Post-Transplant Obliterative Bronchiolitis and Other Late Lung Sequelae in Human Heart-Lung Transplantation

Post-Transplant Obliterative Bronchiolitis and Other Late Lung Sequelae in Human Heart-Lung Transplantation* Conor M. Burke, M.B., M.R.C.~;t james Theodore, M.D.;* Keith D. Dawkins, M.B., M.R.C.~;t SamuelA Yousem, M.D.;§ Norman Blank, M.D.;II Margaret-E. Billingham, M.D.;~ Antonius Van Kessel, B.Sc;# Stuart w jamieson, M.B., F:C.C.~;tt Philip E. Oyer, M.D.;** john C. Baldwin, M.D.;§§ Edward B. Stinson, M.D.;II,II Norman E. Shumway, M.D., F:C.C.~;II,II and Eugene D. Robin, M.D.~~ Sinee March 1981; 19 patients have undergone heart-lung

transplantation for end-stage pulmonary vascular disease, with 14 long-term survivors. In &ve of the survivors, obstructive airway disease has developed with the superimposition of a progressive resbictive ventilatory defect in three of them. None of these 6ve patients showed a tendency for spontaneous improvement of 80w rates. Biopsy and postmortem material was available in four of the ave patients and showed obliterative bronchiolitis (OB) in three. A fourth patient showed clinicaland physiologic data

Since March 1981, 19 patients with end-stage pulmonary vascular disease have undergone heart-lung transplantation at Stanford Medical Center with five deaths occurring in the perioperative or immediate postoperative period. The early clinicalresponse in the remaining 14 patients was gratifying, and all returned to a normal life-style following surgery. We have recently documented the early changes in pulmonary function following transplant. 1 In general, an asymptomatic restrictive ventilatory defect is seen, which improves slowlyand approaches normal values after about one year: The purpose of this article is to document that, in the long-term, fiveof these patients developed significant abnormalities of the transplanted lung. Serial pulmonary function testing has demonstrated an obstructive ventilatory defect in all five patients with symptoms of pulmonary disease. In *From the Departments of Medicine, and CardiovascularSurgery, Pathologyand Radiology, Stanford University School of Medicine, Stanford, California. Sup~rted by grant HL 13108 &omthe National Heart, Lung, and BlOOd Institute, National Institutes of Health, Bethesda, Mary-

land.

tPostdoctoral Scholar. *Associate Professorof Medicine. IInstructoJ; Department of Pathology. IIProfessorof Radiology. 'Associate Professor of Pathology. #Technical Director, Pulmonary Physiology Laboratory. ttAssistant Professor of Cardiovascular Surgery. **Associate Professor of Cardiovascular Surgery. I'Clinical Assistant Professorof CardiovascUlar Surgery. II,IIProfessorof Cardiovascular Surgery. "Professor of Medicine and Physiology. Manuscript received and accepted for publication on August 31. ~nt re~: Dr. Theodore, D'vUWn ofRe"nratory Metllctne,

SlGnford Medical Center, Stanford94305

consistent with obUterative bronchitis, but histologic material was not available. Obstructive lung disease without resbictive features developed in a &fth patient, but no histologic evidence of OB was found at transbroncbial biopsy. In addition to OB, recurrent lung infections were found in all patients, significant pleural 6brosis in two patients, and bronchiectasis in one patient. Despite these long-term sequelae of human heart-lung transplantation, ten of the 14 surviving patients are leading relatively normal bYeS.

addition to airwayobstruction, a progressiverestrictive process has been seen in three cases. The alterations in lung function are associated histologically with obliterative bronchiolitis (OB) in three patients and this diagnosis is probable in a fourth who has not required lung biopsy. OB was not found on transbronchial biopsy in the fifth patient. Additional lung problems have included recurrent pulmonary infections, pleural fibrosis, and bronchiectasis. This late deterioration in pulmonary function has been of life-threatening severity in two cases, and sufficiently severe to cause major symptoms in two others. A fifth patient, who has developed mild airway obstruction, remains asymptomatic. One of the patients with severe pulmonary disease died suddenly from acute myocardial infarction 15 months after surgery. The clinical course of these patients, including pulmonary function studies and radiographic findings, is described to define more clearly the long-term risks of human heart-lung transplant. In addition, the data provide insight into the clinical and physiologic life history of obliterative bronchiolitis. CASE REPORTS CASE

1

This 30-year-old man suffered from Holt-Oram syndrome (ventricularseptal defect, atrialseptal defect and skeletal abnormalities). Immediate postoperative recovery was complicated by mediastinal hemorrhage which required exploration on two occasionsto tie off bleeding vessels in the posterior mediastinum. Impaired movement of the left: hemidiaphragm associated with left lower lobe Poet-li'anspIant 0bIIteraINe BronchIolitis (ButIce ., Ii)

atelectasis and infection required bronchoscopy and removal of mucous plugs on postoperative day 9, and he madea good recovery on therapy with antibiotics. Both diaphragms were later seen to move normally on fluoroscopy prior to discharge. Between postoperative day 16 and 21., transient renal impairment occurred which resolved spontaneously when dosage of cyclosporine was reduced. 1hmsient neurologic signs (left hemiparesis) resolved spontaneously on postoperative day 34 and were probably related to air emboli from the central venous line. Serologic evidence of cyt0megalovirus was fOund on postoperative day 38, and cytomegalovirus was later isolated from throatwashings and urine specimens. No evidence of rejection was fOund on serial cardiac biopsies, and he was discharged on the 42nd postoperative day. Over the course of the next two and one-half years, he remained well, worked full-time and had stable pulmonary function ('Iable 1). He had three episodes of lower respiratory tract infections during this period whichwere diagnosed clinically on the basis ofincreased cough with purulent sputum and responded to antibiotic treatment. On one occasion, 29 months after surgery, hospital admission was necessary fOr treatment of £eve!; cough, purulent sputum and right upper zone patchy consolidation on chest x-ray 6lm. Bronchoscopic examination demonstrated inBammation and mucous plugging of the anterior segment of the right upper lobe. 1hmsbronchial biopsy showed a severe exudative bronchiolitis with squamous metaplasia. Results of cultures ofbiopsy material and blood were negative, and only a small growth of organisms consistent with normal flora was cultured from sputum. As before, he made a good clinical response to empiric antibiotic treatment. Serial radiologic investigations, including chest radiographs, tomograms, and CT scans, showed evidence ofperibronchial in<ration most marked in both bases and

bilateral pleural thickening. Thirty-six months after transplantation, he complained of progressive dyspnea on .exertion fOrthe lint time. Radiologic findings now included new peripheral patchy fOci of consolidation which were most obvious in both upper lobes, but were also present in the lower zones. Results of pulmonary function tests showed a marked obstructive and restrictiw ventilatory defect ('Iable 1).Arterial blood gas determinations (obtained at cardiac catheterization since the patient objected to peripheral arterial puncture) showed a Pa0 l of 71 and PaCOI of 35 mm Hg. Result of cardiac biopsy was normal. Hemodynamic variables included mean pulmonary arterial pressure of 25 mm Hg, pulmonary vascular resistance of 3 Wood units, and cardiac output of 4.6 Um. Coronary arteriography, which showed normal findings one year previously, now demonstrated diSUse distal triple vessel disease compatible with proliferative graft atherosclerosis. Open lung biopsy revealed focal obliterative bronchiolitis with mucous plugging and diSUse pulmonary fibrosis. His clinical course deteriorated while being treated with antibiotics, bronchodilators, aminophylline, and higb-dose steroids. He underwent a second transplant procedure and the original set of donor lungs showed diSUse obliterative bronchiolitis, and generalized bronchiectasis. CASE

2

This26-year-old man su&ered from a ventricular septal defect with Eisenmengers syndrome. Recovery after heart-lung transplantation was complicated by bilateral pleural effusions, and thoracocentesis on the 9th and 12th postoperative days yielded 1,600 ml and 800ml of an exudative pleural effusion from the right and left: sides respec-

tively. On postoperative day 9, a respintory tract infection was

18ble l-PulmonG,." FUnction VtJriablea itaFa H.rl-Lung 1hJruplmat BBdpienIa Patient No 1

2

3

4

5

Months After Surgery 4 9 19

24 36 1 5 13 14 2 4 8 1 6 11 12 14 6 21 26

28 30

FEVI

FEF'; 1.4 (117) 1.2 (100) 1.4 (117) 1.2 (100) 0.2 (17) 1.5 (125) 1.1 (92) 0.3 (25) 0.1 (8) 0.8 (67) 0.4 (33) 0.2 (17) 1.5 (125) 1.1 (92) 1.6 (133) 0.4 (33) 0.2 (17) 1.2 (86) 1.0 (71) 0.4 (29) 0.6 (43) 0.4 (29)

FEV1(L)

FVC(L)

FVC(%)

2.3 (56) 2.8 (68) 2.8 (68) 2.9 (71) 0.8 (20) 3.2 (71) 3.7 (82) 1.1 (24) 0.8 (18) 2.6 (60) 2.2 (51) 1.5 (35) 2.0 (47) 3.0 (70) 2.3 (53) 1.4 (33) 1.0 (23) 3.2 (73) 3.1 (72) 2.5 (58) 2.7 (63) 2.3 (53)

2.6 (50) 3.2 (62) 3.0 (58) 3.3 (63) 1.7 (33) 3.5 (60) 4.4 (77) 1.8 (32) 1.4 (25) 3.3 (59) 3.2 (57) 2.5 (45) 2.1 (40) 3.3 (62) 2.4 (45) 2.1 (40) 2.2 (42) 4.1 (69) 4.1 (71) 3.6 (62) 4.1 (71) 3.6 (62)

89 88 91 87 49 91 85 59 56 77 69 56 95 91 95 68 45

80 77

68 67 64

FVC

FEF..1S (Us)

RV(L)

2.9 (66) 0.9 (56) 3.7(84) 1.5 (94) 3.1 (72) 1.0 (63) 3.5 (81) 1.1 (69) 0.3 (7) 2.0 (125) 4.4 (94) 1.0 (59) 4.2 (91) 1.2 (71) 0.5 (11) 1.8 (106) 0.4 (9) 2.0 (118) 2.2 (49) 2.6 (144) 1.4 (31) 2.0 (Ill) 0.6 (14) 2.0 (Ill) 3.0 (64) 3.0 (200) 3.3 (70) 2.0 (133) 3.6 (77) 1.8 (120) 0.9 (19) 2.4 (160) 0.4 (9) 2.5 (167) 3.8 (90) 1.3 (65) 2.5 (60) 1.6 (SO) 1.4 (33) 1.8 (90) 1.6 (39) 1.7(85) 1.0 (24) 2.3 (115)

TLC(L) 3.6 (53) 4.8 (71) 4.3 (63) 4.5 (66) 3.8 (56) 4.6 (62) 5.8 (78) 3.7 (50) 3.5 (47) 5.9 (SO) 5.5 (74) 4.6 (62) 5.1 (75) 4.9 (72) 4.1 (60) 4.7 (69) 4.9 (72) 5.4 (68) 5.4 (68) 5.3 (67) 5.8 (74) 5.9 (76)

RVI TLC(tf,) 25 31 23

24 53 22

21 49 57 44 36

43 59 41 44 51 51

24 30 34 29 39

Helium Equilibr (Min) 3.0 3.0 3.0 3.0 6.0 2.0 3.5 7.0 7.5 6.0 6.5 6.0 6.0 4.5 7.5 6.0 7.0 4.0 4.0 6.5 6.0 6.0

Pa°i

PaC° (mmHg) 1

Dco (73) (73)

(46) (69)

82/39 58/38

54/42 75/33 72/32

W33

93136 91/38

90136 74/32 67/33

100133

84/34 73135

68134 73135

(44) (64)

(66) (40)

(45) (51)

(97)

(64) (75) (100)

(SO)

(40) (56) (64)

(69) (68) (73) (69)

Figures in parentheses represent percentage of predicted values. FEV1 = forced expiratory volume in 1 second (liters). FVC-forced vital capacity (liters). FEF.lFVC=ratio offOrced expiratory flow at 5()tI, of vital capacity to FVC. FEF..1I = mean forced expiratory flow between 25% and 75'1> of vital capacity (liters/second). RV residual volume (liters). TLC-totallung capacity (liters). Dco = single breath diffusion capacity for carbon monoxide (corrected for hemoglobin).

=

CHEST I 88 I 8 I DECEMBER. 1884

821

diagnosed on the basis of fever and purulent sputum, which responded to antibiotic treatment. Endomyocardial biopsy on postoperative day 23 revealed evidence of cardiac rejection which was treated with methyl prednisolone (1g IV daily fOrthree days). Another endomyocardial biopsy six days later showed on-going rejection, and another course of methyl prednisolone was given. Follow-up biopsies showed resolving rejection until the llOth postoperative day, when full resolution

bad occurred.

The patient was discharged on the 29th hospital day, and pulmonary function tests showed only a mild restrictive defect at this time. He remained clinically well over the next three months, but slowly developed a cough productive of a small amount of mucoid sputum associated with symptoms of persistent rhinitis and post-nasal drainage. One month later, he complained of inability to take a full breath and dyspnea on moderate exertion. Pulmonary function tests (18ble 1)at this time showed no evidence of airway obstruction. Two weeks later, he presented with fever, cough and purulent sputum, and chest radiograph demonstrated peribronchial infiltration in both lower zones, Bronchoscopic examination demonstrated generalized mucosal in8ammation with overlying purulent secretions, and multiple transbronchial biopsies showed organizing bronchopneumonia with patchy obliterative bronchiolitis. Cultures did not detect any pathogenic organisms, but he made a good clinical response to broad spectrum antibiotic treatment. Endomyocardial biopsy showed no evidence of cardiac rejection. Over the next eight months, the clinical course wasremarkable fOr progressive dyspnea on exertion, and productive cough. Pulmonary function deteriorated with the development of severe obstructive and restrictive ventilatory defects associated with progressive impairment of pulmonary gas exchange, despite an extensive airway toilet program and treatment with nebulized bronchodilators, aminophylline, and antibiotics. Serial radiologic investigations showed progressive pleural thickening, bilateral infiltration in a peribronchial distribution, and multiple ~coarse nodular foci (0.5-1.5 em in diameter) in both lower zones. By the 14th postoperative month, deteriorating pulmonary function and gas exchange were treated with high-dose steroid treatment (1 mglkg prednisone daily) and some clinical response wasseen and indicated by significant improvement in gas exchange and a 20 percent improvement in FEV1 and FVC. Chest film at this time showed a new fOcal consolidation (3 cm diameter) in the left upper zone. The patient was afebrile, white blood cell count was normal, and sputum cultures were negative. There were no other clinical or laboratory datato fOrewarn ofthe patients sudden death which occurred while in bed on the night of the 443rd post-transplant day. Evidence of a recent myocardial inf8rction, severe proliferative graftatherosclerosis, patchy pleural and interstitial fibrosis, a localized left upper lobe abscess (&om which a heavy growth of Serrafla marce,CBn8 and a small growth of StrepfococcuB pneumoniae, Staphfllococcua aureus and CanclUltJ alblcaRl was cultured), and a severe extensive obliterative bronchiolitis was fOund on examination at autopsy. No histologic evidence of pulmonary rejection was seen. CASE

3

Post-transplantation recovery of this 33-yeaJ'-Old man, who suffered from ventricular septal defect and Eisenmenger! syndrome, was complicated by pneumonia on the 3rd postoperative day. PHUtlorraoruu tJBrUginoItJ was isolated from sputum and he made a good response to antibiotic treatment. On postoperative day 23, right thoracocentesis produced 400 ml of sterile exudative pleural fluid. On postoperative day 27, the white blood cell count was noted to below (2.0 BIUL) and cytomegalovirus was isolated &om urine and throat washings. On postoperative day 43, the white blood cell count returned to normal and he was discharged well fOurdays later. No evidence of cardiac rejection was found on serial endomyocardial biopsies at any time.

III

He remained well over the course of the next two months except fOrpersistence of chronic rhinitis and postnasal drainage which had been present for many years before surgery. Four months after surgery, he presented with a lower respiratory tract infection (purulent sputum and fever) which responded to treatment with antibiotics. At this time he had evidence of mild obstructive and restrictive ventilatory defects fOrthe first time (18ble 1). Despite the institution of a vigorous airway program including regular nebulized bronchodi1ator treatment, chest percussion, breathing exercises, and postural drainage fOur times daily, he suffers from the chronic expectoration of muco-purulent sputum with intermittent respiratory tract infections responding to antibiotic treatment. Endomyocardial biopsies have been consistently negative fOr rejection. Sequential radiologic investigations (chest radiographs, tomograms, and thoracic CT scans) have demonstrated slowly progressive patchy, coarse nodular densities in both lower zones with bronchial dilatation, peribronchial thickening and bibasal pleural thickening. Pulmonary function tests have shown a progressive obstructive and restrictive ventilatory defect. Clinically, the patient is limited by dyspnea on moderate exertion. No lung biopsy bas been perfOrmed, but the clinical and physiologic picture is consistent with obliterative bronchiolitis. CASE

4

This 22-yeaJ'-Old man suffered from ventricular septal defect with

Eisenmenger! syndrome. Immediate posttransplant recovery was complicated by pneumoniawhich responded to antibiotic treatment Later, on postoperative days 15 and 23, cardiac rejection responded to pulse steroids (1g methyl prednisolone IV fOrthree days). He was discharged on the 39th postoperative day. Six days later, he was readmitted following two episodes of generalized tonie-clonic convulsions. Brain CT scan and lumbar puncture were normal, and EEG showed minor nonspecific changes consistent with encephalopathy, with no fOcal or eleptiformfeatures. A tentative diagnosis of cyclosporine-induced seizures was made, and dilantin was added to his regimen. For the fOllowing seven months, he remained well apart from progressively increasing cough and rhinitis. Chest radiographs, tomograms, and CT thoracic scans revealed a new diffuse reticulonodular interstitial infiltrate most marked in both upper lobes, together with some pleural thickening and two small (0.5 em diameter) nodules in each lower lobe which were unchanged since the first postoperative films. Bronchoscopic examination demonstrated normal bronchial anatomy, and results of cultures of sputum, transtracheal aspirate and bronchial lavage specimens were negative. 'Ihmsbronchial biopsy and later needle aspiration and open lung biopsy showed obliterative bronchiolitis, interstitial fibrosis, and perivascular aggregates of lymphoid cells. An endomyocardial biopsy showed no evidence of rejection. Pulmonary function test results (18ble 1) demonstrated a moderate restrictive defect. The dilantin treatment was stopped in view of its rare association with pulmonary toxicity, and two months of high dose prednisone (1 mrJ kglday) was given. Repeat pulmonary function studies now demonstrated an obstructive ventilatory defect in addition to restrictive disease, and his clinical status was unchanged. Repeat transbronchial biopsy wasessentially unchanged, and the prednisone was weaned to the normal immunosuppressive dose of 10 mg daily without any adverse effects. Repeat cardiac biopsy showed no evidence of rejection. Over the course of the next three months, the patient has complained of significant dyspnea on exertion for the first time since surgery and bas requiredthree courses of therapy with antibiotics fOr treatment of respiratory tract infections manifested by cough, feve~ and purulent sputum. Pulmonary function tests haveshown increasing airway obstruction despite intensive bronchodilator, aminophylline and pulmonary toilet treatment. Endomyocardial biopsies have been consistently negative fOrevidence of rejection, and radiologic

investigations have shown a stable interstitial and coarse irregular nOdular infiltrate. CASE 5

This 4O-ye...-old man underwent heart-lung transplant for a ventricular septal defect with Eisenmengers Syndrome. Immediate postoperative recovery was complicated by mediastinal hemorrhage, and re-exploration on the day of operation was necessary to control bleeding from a large mediutina1 collateral vessel and adhesions from previous thoracic surgery..Severalsmail air leaks on the medial side of the left lung were not amenable to surgical correction. Following the procedure, oliguric renal failure developed which required dialysis mr five days (2nd to 6th postoperative day). Left weal cord paralysis was demonstrated by laryng~pic examination at this time and was treated with Teflon injection nine months later. The chest drains were removed ~llowing resolution of the air leak on the 6th postoperative day. Subsequent postoperative recovery was uncomplicated and he was discharged on the 46th postoperative day. Eleve~ weeks after surgery, endomyocardial biopsy revealed evidence of acute cardiac rejection which was successfully treated with 100 mg prednisone per day tapering by 5 mg daily to a maintenance dosage of 10 mg. His subsequent course was complicated by numerous episodes of upper· respiratory tract ~ons associated wi~ significantpostnasaldrainage. On physicaleumination, mucopurulent secretions were noted in the oropharynx on many occasions. These symptomsand signswere present to a lesser degreefOr many years prior to surgery. In addition, four episodes of lower respiratory tract infection have been documented on the basis offever and purulent sputum. Eachof these episodes responded to empiric broad spectrum antibiotic treatment. 1Wenty-two months after transplantation, he presented with £ew,~ purulent sputum, hemoptysis and a right lower zone infiltrate on chest radiograph. Bronchoscopic examinationdemonstrated retained secretions in the right lower lobe, and transbronchial biopsy showed a marked peribronchial and mild interstitial infiltrate of lymphocytes· and plasma cells which was associated with a focal alveolar 6brinous exudate. No obliterative bronchiolitis or perivUculitis was seen. A heavy growth of Hemoplailul injIuenz:a was cultured from bronchial lavagefluid, and he responded to antibiotic treatment Mild airway obstruction and impairment of pulmonary gas ex- .

c""

change was &rst noted Z6months after transplantation (Table l~ and bas remained stable to date. Radiologic investigations (including chest radiographs, tomography, and cr thoracic scans) reveal persistent peribronchial inSItration, some pleural thickening, and small irregular nodular shadowsin both lower zones. Despite these changes, the patient continues to lead an essentially normal life and is now in full-time employment without functional limitation 30

months posttnnsplantation.

RESVLTS

Four of the five patients showed common clinical and physiologic features. Bronchitic manifestations

h

gh

dId

extensive than those found in most patients with chronic obstructive lung disease. The radiologic features will be described more extensively in a separate publication. Pulmonary function studies (18ble 1) have revealed an obstructive ventilatory defect with progressive global reductions of airflow to very low values. Unlike classic forms of chronic obstructive lung disease, total lung capacity is reduced rather than elevated and coexisting restrictive lung disease is clearly present. The use ofbronchodilators produces little, if any, improvement of flow rates. NOtwithstanding the severe obstructive disease, the helium equilibration time

Table I-Differentisl Fetdura ofl'odIr"upltmltJdon OblilertJtiw ~ Fortna rI Chronic O~ Lung Di-. Feature Bate of development

Clinical features

Chest x-ray &1m findings

Mechanical abnormalities

I ped

suc as cou an mueopuru ent sputum eve 0 within several months following transplantation. Recurrent pulmonary infections have been common. Dyspnea has developed within months of the onset of bronchitic manifestations. The clinical course has been similar to that found in many patients with chronic obstructive lung disease, but telescoped into a period of months and not years (1able 2). Chest radiographs, tomograms and thoracic CT scans have revealed peribronchial and interstitial infiltrates with variable pleural thickening. The infiltrative changes are more

CmaptJretI tDida

Posttranspl. OB

Non-Infectious Chronic Bronchitis

Obstructive Emphysema

Chronic Bronchial Asthma

Rapid; several months to 1-2 years Bronchiticsymptoms followed by early development of dyspnea Distinct inflltrative component

Slow many years Bronchiticsymptoms with delayed development of dyspnea

Slow many years Slowdevelopment of dyspnea whichantedates bronchitic symptoms

Paroxysmal, but usually slow Dyspnea fluctuates as do bronchitic symptoms

Inflltrative component usually not extensive

InBltrative component only under special

Severe obstructive and restrictive lung disease

Obstructive lung disease

No in<rative component except with infection or heartfailure Obstructive lung disease

Decreased

Obstructive lung disease

Total lung capacity Bloodgues Rewmibility with bronchodilaton

Blue pufters Largely irreversible

Increased Blue bloaters Often reversible

Pink puffers Largely irreversible

Increased Depends on severity Frequently reversible

Spontaneous

None

Occasionally

None

Frequently

improvement of flow rates with time

Increased

Circumstance

CHEST I 88 I 8 I DECEMBER. 1884

827

140 II.

> w

120

~ ~

100

~

0

D. ..I

C

i=

i

II.

0

I-

Z w

80 60 40

CJ

a::

w

Q.

20 0

0

4

8

12

16

20

24

28

32

MONTHS AFTER TRANSPLANTATION

reached only mildly abnormal values reflecting the low total lung capacity. For a given degree of depressed flow rates, the values of helium equilibration were more normal than seen in classic obstructive lung disease. Arterial hypoxemia becomes invariant when severe impairment of low flow rates becomes evident, but most of the patients show hypocapnia rather than CO. retention. As a group, then, the patients are "blue puffers." Diffusing capacity of CO, which is minimally depressed in the immediate posttransplant period, becomes moderately depressed. The abnormalities in lung function may occur within four months following transplantation, but are usually fully developed within a year to two following transplantation. No patient showed a tendency for spontaneous improvement of flow rates. As shown in Figure 1, once depressed How rates become manifest, they continue to deteriorate inexorably. Pathologically, obliterative bronchiolar lesions, although patchy, have been extensive. The pathologic changes will be described in detail in a separate publication. In patient 5, dyspnea was not prominent and manifestations of bronchitis were minimal. Physiologic evidence ofairway obstruction was moderate and total lung capacity was only minimally decreased. It is, of course, possible that this patient has OB, notwithstanding a transbronchial biopsy which did not show OB on the limited amount of tissue obtained for examination. DISCUSSION

The introduction of innovations into clinical management presents major problems with the assessment of risks vs benefits for individual patients. Not only are III

36

Figure 1. FEV1 values (expressed as percentage of initialpostoperative values) in five patients after combined heart-lung transplantation. Numbers on graph correspond to patient numbers in text. Note 40 that decrease in flow rates occurred between four and 36 months post-transplantation.

there the obvious problems of predicting potential benefits and the existence ofpredictable risks, but the problem of unexpected long-term risks also exists. 1.3 This has proved to be the case with human heartlung transplantation. Many of the potential benefits have materialized. Approximately two thirds ofa group of terminally ill patients with irreversible pulmonary hypertension have been restored to a satisfactory lifestyle. In isolated patients, predictable risks such as recurrent pulmonary infections, toxic effects of immunosuppressive agents such as cyclosporine, and 0cclusive coronary vascular disease have developed. In the present report, we document the unexpected development of obliterative bronchiolitis in a subpopulation of these patients. The mechanism which accounts for inflammatory and obliterative lesions specifically involving bronchioles in the late posttransplant period is not known. Obliterative bronchiolitis has been described as a reaction to lung injury produced by a variety of etiologic mechanisms. It has been described following toxic exposures as with the inhalation of oxides of nitrogen," following infection" and also linked with autoimmune disease such as rheumatoid arthritts," eosinophilic fasciittstand Sjogrens syndrome." None of these etiologic associations appears likely in our group of patients. Chronic graft vs host reaction (CGVHR) has been reported recently to produce obstructive lung disease within two years following bone marrow transplant in some patients." The process in these patients appears to be quite similar to that described here, but, of course, in the present patients it is the graft and not the host which is the site ofOB. There was no evidence of CGVHR in the skin, mucosa, liver or GI tract in our patients. Conventional forms of host-versus graft reacPost-1tanIpIant 0bI1teraIIve Bronchiolitis (Burlce .t III)

tion (rejection) were not observed in these patients. It is possible that an unusual fonn of rejection could occur as the transplanted lung is repopulated by the lymphoid population of the host. At present, such a possibility is entirely speculative. The lung does contain some 40 different cell types, 10 and it is possible that an unusual form of graft vs graft reaction involving cellular damage produced by one cell type in another cell type could occur; Again, this possibility is entirely speculative. Whatever the mechanism, human heart-lung transplantation does provide a new model for OB and perhaps an experimental model in animals as well. It should be emphasized that OB in these patients occurs along with other disturbances of lung function. The transplanted lungs of these patients are always postsurgical and have undergone a period of ischemia prior to transplant. Pulmonary infection and pleural complications are common and one patient had bronchiectasis. Once a major decline in How rates develops, there has been no evidence ofspontaneous improvement. In addition, the impact of the loss of pulmonary lymphatics, pulmonary innervation and the bronchial circulation complicates interpretation of both the clinical and physiologic data. It should also be emphasized that the number of patients who have been studied is quite small and it would be premature to draw general conclusions about prevalence and importance of abnormal lung function from this report. Despite these problems, the present data do provide a summary ofthe clinical and physiologic features which distinguish this disorder from other forms of chronic obstructive lung disease. Such a summary is provided in 'Iable 2. We know neither the ultimate prevalence of OB in

the transplanted lung nor the degree ofabnormal lung function that will develop in affected patients. However, the present data are consistent with a favorable risk-benefit ratio in selected patients with irreversible lung or lung vascular disease approaching the terminal phase of their illness. The present data should provide a basis for supplying a more informed choice to potential heart-lung candidates. REFERENCES 1 Theodore}, Jamieson S~ Burke CM, Reitz BA, Stinson EB, Van Kessel At et ale Physiologic aspects of human heart-lung transplantation: pulmonary function status of the post-transplanted lung. Chest 1984; 86:349-57 2 Babin ED. Matten of life and death: the risks and bene6ts of medical care. New York: W. Freeman, 1984 3 Gilbert J~ McPeek B, Mosteller E Statistics and ethics in surgery and anesthesia. Science 1977;198:684-89 4 Ramirez RI, Dowell AB. Silo &Deri disease: nitrogen oxide induced lung injury. Ann Intern Med 1971; 74:569-76 5 Becroft DMQ Bronchiolitis obliterans bronchiectasis and other sequalae of adenovirus type 21 infection in young children. JClin Patholl971; 24:72-82 6 Geddes DM, Corrin B, Brewerton DA, Davies R}, 'IumerWarwick M. Progressive airway obliteration in adults and its association with rheumatoid disease. Quart J Med 1977;

46:427-44

7 Epler Gft, Snider GL, Gaensler EA, Cathcart ES, Fitzgerald MK, Carrington CB. Bronchiolitis and bronchitis in connecti~ tissue diseases. JAMA 1979; 242:528-32 8 Newba1l HH, Brahim SA. Chronic aiJway disease in patients with Sjogreni syndrome. Am Rev Respir Dis 1977; 115:295-304 9 Ralph DD, Springmeyer SC, Sullivan ICM, Hackman RC, Storb R, Thomas ED. Rapidly progressive airflow obstruction in marrow transplant recipients. Am Rev Respir Dis 1984; 129:641-44 10 Sorokin S~ In: Nettesheim ~ Hanna Jr MG, Deatherage Jr ~ (eds), The cells of the lung. Morphology of experimental respiratory carcinogenis. Oak Ridge: U. S. Atomic Energy Commission, 1970

CHEST I 88 I 8 I DECEMBER. 1184

121