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The Spectrum of Lung Involvement in Collagen Vascular-Like Diseases Following Allogeneic Hematopoietic Stem Cell Transplantation: Report of 6 Cases and Review of the Literature

Bergeron, Anne MD, PhD; Bengoufa, Djaouida MD; Feuillet, Séverine MD; Meignin, Véronique MD, PhD; de Latour, Régis Peffault MD, PhD; Rybojad, Michel MD; Gossot, Dominique MD; Azoulay, Elie MD, PhD; Socié, Gérard MD, PhD; Tazi, Abdellatif MD, PhD

doi: 10.1097/MD.0b013e31821160af
Original Study

Multisystem autoimmune diseases occurring after allogeneic hematopoietic stem cell transplantation are infrequent, late-onset manifestations that resemble well-defined collagen vascular disorders. Because the lung is frequently involved in the course of connective tissue disorders, we focused on lung manifestations occurring in autoimmune diseases following allogeneic stem cell transplantation. In the present series, we report 6 patients with systemic lupus erythematous, mixed connective tissue disease, Sjögren syndrome, polymyositis, and ANCA-positive vasculitis who presented with a spectrum of pulmonary manifestations affecting the airways, lung parenchyma, and probably respiratory muscles. We identified 3 different histopathologic patterns of interstitial pneumonia consistent with the underlying autoimmune disorder: lymphocytic interstitial pneumonia and non-specific interstitial pneumonia in 2 patients with Sjögren syndrome and diffuse alveolar damage in 1 patient with ANCA-positive vasculitis. These lung manifestations had poor prognoses. Further studies are needed to determine the optimal therapy for these complications.

Abbreviations: ALP = alkaline phosphatase, ALT = alanine aminotransferase, ANA = antinuclear antibodies, ANCA = antineutrophil cytoplasmic antibodies, AST = aspartate aminotransferase, BAL = bronchoalveolar lavage, BMT = bone marrow transplant, BO = bronchiolitis obliterans, BOS = bronchiolitis obliterans syndrome, CRP = C-reactive protein, CT = computed tomography, CTD = connective tissue disorder, FEV1 = forced expiratory volume in the 1st second of expiration, FVC = forced vital capacity, γGT = gamma-glutamyl transpeptidase, GVHD = graft-versus-host disease, HSCT = hematopoietic stem cell transplantation, OP = organizing pneumonia, STIR = short tau inversion recovery, TLC = total lung capacity, TLCO = lung transfer for carbon monoxide.

From Service de Pneumologie (AB, SF, AT), Service d' Immunologie (DB), Service de Pathologie (VM), Service d'Hématologie-Greffe de moelle (RPdL, GS), Service de Dermatologie (MR), Service de Réanimation (EA), Hôpital Saint-Louis, Université Paris 7, UFR Denis Diderot; Assistance Publique-Hôpitaux de Paris, Paris; and Service de Chirurgie thoracique (DG), Institut Mutualiste Montsouris, Paris, France.

Conflict of interest: The authors have no conflicts of interest to report.

Reprints: Anne Bergeron, MD, PhD, Service de Pneumologie, Hôpital Saint-Louis, 1, avenue Claude Vellefaux, 75475, Paris cedex 10, France (e-mail:

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Allogeneic hematopoietic stem cell transplantation (allogeneic HSCT) is part of the treatment for various hematologic diseases, both malignant and nonmalignant. Recent advances in this procedure have significantly improved early patient survival. However, late-onset, noninfectious complications are emerging, usually related to chronic graft-versus-host disease (GVHD), and these need to be better characterized.40

The involvement of the lungs with various clinical presentations is a leading example of these complications and is associated with significant morbidity and mortality. In this context, the most frequent pulmonary disorder is bronchiolitis obliterans (BO), the definitive diagnosis of which relies on conducting a lung biopsy.54 In the absence of a lung biopsy, BO syndrome (BOS) can be diagnosed based on the results of pulmonary function tests and radiologic imaging.54 Although less frequent, organizing pneumonia (OP) (previously termed BOOP) is also a common feature complicating later periods following allogeneic HSCT.15 Other patterns of late-onset, noninfectious pulmonary complications have also been reported, such as poorly defined interstitial lung disease.1

Some of the clinical features of chronic GVHD such as sclerotic skin, myositis, and xerostomia are similar to those observed in systemic connective tissue disorders (CTDs).15 In addition to these clinical manifestations, many patients who undergo allogeneic HSCT develop various autoantibodies.35,36 The clinical significance of these autoantibodies and their relationship to GVHD remains unclear.9,30,35,49 Only scattered case reports and a few small case series have presented patients with an overall clinical and laboratory picture similar to that of well-defined systemic CTDs.2-4,6,7,9-12,16-21,23-29,31-34,38,39,41-46,48,50,51,53,55,58

Pulmonary involvement, including the lung parenchyma, airways, vessels and respiratory muscles, is common in patients with CTDs, and causes considerable morbidity and mortality.5,56 This leads to the hypothesis that a similar spectrum of lung manifestations may be observed in patients with CTDs following allogeneic HSCT, and these manifestations may require specific management.

Here, we report 6 patients who presented with lung involvement in the course of a well-defined CTD, occurring several years after an allogeneic HSCT. We also review the scarce data available in the English-language literature concerning late-onset pulmonary complications occurring in the course of CTDs following allogeneic HSCT.

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At our institution, 120 allogeneic HSCTs are performed each year. In the case of respiratory symptoms, these patients are systematically referred to our Pulmonary Disease Department. We retrospectively retrieved the medical records of 6 patients who presented at our center between 2002 and 2008 with lung manifestations that either complicated the course of a previously diagnosed well-defined CTD occurring after allogeneic HSCT, or that led to the diagnosis of a CTD. Tables 1 and 2 summarize the details of all 6 patients.

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Case 1

A 32-year-old man underwent a myeloablative, geno-identical peripheral blood HSCT for acute lymphoblastic leukemia. His early course after transplantation was complicated by acute GVHD involving both the gut and the skin, which resolved after the introduction of steroids. Two years after transplantation and 2 months following the interruption of steroids, he presented with a cough and shortness of breath. The subsequent workup revealed bilateral, nonspecific, subpleural, ground-glass opacities on lung computed tomography (CT) and a new restrictive pattern on pulmonary function testing: a total lung capacity (TLC) of 4.03 L (61% of predicted), a forced vital capacity (FVC) of 2.47 L (52% of predicted), a forced expiratory volume in the first second of expiration (FEV1) of 2.41 L (60% of predicted) and a FEV1 to FVC ratio of 97%. The patient was then lost to follow-up and returned for evaluation 1 year later with increased dyspnea, cough, xerophthalmia, microangiopathy of the fingers of both hands, and genital lichen sclerosus related to chronic GVHD. At that time, he had stopped all immunosuppressive treatments for a period of 2 months. A lung CT scan revealed extensive subpleural, ground-glass opacities and reticulation (Figure 1A). Pulmonary function tests showed a severe restrictive pattern with a TLC of 2.5 L (38% of predicted), a FVC of 1.57 L (33% of predicted), a residual volume of 0.8 L (48% of predicted), a FEV1 of 1.2 L (30% of predicted), and a FEV1 to FVC ratio of 77%. Arterial blood gas analysis showed a PaO2 of 86 mm Hg and a PaCO2 of 42 mm Hg. A 6-minute walking test revealed a peripheral oxygen saturation at rest of 95% that dropped to 86% at the end of the test, and a walking distance of 68% of the predicted value. His laboratory abnormalities were as follows: 950/mm3 blood eosinophils, polyclonal hypergammaglobulinemia of 24 g/L, 3 N aspartate aminotransferase (AST), 4 N alanine aminotransferase (ALT), 4 N gamma-glutamyl transpeptidase (γGT), positive antinuclear antibodies (ANA) of 1/1600 and positive anti-SSA antibodies. This patient was negative for antineutrophil cytoplasmic antibodies (ANCA). Notably, he was retrospectively found to be negative for ANA at 4 months after allogeneic HSCT. A minor salivary gland biopsy revealed an intense lymphocytic infiltrate corresponding to a Chisholm-Mason score of grade IV. A video-assisted lung biopsy was performed and revealed a diffuse, temporally uniform thickening of the alveolar septa due to mild fibrosis associated with small lymphocytes and plasma cells, along with scattered foci of organizing pneumonia and alveolar type II pneumocyte hyperplasia. The bronchiolar epithelium was normal. Taken together, these features were consistent with a nonspecific interstitial pneumonia (Figure 1B). Soon after lung surgery, the patient's respiratory condition worsened, and despite high doses of intravenous steroids, he died of respiratory failure 1 month later.

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Case 2

A 9-year-old boy underwent a myeloablative, geno-identical bone marrow transplant (BMT) for acute myeloid leukemia. Six years later, his hematologic disease relapsed and he received a second myeloablative, geno-identical HSCT. His posttransplant clinical course was complicated by a posttransfusion hepatitis C viral infection and chronic skin and oral GVHD, which was controlled with mycophenolate mofetil and prednisone. While the patient was being treated with 15 mg/d prednisone and 1.5 g/d mycophenolate mofetil, he reported right chest pain associated with a dry cough, mild dyspnea on exertion, and dysphagia. Crackles were present in the right lung on physical examination. The patient had chronic cutaneous and erosive oral lichenoid GVHD and marked ocular and oral sicca syndrome. A lung CT scan revealed a subpleural alveolar opacity of the right lung (Figure 1C). Bronchoalveolar lavage (BAL) contained 180,000 cells/mL with 80% macrophages, 18% lymphocytes (CD4/CD8 ratio = 0.1), 2% neutrophils, and no pathogens. The patient's pulmonary function tests showed a restrictive pattern with a TLC of 3.95 L (57% of predicted), FVC of 2.24 L (44% of predicted), FEV1 of 1.75 L (39% of predicted), FEV1 to FVC ratio of 78%, and a decreased lung transfer for carbon monoxide (TLCO) (37% predicted). The patient's laboratory abnormalities were as follows: 140 μmol/L creatinine, gammaglobulin levels of 16 g/L, 2.5 N alkaline phosphatase (ALP), 3 N γGT, 46 mg/L C-reactive protein (CRP), ANA of 1/80, positive anti-RNP antibodies, anti-SSA antibodies, and rheumatoid factor. We then tested a previous serum sample from 2 years after the bone marrow transplantation (that is, 5 years before the onset of lung disease) and found ANA of 1/400 without any specificity and positive rheumatoid factor. Hepatitis C viral RNA was undetectable. The patient's total peripheral blood lymphocyte count was 1915/mm3 with (per mm3) 1609 CD3+ (84% of normal), 636 CD3/CD4+ (33%), 958 CD3/CD8+ (50%), and 172 CD19+ (9%). A histologic examination of the video-assisted lung biopsy revealed thickening of the alveolar septa due to a dense lymphocytic and plasmocytic infiltrate predominantly consisting of CD8+ T lymphocytes. A diagnosis of lymphoid interstitial pneumonia secondary to mixed connective tissue disease with Sjögren syndrome was determined. We note that in addition to histologic lesions characteristic of lymphoid interstitial pneumonia, the bronchiolar epithelium was also infiltrated with small lymphocytes and was destroyed by place (Figure 1D). At that time, duodenal biopsies showed active GVHD whereas esophageal biopsies revealed herpetic esophagitis, which was treated with acyclovir. The prednisone dosage was increased to 1 mg/kg per day, and both the lung manifestations and dysphagia improved. Six months later, while the patient was being treated with 15 mg/day prednisone, his lymphoid interstitial pneumonia relapsed, necessitating an increase in the dose of prednisone. The patient died 13 months later from sepsis due to Escherichia coli.

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Case 3

A 46-year-old woman underwent a myeloablative, geno-identical BMT for acute lymphoblastic leukemia with a BCR-ABL translocation. The BMT was first complicated by acute intestinal GHVD that was controlled with steroids. Eight months after the BMT, cyclosporine was stopped because of a convulsive crisis related to thrombotic microangiopathy. One month later the patient experienced gut GVHD, which was treated with steroids. Subsequently, while being treated with 5 mg/d prednisone, she developed a persistent productive cough that did not improve in response to various antibiotics. A lung CT scan revealed alveolar opacities in the 2 lower lobes. An extensive search for infection was negative. The patient's pulmonary function tests were normal except for a moderate decrease in TLCO (59% of predicted). A presumptive diagnosis was made of OP, and the patient was successfully treated with steroids. One year post-BMT, 400 mg/day imatinib was introduced due to a molecular relapse of the acute lymphoblastic leukemia. Two years after BMT, while being treated with 2.5 mg/d prednisone, the patient was hospitalized for asthenia, weight loss, and severe vasculitis with microangiopathy, polyarthritis, paresthesia, myalgia, severe sicca syndrome, oral lichen, dry cough, and dyspnea on exertion. Crackles were present on physical examination of the lungs. An electromyogram revealed right cubital mononeuritis. A duodenal biopsy demonstrated active GVHD. A lung CT scan showed mild, bilateral, basal, patchy, ground-glass opacities. The patient's BAL fluid contained 280,000 cells/mL with 56% macrophages, 43% lymphocytes, 1% neutrophils, and no pathogens. The patient's pulmonary function tests showed a new restrictive pattern with a TLC of 3.07 L (58% of predicted), FVC of 1.67 L (50% of predicted), FEV1 of 1.50 L (53% of predicted), FEV1 to FVC ratio of 90%, and TLCO of 43% of predicted. The patient's laboratory abnormalities were as follows: positive ANCA with anti-PR3 specificity (which was negative 1 year before), 4 N ALT, 2 N AST, 10 N γGT, 1.5 N ALP, and 2N lactate dehydrogenase. Both urinary sediment and renal function were normal. The patient's serum lymphocyte phenotype was 1173 lymphocytes/mm3 with (per mm3) 413 CD3+ (35%), 178 CD3/CD4+ (15%), 227 CD3/CD8+ (19%), and 622 CD19+ (53%). Severe ANCA-positive vasculitis was diagnosed and the patient was started on 1 mg/kg prednisone. Her joint and muscle pains decreased, but no improvement was observed in the skin lesions due to vasculitis or dyspnea. Her shortness of breath progressively increased. A lung CT scan confirmed a dramatic extension of the ground-glass opacities associated with alveolar consolidations (Figure 1E). Two months after the diagnosis of vasculitis, high-dose intravenous methylprednisolone was administered along with an intravenous bolus of cyclophosphamide (600 mg/m2). Despite this treatment, the patient quickly required mechanical ventilation because of respiratory failure, and finally died of refractory hypoxemia. A postmortem lung biopsy revealed many hyaline membranes plastered along the alveolar septa, which were thickened by fibrosis and a mild inflammatory infiltrate (Figure 1F). No capillary or bronchiolar lesions were observed, no pathogens were identified, and no abnormal cells were found. A diagnosis was made of diffuse alveolar damage.

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Case 4

A 30-year-old man with a history of 25 pack-years of smoking underwent a myeloablative, geno-identical BMT for chronic myelogenous leukemia. He experienced acute skin and gut GVHD that was controlled with steroids, mycophenolate mofetil, and tacrolimus. Five months after the steroids were stopped, he developed chronic sclerodermatous skin and liver GVHD with severe ocular and oral sicca syndrome, which necessitated the re-introduction of steroids and mycophenolate mofetil. One year after BMT the patient was hospitalized for respiratory failure. Wheezing was observed on physical examination of the lungs. A lung CT scan showed extensive hypoattenuated lung areas with bronchiectasis in the right middle and lower lobes and air trapping on expiration (Figure 1G). The patient's pulmonary function tests showed an obstructive pattern of small airways associated with air trapping, FEV1 of 2.37 L (69% of predicted), FVC of 2.66 L (62% of predicted), residual volume of 2.84 L (175% of predicted), mean expiratory flow between 25% and 75% of FVC of 2.26 L (50% of predicted), FEV1 to FVC ratio of 89% and a TLC of 6.06 L (101% of predicted). A diagnosis was made of BOS in the context of GVHD, and systemic immunosuppressive treatment was increased. Three months later, the patient developed a left pneumothorax that necessitated surgical pleurodesis. A lung biopsy confirmed the diagnosis of BO (Figure 1H). After surgery the patient's respiratory status became critical and he became dependent on oxygen. He received high-dose steroids along with 500 mg/d erythromycin and continued with 2 g/d mycophenolate mofetil and 0.5 g/d tacrolimus. The patient slowly improved and oxygen could be stopped, although his dyspnea on exertion persisted.

Four years after BMT, while being treated with 20 mg/d prednisone and 1.5 g/d mycophenolate mofetil, the patient complained of diffuse myalgia with major stiffness of the shoulders and trunk and increased dyspnea associated with ocular and oral sicca syndrome. Magnetic resonance imaging revealed a hyperintense signal on T2-weighted and short tau inversion recovery (STIR) images of the trapezius, subscapularis, spinal, iliac, and psoas muscles. Electromyography showed marked myopathic changes. An iliac muscle biopsy was performed that showed small inflammatory lymphocytic infiltrates with myofiber degeneration and necrosis, consistent with an inflammatory myopathy. The patient's laboratory abnormalities were as follows: 3 N creatine phosphokinase, 5 N aldolase, 2 N APL, 7 N γGT and 66 mg/L CRP. His serum lymphocyte phenotype showed hyperlymphocytosis, primarily of B lymphocytes, at 6676 lymphocytes/mm3 with (per mm3) 4372 CD3+ (65% of normal), 2068 CD4+ (31%), 2302 CD8+ (34%), and 1535 CD19+ (23%). The patient's ANA levels were 1/400, with positive anti-PM-Scl antibodies and positive rheumatoid factor (both of which were negative 1 year before). The patient's pulmonary function tests had deteriorated with the appearance of a restrictive pattern associated with the previous obstructive pattern: TLC of 3.82 L (63% of predicted), FVC of 1.06 L (25% of predicted), FEV1 of 0.65 L (19% of predicted), and FEV1 to FVC ratio of 62%. The patient also developed hypercapnia (PCO2 of 51 mm Hg). In this context, both his pulmonary function tests and hypercapnia suggested weakness of the diaphragm. Diffuse autoimmune polymyositis was diagnosed. Prednisone was administered at 1 mg/kg per day with poor improvement after 4 months. At that time, the patient received 2 doses of rituximab (1 g) on day 0 and day 14. Three months later, however, he died of respiratory failure due to severe bronchospasm.

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Case 5

A 53-year-old man received a myeloablative, geno-identical BMT for an eosinophilic myeloproliferative syndrome. The patient's early complications consisted of gut GVHD that resolved with steroids. Twenty months after BMT and 3 months after the steroids were stopped, the patient developed a highly disabling ocular, nasal, and oral sicca syndrome. Three months later he developed a productive cough, followed by progressive dyspnea. A physical examination of the lungs revealed diffuse wheezing, while pulmonary function tests showed a pattern of obstructive lung disease of the small airways with FEV1 of 2.4 L (61% of predicted), FVC of 2.41 L (52% of predicted), FEV1 to FVC ratio of 99%, TLC of 7.03 L (94% of predicted), and residual volume of 3.17 L (131% of predicted). A lung CT scan showed air trapping on expiratory slices, and a sinus CT scan showed hyperplasia of the mucosa of all sinuses. Examination of sputum and nasal wash revealed no bacteria, fungi, or viruses. An ocular examination revealed bilateral keratopathy. The patient's ANA were 1/1600 with positive anti-SSA antibodies, and his gammaglobulins were 17.3 g/L. We note that the patient had positive ANA (1/1600 without any specificity) with no clinical symptoms before the allogeneic HSCT; however, they became negative at 4 and 12 months after the transplant and then recurred with anti-SSA antibodies when the sicca syndrome occurred. A histopathologic examination of the minor salivary glands showed intense lymphocytic periductal and periendothelial inflammatory infiltrates (Chisholm-Mason score grade IV), together with necrosis of the ductal epithelium characteristic of Sjögren syndrome and GVHD. A diagnosis was made of Sjögren syndrome with BOS. Macrolides (500 mg/d erythromycin) and a combination of inhaled steroids and long-acting β2-agonists were initiated for BOS. The patient's lung physical examination was normal at last follow-up and his pulmonary function tests had improved (FEV1 of 2.78 L [72% of predicted], FVC of 3.98 L [86% of predicted], FEV1/FVC ratio of 69%, residual volume of 2.99 L [122% of predicted]), whereas his sicca syndrome remained disabling.

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Case 6

A 37-year-old woman underwent a myeloablative, geno-identical BMT for chronic myelogenous leukemia. Within the first month following the BMT she experienced both acute skin GVHD and chronic skin and liver GVHD. Nine years after the BMT when she was no longer taking immunosuppressive treatment, she experienced an inflammatory polyarthritis with positive rheumatoid factor and was treated with hydroxychloroquine and steroids for 3 years. Three years after stopping this treatment the patient presented with hematemesis related to esophageal varices. Echography and Doppler ultrasound imaging confirmed portal hypertension and detected partial portal thrombosis. A liver biopsy showed nodular regenerative hyperplasia. The patient was subsequently admitted for weight loss associated with diarrhea, dyspnea, a nonproductive cough, severe sicca syndrome, discoid lupus, and alopecia. Physical examination of the lungs revealed squeaks, and a chest X-ray revealed reduced lung volumes. A lung CT scan showed air trapping on expiratory slices with no parenchymal abnormalities, and pulmonary function tests revealed a restrictive pattern with TLC of 3.02 L (59% of predicted), FVC of 1.66 L (55% of predicted), FEV1 of 1.41 L (54% of predicted), residual volume of 0.93 L (50% of predicted), and FEV1 to FVC ratio of 85%. At the same time, an abdominal CT scan showed thickening of the small bowel wall and mild peritoneal fluid. Gastroscopy identified grade I esophageal varices, and jejunal biopsies revealed active GVHD. An ascites puncture revealed transudative fluid. Laboratory studies demonstrated mild cholestasis, a creatinine level of 227 μmol/L with normal proteinuria and urinary sediment, 15 g/L gammaglobulins, ANA of 1/1600, anti-Sm antibodies of 1/100, positive anti-RNP antibodies, anti-SSA antibodies, antiphospholipid IgG, rheumatoid factor with negative anti-double-stranded DNA antibodies, and a decreased 4th fraction of complement (C4). Previous sequential sera were not available for comparison.

Severe systemic lupus erythematous was diagnosed and treated with 80 mg (2 mg/kg per day) of prednisone. Four months later, the patient presented with refractory status epilepticus. The cerebrospinal fluid was free of pathogens but contained 0.47 g/L protein with normal glycorrhachia and no cells. A brain MRI revealed only dural enhancement without cerebral thrombosis, and a small meningioma that was previously known and remained unchanged. Despite high-dose intravenous steroids and plasmapheresis for the treatment of suspected neurologic lupus, this patient died.

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We performed a MEDLINE (National library of Medicine, Bethesda, MD) search for reported cases of CTDs in patients with allogeneic HSCT on all articles published until January 2010. We excluded articles in languages other than English and retrieved 37 articles including 113 patients suffering from vasculitis (4 articles),4,27,42,58 lupus erythematosus (3 articles),17,41,50 Sjögren syndrome (2 articles),18,23 scleroderma (8 articles),9,11,31,39,46,48,53,55 dermatomyositis (3 articles),3,6,28 and polymyositis (17 articles).2,7,10,12,16,19,24,25,29,32-34,38,43-45,51 We reviewed all these articles and retained those in which the reported patients had lung involvement, for a final total of 13 articles.4,6,9,11,24,31,38,39,42-44,48,55

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The 13 retained articles reported on a total of 32 patients. We collected pertinent information from these studies including the type of CTD, the time from allogeneic HSCT to CTD, characteristics of lung disease, treatment, and outcome.

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Patient Characteristics

The patient data summarized in Table 3 were not available for all reported patients. The 29 patients for whom these data were available included 12 women and 17 men. The mean age at the onset of CTD was 30 years (range, 4-47 yr), and the hematologic disease leading to the allogeneic HSCT was malignant in all 26 patients for whom this information was available (see Table 3). The conditioning regimen consisted of total body irradiation and cyclophosphamide for 16 patients, busulfan and cyclophosphamide for 4 patients, cyclophosphamide alone for 4 patients, and fludarabine and cyclophosphamide for the single patient who underwent a nonmyeloablative, allogeneic HSCT. The type of transplant was only specified for 19 patients, and was bone marrow for 16 patients and peripheral blood stem cells for the remaining 3 patients. The transplant was known to be geno-identical for 15 patients and pheno-identical for 4 patients. The mean time between allogeneic HSCT and the diagnosis of CTD was 31 months (range, 7-192 mo). Notably, 2 patients underwent a donor lymphocyte infusion at 6 and 48 months after allogeneic HSCT, and the clinical symptoms of CTD occurred at 1 and 4 months after the donor lymphocyte infusion, respectively, in these patients. Among the 16 patients for whom information was available, 11 had previously developed acute GVHD. At the time that CTD was diagnosed, 24 patients were known to suffer from chronic GVHD in different organs (for example, oral, skin, liver, gut) according to the consensus criteria,15,37 and only 1 patient was known not to have developed documented chronic GVHD.

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Type and Diagnosis of Autoimmune Diseases

The 32 patients contained in these reports included 20 with a diagnosis of diffuse scleroderma, 9 with a diagnosis of polymyositis, 2 with a diagnosis of vasculitis, and 1 with a diagnosis of dermatomyositis. The patients with myositis fulfilled the classical criteria for these diseases:14 muscle weakness, electromyographic findings showing a myopathic pattern, elevated muscle enzymes, and for most, consistent muscle biopsy findings and skin biopsies characteristic of dermatomyositis. The diagnosis of diffuse scleroderma relied on clinical features, skin biopsy findings, and consistent autoantibody levels. Although not all of the patients were tested for the same panel of autoantibodies, ANA were positive for most patients. Anti-Scl70 antibodies were tested in 5 patients and found to be positive in 2. One patient was positive for anti-PM-Scl antibodies (see Table 3). A diagnosis of large vessel vasculitis was suspected based on the clinical and radiologic features of 1 patient, and for another patient, the diagnosis of vasculitis relied on both skin and lung biopsies together with positive perinuclear ANCA.

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Characterization of Lung Involvement

Among the reported patients, lung involvement led to a diagnosis of CTD in 3 cases4,43,55 (see Table 3). For the other patients, lung involvement occurred in the course of a previously diagnosed CTD.

The description of lung involvement in these patients was usually fragmented. For 3 patients with scleroderma, the determination of "lung involvement" without further details was the only available information.

Eight patients had interstitial pneumonia. Only 2 lung biopsies were available in this context. In 1 case, an open lung biopsy showed diffuse alveolar damage with capillaritis at the alveolar septa, leading to a diagnosis of ANCA-associated vasculitis.4 In the other case, a transbronchial biopsy indicated interstitial fibrosis, lymphocytic infiltrate, and BO in a patient with scleroderma.55 For the other 6 patients, interstitial pneumonia was determined without any further details. Five of these 6 patients had scleroderma, and the remaining patient had dermatomyositis (see Table 3).

In 16 of the patients, lung involvement was characterized only by lung function patterns. An obstructive pattern was observed in 8 patients (2 with polymyositis, 5 with scleroderma, and 1 with large-vessel vasculitis). On the other hand, a restrictive pattern was observed in 8 patients with no information available regarding whether or not they had interstitial pneumonia (4 with scleroderma and 4 with polymyositis). Two of the patients with scleroderma had pulmonary hypertension, and 2 of the patients with polymyositis had pleuritis (see Table 3).

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Treatment and Prognosis of CTD Post-Allogeneic HSCT With Lung Involvement

Information about the treatment regimen and disease outcome was available for 27 patients. All but 1 patient received systemic immunosuppressive treatment consisting of various steroid regimens (see Table 3). The mean follow-up period was 85 months (range, 1-300 mo). At last follow-up, 8 of the patients had died: 6 due to respiratory failure (5 with scleroderma and 1 with dermatomyositis), 1 with scleroderma due to an unknown cause, and 1 with polymyositis due to sepsis. Notably, 6 of the 8 patients with interstitial lung disease died.

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In the current study, we characterized the spectrum of pulmonary manifestations occurring in patients with a well-defined CTD after allogeneic HSCT, leading to the following findings: 1) Similar to idiopathic CTD, different lung compartments were involved in these diseases, such as bronchioles, interstitium, and probably respiratory muscles. 2) Three different patterns of interstitial lung diseases consistent with the underlying CTD were identified: a) lymphoid interstitial pneumonia in a mixed CTD associated with Sjögren syndrome, b) nonspecific interstitial pneumonia in Sjögren syndrome, and c) diffuse alveolar damage in ANCA-positive vasculitis. 3) The prognosis of these CTDs was poor, as 5 of the 6 patients died, 3 of whom died due to respiratory failure.

Since the late 1970s, scattered cases have been reported of patients with clinical characteristics resembling multisystem autoimmune disorders with or without circulating autoantibodies following allogeneic HSCT. Most of these cases have concerned scleroderma and polymyositis.

The incidence of these CTDs after allogeneic HSCT remains unknown and would probably be very difficult to establish. Indeed, as seen in our patients, these manifestations may arise very late after allogeneic HSCT, making it difficult for clinicians to make the link between the clinical manifestations and the allogeneic HSCT. Thus, many cases of CTD following allogeneic HSCT are probably overlooked.

Several pathologic mechanisms have been proposed for these autoimmune manifestations, such as genetic predisposition, thymic deficiency, and the expression of an abnormal B-cell and/or T-cell reconstitution or donor-related pathogenic clone transfer.13,47 Notably, none of the donors for our patients developed CTD. Whether these autoimmune manifestations are a specific feature of chronic GVHD remains open to discussion. This hypothesis is supported by the history of acute or chronic GVHD in all of the patients in our study, and further supported by the fact that the symptoms of CTD occurred systematically around the discontinuation or decrease of immunosuppressive treatment.

In settings other than allogeneic HSCT, patients with CTDs are known to be susceptible to respiratory involvement, although the prevalence and pattern of the lung manifestations vary according to the underlying CTD.5,56 Pulmonary involvement has prognostic value and necessitates early diagnosis for the prompt initiation of therapy. All compartments of the respiratory tract may be affected, including the airways, vessels, parenchyma, pleura, and muscles.5

The late-onset pulmonary complications that occur after allogeneic HSCT are variable and poorly defined. Most studies have focused on abnormalities in pulmonary function, whereas clinical, laboratory, and histologic data are usually not specified. Although an obstructive pattern is most frequently observed, restrictive lung disease occurring after allogeneic HSCT has been noted in some studies in which sequential pulmonary function testing was performed during follow-up.52 In our study, restrictive lung disease was associated with either probable diaphragm weakness for Patient 4, who developed inflammatory polymyositis, or interstitial lung disease for another 3 patients (Patients 1, 2, 3). Late-onset interstitial lung disease after allogeneic HSCT is infrequent and poorly characterized. Indeed, very few reports are available concerning the histopathologic pattern of interstitial lung disease in this context.57 According to the current classification of interstitial pneumonias,22 we observed lymphoid interstitial pneumonia in a patient with mixed connective tissue disease and Sjögren syndrome, a nonspecific interstitial pneumonia in another patient with Sjögren syndrome, and diffuse alveolar damage in a patient with ANCA-positive vasculitis. Although the lung biopsy of the latter patient was obtained postmortem after mechanical ventilation, the clinical characteristics of this patient were consistent with acute interstitial pneumonia. It is noteworthy that the different histopathologic patterns of interstitial lung disease observed in our series were similar to those described for interstitial lung involvement in the course of similar idiopathic CTDs.5

Two patients in the current study presented with an obstructive lung defect characterized by 2 different functional patterns: 1 had FEV1 to FVC ratio <70%, the usual definition of an obstructive ventilatory defect, whereas the other had both a FEV1 and FVC <80% of predicted and a normal TLC, reflecting obstruction of the small airways with air trapping. In the context of allogeneic HSCT, these functional profiles usually reflect BO, the most frequent late-onset lung complication following allogeneic HSCT that occurs in approximately 2%-3% of all patients undergoing allogeneic HSCT and 6% of those with chronic GVHD.54 According to the National Institutes of Health consensus, BO can be attributed to chronic lung GVHD.15 In our series, it was striking that Patient 5 developed an obstructive lung disease soon after complaining of disabling sicca syndrome with histopathologic and laboratory criteria for Sjögren syndrome, which includes small airway disease as a well-known feature.56 We note that 3 of our patients developed features of BO together with other lung manifestations: Patient 2 had a histopathologic pattern of lymphoid interstitial pneumonia together with bronchiolar epithelial damage, whereas Patient 4 had both BO and probable diaphragm involvement in the course of polymyositis, and Patient 6 had squeaks (suggestive of bronchiolar involvement) together with restrictive lung disease. These associations could reflect similar pathophysiologic mechanisms underlying the development of these various noninfectious pulmonary complications following allogeneic HSCT.

The patients in our case series had very poor outcomes: 5 of the 6 patients died, with 3 deaths due to respiratory failure (see Table 1). Two of these 3 patients had interstitial lung disease, and the third had both BO and diaphragm impairment. Our data are consistent with data from other reports in the literature (see Table 3). Thus, similar to what is known for the course of idiopathic CTD,5 lung involvement appears to be associated with a poor prognosis for CTDs occurring after allogeneic HSCT.

Corticosteroids are the first-line treatment for both pulmonary involvement associated with CTDs and chronic GVHD.5,8 Although all of our patients received corticosteroids, this treatment had poor efficacy on the lung disease for 3 patients and probably contributed to the development of fatal sepsis in Patient 2. In this context, there is a strong need for the evaluation of alternative treatments. Interestingly, the lymphocyte phenotype was available for 3 of our patients and showed increased numbers of peripheral blood B cells in 2 of them. Furthermore, hypergammaglobulinemia with circulating autoantibodies was noted in 3 patients, consistent with B lymphocyte hyperactivity. Thus, the anti-CD20 monoclonal antibody rituximab could be an attractive alternative treatment in this setting. Patient 4 actually received rituximab but unfortunately died soon after the initiation of this treatment, precluding any evaluation of its potential effects. Similarly, given that cyclophosphamide is a cornerstone treatment in severe ANCA-positive vasculitis, Patient 3 received intravenous boluses of cyclophosphamide but unfortunately showed no improvement. It remains questionable whether rituximab and cyclophosphamide would have been effective if administered earlier.

In summary, the current study shows that a spectrum of well-characterized lung manifestations can occur in the course of various CTDs following allogeneic HSCT. Furthermore, this analysis shows, to our knowledge for the first time, that the current classification of idiopathic interstitial pneumonia is suitable for the characterization of interstitial lung disease in the setting of allogeneic HSCT, similar to the case for idiopathic CTD. We recommend that patients with late-onset, noninfectious pulmonary disease be screened for the presence of autoimmunity and that all patients with CTD following allogeneic HSCT be evaluated for lung involvement. The devastating prognosis suggests that early detection of pulmonary involvement is essential for the prompt initiation of treatment. Cooperative studies are needed to define the incidence and determine the optimal therapeutic management of these severe, late-onset, noninfectious complications following allogeneic HSCT.

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