bronchiolitis obliterans after allo-sct: clinical criteria and treatment options

REVIEW

Bronchiolitis obliterans after allo-SCT: clinical criteria and treatment options

HH Uhlving1,2, F Buchvald1,3, CJ Heilmann1, KG Nielsen1,3, M Gormsen4 and KG Muller1,2

1Paediatric Clinic, National University Hospital Rigshospitalet, Copenhagen, Denmark; 2Department of Rheumatology, Institute ofInflammation Research, National University Hospital Rigshospitalet, Copenhagen, Denmark; 3Paediatric Pulmonary Service,National University Hospital Rigshospitalet, Copenhagen, Denmark and 4Department of Radiology, National University HospitalRigshospitalet, Copenhagen, Denmark

Bronchiolitis obliterans (BO) following allogeneic haemato-poietic SCT (HSCT) is a serious complication affecting1.7–26% of the patients, with a reported mortality rate of21–100%. It is considered a manifestation of chronic graft-versus-host disease, but our knowledge of aetiology andpathogenesis is still limited. Diagnostic criteria are beingdeveloped, and will allow more uniform and comparableresearch activities between centres. At present, no rando-mised controlled trials have been completed that coulddemonstrate an effective treatment. Steroids in combinationwith other immunosuppressive drugs still constitute thebackbone of the treatment strategy, and results from our andother centres suggest that monthly infusions of high-dosepulse i.v. methylprednisolone (HDPM) might stabilise thedisease and hinder progression. This article provides anoverview of the current evidence regarding treatment optionsfor BO and presents the treatment results with HDPM in apaediatric national HSCT-cohort.Bone Marrow Transplantation (2012) 47, 1020–1029;doi:10.1038/bmt.2011.161; published online 29 August 2011Keywords: bronchiolitis obliterans; allogeneic haemato-poietic SCT; chronic graft-versus-host disease; treatmentoutcome; methylprednisolone

Introduction

Bronchiolitis obliterans (BO) is an obstructive lung diseaseseen after allogeneic haematopoietic SCT (HSCT).1 Re-spiratory symptoms include cough, dyspnoea and wheeze,but patients may remain relatively asymptomatic despitemoderate-to-severe obstruction. The pronounced variabil-ity in reported incidences (1.7–26%) and mortality rates(21–100%)2–11 of BO may be because of the lack ofconsistent definitions.11–16 No validated treatment protocolhas been established.

This article reviews our current knowledge of thepathogenesis of BO and outlines the current practice inthe treatment of this serious complication. Finally, wepresent our experience of high-dose i.v. pulse methylpred-nisolone treatment (HDPM) in children with BO afterallogeneic HSCT.

Pathogenesis

Because BO resembles allograft-rejection in lung-transplantrecipients (BO syndrome (BOS)) at a pathological, im-munological and physiological level,17 studies of BO inHSCT patients are discussed along with studies of BOS inlung transplant patients in the following.

Increasing evidence suggests that T-cell-mediated recog-nition of alloantigens expressed in the lung tissue consti-tutes a central event in the pathogenesis of BO. Thus, inlung transplanted patients HLA mismatch confers anincreased risk,18 and signs of BO after HSCT is oftenaccompanied by alloreactivity in other organs (for example,skin, liver and eyes).1,3–8,19–22 The essential role of T-cell-mediated allorecognition was further indicated by a studyshowing reduced frequency of BO in HSCT patientsreceiving a T-cell-depleted graft.23 Other reported riskfactors are BU-based conditioning regimens,9,24–26 theintensity of conditioning,27 time from leukaemia diagnosisto HSCT, peripheral blood-derived stem cell source, gradeII–IV acute GvHD (aGvHD),9 pre-transplant airflowobstruction and viral respiratory tract infection within thefirst 100 days after HSCT.10 The findings are however, notconsistent between studies.

Histopathologically, the BO process begins with lym-phocyte infiltration around the small vessels and beneaththe respiratory epithelial lining in the small airways,followed by epithelial cell necrosis and denudation ofmucosa.28 A secondary cascade of non-specific inflamma-tory mediators attracts other cells, including neutrophils,and leads to migration of fibroblasts, proliferation ofsmooth muscle cells, and eventually collagen depositionand fibrous obliteration of the lumen.29,30

Interestingly, studies of BOS in lung transplant recipientshave suggested a central role of T-cell-mediated reactivitytowards collagen. Thus, infiltrating monocytes as well ascollagen type V (col(V))-specific Th17 cells are seen in the

Received 4 February 2011; revised 4 July 2011; accepted 6 July 2011;published online 29 August 2011

All authors have approved the final version.

Correspondence: Dr HH Uhlving, Paediatric Clinic 4072, NationalUniversity Hospital Rigshospitalet, Blegdamsvej 9, 2100 CopenhagenOe, Denmark.E-mail: [email protected]

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& 2012 Macmillan Publishers Limited All rights reserved 0268-3369/12

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inflammatory focus.31 Col(V), which is essential for lung-tissue elasticity and compliance, is in healthy individualsnot exposed to immune cells. It is conceivable, although notyet shown, that T-cell-mediated recognition of col(V) mayalso play a pathogenetic role in BO after HSCT, wherecol(V) may be exposed as a result of epithelial damage bychemotherapy and/or irradiation.

T-cell activation is initiated by APCs—usually DCs anddifferentiation of T-cells into T helper 1 (Th1), Th2, Th17and/or regulatory T-cells (Treg) is determined by thecytokine profiles in the microenvironment during T-celldifferentiation.32 Animal studies have suggested a mutuallyexclusive differentiation of CD4þ cells into either Th17 orTreg, depending on the presence (Th17) or absence (Treg) ofIL-6.33 The Th17 subset is important in the development ofinflammation and autoimmunity, while Tregs may down-regulate inflammatory activity in autoimmune diseases andinhibit graft rejection in organ transplantation.32 Lungtransplant patients affected with BOS have a lower level ofcirculating CD4þCD25þTreg than patients in a stableclinical condition.34 In line with this, an animal model ofBOS has shown increased local IL-17 production, withdecreased peripheral blood levels of Tregs.

35 IL-17 has beenshown to induce IL-8 secretion,36,37 which in turn is relatedto airway neutrophilia.38,39 This may be of potential clinicalinterest because the number of neutrophils in the airwayshas been associated with clinically defined BOS phenotypesfollowing lung transplantation.40

Increasing interest is rewarded the role of B cells inchronic GvHD.41 Elevated blood levels of B-cell activatingfactor, essential for survival and differentiation of B cells,have been demonstrated in cGvHD-42,43 and BO-patients.44

A study in lung transplant recipients has suggested atemporal relationship between development of anti-HLAantibodies and BOS.45 Murine studies have demonstratedthat specific antibodies towards HLA class I activateparenchymal cells in a tracheal allograft, resulting inproliferation, growth factor production and apoptosis.This process leads to the activation of fibroblasts, tissueremodelling and proliferation of fibrous tissue observedduring BOS development.46

Taken together, these data suggest a model in whichrespiratory insults and extensive inflammation during thetransplantation constitute a ‘primary hit’ that results inupregulation of MHC molecules and exposure of ‘neoanti-gens’ including col(V). This leads to Th17-biased differ-entiation of T-cells, and subsequently IL-8-drivenneutrophilia. B-cell activation, Ag presentation and pro-duction of anti-HLA Abs may result in aggravation andmaintenance of the inflammatory response and ultimatelyepithelial destruction and pulmonary fibrosis.

Efforts to prevent and treat BO have been directedtowards various steps of this cascade, but the limitedclinical success underlines that our knowledge of thiscondition is still sparse.

Diagnosis

Early diagnosis of BO is difficult, because patients are oftenasymptomatic in the early stages of the disease7 and

inconsistency in applied diagnostic criteria have made itdifficult to compare research results with respect toaetiology, treatment and outcome. The National Instituteof Health (NIH) Consensus Development Project pub-lished in 2006 the first comprehensive attempt to defineclinical criteria for the diagnosis.12 Accordingly, thediagnosis of BO requires fulfillment of all of the followingcriteria:

(1) Absence of active infection.(2) Forced expiratory volume in 1 second (FEV1) o75%

of predicted normal and FEV1/forced vital capacity �

ratio o0.7.(3) Evidence of air trapping or small airway thickening or

bronchiectasis on high-resolution computed tomogra-phy, residual volume 4120% of predicted or patholo-gical confirmation of constrictive bronchiolitis

Chronic GvHD may be diagnosed when BO is proven bylung biopsy. BO diagnosed via clinical criteria requires atleast one manifestation in a separate organ system toestablish the diagnosis of cGvHD.12

The term idiopatic pneumonia syndrome is by theAmerican Thoracic Society defined as widespread alveloarinjury evidenced by radiology, signs and symptoms ofpneumonia and either an increased alveolar to arterialoxygen gradient or a restrictive pulmonary function test notattributed to infection, cardiac dysfunction, renal failure oriatrogenic fluid overload.47 Although BO primarily isdefined as an obstructive lung disease, cases of BO willoften also fit the idiopatic pneumonia syndrome definition.Most cases of idiopatic pneumonia syndrome, however,occurs in the first 3 months after SCT.47–50

The need for further development of these criteria is,however, a matter of ongoing discussion. In a retrospectivestudy by Williams et al.,11 only 18% of previouslydiagnosed BO patients with a FEV1 of o55%, met theNIH consensus criteria. As forced vital capacity and totallung capacity in HSCT patients can be falsely low becauseof restriction from scleroderma or myositis, these authorssuggested a definition of obstruction confirmed by eitherFEV1/slow vital capacity or air trapping on high-resolutioncomputed tomography with residual volume or residualvolume/total lung capacity4120%.11

Treatment

Although a number of first- or second-line treatmentstrategies have been described in the literature, norandomised controlled trials have described a long lastingeffect of any treatment modality for BO.51–53 A Medlinesearch on English literature, including prospective andretrospective studies, randomised or not randomised, withmore than three participants published since 2000, revealed18 studies54–72 and 10 treatment modalities (Table 1). Usingthe NIH grading system, no treatment modality reached anevidence level above III (evidence from opinions ofrespected authorities based on clinical experience, descrip-tive studies or reports from expert committees). Thestrength of recommendation was C (insufficient evidenceto support recommendation or outweigh adverse effects or

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Table 1 Clinical studies on treatment strategies for BO and chronic lung GvHD after HSCT

Treatment

regimens

SoR-EL Author Dosage Type of publication cGVHD and BO definitions No. and age of patients enrolled Results

HDPM C-III Ratjen54 i.v. Methylprednisolone

10mg/kg for 3 consecutive

days every 4–6 weeks.

Median 4 treatment cycles

(range 1–6)

Retrospective

paediatric study, no

randomisation or

control group

4/5 of criteria fulfilled: (1) airway

obstruction without reversibility; (2) no

pulmonary infiltrates; (3) no signs of

infection in blood or BAL; (4) reduced

FEV1 without airway restriction; (5)

bronchial dilatation and mosaic pattern

on HRCT

Nine patients, of whom five

were able to perform

spirometry. Median age 8

years (range 1–17)

Significant improvement in FEV1 at 2

months (Po0.02). 7/9 remained clinically

stable. One died from respiratory

failure. Mean follow-up 42±20 months

(range 19–67)

Inhaled

steroids

C-III Bergeron55 Budenosid/formoterol 400/

12 mg� 2/daily

Retrospective study,

no randomisation or

control group

FEV1/VCo5th percentile of normal

value without reversibility OR HRCT

with air-trapping score 45 (maximum

score 18,73). No extrathoracic signs of

cGVHD

13 patients. Median age 44


410% increase in FEV1 in 13/13 patients.

Mean increase in FEV1 36±27%

(P¼ 0.018). Decreased dyspnea in 11/13 pt.

Median follow-up 12.8 months (range 5–

29)

Montelukast C-III Or56 10mg � 1. Median

treatment period 16 months

(range 2–29)

Prospective cohort

study, no

randomisation or

control group

Severe cGVHD with BO according to

the NIH Consensus Criteria12Five patients with BO/19 with

cGVHD. Median age 33 years

(range 17–54)

430% increase in FEV1 in 3/5 patients. 2/5

patients died of end-stage BO. Follow-up

time not reported

Azithromycin C-III Khalid57 500mg � 1 for 3 days,

followed by 250mg three

times/week for 3 months

Observational study,

no randomisation or

control group

Decline in FEV1 of 420%, and evidence

of air trapping on HRCT

Eight patients. Mean age 36


412% improvement in FEV1 in 7/8

patients. Mean increase in FEV1 20.58%

(Po0.0067) and FVC 21.57% (Po0.0052).

Follow-up 12 weeks

Lam58 250mg � 1 for 12 weeks Randomised double-

blinded placebo-

controlled study

FEV1o75%, FEV1/FVC ratioo0.7 and

reduction of FEV1 by 410% compared

with baseline values

12 patients in treatment group,

mean age 44.5 years (range 31–

56), 10 patients control group

mean age 43 years (24–57)

No significant changes in respiratory scores

and FEV1 in the treatment and control

groups

TNF-a

inhibitor

C-III Busca59 Etanercept subcutaneously

25mg twice weekly for 4

weeks, followed by once

weekly for 4 weeks

Retrospective study,

no randomisation or

control group

Steroid-refractory cGVHD with BO

according to the NIH Consensus

Criteria12

Five patients with BO/8 with

cGVHD. Median age all

patients 52 years (range 26–70)

Partial response in 3/5 (450% response in

one evaluable organ without deterioration

of other). Progressive disease in 2/5. 1/5

died of GVHD and septic shock. Median

follow-up 13.5 months (range 10.1–22.5)

Chiang60 Etanercept 25mg (0.4mg/kg

for children) twice weekly for

4 weeks, followed by once

weekly for 4 weeks

Prospective cohort

study, no

randomisation or

control group

Steroid dependent cGVHD involving

lungs (not specified further)

Five patients with lung

involvement/10 with cGVHD.

Median age all patients 38


Partial response in 2/5 (450%

improvement in symptoms, reduction in

steroid dose or immunosuppressive agents).

One died of TTP. Median follow-up all

patients 7 months (range 3–18)

Extracorporal

photopheresis

C-III Flowers61 Three cycles/week for 1 week

followed by twice weekly on

consecutive days during

weeks 2–12

Randomised, single-

blinded multicentre

study

Extensive cGVHD with lung

involvement, as defined by Lee et al.:13

FEV1o80% and a decrease in FEV1/

FVC by 10% in o1 year not explained

by infection, asthma or aspiration.

Stable corticosteroid dose for at least 2

weeks before inclusion

Nine patients with lung

involvement/48 with cGVHD

in ECP group. 7/47 in control

group. Median age ECP group

41 years (range 16–67),

controls 43 years (range 13–67)

Improvement defined as investigators

assessment of complete resolution or

objective improvement: ECP group 11%,

control group 29%; NS. Follow-up

12 weeks

Couriel62 Two to four treatments/week

until partial response,

subsequently tapered by 1/

week. Maintenance regimen

two treatments/2 weeks.

Retrospective,

non-randomised,

single-centre study

cGVHD with symptomatic BO and (1)

decrease in FEV1 420% in 1 year, (2)

air trapping or small-airway thickening

or bronchiectasis on HRCT or

pathologic confirmation of BO and (3)

11 patients with lung




Complete response in 1/11. Partial response

in 5/11 (sustained improvement in FEV1

and/or the ability to taper corticosteroids

by 50% without deterioration of

pulmonary function). Follow-up 6 months

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Table 1 Continued

Treatment

regimens

SoR-EL Author Dosage Type of publication cGVHD and BO definitions No. and age of patients enrolled Results

Median 32 ECP procedures

(range 1–259)

no evidence of active infection.

Refractory to immunosuppressives

Messina63 Two treatments on

consecutive days per week

for 1 month, every 2 weeks

for 2 months, then monthly

for at least 3 months.

Median treatment period not

reported

Retrospective

paediatric,

multicentre non-

randomised study

cGVHD (Sullivan15) failing to respond

to X2 lines of therapy. Obstructive lung

disease characterised as mild (FEV1

70–100%), moderate (FEV1 60–70%),

moderate severe (FEV1 50–60%), severe

(FEV1 34–40%) (American Thoracic

Society74)


involvement/44 with cGVHD

(12 patients with moderate to

severe obstruction). Median

age all patients 8.2 years

(range 0.3–20.5)

Complete response in 4/12 with moderate/

severe lung disease. Partial response in 2/7

with severe disease (450% response in

organ involvement). Follow-up time not

reported

Rubegni64 Two treatments on

consecutive days every 2

weeks for 4 months, then

once monthly for at least 2

months. Median treatment

period not reported

Prospective non-

randomised single-

centre study. No

control group

Steroid refractory cGVHD with lung

involvement assessed by pulmonologist

based on FEV1, FVC, DLCO and

HRCT (criteria not further specified)

Five patients with lung


Median age 35 years (range

25–56)

Partial response in 2/5. Stabilisation in 1/5.

Disease progression in 2/5 (no further

specification). Follow-up time not reported

Lucid65 Two treatments per week for

3–4 weeks, decreased to

every 2–3 weeks.

Maintenance regimen two

treatments/4 weeks. Median

treatment period not

reported

Retrospective single-

centre study

BO according to amended NIH criteria

(Williams11). Refractory to prior therapy

with median five different drugs

(range 2–7)

Nine patients. Median age 38


Stabilized lung function in 6/9 patients.

Symptomatic improvement in 2/3 ‘non-

responders’. Median follow-up 25 days

(range 20–958)

Rituximab C-III Zaja66 375mg/m2 i.v. every week.

Median 4 treatments (range

4–20)

Retrospective

multicentre study

Extensive cGVHD (Revised Seattle

Classification, Lee13) with lung

involvement (FEV1o80%, decreased

FEV1/FVC by 10% in o1 year, no

infection, asthma or aspiration and if no

cGVHD in other organ: air trapping on

HRCT, negative BAL or BO in biopsy)

Nine patients with lung




Partial response (450% regression of

cGVHD) and dose reduction of

immunosuppressives in 3/9. Follow-up 15

months (range 12–22)

Kim67 375mg/m2 i.v. weekly for 4

weeks, then monthly for 4

months

Open-label,

multicentre,

prospective phase II

study

Steroid refractory moderate to severe

cGVHD according to the NIH

consensus criteria (Filipovich12)


involvment/37 with cGVHD.



Partial response in 1/11 (clinical score

reduction in at least one affected organ,

without deterioration in other organ). No

response in 10/11. Follow-up 1 year

Pentostatin C-III Jacobsohn68 4mg/m2 i.v. every 2 weeks

for at least 12 doses. Median

12 doses (range 1–32)

Prospective, non-

randomised, double-

centre study. No

control group

Biopsy proven active cGVHD (increase

in symptoms during, or when tapering,

immunosuppressive medicine) and PFT

o50% of normal values (PFT not

formally included endpoint). Failure of

one or more immunosuppressive in at

least 4 months

Six patients with lung



(range 5–64)

Immunosuppression tapered/discontinued

in 4/6. Median follow-up of responding

patients 175 days (range 1–701)

Imatinib C-III Olivieri69 Initially 100mg/day,

increased over 4 months to

maximum 400mg/day,

depending on the response.

Median treatment period 5

months (range 6–15)

Prospective non-

randomised single

centre phase 1–2 trial

Active cGVHD with fibrotic

scleroderma-like features, resistant to

42 immunosuppressives. BO and/or

extensive lung fibrosis confirmed by

biopsy and/or spirometry, DLCO and

HRCT. Median FEV1 at baseline

70%(range 32–78%). Median DLCO

68% (48–74%)





Complete remission after 6 months in 3/11.

Partial remission in 4/11 (sustained

improvement in PFT or ability to taper

corticosteroids by at least 50% without

deterioration). 9/11 alive at follow-up.

Median follow-up 17 months (range 8–22)

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costs of the approach) for all treatment modalities apartfrom treatment with corticosteroids (A-III), which isdiscussed in the following.

CorticosteroidsIn 2005, Ratjen et al.54 reported their experience withHDPM treatment in a small cohort of nine children. To ourknowledge, no other published study has described thistreatment regimen for BO after HSCT. HDPM treatment isrecommended in other inflammatory lung diseases inchildren.75,76 Reported side effects include transient flush-ing, headache, mood changes77 and sinus bradycardia,78

but no serious long-term events have been described inchildren. HDPM has been the standard treatment of BOsince 1999 at our centre, and we here summarise the results.

HDPM treatment in the Danish paediatric BO cohort. Withinthe recent 12 years BO has been diagnosed in 13 childrenfollowing HSCT (median age 9.3 years, range 0.6–13.4) at thenational paediatric HSCT centre in Denmark. This corre-sponds to 7.3% of Danish SCT patients below 16 years of agein this period. Nine of the patients were able to perform areliable spirometry and had significantly reduced levels offunction (Table 2). In five cases BO was confirmed by openlung biopsy. The final diagnosis of BO was based on acombination of decreased lung function parameters, high-resolution computed tomography findings, lung biopsy and/orclinical symptoms, but none of the nine patients fully met theNIH clinical criteria for BO.

Our patient cohort was treated with a combination ofconventional immunosuppressive agents (Table 3) and i.v.HDPM 15mg/kg for 2–3 consecutive days every 4–6 weeks.Median time from HSCT to first BO symptoms was 141days (range 53–254) and from symptoms to first course ofHDPM 35 days (3–244). Spirometry was performed beforeHSCT, before initiating HDPM therapy, and thenmonthly. Patients with FEV1 o35% and patients whowere unable to taper oral prednisolone within 6 months ofHDPM initiation were given additional treatment withmonthly infusions of infliximab.

One patient (no. 8) died of respiratory insufficiencybecause of CMV-pneumonia 1 month after initiation oftherapy, whereas one patient (no. 6) died of leukaemicrelapse. In the patients tested, a significant increase in FEV1

was seen 3 months (P¼ 0.010) and 1 year (P¼ 0.011) afterinitiation of HDPM (the Wilcoxon rank sum test), withmedian increase in FEV1 from 48.1% at treatmentinitiation to 71.4% and 83.0%, respectively (Figure 1).During further follow-up lung function generally stabilisedat a moderately reduced level.

This small population-based study of a rather hetero-geneous group of patients has obvious limitations, sharedby the majority of the previous studies presented in Table 1,and does not allow firm conclusions. Our data suggests thatstabilisation of lung function in BO patients may beachieved by early commencement on high-dose pulsecorticosteroids in combination with other immunosuppres-sive treatment. The effect of HDPM on relapse rate andinfectious complications cannot be properly assessed in astudy of this size. Further studies, preferebly a multicenterT

able

1Continued

Treatm

ent

regim

ens

SoR-EL

Author

Dosage

Typeofpublication

cGVHD

andBO

definitions

No.andageofpatientsenrolled

Results

Stadler7

0100–400mg/day.Median

treatm

entperiod4months

(range1–17)

Prospective,

single

centre,

open-label

non-randomised

study

Severepulm

onary

cGVHD,resistantto

extensiveim

munosuppressivetherapy.

MedianFEV

129%

(range18–41)

Ninepatients.Medianage45

years

(range24–50)

Recoveryoflungfunction(from

severeto

moderate

reduction)in

1/9.Abilityto

taper

steroidsin

2/9.Nochangein

5/9.2/9

died

ofBO

and/orrelapse.Follow-uptimenot

reported

Thalidomide

C-III

Kulkarni71

Initially50–100mg�3,

increasedgradually

dependingontolerance

and

clinicalresponse

Median

dailydose

400mg(range

50–1200).Mediantreatm

ent

period61days(range

1–1210)

Retrospective,

non-

randomised

study

ExtensivecG

VHD

(presentin

41

organ)withlunginvolvem

ent

(Sullivan,14Akpek

16).No,or

insufficient,response

toprednisolone

andcyclosporineand/orazathioprine

14patients

withlung

involvem

ent/59withcG

VHD.

Medianageallpatients

31.5

years

(range2–52)

Complete

response

3/14.Partialresponse

in

2/14(improved

perform

ance

status,450%

resolutionofsignsandsymptoms).Median

follow-up53months(range5–159)

Abbreviations:BAL¼bronchoalveolarlavage;BO¼bronchiolitisobliterans;cG

VHD¼chronicGVHD;DLCO¼carbonmonoxidediffusingcapacity;EL¼evidence

level;ECP¼extracorporealphotopheresis;

FEV

1¼forced

expiratory

volumein

1second;FVC¼forced

vitalcapacity;HDPM

¼high-dose

pulsei.v.methylprednisolone;

HRCT¼high-resolutioncomputedtomography;HSCT¼haem

atopoieticSCT;

NS¼nonsignificant;NIH

¼NationalInstitute

ofHealth;PFT¼pulm

onary

functiontest;SoR¼strength

ofrecommendation;TTP¼thromboticthrombocytopenic

purpura.


HH Uhlving et al

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randomised study would be needed to properly adress bothtreatment response and possible adverse effects of HDPMtherapy.

Corticosteroids have been the backbone of cGvHDtherapy, since Sullivan et al.14 in 1981 demonstratedimproved outcome in cGvHD patients receiving corticos-teroids in combination with other immunosuppressors.14

The role of prednisolone was further established in tworandomised studies,79,80 where the addition of azathiopr-ine79 and cyclosporine80 did not seem to further improveoutcome in standard risk cGvHD patients. However, theeffect of orally administrated prednisolone on lunginvolvement was not reported in those studies. First-linetreatment of cGVHD mainly consists of prednisolone witha starting dose of 1mg/kg/day orally.52

Inhaled corticosteroids in combination with long-actingbronchodilators are now being tested in BO patients in a

Table 2 The Danish paediatric BO cohort accordance with NIH clinical criteria at time of diagnosis

BO on

biopsy

FEV1% FEV1/

FVC%

HRCT RV% Infection RV/TLC% cGVHD in

other organ

1 Yes 42.8 106.8 Bronchiectasis, air trapping Unknown No Unknown Skin

2 Yes 39 89.4 Air trapping Unknown No Unknown No3 No 53.5 77.4 Bronchiectasis, bronchial thickening, small nodular opacities 111.40 No 137.70 No4 No 29.3 91.0 Air trapping, bronchiectasis, bronchial thickening Unknown No Unknown No5 No 62.0 95 Bronchiectasis, bronchial thickening, air trapping 127 No 142 No6 No 61 85 — 131 No 132 Skin7 Yes 53.5 65.8 Centrilobular opacities and reduced transparency Unknown No Unknown No

8 Yes 40.4 109.3 Air trapping, bronchiectasis, bronchial thickening, groundglass opacities, consolidation of peripheral lung segments

Unknown No Unknown No

9 No 39.8 69.3 Normal Unknown No Unknown No

Abbreviations: BO¼bronchiolitis obliterans; cGVHD¼ chronic GVHD; FEV1¼ forced expiratory volume in 1 second; FVC¼ forced vital capacity;

HRCT¼ high-resolution computed tomography; NIH¼National Institute of Health; RV¼ residual volume; TLC¼ total lung capacity.

Table 3 Patient characteristics

Diagnosis Age at

HSCT

SCT

conditioning

GVHDprophylaxis

Days between

SCT and onset

Days from

symptoms

to HDPM

BO treatment Outcome

1 JMML 11 Bu, Cy,Me, ATG

MTX,Cic/MPA

159 16 HDPM, Po,In, Ra/Ta

Stable for 3 y. Deterioration afterwidened HDPM-intervals. Dead fromend-stage BO 5 years after BO-diagnosis.

2 SAA 4 Bu, Cy, ATG MTX, Cic 57 244 HDPM,Cic/Ta, In

Alive, stable

3 MDS secondary toALL

10 Bu, Cy,Me, ATG

MTX,Cic/MPA

254 35 HDPM, Po Alive, stable

4 Pre-B-ALL 7 Bu, Cy,Et, ATG

MTX, Cic 212 111 HDPM, In Lost to follow-up after 6 months

5 HLH 13 Bu, Cy, ATG MTX, Cic 231 16 HDPM, Po Paraplegia after car-accident6 Pre-B ALL 13 Cy, ATG,

TBIMTX,Cic/MPA

72 21 HDPM, Po Relapse 8 months after BO diagnosis.Dead

7 MLD 9 Bu, Cy, ATG MTX,Cic/MPA

141 86 HDPM, Po Alive, stable

8 T-ALL 10 Cy, ATG,TBI

MTX, Cic 99 3 HDPM, Po Dead from respiratory insufficiency(CMV pneumonia) 1 month afterHDPM initiation.

9 SAA 11 Bu, Cy, ATG MTX,

Cic/MPA

53 106 HDPM, Po,

In, Ra

Alive, stable

Abbreviations: ATG¼ anti-thymocyte globulin; BO¼ bronchiolitis obliterans; Bu¼ busulfex; Cic¼ ciclosporine; Et¼ etophos; HDPM¼ high-dose pulse

i.v. methylprednisolone; HLH¼ haemophagocytic lymphohistiocytosis; HSCT¼haematopoietic SCT; In¼ infliximab; JMML¼ juvenile myelomonocytic

leukaemia; Me¼melphalan; MDS¼myelodysplastic syndrome; MLD¼metachromatic leucodystrophy; MPA¼mycophenolate mofetil; Po¼ oral

prednisolone; Ra¼ rapamune; SAA¼ severe aplastic anemia; Ta¼ tacrolimus.

120

*P =0.010

*P =0.011

Patient 1

Patient 2

Patient 5

Patient 6

Patient 7

Patient 3

Patient 4

11010090

7080

6050

FE

V1%

pre

d

40

2030

100

Bef

ore S

CT

BO d

iagnosi

s

+1 m

onth

+3 m

onths

+6 m

onths

>12

month

s

Figure 1 A significant increase in FEV1 is seen from time of BO diagnosis

and initiation of HDPM compared with 3 months and 1 year after

initiation of therapy.


HH Uhlving et al

1025


prospective multicentre, randomised double-blinded trial.81

A pilot study of 13 patients with respiratory symptoms, butno extrapulmonary signs of cGvHD, showed some effecton lung function parameters55 (Table 1).

TNF-a inhibitorsInsights into the role of proinflammatory cytokines indisease pathogenesis, has led to the use of TNF-a inhibitorsas second-line BO treatment. The three patients in theDanish cohort, who received infliximab due to a decrease inlung function during the standard HDPM regimen,experienced stabilisation after commencement of inflixi-mab. A case study from Texas described completeresolution of symptoms in a patient with steroid refractoryBO on etanercept treatment.82 The two studies on the effectof infliximab described in Table 1(refs 59,60) suggests someimprovement. An ongoing study of etanercept therapy atthe Ann Arbor Cancer Center (NCT00141726) mayprovide further insights.

AzithromycinThe ability of azithromycin to inhibit airway neutrophiliaand IL-8 production39,40 may explain the improvementafter treatment in a subgroup of lung transplant recipientswith BOS.83,84 Similar positive results have been reported ina preliminary study on 8 patients with BO after HSCT57

(Table 1). However, a randomised placebo-controlledclinical trial from Hong Kong58 failed to prove superiorityof azithromycin to placebo when initiated (mean) 4.3 and5.8 years, respectively, after BO diagnosis. A recentlypublished case-series indicates a steroid sparing effect ofazithromycin in combination with inhaled corticosteroidsand montelukast in patients with newly diagnosed BO.85

Further studies are needed to establish an eventual effect ofazythromycin on incipient BO.

Extracorporeal photopheresisSelective downregulation of T-cell-mediated immunity isthought to explain the effect of extracorporeal photopher-esis in the treatment of GvHD.86 Though several studieshave been performed in patients with BO after HSCT61–

65,87–91 and lung transplantation,92–94 the studies are difficultto interpret because of the heterogeneity in the treatmentschedules, diagnostic criteria and response assessmentcriteria (Table 1). A prospective randomised study ofextracorporeal photopheresis treatment performed byFlowers et al.61 revealed a significant improvement ofcGVHD in the skin, and indicated a steroid sparing effecton cGvHD in general. No effect on lung functionparameters was noted.

RituximabAn attempt to attack the B-cell response suspected to be apart of cGvHD aetiology has led to the application of themonoclonal CD20-Ab Rituximab. Although several studieshave suggested an effect on cGvHD in the skin,66,95–98 noconvincing effect on BO has been established.66,67

Conclusion

Solid evidence regarding the efficacy of the variousavailable treatment modalities in BO is still sparse. Ongoingclinical trials together with new insights into the pathogen-esis will hopefully contribute to fill this gap. Thoughestablished clinical criteria are important as a research tool,the experience with the NIH Consensus Criteria mayindicate a need for further development of clinical criteriaand simplification of these. Our experience emphasises theneed for improved diagnostic criteria, in particular for theyoung children who are unable to perform spirometry.

The preliminary experiences with HDPM treatment fromour and other centres suggest that the efficacy of thistreatment regimen, including the long-term effects deservesfurther validation in clinical trials. Though alternativetreatment options may seem promising, corticosteroids arestill likely to remain a mainstay in GvHD treatment in thecoming years. However, with improved insights into thepathogenesis of BO new treatment modalities, includingcytokine antagonists and cellular therapy, may changetreatment strategies fundamentally.

Conflict of interest

The authors declare no conflict of interest.

Acknowledgements

This work was supported by grants from the Danish Children’sCancer Association and the Research Council at the NationalUniversity Hospital Rigshospitalet.

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