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Laboratory diagnosis 1997-otolaryngology---head-and-neck-surgery

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Laboratory diagnosis 1997-otolaryngology---head-and-neck-surgery

Laboratory diagnosis 1997-otolaryngology---head-and-neck-surgery

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  • 1. Laboratorydiagnosis BERRYLINJ. FERGUSON,MD,and RICHARDL. MABRY,MD,Pittsburgh, Pennsylvania, and Dallas, Texas Laboratory studies are performed to confirm or exclude the presence of a suspected disorder or to obtain additional information about that disorder. This section critically reviews the tools that are available to objectively measure nasal function including patency, olfaction, and mucociliary transport (Table 1). Also reviewed are the laboratory tests that are used to diag- nose sinonasal disorders including allergy, immunode- ficiency, mucociliary transport abnormalities, genetic disorders, autoimmune diseases, and disorders of unknown cause that constitute distinct pathologic enti- ties (Table 2). Because imaging studies, nasal endoscopy, and microbiologic cultures are covered elsewhere in this publication, they are alluded to only briefly in this section. NASAL FUNCTION STUDIES Nasal Patency Rhinomanometry. Also called nonacoustic rhi- nometry, rhinomanometry was the first technique introduced to objectively measure nasal patency. Rhinomanometry measures transnasal pressure and airflow simultaneously. With simultaneous measure- ment of pressure and flow, transnasal resistance may be calculated with Ohm's law. The International Committee on Standardization of Rhinomanometry has recommended that nasal patency be expressed as resistance (the ratio of transnasal pres- sure to flow of respiratory air in a patient breathing exclusively through the nose, expressed in centimeters of water per liter per second or in pascals per cubic cen- timeter per second).t The graph of pressure versus flow is a sigmoid curve (Fig. 1). Fromthe Departmentof Otolaryngology(Dr.Ferguson),University of Pittsburgh School of Medicine, and the Department of Otorhinolaryngology (Dr. Mabry), The University of Texas, SouthwesternMedicalSchoolat Dallas. Reprint requests: Berrylin J. Ferguson, MD, the Departmentof Otolaryngology,UniversityofPittsburghSchoolofMedicine,The Eye and Ear Institute Building, Suite 500, 200 Lothrop St., Pittsburgh,PA15213. OtolaryngolHeadNeckSurg1997;117:$12-$26. Copyright© 1997 by the AmericanAcademyof Otolaryngology- Headand NeckSurgeryFoundation,Inc. 0194-5998/97/$5.00 + 0 23/0/83512 $12 Toble 1. Tools commonly used for the objective measurement of nasal function Nasal patency Acoustic rhinometry Rhinomanometry Mucociliary transport Saccharine method Radiolabeledor radiopaque tracers Olfaction Universityof PennsylvaniaSmell IdentificationTest (UPSIT) Various methods can be used to measure both transnasal pressure and transnasal airflow. Methods of measuring transnasal pressure can be combined with any of the methods of transnasal airflow measurement. The three methods of transnasal pressure measurement are as follows: 1. Anteriorly, at the nostril, while the patient breathes exclusively through the contralateral nostril. This method cannot be used in patients with total uni- lateral nasal obstruction or septal perforation.2 2. Posteriorly, with a tube in the oropharynx between the tongue and the palate. The patient may breathe through both nostrils simultaneously with this method. 3. Postnasally, with a pediatric feeding tube placed along the floor of the nasal cavity and into the nasopharynx. With this method the patient may breathe through both nostrils simultaneously. Transnasal airflow is measured by a pneumota- chometer (a resistor that induces laminar flow across it so that the pressure drop varies linearly) and a pressure transducer (an instrument that measures the differential pneumotachometer pressure). Pressure calibration is accomplished with a water manometer. The pneumota- chometer may be attached or connected in one of sev- eral ways: 1. A nozzle inserted into the nasal vestibule. This has the disadvantage of distorting the nasal valve. 2. A face mask. This may distort the facial tissues. Furthermore different types of face masks result in different resistance measurements. Although real- positioning of the mask can result in errors, nasal distortion is less than with the nozzle measurement
  • 2. Otolaryngology- Head and Neck Surgery Volume 117 Number 3 Part 2 FERGUSON and MABRY $13 Table 2. Laboratory tests for the diagnosis of sinonasal disorders Diagnosis = Allergic rhinitis Allergic fungal sinusitis (AFS) Autoimmune disorders Wegener's granulomatosis Polyarteritis nodosa Relapsing polychondritis Cerebrospinal fluid rhinorrhea Cystic fibrosis Disorders of unknown cause Sarcoidosis Churg-Strauss syndrome Immunodeficiency Mucociliary transport abnormalities Primary ciliary dyskinesia (Kartagener's syndrome) Neoplasm Malignant neoplasms Lethal midline granuloma (angiocentric T-cell lymphoma) Benign neoplasms Gold standard Skin testing (prick or intradermal) or in vitro measurement of specific immunoglobulin (Ig) E Mucin histopathology Fungal cultures of mucin Nasal biopsy Nasal biopsy Nasal biopsy I]-2 Transferrin Sweat test Nasal biopsy (diagnosis of exclusion--negative cultures for fungus and acid-fast bacilli) Nasal biopsy (vasculitis is not usually seen in nasal specimens); must be coupled with clinical picture and ung biopsy Documentation of absence of function of a subset of the immune ~ystem Electron microscopy of nasal cilia Ciliary beat function studies Nasal biopsy Nasal biopsy Nasal biopsy Helpful or suggested screening tests Nasal cytology Total IgE IgE and IgG to specific fungus Cytoplasmic antineutrophil cytoplasmic antibody assay (c-ANCA) Erythrocyte sedimentation rate Perinuclear antineutrophil cytoplasmic antibody assay (p-ANCA) Glucose of fluid Sweat patch test Sweat conductivity Angiotensin converting enzyme level Chest radiograph Complete blood count with differential (eosinophil count) Total IgG IgM, IgA, IgG subclasses Complete blood count with differential CH50 or CH100 Mucociliary transport test (saccharine or thallium) Epstein-Barr virus titers if nasopharyngeal carcinoma is suspected Serum electrophoresis if plasmocytoma is suspected Possiblyhelpful or secondary tests Erythrocyte sedimentation rate Complete blood count Nasal action potential Genetic tests Erythrocyte sedimentation rate Kveim test tgG1 deficiency: response to diphtheria and tetanus toxoid vaccine IgG2 deficiency: response to pneumococcal vaccine
  • 3. $14 FERGUSONand MABRY Otolaryngology- Head and Neck Surgery September 1997 ~hinomanomatr~ Report Itnnic: laight: ~ge: Z..3~ T CALCUlaTED : TZST ~3tZSSUILE: -1.50 c= 120 SeXI LZPT R~GIT ~e~sUrement Pre Post Pre Post Resistance (c= I20/L/sec) 6.02 4.45 6.75 5.27 ~roms (c~ }{20/L/sec) 5.99 4.40 6.72 5.24 conductance (cc/s/cm ~20) 166.07 224.91 14g.15 189.72 ~low (cc/ssc) 249.11 337.36 222.22 284.59 ~OTH ~OSTRILS ~re Post Work of ~reathing 2.96 I.~6 I~B = ~ress~ra Out of Bounds TOTIL 3.1~ ~.41 u/~ ~/~ ~.2~ ~x.~ 471.34 621.~5 l~re C h ~ l l e r ~ 3 e U ~ l u e ~ 0.8 : : i , t ! ! i ' i " -'. ! o.s---L-U ! ! . . . . . . llli ""'~• i " " ; I i i i i ~ ~.1-- "I O . O - ! ! I ! ! ! i_lv - - r--T--~.---~ - ' -r-T-~ n - - ! - ! I ~_-o.3_ ~ l--i ! " " ".- I I ! i i ,, i i ill I .~ ! I ', ~. ! i I -o.e - i - I i ~ ' - - 3 . 0 - - I , 8 ~ 0 . 6 0 . 6 1 . 8 3 . 0 P r e . ~ u ~ e { c ~ }4:IND) - - - L~ft N o s t r i l - - R i g h t N o ~ t r i l Te=t done by Po~t Challeng~ U~lu~ 0.8 iil • ! ~. . iii U-~'''~ i I | O.3- ', l t . r - - - . - - ~ ~ iii , ' " /iiiio.o---f-T-]-- , "-~- i- "-- 1 i l ! | : -o. ~ -r-T-T- I ii , _o.8/:1: I--3.0 --1,8 --0.6 0 o6 I .I@ 3.0 Fig. 1. Sample computerized rhinomanometry report. distortion is less than with the nozzle measurement technique of airflow,a 3. Body plethysmography. The face is unrestricted, and results are consistent and reproducible. However, the apparatus is bulky, and considerable patient cooperation is required. 3 Commercially available rhinomanometry units are now computerized (MultiSPIRO, Inc., Irvine, Calif.), and they have disposable probes and masks. These units have real-time graphic data displays that allow easy detection of air leaks and other artifacts that can adversely affect reproducibility or accuracy. Testing can be completed in 2 minutes. Acoustic rhinometry. This modality, which was introduced in 1989,4 assesses the geometry of the nasal cavity by analyzing reflected sound waves. Two mea- surements are commonly obtained. One is the minimal cross-sectional area, and the other is the nasal volume. Occasionally, a total minimal cross-sectional area is calculated by adding the right and left minimal cross- sectional areas. This has the theoretic advantage of negating some of the variation caused by cyclic turbinate engorgement.
  • 4. Otolaryngology- Head and Neck Surgery Volume 117 Number 3 Part 2 FERGUSON and MABRY S15 Analysis Segment: 3.00 to 6.00 Req(cmH20/i/m) Volume(cm^3) Min Area(cm^2) at Length(cm) I. left : 0.353 5.75 0.95 3.06 2. right : 0.951 .2.88 0.83 4.99 4. left : 0.000 0.00 0.00 5.95 3. right : 0.000 0.00 0.00 5.95 2. mig~% / New Da~a ~-- 4i?~?g~.!~.i?~.i~.~?}..!~?!!!!!i?i?!?!}!!!?!!ii!!??!i?!???!i!!!!??i~ii!??~ii!!??~!!?!?~!!ii~?!~!!i!?i?? ~"~Na~'a"1"?"'?a'J;v e"~......"......g......i.....:.!......i......~......i......i......i......i .....- .....~.....- .... • ::~:.q::::~:.~::.::.7:::::.::::::.::::::.:::~:~.:..~::...::.~::r..~..~..".:~...f~:~:~:::~i:ili::~ii'''=-.i~ii@illi~?ii~ 0 . .......":!"!'"!......~ : ~ ~ .......-......?..,....:.:_ ~':"......'.{ i i ~ ~.......- . .-':--. v :I..0 :::::::::::::::::::::::::::::::::::::::::: :::~:::::" ============================================== :::::::::::::::::::::::::::::::::::::::::::::::::::::i'" ============================================================== ........ ~."i ...... ":...... ".''",'{ ...... =.'"r"=. ...... '....... ":...... "" ..... " ...... ":...... "....... < ...... ~:...... "........ :..... ....: i......??i ......? ? i <! ......i......i......i......i......i......t ......t .....t .....t .... ...... i-,~.~i ...... {i...... {---:-{ ...... {...... ".-...... { ..... • ...... " ...... ".-...... {...... {....... ::....... i....... '....... ! ..... ..... i ...... i...... !<i ...... i...... i...... !...... i...... i...... i...... i...... i...... !....... i....... i ......i...... i..... o.o~ ......... I ......... 1......... I.......... I..... m'rl-rr ....... 1......... I......... I'' 'rrrrr -6.0 -4.0 -2.0 0.0 2.0 4.0 6,0 8.0 10.0 1 Distanoe.(cm). Fig. 2. Computerized acoustic rhinometry graph for right and left sides of nose. Segment ana- lyzed for volume can be adjusted. Computerized version can display right and left, before and after, in four different colors for visualization (Hood Laboratories, Pembroke, Mass.). Acoustic rhinometry is now computerized and com- mercially available (Hood Laboratories., Pembroke, Mass.), and the assessment can be performed with ease in less than 1 minute. Because acoustic rhinometry demonstrates the cross-sectional area on the vertical axis and the distance from the front of the nose on the horizontal axis, areas of constriction are easily local- ized (Fig. 2). Sources of error include improper positioning of the nozzle or patient breathing during assessment. The nozzle of the commercially available acoustic rhinometry units can distort and dilate the nasal valve area. ff improperly applied, the nozzle may fail to accurately reflect constric- tion in the nasal valve area. Chin or forehead supports have recently been added to the acoustic rhinometry stand in an effort to improve the reproducibility of findings, particularly at the nasal valve area.5 Patients should be instructed to hold their breath (for approximately 15 sec- onds) while undergoing testing.6 The reported average minimal cross-sectional area is 0.62 cm 2 at 2.35 cm from the nostril. With decongestant sprays the minima1 cross-sectional area moves forward to 2.00 cm from the nostril but increases to only 0.67 cm2.7 Patients with severe septal deflections and a feel- ing of almost total occlusion have a minimal cross-sec- tional area of approximately 0.3 cm2. In one study8 patients who were dissatisfied with the outcome of sep- tal surgery to correct obstruction had an average mini- mal cross-sectional area of 0.45 cm2, whereas those who were satisfied with surgical outcome had an aver- age minimal cross-sectional area of 0.74 cm2. Comparison of rhinomanometry and acoustic rhinometry.Although acoustic rhinometry is generally more accurate and reproducible, rhinomanometry may be superior in certain situations including those in which volume or minimal cross-sectional area must be calculated beyond a severe constriction.9 In their initial description of acoustic rhinometry, Hilberg et al.4 demonstrated that this technique was more accurate and reproducible than three other assess-
  • 5. $16 FERGUSONand MABRY Otolaryngology- Head and Neck Surgery September 1997 ments of nasal anatomy: nonacoustic rhinometry (ante- rior rhinomanometry with a face mask), area measure- ments obtained by computed tomographic (CT) scan- ning, and area measurements obtained by a water dis- placement method. The assessments were performed in a variety of settings including cadavers, normal sub- jects, nasal cast models, and patients with nasal cavity obstructions. The study results showed that the areas measured by acoustic rhinometry were more accurate than those obtained by nonacoustic rhinometry and were more highly correlated with the areas measured by CT scanning (r --- 0.94) or the water displacement method (r = 0.96). Acoustic rhinometry had a coeffi- cient of variation of <2% compared with 15% for nona- coustic rhinometry. Rhinomanometry and acoustic rhinometry may be complementary tests in inhalation challenge studies, because different correlations with nasal congestion under baseline and challenge conditions can be demon- strated with different test groups. 1° Unlike rhino- manometry, acoustic rhinometry does not require flow through the nose for measurement; thus it can be used when the nose is totally occluded. With the commer- cially available units measurements can be obtained in less than 1 minute with acoustic rhinometry compared with approximately 2 minutes with nonacoustic rhi- nometry. Objective measurements of nasal patency do not always correlate with a patient's subjective sensation of nasal congestion. 11-13When a patient reports nasal con- gestion and has normal objective measurements, abnor- malities at the nasal valve area and in the region of the middle turbinate should be specifically evaluated by anterior rhinoscopy and endoscopic examination. In children nasal obstruction is frequently not a subjective complaint, despite objective evidence to the contrary.14 Acoustic rhinometry is not recommended as a test for monitoring the recurrence of tumors of the nasal cavi- ty.15 Mucociliary Transport Normal, coordinated ciliary activity is required to transport mucus toward the nasopharynx, thereby pro- tecting the upper airway. Abnormalities in either the mucus or the function of the cilia can have a variety of causes. Most of these abnormalities are transient, and they are associated with various viral and bacterial infections16-21 or exposures to allergens or environ- mental pollutants such as cigarette smoke.22 More problematic are the nontransient, frequently genetic causes of mucociliary transport dysfunction. These include primary ciliary dyskinesia (in which ciliary anatomy or function is abnormal) and cystic fibrosis (in which ciliary anatomy and function are normal but the mucus is abnormally thick). To assess mucociliary transport, a number of soluble and insoluble tracers have been applied to some part of the nasal mucosa. Care must be taken to place any trac- er at or posterior to the most anterior 1 to 2 cm of the nasal mucosa, because this section of the nasal cavity directs mucociliary transport anteriorly and not posteri- orly. Soluble tracers. A soluble tracer, which presumably dissolves in the mucus, may be a visible dye (e.g., food coloring), an agent that can be tasted by the subject (e.g., saccharine), or a combination of both. It is hypothesized that soluble tracers are transported simi- larly to topically applied drugs or water-soluble inhaled gases. The saccharine method is the safest and most wide- ly used soluble tracer test. In this test a small amount of saccharine powder is placed on the medial aspect of the inferior turbinate 1 to 2 cm behind the leading edge. The patient is instructed to avoid sniffing or blowing the nose and is instructed to swallow frequently. The transport time is the time from the application of the saccharine powder to the time at which the patient detects a sweet saccharine taste. The saccharine particle method time is normally 5 to 8 minutes; 12 minutes is slow, and more than 25 minutes indicates a mucociliary transport disorder.23 The saccharine test measures the fastest transport time.24 A time lapse is required between repeat tests to allow the sweetness to disap- pear. If a dye is used as the tracer, the oropharynx must be examined every minute or so. Alternatively, endoscop- ic nasal techniques may be used as long as the anatom- ic end point of dye transport is specified. Insoluble tracers. Tests with insoluble tracers prob- ably mimic the transport of substances stuck in the thick gel mucus. Examples of these markers include insoluble dyes and small, visible particles such as char- coal powder, colloidal sulphur, or 600-Hm aluminum disks. Radiopaque or radioactively tagged human serum albumin particles or Teflon disks provide an assessment of clearance in the entire nasal cavity. However, these tests subject patients to a small radia- tion exposure. The nasal transit time by insoluble trac- er methods averages approximately 6 minutes.25 Summary of soluble and insoluble tracer mea- surements of mucociliary transport, The saccharine method is the most widely used, because it is easy, inexpensive, and safe. This method measures the fastest transport time, not the total transport time. It reflects the
  • 6. Otolaryngology- Head and Neck Surgery Volume 117 Number 3 Part 2 FERGUSONand MABRY S17 solubility of the marker in mucus, in contradistinction to insoluble markers or tagged radioactive particles. The saccharine test correlates well with measurements with the use of two of the insoluble markers: radioac- tively tagged resin particles and 600-~lm aluminum disks.26 A daily variation ranging from 43% to 74% is noted with all mucociliary transport studies. The least varia- tion is seen with the saccharine test, and the most vari- ation is with radioactively tagged resin particles.26 A delay in mucociliary transport time can suggest the need for an evaluation of known causes of mucocil- iary transport dysfunction. A normal mucociliary trans- port time excludes the diagnosis of primary ciliary dyskinesia. Adjunctive Evaluation of Suspected Mucociliary Dysfunction: Ciliary Beat Function Studies and Ultrastructural Analysis When nasal mucociliary clearance studies indicate that an abnormality is present, appropriate tests may include ciliary beat frequency and orientation analysis with photometric techniques or ultrastructural assess- ment with electron microscopy. With both of these studies a san~ple of cilia must be obtained by biopsy or by scraping the inferior turbinate with a nasal brush or a small mechanical scraper specifically designed to obtain turbinate epithelium (Rhinoprobe, Apotex Scientific Inc., Arlington, Tex.). The tests are comple- mentary. Variants of primary ciliary dyskinesia have been described in which the ultrastructure and the ciliary beat frequency were normal and only the ciliary beat orientation was abnormal.27 Primary ciliary dyskinesia is the preferred term for congenital abnormalities of cil- iary activity including Kartagener's syndrome. The clinical presentation begins at birth, usually with per- sistent rhinosinusitis, otitis media, pulmonary infec- tions, and frequently bronchiectasis. The initial screening examination should be an eval- uation of nasal mucociliary clearance. The identifica- tion of abnormal cilia must be interpreted within the clinical context, because up to 10% of cilia are struc- turally abnormal in patients with normal mucociliary transport times and no nasal pathologic condition or symptoms. Disorders known to cause reversible delays in mucociliary function such as infection and exposure to noxious agents should be treated appropriately. Only if treatment fails and mucociliary transport continues to be delayed should ultrastructural or ciliary function tests be considered.2s,29 Patients with mucociliary transport dysfunction caused by infection may respond to correction of ostiomeatal complex obstruction or other anatomic deformity by endoscopic sinus surgery. At present, there is no treatment to correct primary ciliary dyskinesia. When a patient has absent nasal mucociliary clearance, it is important to consider the cost-effectiveness of pursuing ultrastructural analysis and ciliary beat function tests to make a diagnosis for which there is no therapeutic intervention. It seems rea- sonable to assume that a patient with mucociliary trans- port dysfunction caused by an irreversible ciliary disor- der (documented by electron microscopy or family his- tory combined with ciliary beat function studies) would be less likely to improve after endoscopic sinus surgery than would a patient with a reversible mucociliary transport disorder. Endoscopic sinus surgery or external approaches may be required in both irreversible and reversible causes of mucociliary transport disorders. The decision to operate or reoperate on a patient with a documented irreversible ciliary disorder should be directed at removing infection and allowing wide drainage of the sinuses, not toward restoring function to the sinuses. However, there are no controlled studies to support this approach. Olfaction Smell identification. The most popular olfacto~ test is smell identification by multiple choice of 40 odorants activated by scratching microencapsulated material with a pencil. The patient's score on the test is compared with norms standardized for age and sex. The most widely used tool is the Smell Identification Test (Sensonics, Inc., Haddon Heights, N.J.). The com- mercial test packet includes booklets of microencapsu- lated odors and an administration and scoring manual. Sometimes this test is referred to as the University of Pennsylvania Smell Identification Test.3° A patient's score falls into one of four categories: normal for age and sex, micro-osmic, anosmic, or probably malinger- ing. On a 40-item multiple choice test involving four choices per item, a patient should identify approxi- mately 10 items correctly by chance alone. Patients who miss 35 or more items are probably malinger- ing. A shorter (12-item) screening version of the University of Pennsylvania Smell Identification 40- item test is also available (Sensonics, Inc.). Threshold testing.Odor detection threshold tests have received a great deal of clinical attention. The con- centration of a stimulus is increased (or decreased) incrementally until the stimulus is barely perceived.
  • 7. $18 FERGUSONand MABRY Otolaryngology- Head and Neck Surgery September 1997 The stimuli concentrations, usually in log-step concen- tration, are presented in "sniff' or squeeze bottles. Threshold tests require a considerable amount of administration time, because multiple presentations are required to determine a reliable detection threshold. Consequently, only one or two odorants are usually tested. Phenyl ethyl alcohol, which has a roselike smell and produces little trigeminal reactivity, is commonly used. Most patients who are insensitive to one chemical are also insensitive to other chemicals. However, patients with "smell blindness" in which only a small number of stimuli are involved have been reported.31 For this reason it is recommended that odor identifica- tion tests be used in addition to threshold tests.32 Olfactory biopsy. A hook-shaped instrument (Storz Instrument Co., St. Louis, Mo.) can be used to perform olfactory neuroepithelial biopsy with endoscopy in the office without any objective adverse effect on the sense of smell. Specimens obtained in this way are free of crush artifact and thus are suitable for ultrastructural analysis. More studies are required to determine the correlation of histopathologic and clinical findings, and the use of this technique is currently restricted to research centers.33,34 Disorders of olfaction may be associated with endocrine, neurologic, psychiatric, and nutritional dis- orders. Appropriate specific laboratory testing is required to identify any of these disorders. A lengthy list of these conditions has been well reviewed by Schiffman35 and by Dory et al.36 LABORATORY TESTSFOR DIAGNOSING SINONASAL DISORDERS Allergic Rhinitis Conflicting data exist regarding the incidence of allergy with rhinosinusitis. Before endoscopic sinus surgery was introduced, Friedman37 reported that aller- gy was present in 94% of patients with hyperplastic chronic sinusitis who were treated with sinus surgery. In more recent articles on sinus surgery outcomes in which the presence of allergy was investigated, the inci- dence of allergy has ranged from 14%38 to more than 60%.39 Most articles report that approximately 50% of patients with chronic sinusitis who require endoscopic sinus surgery probably have both allergy and rhinosi- nusitis.4°,41 Parsons and Phillips42 found that allergy was present in 60% of children requiring endoscopic sinus surgery, whereas Lazar et al.43 noted allergy in 49% of 260 children treated with sinus surgery. It is appropriate to perform at least a screening test for inhalant allergy in patients with chronic or recurrent sinusitis. A previously published clinical practice guideline of the American Academy of Otolaryngic Allergy covered the subject of allergy testing in depth and is considered authoritative in this area.44 Allergy testing may be performed by either a skin test (prick or intradermal) or by in vitro means includ- ing radioallergosorbent testing and enzymatic-marker variants such as the enzyme-linked immunosorbent assay. Both skin and in vitro tests accurately and repro- ducibly detect allergen-specific immunoglobulin E (IgE), and both correlate well with the clinical signs and symptoms elicited by antigen exposure.45 A cost- effective screening test with 12 to 15 antigens is an excellent predictor of the presence of significant inhalant allergy46 and may be the basis for successful initial immunotherapy.47 However, additional antigens may subsequently be tested depending on the individual situation. Laboratory diagnostic aids in allergic fungal sinusitis. Allergy is present in all patients with allergic fungal sinusitis. Patients with this type of sinusitis are distinguished from other atopic patients by clinical pre- sentation and histologic, laboratory, and radiographic findings. These patients typically have elevated total IgE levels, and they demonstrate atopy (by either skin tests or a radioallergosorbent test) to both fungal and nonfungal antigens.48,49 Other diagnostic tests that have been suggested include the total eosinophil count and, if available, fungal antigen-specific immunoglob- ulin G (IgG) and precipitating antibodies.5° Clinical and radiologic findings often suggest the presence of allergic fungal sinusitis before surgery, but the diagnosis is confirmed by histopathologic examina- tion of the tenacious allergic mucin found in the sinus- es. The histopathologic features include a dense eosinophilic infiltrate, Charcot-Leyden crystals, and noninvasive fungal hyphae.51,52 Special fungal stains are usually required to identify the hyphae on histolog- ic section. Fungal cultures may or may not be positive. Nasal Cytology The importance of examining smears of nasal secre- tions to differentiate allergic and infectious rhinosinusi- tis was emphasized many years ago by Hansel.53Based on his experience with 10,000 specimens from 1000 allergic patients over a 12-year period, Hansel reported that nasal eosinophilia was strongly associated with allergy, whereas neutrophils were associated with infection. Bryan and Bryan54 coined the term "cytogram" to describe the mixture of epithelial and goblet cells, leukocytes, and mast cells in nasal secre- tions and, along with others,55 believed that they could distinguish allergy, bacterial infection, viral infection, and vasomotor rhinitis from such an examination. No recent investigators have shown a similar expertise.
  • 8. Otolaryngology- Heod and Neck Surgery Volume 117 Number 3 Part 2 FERGUSONand MABRY $|9 Initial methods of cytologic examination involved secretion collection by blowing the nose into waxed paper or by the use of a cotton swab. However, use of the Rhinoprobe can increase the accuracy of nasal cyto- logic examination.56,57 The presence of eosinophils in nasal secretions has been said to indicate the presence of allergy,58-6° whereas neutrophils are more indicative of an infec- tious cause.61-6~However, the administration of topical nasal corticosteroids may significantly reduce the pres- ence of eosinophils in the nose,6t so that patients who are receiving these medications may not show nasal eosinophilia. Furthermore eosinophils may be present in the secretions of patients with nonallergic rhinitis.64 Thus althongh nasal smears remain a helpful adjunctive tool in differentiating allergic from infectious rhinosi- nusitis, other more specific tests may be more useful and definitive. Nasal and Sinus Cultures The relative inaccessibility of the sinus cavities makes it difficult to obtain specimens for bacteriologic cultures. The standard in this area has been puncture of the maxillary antrum, which is the approach required by the U.S. Food and Drag Administralion for drug studies dealing with rhinosinusitis. In clinical practice, however, this sampling technique generally is not nec- essary for the treatment of community-acquired infec- tions unless patients do not respond to empiric thera- py.65 Antral aspiration may also be considered in patients with suspected nosocomial rhinosinusitis66 or serious complications of rhinosinusitis. 67,6sEven if cul- tures are negative, the act of puncturing and lavaging the maxillary antrum may be therapeutic.69 Considerable interest has been shown in obtaining cultures directly from the middle meatus under fiberop- tic endoscopic guidance.7° Although only anecdotal data on the efficacy of this method are currently avail- able, it remains a more appropriate choice than nasal culture. When sinus cultures are required, they should be incubated appropriately and then examined for aero- bic and anaerobic organisms. For determination of their true significance, culture results must be correlated with clinical findings. Based on the findings in a study of samples obtained with endoscopy from the middle meatus with the use of a small calcium alginate swab on a flexible metal shaft, Klossek et al.71 have suggested that this area,contains a commensal flora that represents the bacteria found in the maxillary ,antrum. These same authors are perform- ing additional studies to match culture results from antral lavage and middle meatus samples obtained with endoscopy. Once they have completed their work, fur- Table .3. Clinical situations in which immunodefi- ciency should be suspected A patient with recurrent acute infections (more than four infections per year) who clears completely between episodes when treated with antibiotics but requires antibi- otics to clear and in whom there is no evidence of an anatomic abnormality causing sinus obstruction A patient with recurrent infections in whom there is no evi- dence of a mucociliary defect or an anatomic obstruction (often, an evaluation for immunodeficiency is undertaken after the patient fails to improve after endoscopic sinus surgery and the elimination of a suspected anatomic con- striction) A patient who has a persistent infection that does not respond to adequate antibiotic therapy or who has repeated relapses after adequate antibiotic therapy A patient with infections at other sites (especially meningi- tis, sepsis, pneumonia) A patient wkh unusual pathogens or severe infections (e.g., Pneumocystis carinii, severe varicella infection with pneu- monia or hepatitis, infection from an attenuated virus) A patient with a family history of immunodeficiency ther light may be shed on the utility of this sampling technique.71 immunodeficiency Although allergy, repeated exposure to upper respi- ratory infections (e.g., in day care workers), and anatomic obstruction are the most common causes of persistent or recurrent infectious sinusitis, immunodefi- ciency must be considered when other causes have been excluded. Clinical situations in which immunodeficien- cy should be suspected are presented in Table 3. There is no standard "immunologic work-up." No one test or limited group of tests adequately evaluates all of the more than 50 known immunodeficiency dis- orders. For the purpose of evaluation, immunodeficien- cies can be grouped into five functional groups: anti- body deficiencies, T-cell defects, combined immune deficiencies (antibody and T-cell deficiencies), comple- ment deficiencies, and phagocytic cell dysfunctions. The type of infection directs the immunologic work-up (Table 4).72 Patients with antibody deficien- cies have primarily recurrent or persistent bacterial infections with encapsulated gram-positive and some gram-negative organisms. Fungal, viral, and protozoal infections are absent or rare in these patients, although infections with Pneumocystis and Giardia species may occur. Patients with T-cell defects have fnngal, viral; and protozoal infections, but they rarely have bacterial infections. Patients with complement deficiencies have a more narrow range of infections, and they are partic- ularly susceptible to gram-negativejnfections. Chronic granulomatous disease, a dysfunction of phagocytosis,
  • 9. S20 FERGUSONand MABRY Otolaryngology- Head and Neck Surgery September 1997 Table 4. Correlation of type of infection with the form of immunodeficiency Type of infection Immunodeficiency Bacterial Viral Fungal Protozoan Antibody deficiency +++ + - + T-cell deficiency - +++ +++ +++ T-cell/B-cell deficiency +++ +++ +++ +++ Complement deficiency +++ - - - Phagocytic dysfunction +++ - ++ - +++, Strongcorrelation;++, correlation;+, slight correlation;-, no correlation. Adaptedfrom PoimarSH. Approachto the child withimmunedeficiency.Curt ViewsAllergy Immuno11994;22:1-11.Usedwithpermission. Table 5, Laboratory evaluation based on the suspected form of immunodeficiency* Antibody deficiency Quantitation of serum immunoglobulin (Ig): IgG, IgA, IgM, IgE, and IgG subclasses Measurement of antibodies from previous immunization or infection: diphtheria, tetanus, rubella, rubeola, influenza, varicella Measurement of preimmunization and postimmunization antibody titers: pneumococcal poiysaccharide vaccine, Haemophilusinfluenzaetype B vaccine, diphtheria toxoid, tetanus toxeid T-Lymphocyte deficiency or dysfunction Complete blood count with differential Delayed hypersensitivity skin tests: Candida, tetanus toxoid, diphtheria toxoid, Streptococcus and Proteus extracts T-lymphocyte population and subpopulation counts In vitro lymphocyte stimulation tests Complement deficiency (OH100 or OH50) Serum total hemolytic complement activity (CH50) If positive CH50 abnormality: C3, C4, alternative pathway hemolytic activity assay, circulating immune complexes Phagocytic dysfunction Complete blood count with morphologic examination of leukocytes Nitroblue tetrazolium dye reduction test Measurement of leukocyte adhesion molecules (LFA-1 and Mac-1/CR3) *SeeTable4. Adaptedfrom PolmarSH. Approachto the childwithimmunedeficiency.CurrViewsAllergy Immuno11994;22:1-11.Usedwithpermission. is characterized by recurrent abscesses and infections with catalase-positive bacteria such as Staphylococcus aureus or gram-negative bacteria. Another disorder of phagocytic function is a leukocyte adhesion deficien- cy. Immunofluorescence tests and flow cytometry are required to measure the expression of integrins, LFA-1 and Mac-1/CR3, on leukocytes. Thus the type of infection helps guide the examination of the portion of the immune system that is most likely to be defec- tive.72, 73 An immunodeficiency disorder may be present in as many as 50% of adult patients with recurrent acute or persistent sinusitis.74,75 The most common causes of immunodeficiency associated with chronic recurrent sinusitis are immunoglobulin deficiencies including IgG subclass deficiencies. Once an abnormally low immunoglobulin level is demonstrated, functional tests (e.g., responses to immunization) are required. A mar- ginally low level of an immunoglobulin or an immunoglobulin subset with a normal functional response to antigen exposure is not considered patho- logic. Occasionally, patients have normal levels of all immunoglobulins but demonstrate an absent or strik- ingly low level of functional response.74 T-cell abnormalities are less common than immunoglobulin defects. The most frequent T-cell abnormality is the one seen in patients infected with the human immunodeficiency virus. Sinusitis and abnor- mal sinus radiographs are common in patients with the acquired immunodeficiency syndrome. In such patients therapy should be directed at the symptoms. The laboratory evaluation for patients with recurrent bacterial infections or suspected immunodeficiency is outlined in Table 5.72 The finding of unusual pathogens (i.e., fungi or parasites) supports the need for laboratory testing of T-cell function. Because T cells constitute approximately 70% of the lymphocytic population, a complete blood count with differential should be obtained before the immunologic work-up moves to specific T-cell counts. Because of the prevalence of human immunodeficiency virus infection and its associ- ation with sinusitis and unusual pathogens, a human
  • 10. Otolaryngology- Head and Neck Surgery Volume ] 17 Number 3 Part 2 FERGUSONand MABRY S21 immunodeficiency virus test should be considered in all patients for whom an immunologic work-up is consid- ered. The most abundant immunoglobulin is [gG. Normal serum concentrations for total IgG range from 800 to 1800 mg/dl (8.00 to 18.00 gm/L). There ,are four sub- classes of IgG. 1.The IgG1 subclass is responsible ~or antibody responses to bacterial protein antigens such as tetanus toxoid and diphtheria. Of the total IgG, 67% is IgG1. If a deficiency of IgG1 is identified, a functional assessment of antibody titers should be performed before and after the administration of tetanus or diphtheria toxoid. 2. The IgG2 subclass constitutes 20% to 25% of the total IgG and is primarily responsible for antibod- ies directed against polysaccharide capsules such as Haemophilus influenzae and Streptococcus pneumoniae. 76 Functional assessment is ascer- tained by immunization with pneumococcal vac- cine. A pneumococcal titer obtained 130 days after pneumococcal vaccination should show a twofold to fourfold increase in antibody titers over prevac- cination levels.77 3.The IgG3 subclass is important in the primary response to viral illness and against Moraxella (Branhamella) catarrhalis and the M component of Streptococcus pyogenes. A deficiency of IgG3 is reported to be the most common subclass deficien- cy in adults.78 4.Approximately 15% of the population has IgG4 levels that are not detectable by current assay tech- niques. The significance of an IgG4 deficiency remains unclear.78 The incidence of IgA deficiency is 1 case per 600 to 800 in the general population. The predominant immunoglobulin class on mucosal surfaces is IgA. It is not uncommon to see patients with low IgA levels who have no clinical symptoms. Patients with symptomatic IgA deficiency often have a coexisting [gG subclass deficiency or an autoimmune disorder.74 Serologic Markers Serologic markers may be helpful in diagnosing sev- eral sinonasal disorders. Although a definitive diagno- sis almost ,always requires a biopsy to demonstrate characteristic histopathologic features, ancillary sero- logic tests can be useful in directing the work-up. The erythrocyte sedimentation rate is; elevated in many autoimmune, infectious, idiopathic, and even neoplastic disorders. The erythrocyte sedimentation rate is a very inexpensive test that measures the dis- tance red blood cells fall in 1 hour when they are sus- pended in a vertical tube. A sedimentation rate may be useful in following the course of a chronic autoimmune disorder. Although the presence of a normal sedimenta- tion rate does not eliminate an autoimmune disorder, it makes the diagnosis less likely. Sarcoidosis: Angiotensin-converting enzyme. The cause of sarcoidosis is unknown. Head and neck involvement is present in 9% of patients with this dis- order, and isolated nasal manifestations may be present in 1% of affected individuals. 79 Although most patients with sarcoidosis show some depression of immunologic function including anergy to skin testing, decreased T-cell function, and elevated IgA and IgG levels, these findings are nonspecific. Thus biopsy and histopathologic examination of suspi- cious areas of the nose should be performed. Biopsies of the minor salivary glands from the lower lip have also been used to diagnose sarcoidosis.8° However, the diagnosis of this condition requires the exclusion of other disorders that are associated with the histopatho- logic finding of noncaseating granuloma. High levels of angiotensin-converting enzyme are found in 60% to 100% of patients with active sarcoido- sis.79,81-83 These levels return to normal (44 to t25 nmol/ml/min) after steroid therapy.82 The mechanism of the elevations is unknown. The Kveim test for sarcoidosis is accurate in 80% to 85% of cases and has a false-negative rate of 2%. 84 However, this test is seldom done now because of con- cern about bloodborne pathogen transmission and because a commercial test is not available.85 The Kveim test involves intradermal injection of an antigen extract from a patient with known sarcoidosis. The test is considered positive if a nodule develops at the injec- tion site within 4 to 8 weeks and there is histopatholog- ic evidence of a noncaseating granuloma in the nodule. No definitive diagnostic test for sarcoidosis is avail- able. The basic work-up includes a history, a physical examination, biopsy of suspicious lesions (i.e., lesions demonstrating noncaseating granuloma), negative cul- tures for fungus and acid-fast bacilli, angiotensin-con- verting enzyme levels, a chest radiograph, and skin tests. Wegener's granulomatosis: Anf~ineutrophil cyto- plasmic antibody. The diagnosis of Wegener's granu- lomatosis is based on clinical and pathologic findings. Classically, this disease is characterized by the histopathologic finding of necrotizing granulomas and focal necrotizing vasculitis of the upper and lower res- piratory tracts associated with focal necrotizing glomerulonephritis. Because the histopathologic triad of vasculitis, necrosis, and granulomatous inflamma-
  • 11. $22 FERGUSONand MABRY Otolaryngology- Head and Neck Surgery September 1997 tion is reported to occur in only 26% to 42% of patients, the histopathologic findings must be integrated with the serologic laboratory findings and the clinical presenta- tion.86 Wegener's granulomatosis often begins as a local- ized process, with more than 90% of patients initially experiencing head and neck symptoms.8vMost of these symptoms are chronic rhinitis and nasal airway obstruc- tion (71%), purulent sinusitis (47%), and epistaxis (less than 20%). 88 If Wegener's granulomatosis is diagnosed early (e.g., while it is localized to the nose) and treat- ment is instituted, the patient may never progress to lower respiratory or renal involvement. If left untreated, Wegener's granulomatosis usually progresses to fatal systemic disease, with a mean survival of 5 months and a mortality rate of 90% at 2 years.89 In addition to biopsy of the afflicted area (lung, sinus, or nose), ancillary laboratory assays can be help- ful in diagnosing Wegener's granulomatosis. Probably the most important ancillary assay is the cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) assay. When positive, this test results in a characteristic cyto- plasmic staining pattern produced by autoantibodies. The target antigen responsible for c-ANCA is a serine proteinase (proteinase-3). The c-ANCA assay is highly specific for Wegener's granulomatosis (98%).9o The sensitivity of the assay varies with the status of the dis- ease. During active generalized disease the assay is 95% sensitive, during active limited disease it is 67% sensitive, and during inactive disease it is only 32% sensitive.91 False-positive c-ANCA results have been reported in patients with a number of infectious and neoplastic dis- orders. Thus a positive c-ANCA assay does not obviate the need for tissue diagnosis in a patient with clinical manifestations suggestive of Wegener's granulomato- sis, especially if signs of glomerulonephritis are lack- ing.92 Likewise, a negative c-ANCA assay does not necessarily rule out the diagnosis of Wegener's granu- lomatosis, and histopathologic confirmation is impor- tant. The c-ANCA level can also be used to follow dis- ease activity. Increased c-ANCA levels are present 1 to 2 years before clinical exacerbations in half of patients who relapse. 89'93 However, many patients with Wegener's granulomatosis in remission continue to have high c-ANCA titers for years.9~ A positive perinuclear ANCA (p-ANCA) assay is found in other forms of systemic vascnlitis and glomerulonephritis. Thus the p-ANCA assay is not as specific for Wegener's granulomatosis as the c-ANCA assay. Additional laboratory findings in Wegener's granulomatosis include an elevated erythrocyte sedi- mentation rate, normochromic or normocytic anemia, and thrombocytosis. Cystic Fibrosis Cystic fibrosis (CF) is common, occurring in one of every 2750 live births. The frequency and severity of the clinical manifestations and complications of this disease vary greatly. The sweat test is the gold standard for the diagnosis of CE 94 The following clinical sce- narios are indications for a sweat test in a child or ado- lescent: nasal polyps,95,96recurrent or chronic sinusitis that is refractory to antimicrobial therapy,97 and isola- tion of the mucoid variant of Pseudomonas aeruginosa from a respiratory tract culture.9s In approximately 5% to 10% of cases the diagnosis of CF is made in adolescence or adulthood. 99 The pos- sibility of this disease should be considered in every child or adolescent regardless of race and apparent health who fails to respond as anticipated to therapy for rhinosinusitis. The diagnosis of CF will be missed if the sweat test is not done correctly or if the test is not repeated in a patient with a highly suggestive clinical picture and a negative or borderline sweat test.94 Sweat test. This test must be performed by experi- enced personnel with good quality control. The two test methods that have been approved by the U.S. Cystic Fibrosis Foundation are the Gibson-Cooke proce- dure 1°° and the Macroduct Sweat Collection System (Westcor, Inc., Logan, Utah). 1°1 In both systems local- ized sweating is stimulated by iontophoresis of pilo- carpine into the skin of the flexor surface of the fore- arm, calf, or thigh with an electrical charge of 5 mV for 5 to 10 minutes. The Gibson-Cooke method collects sweat on filter paper or gauze, whereas the Macroduct System collects it in microbore tubing. The amount of sweat is quanti- fied, and the sample is analyzed for chloride or sodium concentrations. It is essential that the sample be obtained from only one site. Pooled samples from sev- eral sites or sweat from the head, trunk, or areas of dif- fuse inflammation or serous or bloody discharge give erroneous results. Both false-positive and false-negative sweat tests can occur. Furthermore sweat test values can vary depending on the method of sweat stimulation, salt intake, sweat secretory rate, and nutritional hydration status. Conditions that can cause elevated sweat test values include untreated adrenal insufficiency, anorex- ia nervosa, untreated hypothyroidism, and hypogam- maglobulinemia. There have been reports of negative sweat tests in patients with CE Genetic testing can be helpful in these cases. 102 Sweat testing may not be feasible until 4 weeks of
  • 12. Otolaryngology- Head and Neck Surgery Volume 117 Number 3 Part 2 FERGUSON and MABRY S23 age because of the difficulty in collecting an adequate sweat sample.94 The diagnosis of CF requires two pos- itive sweat tests or one elevated sweat test and the iden- tification of two CF mutations. Potential difference measurement. The increased sodium absorption and decreased chloride permeability in CF result in a higher maximum transepithelial volt- age, or potential difference, across nasal epithelium. Amiloride, a sodium transport inhibitor, accentuates this reduction of voltage. The in vivo measurement of voltage across the nasal epithelium, coupled with the response to amiloride and isoproterenol (a ~3-adrenergic agonist), can be used to differentiate patients with CF (including those with borderline or even normal sweat test results) from patients with other disorders. 1°3-1°5 Potential difference measurement is available only at a limited number of medical centers; however, its diag- nostic utility is widely confirmed, and it should be con- sidered a useful procedure in ambiguous clinical situa- tions.94 Screening tests. The sweat patch test collects sweat, stimulated by pilocarpine iontopheresis, with a paper patch that changes color if the chloride concen- tration is greater than 45 mmol/L. This is only a screen- ing procedure, and it should not be used for the defini- tive diagnosis of CE The nonselective measurement of ions with a con- ductivity analyzer (Wescor Sweat-Chek, Logan, Utah) has been approved as a screening method by the Cystic Fibrosis Foundation. A sweat conductivity result equal to or greater than 50 mmol/L (equivalent sodium chlo- ride) is positive and should be followed by a quantita- tive sweat test.94 Genetic testing.CF is caused by mutations in the CF transmembrane conduction and regulator gene. These mutations lead to abnormal function of the chlo- ride channel More than 550 mutations have been iden- tified. In the white population of North America, approximately 70% of CF chromosomes have the AF508 mutation. 1°6 Nasal polyposis is more common in patients who are homozygous for the AF508 muta- tion. 1°7 Thirteen mutations occur with a frequency of 1% or greater and account for 87% of CF alleles. The frequency of mutations varies greatly from one popula- tion to another. A screen for 31 CF mutations is avail- able as a blood test. Genetic testing may be recommended when the patient and physician do not have easy access to an experienced sweat test laboratory or when cystic fibro- sis is strongly suspected but the sweat test has been neg- ative. The genetic diversity of patients with CF is great, and patients with unusual mutations may still have CF even in the presence of a negative screening genetic test. In the patient with clinical features consistent with CF, the identification of two CF mutations confirms the diagnosis. The identification of a CF mutation on one allele does not confirm the diagnosis, but it does increase the likelihood that the patient has a variant form of CF, providing useful information for genetic counseling. Mutation analysis is seldom helpful in patients with atypical clinical features or borderline sweat test results, because these individuals often do not carry the mutations present in diagnostic screening panels. In addition, CF should not be diagnosed in the patient who has two CF mutations but does not have a consistent clinical picture. CF is a clinical, not a genetic, diagno- sis. ALTERNATIVES TO RADIOGRAPHIC IMAGING OF THE PARANASAL SINUSES Transiliumination For more than 50 years transillumination has been used to obtain clues about the presence of retained secretions or significant mucosal thickening in the frontal or maxillary sinuses (but in no other sinuses)] °8 Although a series comparing antral and frontal transil- lumination with sinus radiographs ~°9 showed 100% concordance between normal radiographs and transillu- mination, only 55% of patients with positive radi- ographic findings had abnormal transillumination. With transillumination, intraobserver reproducibility is low in assessing the maxillary sinuses (60%) but high in assessing the frontal sinuses (90%).11° At times trans- illumination may be a helpful adjunct, but it should not be the sole basis for making a treatment decision. Ultrasound Scans A-mode ultrasound scans can demonstrate the pres- ence of fluid or tissue filling a sinus. However, if air is present between the anterior sinus wall and the patho- logic sinus content, the ultrasound impulse will be absorbed, and a false-negative ("normal") pattern wilt result.I°9,111 Like transillumination, ultrasound scans are limited in their application to the diagnosis of frontal or astral disease. In a comparison of ultrasound scans and sinus radiographs that used CT scans as a reference, Hl ultra- sound scanning was found to be more sensitive but less specific than radiographs in diagnosing maxillary sinus disease. A-mode ultrasound scanning may be valuable in fol- lowing the course of maxillary sinusitis once a positive diagnosis has been established, because ultrasound examination does not subject a patient to radiation exposure or antral puncture. 112
  • 13. $24 FERGUSON and MABRY Otolaryngology- Head and Neck Surgery September 1997 REFERENCES 1. Clement PAR. Committee report on standardization of rhino- manometry. Rhinology 1984;22:151-5. (grade A) 2. McCaffrey TV. Rhinomanometry and vasoactive drugs affecting nasal patency. In: Getcheli TV, Doty FL, Bartoshuk LM, et al., editors. SmelI and taste in health and disease. New York: Raven Press, 1991:chap 31. (grade C) 3. Lai VW, Corey JR The objective assessment of nasal patency. Ear Nose Throat J 1993;72:395-400. (grade C) 4. Hilberg O, Jackson AC, Swift DL, et al. Acoustic rhinometry: evaluation of nasal cavity geometry by acoustic reflection. J Appl Physiol 1989;66:295-303. (grade A) 5. Fisher EW, Boreham AB. Improving the reproducibility of acoustic rhinometry: a customized stand giving control of height and angle. J Laryngol Otol 1995;109:536-7. (grade C) 6. Tomkinson A, Eccles R. 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