Follicular Bronchiolitis: A Rare Cause of Bronchiolitis Obliterans Syndrome After Lung Transplantation: A Case Report
2009; Elsevier BV; Volume: 9; Issue: 3 Linguagem: Inglês
10.1111/j.1600-6143.2008.02518.x
ISSN1600-6143
AutoresRobin Vos, Bart M. Vanaudenaerde, Stéphanie I. De Vleeschauwer, Dirk Van Raemdonck, Lieven Dupont, Eric Verbeken, Walter De Wever, Geert M. Verleden,
Tópico(s)Polyomavirus and related diseases
ResumoThis case report is the first confirmed case of follicular bronchiolitis (FB), a rare bronchiolar disorder characterized by peribronchiolar lymphoid follicles, in a series of over 400 lung transplantations performed in our center. It is to our knowledge, the first publication describing FB after lung transplantation (LTx), presenting as chronic allograft dysfunction or bronchiolitis obliterans syndrome (BOS). This case report is the first confirmed case of follicular bronchiolitis (FB), a rare bronchiolar disorder characterized by peribronchiolar lymphoid follicles, in a series of over 400 lung transplantations performed in our center. It is to our knowledge, the first publication describing FB after lung transplantation (LTx), presenting as chronic allograft dysfunction or bronchiolitis obliterans syndrome (BOS). Our 24-year-old male Cystic Fibrosis patient, colonized with P. aeruginosa, underwent a sequential bilateral LTx in June 2000. Following induction therapy with rabbit anti-thymocyte globulin, routine immunosuppressives (Methylprednisolone (MP), Azathioprine (AZA), Cyclosporine A (CsA)) were tapered to oral doses. Standard prophylaxis (Acyclovir, Amphotericin B and Sulfamethoxazole-Trimethoprim) and bronchial aspirate culture-guided antibiotic treatment were administered. No major complications were noted neither during the postoperative period, nor the first 2 years post-LTx (Table 1, Figure 1). Because of gastro-intestinal discomfort, CsA was switched to Tacrolimus at 16-month post-LTx.Table 1Summary of the radiological, blood, BAL, sputum and histological characteristics over time after lung transplantationTime post-LTx (mo.)CT findingsBlood EBV-DNA × 103 (copies/mL)Broncho-alveolar lavageSputum CultureTransbronchial biopsyNeutro (%)Lympho (%)Total cells (×103/mL)sIgA (μg/mL)CultureAR (grade)LB grade)Grocott-stain24Normal<0.5Negative27Bilateral patchy ground-glass and centrilobular reticulonodular opacities (‘tree-in-bud’) and peripheral consolidations, predominantly in lower lobes and basal parts of upper lobes.<0.5639.57262.8NegativeP. aeruginosa20Negative29Increase of ground-glass opacities, centrilobular nodules and consolidations. Mild bronchiectasis.<0.5922.52901.7NegativeP. aeruginosa, S. pneumoniae32Negative47No residual ground-glass opacities or nodules. Persistent mild bronchiectasis.<0.5Negative55<0.5855.017942.1P. aeruginosaP. aeruginosa00Negative62Bilateral ground-glass opacities, centrilobular nodules and bronchiectasis with mucus-plugging and airtrapping, predominantly in lower lobes.46.884.67.886513.2P. aeruginosa, A. fumigatusP. aeruginosa22Aspergillus sp.6320.810.4P. aeruginosa23Negative72Decrease of ground-glass opacities, persistent centrilobular nodules and bronchiectasis with mucus-plugging, airtrapping.1.7P. aeruginosa, A. nidulans82No ground-glass opacities, persistent centrilobular nodules and bronchiectasis with mucus-plugging, airtrapping.0.6P. aeruginosaAbbreviations: Blank spaces = not investigated at that time; LTx = lung transplantation; mo. = months; CT = computed tomography; EBV = Epstein-Barr virus; Neutro = neutrophils; Lympho = lymphocytes; sIgA = secretory immunoglobulin A (Immundiagnostik AG, Bensheim, Germany); P. aeruginosa = Pseudomonas aeruginosa; A. fumigatus = Aspergillus fumigatus; Aspergillus sp. = Aspergillus species; A. nidulans = Aspergillus nidulans; S. pneumoniae = Streptococcus pneumoniae; AR = acute (cellular) rejection; LB = lymphocytic bronchi(oli)tis graded according to the International Society for Heart and Lung Transplantation guidelines(17Yousem SA Berry GJ Cagle PT et al.Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group..J Heart Lung Transplant. 1996; 15: 1-15PubMed Google Scholar). Open table in a new tab Abbreviations: Blank spaces = not investigated at that time; LTx = lung transplantation; mo. = months; CT = computed tomography; EBV = Epstein-Barr virus; Neutro = neutrophils; Lympho = lymphocytes; sIgA = secretory immunoglobulin A (Immundiagnostik AG, Bensheim, Germany); P. aeruginosa = Pseudomonas aeruginosa; A. fumigatus = Aspergillus fumigatus; Aspergillus sp. = Aspergillus species; A. nidulans = Aspergillus nidulans; S. pneumoniae = Streptococcus pneumoniae; AR = acute (cellular) rejection; LB = lymphocytic bronchi(oli)tis graded according to the International Society for Heart and Lung Transplantation guidelines(17Yousem SA Berry GJ Cagle PT et al.Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group..J Heart Lung Transplant. 1996; 15: 1-15PubMed Google Scholar). At 27 and 29 months post-LTx, grade A2B0, respectively, A3B1, acute rejection and pseudomonal infection were diagnosed (Table 1, Figure 1), treated with MP, switching immunosuppressives and culture-guided antibiotic therapy. Azithromycin (AZI; 250 mg qd triweekly po) was started at 30-month post-LTx because of unsatisfactory recovery of FEV1 with concurrent airway neutrophilia (BOS 0-p). Thereafter, an initial improvement in FEV1 and accompanying radiological improvement were seen (Table 1, Figure 1). Yet, due to Clostridium colitis AZI had to be discontinued at 43 months post-LTx. Despite resuming AZI, a gradual FEV1-decline was afterward observed in the absence of radiological or endoscopic anomalies, except for persistent airway neutrophilia (Table 1, Figures 1 and 2A). Thus, BOS stages 1 and 2 were diagnosed at 43, respectively 52 months post-LTx for which AZA again was associated (Figure 1). Additionally, besides continuing a high-dose proton pump inhibitor, Erythromycin (250 mg qd triweekly po) was started as a gastroprokinetic agent to diminish the deleterious effects of gastric aspiration. Postoperative gastroparesis and gastroesophageal reflux were confirmed by radiologic evaluation and pH-impedance measurement at this time. Nevertheless, FEV1 progressively declined and BOS stage 3 was diagnosed at 61 months post-LTx (Figure 1), soon after which all macrolides had to be stopped again due to recurrence of colitis. Later, at 62 months post-LTx, grade A2B2 acute rejection together with pulmonary aspergillosis was diagnosed, treated with MP and systemic antifungals. At this time, Epstein—Barr virus (EBV)-reactivation was seen, for which treatment was left unchanged (Table 1). One month thereafter, a grade A2B3 acute rejection was diagnosed, treated with MP. Throughout the subsequent months, the patient was repeatedly treated for pulmonary P. aeruginosa infections, as well as for concomitant invasive pulmonary aspergillosis at 72 months post-LTx (Table 1). During the last hospitalization macrolide therapy (Roxithromycin 100 mg qd po) was again attempted, yet again had to be discontinued because of gastro-intestinal discomfort. Finally, the patient evolved to respiratory failure and was retransplanted at 88 months post-LTx. High-resolution chest computed tomography (HRCT) prior to retransplantation is shown in Figure 2B. Explant histology revealed marked follicular hyperplasia with a dense lymphoid infiltrate and abundant lymphoid follicles distributed along the bronchioles, causing luminal compression (Figure 3A, B). The follicular lesions, homogenously distributed in both lungs, demonstrated a typical cellular distribution of centrally localized B cells surrounded by T cells (Figure 3C). Grocott-staining and EBV in situ staining were negative (Figure 3B) and posttransplant lymphoproliferative disorder (PTLD) was excluded (no evidence for atypical lymphoid cells, plasmacytic hyperplasia, polymorphic B-cell proliferation, monomorphic B- or T-cell lymphoma or Hodgkin lymphoma). Bronchiolar lumina contained a mixed inflammatory exudate of mononuclear cells, polymorphonuclear neutrophils and lymphocytes. Signs of peribronchiolar fibrosis or luminal obliteration were absent. No anomalies were seen at the level of the alveolar parenchyma or the vascular structures. The bronchus-associated lymphoid tissue (BALT) consists of submucosal, perilymphatic, subpleural and intraparenchymal aggregates of lymphoid (T- and immunoglobulin (Ig) A-expressing B-) cells and antigen-processing cells (macrophages and dendritic cells). It is a secondary lymphoid system playing an important role in inducing the adaptive immune response and serves as a processing center for the dissemination of these cells to the draining lymph nodes, spleen and bone marrow (1Bienenstock J McDermott MR et al.Bronchus- and nasal-associated lymphoid tissues..Immunol Rev. 2005; 206: 22-31Crossref PubMed Scopus (163) Google Scholar, 2Tschernig T Pabst R Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases..Pathobiology. 2000; 68: 1-8Crossref PubMed Scopus (191) Google Scholar, 3Hasegawa T Iacono A Yousem SA The significance of bronchus-associated lymphoid tissue in human lung transplantation: Is there an association with acute and chronic rejection?.Transplantation. 1999; 67: 381-385Crossref PubMed Scopus (27) Google Scholar). In humans, BALT is not a constitutive structure and can only be found in children and adolescents (1Bienenstock J McDermott MR et al.Bronchus- and nasal-associated lymphoid tissues..Immunol Rev. 2005; 206: 22-31Crossref PubMed Scopus (163) Google Scholar,2Tschernig T Pabst R Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases..Pathobiology. 2000; 68: 1-8Crossref PubMed Scopus (191) Google Scholar). Exogenous antigen stimulation, such as chronic respiratory infections (e.g. with P. aeruginosa and H. influenzae) or smoking, but also endogenous autoimmune phenomena (e.g. rheumatoid arthritis), can initiate the BALT-formation in adults (1Bienenstock J McDermott MR et al.Bronchus- and nasal-associated lymphoid tissues..Immunol Rev. 2005; 206: 22-31Crossref PubMed Scopus (163) Google Scholar,2Tschernig T Pabst R Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases..Pathobiology. 2000; 68: 1-8Crossref PubMed Scopus (191) Google Scholar). Continuous or repetitive epithelial irritation is thought to release cytokines which initiate the local accumulation of lymphocytes (1Bienenstock J McDermott MR et al.Bronchus- and nasal-associated lymphoid tissues..Immunol Rev. 2005; 206: 22-31Crossref PubMed Scopus (163) Google Scholar,2Tschernig T Pabst R Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases..Pathobiology. 2000; 68: 1-8Crossref PubMed Scopus (191) Google Scholar). When stimulation of the BALT results in a polyclonal hyperplasia of lymphoid follicles around the bronchioles, the term ‘follicular bronchiolitis’ (FB) is used (1Bienenstock J McDermott MR et al.Bronchus- and nasal-associated lymphoid tissues..Immunol Rev. 2005; 206: 22-31Crossref PubMed Scopus (163) Google Scholar,2Tschernig T Pabst R Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases..Pathobiology. 2000; 68: 1-8Crossref PubMed Scopus (191) Google Scholar). These lymphoid follicles typically consist of a reactive germinal center, mainly containing B cells, surrounded by a parafollicular zone of CD4+ T cells and, to a lesser extent, CD8+ T cells (1–4). As the lymphoid follicles are situated in between the bronchioles and the pulmonary arteries, compression of the bronchiolar lumen is often seen, causing variable radiological findings and pulmonary function abnormalities (4Howling SJ Hansell DM Wells AU Nicholson AG Flint JD Muller NL Follicular bronchiolitis: Thin-section CT and histologic findings..Radiology. 1999; 212: 637-642Crossref PubMed Scopus (174) Google Scholar). Radiological findings include bilateral mixed interstitial or alveolar infiltrates on chest X-ray and bilateral centrilobular nodules, mostly ranging in size from 1 to 3 mm, variably associated with peribronchiolar nodules and ground-glass opacities on HRCT. Bronchial dilatation or bronchiectasis, bronchial wall thickening, interlobular septal thickening and peribronchovascular consolidations can also be seen (4Howling SJ Hansell DM Wells AU Nicholson AG Flint JD Muller NL Follicular bronchiolitis: Thin-section CT and histologic findings..Radiology. 1999; 212: 637-642Crossref PubMed Scopus (174) Google Scholar). Most often, patients demonstrate a restrictive ventilatory limitation or a reduced diffusion capacity, which appears to be the most sensitive test, although this was not apparent in our case. An obstructive pattern is uncommon, as is a normal pulmonary function (5Aerni MR Vassallo R Myers JL Lindell RM Ryu JH Follicular bronchiolitis in surgical lung biopsies: Clinical implications in 12 patients..Respir Med. 2008; 102: 307-312Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,6Romero S Barroso E Gil J Aranda I Alonso S Garcia-Pachon E Follicular bronchiolitis: Clinical and pathologic findings in six patients..Lung. 2003; 181: 309-319Crossref PubMed Scopus (33) Google Scholar). FB is overall considered to be a rare disorder (5Aerni MR Vassallo R Myers JL Lindell RM Ryu JH Follicular bronchiolitis in surgical lung biopsies: Clinical implications in 12 patients..Respir Med. 2008; 102: 307-312Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). When it occurs in isolation without identifiable cause, idiopathic FB presents as primary airway-centered lymphoid hyperplasia accompanied by peribronchiolar lymphocytic infiltration, resembling lymphoid interstitial pneumonia (4Howling SJ Hansell DM Wells AU Nicholson AG Flint JD Muller NL Follicular bronchiolitis: Thin-section CT and histologic findings..Radiology. 1999; 212: 637-642Crossref PubMed Scopus (174) Google Scholar). It has been suggested that it may result from a hypersensitivity phenomenon to a yet unidentified antigen as exposure to polyethylene-flock has also been described as a possible cause (6Romero S Barroso E Gil J Aranda I Alonso S Garcia-Pachon E Follicular bronchiolitis: Clinical and pathologic findings in six patients..Lung. 2003; 181: 309-319Crossref PubMed Scopus (33) Google Scholar). FB can also occur as a secondary finding in a variety of lung diseases such as infections (6Romero S Barroso E Gil J Aranda I Alonso S Garcia-Pachon E Follicular bronchiolitis: Clinical and pathologic findings in six patients..Lung. 2003; 181: 309-319Crossref PubMed Scopus (33) Google Scholar,7Masuda T Ishikawa Y Akasaka Y et al.Follicular bronchiolitis associated with Legionella pneumophilia infection..Pediatr Pathol Mol Med. 2002; 21: 41-47Crossref PubMed Google Scholar) or surrounding abscesses and neoplastic lesions (1Bienenstock J McDermott MR et al.Bronchus- and nasal-associated lymphoid tissues..Immunol Rev. 2005; 206: 22-31Crossref PubMed Scopus (163) Google Scholar, 2Tschernig T Pabst R Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases..Pathobiology. 2000; 68: 1-8Crossref PubMed Scopus (191) Google Scholar, 3Hasegawa T Iacono A Yousem SA The significance of bronchus-associated lymphoid tissue in human lung transplantation: Is there an association with acute and chronic rejection?.Transplantation. 1999; 67: 381-385Crossref PubMed Scopus (27) Google Scholar, 4Howling SJ Hansell DM Wells AU Nicholson AG Flint JD Muller NL Follicular bronchiolitis: Thin-section CT and histologic findings..Radiology. 1999; 212: 637-642Crossref PubMed Scopus (174) Google Scholar, 5Aerni MR Vassallo R Myers JL Lindell RM Ryu JH Follicular bronchiolitis in surgical lung biopsies: Clinical implications in 12 patients..Respir Med. 2008; 102: 307-312Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 6Romero S Barroso E Gil J Aranda I Alonso S Garcia-Pachon E Follicular bronchiolitis: Clinical and pathologic findings in six patients..Lung. 2003; 181: 309-319Crossref PubMed Scopus (33) Google Scholar) as well as in systemic connective tissue diseases (particularly rheumatoid arthritis) or immunodeficiency syndromes (AIDS, common variable immunodeficiency) (5Aerni MR Vassallo R Myers JL Lindell RM Ryu JH Follicular bronchiolitis in surgical lung biopsies: Clinical implications in 12 patients..Respir Med. 2008; 102: 307-312Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,6Romero S Barroso E Gil J Aranda I Alonso S Garcia-Pachon E Follicular bronchiolitis: Clinical and pathologic findings in six patients..Lung. 2003; 181: 309-319Crossref PubMed Scopus (33) Google Scholar,8Hayakawa H Sato A Imokawa S Toyoshima M Chida K Iwata M Bronchiolar disease in rheumatoid arthritis..Am J Respir Crit Care Med. 1996; 154: 1531-1536Crossref PubMed Scopus (141) Google Scholar,9Ryu JH Myers JL Swensen SJ Bronchiolar disorders..Am J Respir Crit Care Med. 2003; 168: 1277-1292Crossref PubMed Scopus (286) Google Scholar). Relatively little is known regarding its prognostic implications and treatment, yet a recent report suggests a good clinical course and prognosis for most patients, with progressive lung disease being uncommon (5Aerni MR Vassallo R Myers JL Lindell RM Ryu JH Follicular bronchiolitis in surgical lung biopsies: Clinical implications in 12 patients..Respir Med. 2008; 102: 307-312Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). In general, patients respond favorable to corticosteroid therapy, but initial improvement may be followed by relapse as corticosteroids are tapered (5Aerni MR Vassallo R Myers JL Lindell RM Ryu JH Follicular bronchiolitis in surgical lung biopsies: Clinical implications in 12 patients..Respir Med. 2008; 102: 307-312Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). The role of immunosuppressive drugs, such as AZA or Methotrexate, remains unclear (5Aerni MR Vassallo R Myers JL Lindell RM Ryu JH Follicular bronchiolitis in surgical lung biopsies: Clinical implications in 12 patients..Respir Med. 2008; 102: 307-312Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar). Some authors report a beneficial effect of the macrolides Erythromycin or Azithromycin, possibly due to their immunomodulatory or anti-inflammatory properties (5Aerni MR Vassallo R Myers JL Lindell RM Ryu JH Follicular bronchiolitis in surgical lung biopsies: Clinical implications in 12 patients..Respir Med. 2008; 102: 307-312Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,8Hayakawa H Sato A Imokawa S Toyoshima M Chida K Iwata M Bronchiolar disease in rheumatoid arthritis..Am J Respir Crit Care Med. 1996; 154: 1531-1536Crossref PubMed Scopus (141) Google Scholar,). This case report is, to our knowledge, the first publication to describe FB after LTx, presenting as chronic allograft dysfunction or BOS (10Trulock EP Christie JD Edwards LB et al.Registry of the International Society for Heart and Lung Transplantation: Twenty-fourth official adult lung and heart-lung transplantation report-2007..J Heart Lung Transplant. 2007; 26: 782-795Abstract Full Text Full Text PDF PubMed Scopus (445) Google Scholar). Several risk factors for BOS have been identified, both immunological, of which the single most important one is late or recurrent/refractory acute rejection; and nonimmunological, such as gastroesophageal reflux, viral infections and pseudomonal colonization (11Sharples LD McNeil K Stewart S Wallwork J Risk factors for bronchiolitis obliterans: A systematic review of recent publications..J Heart Lung Transplant. 2002; 21: 271-281Abstract Full Text Full Text PDF PubMed Scopus (316) Google Scholar, 12Khalifah AP Hachem RR Chakinala MM et al.Respiratory viral infections are a distinct risk factor for bronchiolitis obliterans syndrome and death..Am J Respir Crit Care Med. 2004; 170: 181-187Crossref PubMed Google Scholar, 13Vos R Vanaudenaerde BM Geudens N Dupont LJ Van Raemdonck DE Verleden GM Pseudomonal airway colonization: Risk factor for BOS after lung transplantation?.Eur Respir J. 2008; 31: 1037-1045Crossref PubMed Scopus (130) Google Scholar). In rodent models of (acute) allograft rejection, the BALT seems to play a major role in the induction and persistence of the allo-reactive response (1Bienenstock J McDermott MR et al.Bronchus- and nasal-associated lymphoid tissues..Immunol Rev. 2005; 206: 22-31Crossref PubMed Scopus (163) Google Scholar,2Tschernig T Pabst R Bronchus-associated lymphoid tissue (BALT) is not present in the normal adult lung but in different diseases..Pathobiology. 2000; 68: 1-8Crossref PubMed Scopus (191) Google Scholar), however, neither an association with acute nor chronic rejection could be demonstrated in human LTx (3Hasegawa T Iacono A Yousem SA The significance of bronchus-associated lymphoid tissue in human lung transplantation: Is there an association with acute and chronic rejection?.Transplantation. 1999; 67: 381-385Crossref PubMed Scopus (27) Google Scholar). Another study investigated the role of IgA, the predominant Ig in BAL; and secretory IgA (sIgA), which is locally produced by the BALT and may protect against (bacterial) infections (14Bastian A Tunkel C Lins M et al.Immunoglobulin A and secretory immunoglobulin A in the bronchoalveolar lavage from patients after lung transplantation..Clin Transplant. 2000; 14: 580-585Crossref PubMed Scopus (9) Google Scholar). In this study, both BAL IgA and sIgA levels were increased during infection, compared to stable episodes or episodes of rejection after human LTx, which is in accordance with earlier studies in nontransplanted patients suffering from respiratory infections (15Peebles Jr, RS Liu MC Lichtenstein LM Hamilton RG IgA, IgG and IgM quantification in bronchoalveolar lavage fluids from allergic rhinitics, allergic asthmatics, and normal subjects by monoclonal antibody-based immunoenzymetric assays..J Immunol Methods. 1995; 179: 77-86Crossref PubMed Scopus (48) Google Scholar,16Sato T Kitajima A Ohmoto S et al.Determination of human immunoglobulin A and secretory immunoglobulin A in bronchoalveolar lavage fluids by solid phase enzyme immunoassay..Clin Chim Acta. 1993; 220: 145-156Crossref PubMed Scopus (9) Google Scholar). Overall, these data confirm the regulatory role of BALT in microbial stimulation, rather than a role as a key player in transplant rejection. As for this case, several potential triggers for initiating BALT-formation and lymphoid follicles can be identified: colonization/infections with P. aeruginosa, recurrent pulmonary aspergillosis and gastric aspiration, known to induce epithelial injury and airway inflammation; and possibly also recurrent acute cellular rejections and EBV-reactivation. It is, however, remarkable that despite maintenance therapy with corticosteroids, immunosuppressives and macrolides, these follicular lesions did develop. Possibly the intensity and prolonged duration of the epithelial contact with the various triggers initiated a continuous local accumulation of lymphocytes and subsequently the formation of follicular lymphoid aggregates, which could not be blocked by this anti-inflammatory and immunomodulatory therapy. Keeping this in mind, one can also question the transbronchial biopsies during episodes of acute rejection, which besides (grade A) perivascular and interstitial mononuclear infiltrates, also showed marked peribronchiolar infiltration of lymphocytes, generally classified as (grade B) ‘lymphocytic bronchi(oli)tis’ (17Yousem SA Berry GJ Cagle PT et al.Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group..J Heart Lung Transplant. 1996; 15: 1-15PubMed Google Scholar). The latter could retrospectively be interpreted as the presence of excessive BALT or FB, particularly since BAL sIgA levels were increased at the latter episodes (Table 1). It is currently unclear whether FB after LTx represents another, but rare, phenotype of BOS or actually fits into the ‘inflammatory’ (‘Neutrophilic Reversible Allograft Dysfunction’-NRAD) phenotype (18Vanaudenaerde BM Meyts I Vos R et al.A dichotomy in Bronchiolitis Obliterans Syndrome after Lung Transplantation revealed by azithromycin therapy..Eur Respir J. 2008; 32: 832-843Crossref PubMed Scopus (143) Google Scholar) or ‘Exsudative Bronchiolitis’ (EB) recently described (19McManus TE Milne DG Whyte KF Wilsher ML et al.Exudative bronchiolitis after lung transplantation..J Heart Lung Transplant. 2008; 27: 276-281Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar), which both respond well to macrolide treatment and possibly reflect the same clinical picture. Concerning the latter, EB is a mere descriptive HRCT pattern of small airways disease with airway wall thickening and surrounding inflammation, causing centrilobular nodules, ‘tree-in-bud’ lines, lobular consolidation and mild bronchiectasis. Therefore, as this shows much similarity with the radiological pattern seen in FB, it would have been interesting to have more histological information (particularly about peribronchiolar lymphoid aggregates) of the patients described in the latter case series. Finally, it needs to be emphasized that in the current case there was neither evidence for PTLD nor for peribronchiolar fibrosis or luminal obliteration, clearly distinguishing FB from classical ‘obliterative bronchiolitis’ (OB) as a cause of BOS. In conclusion, we herein describe the first case of FB after LTx, presenting as chronic allograft dysfunction or BOS. When cardinal CT findings, including centrilobular nodules, ‘tree-in-bud’ lines, patchy ground-glass opacities and bronchiectasis are present; one should consider the presence of FB and an empirical treatment with corticosteroids or macrolides may be warranted. However, since the clinical and radiological findings can mimic other conditions after LTx, misclassification may be possible when histology is absent. Therefore, exclusion of other conditions (e.g. PTLD) and formal histological confirmation remains essential. As proper histology using transbronchial biopsies may not always be feasible, open lung biopsy or less invasive CT-guided true-cut needle biopsy may be required, depending on the radiological presentation and local experience. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript.
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