Thorax 1986;41:497-502

Editorial

Bone marrow transplantation and the lungBone marrow transplantation is a remarkably easytechnical procedure with enormous therapeuticpotential, which is as yet only partially tappedbecause of a paucity of suitable donors and a highcomplication rate. Nevertheless the procedure offersthe hope of curing the many and diverse clinical disor-ders that result from malfunction of the progeny ofhaemopoietic pleuripotential stem cells. The tech-nique is capable of restoring normal haematologicalfunction in primary red cell, white cell, or platelet dis-orders after ablation of aberrant cells and can be usedto rescue patients with marrow failure secondary tochemical or radiation insult. Immunological com-petence can be restored as grafted haematologicalstem cells are able to differentiate into T and B lym-phocytes. Possibly many immunological disorderswill be treated with bone marrow transplantation inthe forseeable future. Bone marrow transplantation isalso being studied as a form of treatment for meta-bolic disorders, including mucopolysaccharidoses,Gaucher's disease, and adenosine deaminasedeficiency.' By means of a graft of normal stem cellsinto an affected patient erythrocytes, granulocytes,and macrophages are produced and normal enzymesare manufactured, which then diffuse into enzymedeficient tissues. In 1986 two major difficulties, graftversus host disease and pulmonary damage, limit thewidespread exploitation of bone marrow trans-plantation.24

Graft versus host disease is thought to resultbecause donor T lymphocytes recognise the recip-ient's tissues as foreign and, by mounting an immuneresponse, damage them. In the first 100 days acutegraft versus host disease presents as a rash, oftenaccompanied by evidence of damage to the gut andliver, in 25-75% of patients.5 6 Later, chronic graftversus host disease may present by mimicking multi-organ autoimmune disease with rash, oral and oph-thalmic sicca syndrome, hepatic damage, immunedeficiency, and opportunistic infections.7 8 This mayfollow acute graft versus host disease or may occur denovo. For the accurate diagnosis of graft versus hostdisease biopsy and histological examination of theaffected organ is required. Despite increasing under-standing of histocompatibility determinants andrecent advances in manipulating T cell function, inmost centres bone marrow transplantation is confined

Address for reprint requests: Dr ADJ Pearson, Department of ChildHealth, Medical School, Newcastle upon Tyne NE2 4HH.

to patients who have sibling donors who are HLA-AB-Dr identical and whose lymphocytes are non-reactive in mixed lymphocyte culture. But even whenit becomes commonplace to transplant fromunrelated histocompatible donors lung damage willcontinue to complicate and prejudice the clinicalcourse of the patient with a bone marrow transplant.The lung complications described in patients with

bone marrow transplant are very diverse (table). Thegreatest threat after transplantation is interstitialpneumonitis, which in both American and Europeanseries has complicated recovery in up to one third ofall patients treated and has had a mortality rate ofnearly 75%.9-' In over a half of all these patientsactive cytomegalovirus infection has beenpresent.9- 10Bone marrow transplantation is at present gener-

ally performed for patients with aplastic anaemia andhaematological malignancies, acute lymphoblasticleukaemia, acute myeloid leukaemia, and chronicgranulocytic leukaemia. Where appropriate theseconditions are treated by allotransplant. Marrow isharvested from a histocompatible sibling and trans-fused into the patient, who is preferably aged less than45 years since the incidence of graft versus host dis-ease increases substantially with age. The best resultsin acute lymphoblastic and acute myeloid leukaemiaare obtained when the patient is in haematologicalremission with no overt disease in bone marrow or

Early complications (within 100 days ofbone marrowtransplantation)

I Pulmonary oedema(a) Fluid overload(b) Myocardial damage(c) Acute haemorrhagic-cyclosporin toxicity

2 Adult respiratory distress syndrome(a) Septicaemia(b) Idiopathic

3 Bronchopneumonia(a) Bacterial(b) Fungal

4 Interstitial pneumonitis(a) Idiopathic (perhaps due to effect of cytotoxic drugs and

irradiation)(b) Infective-cytomegalovirus, pneumocystis, etc

5 Pulmonary embolism

Late complications (after 100 daysfrom bone marrowtransplantation)

I Bronchopneumonia2 Interstitial pneumonitis3 Restrictive lung disease4 Bronchiolitis obliterans

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cerebrospinal fluid.4 16 In chronic granulocytic leuk-aemia bone marrow transplantation is undertaken inthe early stable phase when little cytotoxic treatmenthas been used.3 17 Immediately before trans-plantation the patient is conditioned with high dosesof cytotoxic treatment, which in aplastic anaemiamay include horse or rabbit antihuman anti-thymocyte immunoglobulin, to which is added inmost cases of haematological malignancy total bodyirradiation. With adequate preparation, graft rejec-tion and continuing marrow failure are not seen.After two to three weeks of peripheral blood pan-cytopenia marrow engraftment ensues. Respectableperipheral blood counts become self sustaining afterabout one month. Restoration of full immu-nocompetence may take several years, T cells remain-ing phenotypically and functionally immature, immu-noglobulin concentrations low, and antibody levelsreduced."8 19 The major threat of infection,however-from various bacterial, fungal, viral, andprotozoal organiSMS20 21-comes within the first sixmonths. Prophylaxis against graft versus host diseasewith methotrexate administration was pioneered inSeattle,22 although in recent years many centres haveused cyclosporin.23 Recently encouraging resultshave been claimed for T cell depletion of donor mar-row.24

Pretransplantation pulmonary functionIn any attempt to assess the importance of pulmonarycomplications after bone marrow transplantation it isimportant to recognise that despite the absence ofclinical disease patients with leukaemias and aplasticanaemia often have abnormal pulmonary functionbefore transplantation.25 In addition, the verydifferent diseases treated with bone marrow trans-plantation have widely different clinical coursesbefore bone marrow transplantation. For example, apatient with acute myeloid leukaemia may have had avery large number of episodes of both septicaemiaand pneumonia before bone marrow transplantation.In contrast, a patient who has a marrow trans-plantation because of chronic granulocytic leukaemiamay never have had an infection. The extent andnature of antibiotic treatment before transplantationvaries widely between different disorders and betweenindividuals. Blood component treatment may or maynot have been substantial and in some diseases cyto-toxic chemotherapy needs to be considered as a possi-ble cause of lung disorder in its own right. Busulphanis used extensively in the treatment of chronic granu-locytic leukaemia and was first reported to cause pul-monary fibrosis in 1961.26 Acute myeloid leukaemiais treated with anthracyclines (daunorubicin andadriamycin), which are associated with cardiac ratherthan pulmonary toxicity; and the antimetabolities

cytosine arabinoside and thioguanine are infrequentlyimplicated as pulmonary toxins.27 Acute lympho-blastic leukaemia is treated with vincristine and pre-dnisolone, which cause little lung damage by them-selves; but to these drugs are added the pulmonarytoxic antimetabolities mercaptopurine and meth-otrexate.2728 In the conditioning programme imme-diately before bone marrow transplantation largedoses of the alkylating agents cyclophosphamide ormelphalan are used. Such drugs in small, long termdoses have been associated with substantial sub-clinical lung damage, but the effects of acute dosingremain to be determined.27 Cytotoxic agents damagepulmonary endothelial cells, which make up 40% ofthe lung cells and have a turnover rate of I % a day inthe steady state, with a potential for acceleratedgrowth when damaged.29 It is thus imperative, whenthe occurrence of pulmonary toxicity after bone mar-row transplantation is being assessed, that previouscytotoxic treatment and radiation are taken intoaccount.

Total body irradiation with doses of the order of 10Gy (1000 rads) is used to condition patients for bonemarrow transplantation. In animal studies radiationof this order is associated with increased vascular per-meability, alveolar wall oedema, and alveolar proteinleak, with gross loss of lung surfactant. Seven to 28days after irradiation alveolar macrophages becomereduced in number, pneumocytes degenerate, andhyaline membranes form. Several months later cellu-lar hyperplasia and fibrosis develop.30 Attempts tominimise radiation damage have centred on fraction-ating the treatment and using low dose rates. Highdose pulmonary irradiation results in considerablyreduced diffusing capacity for the first three monthsfollowed by possible minor improvements over a cou-ple of years." 1525 When cytotoxic chemotherapyhas not been used, as with some solid tumours, radi-ation to the lungs is rarely associated with appreciablechanges in lung volume, forced vital capacity (FVC),forced expiratory volume in one minute (FEV1) orthe FEV,/VC ratio.3' But in the long term survivorsof bone marrow transplantation who have been con-ditioned with high dose chemotherapy and irra-diation restrictive and obstructive lung disease isbeing described (see below).

In studying the effect upon pulmonary morbidity ofallotransplantation between histocompatible siblingsand even unrelated donors it will be important to takeinto account the experience being gained by usingconditioning regimens in which irradiation is replacedby additional chemotherapy.

Complications after transplantationPerhaps the earliest pulmonary complication of bonemarrow transplantation is the rapid onset of pul-

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monary oedema associated with volume overload andcardiac dysfunction attributable to previous anthra-cycline and cyclophosphamide treatment and irra-diation. These causes must be distinguished fromacute haemorrhagic pulmonary oedema associatedwith reduced central venous pressure, fluid retention,hypoalbuminaemia, hypotension, and incipient renalfailure.1432 Histologically, intra-alveolar and occa-sionally interstitial oedema fluid is seen with red cellsand fibrin exudation, but no pneumocyte abnormal-ities are recognisable. This complication has a highmortality rate and occurs characteristically in patientsreceiving mismatched transplants and high doses ofcyclosporin. The adult respiratory distress syndromehas also been described in allogeneic matched siblingtransplants for chronic granulocytic leukaemia.33What causes the pulmonary endothelial damage inthese severely neutropenic patients remains unclearas, in this context, neutrophil derived oxidant prod-ucts seem unlikely to play a part in adult respiratorydistress syndrome.Any patient with pancytopenia and immuno-

suppression is susceptible to infection34 and almostall of these patients have indwelling central venouscatheters and many receive parenteral nutrition.Bronchopneumonia associated with few radiologicalsigns when neutrophil counts are low is generally bac-terial in origin35 and Gram positive organisms oftensensitive only to vancomycin are surprisingly com-

mon. Pneumonias developing in the neutropenicpatient receiving broad spectrum antibiotics may bedue to fungi, among which Candida albicans, Asper-gillusfumigatus, and the fungi causing mucormycosisare the most common. Recently lobar pulmonaryaspergillosis has been linked with sinusitis.36

INTERSTITIAL PNEUMONITIS

Dyspnoea, non-productive cough, fever, widespreadcrackles, bilateral fluffy infiltrates on the chest radio-graph, and hypoxia suggest interstitial pneu-monitis.9- ' Diagnosis has been improved by cyto-logical, bacteriological, and virological examinationof bronchial lavage fluid37 to exclude an infectiouscause, which is demonstrable in half of all cases.Pathologically, interstitial pneumonitis has beendivided into three types depending on the presence ofcytomegalovirus inclusion bodies and type IIpneumocyte atypia and hyperplasia."4Cytomegalovirus is the major concern. It accounts

for most cases of infective interstitial pneumonitisafter bone marrow transplantation and character-istically presents six weeks after grafting. It has an

alarmingly high mortality rate of about 90%.9 Wemust hope that with improvements in early diagnosisafforded by detection of the expression of early cyto-megalo virus antigens38 and the development of inno-

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vative antiviral agents39 improvements in outlookwill occur. The major source of infection is almostcertainly reactivation of latent cytomegalovirus in theprofoundly immunosuppressed recipient of a bonemarrow graft but the contribution of exogenousinfection from donor marrow and blood productsshould not be overlooked.40 Ideally the recipientnegative for cytomegalovirus antibody should receivemarrow and concentrates negative for cytomegalo-virus. Even when this is possible cytomegaloviruspneumonitis still occurs, particularly in olderpatients, who have more severe graft versus hostdisease and have received more intensive immu-nosuppressive conditioning regimens before trans-plantation.9 Other viruses, including herpes simplexand varicella viruses and adenovirus,4 have beenimplicated but surprisingly there are few reports doc-umenting infection with influenza and respiratorysyncytial virus in recipients of bone marrow grafts.Moreover, the long term effects of these pulmonaryinfections are unknown.

Unlike interstitial pneumonitis in the acquiredimmunodeficiency syndrome associated with HTLVIII virus, only 4% of interstitial pneumonitis inimmunocompromised recipients of bone marrowgrafts is due to Pneumocytis carini9 10: the character-istic ground glass appearance on the chest radiographoccurring in the presence of rapidly increasing hyp-oxia but few auscultatory findings has become rarewith the use of prophylactic co-trimoxazole. RecentlyLegionella pneumophila,42 Chlamydia,43 andMycoplasma pneumonias have been reported as causesof interstitial pneumonitis. Because of poor antibodyresponses in these patients open lung biopsy andsophisticated culture techniques are required fordefinitive diagnosis, but empirical treatment witherythromycin may be warranted.The time of onset of an interstitial pneumonitis

after bone marrow transplantation has diagnosticimportance. In the first two weeks few episodes arefound to have an infective cause while most inter-stitial pneumonitis occurring after 100 days is due totreatable infective causes44: pneumocystis with co-trimoxazole and varicella virus with acyclovir.45

Idiopathic interstitial pneumonitis accounts for upto half of all cases reported and is likely to be due tocombined drug and radiation toxicity.91- 5 The Inter-national Bone Marrow Transplant Registry reportsidiopathic interstitial pneumonitis to be more fre-quent in older patients, who have a long intervalbetween primary diagnosis and transplantation, andwho are then treated with cyclosporin and developgraft versus host disease. Low performance statusbefore transplantation is also a risk factor.9 In theSeattle patients radiotherapy seems to be implicated,a lower incidence of pneumonitis being seen when up

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to eight equal fractions, to a total of 12-15 Gy(1200-1500 rads) overall are delivered as opposed to asingle dose of 10 Gy. In the larger registry series suchdiscriminants were not evident, but high radiationdose rates in patients receiving methotrexate seem tobe harmful.9

PULMONARY EMBOLISMDuring marrow harvest fat and bone fragments willinevitably be collected and subsequently infused.Transient hypoxia may occur but no long term paren-chymal damage seems to ensue.4647 Neverthelessabnormalities of pulmonary vasculature are beingrecognised with endothelial changes and intimalthickening predisposing to thrombosis of the arte-rioles, capillaries, and venules that presumablyreflects radiation damage.14 Pulmonary veno-occlusive disease may masquerade as interstitialpneumonitis48 and, intriguingly, fat embolisation hasbeen seen as a late complication of bone marrowtransplantation.49

RESTRICTIVE AND OBSTRUCTIVE LUNG DISEASEAmong the later complications of bone marrowtransplantation restrictive and obstructive defects ofventilatory function have been reported in subjectswho have had pretransplantation conditioning withhigh dose chemotherapy and irradiation. In over 300patients with marrow transplants studied in Seattle amean loss of 0.81 litres of total lung capacity, 0.541 ofvital capacity, and 4.4 ml/min/mm Hg of diffusingcapacity (1.5 mmol min- 1 kPa-' of transfer factor)was evident one year after transplantation.' 5 In mostpatients these changes improved over the next threeto four years. Obstructive lung disease seems tobecome more prominent with the passage of time.Reduction in FEV1/VC to less than 50%, 60%, and70% predicted was seen in 0%, 2%, and 11% at threemonths but in 8%, 18%, and 29% by three years.Unfortunately the pathological findings in patientsreported in this study are unknown. What is causingsuch lung damage remains something of an enigma,since severe obstruction was not attributable in thisseries to previous whole body irradiation, interstitialpneumonitis, or chronic graft versus host disease.

GRAFT VERSUS HOST DISEASE ANDBRONCHIOLITIS OBLITERANSThe relationship between graft versus host diseaseand the lung remains uncertain. Although several pul-monary entities have been linked with graft versushost disease, definite evidence that these are true man-ifestations of graft versus host disease is lacking.Lymphocytic bronchitis with the histological demon-stration of lymphocytic infiltration of the bronchialmucosa, loss of cilia and goblet cells, and even necro-

sis of mucosa and submucosa has been described as apostmortem finding in 25% of patients dying afterbone marrow transplantation,50 many patients hav-ing had cough and dyspnoea. Recent studies suggestthat these findings relate poorly if at all to the pres-ence of graft versus host disease and are probably dueto earlier chemotherapy.5' Lymphocytic interstitialpneumonitis has also been reported as a late compli-cation of bone marrow transplantation,52 but therelationship of such an entity to graft versus host dis-ease is uncertain and further studies of the lungs ofpatients with no other evidence of graft versus hostdisease are needed. In 1982 the first cases of severeirreversible airways obstruction occurring within fivemonths of bone marrow transplantation and in thecontext of chronic graft versus host disease werereported.53 The chest radiograph may be normal, buthyperinflation flat diaphragms and pneumothoraceshave been reported, in association with reduced elas-tic recoil pressure. Histological appearances are thoseof bronchiolitis obliterans. The clinical course is vari-able. Treatment with corticosteroids and azathioprinemay be of benefit, although the mortality rate remainshigh.53-58 Workers in one centre contend that asmany as 13% of all recipients of marrow grafts havethis complication.54 Its aetiology may be multi-factorial, and it may not necessarily be directly attri-butable to graft versus host disease itself but mayresult from recurrent infection or recurrent gastro-oesophageal regurgitation. Others contend that it isrelated to the fibrotic chronic mucositis of the mouthand oesophagus seen in many cases of chronic graftversus host disease.The contributions, if any, of graft versus host dis-

ease and its prophylaxis to pulmonary sequelae afterBMT may become clearer by studying the patientwho has received an autotransplant. Here marrow isharvested from the patient himself, preserved, andreinfused after intensive chemotherapy or radiationtherapy (or both) has been used to control resistantdisease. The patient is rescued from bone marrow fail-ure by his own marrow. Such treatment is of potentialuse in the treatment of solid tumours and is beingexplored in haematological malignancies, particularlywhere resistant disease is present in sanctuary sites.The seriousness of pulmonary damage to patients

who have bone marrow transplantation must not beunderestimated. Many further studies are needed.Sufficient numbers of patients with similar underlyingdisorders must be studied. Investigations must detailpretransplant pulmonary function, previous infec-tions, chemotherapy, radiotherapy, transfusions, andsmoking history. Sequential assessment of pulmonaryfunction must be performed in relation to clinicalevents and combined with detailed bacteriologicaland virological monitoring. Episodes of graft versus

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host disease need to be defined in terms of biopsychanges in relevant tissues. Many more reports oflung biopsy material studied by histological andimmunohistochemical means are needed in conjunc-tion with evidence of intensive search for infectiveorganisms, particularly viruses. In this way the causesof pulmonary morbidity may be determined moreprecisely and the way prepared for prevention and therealisation of the wider application of bone marrowtransplantation.

PJ HAMILTONDepartment of Haematology

Royal Victoria Infirmaryand University of Newcastle upon Tyne

ADJ PEARSONDepartment of Child Health

University of Newcastle upon Tyne

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