chronic cor pulmonale in pulmonary sarcoidosis · cor pulmonale in pulmonary sarcoidosis....

Thorax, 1978, 33, 76-84

Chronic cor pulmonale in pulmonary sarcoidosisJ. P. BATTESTI, R. GEORGES, F. BASSET, AND G. SAUMON

From CHU Bobigny-Paris 13, Service de Pneumologie and INSERM, Groupe de Recherches U 82,Paris, France

Battesti, J. P., Georges, R., Basset, F., and Saumon, G. (1978). Thorax, 33, 76-84. Chroniccor pulmonale in pulmonary sarcoidosis. Right-heart overload happens relatively rarely insarcoidosis, even with fibroemphysematous changes. Of 21 cases that we studied, six (28%) hadclinical and/or electrocardiographic features of cor pulmonale. The cause of cor pulmonaleoften evoked is an invasion of the walls of pulmonary vessels by sarcoid granulomas or theircompression by the fibrotic process. Pathological studies in one patient showed compression oflarge pulmonary arteries associated with specific sarcoid lesions in small and medium-sizedarteries.

The development of chronic cor pulmonale due topulmonary hypertension has rarely been describedin pulmonary sarcoidosis, even in chronic fibro-emphysematous forms. The mechanisms oftenevoked to explain the occurrence of pulmonaryhypertension are based on histological findings, theperivascular occurrence of granulomas with thefibrosis which sometimes results, and the possibilityof thrombosis or invasion of arterial and vein wallsby granulomas.

Material and methods

Twenty-one cases of chronic sarcoidosis werestudied.The diagnosis was made using clinical, radio-

logical, pathological (bronchial biopsy), and im-munological (Kveim test, tuberculin anergy)findings. Such a diagnosis was confirmed in life bythese methods even in the two cases (2 and 5)where no definite evidence of sarcoidosis wasfound at necropsy many years later.The radiographic classification was based on

postero-anterior and lateral views, occasionallyconfirmed by tomography.

Evidence of right-sided heart involvement wasbased upon clinical examination and six electro-cardiographic criteria (Schaub, 1966):

1 QRS vector angle in the frontal plane(angle a)>+900.

2 Negative T wave in S2 and S3 or S, andca. +900.

3 S wave in V, and V >07 mV.4 R wave in V,+S wave in V5>1 mV.

5 QRS direction to the right and posterior:rS of V1 to V4, sometimes rS or Qs of V1 toV6 with positive or flattened T waves.

6 Incomplete right bundle-branch block: rSR' in V1 with R' in V1>10 mV.

Radiological measurement of the size of the rightheart chambers and the diameter of the pulmonaryarteries was in most cases impossible because ofthe perihilar pulmonary opacities which obscuredthe cardiac and arterial contours. Thus radio-logical criteria were not taken into account.

Results

ANALYSIS OF THE 21 CASESThe main results are shown in the Table. Threeradiological groups may be distinguished:Type I (5 cases) Very dense perihilar 'pseudo-tumour' shadows (with or without cavities); retrac-tion of the upper lobes and transradiancy withoutbullous formation of the lower lobes (Fig. 1)Type II (11 cases) Diffuse reticulonodulation.Two subgroups can be formed:

Ila (6 cases) Reticulation of either micro-nodular or honeycomb types evenly distributedthroughout both lungs (Fig. 2).

Ilb (5 cases) Irregular pulmonary reticulationwith dense linear opacities scattered throughoutthe lungs.Type 1II (5 cases) Thin-walled transradianciesand dense linear opacities, suggesting bullousemphysema associated with linear fibrosis (Fig. 3).

In all patients, the radiographic abnormalitiesremained unchanged for several years in spite of

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Chronic cor pulmonale in pulmonary sarcoidosis

Table Radiographic and cardiac features

Case Radiologi- Frontal Electrocardiographic Clinicalcalgroup QRS criteria right

vector heart(a) failure

1 1 + 90 C2 +2 I ±603 + 304 I + 305 1 +160 C1+C2-,C3+C4+C6 +6 Ila + 707 Ila - 80 CI+C2+C3+C4+C5 +8 Ila + 209 Ila +120 C1+C2+C3+C4+C6 +10 Ila + 1011 hIa + 90 C2 + C312 Ilb + 3013 IIb 014 Ilb +120 C115 lIb 016 llb - 301 7 III - 3018 III + 6019 III + 3020 III + 6021 III -30

prolonged corticosteroid therapy. Clinical right-sided heart failure was observed in four cases andelectrocardiographic patterns suggestive of corpulmonale were noted in six cases. All cases withclinical right heart failure showed electrocardio-graphic abnormalities, usually with the associationof several criteria. Electrocardiographic changes

were observed in radiological groups I and Ila 5times out of 11.

ANALYSIS OF CASE 7A 49-year-old white woman was admitted tohospital in January 1975. She had isolated pul-monary sarcoidosis with dyspnoea on exertionand a bilateral diffuse nodulo-infiltrative appear-ance on chest radiography with a massive lingularinfiltrate; the diagnosis was made by bronchialbiopsy and immunological findings. The electro-cardiogram showed signs of cor pulmonale (Table).Worsening of her dyspnoea and the rapid onset ofclinical heart failure suggested pulmonary em-bolism. Angiography (Fig. 4) through a venouscatheter revealed complete obstruction of the leftupper lobe artery and stenosis with secondaryrecanalisation of the right lower and upper lobearteries. Death occurred in March 1975.

Necropsy showed numerous calcified para-tracheal and interbronchial nodes, which com-pressed the proximal pulmonary arteries (Fig. 5).The lungs showed fibrotic areas in the upper lobesand a subpleural infarct in the right lower lobe.

Several types of lesion were observed in histo-logical sections. There was severe congestion, thealveolar exudates showing oedema, haemorrhage,and macrophages. On this background two typesof focal lesions stood out. The first consisted of

, .............

E ....... ..

E Fig. 1 Radiological picture characteristicof type I (case 2).

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J. P. Battesti, R. Georges, F. Basset, and G. Saumon

Fig. 2 Radiological picturecharacteristic of type II: enlargeddetail of diffuse reticulomicro-nodular infiltrates (case 9).

Fig. 3 Radiological picture characteristicof type Ill (case 19).

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Fig. 4 Pulmonary arteriogram (postero-anterior view) showing obstruction ofpulmonary vessels (case 7).

0 *~~~~~~~~~~~IE

Fig. 5 Gross section of left lung showing white fibrotic areas with tiny arterial lumina, one of which(arrow) is especially narrowed.

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J. P. Battesti, R. Georges, F. Basset, and G. Sanmnon

infarcts, not only the large one in the right lower ,.-:lobe, but also smaller, more recent ones. Theother type of lesion consisted of tuberculoidgranulomas without necrosis. They were usually Xfound along the bronchovascular sheaths, invad-ing the bronchial and, to a lesser degree, thevascular walls. They were also numerous at the - --^-] - ;;Sedges of large fibrotic areas, apparently in pul- -- -monary tissue. However, their proximity to large ^ i 2 X ~; E..bronchi and vessels and the presence of a i_ahyalinised border and central anthracotic pig- wgl->msehntatiionn lded us tho interpret these fibrous areas i~if

vascuhy ainsed lymph nodeas. ueos tte

In the wallsof large bronchi, follcular lesionsiat every stage, without any signs of caseousrgenecrosis, werea ssociated with shrinkage of a Oadjoining bronchiallumina with disruption of the /ig

Mostvessels exhibited important changes. Their Twallsw erethickened by fibrosis, either loose ands

cellular,or compact (Fig. 6). The lumen wasnarrow when present,or wasreplaced by tinyrecanalisation channels (Fig. 7). Embedded in the

S ~~~~~~~~~~~~~Fig.7 Higher magnfiction of Fig 6,showin

bronchialcartilageml ula ons somtimues

Most In larger arteries thereweree thr i ofv.arrywallswerathickenedand size adhegttshewter(lo6asliidrtbcellular,orcompact aggreg.ats withe l ent C all maeies,aeionswere pumnle w sevrarlycells whe n present, narrowte lina and afdisorganisedatssm oormusc

recnalsaton hanel (Fg 7ayeEmFigsldandl2)e

!!i.-K NO-4--p l o ar is e

Fin. aditiohtothmabovevasulaaeions,fFigthereoinweasnalisatonaeucinXnsieofte5reredet

wathei flcmprlessionsbthmethainisedhisarupelymheV ~ ~ ~ ~~~oelsti (particuaryis the let an umoayn

-~ ~ A the uppger lfloearteries).hrewr thrmisvascuarycom-..... ag~~pessind wsiz furher increasedebyltheiconractura

smafibrosisiof,allsthis wregion,forcauing bevronhal

Mdisto tionandtebenigolymph nodesianaperntolumeisvisblen te lft o th piturewit asimcuia o ta ftehaiie assatcepartiallyoccludingthrclun'mbuse, wichTheanarteriallreawallofibrousandthickenedandrpretigtheeblackastainedodeelastict

lamiaisdisupteby ellaggrgate wih gintwCanials manifestationinsizofco tuloaeartere rarelyocellsVerhoefsstain XiS)heportdifoprsixed fbro-hemphyalnsemaou folrmsymof

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Chionic cor pulmonale in pulmonary sarcoidosis

Fig. 8 Close to a hyalinised area, an arterial lesion with intimal fibrosis and a few recanalisationvessels. Several epithelioid and giant-cell granulomas disrupt or distort the elastic lamina(Verhoeff's stain X40).

Fig. 9 Higher magnification of Fig. 8, showing loose cellular infiltrates, giant cells. and changesin the elastic lamina (X165).

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Fig. 10 Low-power view of a group of follicular lesions involving a bronchus (cutlengthwise, on the right side of the picture) and a narrow artery with a disrupted elasticlamina (Verhoeff's stain X 165).

Fig. 11 Obliquely cut vessel, the wall of which is in close contact with a granuloma(Haematoxylin and eosin X 135).

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Fig. 12 Plexiform lesion (Haematoxylin and eosin X135).

pulmonary sarcoidosis. Among 13 patients whodied from sarcoid pulmonary fibrosis, Scadding(1967) observed three with clinical right ventri-cular failure and one with isolated electrocardio-graphic right ventricular hypertrophy, thusfinding evidence of chronic cor pulmonale in30% of cases. According to this author, theassociation with chronic bronchitis is an importantaetiological factor. Out of 11 necropsies ofsarcoid fibrosis, Sones and Israel (1960) observedfour cases of chronic cor pulmonale (36%);Mayock et al. (1963) noted three cases out of ninedeaths. In our group, chronic cor pulmonalemanifestations with or without right heart failurewere observed in six out of 21 cases (28 6%).

Studies of the pathology of pulmonary hyper-tension in sarcoidosis have shown in the majorityof cases only the small and medium-sized arteriesto be clearly affected. Lesions consist of generallyincomplete thrombosis provoked by either peri-bronchovascular fibrosis or granulomatous in-vasion of the vascular walls (Mallory, 1948;Longcope and Freiman, 1952; Thompson, 1966;Turiaf et al., 1973). Thromboembolism may besuperimposed in some cases. On the other hand,involvement of the large branches of the pul-monary artery is exceptional. Schermuly andBehrend (1968) performed pulmonary angiography

on 150 subjects suffering from sarcoidosis andobserved modifications in the orientation of theproximal arteries. These modifications were attri-buted to the fibrosis, but no change in size of thepulmonary vessels provoked by lymph-node com-pression was noted. The authors did not specifythe stage of evolution of the illness (in particular,the presence or absence of mediastinal adeno-pathies).

Shibel et al. (1969) studied 31 subjects sufferingfrom sarcoidosis and noticed abnormalities in peri-pheral perfusion detected by scintigraphy in twocases where isolated mediastinal adenopathy waspresent. The authors postulated either the exist-ence of pulmonary impairment undetected byradiography or a decrease in the diameter of theproximal vessels. Westcott and de Graff (1973)reported the case of a 29-year-old coloured manwith mediastinal lymph adenopathy. Scintigraphyrevealed a perfusion defect of the upper right lobe,suggesting pulmonary embolism. A right pul-monary arteriogram showed compression of theright upper lobe artery by hilar nodes. Elevenmonths later, the chest radiograph and scin-tigraphy spontaneously returned to normal.Gordonson et al. (1973) reported a case of com-pression by an enlarged right paratracheal node ofthe superior vena cava. This was completely

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asymptomatic and diagnosed by venacavagram.Enlarged sarcoid mediastinal lymph nodes can

thus compress the large pulmonary vessels. Whensuch nodes are recent and have an essentiallygranulomatous structure, compression is certainlyvery exceptional and, in any case, reversible. Atthe fibroemphysematous stage, when the enlargednodes have undergone fibrohyaline transformationand are sometimes the site of calcification,irreversible compression of the large pulmonaryvessels can be more easily explained. Its frequencyis difficult to assess in the absence of angiographicinformation. In our case 7, the role of lymphnodes in compression and obstruction of the largevessels is particularly evident, but the presence ofsarcoid lesions in vascular walls appears to occuralso throughout the whole vascular tree.

We are grateful to Mrs. Mazin and Miss Jarlandfor their skilful technical assistance.

References

Gordonson, J., Trachtenberg, S., and Sargent, E. N.(1973). Superior vena cava obstruction due tosarcoidosis. Chest, 63, 292-293.

Longcope, W. T., and Freiman, D. G. (1952). A studyof sarcoidosis. Medicine, 31, 1-32.

Mallory, T. B. (1948). Pathology of pulmonaryfibrosis including chronic pulmonary sarcoidosis.Radiology, 51, 468-476.

Mayock, R. L., Bertrand, P., Morisson, C. E., andScott, J. H. (1963). Manifestations of sarcoidosis.American Journal of Medicine. 35, 67-89.

Scadding, J. G. (1967). Sarcoidosis, p. 302. Eyre andSpottiswoode, London.

Schaub, F. A. (1966). Precis d'ElectrocardiographieClinique. J. R. Geigy. Bale.

Schermuly, W., and Behrend, H. (1968). Die Angio-graphie der Lungensarkoidose. Radiologe, 8, 116-123.

Shibel, E. M., Tisi, G. M., and Moser, K. M. (1969).Pulmonary photoscan roentgenographic comparisonsin sarcoidosis. American Journal of Roentgenology,106, 770-777.

Sones, M., and Israel, H. L. (1960). Course and prog-nosis of sarcoidosis. American Journal of Medicine,29, 84-93.

Thompson, J. R. (1966). Vascular changes in sar-coidosis. Diseases of the Chest, 50, 357-361.

Turiaf, J., Battesti, J. P., Georges, R., and Basset, F.(1973). Le stade III ou stade de fibrose de lasarcoidose pulmonaire. Revue Fran§aise desMaladies Respiratoires, 1, 1089-1108.

Westcott, J. L., and de Graff, C. (1973). Sarcoidosishilar adenopathy and pulmonary artery narrowing.Radiology, 108, 585-586.

Requests for reprints to: Professor J. P. Battesti,Service de Pneumologie, Hopital Franco-Musulman,125 rue de Stalingrad, F 93009 Bobigny, France.

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Asthma relieved by aspirin and by other cyclo-oxygenase inhibitors

function are presented in the table. The patientwas restudied four months later, and the resultswith analgesics were very much the same.

Comment

Airways obstruction was strikingly relieved byaspirin in the patient studied. Similar beneficialeffects were produced by three other cyclo-oxygenase inhibitors, that is, by indomethacin,mefenamate, and fenoprofen, but not by two re-maining analgesics-salicylamide and benzyda-mine-which do not inhibit PG biosynthesis (Vane,1976; Szczeklik et al, 1977). It was, therefore,logical to assume that the pharmacological removalof a product of arachidonic acid (AA) cyclo-oxygenation from his respiratory tract helped ourpatient to overcome the airways obstruction. Per-haps this product was a bronchoconstrictor PGF2a,TXA2, or other as yet unknown metabolite. What-ever the metabolite was, it could not have been aphysiological one, since we have found that bron-chodilator PGI2 and PGE2 are two major productsof AA transformation in the lungs (Gryglewski etal, 1978).

In our patient the suspected abnormality inarachidonate metabolism was restricted to therespiratory system. Detailed platelet functionstudies, particularly those related to arachidonicpathway, failed to show any differences from thenormal. The transient petechiae were most likelydue to increased vascular fragility secondary totriamcinolone administration.The number of asthmatic patients who might

benefit from aspirin is not known. Trial of aspirintreatment might seem warranted in asthma, sinceit could allow the steroid dose to be reduced, asin our case. Great care, however, would be necess-ary at the beginning of such treatment, and the

initial dose of aspirin should not exceed 20-40 mg,as the same cyclo-oxygenase inhibitors, whichproved to be so efficient in relieving bronchocon-striction in our patient, may produce bronchocon-striction in other asthmatics suffering from so-called aspirin-induced asthma (Szczeklik et al,1975; 1977). Thus two opposite reactions can becaused in asthmatics by the same specific inhibi-tors. This indicates that different mediators, evenderived from the same precursor, might play adifferent role in various types of asthma.

Discussion

Gryglewski, R J, Korbut, R, Ocetkiewicz, A (1978).Generation of prostacyclin by lungs in vivo and itsrelease into arterial circulation. Nature, 273, 765-767.

Szczeklik, A, Gryglewski, R J, and Czerniawska-Mysik, G (1975). Relationship of inhibition ofprostaglandin biosynthesis by analgesics to asthmaattacks in aspirin-sensitive patients. British MedicalJournal, 1, 67-69.

Szczeklik, A, Gryglewski, R J, and Czerniawska-Mysik, G (1977). Clinical patterns of hypersensitivityto nonsteroidal anti-inflammatory drugs and theirpathogenesis. Journal of Allergy and Clinical Im-munology, 60, 276-284.

Szczeklik, A, Gryglewski, R J, Musial, J, Grodzifiska,L, Serwoi¶ska, M, and Marcinkiewicz, E (1978).Thromboxane generation and platelet aggregation insurvivals of myocardial infarction. Thrombosis andHaemostasis. (In press.)

Vane, J R (1976). The mode of action of aspirin andsimilar compounds. Journal of Allergy and ClinicalImmunology, 58, 691-704.

Requests for reprints to: Dr A Szczeklik, CopernicusAcademy of Medicine, Skawi6ska 8, 31-066 Cracow,Poland.

Corrections

1 Warren, C P W et al. Mechanical properties of thelung in extrinsic allergic alveolitis. Thorax, 1978,33, 315-321.

The caption to figure 1 should show (a) four weeksand (b) one week.

2 Battesti, V P et al. Chronic cor pulmonale in pul-monary sarcoidosis. Thorax, 1978, 33, 76-84.

The authors regret that they omitted to acknowl-edge Professor J Turiaf, who originally studied thepatients.

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chronic cor pulmonale in pulmonary sarcoidosis · cor pulmonale in pulmonary sarcoidosis....

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