only one that has been prospectively validated in a primary care population of both children and adults is by McIssac22,23Table 1. Patients with a low risk of GABHS require no further testing; those with an intermediate risk should undergo rapid strep antigen testing; and those with a high risk of GABHS should either under rapid strep antigen testing with culture follow-up or empiric therapy. Culture for group A streptococcus is the most reliable means of diagnosis, but requires withholding treatment for 48 hours while awaiting the result.24
Infectious mononucleosis can also cause exudative pharyngitis. Palatine petechiae, posterior auricular and posterior cervical adenopathy, marked axillary adenopathy, and inguinal adenopathy are all associated with infectious mononucleosis,25 and if any of these signs are present a heterophile antibody test may be indicated to confirm the diagnosis.
Cough
Many patients with ARTI present with cough as a primary symptom. While the differential diagnosis for undifferentiated cough is long, in the setting of ARTI the primary diagnostic consideration is to rule out pneumonia. Decision rules by Heckerling11 and Diehr26 have been well validated Table 2, Table 3. If the patient does not have temperature higher than 100 ÞF, pulse rate higher than 100, rales, decreased breath sounds, or absence of wheezing, then pneumonia is very unlikely (negative likelihood ratio = 0.06). As the number of signs increases, the likelihood ratio increases, but the decision rule does not have sufficient positive predictive value to be used as a basis for antibiotic treatment. Purulent sputum is not predictive of pneumonia (LR+=1.3).11,27 Empiric antibiotics for pneumonia should not be given without a confirmatory chest x-ray.1
Treatment
Undifferentiated ARTI
The level of evidence supporting different interventions is summarized in Table 4, and each is discussed in more detail below.
Antibiotics. There have been numerous double blind placebo controlled randomized trials of antibiotics in patients with undifferentiated ARTI symptoms. All of these trials have been evaluated in a recent Cochrane systematic review.28 The review concludes that there is no consistent evidence of benefit from any antibiotic treatment and that there is a significant increase in adverse effects associated with antibiotic use. Increased cost and increased bacterial resistance in the patient and community are additional concerns.
Education. One of the reasons for inappropriate antibiotic use in ARTI is patient pressure for antibiotics. This can be subtle as well as direct and is difficult for physicians to resist.29 Several studies have shown that patient expectation for antibiotics is related to having been given antibiotics for respiratory infections in the past.30-32 Furthermore, McFarlane has shown that simple patient education techniques reduce both visits for ARTI and antibiotic usage.33 An essential part of treatment of these infections, therefore, is educating patients about the viral nature of the illness, the usual course and duration of symptoms (10 days for most, up to 3 weeks for some), the ineffectiveness of antibiotics for treatment, and the harm antibiotics can cause both to the patient and the community. Patient satisfaction has been shown to increase after this sort of intervention, even when patients initially had an expectation for antibiotic prescription.30,34 Some have advocated avoiding terms such as sinusitis and bronchitis with patients, instead using the terms head cold and chest cold to emphasize the viral nature of these illnesses.
Naproxen Sodium. Naproxen sodium was evaluated in a well-designed randomized placebo controlled trial using experimentally induced rhinovirus infections in volunteers.35 A statistically significant 29% reduction in total 5-day symptom scores was found. Specific symptoms that improved included sneezing, rhinnorrhea, nasal obstruction, sore throat, cough, headache, malaise and chilliness.
Vitamin C. A Cochrane Library meta-analysis of all the trials for ascorbic acid showed a small but significant effect on decreasing duration (.55 days per episode) and a modest effect on severity of symptoms.36 There was no evidence for an effect when taken prophylactically.
Zinc. Randomized trials of zinc have shown marked heterogeneity, but this may have been due to use of different preparations with different bioavailability.37 A more recent randomized trial used zinc acetate lozenges.38 Increased plasma zinc levels were documented in the treatment group. The lozenges contained 42.96 mg of zinc acetate dihydrate, and were administered every 2 to 3 hours, beginning 24 hours or less after the onset of symptoms. The treatment group had a reduction from 8.1 to 4.5 days in total duration of symptoms (number needed to treat [NNT] =3 at 5 days) and a 50% reduction in symptom scores compared to the placebo group. Symptoms included in the score were sore throat, nasal discharge, nasal congestion, sneezing, cough, scratchy throat, hoarseness, muscle ache, fever, and headache.
Echinacea. Echinacea was evaluated in another Cochrane Library Systematic Review.39 Sixteen trials were evaluated, two thirds of which had insufficient quality of reporting. There were many different extracts used, which made comparability of the results a problem. Most trials showed positive results, suggesting that preparations containing extract of echinacea may have some beneficial effect on prevention and treatment.
Intranasal Fluticasone. Intranasal fluticasone was evaluated in a randomized trial of 200 young adults with common cold symptoms.40 No clinically significant differences were noted in either duration or severity of symptoms between treatment and control groups.
Nasal Discharge
Antibiotics. As noted above under undifferentiated ARTI, a Cochrane systematic review of randomized antibiotic trials found no evidence of benefit of antibiotic treatment for clear or purulent rhinnorrhea.28 Another Cochrane systematic review focused on randomized trials of antibiotic treatment for sinusitis.41 There was modest benefit from amoxicillin treatment in patients with acute maxillary sinusitis confirmed radiographically (NNT=4). There was no evidence, even from more recent studies, that other antibiotics were any more effective than amoxicillin. Lindbaek was able to demonstrate in a randomized controlled trial of amoxicillin that the only patients who benefited from treatment were those who had either complete opacification of a sinus, or an air fluid level.42 Patients who had mucosal thickening alone showed no difference from the placebo group. Of the patients in the placebo group who did have opacification or air fluid level, half were well or much better within 10 days. There is also some evidence that patients who present with moderate to severe unilateral facial pain benefit from antibiotics.43 In children, a recent antibiotic trial of patients who had a clinical diagnosis of sinusitis with symptoms for between 14 and 28 days showed no difference in any outcome measure between treatment and placebo groups.44
Based on Lindbaek’s data for adults, assuming that 42% of patients with suspected bacterial sinusitis actually have the disease, the number needed to treat to benefit one patient is 8. The number needed to harm by adverse effects from antibiotics is 4, so harm may outweigh any benefit. Frontal sinusitis seems to represent a different disease process because of the anatomy of drainage from the frontal sinuses. These patients usually present with high fever, severe pain, are quite ill, and may require hospitalization, parenteral antibiotics and surgery.1,45,46 A practical approach is to treat all patients with nasal discharge symptomatically, unless they have severe pain, or appear very ill, in which case sinus films should be considered to rule out frontal sinusitis, or opacification or air fluid level in any sinus. Also, adult patients who have had sinus symptoms for more than two weeks without improvement are more likely to benefit from antibiotic treatment.42
Ipratropium. Ipratopium nasal spray used in a randomized controlled trial, reduced rhinnorrhea and sneezing in patients with cold symptoms by 31% compared to placebo saline nasal spray (ARR=16% NNT=7), and by 78% when compared with untreated patients (ARR=63% NNT=2).47
Brompheniramine. Brompheniramine likewise has a temporary modest effect on rhinnorrhea in adults. Brompheniramine was evaluated in a randomized controlled trial in volunteers infected with rhinovirus.48 The treatment group had a 20% reduction in symptom score on day 1 and a 26% reduction on day 2. The main symptoms improved were sneeze frequency, sneeze severity, and cough count. Drowsiness was a troubling side effect. Neither decongestants nor antihistamines, nor combinations of the 2 have shown any effect in randomized trials in children.49
Nasal Decongestants. The efficacy of oral psuedoephedrine or metalazone nasal spray were evaluated in a Cochrane Library meta-analysis.50 There was a 13% reduction in symptom score (subjective rating of severity of nasal congestion) after a single use of either agent, but no difference in combined symptom scores after use for 5 days.
Heated Humidified Air. Published studies of effectiveness of breathing heated humidified air for cold symptoms were evaluated in a Cochrane Library Systematic Review.51 Six studies were evaluated and the results were quite heterogeneous. One study in Israel and two in the UK showed significant improvement, while three in the US showed no difference between treatment and placebo groups.
Sore Throat
Antibiotics. The data for sore throat should reassure physicians who worry about the consequences of missing streptococcal pharyngitis. A Cochrane meta-analysis showed that treatment of streptococcal pharyngitis with penicillin did reduce duration of illness, but only by approximately half a day.52 There was only a minimal effect on prevention of suppurative complications as well (NNT=30 for children and NNT=145 for adults to prevent one case of otitis media). The incidence of rheumatic fever is so low in the industrialized world (.5 per 100,000 in the pediatric population in the United States )53 that the number needed to treat to prevent 1 case of rheumatic fever is exceedingly high. In fact, Howie54 has estimated that for a general practitioner in Scotland the NNT exceeds the number of patients he or she would see in his or her lifetime. Furthermore, it is estimated than only approximately 15% of patients with streptococcal pharyngitis ever present for treatment, further reducing the opportunity to prevent complications.52 Most of the symptomatic improvement from antibiotics comes in the first 3 days of illness, so that if culture is used as a treatment criterion, most patients will already be better by the time the results are available.55
Analgesics. Acetominophen, aspirin, ibuprofen, flurbiprofen, and the combination of aspirin and caffeine have all been shown to be effective for sore throat pain in randomized trials.56-60 Ibuprofen was found to be superior to acetominophen60 and aspirin/caffeine was found to be superior to aspirin alone.57
Benzocaine. I could find only one study evaluating benzocaine containing lozenges for sore throat61 and it did not include a placebo group. Although one lozenge (Merocaine) produced significantly better pain relief than the other (Tyrozets), the lack of a placebo comparison makes interpretation of these results problematic.
Cough
Antibiotics. There is no evidence, in the absence of pneumonia or pertussis, that antibiotics are effective for the treatment of acute cough, including cough productive of colored sputum in otherwise healthy patients.62 This does not include patients with acute exacerbation of chronic pulmonary disease.
Codeine, Dextromethorphan, Guaifenesin. There are few studies evaluating the effectiveness of cough medicines that contain combinations of guaifenesin and codeine or dextromethorphan. One randomized trial of the effectiveness of codeine for cough related to ARTI showed no difference between experimental and placebo groups.63 Another study found no difference between cough medicines containing guaifenesin alone, guaifenesin and codeine, and guaifenesin and dextromethorphan.64 Therefore, although studies are few, there is no evidence to suggest that any of these agents is effective for treatment of cough associated with ARTI. It is interesting to note that all studies showed a marked placebo effect.
b2 -Agonists. Initial studies appeared to show some benefit for inhaled b2-agonists in the treatment of cough.65-67 A recent systematic review by Smucny, however, found that only patients with demonstrated hyperreactivity of airways benefited from this treatment.68
A flow diagram depicting an algorithm for when to use antibiotic in addition to symptomatic treatment for ARTI is shown in the Figure 1. This closely approximates the most recent CDC guidelines on the judicious use of antibiotics for respiratory infections in children and adults. Table 5 summarizes the best clinical trial evidence regarding the use of antibiotics in ARTI.
Prognosis
The mean duration of symptoms for untreated ARTI is approximately 10 days.38,42,69 It is not unusual for symptoms, particularly nasal congestion and cough, however, to last for up to 3 weeks. One study of lower respiratory tract infection in primary care patients found that 60% were still coughing after 10 days.70 Another study of ARTI in children in Norway found that 50% still had nasal discharge and cough after 3 weeks.71 Complications are rare in primary care patients. Less than 2% of patients with ARTI go on to develop secondary bacterial infection requiring antibiotic treatment.1 Although there are no data in adults which specifically address whether antibiotic treatment prevents bacterial infection,72 there are at least 2 studies that demonstrate that antibiotic treatment of children with undifferentiated ARTI does not prevent pneumonia or otitis media.73,74
1. Gonzales R, Bartlett JG, Besser RE, Richelle JC, Hickner J, Jerome R, Hoffman JR. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults. Ann Intern Med 2001;134.-
2. Hueston WJ, Mainous AG, 3rd, Dacus EN, Hopper JE. Does acute bronchitis really exist? A reconceptualization of acute viral respiratory infections. J Fam Pract 2000;49:401-6.
3. Woodwell DA. National Ambulatory Medical Care Survey: 1996 summary. Adv Data 1997;1-25.
4. Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997;278:901-4.
5. Mainous AG, 3rd, Hueston WJ. The cost of antibiotics in treating upper respiratory tract infections in a Medicaid population . Arch Fam Med 1998;7:45-9.
6. Makela MJ, Puhakka T, Ruuskanen O, et al. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol 1998;36:539-42.
7. Ruoff G. Upper respiratory tract infections in family practice. Pediatr Infect Dis J 1998;17:S73-8.
8. Dowell SF, Schwartz B, Phillips WR. Appropriate use of antibiotics for URIs in children: Part II. Cough, pharyngitis and the common cold. The Pediatric URI Consensus Team. Am Fam Physician 1998;58:1335-42, 1345.
9. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: background, specific aims, and methods. Ann Intern Med 2001;134:479-86.
10. Lindbaek M, Hjortdahl P, Johnsen UL. Use of symptoms, signs, and blood tests to diagnose acute sinus infections in primary care: comparison with computed tomography. Fam Med 1996;28:183-8.
11. Heckerling PS, Tape TG, Wigton RS, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med 1990;113:664-70.
12. Hansen JG, Schmidt H, Rosborg J, Lund E. Predicting acute maxillary sinusitis in a general practice population. BMJ 1995;311:233-6.
13. Williams JW, Jr, Simel DL, Roberts L, Samsa GP. Clinical evaluation for sinusitis. Making the diagnosis by history and physical examination. Ann Intern Med 1992;117:705-10.
14. Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann Intern Med 2001;134:498-505.
15. Gunnarsson RK, Holm SE, Soderstrom M. The prevalence of potential pathogenic bacteria in nasopharyngeal samples from individuals with a respiratory tract infection and a sore throat—implications for the diagnosis of pharyngotonsillitis. Fam Pract 2001;18:266-71.
16. Pokorski SJ, Vetter EA, Wollan PC, Cockerill FR, 3rd. Comparison of Gen-Probe Group A streptococcus Direct Test with culture for diagnosing streptococcal pharyngitis. J Clin Microbiol 1994;32:1440-3.
17. Dagnelie CF, Bartelink ML, van der Graaf Y, Goessens W, de Melker RA. Towards a better diagnosis of throat infections (with group A beta-haemolytic streptococcus) in general practice. Br J Gen Pract 1998;48:959-62.
18. Hart AP, Buck LL, Morgan S, Saverio S, McLaughlin JC. A comparison of the BioStar Strep A OIA rapid antigen assay, group A Selective Strep Agar (ssA), and Todd-Hewitt broth cultures for the detection of group A Streptococcus in an outpatient family practice setting. Diagn Microbiol Infect Dis 1997;29:139-45.
19. Smith TD, Wilkinson V, Kaplan EL. Group A streptococcus-associated upper respiratory tract infections in a day-care center. Pediatrics 1989;83:380-4.
20. Drulak M, Raybould TJ, Yong J, Hsiung D, Smith H, Winston S. Comparison of Visuwell enzyme immunoassay to culture for detection of group A Streptococcus in throat swab specimens. Diagn Microbiol Infect Dis 1988;11:181-7.
21. Ebell MH SM, Barry HC, Ives K, Carey BS. Does this patient have strep throat? JAMA 2000;284:2912-2918.
22. McIsaac WJ, Goel V, To T, Low DE. The validity of a sore throat score in family practice. CMAJ 2000;163:811-5.
23. McIsaac WJ, White D, Tannenbaum D, Low DE. A clinical score to reduce unnecessary antibiotic use in patients with sore throat. CMAJ 1998;158:75-83.
24. Reed BD, Huck W, French T. Diagnosis of group A beta-hemolytic Streptococcus using clinical scoring criteria, Directigen 1-2-3 group A streptococcal test, and culture. Arch Intern Med 1990;150:1727-32.
25. Aronson MD, Komaroff AL, Pass TM, Ervin CT, Branch WT. Heterophil antibody in adults with sore throat: frequency and clinical presentation. Ann Intern Med 1982;96:505-8.
26. Diehr P, Wood RW, Bushyhead J, Krueger L, Wolcott B, Tompkins RK. Prediction of pneumonia in outpatients with acute cough—a statistical approach. J Chronic Dis 1984;37:215-25.
27. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997;278:1440-5.
28. Arroll B, Kenealy T. Antibiotics for the common cold. Cochrane Database Syst Rev 2000;CD000247.-
29. Scott J, Cohen D, Dicicco-Bloom B, Orzano A, Jaen C, Crabtree BF. Unnecessary antibiotic use in acute respiratory Infections. JAMA 2001; In press.
30. Hamm RM, Hicks RJ, Bemben DA. Antibiotics and respiratory infections: do antibiotic prescriptions improve outcomes? J Okla State Med Assoc 1996;89:267-74.
31. Mainous AG, 3rd, Zoorob RJ, Oler MJ, Haynes DM. Patient knowledge of upper respiratory infections: implications for antibiotic expectations and unnecessary utilization. J Fam Pract 1997;45:75-83.
32. Little P, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL. Open randomised trial of prescribing strategies in managing sore throat. BMJ 1997;314:722-7.
33. Macfarlane JT, Holmes WF, Macfarlane RM. Reducing reconsultations for acute lower respiratory tract illness with an information leaflet: a randomized controlled study of patients in primary care. Br J Gen Pract 1997;47:719-22.
34. Sanchez-Menegay C, Hudes ES, Cummings SR. Patient expectations and satisfaction with medical care for upper respiratory infections. J Gen Intern Med 1992;7:432-4.
35. Sperber SJ, Hendley JO, Hayden FG, Riker DK, Sorrentino JV, Gwaltney JM, Jr. Effects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial. Ann Intern Med 1992;117:37-41.
36. Douglas RM, Chalker EB, Treacy B. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2000;2.-
37. Marshall I. Zinc for the common cold. Cochrane Database Syst Rev 2000;2.-
38. Prasad AS, Fitzgerald JT, Bao B, Beck FW, Chandrasekar PH. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000;133:245-52.
39. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2000;2.-
40. Puhakka T, Makela MJ, Malmstrom K, et al. The common cold: effects of intranasal fluticasone propionate treatment. J Allergy Clin Immunol 1998;101:726-31.
41. Williams JW, Jr, Aguilar C, Makela M, et al. Antibiotics for acute maxillary sinusitis. Cochrane Database Syst Rev 2000;CD000243.-
42. Lindbaek M, Hjortdahl P, Johnsen UL. Randomised, double blind, placebo controlled trial of penicillin V and amoxycillin in treatment of acute sinus infections in adults. BMJ 1996;313:325-9.
43. Hansen JG, Schmidt H, Grinsted P. Randomised, double blind, placebo controlled trial of penicillin V in the treatment of acute maxillary sinusitis in adults in general practice. Scand J Prim Health Care 2000;18:44-7.
44. Garbutt JMMF, Goldstein MDDS, Gellman EMD, Shannon WP, Littenberg BMD. A randomized, placebo-controlled trial of antimicrobial treatment for children with clinically diagnosed acute sinusitis. Pediatrics April 2001;107:619-625.
45. Altman KW, Austin MB, Tom LW, Knox GW. Complications of frontal sinusitis in adolescents: case presentations and treatment options. Int J Pediatr Otorhinolaryngol 1997;41:9-20.
46. Giannoni CM, Stewart MG, Alford EL. Intracranial complications of sinusitis. Laryngoscope 1997;107:863-7.
47. Hayden FG, Diamond L, Wood PB, Korts DC, Wecker MT. Effectiveness and safety of intranasal ipratropium bromide in common colds. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996;125:89-97.
48. Gwaltney JM, Druce HM. Efficacy of brompheniramine maleate for the treatment of rhinovirus colds. Clin Infect Dis 1997;25:1188-94.
49. Clemens CJ, Taylor JA, Almquist JR, Quinn HC, Mehta A, Naylor GS. Is an antihistamine-decongestant combination effective in temporarily relieving symptoms of the common cold in preschool children? J Pediatr 1997;130:463-6.
50. Taverner D, Bickford L, Draper M. Nasal decongestants for the common cold. Cochrane Database Syst Rev 2000;2.-
51. Singh M. Heated, humidified air for the common cold. Cochrane Database Syst Rev;2000;CD001728.-
52. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database Syst Rev;2000;CD000023.-
53. Olivier C. Rheumatic fever—is it still a problem? J Antimicrob Chemother 2000;45 Suppl:13-21.
54. Howie JG, Foggo BA. Antibiotics, sore throats and rheumatic fever. J R Coll Gen Pract 1985;35:223-4.
55. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-9.
56. Schachtel BP, Fillingim JM, Thoden WR, Lane AC, Baybutt RI. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther 1988;44:704-11.
57. Schachtel BP, Fillingim JM, Lane AC, Thoden WR, Baybutt RI. Caffeine as an analgesic adjuvant. A double-blind study comparing aspirin with caffeine to aspirin and placebo in patients with sore throat. Arch Intern Med 1991;151:733-7.
58. Wethington JF. Double-blind study of benzydamine hydrochloride, a new treatment for sore throat. Clinical Therapeutics 1985;7:641-6.
59. Watson N, Nimmo WS, Christian J, Charlesworth A, Speight J, Miller K. Relief of sore throat with the anti-inflammatory throat lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy and safety. Int J Clin Pract 2000;54:490-6.
60. Schachtel BP, Thoden WR. A placebo-controlled model for assaying systemic analgesics in children. Pract Clin Pharmacol Ther 1993;53:593-601.
61. Kagan G, Huddlestone L, Wolstencroft P. Two lozenges containing benzocaine assessed in the relief of sore throat. J Int Med Res 1982;10:443-6.
62. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. Ann Intern Med 2001;134:521-9.
63. Eccles R, Morris S, Jawad M. Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection. J Clin Pharm Ther 1992;17:175-80.
64. Croughan-Minihane MS, Petitti DB, Rodnick JE, Eliaser G. Clinical trial examining effectiveness of three cough syrups. J Am Board Fam Pract 1993;6:109-15.
65. Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson CF. A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 1998;79:6-11.
66. Hueston WJ. A comparison of albuterol and erythromycin for the treatment of acute bronchitis. J Fam Pract 1991;33:476-80.
67. Hueston WJ. Albuterol delivered by metered-dose inhaler to treat acute bronchitis. J Fam Pract 1994;39:437-40.
68. Smucny J, Flynn C, Becker L, Glazier R. Beta2-agonists for acute bronchitis [Systematic Review]. Cochrane Database of Systematic Reviews 2001;1.-
69. Gwaltney JM, Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. N Engl J Med 1994;330:25-30.
70. Holmes WF, Macfarlane JT, Macfarlane RM, Hubbard R. Symptoms, signs, and prescribing for acute lower respiratory tract illness. Br J Gen Pract 2001;51:177-81.
71. Gulbrandsen P, Fugelli P, Kvarstein G, Moland L. The duration of acute respiratory tract infections in children. Scand J Prim Health Care 1989;7:219-23.
72. Gonzales R, Bartlett JG, Besser RE, Hickner JM, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for treatment of nonspecific upper respiratory tract infections in adults: background. Ann Intern Med 2001;134:490-4.
73. Gadomski AM. Potential interventions for preventing pneumonia among young children: lack of effect of antibiotic treatment for upper respiratory infections. Pediatr Infect Dis J 1993;12:115-20.
74. Heikkinen T, Ruuskanen O, Ziegler T, Waris M, Puhakka H. Short-term use of amoxicillin-clavulanate during upper respiratory tract infection for prevention of acute otitis media. J Pediatr 1995;126:313-6.
The term acute upper respiratory tract infection (ARTI) refers to an infection, almost always viral,1 predominantly involving the nasopharynx, sinuses, and large bronchi. It encompasses what is frequently referred to as the common cold, sinusitis, pharyngitis, bronchitis, and otitis media. This review will focus primarily on the common cold, or undifferentiated ARTI, but there will be considerable overlap with the other diagnoses. The rationale for grouping these traditionally separate diagnostic categories together is straightforward. ARTI almost always presents with some combination of nasal congestion, rhinnorrhea, sore throat, and cough. Sometimes one or another of these symptoms predominates, but there is good reason to suggest that the traditional diagnostic distinctions are arbitrary.2 The overlap between the clinical signs, symptoms, and x-ray findings is so extensive that these terms are not very useful diagnostically. This symptom complex is among the top 3 reasons for visits to primary care doctors3 and accounts for approximately 100 million office visits in the United States per year4 at an annual cost of considerably more than 1 billion dollars.5 Overuse of antibiotics adds more than $11 to the cost of each encounter for ARTI.5
This review will summarize the evidence that patients who present with undifferentiated ARTI usually have self-limited disease, that complications are rare, effective treatments for symptoms are available, and antibiotics are not often indicated. The evidence is based on only adults and children over age 2 who have normal immune systems and do not have chronic respiratory disease. (J Fam Pract; 50:1070-1077)
Pathophysiology
Patients with undifferentiated ARTI present with any or all of the following symptoms: rhinnorrhea (which may be either clear or colored), nasal congestion, cough, sore throat, facial pain, malaise, headache, or fever. The etiology is almost always viral, most commonly rhinovirus, but other viruses have been implicated as well, particularly corona-viruses, parainfluenza, and influenza.6 Bacterial infection is rare in undifferentiated ARTI, occurring in approximately 2% of patients.1 The most common bacteria implicated are group A Streptococcus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.7 Chlamydia pnuemoniae and Mycoplasma pnuemoniae have rarely been identified as well.6 Bordatella pertussis can occasionally be the cause of persistent cough in children and adults.8, 9
Diagnosis
The major diagnostic consideration in a patient who presents with ARTI symptoms is to rule out a more serious illness which would require aggressive treatment. These include pneumonia, pharyngitis caused by group A streptococci, and bacterial sinusitis. The traditional symptoms and signs that physicians use to distinguish viral from bacterial infection have not been determined helpful in making this distinction. Both a history of colored nasal discharge and maxillary sinus tenderness to palpation have a positive likelihood ratio (LR+) near 1 in predicting computed tomography–based diagnosis of acute bacterial sinusitis (a likelihood ratio of 1 indicates that the result does not change the likelihood of disease).10 Purulent sputum does not distinguish between viral ARTI and bacterial pneumonia.11 Combinations of symptoms, however, in the form of clinical decision rules, can be useful at ruling out more serious conditions.
Nasal Discharge
In patients who present primarily with nasal discharge, a study that correlated computed tomography (CT) scans with direct sinus puncture demonstrated that 90% of primary care patients with CT findings of total opacification or air fluid level in the maxillary sinuses have a bacterial etiology.12 Unfortunately, there is no combination of clinical signs or symptoms that reliably predicts opacification or air fluid levels.12 There have been 3 decision rules published based on clinical findings that may be useful, particularly in helping clinicians identify the most important symptoms on which they should focus during their examination. However, 2 of the rules require a sedimentation rate or C-reactive protein value,10,12 not typically available in a routine office visit. The only other rule based on clinical findings included adult men and used x-ray as the reference standard, making it less useful.13
The suspicion of sinusitis by a generalist is actually quite accurate diagnostically, since about 40% of patients with suspected sinusitis have the diagnosis confirmed by aspiration or CT imaging.14 One must therefore be guided by overall clinical judgment in these patients, but a practical approach to empiric treatment is presented in the section on treatment.
Sore Throat
In patients who present primarily with sore throat, the important consideration is to rule out group A streptococcus as the etiology. The prevalence of streptococcal pharyngitis varies markedly with age, season of the year, and presence or absence of an outbreak in the community. For children prevalences have been reported ranging from 12% to 35%. Prevalence seems to peak in the 5 years to 9 years age range, and in the autumn. Reported prevalences for adults range from 5% to 15%.15-20
A recent systematic review noted nine published decision rules for diagnosis of streptococcal pharyngitis,21 but the only one that has been prospectively validated in a primary care population of both children and adults is by McIssac22,23Table 1. Patients with a low risk of GABHS require no further testing; those with an intermediate risk should undergo rapid strep antigen testing; and those with a high risk of GABHS should either under rapid strep antigen testing with culture follow-up or empiric therapy. Culture for group A streptococcus is the most reliable means of diagnosis, but requires withholding treatment for 48 hours while awaiting the result.24
Infectious mononucleosis can also cause exudative pharyngitis. Palatine petechiae, posterior auricular and posterior cervical adenopathy, marked axillary adenopathy, and inguinal adenopathy are all associated with infectious mononucleosis,25 and if any of these signs are present a heterophile antibody test may be indicated to confirm the diagnosis.
Cough
Many patients with ARTI present with cough as a primary symptom. While the differential diagnosis for undifferentiated cough is long, in the setting of ARTI the primary diagnostic consideration is to rule out pneumonia. Decision rules by Heckerling11 and Diehr26 have been well validated Table 2, Table 3. If the patient does not have temperature higher than 100 ÞF, pulse rate higher than 100, rales, decreased breath sounds, or absence of wheezing, then pneumonia is very unlikely (negative likelihood ratio = 0.06). As the number of signs increases, the likelihood ratio increases, but the decision rule does not have sufficient positive predictive value to be used as a basis for antibiotic treatment. Purulent sputum is not predictive of pneumonia (LR+=1.3).11,27 Empiric antibiotics for pneumonia should not be given without a confirmatory chest x-ray.1
Treatment
Undifferentiated ARTI
The level of evidence supporting different interventions is summarized in Table 4, and each is discussed in more detail below.
Antibiotics. There have been numerous double blind placebo controlled randomized trials of antibiotics in patients with undifferentiated ARTI symptoms. All of these trials have been evaluated in a recent Cochrane systematic review.28 The review concludes that there is no consistent evidence of benefit from any antibiotic treatment and that there is a significant increase in adverse effects associated with antibiotic use. Increased cost and increased bacterial resistance in the patient and community are additional concerns.
Education. One of the reasons for inappropriate antibiotic use in ARTI is patient pressure for antibiotics. This can be subtle as well as direct and is difficult for physicians to resist.29 Several studies have shown that patient expectation for antibiotics is related to having been given antibiotics for respiratory infections in the past.30-32 Furthermore, McFarlane has shown that simple patient education techniques reduce both visits for ARTI and antibiotic usage.33 An essential part of treatment of these infections, therefore, is educating patients about the viral nature of the illness, the usual course and duration of symptoms (10 days for most, up to 3 weeks for some), the ineffectiveness of antibiotics for treatment, and the harm antibiotics can cause both to the patient and the community. Patient satisfaction has been shown to increase after this sort of intervention, even when patients initially had an expectation for antibiotic prescription.30,34 Some have advocated avoiding terms such as sinusitis and bronchitis with patients, instead using the terms head cold and chest cold to emphasize the viral nature of these illnesses.
Naproxen Sodium. Naproxen sodium was evaluated in a well-designed randomized placebo controlled trial using experimentally induced rhinovirus infections in volunteers.35 A statistically significant 29% reduction in total 5-day symptom scores was found. Specific symptoms that improved included sneezing, rhinnorrhea, nasal obstruction, sore throat, cough, headache, malaise and chilliness.
Vitamin C. A Cochrane Library meta-analysis of all the trials for ascorbic acid showed a small but significant effect on decreasing duration (.55 days per episode) and a modest effect on severity of symptoms.36 There was no evidence for an effect when taken prophylactically.
Zinc. Randomized trials of zinc have shown marked heterogeneity, but this may have been due to use of different preparations with different bioavailability.37 A more recent randomized trial used zinc acetate lozenges.38 Increased plasma zinc levels were documented in the treatment group. The lozenges contained 42.96 mg of zinc acetate dihydrate, and were administered every 2 to 3 hours, beginning 24 hours or less after the onset of symptoms. The treatment group had a reduction from 8.1 to 4.5 days in total duration of symptoms (number needed to treat [NNT] =3 at 5 days) and a 50% reduction in symptom scores compared to the placebo group. Symptoms included in the score were sore throat, nasal discharge, nasal congestion, sneezing, cough, scratchy throat, hoarseness, muscle ache, fever, and headache.
Echinacea. Echinacea was evaluated in another Cochrane Library Systematic Review.39 Sixteen trials were evaluated, two thirds of which had insufficient quality of reporting. There were many different extracts used, which made comparability of the results a problem. Most trials showed positive results, suggesting that preparations containing extract of echinacea may have some beneficial effect on prevention and treatment.
Intranasal Fluticasone. Intranasal fluticasone was evaluated in a randomized trial of 200 young adults with common cold symptoms.40 No clinically significant differences were noted in either duration or severity of symptoms between treatment and control groups.
Nasal Discharge
Antibiotics. As noted above under undifferentiated ARTI, a Cochrane systematic review of randomized antibiotic trials found no evidence of benefit of antibiotic treatment for clear or purulent rhinnorrhea.28 Another Cochrane systematic review focused on randomized trials of antibiotic treatment for sinusitis.41 There was modest benefit from amoxicillin treatment in patients with acute maxillary sinusitis confirmed radiographically (NNT=4). There was no evidence, even from more recent studies, that other antibiotics were any more effective than amoxicillin. Lindbaek was able to demonstrate in a randomized controlled trial of amoxicillin that the only patients who benefited from treatment were those who had either complete opacification of a sinus, or an air fluid level.42 Patients who had mucosal thickening alone showed no difference from the placebo group. Of the patients in the placebo group who did have opacification or air fluid level, half were well or much better within 10 days. There is also some evidence that patients who present with moderate to severe unilateral facial pain benefit from antibiotics.43 In children, a recent antibiotic trial of patients who had a clinical diagnosis of sinusitis with symptoms for between 14 and 28 days showed no difference in any outcome measure between treatment and placebo groups.44
Based on Lindbaek’s data for adults, assuming that 42% of patients with suspected bacterial sinusitis actually have the disease, the number needed to treat to benefit one patient is 8. The number needed to harm by adverse effects from antibiotics is 4, so harm may outweigh any benefit. Frontal sinusitis seems to represent a different disease process because of the anatomy of drainage from the frontal sinuses. These patients usually present with high fever, severe pain, are quite ill, and may require hospitalization, parenteral antibiotics and surgery.1,45,46 A practical approach is to treat all patients with nasal discharge symptomatically, unless they have severe pain, or appear very ill, in which case sinus films should be considered to rule out frontal sinusitis, or opacification or air fluid level in any sinus. Also, adult patients who have had sinus symptoms for more than two weeks without improvement are more likely to benefit from antibiotic treatment.42
Ipratropium. Ipratopium nasal spray used in a randomized controlled trial, reduced rhinnorrhea and sneezing in patients with cold symptoms by 31% compared to placebo saline nasal spray (ARR=16% NNT=7), and by 78% when compared with untreated patients (ARR=63% NNT=2).47
Brompheniramine. Brompheniramine likewise has a temporary modest effect on rhinnorrhea in adults. Brompheniramine was evaluated in a randomized controlled trial in volunteers infected with rhinovirus.48 The treatment group had a 20% reduction in symptom score on day 1 and a 26% reduction on day 2. The main symptoms improved were sneeze frequency, sneeze severity, and cough count. Drowsiness was a troubling side effect. Neither decongestants nor antihistamines, nor combinations of the 2 have shown any effect in randomized trials in children.49
Nasal Decongestants. The efficacy of oral psuedoephedrine or metalazone nasal spray were evaluated in a Cochrane Library meta-analysis.50 There was a 13% reduction in symptom score (subjective rating of severity of nasal congestion) after a single use of either agent, but no difference in combined symptom scores after use for 5 days.
Heated Humidified Air. Published studies of effectiveness of breathing heated humidified air for cold symptoms were evaluated in a Cochrane Library Systematic Review.51 Six studies were evaluated and the results were quite heterogeneous. One study in Israel and two in the UK showed significant improvement, while three in the US showed no difference between treatment and placebo groups.
Sore Throat
Antibiotics. The data for sore throat should reassure physicians who worry about the consequences of missing streptococcal pharyngitis. A Cochrane meta-analysis showed that treatment of streptococcal pharyngitis with penicillin did reduce duration of illness, but only by approximately half a day.52 There was only a minimal effect on prevention of suppurative complications as well (NNT=30 for children and NNT=145 for adults to prevent one case of otitis media). The incidence of rheumatic fever is so low in the industrialized world (.5 per 100,000 in the pediatric population in the United States )53 that the number needed to treat to prevent 1 case of rheumatic fever is exceedingly high. In fact, Howie54 has estimated that for a general practitioner in Scotland the NNT exceeds the number of patients he or she would see in his or her lifetime. Furthermore, it is estimated than only approximately 15% of patients with streptococcal pharyngitis ever present for treatment, further reducing the opportunity to prevent complications.52 Most of the symptomatic improvement from antibiotics comes in the first 3 days of illness, so that if culture is used as a treatment criterion, most patients will already be better by the time the results are available.55
Analgesics. Acetominophen, aspirin, ibuprofen, flurbiprofen, and the combination of aspirin and caffeine have all been shown to be effective for sore throat pain in randomized trials.56-60 Ibuprofen was found to be superior to acetominophen60 and aspirin/caffeine was found to be superior to aspirin alone.57
Benzocaine. I could find only one study evaluating benzocaine containing lozenges for sore throat61 and it did not include a placebo group. Although one lozenge (Merocaine) produced significantly better pain relief than the other (Tyrozets), the lack of a placebo comparison makes interpretation of these results problematic.
Cough
Antibiotics. There is no evidence, in the absence of pneumonia or pertussis, that antibiotics are effective for the treatment of acute cough, including cough productive of colored sputum in otherwise healthy patients.62 This does not include patients with acute exacerbation of chronic pulmonary disease.
Codeine, Dextromethorphan, Guaifenesin. There are few studies evaluating the effectiveness of cough medicines that contain combinations of guaifenesin and codeine or dextromethorphan. One randomized trial of the effectiveness of codeine for cough related to ARTI showed no difference between experimental and placebo groups.63 Another study found no difference between cough medicines containing guaifenesin alone, guaifenesin and codeine, and guaifenesin and dextromethorphan.64 Therefore, although studies are few, there is no evidence to suggest that any of these agents is effective for treatment of cough associated with ARTI. It is interesting to note that all studies showed a marked placebo effect.
b2 -Agonists. Initial studies appeared to show some benefit for inhaled b2-agonists in the treatment of cough.65-67 A recent systematic review by Smucny, however, found that only patients with demonstrated hyperreactivity of airways benefited from this treatment.68
A flow diagram depicting an algorithm for when to use antibiotic in addition to symptomatic treatment for ARTI is shown in the Figure 1. This closely approximates the most recent CDC guidelines on the judicious use of antibiotics for respiratory infections in children and adults. Table 5 summarizes the best clinical trial evidence regarding the use of antibiotics in ARTI.
Prognosis
The mean duration of symptoms for untreated ARTI is approximately 10 days.38,42,69 It is not unusual for symptoms, particularly nasal congestion and cough, however, to last for up to 3 weeks. One study of lower respiratory tract infection in primary care patients found that 60% were still coughing after 10 days.70 Another study of ARTI in children in Norway found that 50% still had nasal discharge and cough after 3 weeks.71 Complications are rare in primary care patients. Less than 2% of patients with ARTI go on to develop secondary bacterial infection requiring antibiotic treatment.1 Although there are no data in adults which specifically address whether antibiotic treatment prevents bacterial infection,72 there are at least 2 studies that demonstrate that antibiotic treatment of children with undifferentiated ARTI does not prevent pneumonia or otitis media.73,74
The term acute upper respiratory tract infection (ARTI) refers to an infection, almost always viral,1 predominantly involving the nasopharynx, sinuses, and large bronchi. It encompasses what is frequently referred to as the common cold, sinusitis, pharyngitis, bronchitis, and otitis media. This review will focus primarily on the common cold, or undifferentiated ARTI, but there will be considerable overlap with the other diagnoses. The rationale for grouping these traditionally separate diagnostic categories together is straightforward. ARTI almost always presents with some combination of nasal congestion, rhinnorrhea, sore throat, and cough. Sometimes one or another of these symptoms predominates, but there is good reason to suggest that the traditional diagnostic distinctions are arbitrary.2 The overlap between the clinical signs, symptoms, and x-ray findings is so extensive that these terms are not very useful diagnostically. This symptom complex is among the top 3 reasons for visits to primary care doctors3 and accounts for approximately 100 million office visits in the United States per year4 at an annual cost of considerably more than 1 billion dollars.5 Overuse of antibiotics adds more than $11 to the cost of each encounter for ARTI.5
This review will summarize the evidence that patients who present with undifferentiated ARTI usually have self-limited disease, that complications are rare, effective treatments for symptoms are available, and antibiotics are not often indicated. The evidence is based on only adults and children over age 2 who have normal immune systems and do not have chronic respiratory disease. (J Fam Pract; 50:1070-1077)
Pathophysiology
Patients with undifferentiated ARTI present with any or all of the following symptoms: rhinnorrhea (which may be either clear or colored), nasal congestion, cough, sore throat, facial pain, malaise, headache, or fever. The etiology is almost always viral, most commonly rhinovirus, but other viruses have been implicated as well, particularly corona-viruses, parainfluenza, and influenza.6 Bacterial infection is rare in undifferentiated ARTI, occurring in approximately 2% of patients.1 The most common bacteria implicated are group A Streptococcus, Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis.7 Chlamydia pnuemoniae and Mycoplasma pnuemoniae have rarely been identified as well.6 Bordatella pertussis can occasionally be the cause of persistent cough in children and adults.8, 9
Diagnosis
The major diagnostic consideration in a patient who presents with ARTI symptoms is to rule out a more serious illness which would require aggressive treatment. These include pneumonia, pharyngitis caused by group A streptococci, and bacterial sinusitis. The traditional symptoms and signs that physicians use to distinguish viral from bacterial infection have not been determined helpful in making this distinction. Both a history of colored nasal discharge and maxillary sinus tenderness to palpation have a positive likelihood ratio (LR+) near 1 in predicting computed tomography–based diagnosis of acute bacterial sinusitis (a likelihood ratio of 1 indicates that the result does not change the likelihood of disease).10 Purulent sputum does not distinguish between viral ARTI and bacterial pneumonia.11 Combinations of symptoms, however, in the form of clinical decision rules, can be useful at ruling out more serious conditions.
Nasal Discharge
In patients who present primarily with nasal discharge, a study that correlated computed tomography (CT) scans with direct sinus puncture demonstrated that 90% of primary care patients with CT findings of total opacification or air fluid level in the maxillary sinuses have a bacterial etiology.12 Unfortunately, there is no combination of clinical signs or symptoms that reliably predicts opacification or air fluid levels.12 There have been 3 decision rules published based on clinical findings that may be useful, particularly in helping clinicians identify the most important symptoms on which they should focus during their examination. However, 2 of the rules require a sedimentation rate or C-reactive protein value,10,12 not typically available in a routine office visit. The only other rule based on clinical findings included adult men and used x-ray as the reference standard, making it less useful.13
The suspicion of sinusitis by a generalist is actually quite accurate diagnostically, since about 40% of patients with suspected sinusitis have the diagnosis confirmed by aspiration or CT imaging.14 One must therefore be guided by overall clinical judgment in these patients, but a practical approach to empiric treatment is presented in the section on treatment.
Sore Throat
In patients who present primarily with sore throat, the important consideration is to rule out group A streptococcus as the etiology. The prevalence of streptococcal pharyngitis varies markedly with age, season of the year, and presence or absence of an outbreak in the community. For children prevalences have been reported ranging from 12% to 35%. Prevalence seems to peak in the 5 years to 9 years age range, and in the autumn. Reported prevalences for adults range from 5% to 15%.15-20
A recent systematic review noted nine published decision rules for diagnosis of streptococcal pharyngitis,21 but the only one that has been prospectively validated in a primary care population of both children and adults is by McIssac22,23Table 1. Patients with a low risk of GABHS require no further testing; those with an intermediate risk should undergo rapid strep antigen testing; and those with a high risk of GABHS should either under rapid strep antigen testing with culture follow-up or empiric therapy. Culture for group A streptococcus is the most reliable means of diagnosis, but requires withholding treatment for 48 hours while awaiting the result.24
Infectious mononucleosis can also cause exudative pharyngitis. Palatine petechiae, posterior auricular and posterior cervical adenopathy, marked axillary adenopathy, and inguinal adenopathy are all associated with infectious mononucleosis,25 and if any of these signs are present a heterophile antibody test may be indicated to confirm the diagnosis.
Cough
Many patients with ARTI present with cough as a primary symptom. While the differential diagnosis for undifferentiated cough is long, in the setting of ARTI the primary diagnostic consideration is to rule out pneumonia. Decision rules by Heckerling11 and Diehr26 have been well validated Table 2, Table 3. If the patient does not have temperature higher than 100 ÞF, pulse rate higher than 100, rales, decreased breath sounds, or absence of wheezing, then pneumonia is very unlikely (negative likelihood ratio = 0.06). As the number of signs increases, the likelihood ratio increases, but the decision rule does not have sufficient positive predictive value to be used as a basis for antibiotic treatment. Purulent sputum is not predictive of pneumonia (LR+=1.3).11,27 Empiric antibiotics for pneumonia should not be given without a confirmatory chest x-ray.1
Treatment
Undifferentiated ARTI
The level of evidence supporting different interventions is summarized in Table 4, and each is discussed in more detail below.
Antibiotics. There have been numerous double blind placebo controlled randomized trials of antibiotics in patients with undifferentiated ARTI symptoms. All of these trials have been evaluated in a recent Cochrane systematic review.28 The review concludes that there is no consistent evidence of benefit from any antibiotic treatment and that there is a significant increase in adverse effects associated with antibiotic use. Increased cost and increased bacterial resistance in the patient and community are additional concerns.
Education. One of the reasons for inappropriate antibiotic use in ARTI is patient pressure for antibiotics. This can be subtle as well as direct and is difficult for physicians to resist.29 Several studies have shown that patient expectation for antibiotics is related to having been given antibiotics for respiratory infections in the past.30-32 Furthermore, McFarlane has shown that simple patient education techniques reduce both visits for ARTI and antibiotic usage.33 An essential part of treatment of these infections, therefore, is educating patients about the viral nature of the illness, the usual course and duration of symptoms (10 days for most, up to 3 weeks for some), the ineffectiveness of antibiotics for treatment, and the harm antibiotics can cause both to the patient and the community. Patient satisfaction has been shown to increase after this sort of intervention, even when patients initially had an expectation for antibiotic prescription.30,34 Some have advocated avoiding terms such as sinusitis and bronchitis with patients, instead using the terms head cold and chest cold to emphasize the viral nature of these illnesses.
Naproxen Sodium. Naproxen sodium was evaluated in a well-designed randomized placebo controlled trial using experimentally induced rhinovirus infections in volunteers.35 A statistically significant 29% reduction in total 5-day symptom scores was found. Specific symptoms that improved included sneezing, rhinnorrhea, nasal obstruction, sore throat, cough, headache, malaise and chilliness.
Vitamin C. A Cochrane Library meta-analysis of all the trials for ascorbic acid showed a small but significant effect on decreasing duration (.55 days per episode) and a modest effect on severity of symptoms.36 There was no evidence for an effect when taken prophylactically.
Zinc. Randomized trials of zinc have shown marked heterogeneity, but this may have been due to use of different preparations with different bioavailability.37 A more recent randomized trial used zinc acetate lozenges.38 Increased plasma zinc levels were documented in the treatment group. The lozenges contained 42.96 mg of zinc acetate dihydrate, and were administered every 2 to 3 hours, beginning 24 hours or less after the onset of symptoms. The treatment group had a reduction from 8.1 to 4.5 days in total duration of symptoms (number needed to treat [NNT] =3 at 5 days) and a 50% reduction in symptom scores compared to the placebo group. Symptoms included in the score were sore throat, nasal discharge, nasal congestion, sneezing, cough, scratchy throat, hoarseness, muscle ache, fever, and headache.
Echinacea. Echinacea was evaluated in another Cochrane Library Systematic Review.39 Sixteen trials were evaluated, two thirds of which had insufficient quality of reporting. There were many different extracts used, which made comparability of the results a problem. Most trials showed positive results, suggesting that preparations containing extract of echinacea may have some beneficial effect on prevention and treatment.
Intranasal Fluticasone. Intranasal fluticasone was evaluated in a randomized trial of 200 young adults with common cold symptoms.40 No clinically significant differences were noted in either duration or severity of symptoms between treatment and control groups.
Nasal Discharge
Antibiotics. As noted above under undifferentiated ARTI, a Cochrane systematic review of randomized antibiotic trials found no evidence of benefit of antibiotic treatment for clear or purulent rhinnorrhea.28 Another Cochrane systematic review focused on randomized trials of antibiotic treatment for sinusitis.41 There was modest benefit from amoxicillin treatment in patients with acute maxillary sinusitis confirmed radiographically (NNT=4). There was no evidence, even from more recent studies, that other antibiotics were any more effective than amoxicillin. Lindbaek was able to demonstrate in a randomized controlled trial of amoxicillin that the only patients who benefited from treatment were those who had either complete opacification of a sinus, or an air fluid level.42 Patients who had mucosal thickening alone showed no difference from the placebo group. Of the patients in the placebo group who did have opacification or air fluid level, half were well or much better within 10 days. There is also some evidence that patients who present with moderate to severe unilateral facial pain benefit from antibiotics.43 In children, a recent antibiotic trial of patients who had a clinical diagnosis of sinusitis with symptoms for between 14 and 28 days showed no difference in any outcome measure between treatment and placebo groups.44
Based on Lindbaek’s data for adults, assuming that 42% of patients with suspected bacterial sinusitis actually have the disease, the number needed to treat to benefit one patient is 8. The number needed to harm by adverse effects from antibiotics is 4, so harm may outweigh any benefit. Frontal sinusitis seems to represent a different disease process because of the anatomy of drainage from the frontal sinuses. These patients usually present with high fever, severe pain, are quite ill, and may require hospitalization, parenteral antibiotics and surgery.1,45,46 A practical approach is to treat all patients with nasal discharge symptomatically, unless they have severe pain, or appear very ill, in which case sinus films should be considered to rule out frontal sinusitis, or opacification or air fluid level in any sinus. Also, adult patients who have had sinus symptoms for more than two weeks without improvement are more likely to benefit from antibiotic treatment.42
Ipratropium. Ipratopium nasal spray used in a randomized controlled trial, reduced rhinnorrhea and sneezing in patients with cold symptoms by 31% compared to placebo saline nasal spray (ARR=16% NNT=7), and by 78% when compared with untreated patients (ARR=63% NNT=2).47
Brompheniramine. Brompheniramine likewise has a temporary modest effect on rhinnorrhea in adults. Brompheniramine was evaluated in a randomized controlled trial in volunteers infected with rhinovirus.48 The treatment group had a 20% reduction in symptom score on day 1 and a 26% reduction on day 2. The main symptoms improved were sneeze frequency, sneeze severity, and cough count. Drowsiness was a troubling side effect. Neither decongestants nor antihistamines, nor combinations of the 2 have shown any effect in randomized trials in children.49
Nasal Decongestants. The efficacy of oral psuedoephedrine or metalazone nasal spray were evaluated in a Cochrane Library meta-analysis.50 There was a 13% reduction in symptom score (subjective rating of severity of nasal congestion) after a single use of either agent, but no difference in combined symptom scores after use for 5 days.
Heated Humidified Air. Published studies of effectiveness of breathing heated humidified air for cold symptoms were evaluated in a Cochrane Library Systematic Review.51 Six studies were evaluated and the results were quite heterogeneous. One study in Israel and two in the UK showed significant improvement, while three in the US showed no difference between treatment and placebo groups.
Sore Throat
Antibiotics. The data for sore throat should reassure physicians who worry about the consequences of missing streptococcal pharyngitis. A Cochrane meta-analysis showed that treatment of streptococcal pharyngitis with penicillin did reduce duration of illness, but only by approximately half a day.52 There was only a minimal effect on prevention of suppurative complications as well (NNT=30 for children and NNT=145 for adults to prevent one case of otitis media). The incidence of rheumatic fever is so low in the industrialized world (.5 per 100,000 in the pediatric population in the United States )53 that the number needed to treat to prevent 1 case of rheumatic fever is exceedingly high. In fact, Howie54 has estimated that for a general practitioner in Scotland the NNT exceeds the number of patients he or she would see in his or her lifetime. Furthermore, it is estimated than only approximately 15% of patients with streptococcal pharyngitis ever present for treatment, further reducing the opportunity to prevent complications.52 Most of the symptomatic improvement from antibiotics comes in the first 3 days of illness, so that if culture is used as a treatment criterion, most patients will already be better by the time the results are available.55
Analgesics. Acetominophen, aspirin, ibuprofen, flurbiprofen, and the combination of aspirin and caffeine have all been shown to be effective for sore throat pain in randomized trials.56-60 Ibuprofen was found to be superior to acetominophen60 and aspirin/caffeine was found to be superior to aspirin alone.57
Benzocaine. I could find only one study evaluating benzocaine containing lozenges for sore throat61 and it did not include a placebo group. Although one lozenge (Merocaine) produced significantly better pain relief than the other (Tyrozets), the lack of a placebo comparison makes interpretation of these results problematic.
Cough
Antibiotics. There is no evidence, in the absence of pneumonia or pertussis, that antibiotics are effective for the treatment of acute cough, including cough productive of colored sputum in otherwise healthy patients.62 This does not include patients with acute exacerbation of chronic pulmonary disease.
Codeine, Dextromethorphan, Guaifenesin. There are few studies evaluating the effectiveness of cough medicines that contain combinations of guaifenesin and codeine or dextromethorphan. One randomized trial of the effectiveness of codeine for cough related to ARTI showed no difference between experimental and placebo groups.63 Another study found no difference between cough medicines containing guaifenesin alone, guaifenesin and codeine, and guaifenesin and dextromethorphan.64 Therefore, although studies are few, there is no evidence to suggest that any of these agents is effective for treatment of cough associated with ARTI. It is interesting to note that all studies showed a marked placebo effect.
b2 -Agonists. Initial studies appeared to show some benefit for inhaled b2-agonists in the treatment of cough.65-67 A recent systematic review by Smucny, however, found that only patients with demonstrated hyperreactivity of airways benefited from this treatment.68
A flow diagram depicting an algorithm for when to use antibiotic in addition to symptomatic treatment for ARTI is shown in the Figure 1. This closely approximates the most recent CDC guidelines on the judicious use of antibiotics for respiratory infections in children and adults. Table 5 summarizes the best clinical trial evidence regarding the use of antibiotics in ARTI.
Prognosis
The mean duration of symptoms for untreated ARTI is approximately 10 days.38,42,69 It is not unusual for symptoms, particularly nasal congestion and cough, however, to last for up to 3 weeks. One study of lower respiratory tract infection in primary care patients found that 60% were still coughing after 10 days.70 Another study of ARTI in children in Norway found that 50% still had nasal discharge and cough after 3 weeks.71 Complications are rare in primary care patients. Less than 2% of patients with ARTI go on to develop secondary bacterial infection requiring antibiotic treatment.1 Although there are no data in adults which specifically address whether antibiotic treatment prevents bacterial infection,72 there are at least 2 studies that demonstrate that antibiotic treatment of children with undifferentiated ARTI does not prevent pneumonia or otitis media.73,74
1. Gonzales R, Bartlett JG, Besser RE, Richelle JC, Hickner J, Jerome R, Hoffman JR. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults. Ann Intern Med 2001;134.-
2. Hueston WJ, Mainous AG, 3rd, Dacus EN, Hopper JE. Does acute bronchitis really exist? A reconceptualization of acute viral respiratory infections. J Fam Pract 2000;49:401-6.
3. Woodwell DA. National Ambulatory Medical Care Survey: 1996 summary. Adv Data 1997;1-25.
4. Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997;278:901-4.
5. Mainous AG, 3rd, Hueston WJ. The cost of antibiotics in treating upper respiratory tract infections in a Medicaid population . Arch Fam Med 1998;7:45-9.
6. Makela MJ, Puhakka T, Ruuskanen O, et al. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol 1998;36:539-42.
7. Ruoff G. Upper respiratory tract infections in family practice. Pediatr Infect Dis J 1998;17:S73-8.
8. Dowell SF, Schwartz B, Phillips WR. Appropriate use of antibiotics for URIs in children: Part II. Cough, pharyngitis and the common cold. The Pediatric URI Consensus Team. Am Fam Physician 1998;58:1335-42, 1345.
9. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: background, specific aims, and methods. Ann Intern Med 2001;134:479-86.
10. Lindbaek M, Hjortdahl P, Johnsen UL. Use of symptoms, signs, and blood tests to diagnose acute sinus infections in primary care: comparison with computed tomography. Fam Med 1996;28:183-8.
11. Heckerling PS, Tape TG, Wigton RS, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med 1990;113:664-70.
12. Hansen JG, Schmidt H, Rosborg J, Lund E. Predicting acute maxillary sinusitis in a general practice population. BMJ 1995;311:233-6.
13. Williams JW, Jr, Simel DL, Roberts L, Samsa GP. Clinical evaluation for sinusitis. Making the diagnosis by history and physical examination. Ann Intern Med 1992;117:705-10.
14. Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann Intern Med 2001;134:498-505.
15. Gunnarsson RK, Holm SE, Soderstrom M. The prevalence of potential pathogenic bacteria in nasopharyngeal samples from individuals with a respiratory tract infection and a sore throat—implications for the diagnosis of pharyngotonsillitis. Fam Pract 2001;18:266-71.
16. Pokorski SJ, Vetter EA, Wollan PC, Cockerill FR, 3rd. Comparison of Gen-Probe Group A streptococcus Direct Test with culture for diagnosing streptococcal pharyngitis. J Clin Microbiol 1994;32:1440-3.
17. Dagnelie CF, Bartelink ML, van der Graaf Y, Goessens W, de Melker RA. Towards a better diagnosis of throat infections (with group A beta-haemolytic streptococcus) in general practice. Br J Gen Pract 1998;48:959-62.
18. Hart AP, Buck LL, Morgan S, Saverio S, McLaughlin JC. A comparison of the BioStar Strep A OIA rapid antigen assay, group A Selective Strep Agar (ssA), and Todd-Hewitt broth cultures for the detection of group A Streptococcus in an outpatient family practice setting. Diagn Microbiol Infect Dis 1997;29:139-45.
19. Smith TD, Wilkinson V, Kaplan EL. Group A streptococcus-associated upper respiratory tract infections in a day-care center. Pediatrics 1989;83:380-4.
20. Drulak M, Raybould TJ, Yong J, Hsiung D, Smith H, Winston S. Comparison of Visuwell enzyme immunoassay to culture for detection of group A Streptococcus in throat swab specimens. Diagn Microbiol Infect Dis 1988;11:181-7.
21. Ebell MH SM, Barry HC, Ives K, Carey BS. Does this patient have strep throat? JAMA 2000;284:2912-2918.
22. McIsaac WJ, Goel V, To T, Low DE. The validity of a sore throat score in family practice. CMAJ 2000;163:811-5.
23. McIsaac WJ, White D, Tannenbaum D, Low DE. A clinical score to reduce unnecessary antibiotic use in patients with sore throat. CMAJ 1998;158:75-83.
24. Reed BD, Huck W, French T. Diagnosis of group A beta-hemolytic Streptococcus using clinical scoring criteria, Directigen 1-2-3 group A streptococcal test, and culture. Arch Intern Med 1990;150:1727-32.
25. Aronson MD, Komaroff AL, Pass TM, Ervin CT, Branch WT. Heterophil antibody in adults with sore throat: frequency and clinical presentation. Ann Intern Med 1982;96:505-8.
26. Diehr P, Wood RW, Bushyhead J, Krueger L, Wolcott B, Tompkins RK. Prediction of pneumonia in outpatients with acute cough—a statistical approach. J Chronic Dis 1984;37:215-25.
27. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997;278:1440-5.
28. Arroll B, Kenealy T. Antibiotics for the common cold. Cochrane Database Syst Rev 2000;CD000247.-
29. Scott J, Cohen D, Dicicco-Bloom B, Orzano A, Jaen C, Crabtree BF. Unnecessary antibiotic use in acute respiratory Infections. JAMA 2001; In press.
30. Hamm RM, Hicks RJ, Bemben DA. Antibiotics and respiratory infections: do antibiotic prescriptions improve outcomes? J Okla State Med Assoc 1996;89:267-74.
31. Mainous AG, 3rd, Zoorob RJ, Oler MJ, Haynes DM. Patient knowledge of upper respiratory infections: implications for antibiotic expectations and unnecessary utilization. J Fam Pract 1997;45:75-83.
32. Little P, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL. Open randomised trial of prescribing strategies in managing sore throat. BMJ 1997;314:722-7.
33. Macfarlane JT, Holmes WF, Macfarlane RM. Reducing reconsultations for acute lower respiratory tract illness with an information leaflet: a randomized controlled study of patients in primary care. Br J Gen Pract 1997;47:719-22.
34. Sanchez-Menegay C, Hudes ES, Cummings SR. Patient expectations and satisfaction with medical care for upper respiratory infections. J Gen Intern Med 1992;7:432-4.
35. Sperber SJ, Hendley JO, Hayden FG, Riker DK, Sorrentino JV, Gwaltney JM, Jr. Effects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial. Ann Intern Med 1992;117:37-41.
36. Douglas RM, Chalker EB, Treacy B. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2000;2.-
37. Marshall I. Zinc for the common cold. Cochrane Database Syst Rev 2000;2.-
38. Prasad AS, Fitzgerald JT, Bao B, Beck FW, Chandrasekar PH. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000;133:245-52.
39. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2000;2.-
40. Puhakka T, Makela MJ, Malmstrom K, et al. The common cold: effects of intranasal fluticasone propionate treatment. J Allergy Clin Immunol 1998;101:726-31.
41. Williams JW, Jr, Aguilar C, Makela M, et al. Antibiotics for acute maxillary sinusitis. Cochrane Database Syst Rev 2000;CD000243.-
42. Lindbaek M, Hjortdahl P, Johnsen UL. Randomised, double blind, placebo controlled trial of penicillin V and amoxycillin in treatment of acute sinus infections in adults. BMJ 1996;313:325-9.
43. Hansen JG, Schmidt H, Grinsted P. Randomised, double blind, placebo controlled trial of penicillin V in the treatment of acute maxillary sinusitis in adults in general practice. Scand J Prim Health Care 2000;18:44-7.
44. Garbutt JMMF, Goldstein MDDS, Gellman EMD, Shannon WP, Littenberg BMD. A randomized, placebo-controlled trial of antimicrobial treatment for children with clinically diagnosed acute sinusitis. Pediatrics April 2001;107:619-625.
45. Altman KW, Austin MB, Tom LW, Knox GW. Complications of frontal sinusitis in adolescents: case presentations and treatment options. Int J Pediatr Otorhinolaryngol 1997;41:9-20.
46. Giannoni CM, Stewart MG, Alford EL. Intracranial complications of sinusitis. Laryngoscope 1997;107:863-7.
47. Hayden FG, Diamond L, Wood PB, Korts DC, Wecker MT. Effectiveness and safety of intranasal ipratropium bromide in common colds. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996;125:89-97.
48. Gwaltney JM, Druce HM. Efficacy of brompheniramine maleate for the treatment of rhinovirus colds. Clin Infect Dis 1997;25:1188-94.
49. Clemens CJ, Taylor JA, Almquist JR, Quinn HC, Mehta A, Naylor GS. Is an antihistamine-decongestant combination effective in temporarily relieving symptoms of the common cold in preschool children? J Pediatr 1997;130:463-6.
50. Taverner D, Bickford L, Draper M. Nasal decongestants for the common cold. Cochrane Database Syst Rev 2000;2.-
51. Singh M. Heated, humidified air for the common cold. Cochrane Database Syst Rev;2000;CD001728.-
52. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database Syst Rev;2000;CD000023.-
53. Olivier C. Rheumatic fever—is it still a problem? J Antimicrob Chemother 2000;45 Suppl:13-21.
54. Howie JG, Foggo BA. Antibiotics, sore throats and rheumatic fever. J R Coll Gen Pract 1985;35:223-4.
55. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-9.
56. Schachtel BP, Fillingim JM, Thoden WR, Lane AC, Baybutt RI. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther 1988;44:704-11.
57. Schachtel BP, Fillingim JM, Lane AC, Thoden WR, Baybutt RI. Caffeine as an analgesic adjuvant. A double-blind study comparing aspirin with caffeine to aspirin and placebo in patients with sore throat. Arch Intern Med 1991;151:733-7.
58. Wethington JF. Double-blind study of benzydamine hydrochloride, a new treatment for sore throat. Clinical Therapeutics 1985;7:641-6.
59. Watson N, Nimmo WS, Christian J, Charlesworth A, Speight J, Miller K. Relief of sore throat with the anti-inflammatory throat lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy and safety. Int J Clin Pract 2000;54:490-6.
60. Schachtel BP, Thoden WR. A placebo-controlled model for assaying systemic analgesics in children. Pract Clin Pharmacol Ther 1993;53:593-601.
61. Kagan G, Huddlestone L, Wolstencroft P. Two lozenges containing benzocaine assessed in the relief of sore throat. J Int Med Res 1982;10:443-6.
62. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. Ann Intern Med 2001;134:521-9.
63. Eccles R, Morris S, Jawad M. Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection. J Clin Pharm Ther 1992;17:175-80.
64. Croughan-Minihane MS, Petitti DB, Rodnick JE, Eliaser G. Clinical trial examining effectiveness of three cough syrups. J Am Board Fam Pract 1993;6:109-15.
65. Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson CF. A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 1998;79:6-11.
66. Hueston WJ. A comparison of albuterol and erythromycin for the treatment of acute bronchitis. J Fam Pract 1991;33:476-80.
67. Hueston WJ. Albuterol delivered by metered-dose inhaler to treat acute bronchitis. J Fam Pract 1994;39:437-40.
68. Smucny J, Flynn C, Becker L, Glazier R. Beta2-agonists for acute bronchitis [Systematic Review]. Cochrane Database of Systematic Reviews 2001;1.-
69. Gwaltney JM, Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. N Engl J Med 1994;330:25-30.
70. Holmes WF, Macfarlane JT, Macfarlane RM, Hubbard R. Symptoms, signs, and prescribing for acute lower respiratory tract illness. Br J Gen Pract 2001;51:177-81.
71. Gulbrandsen P, Fugelli P, Kvarstein G, Moland L. The duration of acute respiratory tract infections in children. Scand J Prim Health Care 1989;7:219-23.
72. Gonzales R, Bartlett JG, Besser RE, Hickner JM, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for treatment of nonspecific upper respiratory tract infections in adults: background. Ann Intern Med 2001;134:490-4.
73. Gadomski AM. Potential interventions for preventing pneumonia among young children: lack of effect of antibiotic treatment for upper respiratory infections. Pediatr Infect Dis J 1993;12:115-20.
74. Heikkinen T, Ruuskanen O, Ziegler T, Waris M, Puhakka H. Short-term use of amoxicillin-clavulanate during upper respiratory tract infection for prevention of acute otitis media. J Pediatr 1995;126:313-6.
1. Gonzales R, Bartlett JG, Besser RE, Richelle JC, Hickner J, Jerome R, Hoffman JR. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults. Ann Intern Med 2001;134.-
2. Hueston WJ, Mainous AG, 3rd, Dacus EN, Hopper JE. Does acute bronchitis really exist? A reconceptualization of acute viral respiratory infections. J Fam Pract 2000;49:401-6.
3. Woodwell DA. National Ambulatory Medical Care Survey: 1996 summary. Adv Data 1997;1-25.
4. Gonzales R, Steiner JF, Sande MA. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. JAMA 1997;278:901-4.
5. Mainous AG, 3rd, Hueston WJ. The cost of antibiotics in treating upper respiratory tract infections in a Medicaid population . Arch Fam Med 1998;7:45-9.
6. Makela MJ, Puhakka T, Ruuskanen O, et al. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol 1998;36:539-42.
7. Ruoff G. Upper respiratory tract infections in family practice. Pediatr Infect Dis J 1998;17:S73-8.
8. Dowell SF, Schwartz B, Phillips WR. Appropriate use of antibiotics for URIs in children: Part II. Cough, pharyngitis and the common cold. The Pediatric URI Consensus Team. Am Fam Physician 1998;58:1335-42, 1345.
9. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of acute respiratory tract infections in adults: background, specific aims, and methods. Ann Intern Med 2001;134:479-86.
10. Lindbaek M, Hjortdahl P, Johnsen UL. Use of symptoms, signs, and blood tests to diagnose acute sinus infections in primary care: comparison with computed tomography. Fam Med 1996;28:183-8.
11. Heckerling PS, Tape TG, Wigton RS, et al. Clinical prediction rule for pulmonary infiltrates. Ann Intern Med 1990;113:664-70.
12. Hansen JG, Schmidt H, Rosborg J, Lund E. Predicting acute maxillary sinusitis in a general practice population. BMJ 1995;311:233-6.
13. Williams JW, Jr, Simel DL, Roberts L, Samsa GP. Clinical evaluation for sinusitis. Making the diagnosis by history and physical examination. Ann Intern Med 1992;117:705-10.
14. Hickner JM, Bartlett JG, Besser RE, Gonzales R, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for acute rhinosinusitis in adults: background. Ann Intern Med 2001;134:498-505.
15. Gunnarsson RK, Holm SE, Soderstrom M. The prevalence of potential pathogenic bacteria in nasopharyngeal samples from individuals with a respiratory tract infection and a sore throat—implications for the diagnosis of pharyngotonsillitis. Fam Pract 2001;18:266-71.
16. Pokorski SJ, Vetter EA, Wollan PC, Cockerill FR, 3rd. Comparison of Gen-Probe Group A streptococcus Direct Test with culture for diagnosing streptococcal pharyngitis. J Clin Microbiol 1994;32:1440-3.
17. Dagnelie CF, Bartelink ML, van der Graaf Y, Goessens W, de Melker RA. Towards a better diagnosis of throat infections (with group A beta-haemolytic streptococcus) in general practice. Br J Gen Pract 1998;48:959-62.
18. Hart AP, Buck LL, Morgan S, Saverio S, McLaughlin JC. A comparison of the BioStar Strep A OIA rapid antigen assay, group A Selective Strep Agar (ssA), and Todd-Hewitt broth cultures for the detection of group A Streptococcus in an outpatient family practice setting. Diagn Microbiol Infect Dis 1997;29:139-45.
19. Smith TD, Wilkinson V, Kaplan EL. Group A streptococcus-associated upper respiratory tract infections in a day-care center. Pediatrics 1989;83:380-4.
20. Drulak M, Raybould TJ, Yong J, Hsiung D, Smith H, Winston S. Comparison of Visuwell enzyme immunoassay to culture for detection of group A Streptococcus in throat swab specimens. Diagn Microbiol Infect Dis 1988;11:181-7.
21. Ebell MH SM, Barry HC, Ives K, Carey BS. Does this patient have strep throat? JAMA 2000;284:2912-2918.
22. McIsaac WJ, Goel V, To T, Low DE. The validity of a sore throat score in family practice. CMAJ 2000;163:811-5.
23. McIsaac WJ, White D, Tannenbaum D, Low DE. A clinical score to reduce unnecessary antibiotic use in patients with sore throat. CMAJ 1998;158:75-83.
24. Reed BD, Huck W, French T. Diagnosis of group A beta-hemolytic Streptococcus using clinical scoring criteria, Directigen 1-2-3 group A streptococcal test, and culture. Arch Intern Med 1990;150:1727-32.
25. Aronson MD, Komaroff AL, Pass TM, Ervin CT, Branch WT. Heterophil antibody in adults with sore throat: frequency and clinical presentation. Ann Intern Med 1982;96:505-8.
26. Diehr P, Wood RW, Bushyhead J, Krueger L, Wolcott B, Tompkins RK. Prediction of pneumonia in outpatients with acute cough—a statistical approach. J Chronic Dis 1984;37:215-25.
27. Metlay JP, Kapoor WN, Fine MJ. Does this patient have community-acquired pneumonia? Diagnosing pneumonia by history and physical examination. JAMA 1997;278:1440-5.
28. Arroll B, Kenealy T. Antibiotics for the common cold. Cochrane Database Syst Rev 2000;CD000247.-
29. Scott J, Cohen D, Dicicco-Bloom B, Orzano A, Jaen C, Crabtree BF. Unnecessary antibiotic use in acute respiratory Infections. JAMA 2001; In press.
30. Hamm RM, Hicks RJ, Bemben DA. Antibiotics and respiratory infections: do antibiotic prescriptions improve outcomes? J Okla State Med Assoc 1996;89:267-74.
31. Mainous AG, 3rd, Zoorob RJ, Oler MJ, Haynes DM. Patient knowledge of upper respiratory infections: implications for antibiotic expectations and unnecessary utilization. J Fam Pract 1997;45:75-83.
32. Little P, Williamson I, Warner G, Gould C, Gantley M, Kinmonth AL. Open randomised trial of prescribing strategies in managing sore throat. BMJ 1997;314:722-7.
33. Macfarlane JT, Holmes WF, Macfarlane RM. Reducing reconsultations for acute lower respiratory tract illness with an information leaflet: a randomized controlled study of patients in primary care. Br J Gen Pract 1997;47:719-22.
34. Sanchez-Menegay C, Hudes ES, Cummings SR. Patient expectations and satisfaction with medical care for upper respiratory infections. J Gen Intern Med 1992;7:432-4.
35. Sperber SJ, Hendley JO, Hayden FG, Riker DK, Sorrentino JV, Gwaltney JM, Jr. Effects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial. Ann Intern Med 1992;117:37-41.
36. Douglas RM, Chalker EB, Treacy B. Vitamin C for preventing and treating the common cold. Cochrane Database Syst Rev 2000;2.-
37. Marshall I. Zinc for the common cold. Cochrane Database Syst Rev 2000;2.-
38. Prasad AS, Fitzgerald JT, Bao B, Beck FW, Chandrasekar PH. Duration of symptoms and plasma cytokine levels in patients with the common cold treated with zinc acetate. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2000;133:245-52.
39. Melchart D, Linde K, Fischer P, Kaesmayr J. Echinacea for preventing and treating the common cold. Cochrane Database Syst Rev 2000;2.-
40. Puhakka T, Makela MJ, Malmstrom K, et al. The common cold: effects of intranasal fluticasone propionate treatment. J Allergy Clin Immunol 1998;101:726-31.
41. Williams JW, Jr, Aguilar C, Makela M, et al. Antibiotics for acute maxillary sinusitis. Cochrane Database Syst Rev 2000;CD000243.-
42. Lindbaek M, Hjortdahl P, Johnsen UL. Randomised, double blind, placebo controlled trial of penicillin V and amoxycillin in treatment of acute sinus infections in adults. BMJ 1996;313:325-9.
43. Hansen JG, Schmidt H, Grinsted P. Randomised, double blind, placebo controlled trial of penicillin V in the treatment of acute maxillary sinusitis in adults in general practice. Scand J Prim Health Care 2000;18:44-7.
44. Garbutt JMMF, Goldstein MDDS, Gellman EMD, Shannon WP, Littenberg BMD. A randomized, placebo-controlled trial of antimicrobial treatment for children with clinically diagnosed acute sinusitis. Pediatrics April 2001;107:619-625.
45. Altman KW, Austin MB, Tom LW, Knox GW. Complications of frontal sinusitis in adolescents: case presentations and treatment options. Int J Pediatr Otorhinolaryngol 1997;41:9-20.
46. Giannoni CM, Stewart MG, Alford EL. Intracranial complications of sinusitis. Laryngoscope 1997;107:863-7.
47. Hayden FG, Diamond L, Wood PB, Korts DC, Wecker MT. Effectiveness and safety of intranasal ipratropium bromide in common colds. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 1996;125:89-97.
48. Gwaltney JM, Druce HM. Efficacy of brompheniramine maleate for the treatment of rhinovirus colds. Clin Infect Dis 1997;25:1188-94.
49. Clemens CJ, Taylor JA, Almquist JR, Quinn HC, Mehta A, Naylor GS. Is an antihistamine-decongestant combination effective in temporarily relieving symptoms of the common cold in preschool children? J Pediatr 1997;130:463-6.
50. Taverner D, Bickford L, Draper M. Nasal decongestants for the common cold. Cochrane Database Syst Rev 2000;2.-
51. Singh M. Heated, humidified air for the common cold. Cochrane Database Syst Rev;2000;CD001728.-
52. Del Mar CB, Glasziou PP, Spinks AB. Antibiotics for sore throat. Cochrane Database Syst Rev;2000;CD000023.-
53. Olivier C. Rheumatic fever—is it still a problem? J Antimicrob Chemother 2000;45 Suppl:13-21.
54. Howie JG, Foggo BA. Antibiotics, sore throats and rheumatic fever. J R Coll Gen Pract 1985;35:223-4.
55. Del Mar C, Glasziou P, Hayem M. Are antibiotics indicated as initial treatment for children with acute otitis media? A meta-analysis. BMJ 1997;314:1526-9.
56. Schachtel BP, Fillingim JM, Thoden WR, Lane AC, Baybutt RI. Sore throat pain in the evaluation of mild analgesics. Clin Pharmacol Ther 1988;44:704-11.
57. Schachtel BP, Fillingim JM, Lane AC, Thoden WR, Baybutt RI. Caffeine as an analgesic adjuvant. A double-blind study comparing aspirin with caffeine to aspirin and placebo in patients with sore throat. Arch Intern Med 1991;151:733-7.
58. Wethington JF. Double-blind study of benzydamine hydrochloride, a new treatment for sore throat. Clinical Therapeutics 1985;7:641-6.
59. Watson N, Nimmo WS, Christian J, Charlesworth A, Speight J, Miller K. Relief of sore throat with the anti-inflammatory throat lozenge flurbiprofen 8.75 mg: a randomised, double-blind, placebo-controlled study of efficacy and safety. Int J Clin Pract 2000;54:490-6.
60. Schachtel BP, Thoden WR. A placebo-controlled model for assaying systemic analgesics in children. Pract Clin Pharmacol Ther 1993;53:593-601.
61. Kagan G, Huddlestone L, Wolstencroft P. Two lozenges containing benzocaine assessed in the relief of sore throat. J Int Med Res 1982;10:443-6.
62. Gonzales R, Bartlett JG, Besser RE, et al. Principles of appropriate antibiotic use for treatment of uncomplicated acute bronchitis: background. Ann Intern Med 2001;134:521-9.
63. Eccles R, Morris S, Jawad M. Lack of effect of codeine in the treatment of cough associated with acute upper respiratory tract infection. J Clin Pharm Ther 1992;17:175-80.
64. Croughan-Minihane MS, Petitti DB, Rodnick JE, Eliaser G. Clinical trial examining effectiveness of three cough syrups. J Am Board Fam Pract 1993;6:109-15.
65. Chang AB, Phelan PD, Carlin JB, Sawyer SM, Robertson CF. A randomised, placebo controlled trial of inhaled salbutamol and beclomethasone for recurrent cough. Arch Dis Child 1998;79:6-11.
66. Hueston WJ. A comparison of albuterol and erythromycin for the treatment of acute bronchitis. J Fam Pract 1991;33:476-80.
67. Hueston WJ. Albuterol delivered by metered-dose inhaler to treat acute bronchitis. J Fam Pract 1994;39:437-40.
68. Smucny J, Flynn C, Becker L, Glazier R. Beta2-agonists for acute bronchitis [Systematic Review]. Cochrane Database of Systematic Reviews 2001;1.-
69. Gwaltney JM, Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. N Engl J Med 1994;330:25-30.
70. Holmes WF, Macfarlane JT, Macfarlane RM, Hubbard R. Symptoms, signs, and prescribing for acute lower respiratory tract illness. Br J Gen Pract 2001;51:177-81.
71. Gulbrandsen P, Fugelli P, Kvarstein G, Moland L. The duration of acute respiratory tract infections in children. Scand J Prim Health Care 1989;7:219-23.
72. Gonzales R, Bartlett JG, Besser RE, Hickner JM, Hoffman JR, Sande MA. Principles of appropriate antibiotic use for treatment of nonspecific upper respiratory tract infections in adults: background. Ann Intern Med 2001;134:490-4.
73. Gadomski AM. Potential interventions for preventing pneumonia among young children: lack of effect of antibiotic treatment for upper respiratory infections. Pediatr Infect Dis J 1993;12:115-20.
74. Heikkinen T, Ruuskanen O, Ziegler T, Waris M, Puhakka H. Short-term use of amoxicillin-clavulanate during upper respiratory tract infection for prevention of acute otitis media. J Pediatr 1995;126:313-6.