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5.3.5.8.1. Rationale

Until recently most blood tests in patients with CRS are to diagnose immunodeficiences and vasculitic disease with sinona-Figure 5.3.34. Delphi: Is it essential to do histopathologybiopsy at initial

presentation in secondary care with highly suggestive symptoms of CRS and abnormal endoscopy ?

Figure 5.3.35. Delphi: Is it essential to do histopathologybiopsy at initial presentation in secondary care in patients with highly suggestive symptoms of CRS but normal endoscopy ?

Figure 5.3.36. Delphi: Is it essential to do histopathologybiopsy in CRS after failure of appropriate medical or surgical treatment in ENTsecondary care with continued symptoms and abnormal mucosa on endoscopy ?

sal manifestations. However, recently the options to treat with biologicals has put more emphasis on markers of type 2 disease although until today we are not aware of biomarkers that can predict response to biologicals in CRS⁽⁷²¹⁾.

Immunodeficiencies can be the cause or a contributing factor in CRS (see 5.1.2.4. Immune deficiencies and 9.2 Immunodeficien-cies and their role in CRS). The testing of immune function in all patients who present with CRS is almost certainly unwarranted as it is likely to produce more false positive results than true positives. However, it is recommended that the clinical features listed below are used to identify those patients who warrant some form of immune testing for testing.

The most common immunoglobulin deficiency in the general population is IgA deficiency with a prevalence between 1:173 and 1:3024⁽⁷²²⁾. Most patients are asymptomatic, but a deficiency of IgA would appear to predispose patients to rhinosinusitis and allergies⁽⁷²³⁾.

CRS secondary to hypogammaglobulinaemia may present to a rhinologist in a manner identical to idiopathic CRS. There are some clinical features that may elevate suspicion: association with lower respiratory tract infections (pneumonia, particularly if recurrent, or bronchiectasis) and recalcitrance to standard treatments (and particularly rapid recurrence of symptoms after stopping antibiotics).

5.3.5.8.2. Tests

5.3.5.8.2.1. Markers of type 2 disease

The main biomarkers used at the moment to define type 2 disease are eosinophils, IgE levels, and in some more specialized centres periostin. Other biomarkers are currently under investi-gation and may provider further guidance in the future.

There is quite some evidence showing that eosinophils are a reasonable surrogate marker for type 2 disease, and that blood eosinophils are a reasonable biomarker to predict eosinophilic CRS with or without nasal polyps(695, 724, 725). Blood eosinophil counts were found to be significantly correlated with the Lund–

Mackay CT and Lund–Kennedy endoscopic scores in patients with nasal polyps (r=0.353, p=0.010 and r=0.444, p=0.001, respectively)(724).

Receiver operating characteristic curve analysis predicted high tissue eosinophilia at blood eosinophil levels above 0.24109/L [sensitivity 70.9%, specificity 78.4%, area under the curve (AUC):

0.792, p<0.01]. eCRS was predicted at eosinophil above 4.27%

of total WCC (sensitivity 64.1%, specificity 88.5%, AUC 0.797;

p<0.01; positive predictive value 89.2%, negative predictive value 62.4%, positive likelihood ratio 5.57, and diagnostic odds ratio 13.71)⁽⁶⁹⁵⁾. A cut-off point of blood eosinophils >0.24 109/L or eosinophil ratio >4.27% of total WCC was proposed by Ho et al.⁽⁶⁹⁵⁾.

The EPOS2020 steering group were unclear as to whether it was

Figure 5.3.37. Delphi: Is it essential to do cytology brushings or lavage at initial presentation in secondary care with highly suggestive symptoms of CRS and abnormal endoscopy ?

Figure 5.3.38. Delphi: Is it essential to do cytology brushings or lavage at initial presentation in secondary care in patients with highly suggestive symptoms of CRS but normal endoscopy ?

Figure 5.3.39. Delphi: Is it essential to do cytology brushings or lav-age in CRS after failure of appropriate medical or surgical treatment in ENTsecondary care with continued symptoms and abnormal mucosa ?

essential to evaluate blood eosinophilia either at initial presen-tation to ENT / secondary care with highly suggestive symptoms of CRS irrespective of whether the mucosa was abnormal or normal on endoscopy or after failure of appropriate medical or surgical treatment in ENT / secondary care with continued symptoms and abnormal mucosa on endoscopy (Figure 5.3.40., 5.3.41., 5.3.42.).

Anti-IgE treatment has been shown to be effective in the treat-ment of CRSwNP (see 6.1.14). There is an association between increased levels of total IgE, specific IgE, and eosinophilic inflammation in NPs, which may be of relevance in the pathop-hysiology of nasal polyposis⁽⁷²⁶⁾. Increased serum IgE has been described in a subset of patients with N-ERD(727). A serum IgE cut of value of 96 kU/L was shown to be a bad predictor of CRSwNP (44% in CRSwNP group versus 28% in CRSsNP and 30%

in controls)⁽⁷²⁸⁾.

The EPOS2020 steering group were unclear as to whether it was essential to measure total IgE either at initial presentation to ENT / secondary care with highly suggestive symptoms of CRS irrespective of whether the mucosa was abnormal or normal on endoscopy or after failure of appropriate medical or surgical tre-atment in ENT / secondary care with continued symptoms and abnormal mucosa on endoscopy (Figure 5.3.43., 5.3.44., 5.3.45.).

Periostin is both an extracellular matrix protein and matricel-lular protein that is capable of activating cells by linking integrin molecules to cell receptors, promoting tissue remodeling. It may be an important biomarker for type 2 immunity and airway aller-gic inflammation exacerbations⁽⁷²⁹⁾. It has been established that periostin is a downstream molecule of interleukin (IL)-13, and that asthmatic patients with high serum periostin react more favourable to anti-IL-13 antibodies (lebrikizumab) and anti-IgE antibodies (omalizumab)⁽⁷³⁰⁾. Methylprednisolone and omali-zumab significantly reduced serum periostin levels in CRSwNP patients⁽⁷³¹⁾.

Serum periostin was found to be the sole biomarker among those tested for detecting the presence of nasal polyps and it significantly correlated with Lund-Mackay score in patients with chronic rhinosinusitis and asthma⁽⁷³²⁾. Mean serum periostin levels were markedly elevated in patients with CRS versus con-trols. In addition, mean periostin levels were significantly higher in CRS patients with nasal polyps as compared with those wit-hout polyps^{(728, 733)}. In the study of Maxfield et al. periostin levels did not correlate with sex, smoking history, N-ERD, oral steroid use within 1 month of surgery, use of topical steroid nasal spray or number of prior sinus operations⁽⁷³³⁾.

5.3.5.8.2.2. Immunoglobulin

It is not clear how much of the immunological testing should be undertaken by the rhinologist before referral to an immuno-logist, and this decision may reflect the individual knowledge and expertise of the rhinologist. For CRS patients suspected

Figure 5.3.40. Delphi: Is it essential to evaluate blood eosinophilia at initial presentation to ENT/secondary care with highly suggestive symptoms of CRS and abnormal mucosa on endoscopy ?

Figure 5.3.41. Delphi: Is it essential to evaluate blood eosinophilia at initial presentation to ENT/secondary care in patients with highly suggestive symptoms of CRS but normal endoscopy ?

Figure 5.3.42. Delphi: Is it essential to evaluate blood eosinophilia in CRS after failure of appropriate medical or surgical treatment in ENT/secondary care with continued symptoms and abnormal mucosa on endoscopy?

of having humoral immunodeficiency because of the charac-teristics of their presentation or their response to treatment, measurement of serum immunoglobulin levels (IgA and IgG) is the key investigation. The best approach for confirming a di-agnosis of an antibody-deficiency disorder is the measurement of serum-specific antibody titers (usually IgG) in response to vaccine antigens. This approach involves immunizing a patient with protein antigens (e.g., tetanus toxoid) and polysaccharide antigens (e.g., pneumococcus) and assessing pre- and post-immunization antibody levels⁽⁷³⁴⁾. If the levels are normal, but the suspicion of humoral immunodeficiency is high, referral to a clinical immunologist is optimal. Further studies, such as flow cytometry can then be organized by an expert in the interpreta-tion of these tests.

The EPOS2020 steering group did not consider it essential to do an objective test of immunodeficiency at initial presentation to ENT/ secondary care with highly suggestive symptoms of CRS irrespective of whether the mucosa was abnormal or normal on endoscopy.

Their responses were unclear regarding whether this was es-sential after failure of appropriate medical or surgical treatment in ENT/secondary care with continued symptoms and abnormal mucosa on endoscopy (Figure 5.3.46., 5.3.47., 5.3.48.).

5.3.5.8.2.3. Testing for vasculitis

Vasculitic diseases with sinonasal manifestations usually but not always involve multiple organs. Rhinitis, sinusitis, septal perfora-tion and epistaxis are the most common nasal features related to these diseases. There are two relatively common vasculitides in the sinunasal tract:

Granulomatosis with polyangiitis (GPA, formerly Wegener’s granulomatosis) and Eosinophilic granulomatosis with polyan-giitis (EGPA, formerly Churg–Strauss syndrome). Patients with granulomatosis with polyangiitis (GPA) affecting the sinonasal cavity usually have persistent bleeding, crusting and obstruc-tion, and may develop a septal perforation. Sometimes the manifestations of this vasculitic condition are limited to the sinonasal cavity. GPA is strongly associated with anti-neutrophil cytoplasmic antibodies (ANCA), and the more widespread and severe the presentation, the more likely the serum ANCA is to be positive⁽⁷³⁵⁾. In cases limited to the sinonasal tract the ANCA can be negative, making the diagnosis challenging. The combina-tion of clinical features, positive ANCA serology, necrotizing vasculitis and granulomatous inflammation on biopsy esta-blish the diagnosis⁽⁷³⁶⁾. However, nasal biopsies often do not have enough features specific to this condition to confirm the diagnosis, and so biopsies from other involved organs may be required. Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg–Strauss syndrome) is a necrotizing vasculitis of small and medium-sized vessels. Among a wide spectrum of non-pulmonary symptoms, nasal and sinonasal features are

Figure 5.3.43. Delphi: Is it essential to measure total IgE at initial presenta-tion to ENT/secondary care with highly suggestive symptoms of CRS and abnormal mucosa on endoscopy ?

Figure 5.3.44. Delphi: Is it essential to measure total IgE at initial presenta-tion to ENT/secondary care in patients with highly suggestive symptoms of CRS but normal endoscopy ?

Figure 5.3.45. Delphi: Is it essential to measure total IgE in CRS after failure of appropriate medical or surgical treatment in ENTsecondary care with continued symptoms and abnormal mucosa on endoscopy ?

common and part of the diagnostic criteria for EGPA⁽⁷³⁷⁾. This condition typically develops in patients with adult onset asthma and the sinonasal manifestation is chronic rhinosinusitis with eosinophilic nasal polyps. Many of these patients also have mid-dle ear disease⁽⁷³⁸⁾.

Anti-neutrophil cytoplasmic antibodies (ANCAs) are a group of autoantibodies, mainly of the IgG type, against antigens in the cytoplasm of neutrophil granulocytes and monocytes. They are detected as a blood test in a number of autoimmune disorders, but are particularly associated with systemic vasculitis, so called ANCA-associated vasculitides. ANCAs are associated with small vessel vasculitides including granulomatosis with polyangiitis, microscopic polyangiitis, primary pauci-immune necrotizing crescentic glomerulonephritis (a type of renal-limited microsco-pic polyangiitis), eosinophilic granulomatosis with polyangiitis and drug induced vasculitides. PR3 directed c-ANCA is present in 80-90% of granulomatosis with polyangiitis, 20-40% of microscopic polyangiitis, 20-40% of pauci-immune crescentic glomerulonephritis and 35% of eosinophilic granulomatosis with polyangiitis. c-ANCA (atypical) is present in 80% of cystic fibrosis (with BPI as the target antigen) and also in inflammatory bowel disease, primary sclerosing cholangitis and rheumatoid arthritis (with antibodies to multiple antigenic targets). p-ANCA with MPO specificity is found 35% of eosinophilic granulomato-sis with polyangiitis. p-ANCA with specificity to other antigens are associated with inflammatory bowel disease, rheumatoid arthritis, drug-induced vasculitis, autoimmune liver disease, drug induced syndromes and parasitic infections.

Cocaine and levamisole, which is a common adulterant of co-caine, can cause an ANCA positive vasculitis^(739-741).

The EPOS2020 steering group did not consider it essential to do an objective test for vasculitis at initial presentation to ENT/ secondary care with highly suggestive symptoms of CRS irrespective of whether the mucosa was abnormal or normal on endoscopy but their responses were unclear regarding whether this was essential after failure of appropriate medical or surgical treatment in ENT/secondary care with continued symptoms and abnormal mucosa on endoscopy (Figure 5.3.49., 5.3.50., 5.3.51.).

5.3.5.8.2.4. Testing for sarcoidosis

Sarcoidosis is a complex disease with manifold clinical manifes-tations. A case suspicious for sarcoidosis requires clinical, radio-logical and historadio-logical evidence of non-caseating granulomas.

Serum soluble interleukin-2 (sIL-2R), angiotensin converting enzyme (ACE) and lysozyme levels have become useful tools in the diagnosis of sarcoidosis and for evaluating disease activity, in addition to fluorodeoxyglucose-positron emission tomograp-hy (FDG-PET). Serum ACE is the most widely used laboratory test for the investigation of sarcoidosis⁽⁷⁴²⁾. Elevated serum levels of ACE, IL-2R, and lysozyme are usually associated with more ag-gressive disease and multiple-organ involvement⁽⁷⁴³⁾.

Figure 5.3.46. Delphi: Is it essential to do an objective test of immunodefi-ciency at initial presentation in secondary care with highly suggestive symp-toms of CRS and abnormal endoscopy ?

Figure 5.3.47. Delphi: Is it essential to do an objective test of immunodefi-ciency at initial presentation in secondary care in patients with highly sug-gestive symptoms of CRS but normal endoscopy ?

Figure 5.3.48. Delphi: Is it essential to do an objective test of immunodefi-ciency in CRS after failure of appropriate medical or surgical treatment in ENT/secondary care with continued symptoms and abnormal mucosa ?

5.3.5.8.2.5. Testing for N-ERD

Oral provocation test with aspirin is the most common inves-tigation used to identify hypersensitivity reactions to aspirin (see 5.3.5.14). For details how to perform see the recently published EAACI position paper: Diagnosis and management of NSAID-Exacerbated Respiratory Disease (N-ERD)⁽³⁹⁾. However, for those patients who have a higher risk of severe reactions, flow cytometry-assisted basophil activation testing (FAST) and functional-eicosanoid-test (FET) can be helpful tools to elucidate the diagnosis, if they are available^{(744, 745)}.

5.3.5.9. Microbiology

5.3.5.9. 1. Rationale

Sinonasal microbiological sampling is important in the diagnos-tic work-up of patients with rhinosinusitis. The importance of microbes in the aetiology of acute bacterial rhinosinusitis (ABRS) is well recognized⁽⁵⁵³⁾ whereas the situation in CRS is less clear but is of increasing interest, facilitated by improved identifica-tion techniques^{(746, 747)}.

5.3.5.9.2. Tests

5.3.5.9.2.1. Culture-dependent Techniques Sinus aspirates

A maxillary sinus tap (MST) has historically been the gold standard technique for obtaining sinus cultures by providing a representative specimen of the antral contents with minimal nasal contamination^{(748, 749)}. It can be performed under local anaesthesia via the inferior meatus or canine fossa but is often associated with discomfort, potentially risks orbital, dental and nerve injury and only provides information on the maxillary sinus⁽⁷⁴⁸⁾.

The sphenoid sinus can also be approached directly to obtain an aspirate for culture⁽⁷⁵⁰⁾. In the past the frontal sinus has also been

‘punctured’ through the anterior wall to obtain a sample⁽⁷⁵¹⁾ but this is of greater magnitude, usually requires a general anaes-thetic and is generally part of a therapeutic surgical procedure rather than being purely diagnostic⁽⁷⁵²⁾.

Nasal swabs

Nasal swabs are the most commonly used sampling method in the nasal cavity as they are easy to use, non-invasive and generally well tolerated without the need for local anaesthesia.

However, there is a poor correlation between undirected nasal/

nasopharyngeal and endoscopically directed middle meatal (EDMM) culture swabs, largely due to contamination from the nasal vestibule and cavity. EDMM swabs show a high concor-dance with maxillary sinus aspirates and cultures^(753-758) and thus have become the mainstay of microbial sampling in patients with rhinosinusitis (Table 5.3.7.). A meta-analysis confirmed that

Figure 5.3.49. Delphi: Is it essential to do an objective test for vasculitis at initial presentation in secondary care with highly suggestive symptoms of CRS and abnormal endoscopy ?

Figure 5.3.50. Delphi: Is it essential to do an objective test for vasculitis at initial presentation in secondary care in patients with highly suggestive symptoms of CRS but normal endoscopy ?

Figure 5.3.51. Delphi: Is it essential to do an objective test for vasculi-tis in CRS after failure of appropriate medical or surgical treatment in ENTsecondary care with continued symptoms and abnormal mucosa on endoscopy ?

EDMM is a highly sensitive and accurate culture method for ABRS and may be more sensitive than maxillary sinus taps (MST) given the presence of pathogenic bacteria not found on antral lavage⁽⁷⁵⁹⁾. For known pathogenic bacteria for ABRS and in com-parison to MST, EDMM had a sensitivity of 80.9%, a specificity of 90.5%, a positive predictive value of 82.6%, a negative predictive value of 89.4%, and an overall accuracy of 87.0% (95% confi-dence interval, 81.3%-92.8%).

The more recent meta-analysis by Smith et al. showed that bac-terial pathogens are recovered by sinus puncture or EDMM cul-ture in 53% of patients with suspected ABRS, based on studies requiring patients to meet clinical criteria, with most studies also requiring radiographic and/or endoscopic confirmation.

There is limited research on how representative middle meatal swabs are for the remaining sinuses. Although not a direct com-parative study, a recent retrospective study by Miller et al.⁽⁷⁶⁰⁾ de-monstrated different pathogens in two or more of the swabs of 40% of patients undergoing multiple sinus cultures. While only 5% of the patients in this study received clinical benefit from changing the antibiotic, it does suggest that bacterial cultures from the middle meatus may not be entirely representative of all the sinuses.

EDMM culture swabs have become the mainstay of microbial sampling in patients with rhinosinusitis.

Nasal blown secretions

Nasal blown secretions may be readily obtained in primary care, particularly for paediatric patients as it avoids the discomfort of a nasal swab. The few comparative studies comparing expel-led mucus to standard culture swab techniques suggest a high concordance rate (>90%) for the detection of common upper airway pathogens when nasal secretions are present, but as might be expected, this rate reduces to less than 50% but in the absence of obvious secretions^{(710, 761)}.

Nasal and sinus lavage

Nasal lavage is not an accurate technique for the culturing of sinus contents due to contamination by nasal flora and minimal

Table 5.3.7. Bacteriology of rhinosinusitis. Correlation of middle meatus versus maxillary sinus.

Author, year, ^(ref) Number of samples

Type of rhinosi-nusitis

Technique Concordance

Joniau 2005⁽⁷⁵⁶⁾ 26 ARS Endoscopic swab (MM) vs. maxillary sinus tap 88.5%

Casiano 2001⁽⁷⁵⁵⁾ 29 ARS (intensive care) Endoscopic tissue culture (MM) vs. maxillary sinus tap 60.0%

Talbot 2001⁽⁸⁴⁰⁾ 46 ARS Endoscopic swab (MM) vs. maxillary sinus tap 90.6%

Vogan 2000⁽⁷⁵⁴⁾ 16 ARS Endoscopic swab (MM) vs. maxillary sinus tap 93.0%

Gold and Tami 1997⁽⁸⁴¹⁾ 21 CRS Endoscopic tap (MM) vs. maxillary aspiration during ESS 85.7%

Klossek 1996⁽⁷⁵⁷⁾ 65 CRS Endoscopic swab (MM) vs. maxillary aspiration during ESS 73.8%

sinus penetration in an unoperated patient. These issues may be circumvented by direct sinus lavage through an endoscopically placed maxillary sinus catheter. Studies comparing direct sinus lavage to EDMM swabs have demonstrated higher bacterial yields and increased recovery of anaerobic pathogens using the former technique^{(762, 763)} and this sampling technique could be facilitated by balloon technology as many devices have inbuilt catheters that can be used for lavage drainage and antibiotic irrigation. The clinical relevance of the anaerobic organisms and the targeted culture and treatment of isolated infected sinuses remain to be studied.

5.3.5.9.2.2. Culture-independent techniques

Standard culture approaches offer only a limited range of de-fined conditions for microbial growth and , therefore, omits taxa that require alternative conditions, including slower-growing organisms that are outcompeted for a limited range of nutrient sources or those that depend upon cooperation to survive in vivo (such as cross-feeding relationships). The disparity between the identification of microbes by culture and those (viable but nonculturable or difficult to culture) identified by molecular methods has been termed “the great plate count anomaly,” with estimates of the nonculturable portion of microbial communi-ties ranging between 25% and 99%^{(764, 765)}.

Next generation sequencing

Next generation sequencing techniques have enabled identifi-cation of micro-organisms previously unidentifiable on routine culture studies⁽⁴⁵⁰⁾. Samples can be obtained using guarded, flocculated microbial swabs or by tissue biopsy with high

Next generation sequencing techniques have enabled identifi-cation of micro-organisms previously unidentifiable on routine culture studies⁽⁴⁵⁰⁾. Samples can be obtained using guarded, flocculated microbial swabs or by tissue biopsy with high