Case-Based Review

Management of Late Pulmonary Complications After Hematopoietic Stem Cell Transplantation

2018 March/April;13(2):41-48

References

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21. Meyer KC, Raghu G, Verleden GM, et al. An international ISHLT/ATS/ERS clinical practice guideline: diagnosis and management of bronchiolitis obliterans syndrome. Eur Respir J 2014;44:1479–1503.

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23. Carpenter PA, Kitko CL, Elad S, et al. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group Report. Biol Blood Marrow Transplant 2015;21:1167–87.

24. Norman BC, Jacobsohn DA, Williams KM, et al. Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transplant 2011;46:1369–73.

25. Williams KM, Cheng GS, Pusic I, et al. Fluticasone, azithromycin, and montelukast treatment for new-onset bronchiolitis obliterans syndrome after hematopoietic cell transplantation. Biol Blood Marrow Transplant 2016;22:710–6.

26. Or R, Gesundheit B, Resnick I, et al. Sparing effect by montelukast treatment for chronic graft versus host disease: a pilot study. Transplantation 2007;83:577–81.

27. Cheng GS, Storer B, Chien JW, et al. Lung function trajectory in bronchiolitis obliterans syndrome after allogeneic hematopoietic cell transplant. Ann Am Thorac Soc 2016;13:1932–9.

28. Bergeron A, Belle A, Chevret S, et al. Combined inhaled steroids and bronchodilatators in obstructive airway disease after allogeneic stem cell transplantation. Bone Marrow Transplant 2007;39:547–53.

29. Bashoura L, Gupta S, Jain A, et al. Inhaled corticosteroids stabilize constrictive bronchiolitis after hematopoietic stem cell transplantation. Bone Marrow Transplant 2008;41:63–7.

30. Bergeron A, Chevret S, Granata A, et al. Effect of azithromycin on airflow decline-free survival after allogeneic hematopoietic stem cell transplant: the ALLOZITHRO randomized clinical trial. JAMA 2017;318:557–66.

31. Gerhardt SG, McDyer JF, Girgis RE, et al. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome: results of a pilot study. Am J Respir Crit Care Med 2003;168:121–5.

32. Khalid M, Al Saghir A, Saleemi S, et al. Azithromycin in bronchiolitis obliterans complicating bone marrow transplantation: a preliminary study. Eur Respir J 2005;25:490–3.

33. Maimon N, Lipton JH, Chan CK, Marras TK. Macrolides in the treatment of bronchiolitis obliterans in allograft recipients. Bone Marrow Transplant 2009;44:69–73.

34. Lam DC, Lam B, Wong MK, et al. Effects of azithromycin in bronchiolitis obliterans syndrome after hematopoietic SCT--a randomized double-blinded placebo-controlled study. Bone Marrow Transplant 2011;46:1551–6.

35. Yadav H, Peters SG, Keogh KA, et al. Azithromycin for the treatment of obliterative bronchiolitis after hematopoietic stem cell transplantation: a systematic review and meta-analysis. Biol Blood Marrow Transplant 2016;22:2264–9.

36. Vos R, Vanaudenaerde BM, Verleden SE, et al. A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation. Eur Respir J 2011;37:164–72.

37. Svanstrom H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med 2013;368:1704–12.

38. Albert RK, Connett J, Bailey WC, et al. Azithromycin for prevention of exacerbations of COPD. N Engl J Med 2011;365:689–98.

39. Tran J, Norder EE, Diaz PT, et al. Pulmonary rehabilitation for bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2012;18:1250–4.

40. Lucid CE, Savani BN, Engelhardt BG, et al. Extracorporeal photopheresis in patients with refractory bronchiolitis obliterans developing after allo-SCT. Bone Marrow Transplant 2011;46:426–9.

41. Hostettler KE, Halter JP, Gerull S, et al. Calcineurin inhibitors in bronchiolitis obliterans syndrome following stem cell transplantation. Eur Respir J 2014;43:221–32.

42. Holm AM, Riise GC, Brinch L, et al. Lung transplantation for bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: unresolved questions. Transplantation 2013;96:e21–22.

43. Cheng GS, Edelman JD, Madtes DK, et al. Outcomes of lung transplantation after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2014;20:1169–75.

44. Okumura H, Ohtake S, Ontachi Y, et al. Living-donor lobar lung transplantation for broncho-bronchiolitis obliterans after allogeneic hematopoietic stem cell transplantation: does bronchiolitis obliterans recur in transplanted lungs? Int J Hematol 2007;86:369–73.

45. Olivieri A, Cimminiello M, Corradini P, et al. Long-term outcome and prospective validation of NIH response criteria in 39 patients receiving imatinib for steroid-refractory chronic GVHD. Blood 2013;122:4111–8.

46. Rahmanian S, Wood KL. Bronchiolitis obliterans and the risk of pneumothorax after transbronchial biopsy. Respiratory Medicine CME 2010;3:87–9.

47. Sakai R, Kanamori H, Nakaseko C, et al. Air-leak syndrome following allo-SCT in adult patients: report from the Kanto Study Group for Cell Therapy in Japan. Bone Marrow Transplant 2011;46:379–84.

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49. Cordier JF. Cryptogenic organising pneumonia. Eur Respir J 2006;28:422–46.

50. Nishio N, Yagasaki H, Takahashi Y, et al. Late-onset non-infectious pulmonary complications following allogeneic hematopoietic stem cell transplantation in children. Bone Marrow Transplant 2009;44:303–8.

51. Ueda K, Watadani T, Maeda E, et al. Outcome and treatment of late-onset noninfectious pulmonary complications after allogeneic haematopoietic SCT. Bone Marrow Transplant 2010;45:1719–27.

52. Schlemmer F, Chevret S, Lorillon G, et al. Late-onset noninfectious interstitial lung disease after allogeneic hematopoietic stem cell transplantation. Respir Med 2014;108:1525–33.

53. Palmas A, Tefferi A, Myers JL, et al. Late-onset noninfectious pulmonary complications after allogeneic bone marrow transplantation. Br J Haematol 1998;100:680–7.

54. Sakaida E, Nakaseko C, Harima A, et al. Late-onset noninfectious pulmonary complications after allogeneic stem cell transplantation are significantly associated with chronic graft-versus-host disease and with the graft-versus-leukemia effect. Blood 2003;102:4236–42.

55. Solh M, Arat M, Cao Q, et al. Late-onset noninfectious pulmonary complications in adult allogeneic hematopoietic cell transplant recipients. Transplantation 2011;91:798–803.

56. Dandoy CE, Hirsch R, Chima R, et al. Pulmonary hypertension after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2013;19:1546–56.

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62. Kovalszki A, Schumaker GL, Klein A, et al. Reduced respiratory and skeletal muscle strength in survivors of sibling or unrelated donor hematopoietic stem cell transplantation. Bone Marrow Transplant 2008;41:965–9.

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The 2005 National Institutes of Health (NIH) consensus development project on criteria for clinical trials in chronic GVHD developed a clinical strategy for diagnosing BOS using the following criteria: absence of active infection, decreased forced expiratory volume in 1 second (FEV₁) < 75%, FEV₁/forced vital capacity (FVC) ratio of < 70%, and evidence of air trapping on high-resolution computed tomography (HRCT) or PFTs (residual volume > 120%). These diagnostic criteria were applied to a small series of patients with clinically identified bronchiolitis obliterans or biopsy-proven bronchiolitis obliterans. Only 18% of these patients met the requirements for the NIH consensus definition.⁵ A 2011 study that applied the NIH criteria found an overall prevalence of 5.5% among all transplant recipients but a prevalence of 14% in patients with GVHD.⁹ In 2014, the NIH consensus development group updated their recommendations. The new criteria for diagnosis of BOS require the presence of airflow obstruction (FEV₁/FVC < 70% or 5^th percentile of predicted), FEV₁ < 75% predicted with a ≥ 10% decline in fewer than 2 years, absence of infection, and presence of air trapping (by expiratory computed tomography [CT] scan or PFT with residual volume >120% predicted) (Table 2).

When there is another manifestation of chronic GVHD, only the first 3 criteria are necessary.¹⁰

Some issues must be considered when determining airflow obstruction. The 2005 NIH working group recommends using Crapo as the reference set,¹¹ but the National Health and Nutrition Examination Survey (NHANES) III reference values are the preferred reference set at this time¹² and should be used in the United States. A recent article showed that the NHANES values were superior to older reference sets (however, they did not use Crapo as the comparison), although this study used the lower limit of normal as compared with the fixed 70% ratio.¹³ The 2014 NIH consensus group does not recommend a specific reference set and recognizes an FEV₁/FVC ratio of 70% or less than the lower limit of normal as the cutoff value for airflow obstruction.¹⁰

Another issue in PFT interpretation is the finding of a decrease in FEV1 and FVC and normal total lung capacity, which is termed a nonspecific pattern. This pattern has been reported to occur in 9% of all PFTs and usually is associated with obstructive lung disease or obesity.¹⁴ A 2013 study described the nonspecific pattern as a BOS subgroup occurring in up to 31% of bronchiolitis obliterans patients.¹⁵

What are the radiographic findings of BOS?

Chest radiograph is often normal in BOS. As discussed, air trapping can be documented using HRCT, according to the NIH clinical definition of bronchiolitis obliterans.¹⁶ A study that explored findings and trends seen on HRCT in HSCT patients with BOS found that the syndrome in these patients is characterized by central airway dilatation.¹⁷ Expiratory airway trapping on HRCT is the main finding, and this is best demonstrated on HRCT during inspiratory and expiratory phases.¹⁸ Other findings are bronchial wall thickening, parenchymal hypoattenuation, bronchiectasis, and centrilobular nodules.¹⁹

Galbán and colleagues developed a new technique called parametric response mapping that uses CT scanners to quantify normal parenchyma, functional small airway disease, emphysema, and parenchymal disease as relative lung volumes.²⁰ This technique can detect airflow obstruction and small airway disease and was found to be a good method for detecting BOS after HSCT. In their study of parametric response mapping, the authors found that functional small airway disease affecting 28% or more of the total lung was highly indicative of bronchiolitis obliterans.²⁰

What therapies are used to treat BOS?

Traditionally, BOS has been treated with systemic immunosuppression. The recommended treatment had been systemic steroids at approximately 1 mg/ kg. However, it is increasingly recognized that BOS responds poorly to systemic steroids, and systemic steroids may actually be harmful and associated with increased mortality.^15,21 The chronic GVHD recommendations from 2005 recommend ancillary therapy with inhaled corticosteroids and pulmonary rehabilitation.¹¹The updated 2011 German consensus statement lays out a clear management strategy for mild and moderate-severe disease with monitoring recommendations.²² The 2014 NIH chronic GVHD working group recommends fluticasone, azithromycin, and montelukast (ie, the FAM protocol) for treating BOS.²³ FAM therapy in BOS may help lower the systemic steroid dose.^24,25 Montelukast is not considered a treatment mainstay for BOS after lung transplant, but there is a study showing possible benefit in chronic GVHD.²⁶ An evaluation of the natural history of a cohort of BOS patients treated with FAM therapy showed a rapid decline of FEV₁ in the 6 months prior to diagnosis and treatment of BOS and subsequent stabilization following diagnosis and treatment.²⁷ The benefit of high-dose inhaled corticosteroids or the combination of inhaled corticosteroids and long-acting beta-agonists has been demonstrated in small studies, which showed that these agents stabilized FEV₁ and avoided the untoward side effects of systemic corticosteroids.^28–30

Macrolide antibiotics have been explored as a treatment for BOS post HSCT because pilot studies suggested that azithromycin improved or stabilized FEV₁ in patients with BOS after lung transplant or HSCT.^31–33 Other studies of azithromycin have not shown benefit in the HSCT population after 3 months of therapy.³⁴ A recent meta-analysis could neither support or refute the benefit of azithromycin for BOS after HSCT.³⁵ In the lung transplant population, a study showed that patients who were started on azithromycin after transplant and continued on it 3 times a week had improved FEV₁; these patients also had a reduced rate of BOS and improved overall and BOS-free survival 2 years after transplant.³⁶ However, these benefits of azithromycin have not been observed in patients after HSCT. In fact, the ALLOZITHRO trial was stopped early because prophylactic azithromycin started at the time of the conditioning regimen with HSCT was associated with increased hematologic disease relapse, a decrease in airflow-decline-free survival, and reduced 2-year survival.³⁰