Late-onset noninfectious interstitial lung disease after allogeneic hematopoietic stem cell transplantation

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Late-onset noninfectious interstitial lung

disease after allogeneic hematopoietic stem

cell transplantation

Fre

´de

´ric Schlemmer

a

, Sylvie Chevret

b,c

, Gwenae

¨l Lorillon

a

,

Ce

´dric De Bazelaire

d

, Re

´gis Peffault de Latour

e

,

Ve

´ronique Meignin

f

, Mauricette Michallet

g

, Eric Hermet

h

,

Benjamin Wyplosz

i

, Ve

´ronique Houdouin

j

,

Sylvain Marchand-Adam

k

, Ge

´rard Socie

´

e

, Abdellatif Tazi

a,b

,

Anne Bergeron

a,b,

*

aUniv Paris Diderot, Sorbonne Paris-Cite´, AP-HP, Hoˆpital Saint-Louis, Service de Pneumologie,

F-75010 Paris, France

bBiostatistics and Clinical Epidemiology Research Team (ECSTRA), UMR 1153 INSERM,

Univ Paris Diderot, Sorbonne Paris Cite´, France

c

Univ Paris Diderot, Sorbonne Paris-Cite´, De´partement de Biostatistique et Informatique Me´dicale, AP-HP, Hoˆpital Saint Louis, Paris, France

d

Univ Paris Diderot, Sorbonne Paris-Cite´, Service de Radiologie, AP-HP, Hoˆpital Saint Louis, Paris, France

e

Univ Paris Diderot, Sorbonne Paris-Cite´, He´matologie-Greffe, APHP, Hoˆpital Saint-Louis, Paris, France

f

Univ Paris Diderot, Sorbonne Paris-Cite´, Pathologie, APHP, Hoˆpital Saint-Louis, Paris, France

gCentre Hospitalier Lyon Sud, He´matologie, Hospices Civils de Lyon, France h

Service de The´rapie Cellulaire et d’he´matologie Clinique Adulte, Universite´ d’Auvergne CREaTe EA 7283, INSERM CIC-501, CHU Clermont-Ferrand Hoˆpital Estaing, France

i

Service des Maladies Infectieuses et Tropicales, Hoˆpital de Biceˆtre, Le Kremlin-Biceˆtre, France

j

Univ Paris Diderot, Sorbonne Paris-Cite´, Service des Maladies Digestives et Respiratoires de l’Enfant, AP-HP, Hoˆpital Robert Debre´, Paris, France

k

Univ Franc¸ois Rabelais, INSERM UMR 1100, Centre d’Etude des Pathologies Respiratoires, CHRU de Tours, Service de Pneumologie, F-37000 Tours, France

Received 18 July 2014; accepted 8 September 2014

Available online 16 September 2014

* Corresponding author. Service de Pneumologie, Hoˆpital Saint-Louis, 1, avenue Claude Vellefaux, 75475 Paris cedex 10, France. Tel.:þ33 1 42 49 41 66; fax:þ33 1 42 49 93 95.

E-mail address:anne.bergeron-lafaurie@sls.aphp.fr(A. Bergeron).

http://dx.doi.org/10.1016/j.rmed.2014.09.006

0954-6111/ª 2014 Elsevier Ltd. All rights reserved.

Available online atwww.sciencedirect.com

ScienceDirect

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / r m e d Respiratory Medicine (2014) 108, 1525e1533

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KEYWORDS Interstitial lung disease; Bone marrow transplantation; Organizing pneumonia; Nonspecific interstitial lung pneumonia; Diffuse alveolar damage; Lymphoid interstitial pneumonia Summary

Background: Various late-onset noninfectious pulmonary complications may occur after alloge-neic hematopoietic stem cell transplantation (HSCT). Interstitial lung diseases (ILD) are often overlooked, and few data are available.

Methods: We retrospectively analyzed the clinical features, pulmonary function tests, radio-logical features and outcomes of allogeneic HSCT recipients who were diagnosed with a nonin-fectious ILD and were managed in our center between 2001 and 2010.

Results: Forty patients were analyzed. The median time from transplant to ILD was 11.3 months. The donor hematopoietic stem cell source was peripheral blood stem cells in 75% of the cases. Seventy percent of the patients had extra-thoracic chronic graft versus host disease at ILD diagnosis. We identified two lung computed tomography (CT) scan patterns according to the predominance of ground glass opacities or alveolar consolidations. Restrictive ventilatory defect was the main pulmonary function pattern. Lung histology was available for seven pa-tients and showed diffuse alveolar damage, non-specific interstitial pneumonia, organizing pneumonia or lymphoid interstitial pneumonia. Thirty-five patients (87.5%) were treated with systemic steroids. Thirteen patients died (32.5%), 10 of respiratory failure. The median survival rate at 24 months was 61%.

Conclusion: This study highlights the existence of noninfectious post-allogeneic HSCT ILD and provides new insights into the characteristics of these illnesses.

ª 2014 Elsevier Ltd. All rights reserved.

Background

Late onset noninfectious pulmonary complications (LONIPCs) might follow allogeneic hematopoietic stem cell

transplantation (HSCT) and have a significant effect on patient outcomes [1e3]. Previous publications have focused on bronchiolitis obliterans (BO), which is the most common LONIPC[4e6]. Some epidemiological retrospective studies [2,7e9] have reported interstitial lung diseases (ILD) among LONIPCs. Although individual cases of post allogeneic HSCT ILD have been published[10e13], no series have described the spectrum of these ILD using an overall pulmonologic approach. Post HSCT noninfectious ILD are likely misdiagnosed and overlooked. Conversely to BO[6], ILD is characterized by the presence of diffuse lung parenchymal opacities on a CT scan. In the current prac-tice, an infectious cause is first considered. Concomitantly, the patient might be diagnosed with an extra thoracic graft versus host disease (GVHD) and treated with corticoste-roids. In this context, these patients are usually treated with a combined treatment associating empirical anti-microbiological drugs and steroids that may explain why these noninfectious ILD are misdiagnosed.

The process of achieving a multidisciplinary diagnosis in a patient with ILD requires close communication between clinician, radiologist, and when appropriate, pathologist [14]. The multidisciplinary approach usually allows to determine whether the noninvasive approach based on clinical, radiological, lung function, bronchoalveolar lavage (BAL) and laboratory findings is informative enough or if a lung biopsy is needed[14]. Besides idiopathic ILD, several medical settings such as exposure or collagen vascular diseases have been shown to cause ILD. In these contexts, knowledge of the clinical characteristics of these ILD has led to an improvement in their management with a dra-matic decrease in the indications for lung biopsies[14e19]. In the setting of allogeneic HSCT, two pathological studies identified 6 cases of diffuse alveolar damage (DAD) 8 cases of organizing pneumonia (OP), one case of lymphoid interstitial pneumonia (LIP) and 13 cases of non-classified Abbreviations

AML acute myeloid leukemia ALL acute lymphoid leukemia BAL bronchoalveolar lavage

CT computed tomography

DAD diffuse alveolar damage

DLCO diffusion capacity for carbon monoxide

FEV1 forced expiratory volume in 1 s

FVC forced vital capacity GVHD graft-versus-host disease

HRCT high-resolution computed tomography HSCT hematopoietic stem cell transplantation ILD interstitial lung disease

IPS idiopathic pneumonia syndrome IQR inter-quartile range

LIP lymphoid interstitial pneumonia LONIPC late-onset non-infectious pulmonary

complication

PFT pulmonary function test NYHA New York Heart Association NSIP non-specific interstitial pneumonia OLD obstructive lung disease

OP organizing pneumonia PBSC peripheral blood stem cells RLD restrictive lung disease SLB surgical lung biopsy TBI total body irradiation TLC total lung capacity

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ILD[20,21]. In HSCT recipients, ILD management based on surgical lung biopsies is, however, questionable: first, a lung biopsy is an invasive and high-risk procedure in this setting [22,23]; second, no correlation between patholog-ical findings and prognosis exists for post allogeneic HSCT ILD that would allow to guide the treatment; and third, the efficient microbiological tools applied to samples obtained from less invasive techniques such as BAL or nasal aspirate often help differentiate ILD from infectious pneumonia [24e26].

Because post HSCT ILD are infrequent, it was important to retrospectively analyze the patients diagnosed with an ILD to describe their clinical presentations based on the pulmonary investigation techniques used in clinical practice and to analyze the outcomes of these patients.

Patients and methods

This retrospective study was approved by the institutional review board of the French learned society for respiratory medicine CEPRO 2011-055. All of the allogeneic HSCT re-cipients diagnosed with a noninfectious ILD in our center between 2001 and 2010 were eligible for this study. In addition, patients who underwent an allogeneic HSCT in another French bone marrow transplantation department and who were referred to our respiratory diseases depart-ment for the managedepart-ment of an ILD were included. We collected data from individual medical records.

Diagnosis of noninfectious ILD

A noninfectious ILD was diagnosed when infiltrative opaci-ties were present on HRCT and 1) no pathogens were identified in the respiratory samples (BAL and/or nasal aspirate and/or sputum); and/or 2) no clinical or radiolog-ical improvements were observed despite broad antimi-crobial treatment; and/or 3) clinical and radiological improvements occurred after initiating or increasing the immunosuppressive treatment; and/or 4) no pathogens were found on the lung biopsy (if it was performed).

Clinical characterization of ILD

As is conventional in pulmonology practice, ILD were characterized by clinical symptoms, high-resolution computed tomography (HRCT), pulmonary function testing (PFT), BAL analysis, and lung histology. HRCT scans per-formed at the time of ILD diagnosis and during follow-up were reviewed by an experienced radiologist (CDB) and two pulmonologists (FS and AB). The following features were noted: alveolar consolidations, ground glass opacities, septal thickening, subpleural reticulations, honeycombing, bronchiectasis, bronchial thickening and pleural abnor-malities. To assess lesion distribution, each lung was divided into three areas (upper/medial/lower) from the lung apices to the domes of the diaphragm. Conclusions were reached by consensus. The clinical data, PFT and BAL findings were collected. An extensive search for viruses (as described in thee-appendix), bacteria (direct examination and culture) and fungi (immunofluorescence and molecular biology for Pneumocystis jiroveci; direct examination and

culture for other species) was performed on the BAL. When bronchoscopy could not be performed, bacteria and fungi were searched for in the sputum, P. jiroveci was searched for in induced sputum samples and respiratory viruses were searched for in nasal aspirates (e-appendix). The total and differential cell counts in the BAL were analyzed. Pulmo-nary function tests were performed using a body plethys-mograph (Jaeger Masterscreen Body; Jaeger, GmBH; Wurzburg, Germany). The diffusing capacity of carbon monoxide (DLCO) was measured using the single breath

method, and the results were adjusted to the last available hemoglobin level. Predictive values were determined as previously described [27]. Obstruction was defined as an FEV1/FVC ratio<0.7[28], and restriction was defined as a

TLC < 80% of the predicted value. A DLCO <80% of the

predicted value was considered abnormal. An experienced pathologist (VM) analyzed the lung tissue specimen from patients who underwent a surgical lung biopsy. The diag-nosis and severity of GVHD were reported based on the clinical grading scores[29,30].

Statistical analyses

Descriptive statistics are presented as the median and inter-quartile range (IQR) [IQR: 25 to 75th percentiles] for continuous parameters and as the number and percentage for non-continuous and qualitative parameters. Survival after ILD diagnosis and ILD incidence were estimated using the KaplaneMeier method. The prognostic analysis of post-ILD survival was univariate, based on a log rank test for non-continuous parameters or logistic regression with a Cox model for continuous parameters. Given the sample size and number of observed events, no multivariate analyses were performed. Every statistical analysis had a bilateral formulation, and P< 0.05 was considered significant.

Results

Patient characteristics

Between 2001 and 2010, 1277 allogeneic HSCTs were per-formed in our center, including 35% using a myeloablative conditioning regimen, and 65% using a nonmyeloablative conditioning regimen with stem cell sources as followed: 60% peripheral blood stem cells, 25% bone marrow and 15% cord blood.

Thirty-one allogeneic HSCT recipients were identified as having a noninfectious ILD (2.4%). Three patients from a previous study were included[11]. Nine additional patients, referred to our department because of an ILD during the study period, were included. Sixteen patients were diag-nosed between 2001 and 2007 and 24 patients between 2008. The clinical characteristics of the patients are sum-marized inTable 1. All ILD occurred within the first three years after allogeneic HSCT. The median time from trans-plantation to ILD was 11.3 months [IQR: 5.9e19.2]. Most of the patients had received prior chemotherapy, and 30% had experienced a prior autologous transplantation. The donor hematopoietic stem cell sources were peripheral blood stem cells in 75% of the cases, and the conditioning regimen was non-myeloablative in 57.5% of the cases.

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ILD characteristics

Clinical characteristics

The most frequent clinical symptoms were dyspnea (n Z 35, 87.5%; New York Heart Association (NYHA)  3: nZ 12, 40%), fever (n Z 20, 50%), and cough (n Z 24, 60%).

The median time from the onset of symptoms to ILD diag-nosis was 15 days [IQR: 2e71].

At the time of ILD diagnosis, 27 patients (67.5%) were receiving systemic immunosuppressive treatment calci-neurin inhibitors (n Z 12), mycophenolate mofetil (n Z 9), everolimus (n Z 1), etanercept (n Z 1) or imatinib (nZ 1); 16 were receiving a single drug, and 10 were receiving two or more drugs. Forty percent of the patients were receiving systemic steroids (median dose of prednisone; 25 mg per day, [IQR: 20e40]) for coexisting GVHD.

Overall, 34 patients (85%) had a history of GVHD, either acute and/or chronic (Table 1). Chronic GVHD was present in 28 patients (70%) at the time of ILD diagnosis and involved the skin and/or mucosa (42.5%), the gut (20%) or the liver (17.5%; Table 1). Four more patients developed GVHD after the ILD diagnosis.

No patients had a history suggestive of an ILD associated with an inhalational exposure.

Thoracic imaging

The HRCT characteristics of ILD are summarized inTable 2. Two different HRCT patterns were identified according to the predominance of alveolar consolidations (nZ 22, 55%, Fig. 1A) or ground glass opacities (n Z 18, 45%,Fig. 1B). Other HRCT abnormalities were infrequent. Patients with a ground glass opacity pattern or alveolar consolidation pattern did not differ in their clinical characteristics or time from allogeneic HSCT to ILD diagnosis.

Lung function

The results of the pulmonary function tests (PFTs) are presented inTable 3. Lung volumes and DLCOwere available

for 29 and 18 patients, respectively. At ILD diagnosis, 24 patients (83%) had a restrictive lung disease (RLD), eight patients (28%) had an obstructive lung disease (OLD) and four patients (14%) had a mixed pattern. Only two patients (7%) had normal lung volumes. The DLCOwas decreased in

all of the patients tested.

Table 1 Clinical characteristics of the 40 patients at ILD diagnosis.

Clinical variables Median [IQR]; N (%)

Age at transplant, years 40.5 [27.5e51.5]

Male 28 (70)

Smoking history 17 (43)

Age at ILD, years 40.6 [28.5; 51.8] Time from transplantation

to ILD, months

11.3 [5.9e19.2] History of an infectious

pneumonia in the time

between the transplant and ILD

11 (27.5) Hematological diseases AL 15 (37.5) CML 2 (5) Lymphoma 13 (32.5) Myeloma 2 (5) Othersa 8 (20)

Status of disease at time of transplant

Complete response 28 (70)

Relapse 2 (5)

Chronic phase/partial response 2 (5)

NA 8 (20)

Stem cell source

PBSCs 30 (75)

Bone marrow 9 (22.5)

Cord blood 1 (2.5)

Donor HLA status

Related 23 (57.5) Unrelatedb 17 (42.5) Conditioning regimen Non-myeloablative 23 (57.5) Busulfan-based 10 (25) TBI 25 (62.5) GVHD prophylaxis Cyclosporine alone 6 (15) Cyclosporine-mycophenolate mofetil 24 (60) Cyclosporine-methotrexate 10 (25) Acute GVHD 22 (55) Grade2 14 (35) Chronic GVHD 28 (70) Limited 21 (52.5) Extensive 7 (17.5)

ILD, interstitial lung disease; AL, acute leukemia; CML, chronic myeloid leukemia; NA, not available; HLA, human leukocyte antigen; PBSCs, peripheral blood stem cells; TBI, total body irradiation; GVHD, graft-versus-host disease.

a Myelodysplasic syndrome, myeloproliferative disease other

than CML, aplastic anemia.

b 10/10 and 9/10 allelic unrelated donors and cord blood

transplant.

Table 2 Lung HRCT findings in patients at diagnosis of ILD after allogeneic hematopoietic stem cell transplantation. Imaging finding N (%) of patients

(NZ 40) Alveolar consolidations 30 (75)

Bilateral 19 (63)

Ground glass opacities 29 (72)

Bilateral 24 (83)

Involvement of>3 lung areasa,b 15 (37) Exclusive upper lung area involvementb 5 (12) Exclusive lower lung area involvementb 9 (22)

Reticulation 3 (7)

Septal thickening 1 (2)

Honeycombing 1 (2)

Bronchial thickening 4 (10)

Pneumomediastinum 3 (7)

aEach lung was divided into three areas: upper, medial and

lower.

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Bronchoalveolar lavage cell count

BAL was performed in 30 patients. The total and differen-tial cell counts are shown inTable 4. Except for three pa-tients (10%) who had normal BAL cell counts, all papa-tients had an alveolitis. Lymphocytic alveolitis (defined by a lymphocyte count 15% of total cells) was the most frequent and was found in 20 patients (67%). Among these patients, the median percentage of alveolar lymphocytes was 40% [IQR: 21e56%] and seven patients had a concomi-tant neutrophil count10% of total cells. Three other pa-tients had a neutrophil count10% of total cells (median 20%, [IQR: 15e33%]). Four patients had an eosinophil count 10% of total cells, including two with an eosinophil count 20% of total cells, suggesting an eosinophilic pneumonia.

Both PFT and BAL results were similar whether patients had a ground glass opacities HRCT pattern or an alveolar consolidation pattern.

Lung histology

Eleven lung biopsies were available for 10 patients. Four patients had CT scan-guided percutaneous lung biopsies, and seven patients had surgical lung biopsies (six with video-assisted thoracoscopy). Four of these 10 patients (40%) experienced postoperative morbidity or mortality; two patients required prolonged chest tube aspiration (one required another surgery), and two patients died within 15 days following surgery (one from respiratory failure and the other from septic shock with multisystem organ failure). A

Figure 1 Lung HRCT patterns of ILD after allogeneic hematopoietic stem cell transplantation. Two patterns were identified: one with predominant alveolar opacities (A), and one with predominant ground glass opacities (B).

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definite histological diagnosis was obtained in 7/10 (70%) patients and consisted of DAD (nZ 2), nonspecific inter-stitial pneumonia (NSIP) (n Z 2), OP (n Z 2) and LIP (nZ 1). Patients diagnosed with DAD had either an alveolar consolidation or a ground glass opacities HRCT pattern. The two patients diagnosed with OP and the patient diagnosed with LIP had an alveolar consolidations pattern; both of the patients diagnosed with NSIP had a ground glass opacities HRCT pattern.

Treatment and outcome

The median follow-up after diagnosis of ILD was 9.3 months [IQR: 2.1e32]. The patients of both HRCT phenotypes were treated similarly. Thirty-five patients (87.5%) received sys-temic steroids for the treatment of ILD (introduction or increase), and 13 of these patients (32.5%) received high-dose intravenous steroids (pulse methylprednisolone 5e10 mg/kg for 3 days). One patient received cyclophos-phamide together with pulse methylprednisolone. Five patients did not receive steroids at the time ILD was diag-nosed. Among these five patients, one patient finally received high-dose pulsed methylprednisolone one year after ILD diagnosis because of progressive lung disease; three patients required steroids 2e6 months after the ILD diagnosis for extra thoracic GVHD. One patient presented spontaneous resolution of ILD.

Thirteen patients died (33%). Ten patients died of res-piratory failure; these patients were receiving systemic steroids for ILD treatment. The lung histology available for two of these patients showed DAD for one and NSIP for the other. The three other patients died of refractory gut cGVHD associated with severe sepsis, septic shock and en-cephalopathy syndrome. The survival rate was estimated at 77% [IQR: 64e92%], 70% [IQR: 56e88%] and 61% [IQR: 45e82%] at 6, 12 and 24 months, respectively, after ILD diagnosis (Fig. 2).

Evolution of HRCT and PFT

Although the overall prognosis of ILD was poor, a significant number of patients had a favorable outcome regarding HRCT and PFT. We did not find any association between the evolution of both HRCT and PFT and the HRCT scan pattern at ILD diagnosis.

Among the survivors, at least two serial HRCT scans were available for 18 patients (alveolar consolidations HRCT

Table 3 Pulmonary function testing in overall patients and according to the lung HRCT pattern at the time of ILD diagnosis.

Median [IQR] FEV1 FVC FEV1/FVC

%

TLC DLCO

(L) % pred (L) % pred (L) % pred % pred

All patients (nZ 29) 1.805 [1.54e2.39] 53 [42e72] 2.38 [1.82e2.85] 52 [42.5e72] 81.9 [71.5e87] 4.05 [3.53e5.17] 63 [58e77] 41 [36e47] Ground glass patterna

(nZ 13) 1.675 [1.54e2.25] 52.5 [42.6e61.2] 2.18 [1.82e2.55] 52 [43.9e60.5] 81.9 [70.6e88.9] 4.04 [3.65e5.18] 63.5 [60.1e74.2] 43 [36e47] Alveolar consolidations patterna (nZ 16) 2.065 [1.54e2.51] 53 [42e77.5] 2.485 [2.03e3.03] 56 [42.7e80.2] 81.65 [72.5e85.5] 4.09 [3.53e4.33] 63 [57e79] 39 [37e44]

a Lung CT scan pattern; FEV

1, forced expiratory volume in 1 s; FVC, forced vital capacity; TLC, total lung capacity; DLCO, diffusing

capacity of carbon oxide; pred, predicted.

Table 4 Bronchoalveolar lavage cell counts in overall patients and according to the lung HRCT pattern.

Median [IQR] Total cell count/mm3 Ma % Ly % Neu % Eo % All patients (nZ 30) 280 [180e460] 54 [35e82] 20.5 [8e48] 6 [2e15] 0 [0e3] Ground glass patterna (nZ 15) 250 [150e280] 67 [25e88] 19 [5e48] 5 [1e11] 0 [0e5] Alveolar consolidations patterna (nZ 15) 315 [225e465] 50 [35e77] 23 [18e52] 7 [2e18] 0 [0e2]

a Lung CT scan pattern; Ma, macrophages; Ly, lymphocytes;

Neu, neutrophils; Eo, eosinophils.

Figure 2 The estimated overall survival distribution after ILD diagnosis in the study population. The dashed lines represent the 95% CI of survival estimates over time.

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pattern (n Z 11), ground glass opacities HRCT pattern (nZ 7)). For these patients, the last available HRCT scan was performed at a median time of 10.3 months after ILD diagnosis [IQR: 2e23]. At last follow-up, complete resolu-tion of radiological abnormalities was observed in five pa-tients (alveolar consolidations pattern (n Z 4)) and persisted in 13 patients (ground glass opacities pattern (n Z 6), alveolar consolidations (n Z 7)). After being characterized as having a particular phenotype by a CT scan at the time of diagnosis, none of the patients evolved to the other phenotype.

All the patients who had PFT at ILD diagnosis had two or more PFTs during the follow-up with a similar distribution between both HRCT pattern; for these patients, the last available PFT was performed at a median time of 7 months [IQR: 3e18] after the first PFT. Fourteen patients (45%) showed greater than 10% improvement of FVC or FEV1

relative to the baseline.

Prognostic analysis

In the univariate analysis, no prognostic factor was identi-fied to be associated with survival (e-Table 1). The patients with an alveolar consolidation pattern tended to have better survival than those with a ground glass opacity pattern (78% vs. 60% at 12 months, 71% vs. 48% at 24 months), although the difference did not reach statistical significance (pZ 0.19;e-Fig. 1).

Discussion

This retrospective study is the largest series on allogeneic post-HSCT non-infectious ILD. Our study highlights the ex-istence of post-allogeneic HSCT non-infectious ILD and provides new insights into the clinical characteristics of this complication. Previous studies have focused on epidemio-logical data and anecdotal reports. We observed the following: 1) post-allogeneic HSCT ILD typically occur within the first 3 years after transplantation and are frequently associated with extra pulmonary GVHD mani-festations; 2) ILD include different histological entities; 3) two distinct lung HRCT patterns were observed according to the predominance of ground glass opacities or alveolar consolidations; 4) lung function restriction and BAL lym-phocytic alveolitis were frequent; and 5) the prognosis was globally poor, although in some cases, ILD might improve or resolve with corticosteroids.

In the context of allogeneic HSCT, the occurrence of ILD is often attributed to idiopathic pneumonia syndrome (IPS) or to OP[4,31]. IPS is not a well-defined pulmonary disease and includes various conditions [31,32]. The diagnosis of IPS, which has recently been reviewed, relies on diffuse lung opacities on the chest X-ray and the exclusion of several diagnoses, such as lung infection or pulmonary edema[31]. The median time of onset for IPS is reported to be 19 days (range, 4e106 days) after HSCT. The intensity and type of HSCT conditioning have been associated with the development of IPS, which is consistent with data generated from mouse models [31]. The ILD described in our study differ in various respects from IPS. ILD occurred later after transplantation, predominantly in patients who

underwent non-myeloablative conditioning. Only 60% of our patients underwent pre-transplant total body irradiation, and none of our patients received carmustine; both of these factors are associated with IPS. Thus, the ILD we described do not match the current IPS criteria. Conversely, the time of onset after the HSCT and the clinical, pulmo-nary and radiological characteristics of some of our patients were similar to the characteristics described in cases of post-allogeneic HSCT OP[13,33]. However, based on the lung biopsy results, other ILD entities (NSIP, DAD and LIP) were observed in our patients.

At present, only biopsy-proven BO has been firmly recognized as a manifestation of lung GVHD based on epidemiological studies that show a strong association be-tween BO and extra-thoracic chronic GVHD. In several studies, OP has also been associated with GVHD[4,13,15]. A feature of our findings is that almost all patients who developed late onset ILD had a history of acute and/or chronic GVHD. Unfortunately, due to the retrospective design of our study, we could not evaluate the incidence of GVHD in our population of HSCT recipients who did not develop ILD during the study period. Thus, although our findings suggest that the ILD spectrum may reflect lung GVHD, we could not formally conclude. However, the presence of an OLD in some of our patients, suggesting BO associated with ILD, further strengthens this hypothesis. Although the history of the patients was not suggestive, the role of drug pulmonary toxicity in patients receiving mul-tiple treatments cannot be formally ruled out.

One finding of our study is that, conversely to what is known for the treatment of BO [6,34], a significant pro-portion of our patients who were treated with steroids had either complete resolution of their ILD or a significant improvement in their PFT. These data emphasize the importance of identifying these ILD to promptly administer steroids. However, only a randomized study could demon-strate the efficacy of steroids in post allogeneic non-infectious ILD.

The retrospective design and the relatively small num-ber of patients did not allow us to reach firm conclusions on several points. First, we could not correlate the radiological and clinical diagnosis with the underlying histological dis-ease because of the small number of patients who under-went a surgical lung biopsy. Of note, in our few patients who underwent a lung biopsy, alveolar consolidations HRCT pattern could be associated with either DAD, OP or LIP whereas ground glass opacities pattern was associated with NSIP or DAD. Second, during the follow-up period, we did not report any changes in the HRCT scan patterns. However, follow up HRCT scans were not available for all of the pa-tients. Thus, we could not firmly exclude that both HRCT scan patterns are a spectrum of the same lung disease entity. Third, we could not identify any prognostic factors, although the patients with an alveolar consolidation pattern tended to have better survival than the patients with a ground glass opacities pattern.

In summary, because of the increasing number of long-term HSCT survivors, an understanding of new late onset noninfectious complications is important. Herein, we described the characteristics of ILD occurring after alloge-neic HSCT according to the usual approach of ILD. As typi-cally occurs in clinical practices, the majority of these

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patients did not undergo lung biopsies. Our data provide information regarding the management of these patients. Further studies are needed to clarify the physiopathology, identify the risk factors and optimize the treatment of these lung disorders to improve the prognosis.

Authors’ contribution

FS: Data acquisition, analysis and interpretation, drafting the article, final approval of the version to be published. SC: Statistical analysis of the data, drafting the article, final approval of the version to be published. GL: Data analysis and interpretation, final approval of the version to be published. CDB: Data acquisition, final approval of the version to be published.

RPDL: Data analysis and interpretation, final approval of the version to be published. VM: Data acquisition, final approval of the version to be published. MM: Data acquisi-tion, final approval of the version to be published. EH: Data acquisition, final approval of the version to be published. BW: Data acquisition, final approval of the version to be published.

VH:Data acquisition, final approval of the version to be published. SMA: Data acquisition, final approval of the version to be published. GS: Data analysis and interpreta-tion, final approval of the version to be published. AT: Study conception and design, data analysis and interpretation, final approval of the version to be published. AB: Study conception and design, data acquisition, analysis and interpretation, drafting the article, final approval of the version to be published.

Funding

None.

Conflict of interest

None declared.

Acknowledgments

We thank Elisabeth Savariau and Robin Nancel for their excellent technical assistance. We thank EGMOS, which is an association of bone marrow transplant recipients.

Appendix A. Supplementary data

Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.rmed.2014.09.006.

References

[1]Patriarca F, Skert C, Bonifazi F, Sperotto A, Fili C, Stanzani M, et al. Effect on survival of the development of late-onset non-infectious pulmonary complications after stem cell trans-plantation. Haematologica 2006;91:1268e72.

[2] Palmas A, Tefferi A, Myers JL, Scott JP, Swensen SJ, Chen MG, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998; 100:680e7.

[3] Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ. Bronchiolitis obliterans in chronic graft-versus-host disease: analysis of risk factors and treatment outcomes. Biol Blood Marrow Trans-plant 2003;9:657e66.

[4] Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR, Lee SJ, et al. National Institutes of Health consensus devel-opment project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and staging working group report. Biol Blood Marrow Transplant 2005;11:945e56. [5] Chien JW, Martin PJ, Gooley TA, Flowers ME, Heckbert SR,

Nichols WG, et al. Airflow obstruction after myeloablative allogeneic hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2003;168:208e14.

[6] Barker AF, Bergeron A, Rom WN, Hertz MI. Obliterative bron-chiolitis. N Engl J Med 2014;370:1820e8.

[7] Patriarca F, Skert C, Sperotto A, Damiani D, Cerno M, Geromin A, et al. Incidence, outcome, and risk factors of late-onset noninfectious pulmonary complications after unrelated donor stem cell transplantation. Bone Marrow Transplant 2004;33:751e8.

[8] Huisman C, van der Straaten HM, Canninga-van Dijk MR, Fijnheer R, Verdonck LF. Pulmonary complications after T-cell-depleted allogeneic stem cell transplantation: low inci-dence and strong association with acute graft-versus-host disease. Bone Marrow Transplant 2006;38:561e6.

[9] Sakaida E, Nakaseko C, Harima A, Yokota A, Cho R, Saito Y, et al. Late-onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associ-ated with chronic versus-host disease and with the graft-versus-leukemia effect. Blood 2003;102:4236e42.

[10] Perreault C, Cousineau S, D’Angelo G, Gyger M, Nepveu F, Boileau J, et al. Lymphoid interstitial pneumonia after allo-geneic bone marrow transplantation. A possible manifestation of chronic graft-versus-host disease. Cancer 1985;55:1e9. [11] Bergeron A, Bengoufa D, Feuillet S, Meignin V, Peffault de

Latour R, Rybojad M, et al. The spectrum of lung involvement in collagen vascular-like diseases following allogeneic he-matopoietic stem cell transplantation: report of 6 cases and review of the literature. Med Baltim 2011;90:146e57. [12] Wolff D, Reichenberger F, Steiner B, Kahl C, Leithauser M,

Skibbe T, et al. Progressive interstitial fibrosis of the lung in sclerodermoid chronic graft-versus-host disease. Bone Marrow Transplant 2002;29:357e60.

[13] Freudenberger TD, Madtes DK, Curtis JR, Cummings P, Storer BE, Hackman RC. Association between acute and chronic graft-versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of hematopoietic stem cell transplants. Blood 2003;102:3822e8.

[14] Travis WD, Costabel U, Hansell DM, King Jr TE, Lynch DA, Nicholson AG, et al. An Official American Thoracic Soci-ety/European Respiratory Society Statement: update of the International Multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188: 733e48.

[15] Daniele RP, Elias JA, Epstein PE, Rossman MD. Bronchoalveolar lavage: role in the pathogenesis, diagnosis, and management of interstitial lung disease. Ann Intern Med 1985;102:93e108. [16] Ryu JH, Olson EJ, Midthun DE, Swensen SJ. Diagnostic approach to the patient with diffuse lung disease. Mayo Clin Proc 2002;77:1221e7.

[17] Meyer KC. The role of bronchoalveolar lavage in interstitial lung disease. Clin Chest Med 2004;25:637e49.

[18] Johkoh T. Imaging of idiopathic interstitial pneumonias. Clin Chest Med 2008;29:133e47.

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[19] Kowal-Bielecka O, Kowal K, Chyczewska E. Utility of bron-choalveolar lavage in evaluation of patients with connective tissue diseases. Clin Chest Med 2010;31:423e31.

[20] Yousem SA. The histological spectrum of pulmonary graft-versus-host disease in bone marrow transplant recipients. Hum Pathol 1995;26:668e75.

[21] Xu L, Drachenberg C, Tavora F, Burke A. Histologic findings in lung biopsies in patients with suspected graft-versus-host disease. Hum Pathol 2013;44:1233e40.

[22] Zihlif M, Khanchandani G, Ahmed HP, Soubani AO. Surgical lung biopsy in patients with hematological malignancy or he-matopoietic stem cell transplantation and unexplained pul-monary infiltrates: improved outcome with specific diagnosis. Am J Hematol 2005;78:94e9.

[23] Wingard JR, Hiemenz JW, Jantz MA. How I manage pulmonary nodular lesions and nodular infiltrates in patients with he-matologic malignancies or undergoing hematopoietic cell transplantation. Blood 2012;120:1791e800.

[24] Azoulay E, Mokart D, Rabbat A, Pene F, Kouatchet A, Bruneel F, et al. Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data. Crit Care Med 2008;36:100e7.

[25] Azoulay E, Mokart D, Lambert J, Lemiale V, Rabbat A, Kouatchet A, et al. Diagnostic strategy for hematology and oncology patients with acute respiratory failure: randomized controlled trial. Am J Respir Crit Care Med 2010;182:1038e46. [26] Forslow U, Remberger M, Nordlander A, Mattsson J. The clinical importance of bronchoalveolar lavage in allogeneic SCT patients with pneumonia. Bone Marrow Transplant 2010; 45:945e50.

[27] Standardized lung function testing. Official statement of the European Respiratory Society. Eur Respir J Suppl 1993;16:1e100. [28] Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO global initiative for chronic obstructive lung disease (GOLD) workshop summary. Am J Respir Crit Care Med 2001;163:1256e76. [29] Przepiorka D, Weisdorf D, Martin P, et al. 1994 consensus

conference on acute GVHD grading. Bone Marrow Transplant 1995;15:825e8.

[30] Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients. Am J Med 1980;69:204e17. [31] Panoskaltsis-Mortari A, Griese M, Madtes DK, Belperio JA,

Haddad IY, Folz RJ, et al. An official American Thoracic So-ciety research statement: noninfectious lung injury after he-matopoietic stem cell transplantation: idiopathic pneumonia syndrome. Am J Respir Crit Care Med 2011;183:1262e79. [32] Clark JG, Hansen JA, Hertz MI, Parkman R, Jensen L,

Peavy HH. NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis 1993;147:1601e6.

[33] Pipavath SN, Chung JH, Chien JW, Godwin JD. Organizing pneu-monia in recipients of hematopoietic stem cell transplantation: CT features in 16 patients. J Comput Assist Tomogr 2012;36: 431e6.

[34] Bergeron A, Godet C, Chevret S, Lorillon G, Peffault de Latour R, de Revel T, et al. Bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: phenotypes and prog-nosis. Bone Marrow Transplant 2013;48:819e24.

Figure

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References

  1. http://dx.doi.org/10.1016/j.rmed.2014.09.006
  2. www.sciencedirect.com
  3. w w w . e l s e v i e r . c o m / l o c a t e / r m e d
  4. Metadata, citation and similar papers at core.ac.ukProvided by Elsevier - Publisher Connector
  5. Patriarca F, Skert C, Bonifazi F, Sperotto A, Fili C, Stanzani M,et al. Effect on survival of the development of late-onset
  6. Palmas A, Tefferi A, Myers JL, Scott JP, Swensen SJ, Chen MG,et al. Late-onset noninfectious pulmonary complications after
  7. Dudek AZ, Mahaseth H, DeFor TE, Weisdorf DJ. Bronchiolitisobliterans in chronic graft-versus-host disease: analysis of risk
  8. Filipovich AH, Weisdorf D, Pavletic S, Socie G, Wingard JR,Lee SJ, et al. National Institutes of Health consensus
  9. Chien JW, Martin PJ, Gooley TA, Flowers ME, Heckbert SR,Nichols WG, et al. Airflow obstruction after myeloablative
  10. Barker AF, Bergeron A, Rom WN, Hertz MI. Obliterative bron-chiolitis. N Engl J Med 2014;370:1820
  11. 2004;33:751e8
  12. Huisman C, van der Straaten HM, Canninga-van Dijk MR,Fijnheer R, Verdonck LF. Pulmonary complications after
  13. Sakaida E, Nakaseko C, Harima A, Yokota A, Cho R, Saito Y,et al. Late-onset noninfectious pulmonary complications after
  14. Perreault C, Cousineau S, D’Angelo G, Gyger M, Nepveu F,Boileau J, et al. Lymphoid interstitial pneumonia after
  15. Bergeron A, Bengoufa D, Feuillet S, Meignin V, Peffault deLatour R, Rybojad M, et al. The spectrum of lung involvement
  16. Wolff D, Reichenberger F, Steiner B, Kahl C, Leithauser M,Skibbe T, et al. Progressive interstitial fibrosis of the lung in
  17. Freudenberger TD, Madtes DK, Curtis JR, Cummings P,Storer BE, Hackman RC. Association between acute and
  18. Travis WD, Costabel U, Hansell DM, King Jr TE, Lynch DA,Nicholson AG, et al. An Official American Thoracic
  19. Daniele RP, Elias JA, Epstein PE, Rossman MD. Bronchoalveolarlavage: role in the pathogenesis, diagnosis, and management
  20. Ryu JH, Olson EJ, Midthun DE, Swensen SJ. Diagnosticapproach to the patient with diffuse lung disease. Mayo Clin
  21. Meyer KC. The role of bronchoalveolar lavage in interstitiallung disease. Clin Chest Med 2004;25:637
  22. Johkoh T. Imaging of idiopathic interstitial pneumonias. ClinChest Med 2008;29:133
  23. Kowal-Bielecka O, Kowal K, Chyczewska E. Utility of bron-choalveolar lavage in evaluation of patients with connective
  24. Yousem SA. The histological spectrum of pulmonary graft-versus-host disease in bone marrow transplant recipients.
  25. Xu L, Drachenberg C, Tavora F, Burke A. Histologic findings inlung biopsies in patients with suspected graft-versus-host
  26. Zihlif M, Khanchandani G, Ahmed HP, Soubani AO. Surgicallung biopsy in patients with hematological malignancy or
  27. Wingard JR, Hiemenz JW, Jantz MA. How I manage pulmonarynodular lesions and nodular infiltrates in patients with
  28. Azoulay E, Mokart D, Rabbat A, Pene F, Kouatchet A,Bruneel F, et al. Diagnostic bronchoscopy in hematology and
  29. Azoulay E, Mokart D, Lambert J, Lemiale V, Rabbat A,Kouatchet A, et al. Diagnostic strategy for hematology and
  30. Forslow U, Remberger M, Nordlander A, Mattsson J. Theclinical importance of bronchoalveolar lavage in allogeneic
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