Respiratory complications of relapsing polychondritis · of the trachea in relapsing polychondritis has perhaps implied that the airflow obstruction is a dynamiceffect dueto loss

Thorax (1974), 29, 726.

Respiratory complications of relapsingpolychondritis

G. J. GIBSON and P. DAVIS

Department of Medicine, Royal Postgraduate Medical School,Hammersmith Hospital, London W12

Gibson, G. J. and Davis, P. (1974). Thorax, 29, 726-731. Respiratory complications ofrelapsing polychondritis. The respiratory function of a patient with relapsing polychon-dritis is described. He had severe airflow obstruction due to disease of both the extraand intrathoracic large airways. Evidence of small airways disease was lacking. Theairflow obstruction was probably due to a combination of structural narrowing and anenhanced dynamic effect. Despite the severity of his disease the patient's exercisecapacity was only slightly reduced but he developed carbon dioxide retention on exercise.Involvement of the airways is a common feature of this rare disease and demands fullphysiological and radiographic assessment if tracheostomy or other surgical procedureis contemplated.

Relapsing polychondritis, first described byJaksch-Wartenhorst (1923), is a rare inflammatorydisease affecting cartilage-containing tissues. Theclinical features have been the subject of severalreviews (Pearson, Kline, and Newcomer, 1960;Kaye and Sones, 1964; Dolan, Lemmon, andTeitelbaum, 1966; Hughes, Berry, Seifert, andLessof, 1972; leading article, 1973); many tissuesmay be affected, including the nose, ears, costalcartilages, joints, and eyes. A poor prognos-tic feature is said to be involvement of the car-tilage of the upper airway leading to 'collapse'of the larynx or trachea, and respiratory compli-cations have accounted for most of the reporteddeaths. To avoid these complications early trache-ostomy has been suggested but as there is littleinformation on the extent of airway involvement,its value is uncertain. Neither is it establishedwhether the airway 'collapse' is due to fixedobstruction or to abnormal dynamic effects in anairway whose compliance has been increased bydestruction of cartilage. Assessment of both thesefactors is clearly important if any attempt atsurgical replacement or support of the diseasedairway is contemplated. Accounts of pulmonaryfunction in this condition are few and usuallylimited to spirometric measurements. We herepresent the results of investigation of a patientwith relapsing polychondritis in whom respiratorysymptoms were prominent.

CASE REPORT

A 36-year-old non-smoking Iranian developed cough,mucoid sputum, attacks of 'bronchospasm', andpyrexia in March 1972. He was treated initially as acase of 'asthmatic bronchitis' but failed to respond toantibiotics and bronchodilators. By June 1972 hisrespiratory symptoms had progressed and he haddeveloped expiratory stridor. He had lost 12 kg inweight and complained of pain in the nasal cartilageand manubriosternal joint. A clinical diagnosis ofrelapsing polychondritis was made and he was treatedwith prednisone.

In December 1972 the patient was referred to theHammersmith Hospital. On examination he waspyrexial and showed the characteristic facies of thedisease with flattening of the bridge of the nose; therewas tenderness and hypermobility of the nasal andaural cartilages and tenderness of the rib cartilagesand trachea. Examination of the chest showed tachy-pnoea, bovine cough, and low-pitched expiratorystridor; the lung fields were otherwise clear on auscul-tation. Examination of the cardiovascular system,abdomen, and central nervous system was negative;there was no evidence of involvement of the jointsor eyes.

INVESTIGATIONS Haemoglobin 14-5 g/ 100 ml. Whitecell count 6,000/mm', film normal. ESR 77 mm infirst hour (Westergren). Total serum protein 6-6 g/100 ml; albumin 3-3 g/100 ml; globulin 3-3 g/100 ml.Electrophoretic pattern-increased a, and a2 globulins.Immunoglobulins normal. Wassermann reaction nega-

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Respiratory complications of relapsing polychondritis

tive. Rose Waaler, latex, and antinuclear factor nega-tive. Human fetal cartilage antibody strongly positive.Electrocardiogram normal.A chest radiograph showed normal lung fields with

narrowing of the trachea and main bronchi, whichwas more evident on tomography (Fig. 1).

FIG. 1. Tomogram of larynx and trachea showingextensive narrowing. Film taken during breath holdingin inspiration. The lower trachea and main bronchishowed similar changes.

RESPIRATORY FUNCTION Measurements of lungvolumes, specific airways conductance, transfer factor(single-breath method), and resting arterialized earlobe capillary blood gases are shown in Table I andare compared with predicted values. There was agreatly reduced one-second forced expiratory volume(FEV1) and a normal vital capacity (VC) together

TABLE IRESPIRATORY FUNCTION AT REST

Measured Predicted

Lung volumes (litres)FEV, 0-8 3-7FIV1 1-5 > 3-7Vital capacity 4-1 4-4Total lung capacity 6-0 6-2Residual volume 1-9 1-8

Specific airways conductance(sec-I cmHsO-1) 0 03 > 0-13

Transfer factor (ml mnn-1 mmHg-' 40-0 30-1Arterialized blood gases

PO, (mmHg) 93PCO2 (mmHg) 39

with a low airways conductance, indicating severeairflow obstruction. The one-second forced inspiratoryvolume (FIV,) was also low but greater than the FEV1;static lung volumes, transfer factor, and blood gases atrest were all normal.Maximum expiratory and inspiratory flow-volume

curves are shown in Fig. 2 with normal curves forcomparison. The recording showed unusually wideoscillation of expiratory flow rate corresponding tothe expiratory stridor. No similar oscillation occurredon inspiration. Maximum flow rates throughout thevital capacity were reduced but the reduction was con-siderably greater on expiration than inspiration.

'Closing volume' was measured by the argon bolustechnique (McCarthy and Milic-Emili, 1973) and arepresentative example of the expired argon tracemeasured by a mass spectrometer is shown (Fig. 3).The ratio of 'phase IV' to VC was 17% which is nor-mal for the patient's age (Maberly and Freedman,unpublished). A second noteworthy feature of thetrace was the near horizontal alveolar plateau ('phaseIII'), indicating even emptying of lung units.

Exercise tolerance was assessed by progressiveexercise on a bicycle ergometer, the power outputbeing increased by 100 kpm min-' each minute. Thepatient comfortably achieved a power output of700 kpm min-' which represents only a mild reductionof exercise capacity for his age. At this level hisventilation was 27 1. min-' which is very close to hispredicted maximum breathing capacity (FEV1X 35;Gandevia and Hugh-Jones, 1957). Further analysisof the patient's excercise response and pulmonarygas exchange was obtained by steady-state exercise ata power output of 350 kpm min-' with sampling ofear lobe capillary blood. The results are comparedwith values at rest in Table II. The most strikingabnormality on exercise was the rise in arterial C02tension from 39 to 50 mmHg, indicating alveolarunderventilation. The mixed expired C02 tension washigh and total ventilation correspondingly low. Thearterial oxygen tension fell from 93 to 86 mmHg butthe alveolar-arterial oxygen tension difference andcalculated physiological shunt remained normal. This,

TABLE IIRESPONSE TO EXERCISE

ExerciseRest 350 Kpm min-

(58 watts)

Minute ventilation (1 min-') 13-0 21 9Frequency (per minute) 25 21Tidal volume (ml) 520 1042CO, production (ml min-) 366 1090Oxygen uptake (ml min-) 416 1165Respiratory exchange ratio 0-88 0 94Arterialized capillary gases

PaOs (mmHg) 93 86PaCO, (mmHg) 39 50

Mixed venous PCO, (mmHg) 51-5 72-5Expired PCO2 (mmHg) 24-4 43-2Dead space tidal volume ratio % 26 8Alveolar-arterial oxygen

tension difference (mmHg) 13 11% venous admixture - 2-2

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PATIENT

VE

L/sec

,-

2 3 /VOLUME (l. below TX

L/sec

mean signal with-- - - - amplitude of

oscillation

FIG. 2. Maximum expiratory and :inspiratory flow-volume curves of the patient with normal curves for com-

parison. Expiratory curve obtained by forced vital capacity manoeuvre from full 'inflation. Inspiratory curve

obtained after slow expiration to residual volume.

EXPIRED

ARGONCONCE NTRATION

(arbitrary scale)I

||4PHASE m . ,PHASE1S

III1

I It0 2 3 4

EXPIRED VOLUME l.

FIG. 3. Expired argon trace during slow expirationfrom total lung capacity to residual volume. (A bolusof argon had been injected at the mouth while thepatient held his breath at residual volume and a slowfull inspiration preceded the recording.) The point ofinflexion between phases III and IV marks the'closing volume'.

together with the normal physiological dead space,indicates normal matching of ventilation andperfusion.

Ventilatory response to CO2 measured by the re-breathing technique of Read (1967) was 0 56 litremin-1 mmHg-' which is at the lower limit of the widenormal range quoted by Rebuck and Read (1971).

DISCUSSION

The aetiology of relapsing polychondritis remainsobscure. Though inflammation is localized intissues with high glycosoaminoglycan concentra-tion there is little evidence that the disease is pri-marily a disorder of metabolism. The occasionalassociation with aortitis, iritis, and vasculitissupports the more widely held view that it isrelated to the connective tissue diseases. Theremay be an autoimmune basis: chondroitin sul-phate has been shown to produce a humoralantibody response in rabbits (Glynn and Hol-borow, 1952) and lymphocyte transformation hasbeen induced with chondromucoprotein in somepatients (Herman and Hess, 1971). In addition,antibodies to fetal human cartilage were foundin two of the three cases reported by Hughes et al.(1972). None of these findings, however, is specificfor relapsing polychondritis.Of the typical features of the disease, our

patient showed inflammation of nasal, aural, andcostal cartilages and antibodies in the serum to

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fetal cartilage. However, the most important, andpotentially lethal, complication was involvementof the airways. Our studies of respiratory functionwere aimed at assessing (1) the severity of theairflow obstruction, (2) its site and extent, (3) itsnature, i.e., whether due to fixed obstruction or toabnormal dynamic effects, and (4) the degree ofimpairment of the patient's exercise capacity andthe pattern of his response to exercise.The degree of airflow obstruction, as judged by

the FEV, and conductance, was severe and therewas no improvement after bronchodilator.Though there was radiological evidence of abnor-mality of the extrathoracic trachea, the FIV, andinspiratory flow rates were reduced less thanthe expiratory measurements, the typical patternof intrathoracic airways obstruction (Miller andHyatt, 1969; Clark, 1970).The radiological and functional studies together

show evidence of narrowing of at least the largerintrathoracic airways. However, the indices of gas

exchange such as the expired gas trace, alveolararterial oxygen tension difference, and transferfactor, were normal. This is quite unlike theusual forms of intrathoracic airflow obstruc-tion-chronic bronchitis, asthma or emphysema-where the disease process is probably maximal insmaller airways of 2 mm diameter or less. Thoughcartilage in the normal bronchial tree is presentin airways down to 1 mm diameter (Bates,Macklem, and Christie, 1971) it is of less impor-tance for bronchial stability in these smallerintrapulmonary airways which are supported bysurrounding lung, and its loss should producelittle effect on pulmonary function. The fewnecropsy studies of the airways in relapsing poly-chondritis show, however, in addition to loss ofcartilage, areas of extensive narrowing and dis-tortion with granulation tissue and fibrosis (e.g.,Harwood, 1958). Though the pathological evi-dence is confined to the larger airways, one wouldexpect similar changes in smaller airways con-

siderably to affect pulmonary gas exchange andproduce abnormalities of the alveolar-arterialoxygen tension difference or the 'alveolar' plateauon the expired gas trace. The normality of thesetests in our patient makes it unlikely that thedisease extends far beyond the main bronchi. Thiscould have been further assessed by bronchoscopicstudies but these were thought to be potentiallyhazardous to our patient and were not performed.The emphasis of various authors on 'collapse'

of the trachea in relapsing polychondritis hasperhaps implied that the airflow obstruction is a

dynamic effect due to loss of rigidity of the airway

walls. However, our patient's low specific con-ductance, which is measured during panting, re-flects an abnormally high resistance of the airwaysat low flow rates and together with the radio-graphs indicates severe 'intrinsic' narrowing.More sophisticated studies, including intraluminalpressure measurements, would be required toestablish whether in addition dynamic narrowingof the large intrathoracic airways was excessiveand to determine whether this was secondary toperipheral obstruction or to enhanced complianceof the central airways. A cine film of the majorairways did, however, appear to show an abnormaldynamic effect even during tidal breathing, which,in view of the probable normality of the peri-pheral airways, supports the concept of increasedcompressibility of the affected large airways.The patient's response to exercise was unusual;

by allowing the arterial C02 tension to rise he wasable to achieve a surprisingly high level of exer-cise at a low ventilation. The rise of 11 mmHg isgreater than is usually seen in chronic bronchitis(Spiro, Hahn, Edwards, and Pride, 1975); it wasaccompanied by only a slight fall in arterialoxygen tension and, unlike chronic bronchitis,there was no evidence of ventilation/perfusioninequality. It is interesting that alveolar under-ventilation occurs on exercise in normal subjectsbreathing through an external resistance (Gee,Burton, Vassallo, and Gregg, 1968) and Al-Bazzazand Kazemi (1972) have reported slight alveolarunderventilation as the response to exercise inpatients with upper (extrathoracic) airway ob-struction; perhaps this pattern is characteristic ofobstruction of the larger airways. Our patient'sapparent insensitivity to C02 iS confirmed by thelow ventilatory response during rebreathing. Thisdoes not necessarily indicate insensitivity of therespiratory centre but is more likely a conse-quence of the severe ventilatory limitation.

In conclusion, the physiological and radio-graphic studies together show that in this patientboth extra and intrathoracic airways are diseasedbut the peripheral airways are unlikely to beinvolved and the airway resistance is increaseddue to a diminution of resting calibre as well asto dynamic narrowing on expiration.Although involvement of the airways in re-

lapsing polychondritis was noted by Hughes et al.(1972) in 47% of the reported cases, there havebeen few assessments of the resulting functionalabnormalities or of the underlying pathologicalchanges. The only other extensive physiologicalstudy of a patient with relapsing polychondritisof which we are aware is that published by

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Vaudour, Payot, Diebold, and le Melletien(1967). They described a patient with widespreadtracheobronchial involvement whose functionalpattern bears several similarities to the presentcase-severe airways obstruction (FEV, 033 1.,VC 1P71 I.) with FIV, (0-96 1.) greater than theFEV1, a normal residual volume and arterial oxy-gen saturation. Others have noted a reducedmaximum breathing capacity (Pearson et al.,1960) or an obstructive ventilatory defect (Hornsand O'Loughlin, 1962).Death in patients with relapsing polychondritis

has usually been attributed to respiratory compli-cations (Harwood, 1958; Purcelli, Nahum, andMonell, 1962; Jensen and Jensen, 1967). Atnecropsy, the affected airway macroscopicallyshows loss of normal rigidity together with con-centric thickening of the wall. Microscopicallythe lesionr resemble those in other cartilaginoustissues. The cartilage plates are degenerate orabsent, with infiltration by lymphocytes andplasma cells and replacement by fibrous tissue;sometimes there seem to be areas of regeneratingcartilage and bone (Self, Hammarsten, Lyne, andPeterson, 1967) even with foci of haemopoiesis(Verity, Larson, and Madden, 1963). The lesionsmay be discrete and localized or extensive, involv-ing the whole of the upper airway (Purcelli et al.,1962). Though most attention- has been paid to thelarynx and trachea, bronchial involvement wasrecorded in an early case (Altherr, 1936) and hasbeen noted many times since (Verity et al., 1963;Thould, Stansfeld, and Wykeham Balme, 1965;Vaudour et al., 1967). There is, however, noinformation available on the condition of airwaysdistal to secondary bronchi, and more detailednecropsy studies are needed.Involvement of the airways in relapsing poly-

chondritis is said to be a bad prognostic sign(Thould et al., 1965; Dolan et al., 1966) oftenleading to sudden unexpected death. The naturalhistory, however, is variable, and the patient ofVaudour et al. (1967) whose respiratory functionwas well documented survived three years withsevere airways involvement. Other patients withlesions in the airways have lived for up to 24 years(Kaye and Sones, 1964) but it is not clear for howlong the airways were affected.Our patient had been treated with steroids for

six months before his respiratory function wasfirst assessed. Between December 1972 and June1974, when he was seen for reassessment, he con-tinued to lead an active life with no symptomaticdeterioration on a daily dose of 10 mg prednisone.Repeat function testing in June 1974 however

showed a slight overall deterioration. In particu-lar, the FEV1 had fallen to 0-6 1. and there was afurther reduction in maximum flow rates at alllung volumes but the pattern remained that ofpredominantly intrathoracic airflow obstruction;his exercise capacity (in a progressive test) wasreduced to 600 kpm min-'; the resting arterialPco, was slightly higher at 46 mmHg and duringsteady state exercise at the same work load as pre-viously (350 kpm min') the hypercapnia was moresevere (Paco2 62 mmHg); despite this deteriora-tion the physiological dead space and calculatedvenous admixture remained normal.The relapsing nature of the disease implied by

its title as well as its comparative rarity makeassessment of treatment difficult. Most authoritiesfavour the use of steroids and some (Dolan et al.,1966) say that their efficacy is greatest for laryngo-tracheobronchial manifestations, but this is diffi-cult to substantiate in the absence of objectivetests of ventilatory function. Many of the patientsdescribed with tracheal involvement have under-gone tracheostomy, and on one occasion (Daly,1966) a localized segment of the upper tracheawas temporarily replaced by a prosthesis withapparent success. Early tracheostomy has beenrecommended but is likely to benefit only patientswith localized tracheal involvement and will beuseless in those with more extensive disease. Like-wise supportive splinting of the airway might beof value in localized lesions if dynamic effectswere predominant. Clearly full radiographic andfunctional assessment is indicated before anysurgical procedure is undertaken.

We wish to thank Professor E. G. L. Bywaters forpermission to study the patient and Dr. N. B. Pridefor helpful discussion.

REFERENCES

Al-Bazzaz, F. and Kazemi, H. (1972). Mechanisms ofexercise hypoxemia and dyspnea in trachealstenosis. American Review of RespiratoryDisease, 105, 1002.

Altherr, F. (1936). Vber einem Fall von systematisier-ter Chondromalacie. Virchow's Archiv fur patho-logische Anatomie und Physiologie und fiurklinische Medizin, 297, 445.

Bates, D. V., Macklem, P. T., and Christie, R. V.(1971). Respiratory Function in Disease, 2nd ed.,p. 2. Saunders, Philadelphia.

Clark. T. J. H. (1970). Inspiratory obstruction. BritishMedical Journal, 3, 682.

Daly, J. F. (1966). Relapsing polychondritis of thelarynx and trachea. Archives of Otolaryngology,84, 570.

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Dolan, D. L., Lemmon, G. B. Jr., and Teitelbaum,S. L. (1966). Relapsing polychondritis, analyticalliterature review and studies on pathogenesis.American Journal of Medicine, 41, 285.

Gandevia, B. and Hugh-Jones, P. (1957). Terminologyfor measurements of ventilatory capacity. Thorax,12, 290.

Gee, J. B. L., Burton, G., Vassallo, C., and Gregg, J.(1968). Effects of external airway obstruction onwork capacity and pulmonary gas exchange.American Review of Respiratory Disease, 98,1003.

Glynn, L. E. and Holborow, E. J. (1952). Conversionof tissue polysaccharides to auto-antigens bygroup-A beta-haemolytic streptococci. Lancet, 2,449.

Harwood, T. R. (1958). Diffuse perichondritis, chond-ritis, and iritis. Archives of Pathology, 65, 81.

Herman, J. H. and Hess, E. V. (1971). Immunopatho-logic studies in relapsing polychondritis. Abstractsof the 7th European Rheumatology Congress,12, 4.

Horns, J. W. and O'Loughlin, B. J. (1962). Trachealcollapse in polychondritis. American Journal ofRoentgenology, 87, 844.

Hughes, R. A. C., Berry, C. L., Seifert, M., andLessof, M. H. (1972). Relapsing polychondritis.Quarterly Journal of Medicine, 41, 363.

Jaksch-Wartenhorst, R. (1923). Polychondropathia.Wiener Archiv fur innere Medizin, 6, 93.

Jensen, 0. A. and Jensen, F. (1967). Relapsing poly-chondritis. Acta Pathologica et MicrobiologicaScandinavica, 69, 357.

Kaye, R. L. and Sones, D. A. (1964). Relapsing poly-chondritis. A nnals of Internal Medicine, 60,653.

Leading article (1973). Relapsing polychondritis.British Medical Journal, 2, 627.

McCarthy, D. and Milic-Emili, J. (1973). Closingvolume in asymptomatic asthma. AmericanReview of Respiratory Disease, 107, 559.

Miller, R. D. and Hyatt, R. E. (1969). Obstructinglesions of the larynx and trachea; clinical andphysiologic characteristics. Mayo Clinic Proceed-ings, 44, 145.

Pearson, C. M., Kline, H. M., and Newcomer, V. D.(1960). Relapsing polychondritis. New EnglandJournal of Medicine, 263, 51.

Purcelli, F. M., Nahum, A., and Monell, C. (1962).Relapsing polychondritis with tracheal collapse.Annals of Otology, Rhinology and Laryngology,71, 1120.

Read, D. (1967). Clinical investigation of the regula-tion of breathing. MD thesis, University ofSydney.

Rebuck, A. S. and Read, J. (1971). Patterns of venti-latory response to carbon dioxide during recoveryfrom severe asthma. Clinical Science, 41, 13.

Self, J., Hammarsten, J. F., Lyne, B., and Peterson,D. A. (1967). Relapsing polychondritis. Archivesof Internal Medicine, 120, 109.

Spiro, S. G., Hahn, H. L., Edwards, R. H. T., anidPride, N. B. (1975). Analysis of the physiologicalstrain of submaximal exercise in patients withchronic obstructive bronchitis. Submitted forpublication.

Thould, A. K., Stansfeld, A. G., and Wykeham Balme,H. (1965). Chronic atrophic perichondritis.Annals of Rheumatic Diseases, 24, 563.

Vaudour, X., Payot, J., Diebold, J., and le Melletien,J. (1967). Les manifestations respiratoires de lapolychondrite chronique atrophiante. JournalFranqais de Medicine et Chirurgie Thoraciques,21, 383.

Verity, M. A., Larson, W. M., and Madden, S. C.(1963). Relapsing polychondritis. American Jour-nal of Pathology, 42, 251.

Requests for reprints to: Dr. G. J. Gibson, Depart-ment of Medicine, Royal Postgraduate MedicalSchool, Hammersmith Hospital, London W12.

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Respiratory complications of relapsing polychondritis · of the trachea in relapsing polychondritis has perhaps implied that the airflow obstruction is a dynamiceffect dueto loss