Case-Based Review

Management of Early Pulmonary Complications After Hematopoietic Stem Cell Transplantation

2018 January/February;13(1):36-48

References

1. Gratwohl A, Baldomero H, Aljurf M, et al. Hematopoietic stem cell transplantation: a global perspective. JAMA 2010;303:1617–24.

2. Kotloff RM, Ahya VN, Crawford SW. Pulmonary complications of solid organ and hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2004;170:22–48.

3. Matulis M, High KP. Immune reconstitution after hematopoietic stem-cell transplantation and its influence on respiratory infections. Semin Respir Infect 2002;17:130–9.

4. Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med 2006;354:1813–26.

5. Anasetti C, Logan BR, Lee SJ, et al. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med 2012;367:1487–96.

6. Giralt S, Ballen K, Rizzo D, et al. Reduced-intensity conditioning regimen workshop: defining the dose spectrum. Report of a workshop convened by the center for international blood and marrow transplant research. Biol Blood Marrow Transplant 2009;15:367–9.

7. Shulman HM, Kleiner D, Lee SJ, et al. Histopathologic diagnosis of chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: II. Pathology Working Group Report. Biol Blood Marrow Transplant 2006;12:31–47.

8. Afessa B, Abdulai RM, Kremers WK, et al. Risk factors and outcome of pulmonary complications after autologous hematopoietic stem cell transplant. Chest 2012;141:442–50.

9. Bolwell BJ. Are predictive factors clinically useful in bone marrow transplantation? Bone Marrow Transplant 2003;32:853–61.

10. Carlson K, Backlund L, Smedmyr B, et al. Pulmonary function and complications subsequent to autologous bone marrow transplantation. Bone Marrow Transplant 1994;14:805–11.

11. Clark JG, Schwartz DA, Flournoy N, et al. Risk factors for airflow obstruction in recipients of bone marrow transplants. Ann Intern Med 1987;107:648–56.

12. Crawford SW, Fisher L. Predictive value of pulmonary function tests before marrow transplantation. Chest 1992; 101:1257–64.

13. Ghalie R, Szidon JP, Thompson L, et al. Evaluation of pulmonary complications after bone marrow transplantation: the role of pretransplant pulmonary function tests. Bone Marrow Transplant 1992;10:359–65.

14. Ho VT, Weller E, Lee SJ, et al. Prognostic factors for early severe pulmonary complications after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001;7:223–9.

15. Horak DA, Schmidt GM, Zaia JA, et al. Pretransplant pulmonary function predicts cytomegalovirus-associated interstitial pneumonia following bone marrow transplantation. Chest 1992;102:1484–90.

16. Ramirez-Sarmiento A, Orozco-Levi M, Walter EC, et al. Influence of pretransplantation restrictive lung disease on allogeneic hematopoietic cell transplantation outcomes. Biol Blood Marrow Transplant 2010;16:199–206.

17. White AC, Terrin N, Miller KB, Ryan HF. Impaired respiratory and skeletal muscle strength in patients prior to hematopoietic stem-cell transplantation. Chest 2005;128145–52.

18. Afessa B. Pretransplant pulmonary evaluation of the blood and marrow transplant recipient. Chest 2005;128:8–10.

19. Parimon T, Madtes DK, Au DH, et al. Pretransplant lung function, respiratory failure, and mortality after stem cell transplantation. Am J Respir Crit Care Med 2005;172:384–90.

20. Pavletic SZ, Martin P, Lee SJ, et al. Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. Response Criteria Working Group report. Biol Blood Marrow Transplant 2006;12:252–66.

21. Parimon T, Au DH, Martin PJ, Chien JW. A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med 2006;144:407–14.

22. Au BK, Gooley TA, Armand P, et al. Reevaluation of the pretransplant assessment of mortality score after allogeneic hematopoietic transplantation. Biol Blood Marrow Transplant 2015;21:848–54.

23. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005;106:2912–9.

24. Chien JW, Sullivan KM. Carbon monoxide diffusion capacity: how low can you go for hematopoietic cell transplantation eligibility? Biol Blood Marrow Transplant 2009;15: 447–53.

25. Coffey DG, Pollyea DA, Myint H, et al. Adjusting DLCO for Hb and its effects on the Hematopoietic Cell Transplantation-specific Comorbidity Index. Bone Marrow Transplant 2013;48:1253–6.

26. Kasow KA, Krueger J, Srivastava DK, et al. Clinical utility of computed tomography screening of chest, abdomen, and sinuses before hematopoietic stem cell transplantation: the St. Jude experience. Biol Blood Marrow Transplant 2009;15:490–5.

27. Hamadani M, Craig M, Awan FT, Devine SM. How we approach patient evaluation for hematopoietic stem cell transplantation. Bone Marrow Transplant 2010;45: 1259–68.

28. Savani BN, Montero A, Wu C, et al. Prediction and prevention of transplant-related mortality from pulmonary causes after total body irradiation and allogeneic stem cell transplantation. Biol Blood Marrow Transplant 2005;11:223–30.

29. Ehlers SL, Gastineau DA, Patten CA, et al. The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia. Bone Marrow Transplant 2011;46:285–90.

30. Marks DI, Ballen K, Logan BR, et al. The effect of smoking on allogeneic transplant outcomes. Biol Blood Marrow Transplant 2009;15:1277–87.

31. Tran BT, Halperin A, Chien JW. Cigarette smoking and outcomes after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2011;17:1004–11.

32. Lucena CM, Torres A, Rovira M, et al. Pulmonary complications in hematopoietic SCT: a prospective study. Bone Marrow Transplant 2014;49:1293–9.

33. Chi AK, Soubani AO, White AC, Miller KB. An update on pulmonary complications of hematopoietic stem cell transplantation. Chest 2013;144:1913–22.

34. Dunagan DP, Baker AM, Hurd DD, Haponik EF. Bronchoscopic evaluation of pulmonary infiltrates following bone marrow transplantation. Chest 1997;111:135–41.

35. Naeem N, Reed MD, Creger RJ, et al. Transfer of the hematopoietic stem cell transplant patient to the intensive care unit: does it really matter? Bone Marrow Transplant 2006;37:119–33.

36. Afessa B, Tefferi A, Hoagland HC, et al. Outcome of recipients of bone marrow transplants who require intensive care unit support. Mayo Clin Proc 1992;67:117–22.

37. Parody R, Martino R, de la Camara R, et al. Fungal and viral infections after allogeneic hematopoietic transplantation from unrelated donors in adults: improving outcomes over time. Bone Marrow Transplant 2015;50:274–81.

38. Orasch C, Weisser M, Mertz D, et al. Comparison of infectious complications during induction/consolidation chemotherapy versus allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2010;45:521–6.

39. Aguilar-Guisado M, Jimenez-Jambrina M, Espigado I, et al. Pneumonia in allogeneic stem cell transplantation recipients: a multicenter prospective study. Clin Transplant 2011;25:E629–38.

40. Palacios G, Hornig M, Cisterna D, et al. Streptococcus pneumoniae coinfection is correlated with the severity of H1N1 pandemic influenza. PLoS One 2009;4:e8540.

41. Hynicka LM, Ensor CR. Prophylaxis and treatment of respiratory syncytial virus in adult immunocompromised patients. Ann Pharmacother 2012;46:558–66.

42. Shah JN, Chemaly RF. Management of RSV infections in adult recipients of hematopoietic stem cell transplantation. Blood 2011;2755–63.

43. Marr KA, Bowden RA. Fungal infections in patients undergoing blood and marrow transplantation. Transpl Infect Dis 1999;1:237–46.

44. Wald A, Leisenring W, van Burik JA, Bowden RA. Epidemiology of Aspergillus infections in a large cohort of patients undergoing bone marrow transplantation. J Infect Dis 1997;175:1459–66.

45. Ascioglu S, Rex JH, de Pauw B, et al. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 2002;34:7–14.

46. Fisher CE, Stevens AM, Leisenring W, et al. Independent contribution of bronchoalveolar lavage and serum galactomannan in the diagnosis of invasive pulmonary aspergillosis. Transpl Infect Dis 2014;16:505–10.

47. Kojima R, Tateishi U, Kami M, et al. Chest computed tomography of late invasive aspergillosis after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2005;11:506–11.

48. Salmeron G, Porcher R, Bergeron A, et al. Persistent poor long-term prognosis of allogeneic hematopoietic stem cell transplant recipients surviving invasive aspergillosis. Haematologica 2012;97:1357–63.

49. McNulty JS. Rhinocerebral mucormycosis: predisposing factors. Laryngoscope 1982;92(10 Pt 1):1140.

50. Walsh TJ, Gamaletsou MN, McGinnis MR, et al. Early clinical and laboratory diagnosis of invasive pulmonary, extrapulmonary, and disseminated mucormycosis (zygomycosis). Clin Infect Dis 2012;54 Suppl 1:S55–60.

51. Klingspor L, Saaedi B, Ljungman P, Szakos A. Epidemiology and outcomes of patients with invasive mould infections: a retrospective observational study from a single centre (2005-2009). Mycoses 2015;58:470–7.

52. Danion F, Aguilar C, Catherinot E, et al. Mucormycosis: new developments in a persistently devastating infection. Semin Respir Crit Care Med 2015;36:692–70.

53. Rano A, Agusti C, Jimenez P, et al. Pulmonary infiltrates in non-HIV immunocompromised patients: a diagnostic approach using non-invasive and bronchoscopic procedures. Thorax 2001;56:379–87.

54. Azoulay E, Mokart D, Rabbat A, et al. Diagnostic bronchoscopy in hematology and oncology patients with acute respiratory failure: prospective multicenter data. Crit Care Med 2008;36:100–7.

55. Jain P, Sandur S, Meli Y, et al. Role of flexible bronchoscopy in immunocompromised patients with lung infiltrates. Chest 2004;125:712–22.

56. Rano A, Agusti C, Benito N, et al. Prognostic factors of non-HIV immunocompromised patients with pulmonary infiltrates. Chest 2002;122:253–61.

57. Shannon VR, Andersson BS, Lei X, et al. Utility of early versus late fiberoptic bronchoscopy in the evaluation of new pulmonary infiltrates following hematopoietic stem cell transplantation. Bone Marrow Transplant 2010;45:647–55.

58. Patel NR, Lee PS, Kim JH, et al. The influence of diagnostic bronchoscopy on clinical outcomes comparing adult autologous and allogeneic bone marrow transplant patients. Chest 2005;127:1388–96.

59. Chellapandian D, Lehrnbecher T, Phillips B, et al. Bronchoalveolar lavage and lung biopsy in patients with cancer and hematopoietic stem-cell transplantation recipients: a systematic review and meta-analysis. J Clin Oncol 2015;33:501–9.

60. Carr IM, Koegelenberg CF, von Groote-Bidlingmaier F, et al. Blood loss during flexible bronchoscopy: a prospective observational study. Respiration 2012;84:312–8.

61. Miyamoto M, Onizuka M, Machida S, et al. ACE deletion polymorphism is associated with a high risk of non-infectious pulmonary complications after stem cell transplantation. Int J Hematol 2014;99:175–83.

62. Capizzi SA, Kumar S, Huneke NE, et al. Peri-engraftment respiratory distress syndrome during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;27:1299–303.

63. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;27:893–8.

64. Wanko SO, Broadwater G, Folz RJ, Chao NJ. Diffuse alveolar hemorrhage: retrospective review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid. Biol Blood Marrow Transplant 2006;12:949–53.

65. Metcalf JP, Rennard SI, Reed EC, et al. Corticosteroids as adjunctive therapy for diffuse alveolar hemorrhage associated with bone marrow transplantation. University of Nebraska Medical Center Bone Marrow Transplant Group. Am J Med 1994;96:327–34.

66. Rathi NK, Tanner AR, Dinh A, et al. Low-, medium- and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage. Bone Marrow Transplant 2015;50:420–6.

67. Afessa B, Tefferi A, Litzow MR, Peters SG. Outcome of diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med 2002;166:1364–8.

68. Panoskaltsis-Mortari A, Griese M, Madtes DK, et al. An official American Thoracic Society research statement: noninfectious lung injury after hematopoietic stem cell transplantation: idiopathic pneumonia syndrome. Am J Respir Crit Care Med 2011;183:1262–79.

69. Clark JG, Hansen JA, Hertz MI, Pet al. NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Resp Dis 1993;147:1601–6.

70. Vande Vusse LK, Madtes DK. Early onset noninfectious pulmonary syndromes after hematopoietic cell transplantation. Clin Chest Med 2017;38:233–48.

71. Fukuda T, Hackman RC, Guthrie KA, et al. Risks and outcomes of idiopathic pneumonia syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic hematopoietic stem cell transplantation. Blood 2003;102:2777–85.

72. Englund JA, Boeckh M, Kuypers J, et al. Brief communication: fatal human metapneumovirus infection in stem-cell transplant recipients. Ann Intern Med 2006;144:344–9.

73. Seo S, Renaud C, Kuypers JM, et al. Idiopathic pneumonia syndrome after hematopoietic cell transplantation: evidence of occult infectious etiologies. Blood 2015;125:3789–97.

74. Nakane T, Nakamae H, Kamoi H, et al. Prognostic value of serum surfactant protein D level prior to transplant for the development of bronchiolitis obliterans syndrome and idiopathic pneumonia syndrome following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2008;42:43–9.

75. Gilbert CR, Lerner A, Baram M, Awsare BK. Utility of flexible bronchoscopy in the evaluation of pulmonary infiltrates in the hematopoietic stem cell transplant population—a single center fourteen year experience. Arch Bronconeumol 2013;49:189–95.

76. Yanik GA, Horowitz MM, Weisdorf DJ, et al. Randomized, double-blind, placebo-controlled trial of soluble tumor necrosis factor receptor: enbrel (etanercept) for the treatment of idiopathic pneumonia syndrome after allogeneic stem cell transplantation: blood and marrow transplant clinical trials network protocol. Biol Blood Marrow Transplant 2014;20:858–64.

77. Levine JE, Paczesny S, Mineishi S, et al. Etanercept plus methylprednisolone as initial therapy for acute graft-versus-host disease. Blood 2008;111:2470–5.

78. Yanik GA, Grupp SA, Pulsipher MA, et al. TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Blood and Marrow Transplant Consortium and Children’s Oncology Group Study (ASCT0521). Biol Blood Marrow Transplant 2015;21:67–73.

79. Thompson J, Yin Z, D’Souza A, et al. Etanercept and corticosteroid therapy for the treatment of late-onset idiopathic pneumonia syndrome. Biol Blood Marrow Transplant J 2017; 23:1955–60.

What test should be performed to evaluate for infectious causes of pneumonia?

Role of Flexible Fiberoptic Bronchoscopy

The utility of flexible fiberoptic bronchoscopy (FOB) in immune-compromised patients for the evaluation of pulmonary infiltrates is a frequently debated topic. Current studies suggest a diagnosis can be made in approximately 80% of cases in the immune-compromised population.^32,53 Noninvasive testing such as urine and serum antigens, sputum cultures, Aspergillus galactomannan assays, viral nasal swabs, and PCR studies often lead to a diagnosis in appropriate clinical scenarios. Conservative management would dictate the use of noninvasive testing whenever possible, and randomized controlled trials have shown noninvasive testing to be noninferior to FOB in preventing need for mechanical ventilation, with no difference in overall mortality.⁵⁴ FOB has been shown to be most useful in establishing a diagnosis when an infectious etiology is suspected.⁵⁵ In multivariate analysis, a delay in the identification of the etiology of pulmonary infiltrate was associated with increased mortality.⁵⁶ Additionally, early FOB was found to be superior to late FOB in revealing a diagnosis.^32,57 Despite its ability to detect the cause of pulmonary disease, direct antibiotic therapy, and possibly change therapy, FOB with diagnostic maneuvers has not been shown to affect mortality.⁵⁸ In a large case series, FOB with bronchoalveolar lavage (BAL) revealed a diagnosis in approximately 30% to 50% of cases. The addition of transbronchial biopsy did not improve diagnostic utility.⁵⁸ More recent studies have confirmed that the addition of transbronchial biopsy does not add to diagnostic yield and is associated with increased adverse events.⁵⁹ The appropriate use of advanced techniques such as endobronchial ultrasound–guided transbronchial needle aspirations, endobronchial biopsy, and CT-guided navigational bronchoscopy has not been established and should be considered on a case-by-case basis. In summary, routine early BAL is the diagnostic test of choice, especially when infectious pulmonary complications are suspected.

Contraindications for FOB in this population mirror those in the general population. These include acute severe hypoxemic respiratory failure, myocardial ischemia or acute coronary syndrome within 2 weeks of procedure, severe thrombocytopenia, and inability to provide or obtain informed consent from patient or health care power of attorney. Coagulopathy and thrombocytopenia are common comorbid conditions in the HSCT population. A platelet count of < 20 × 10³/µL has generally been used as a cut-off for routine FOB with BAL.⁶⁰ Risks of the procedures should be discussed clearly with the patient, but simple FOB for airway evaluation and BAL is generally well tolerated even under these conditions.

Early Nonifectious Pulmonary Complications

Case Patient 2 Continued

Bronchoscopy with BAL performed the day after admission is unremarkable and stains and cultures are negative for viral, bacterial, and fungal organisms. The patient is initially started on broad-spectrum antibiotics, but his oxygenation continues to worsen to the point that he is placed on noninvasive positive pressure ventilation. He is started empirically on amphotericin B and eventually is intubated. VATS lung biopsy is ultimately performed and pathology is consistent with diffuse alveolar damage.

Based on these biopsy findings, what is the diagnosis?

Based on the pathology consistent with diffuse alveolar damage, a diagnosis of idiopathic pneumonia syndrome (IPS) is made.

What noninfectious pulmonary complications occur in the early post-transplant period?

The overall incidence of noninfectious pulmonary complications after HSCT is generally estimated at 20% to 30%.³² Acute pulmonary edema is a common very early noninfectious pulmonary complication and clinically the most straightforward to treat. Three distinct clinical syndromes—peri-engraftment respiratory distress syndrome (PERDS), diffuse alveolar hemorrhage (DAH), and IPS—comprise the remainder of the pertinent early noninfectious complications. Clinical presentation differs based upon the disease entity. Recent studies have evaluated the role of angiotensin-converting enzyme polymorphisms as a predictive marker for risk of developing early noninfectious pulmonary complications.⁶¹

Peri-Engraftment Respiratory Distress Syndrome

PERDS is a clinical syndrome comprising the cardinal features of erythematous rash and fever along with noncardiogenic pulmonary infiltrates and hypoxemia that occur in the peri-engraftment period, defined as recovery of absolute neutrophil count to > 500/μL on 2 consecutive days.⁶² PERDS occurs in the autologous HSCT population and may be a clinical correlate to early GVHD in the allogeneic HSCT population. It is hypothesized that the pathophysiology underlying PERDS is an autoimmune-related capillary leak caused by pro-inflammatory cytokine release.⁶³ Treatment remains anecdotal and currently consists of supportive care and high-dose corticosteroids. Some have favored limiting the use of gCSF given its role in stimulating rapid white blood cell recovery.³³ Prognosis is favorable, but progression to fulminant respiratory failure requiring mechanical ventilation portends a poor prognosis.