Prokopakis, Emmanuel; Vlastos, Ioannis; Pant, Harshita; Ferguson, Berrylin J.
The paucity of high-quality evidence on management of chronic rhinosinusitis (CRS) contrasts with the widespread affliction of patients with symptoms of CRS. Proposed diagnostic processes and management vary significantly, from an observational period with simple nasal irrigations with normal saline to more extensive medical and surgical treatment options. We propose a practical algorithm of medical management for CRS drawn from published work on the issue.
Probably most controversial in the medical management of CRS is the use of antibiotics. Currently, there is no evidence from well conducted clinical trials for antibiotic efficacy in CRS, although antibiotics are regarded as useful for acute exacerbations based on expert opinion, not supported by level one evidence [1–4,5▪▪]. Consensus recommendations [4,5▪▪] in the past acknowledge evidence for use of low-dose macrolide antibiotics for 12 weeks, but further larger placebo-controlled studies failed to show efficacy [6▪]. Studies in a more defined population with different dosage regimen may yet show that macrolides are beneficial, but at this point in time, there is no evidence to advocate low-dose, long-term macrolide therapy in CRS. Possible reasons that antibiotic trials in CRS have failed to show efficacy, beyond the possibility that they are ineffective, include failure to restrict studies to patients with pathogenic bacteria on culture and the criteria utilized to diagnose CRS.
The incidence of CRS is overestimated when classified solely on symptomatic criteria [7▪▪]. This explains the relatively high incidence of CRS reported in various surveys [5▪▪,8]. For example, CRS, as a self-reported chronic condition in the United States, affects approximately 15.5% of the population . However, the prevalence of doctor-diagnosed CRS based on use of International Classification of Disease-9 codes is approximately 2% , which highlights the heterogeneity and diagnostic inconsistencies associated with the condition. In a recent prospective study [7▪▪], we found that a third of patients with CRS symptoms had no evidence of sinus disease by computed tomography (CT) scan or endoscopy. In the same study [7▪▪], we also found that approximately 25% of patients with objective CRS by CT had purulence present in the nose on endoscopic examination, and even more importantly, that all 50 patients, in this series of 125 patients, who had normal sinus CTs had no evidence of purulence in the nose.
In other words, when the diagnosis of CRS is based solely on symptoms (at least two of the following: nasal congestion, facial pain/pressure, anterior or posterior nasal drainage, and reduced or absent sense of smell of greater than 12 weeks of duration), the likelihood of appropriate antibiotic use in patients with sinus symptoms is decreased, in comparison to cases in which objective evidence of sinus disease by means of direct visualization or imaging studies is applied. An accurate diagnosis of CRS with positive endoscopic and/or radiologic studies and the use of culture-directed antibiotic therapy with nasopharyngeal swabs may aid the clinician in proper identification of antibiotic sensitivities and help in clarifying the true role of antibiotic therapy in CRS. To date, such studies have not been performed. Finally, regarding topical antimicrobials, a recent systematic review concluded that there is some evidence for the use of antibiotic nasal irrigations or nebulizations . In the 2012 European Position Paper on Rhinosinusitis and Nasal Polyps document review, topical antibiotic trials were effective in 40–70% of patients with CRS without nasal polyps; in noncomparative studies, however, in the three placebo-controlled trials, no difference in efficacy was apparent.
COMMONLY USED REGIMENS
Commonly used medical regimens include nasal saline irrigations and nasal corticosteroids; both regimens are recommended in each of the recent rhinosinusitis consensus documents [1,4–5▪▪]. They can improve allergic rhinitis symptoms, which often coexist or are misinterpreted for CRS and reduce nasal mucosa inflammation. This can apply for every coexisting condition that contributes to CRS; however, in patients with obstructing nasal polyps, topical therapy is usually ineffective, and a course of systemic corticosteroids may be necessary.
Despite the fact that there has not been definitive evidence to separate or absolutely link allergic rhinitis with CRS, the symptom management for both groups is certainly overlapping. Nasal steroid and antihistamine sprays, oral antihistamines, leukotriene-modifying agents, and decongestants are among the agents that can be used to provide symptom relief. Other considerations include recommendation of an elimination challenge diet if the patient has coinciding gastrointestinal symptoms that may indicate a nonimmunoglobulin E (IgE) mediated food allergy, such as bloating, abdominal cramping, and fatigue. This includes the elimination of wheat, dairy, corn, and soy in a stepwise fashion or any other food category commonly consumed in specific countries. The food is eliminated for 5–10 days and then the patient is asked to reintroduce the food into the diet with close monitoring of symptoms 15 min to 24 h after ingestion. Symptoms such as headache, fatigue, nasal congestion, bloating, muscle or joint aches/swelling may indicate a non-IgE-mediated food allergy. If a food is identified as causing symptoms, patients are advised to eliminate the food from the diet for 2–3 months, at which point in most patients it can be safely reintroduced on a restricted schedule in which it is not eaten more than once every 5 days. Most patients tolerate a reintroduced food at this level, once the desensitization period has been reached.
In general, although the pathophysiology of CRS is currently unknown, it is logical that targeted and symptom-specific therapy and avoidance can potentially improve conditions that mimic CRS or ameliorate potential drivers of inflammation. These conditions include allergy, asthma, immunodeficiency, environmental pollutants, cigarette smoke exposure, gastroesophageal reflux disease, and aspirin sensitivity.
Characteristically, patients with immunodeficiency improve while receiving antibiotics for sinus symptoms, with recurrent acute sinusitis in between courses of antibiotics. Up to 10% of patients with severe chronic upper airway disease or recalcitrant CRS have common variable immune deficiency (CVID) . This is the most common primary immune deficiency in adults. Testing may include a complete blood count, quantitative immunoglobulin levels and subclasses, T-cell subpopulations, and pneumococcal antibody titers before and after immunization. Acquired forms of immunodeficiency attributable to the HIV should also be tested for in case of suspicion. Patients diagnosed with CVID can be treated with replacement IgG. Because other diseases can develop in this population, they should be monitored after diagnosis by an immunologist [13▪].
Gastroesophageal reflux, specifically laryngopharyngeal reflux, has been proposed as a contributive factor to CRS. Although there are no controlled studies demonstrating improvement of CRS by means of antireflux therapy, lifestyle modification, and acid-suppressing medications such as H-2 blockers and/or proton pump inhibitors can be recommended to patients with postnasal drip as a dominant symptom of their CRS [13▪]. It has been shown that, in patients with symptoms of postnasal drainage but no CT evidence of sinusitis or allergies by testing, an 8-week trial of a proton pump inhibitor significantly improved postnasal drainage symptoms .
Another disease process that can be overlooked, if not routinely evaluated for, is periapical dental infection. Often the common plain film imaging used in the dental field to diagnose and treat caries can miss periapical tooth root disease that can contribute to sinusitis . Careful evaluation of a sinus CT, especially in coronal orientation, may show halo-type lucency around a tooth root, adjacent to the maxillary sinus floor indicating a periapical abscess warranting dental treatment or extraction of the involved tooth (Fig. 1). Finally, various adjunctive therapies have been proposed with some of them referring back to empirical and anecdotal evidence of ancient times . Although there is little evidence supporting use of phytomedical preparations, mucolytics agents such as S-carboxymethylcysteine  or expectorants such as Guaifenesin are in common use among some patients and clinicians.
THE RATIONAL PATIENT EXPERIMENT AND BEYOND
A stepwise approach to the medical management of patients with allergic rhinitis and chronic sinusitis, called the ‘Rational Patient Experiment’ (Table 1), has been described in detail elsewhere [13▪,18]. As it is often difficult to differentiate allergic rhinitis from sinusitis because of overlapping symptomatology, we advocate the assessment for allergy by either history or testing in all CRS patients. Patients responding to initial therapy may also benefit from allergy testing and identification of allergens for targeted environmental controls and/or immunotherapy. Immunotherapy is appropriate for those allergic patients with inadequate relief with environmental controls in conjunction with medical therapy or for patients with symptoms for at least 6 months of the year.
The ‘Rational Patient Experiment’ is an algorithm that includes progressive addition or replacement of medications individualized to the patient's symptoms. Prior medications that have failed to bring relief despite appropriate use are eliminated from the patient's regimen. Patients are instructed to initiate one medication or intervention at a time so that efficacy can be determined independently. If complete relief is attained, the patient is instructed to continue that medication, and no further medications are added. If the medication provides no relief, then it is discontinued, and the next medication is started in the order prescribed. If a partial response is attained, then the patient continues that medication and adds the next. After symptoms are controlled with a given regimen, patients are instructed to deescalate therapy in a similar manner, again with removing one intervention at a time, and to reinitiate therapy if symptoms return.
Although the ‘Rational Patient Experiment’ requires more extensive education at the first office consultation, this approach may prevent two or three subsequent office visits, as the patient is educated to try additional interventions. Written educational material and an outline that can be personalized for the patient facilitates understanding and compliance. It is very important also to explain the order, length, and potential side effects of each intervention necessary to assess efficacy.
As already mentioned, in addition to the medications approved for the treatment of allergic rhinitis, we include medications in our treatment algorithm that either treat conditions that can cause symptoms often misdiagnosed as resulting from allergic rhinitis or CRS or are regarded as beneficial in specific cases. Specifically, in patients with CRS with nasal polyps, unless contraindicated, systemic glucocorticosteroid is always considered. If endoscopy is positive for pus, culture-directed prescription of antibiotics is recommended and possibly immune deficiency workup (Fig. 2).
Finally, several other regimens are under development of testing. For instance, anti-IgE therapy (omalizumab)  and anti-IL-5 therapy (mepolizumab) [20▪] show promise in treating patients with refractory inflammatory disease. In the future, we expect that specific therapy to correct dysregulated pathways in the innate and adaptive immune systems, which underlie much of chronic upper and lower airway disease, will be developed for patients with uncontrolled inflammation seen in allergic rhinitis, asthma, and CRS [13▪]. For example, signaling pathways of vitamin D are currently under investigation. Vitamin D, the so called ‘sunshine hormone’, exerts profound effects on both adaptive and innate immune functions , including increasing phagocytic, proliferative, and chemotactic ability of monocytes, and decreasing the expression of several surface antigens, and affecting Toll-like receptor signal transduction. Recent studies  confirm previous observations that westernization has probably increased allergic diseases. This may have an effect on prevalence of CRS, as a recent Global Allergy and Asthma European Network survey showed that 56.7% of those reporting symptoms that fulfilled the European Position Paper on Rhinosinusitis and Nasal Polyps Group criteria for CRS also reported symptoms of allergy [23▪▪]. Currently, several basic research groups are focusing on specific molecular pathways involving the immune system, and more sophisticated and targeted regimens are expected to be discovered.
We recommend that treatment for patients with CRS symptoms be initiated using the Rational Patient Experiment, starting with the well tolerated regimens of saline nasal irrigations and intranasal corticosteroid sprays. In the general practice setting, patients who remain symptomatic can then be referred on to an otolaryngologist wherein nasal endoscopy findings would guide further management. If purulence or nasal polyps are found upon nasal endoscopy, then culture-directed antibiotics or glucocorticosteroids, respectively, can be introduced prior to ordering a sinus CT scan. A sinus CT scan is warranted to assess for sinus mucosal disease, periapical dental infection, possible allergic fungal sinusitis or fungus ball, or other locoregional disorders requiring further pathologic evaluation. This stepwise approach of the Rational Patient Experiment should be clearly explained to the patient to allow best personalized therapeutic care of the patient.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 120).
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This study shows that the incidence of CRS based solely on symptoms is overestimated, and this may explain at least in part the ineffectiveness of antibiotics in some cases. Forty percent of patients with CRS symptoms have no evidence of sinus disease on CT or endoscopy and were more likely to have facial pain and headache than patients with sinus disease on CT.
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This study examined the effect of mepolizumab in patients with recalcitrant CRS with polyposis and provides evidence for use of this novel therapy to reduce inflammation in these patients.
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This study surveyed 52 000 adults and examines the relationship between CRS, asthma, and allergic rhinitis.
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