Bronchiolitis obliterans after allo-SCT: clinical criteria and ... - Nature

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Aug 29, 2011 - 1Paediatric Clinic, National University Hospital Rigshospitalet, Copenhagen, Denmark; 2Department of Rheumatology, Institute of.

Bone Marrow Transplantation (2012) 47, 1020–1029 & 2012 Macmillan Publishers Limited All rights reserved 0268-3369/12

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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 Mu¨ller1,2 1

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

Bronchiolitis obliterans (BO) following allogeneic haematopoietic SCT (HSCT) is a serious complication affecting 1.7–26% of the patients, with a reported mortality rate of 21–100%. It is considered a manifestation of chronic graftversus-host disease, but our knowledge of aetiology and pathogenesis is still limited. Diagnostic criteria are being developed, and will allow more uniform and comparable research activities between centres. At present, no randomised controlled trials have been completed that could demonstrate an effective treatment. Steroids in combination with other immunosuppressive drugs still constitute the backbone of the treatment strategy, and results from our and other centres suggest that monthly infusions of high-dose pulse i.v. methylprednisolone (HDPM) might stabilise the disease and hinder progression. This article provides an overview of the current evidence regarding treatment options for BO and presents the treatment results with HDPM in a paediatric national HSCT-cohort. Bone Marrow Transplantation (2012) 47, 1020– 1029; doi:10.1038/bmt.2011.161; published online 29 August 2011 Keywords: bronchiolitis obliterans; allogeneic haematopoietic SCT; chronic graft-versus-host disease; treatment outcome; methylprednisolone

Introduction Bronchiolitis obliterans (BO) is an obstructive lung disease seen after allogeneic haematopoietic SCT (HSCT).1 Respiratory symptoms include cough, dyspnoea and wheeze, but patients may remain relatively asymptomatic despite moderate-to-severe obstruction. The pronounced variability in reported incidences (1.7–26%) and mortality rates (21–100%)2–11 of BO may be because of the lack of consistent definitions.11–16 No validated treatment protocol has been established.

Correspondence: Dr HH Uhlving, Paediatric Clinic 4072, National University Hospital Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Oe, Denmark. E-mail: [email protected] All authors have approved the final version. Received 4 February 2011; revised 4 July 2011; accepted 6 July 2011; published online 29 August 2011

This article reviews our current knowledge of the pathogenesis of BO and outlines the current practice in the treatment of this serious complication. Finally, we present our experience of high-dose i.v. pulse methylprednisolone treatment (HDPM) in children with BO after allogeneic HSCT.

Pathogenesis Because BO resembles allograft-rejection in lung-transplant recipients (BO syndrome (BOS)) at a pathological, immunological and physiological level,17 studies of BO in HSCT patients are discussed along with studies of BOS in lung transplant patients in the following. Increasing evidence suggests that T-cell-mediated recognition of alloantigens expressed in the lung tissue constitutes a central event in the pathogenesis of BO. Thus, in lung transplanted patients HLA mismatch confers an increased risk,18 and signs of BO after HSCT is often accompanied by alloreactivity in other organs (for example, skin, liver and eyes).1,3–8,19–22 The essential role of T-cellmediated allorecognition was further indicated by a study showing reduced frequency of BO in HSCT patients receiving a T-cell-depleted graft.23 Other reported risk factors are BU-based conditioning regimens,9,24–26 the intensity of conditioning,27 time from leukaemia diagnosis to HSCT, peripheral blood-derived stem cell source, grade II–IV acute GvHD (aGvHD),9 pre-transplant airflow obstruction and viral respiratory tract infection within the first 100 days after HSCT.10 The findings are however, not consistent between studies. Histopathologically, the BO process begins with lymphocyte infiltration around the small vessels and beneath the respiratory epithelial lining in the small airways, followed by epithelial cell necrosis and denudation of mucosa.28 A secondary cascade of non-specific inflammatory mediators attracts other cells, including neutrophils, and leads to migration of fibroblasts, proliferation of smooth muscle cells, and eventually collagen deposition and fibrous obliteration of the lumen.29,30 Interestingly, studies of BOS in lung transplant recipients have suggested a central role of T-cell-mediated reactivity towards collagen. Thus, infiltrating monocytes as well as collagen type V (col(V))-specific Th17 cells are seen in the

Bronchiolitis obliterans in clinical practice HH Uhlving et al

1021

inflammatory focus.31 Col(V), which is essential for lungtissue elasticity and compliance, is in healthy individuals not exposed to immune cells. It is conceivable, although not yet shown, that T-cell-mediated recognition of col(V) may also play a pathogenetic role in BO after HSCT, where col(V) may be exposed as a result of epithelial damage by chemotherapy and/or irradiation. T-cell activation is initiated by APCs—usually DCs and differentiation of T-cells into T helper 1 (Th1), Th2, Th17 and/or regulatory T-cells (Treg) is determined by the cytokine profiles in the microenvironment during T-cell differentiation.32 Animal studies have suggested a mutually exclusive differentiation of CD4 þ cells into either Th17 or Treg, depending on the presence (Th17) or absence (Treg) of IL-6.33 The Th17 subset is important in the development of inflammation and autoimmunity, while Tregs may downregulate inflammatory activity in autoimmune diseases and inhibit graft rejection in organ transplantation.32 Lung transplant patients affected with BOS have a lower level of circulating CD4 þ CD25 þ Treg than patients in a stable clinical condition.34 In line with this, an animal model of BOS has shown increased local IL-17 production, with decreased peripheral blood levels of Tregs.35 IL-17 has been shown to induce IL-8 secretion,36,37 which in turn is related to airway neutrophilia.38,39 This may be of potential clinical interest because the number of neutrophils in the airways has been associated with clinically defined BOS phenotypes following lung transplantation.40 Increasing interest is rewarded the role of B cells in chronic GvHD.41 Elevated blood levels of B-cell activating factor, 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 a temporal relationship between development of anti-HLA antibodies and BOS.45 Murine studies have demonstrated that specific antibodies towards HLA class I activate parenchymal cells in a tracheal allograft, resulting in proliferation, growth factor production and apoptosis. This process leads to the activation of fibroblasts, tissue remodelling and proliferation of fibrous tissue observed during BOS development.46 Taken together, these data suggest a model in which respiratory insults and extensive inflammation during the transplantation constitute a ‘primary hit’ that results in upregulation of MHC molecules and exposure of ‘neoantigens’ including col(V). This leads to Th17-biased differentiation of T-cells, and subsequently IL-8-driven neutrophilia. B-cell activation, Ag presentation and production of anti-HLA Abs may result in aggravation and maintenance of the inflammatory response and ultimately epithelial destruction and pulmonary fibrosis. Efforts to prevent and treat BO have been directed towards various steps of this cascade, but the limited clinical success underlines that our knowledge of this condition is still sparse.

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

inconsistency in applied diagnostic criteria have made it difficult to compare research results with respect to aetiology, treatment and outcome. The National Institute of Health (NIH) Consensus Development Project published in 2006 the first comprehensive attempt to define clinical criteria for the diagnosis.12 Accordingly, the diagnosis of BO requires fulfillment of all of the following criteria: (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 tomography, residual volume 4120% of predicted or pathological confirmation of constrictive bronchiolitis Chronic GvHD may be diagnosed when BO is proven by lung biopsy. BO diagnosed via clinical criteria requires at least one manifestation in a separate organ system to establish the diagnosis of cGvHD.12 The term idiopatic pneumonia syndrome is by the American Thoracic Society defined as widespread alveloar injury evidenced by radiology, signs and symptoms of pneumonia and either an increased alveolar to arterial oxygen gradient or a restrictive pulmonary function test not attributed to infection, cardiac dysfunction, renal failure or iatrogenic fluid overload.47 Although BO primarily is defined as an obstructive lung disease, cases of BO will often 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 retrospective study by Williams et al.,11 only 18% of previously diagnosed BO patients with a FEV1 of o55%, met the NIH consensus criteria. As forced vital capacity and total lung capacity in HSCT patients can be falsely low because of restriction from scleroderma or myositis, these authors suggested a definition of obstruction confirmed by either FEV1/slow vital capacity or air trapping on high-resolution computed tomography with residual volume or residual volume/total lung capacity4120%.11

Treatment Although a number of first- or second-line treatment strategies have been described in the literature, no randomised controlled trials have described a long lasting effect of any treatment modality for BO.51–53 A Medline search on English literature, including prospective and retrospective studies, randomised or not randomised, with more than three participants published since 2000, revealed 18 studies54–72 and 10 treatment modalities (Table 1). Using the NIH grading system, no treatment modality reached an evidence level above III (evidence from opinions of respected authorities based on clinical experience, descriptive studies or reports from expert committees). The strength of recommendation was C (insufficient evidence to support recommendation or outweigh adverse effects or Bone Marrow Transplantation

SoR-EL

C-III

C-III

C-III

C-III

C-III

C-III

HDPM

Inhaled steroids

Bone Marrow Transplantation

Montelukast

Azithromycin

TNF-a inhibitor

Extracorporal photopheresis

Severe cGVHD with BO according to the NIH Consensus Criteria12

Prospective cohort study, no randomisation or control group

Observational study, Decline in FEV1 of 420%, and evidence Eight patients. Mean age 36 no randomisation or of air trapping on HRCT years (range 18–63) control group

Randomised double- FEV1o75%, FEV1/FVC ratio o0.7 and 12 patients in treatment group, No significant changes in respiratory scores blinded placeboreduction of FEV1 by 410% compared mean age 44.5 years (range 31– and FEV1 in the treatment and control with baseline values controlled study 56), 10 patients control group groups mean age 43 years (24–57)

10 mg  1. Median treatment period 16 months (range 2–29)

500 mg  1 for 3 days, followed by 250 mg three times/week for 3 months

250 mg  1 for 12 weeks

Etanercept subcutaneously 25 mg twice weekly for 4 weeks, followed by once weekly for 4 weeks

Etanercept 25 mg (0.4 mg/kg for children) twice weekly for 4 weeks, followed by once weekly for 4 weeks

Three cycles/week for 1 week Randomised, singlefollowed by twice weekly on blinded multicentre consecutive days during study weeks 2–12

Two to four treatments/week Retrospective, until partial response, non-randomised, subsequently tapered by 1/ single-centre study week. Maintenance regimen two treatments/2 weeks.

Khalid57

Lam58

Busca59

Chiang60

Flowers61

Couriel62

Prospective cohort study, no randomisation or control group

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)

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

Steroid dependent cGVHD involving lungs (not specified further)

Retrospective study, Steroid-refractory cGVHD with BO no randomisation or according to the NIH Consensus control group Criteria12

11 patients with lung involvement/71 with cGVHD. Median age all patients 39 years (range 5–70)

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)

Five patients with lung involvement/10 with cGVHD. Median age all patients 38 years (range 3–48)

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

Improvement defined as investigators assessment of complete resolution or objective improvement: ECP group 11%, control group 29%; NS. Follow-up 12 weeks

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)

Five patients with BO/8 with Partial response in 3/5 (450% response in cGVHD. Median age all one evaluable organ without deterioration patients 52 years (range 26–70) 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)

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

Five patients with BO/19 with 430% increase in FEV1 in 3/5 patients. 2/5 cGVHD. Median age 33 years patients died of end-stage BO. Follow-up (range 17–54) time not reported

410% increase in FEV1 in 13/13 patients. Mean increase in FEV1 36±27% (P ¼ 0.018). Decreased dyspnea in 11/13 pt. Median follow-up 12.8 months (range 5– 29)

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)

Or56

13 patients. Median age 44 years (range 16–57)

Nine patients, of whom five were able to perform spirometry. Median age 8 years (range 1–17)

Retrospective study, FEV1/VCo5th percentile of normal no randomisation or value without reversibility OR HRCT control group with air-trapping score 45 (maximum score 18,73). No extrathoracic signs of cGVHD

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

Budenosid/formoterol 400/ 12 mg  2/daily

Retrospective paediatric study, no randomisation or control group

Bergeron55

No. and age of patients enrolled Results

i.v. Methylprednisolone 10 mg/kg for 3 consecutive days every 4–6 weeks. Median 4 treatment cycles (range 1–6)

cGVHD and BO definitions

Ratjen54

Type of publication

Dosage

Author

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

Treatment regimens

Table 1

Bronchiolitis obliterans in clinical practice HH Uhlving et al

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Continued

SoR-EL

C-III

C-III

C-III

Table 1

Treatment regimens

Rituximab

Pentostatin

Imatinib

Two treatments per week for Retrospective singlecentre study 3–4 weeks, decreased to every 2–3 weeks. Maintenance regimen two treatments/4 weeks. Median treatment period not reported Retrospective multicentre study

Open-label, multicentre, prospective phase II study

375 mg/m2 i.v. every week. Median 4 treatments (range 4–20)

375 mg/m2 i.v. weekly for 4 weeks, then monthly for 4 months

Lucid65

Zaja66

Kim67

Olivieri69

Initially 100 mg/day, increased over 4 months to maximum 400 mg/day, depending on the response. Median treatment period 5 months (range 6–15)

Five patients with lung involvement/32 with cGVHD. Median age 35 years (range 25–56)

14 patients with lung involvement/44 with cGVHD (12 patients with moderate to severe obstruction). Median age all patients 8.2 years (range 0.3–20.5)

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

Steroid refractory moderate to severe cGVHD according to the NIH consensus criteria (Filipovich12)

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)

11 patients with lung involvement/19 with cGVHD. Median age all patients 29 years (range 10–62)

Six patients with lung involvement/58 with cGVHD. Median age all patients 33 (range 5–64)

11 patients with lung involvment/37 with cGVHD. Median age all patients 29 years (range 8–57)

Nine patients with lung involvement/38 with cGVHD. Median age all patients 48 years (range 22–61)

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)

Immunosuppression tapered/discontinued in 4/6. Median follow-up of responding patients 175 days (range 1–701)

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

Partial response (450% regression of cGVHD) and dose reduction of immunosuppressives in 3/9. Follow-up 15 months (range 12–22)

Stabilized lung function in 6/9 patients. Symptomatic improvement in 2/3 ‘nonresponders’. Median follow-up 25 days (range 20–958)

Partial response in 2/5. Stabilisation in 1/5. Disease progression in 2/5 (no further specification). Follow-up time not reported

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

No. and age of patients enrolled Results

BO according to amended NIH criteria Nine patients. Median age 38 (Williams11). Refractory to prior therapy years (range 21–54) with median five different drugs (range 2–7)

Steroid refractory cGVHD with lung involvement assessed by pulmonologist based on FEV1, FVC, DLCO and HRCT (criteria not further specified)

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)

no evidence of active infection. Refractory to immunosuppressives

cGVHD and BO definitions

Prospective nonActive cGVHD with fibrotic randomised single scleroderma-like features, resistant to centre phase 1–2 trial 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%)

Jacobsohn68 4 mg/m2 i.v. every 2 weeks Prospective, nonfor at least 12 doses. Median randomised, double12 doses (range 1–32) centre study. No control group

Prospective nonrandomised singlecentre study. No control group

Two treatments on consecutive days every 2 weeks for 4 months, then once monthly for at least 2 months. Median treatment period not reported

Rubegni64

Retrospective paediatric, multicentre nonrandomised study

Type of publication

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

Median 32 ECP procedures (range 1–259)

Dosage

Messina63

Author

Bronchiolitis obliterans in clinical practice HH Uhlving et al

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Bone Marrow Transplantation

Complete response 3/14. Partial response in 2/14 (improved performance status, 450% resolution of signs and symptoms). Median follow-up 53 months (range 5–159) 14 patients with lung involvement/59 with cGVHD. Median age all patients 31.5 years (range 2–52) Retrospective, nonrandomised study Initially 50–100 mg  3, increased gradually depending on tolerance and clinical response Median daily dose 400 mg (range 50–1200). Median treatment period 61 days (range 1–1210) Kulkarni71

Extensive cGVHD (present in 41 organ) with lung involvement (Sullivan,14 Akpek16). No, or insufficient, response to prednisolone and cyclosporine and/or azathioprine

Recovery of lung function (from severe to moderate reduction) in 1/9. Ability to taper steroids in 2/9. No change in 5/9. 2/9 died of BO and/or relapse. Follow-up time not reported Nine patients. Median age 45 years (range 24–50) Severe pulmonary cGVHD, resistant to extensive immunosuppressive therapy. Median FEV1 29% (range 18–41) Prospective, single centre, open-label non-randomised study 100–400 mg/day. Median treatment period 4 months (range 1–17) Stadler70

Continued

SoR-EL

C-III

Table 1

Treatment regimens

Thalidomide

Type of publication Dosage Author

cGVHD and BO definitions

No. and age of patients enrolled Results

1024

Bone Marrow Transplantation

Abbreviations: BAL ¼ bronchoalveolar lavage; BO ¼ bronchiolitis obliterans; cGVHD ¼ chronic GVHD; DLCO ¼ carbon monoxide diffusing capacity; EL ¼ evidence level; ECP ¼ extracorporeal photopheresis; FEV1 ¼ forced expiratory volume in 1 second; FVC ¼ forced vital capacity; HDPM ¼ high-dose pulse i.v. methylprednisolone; HRCT ¼ high-resolution computed tomography; HSCT ¼ haematopoietic SCT; NS ¼ non significant; NIH ¼ National Institute of Health; PFT ¼ pulmonary function test; SoR ¼ strength of recommendation; TTP ¼ thrombotic thrombocytopenic purpura.

Bronchiolitis obliterans in clinical practice HH Uhlving et al

costs of the approach) for all treatment modalities apart from treatment with corticosteroids (A-III), which is discussed in the following.

Corticosteroids In 2005, Ratjen et al.54 reported their experience with HDPM treatment in a small cohort of nine children. To our knowledge, no other published study has described this treatment regimen for BO after HSCT. HDPM treatment is recommended in other inflammatory lung diseases in children.75,76 Reported side effects include transient flushing, headache, mood changes77 and sinus bradycardia,78 but no serious long-term events have been described in children. HDPM has been the standard treatment of BO since 1999 at our centre, and we here summarise the results. HDPM treatment in the Danish paediatric BO cohort. Within the recent 12 years BO has been diagnosed in 13 children following HSCT (median age 9.3 years, range 0.6–13.4) at the national paediatric HSCT centre in Denmark. This corresponds to 7.3% of Danish SCT patients below 16 years of age in this period. Nine of the patients were able to perform a reliable spirometry and had significantly reduced levels of function (Table 2). In five cases BO was confirmed by open lung biopsy. The final diagnosis of BO was based on a combination of decreased lung function parameters, highresolution computed tomography findings, lung biopsy and/or clinical symptoms, but none of the nine patients fully met the NIH clinical criteria for BO. Our patient cohort was treated with a combination of conventional immunosuppressive agents (Table 3) and i.v. HDPM 15 mg/kg for 2–3 consecutive days every 4–6 weeks. Median time from HSCT to first BO symptoms was 141 days (range 53–254) and from symptoms to first course of HDPM 35 days (3–244). Spirometry was performed before HSCT, before initiating HDPM therapy, and then monthly. Patients with FEV1 o35% and patients who were unable to taper oral prednisolone within 6 months of HDPM initiation were given additional treatment with monthly infusions of infliximab. One patient (no. 8) died of respiratory insufficiency because of CMV-pneumonia 1 month after initiation of therapy, whereas one patient (no. 6) died of leukaemic relapse. In the patients tested, a significant increase in FEV1 was seen 3 months (P ¼ 0.010) and 1 year (P ¼ 0.011) after initiation of HDPM (the Wilcoxon rank sum test), with median increase in FEV1 from 48.1% at treatment initiation to 71.4% and 83.0%, respectively (Figure 1). During further follow-up lung function generally stabilised at a moderately reduced level. This small population-based study of a rather heterogeneous group of patients has obvious limitations, shared by the majority of the previous studies presented in Table 1, and does not allow firm conclusions. Our data suggests that stabilisation of lung function in BO patients may be achieved by early commencement on high-dose pulse corticosteroids in combination with other immunosuppressive treatment. The effect of HDPM on relapse rate and infectious complications cannot be properly assessed in a study of this size. Further studies, preferebly a multicenter

Bronchiolitis obliterans in clinical practice HH Uhlving et al

1025 The Danish paediatric BO cohort accordance with NIH clinical criteria at time of diagnosis

Table 2 BO on biopsy

FEV1%

FEV1/ FVC%

1 2 3 4 5 6 7 8

Yes Yes No No No No Yes Yes

42.8 39 53.5 29.3 62.0 61 53.5 40.4

106.8 89.4 77.4 91.0 95 85 65.8 109.3

9

No

39.8

69.3

HRCT Bronchiectasis, air trapping Air trapping Bronchiectasis, bronchial thickening, small nodular opacities Air trapping, bronchiectasis, bronchial thickening Bronchiectasis, bronchial thickening, air trapping — Centrilobular opacities and reduced transparency Air trapping, bronchiectasis, bronchial thickening, ground glass opacities, consolidation of peripheral lung segments Normal

RV%

Infection

RV/TLC%

cGVHD in other organ

Unknown Unknown 111.40 Unknown 127 131 Unknown Unknown

No No No No No No No No

Unknown Unknown 137.70 Unknown 142 132 Unknown Unknown

Skin No No No No Skin No No

Unknown

No

Unknown

No

Abbreviations: BO ¼ bronchiolitis obliterans; cGVHD ¼ chronic GVHD; FEV1 ¼ forced expiratory volume in 1 second; FVC ¼ forced vital capacity; HRCT ¼ high-resolution computed tomography; NIH ¼ National Institute of Health; RV ¼ residual volume; TLC ¼ total lung capacity.

Patient characteristics

Table 3 Diagnosis

Age at SCT HSCT conditioning

1 JMML

11

2 SAA

Bu, Cy, Me, ATG

4

3 MDS secondary to ALL 4 Pre-B-ALL

10

5 HLH 6 Pre-B ALL

13 13

MTX, Cic/MPA

Bu, Cy, ATG MTX, Cic Bu, Cy, Me, ATG Bu, Cy, Et, ATG Bu, Cy, ATG Cy, ATG, TBI Bu, Cy, ATG

7

7 MLD

GVHD Days between Days from BO treatment Outcome prophylaxis SCT and onset symptoms to HDPM

9

MTX, Cic/MPA MTX, Cic MTX, Cic MTX, Cic/MPA MTX, Cic/MPA MTX, Cic

8 T-ALL

10

Cy, ATG, TBI

9 SAA

11

Bu, Cy, ATG MTX, Cic/MPA

159

16

HDPM, Po, In, Ra/Ta

Stable for 3 y. Deterioration after widened HDPM-intervals. Dead from end-stage BO 5 years after BO-diagnosis. Alive, stable

57

244

254

35

HDPM, Cic/Ta, In HDPM, Po

Alive, stable

212

111

HDPM, In

Lost to follow-up after 6 months

231 72

16 21

HDPM, Po HDPM, Po

141

86

HDPM, Po

Paraplegia after car-accident Relapse 8 months after BO diagnosis. Dead Alive, stable

99

3

HDPM, Po

53

106

HDPM, Po, In, Ra

Dead from respiratory insufficiency (CMV pneumonia) 1 month after HDPM initiation. Alive, stable

120 110 100 90 80 70 60 50 40 30 20 10 0

*P =0.011 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7

>1 2

on

th s m on th s

s th m

on m

m

on +3

+6

s si +1

di

ag

no

SC e BO

fo r Be

th

*P =0.010

T

FEV1% pred

Abbreviations: ATG ¼ anti-thymocyte globulin; BO ¼ bronchiolitis obliterans; Bu ¼ busulfex; Cic ¼ ciclosporine; Et ¼ etophos; HDPM ¼ high-dose pulse i.v. methylprednisolone; HLH ¼ haemophagocytic lymphohistiocytosis; HSCT ¼ haematopoietic SCT; In ¼ infliximab; JMML ¼ juvenile myelomonocytic leukaemia; Me ¼ melphalan; MDS ¼ myelodysplastic syndrome; MLD ¼ metachromatic leucodystrophy; MPA ¼ mycophenolate mofetil; Po ¼ oral prednisolone; Ra ¼ rapamune; SAA ¼ severe aplastic anemia; Ta ¼ tacrolimus.

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.

randomised study would be needed to properly adress both treatment response and possible adverse effects of HDPM therapy. Corticosteroids have been the backbone of cGvHD therapy, since Sullivan et al.14 in 1981 demonstrated improved outcome in cGvHD patients receiving corticosteroids in combination with other immunosuppressors.14 The role of prednisolone was further established in two randomised studies,79,80 where the addition of azathioprine79 and cyclosporine80 did not seem to further improve outcome in standard risk cGvHD patients. However, the effect of orally administrated prednisolone on lung involvement was not reported in those studies. First-line treatment of cGVHD mainly consists of prednisolone with a starting dose of 1 mg/kg/day orally.52 Inhaled corticosteroids in combination with long-acting bronchodilators are now being tested in BO patients in a Bone Marrow Transplantation

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prospective multicentre, randomised double-blinded trial.81 A pilot study of 13 patients with respiratory symptoms, but no extrapulmonary signs of cGvHD, showed some effect on lung function parameters55 (Table 1).

TNF-a inhibitors Insights into the role of proinflammatory cytokines in disease pathogenesis, has led to the use of TNF-a inhibitors as second-line BO treatment. The three patients in the Danish cohort, who received infliximab due to a decrease in lung function during the standard HDPM regimen, experienced stabilisation after commencement of infliximab. A case study from Texas described complete resolution of symptoms in a patient with steroid refractory BO on etanercept treatment.82 The two studies on the effect of infliximab described in Table 1(refs 59,60) suggests some improvement. An ongoing study of etanercept therapy at the Ann Arbor Cancer Center (NCT00141726) may provide further insights. Azithromycin The ability of azithromycin to inhibit airway neutrophilia and IL-8 production39,40 may explain the improvement after treatment in a subgroup of lung transplant recipients with BOS.83,84 Similar positive results have been reported in a preliminary study on 8 patients with BO after HSCT57 (Table 1). However, a randomised placebo-controlled clinical trial from Hong Kong58 failed to prove superiority of azithromycin to placebo when initiated (mean) 4.3 and 5.8 years, respectively, after BO diagnosis. A recently published case-series indicates a steroid sparing effect of azithromycin in combination with inhaled corticosteroids and montelukast in patients with newly diagnosed BO.85 Further studies are needed to establish an eventual effect of azythromycin on incipient BO. Extracorporeal photopheresis Selective downregulation of T-cell-mediated immunity is thought to explain the effect of extracorporeal photopheresis in the treatment of GvHD.86 Though several studies have been performed in patients with BO after HSCT61– 65,87–91 and lung transplantation,92–94 the studies are difficult to interpret because of the heterogeneity in the treatment schedules, diagnostic criteria and response assessment criteria (Table 1). A prospective randomised study of extracorporeal photopheresis treatment performed by Flowers et al.61 revealed a significant improvement of cGVHD in the skin, and indicated a steroid sparing effect on cGvHD in general. No effect on lung function parameters was noted. Rituximab An attempt to attack the B-cell response suspected to be a part of cGvHD aetiology has led to the application of the monoclonal CD20-Ab Rituximab. Although several studies have suggested an effect on cGvHD in the skin,66,95–98 no convincing effect on BO has been established.66,67 Bone Marrow Transplantation

Conclusion Solid evidence regarding the efficacy of the various available treatment modalities in BO is still sparse. Ongoing clinical trials together with new insights into the pathogenesis will hopefully contribute to fill this gap. Though established clinical criteria are important as a research tool, the experience with the NIH Consensus Criteria may indicate a need for further development of clinical criteria and simplification of these. Our experience emphasises the need for improved diagnostic criteria, in particular for the young children who are unable to perform spirometry. The preliminary experiences with HDPM treatment from our and other centres suggest that the efficacy of this treatment regimen, including the long-term effects deserves further validation in clinical trials. Though alternative treatment options may seem promising, corticosteroids are still likely to remain a mainstay in GvHD treatment in the coming years. However, with improved insights into the pathogenesis of BO new treatment modalities, including cytokine antagonists and cellular therapy, may change treatment strategies fundamentally.

Conflict of interest The authors declare no conflict of interest.

Acknowledgements This work was supported by grants from the Danish Children’s Cancer Association and the Research Council at the National University Hospital Rigshospitalet.

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