An immunological approach to chronic and recurrent sinusitis

Copyrigh An immunological approach to chronic and recurrent sinusitis Marshall T. Wise and David D. Hagaman Purpose of review Sinusi primar however, can care a the ap broad focusi clinica Recen Immun chroni worku undert been u visuali compl obviat Summ Elucid diseas evalua evalua sinus i to red surgic Keyw chroni Curr Opin O Wilkins. Vanderbilt Correspond Nashville, T E-mail: dav Current O 15:10–17 Abbreviat AFS a CHES c CRS c CT c CVID c � 2007 Li 1068-9508 Introd siti U illi nc ]. C m mo iple ify ary ug ove o i hs s [ f s ired fla s u m in- fo rea sib on sa c v ro ion rta an no re itis us CT dv inu in . I n on scopy looking for purulence or polyps is an alternative 10 diagnostic tool. Endoscopy offers the advantage of obtain- ing a culture. Contamination of the sample is a possibility, lly important aspect of the sinusitis workup. t findings e deficiency is prevalent in patients with recurrent or c sinus disease. An immunologic workup, as well as a p for other chronic treatable diseases, should be aken before sinus surgery or in patients who have nresponsive to surgery. This approach can enhance zation during surgery, minimize postoperative ications, improve surgical outcomes, and possibly e the need for surgery altogether. ary ating the cause of recurrent or refractory sinus e can be challenging. Allergic disease should be ted and treated early in the process. An immunologic tion should be performed and uncommon causes of nflammation should be addressed later in the course uce inflammation either to avoid surgery or improve al outcomes. ords c rhinosinusitis, chronic sinusitis, immune deficiency tolaryngol Head Neck Surg 15:10–17. � 2007 Lippincott Williams & University Medical Center, Nashville, Tennessee, USA ence to David D. Hagaman, MD, 2611 West End Ave, Suite 265, N 37203, USA id.hagaman@vanderbilt.edu pinion in Otolaryngology & Head and Neck Surgery 2007, ions llergic fungal sinusitis hronic hyperplastic eosinophilic sinusitis hronic rhinosinusitis omputed tomography ommon variable immunodeficiency ppincott Williams & Wilkins mult ident In L altho impr had n mont other up) o requ the in state outco The is the and t rever venti muco tomi and p funct impo toms Diag Figu sinus of sin phy ( the a the s level acute matio a chr Endo ng on im t © L mune deficiency, an often overlooked but lasts overview of the workup of chronic rhinosinusitis, inflam proach to recurrent or chronic sinusitis. We give a [2–5 nd subsp be frustrating for patients as well as primary ecialty providers. The present review details 22 m evide tis is an illness that is often successfully treated by y care physicians. Recurrent or chronic rhinosinusitis, Sinu in the ippincott Williams & Wilkins. Unauthorized uction s is one of the most common healthcare problems SA, leading to a $5.8 billion expenditure with 18– on physician office visits annually [1,2]. There is e that it is increasing in prevalence and incidence hronic rhinosinusitis (CRS) is characterized by ation of the mucosal lining of the sinuses that re than 12 weeks [6�]. CRS is a disorder that has phenotypes. The immunologic workup helps these phenotypes and guides treatment. ngoscope in 1992, Kennedy [7] reported that h more than 95% of patients had subjective ment of symptoms after sinus surgery, only 45% nflammation in their sinuses endoscopically at 18 postoperatively. In 1998, Senior, Kennedy, and 8] looked at the long-term results (8-year follow- inus surgery. Although most did well, almost 20% subsequent surgical procedures. By addressing mmatory reaction of CRS we will identify disease nresponsive to surgery as well as improve surgical es by decreasing inflammation. depth evaluation of chronic or recurrent sinusitis cus of this paper. Following standard evaluation tment for sinusitis, we propose an evaluation for le causes of inflammation not addressed by con- al initial treatment. Decreasing inflammation and l edema before surgery may facilitate better ana- isualization, minimize postoperative infection, mote faster postoperative recovery of mucociliary [9]. In addition, addressing inflammation is nt in postoperative CRS patients whose symp- d infections have returned. sis 1 outlines the initial evaluation and treatment of . Prior to an immunologic workup, the diagnosis itis should be confirmed by computed tomogra- ) scan or nasal endoscopy [6�,10]. CT scans have antage of providing insight into the chronicity of sitis. If inflammation is present as an air–fluid a limited number of sinuses, the process is likely f there is a rounded appearance to the inflam- and involvement of multiple sinuses, this implies ic process. reproduction of this article is prohibited. Copyrig howeve using an nation, c wall or v the mid Treatm Little i bacteria it is sta antibiot uncerta common acute si sitis are and Mo Amoxic ability a Chronic and recurrent sinusitis Wise and Hagaman 11 Figure 1 Initial evaluation and treatment AH, antihistamine; CT, computed tomography; IT, immunoth (irritant) rh end ati tis a atio Tre entu rea Ant erapy; NS, nasal steroid; VMR, vasomotor initis. CT vs. confirm sinusi examin – 1. ev 2. T 3. Consider CT for confirmation if endoscopy negative ht © Lippincott Williams & Wilkins. Unauthorized r, especially without sampling frank purulence appropriate technique. To minimize contami- are must be taken to avoid contact with the nasal estibule and the culture should be obtained from dle meatus or the sphenoethmoid recess [11]. ent s known about the sinus mucosal response to l infection. It has been recommended [9], and ndard practice, to treat patients with CRS with ics [12,13]. The role of bacteria is especially in in cases involving nasal polyps [14]. The most bacteria observed in acute sinusitis, recurrent nusitis, and acute exacerbations of chronic sinu- Streptococcus pneumoniae, Haemophilus influenzae raxella catarrhalis [15,16]. illin is a good first-line antibiotic because of toler- nd expense. A drawback, however, is its lack of effectiv Alternat methop these a spectrum a macro until the Systemi of sinus conjunc on the lo corticos better o Initial Once si common inflamm +/– 5–1 4. +/– oral de N S Response Suspected sinusitis oscopy for on of nd n for polyps Allergy skin testing + at allergic disease (AH + NS, ally IT if necessary) t polyps (NS +/– steroids +/– antibiotics) ibiotics (+/– culture guided) x 14 days Treat allergic disease with AH + NS + Treat VMR with NS + nasal AH – reproduction of this article is prohibited. eness against b-lactamase producing organisms. ive first-line agents include cephalosporins or tri- rim–sulfamethoxazole. Patients unresponsive to gents after 3–5 days should switch to a broad antibiotic, including amoxicillin–clauvulanate, lide, or a quinolone [17]. CRS should be treated patient is well for 7 days before stopping therapy. c steroids have not been studied in the treatment itis, but many physicians use systemic steroids in tion with antibiotics. This use of steroids is based gical assumption that treating inflammation (with teroids) and infection (with antibiotics) results in utcomes in difficult-to-treat sinus disease. workup nusitis is confirmed, an initial workup for the most causes of nasal inflammation is in order. Nasal ation is thought to occlude the sinus ostia and 4 days of systemic corticosteroid Saline lavage, topical decongestants, congestants o response: ee Fig. 2 Partial response: Continue antibiotics for 10–14 more days OR change to broad-spectrum antibiotic +/– addition of anaerobic coverage Copyrigh lead to sinusitis. Given the prevalence of allergic rhinitis, allergy skin testing is an essential part of the initial evaluati of allerg is a hi with in patients immuno cation re tive trea be eval step in If allerg rhinitis many as tioned fumes, steroids CRS can inflamm endosco steroids to decre with CR least 6 Systemi polyp si made if [11]. N sinusitis have be isting al Saline l secretio and phe ostia, bu of the ri like ph drainage On reas to treat continu broad-sp anaerob is a rea treatme Recurre per yea those w may be of their fungal sinusitis, sarcoidosis, aspirin sensitivity, hyperplas- tic eosinophilic sinusitis and cystic fibrosis (Fig. 2). un up te m su un un ic m sin sco ed re of rat y. ora de , (i re s t ure ora has on tai re ism nts p rm tot CV s b ev 3– y p efi rs ien /l, th lin efi an uno uno ha tiv de 12 Nose and paranasal sinuses on of sinusitis. There is an increased association ic rhinitis in patients with CRS [18,19]. There gher incidence of sinus disease in patients halant sensitivity [20–22]. Antihistamine use in with sinusitis improves symptoms [23], and therapy improves surgical outcomes [24]. Edu- garding allergen avoidance is appropriate adjunc- tment. The presence of inhalant allergies must uated and allergies must be treated as an initial sinusitis management. y skin testing is negative, vasomotor (irritant) should be considered. Irritant rhinitis affects as 17 million Americans. Patients should be ques- about worsening symptoms around smoke, per- exhaust fumes, etc. Treatment consists of nasal and/or nasal antihistamines [25]. often be managed with adequate control of nasal ation. Nasal polyps, often found on CT or with py, are a sign of advanced inflammation. Nasal are first-line treatment, as they have been shown ase polyp size and improve symptoms in patients S [26,27]. Nasal steroids should be used for at months, and continued as long as necessary. c corticosteroids are also effective in reducing ze [28]. Consideration of antibiotic therapy can be there is compelling evidence of sinus infection asal steroids remain the first-line treatment for , even without the presence of polyps [11], and en shown to be particularly effective with coex- lergy [29,30]. avage may help facilitate drainage by removing ns. Topical decongestants such as oxymetazoline nylephrine may enhance drainage from the sinus t should not be used for more than 5 days because sk of rhinitis medicamentosa. Oral decongestants enylephrine may decrease edema and improve . sessment, if the patient has had a partial response ment, the current antibiotic treatment may be ed for 10–14 additional days. Alternatively, ectrum antibiotic treatment, with or without ic coverage with metronidazole or clindamycin, sonable option. Patients unresponsive to these nts need further workup. nt sinusitis is defined as three or more infections r. Patients with recurrent sinusitis, especially ith symptoms that are difficult to eradicate, nefit from further investigation into the etiology disease. The next phase includes investigation for Imm work obvia outco after Imm Imm chron an im had a endo show they part Labo cienc hum inclu IgM) body IgG i meas hum and comm enter the p be d patie It is abno with with ation IgG l only Man IgA d occu defic 0.07 g older globu IgA d have imm imm they selec class t © Lippincott Williams & Wilkins. Unauthorized ologic evaluation is also a crucial part of this (Fig. 3). Consideration of these factors may the need for surgery or may improve surgical es by decreasing inflammation before and rgery. ologic evaluation e deficiency is an underdiagnosed cause of sinusitis. In 2001, Chee et al. [31] performed unologic workup of 79 patients who had either us surgery or three sinus infections diagnosed by py or CT scan in the past year. Their results a high incidence of immune dysfunction, and commended immunologic testing as an integral the workup for refractory sinusitis. ory studies are crucial in defining immunodefi- Laboratory evaluation includes studies of l and cellular immunity. Appropriate studies (i) quantitative immunoglobulins (IgG, IgA, i) quantifying IgG subclasses, (iii) specific anti- sponses to vaccines, and (iv) HIV testing. he most abundant immunoglobulin in serum, and ment of IgG is central to an evaluation of l immunity. If the patient is older than 2 years, low immunoglobulin levels, the diagnosis of variable immunodeficiency (CVID) should be ned. A low normal IgG level, especially in sence of chronic bacterial infection, should not issed [32–34]. In the presence of infection, should have IgG levels in the high-normal range. rudent to suspect an underlying immunologic ality when a patient with chronic infection presents al IgG levels in the low range for normal. Patients ID will often have IgG levels two standard devi- elow the mean [35,36]. Systemic steroids can affect els; one study showed a 22% decrease in IgG after 5 days of systemic steroids [37]. atients will also have low levels of IgA. Selective ciency is the most common immunodeficiency and in as many as 1/500 individuals. Selective IgA cy is defined as a serum IgA level of less than but with normal IgG and IgM levels in patients an 4 years in whom other causes of hypogamma- emia have been excluded [38�]. Many people with ciency are not predisposed to infection, but some increased infection risk [39], and may benefit from globulin therapy [40]. These patients will require globulin products containing low or minimal IgA if ve high levels of IgA antibodies. Individuals with e IgA deficiency should be screened for IgG sub- ficiency, as IgA deficiency in combination with IgG reproduction of this article is prohibited. Copyrig subclass results respirato There a portion currentl The mo subclass deficien has bee subclass Chronic and recurrent sinusitis Wise and Hagaman 13 Figure 2 Workup for persistent or recurrent sinusitis ACE, angiotensin converting enzyme; CHES, chronic hyperplas ork sin ype tic eosinophilic sinusitis. W Biopsy of mucosa Granulomas H ht © Lippincott Williams & Wilkins. Unauthorized deficiency has been reported, and apparently in more severe problems with upper and lower ry tract disease [41]. re four IgG subclasses. IgG1 comprises the largest of total IgG, thus IgG1 deficiency occurs con- y in patients with low total IgG, i.e. CVID [42]. st common subclass deficiency in children is IgG2 deficiency [43]. An association between IgG2 cy and clinical disease, including rhinosinusitis, n clearly established [43–47]. The most common deficiency in adults has been reported to be IgG3 subclass sinopulm difficult immuni nificanc [50]. Immun nosing protein be eval evaluate Consider diagnosis of sarcoidosis Con diag of C ACE level Normal Elevated: consider sarcoidosis Imm up for persistent or recurrent sinusitis us reosinophilia Laboratory evaluation reproduction of this article is prohibited. deficiency and has also been linked to recurrent onary infections [43,47–49]. IgG4 deficiency is to assay with accuracy, and its use in assessing ty is controversial [42]. In fact, the clinical sig- e of any abnormal IgG subclass levels is unclear e responses to vaccines are important when diag- immunodeficiency. The body’s response to vaccines, like tetanus and diphtheria, should uated. Polysaccharide antigen response can be d by vaccine response to H. influenzae type B and sider nosis HES Consider diagnosis of aspirin-sensitive rhinosinusitis Laboratory evaluation IgE levels, eosinophil count Elevated Consider allergic fungal sinusitis if allergic mucin present une system evaluation: See Fig. 3 Sweat chloride test Negative Positive Cystic fibrosis Normal Copyrigh pneumo antigen than 8 y respons most clo Docum essentia Testing immuno sitis in Specific mal in H 14 Nose and paranasal sinuses Figure 3 Immunologic workup of chronic rhinosinusitis CVID, common variable immunodeficiency; IVIG, intravenou log Im buli s immunoglobulin. Immuno Quantitative immunoglo t © Lippincott Williams & Wilkins. Unauthorized coccus. Antibody responses to pneumococcal s may be useful, but the response of children less ears old may not be complete [51]. Poor antibody es to pneumococcal serotypes 3 and 7 correlate sely with defects in humoral immunity [52–56]. enting poor responses to one or more vaccines is l to the diagnosis of CVID [38�]. for HIV is another crucial component of the logic workup of sinusitis. The incidence of sinu- HIV infection varies from 30% to 68% [57–60]. antibody responses to pneumococcus are abnor- IV. The microbiology of sinusitis in patients with HIV is s and chr patients but with Allerg Allergic alent to diagnos graphs a mucin i fungal Unilate Low levels of IgG or IgA < 0.07 g/l Consider treatment with IVIG if picture consistent with CVID or IgA deficiency Abnormal Ig d Consider treatme with IVIG ic workup of chronic rhinosinusitis mune system evaluation HIV testing ns Immune response to vaccines reproduction of this article is prohibited. imilar to that seen in other patients with recurrent onic sinusitis. The treatment of sinusitis in these is similar to that of immunocompetent patients a longer duration of therapy [61]. ic fungal sinusitis fungal sinusitis (AFS) is the upper airway equiv- allergic bronchopulmonary aspergillosis. The is depends on mucosal thickening on sinus radio- s well as the presence of ‘allergic mucin’. Allergic s a thick, gluey, brownish eosinophilic mucus with hyphae and Charcot-Leyden crystals [62–64]. ral sinus opacification on radiographs is common. Normal IgG subsets Normal Normal Abnormal Consider treatment with IVIG if picture consistent with CVID A eficiency nt Copyrig There is substantial evidence based on skin testing, in-vitro testing, and total serum IgE to support an allergic basis for In a cas all patie least on cultured is prese Studies IgE and late-pha eosinop clinician treatme allergic being a allergic Sarcoi Patients have in disease conside especial angioten used as specific ogy are often sh nose sim Aspirin In 1968 referred steroid- Aspirin- blood e nasal an kotriene increase include anti-infl steroids desensi Chron Chronic cause of nophils this diso with mu facial pa to decr includin improve 400 mg/ treatment is not without risk, and the risks and benefits of long-term macrolide treatment must be examined � . T top cs to py [73 ic ic siv cy . C uct r t ase nti cy fes nu per rem cal re se ha iot flue lde om m an clu siti ) co ate ev s o e co oid re of p ighl spe out nal Lite y N 96: lin Im nnin ute sea tion rvey r He Chronic and recurrent sinusitis Wise and Hagaman 15 the pathogenesis of allergic fungal sinusitis [65]. e–control series of 16 patients with definite AFS, nts had a positive radioallergosorbent test to at e fungal antigen in the family of organisms from their sinuses [65]. Peripheral eosinophilia nt in more than 60% of patients with AFS [63]. have shown that AFS is an antigen-triggered, IgG-mediated hypersensitivity response with a se inflammatory reaction involving release of hilic mediators [66]. Given this association, some s use serum eosinophilia to follow AFS during nt. Treatment involves surgical removal of the mucin and systemic corticosteroids [64], with IgE helpful guide to the steroid management, as in bronchopulmonary aspergillosis. d with sarcoidosis presenting with sinusitis often volvement in multiple organs, but isolated sinus is possible. Sarcoidosis of the sinuses should be red in the differential diagnosis of sinusitis, ly in association with nasal polyposis. Serum sin converting enzyme level activity has been a diagnostic indicator but has low sensitivity and ity [67]. Noncaseating granulomas on histopathol- necessary for diagnosis. Radiographic studies ow complete opacification of the sinuses and ilar to that seen in diffuse polyposis [68]. -sensitive rhinosinusitis , Samter and Beers [69] described what is often to as ‘Samter’s triad’ of aspirin sensitivity, dependent asthma, and nasal polyposis. sensitive rhinosinusitis is characterized by raised osinophil cou