Lung injury occurs frequently following HSCT and significantly contributes to morbidity and mortality in the immediate post transplant period and in the months and years that follow.
52.1. Introduction
Lung injury occurs frequently following HSCT and significantly contributes to morbidity and mortality in the immediate post transplant period and in the months and years that follow. It can be observed in 25–55% of recipients (Cooke and Yanik 2016).
Historically, approximately half of all pulmonary complications seen after HSCT were secondary to infection, but the judicious use of broad-spectrum antimicrobial agents has tipped the balance toward noninfectious causes.
Noninfectious lung injury following HSCT may be mediated by either immune or nonimmune mechanisms and could represent up to the 50% of noninfectious mortality after allo-HSCT.
These complications have been classified by the American Thoracic Society according to the tissue primarily injured and its etiology (Panoskaltsis-Mortari et al. 2011) (Table ).
Noninfectious pulmonary complications after HSCTa
52.2. Diagnostic Methodology of Pulmonary Complications
Ideally, any respiratory/pulmonary complication observed after HSCT must be evaluated following a predetermined institutional protocol (Lucena et al. 2014), which should include:
- 1.
Noninvasive tests: Blood samples for culture and antigen determination, sputum culture, nasopharyngeal swabs testing CMV, respiratory syncytial virus (RSV), Legionella, Pneumocystis jirovecii (PJ), parainfluenza virus (PIV), adenovirus (ADV), as well as urinary antigen tests and chest x-ray.
- 2.
If negative → empirical treatment (variable behavior; some centers start empirical treatment before the BAL, but many others start the treatment after BAL).
- 3.
If no response in a maximum of 2–3 days (or if galactomannan (GM) +) →
- (a)
High-resolution chest-computed tomography (HRCT).
- (b)
Fiber-optic bronchoscopy (FOB) including bronchial aspiration and BAL to analyze: PCR for Legionella, Mycoplasma, Chlamydia, herpesvirus (all), polyomavirus, ADV, parvovirus, enterovirus, and respiratory virus (RSV; influenza a, B, and C; PIV types 1–4; rhinovirus; bocavirus; metapneumovirus; and others) and GM.
- 4.
In some selected cases, a transbronchial biopsy could be considered.
52.2.1. Results Reported Using this Methodology (Seo et al. 2015; Lucena et al. 2014; Shannon et al. 2010)
Diagnostic yield could be as high as 80%.
Sixty percent of diagnosis is achieved with noninvasive techniques.
FOB/BAL permits an etiological diagnosis in up to 78% of cases.
In suspected IPS, a BAL study may detect a pathogen in ~50% of cases.
For pathogen detection, early FOB (<5 days) offer better yield than late FOB.
The risk of complications with FOB is <5%.
52.3. Pulmonary Edema Due to Fluid Overload
Despite not being included in most classifications of pulmonary complications after HSCT, pulmonary edema (PE) as a consequence of a fluid overload (FO) is extremely frequent (Rondón et al. 2017).
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| Incidence | FO may be observed in up to 60% of patients in the first days after HSCT. The exact incidence of PE is not established although it could be higher than 20% |
| Symptoms and signs | – Weight gain, moderate breathlessness, nonproductive cough, moderate hypoxemia
– Crackles and rales in both lung bases
– Chest radiology with diffuse alveolar/interstitial infiltrates |
| Diagnosis | PE should be suspected in the context of weight gain, an increased cardiothoracic index, and crackles/rales. Though rarely necessary, the diagnosis can be confirmed by pulmonary pressure measurements |
| Differential diagnosis | – Heart failure (prior anthracycline toxicity or conditioning with CY)
– Endothelial syndromes: SOS, CLS, ES (see Chaps. 42 and 49)
– Respiratory tract infections
– Post transfusion reactions |
| Treatment | Hydro-saline restriction, diuretics |
52.4. Idiopathic Pneumonia Syndrome
52.4.1. Definition
Widespread alveolar injury in absence of active lower respiratory tract infection, cardiac or renal dysfunction, and iatrogenic fluid overload (Clark et al. 1993; Panoskaltsis-Mortari et al. 2011)
52.4.2. Clinical Manifestations
Characterized by development around day +20 after HSCT of fever and nonproductive cough, dyspnea, tachypnea, hypoxemia, rales, and diffuse alveolar or interstitial infiltrates on x-rays or CT scans.
52.4.3. Diagnosis
All of the following must be present for accepting the IPS diagnosis:
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| 1. Evidence of widespread alveolar injury
|
(a) Multilobar infiltrates on chest radiographs or CT
(b) Symptoms and signs of pneumonia (cough, dyspnea, tachypnea, crackles/rales)
(c) Evidence of abnormal pulmonary physiology
Increased alveolar to arterial oxygen difference; need for supplemental O2 therapy
New or increased restrictive PFTs abnormality |
| 2. Absence of active lower respiratory tract infection based upon
|
(a) BAL negative for significant bacterial pathogens including acid-fast bacilli, Nocardia, and Legionella species
(b) BAL negative for pathogenic nonbacterial microorganisms (Note of the authors: Most of the following diagnostic methods despite included in the initial diagnostic methodology have nowadays largely been replaced by PCR techniques)
Routine culture for viruses and fungi
Shell vial culture for CMV and respiratory RSV
Cytology for CMV inclusions, fungi, and Pneumocystis jirovecii
Direct fluorescence staining with antibodies against CMV, RSV, HSV, VZV, influenza virus, parainfluenza virus, adenovirus, and other organisms
(c) Other organisms/tests to also consider:
PCR for human metapneumovirus, rhinovirus, coronavirus, and HHV6
PCR for Chlamydia, Mycoplasma, and Aspergillus spp.
Serum and BAL fluid GM for Aspergillus species
(d) Transbronchial biopsy if condition of the patient permits |
| 3. Absence of
|
| Cardiac dysfunction, acute renal failure, or iatrogenic fluid overload as etiology for pulmonary dysfunction |
52.4.4. Pathogenesis, Incidence, Presentation, and Risk Factors
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| Pathogenesis | The pathophysiology of IPS is complex. Data generated using experimental models support that IPS is a process in which the lung is susceptible to two distinct but interrelated pathways of immune-mediated injury: a T-cell axis and an inflammatory cytokine axis. These distinct but related pathways of inflammation culminate in the recruitment of immune cells to the lung leading to tissue damage and dysfunction (Cooke and Yanik 2016) |
| Incidence | – The strict methodology required to establish IPS diagnosis and the increased use of RIC have reduced its incidence of 20% to 25% observed 20 years ago (at that time IPS was called idiopathic pneumonia)
– This reduction runs in parallel of the improvement in the diagnostic methodologies to detect infectious pathogens. However, the frequent absence of response to the specific treatment against a detected pathogen suggests that the true incidence of IPS may be underestimated
– Nowadays: <10% of allo-HSCT (8% after MAC; 2% after RIC) |
| Timing | – Within first 120 days after BMT, usually observed between days +18 and +21 (20 years ago: around days +40 to +50)
– Late IPS can be observed but they are exceptional (Thompson et al. 2017) |
| Risk factors (from Cooke and Yanik 2016) | Older age / Karnofsky index <90 / higher interval diagnosis-HSCT
MAC or TBI (≥12 Gy) / HLA disparity / GVHD prophylaxis with MTX
Acute GVHD/previous viral infection / other malignancies than leukemia |
52.4.5. Treatment and Prognosis
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| Supportive measures | – Supplemental O2 therapy
– Mechanical ventilation (invasive or not [high-flow nasal O2, CPAP])
– Empiric broad-spectrum antimicrobials
– Strict control of fluids balance/hemofiltration |
| Specific treatment | As mentioned, lung injury in IPS can occur through two pathways, the TNF-alfa/LPS dependent and IL6/IL17 dependent (Cooke and Yanik 2016); consequently, treatment options are focused in these directions
• Methyl-PDN ≤ 2 mg/kg/d; if not clear response, consider as soon as possible:
• Anti-TNFα: Etanercept 0.4 mg/kg twice weekly (maximum of 8 doses) + systemic steroids (2 mg/kg/d). The randomized study of etanercept + steroids vs. steroids + placebo was terminated prematurely due to slow accrual. In the limited number of patients examined, there were no differences in response rates (≈60%) at day +28. These results do not necessarily imply that this agent is not effective (lack of evidence does not imply lack of effectiveness) (Yanik et al. 2014). In a phase II trial in children, the CR rate was 71% and 1 y survival was 63% (Yanik et al. 2015). This combination has also been shown to be effective in exceptional cases of late IPS with a 42% of CR and a 2 y survival of 62% among responders (Thompson et al. 2017)
• Other investigational agents such as
– MoAb anti-IL6: Tocilizumab (experimental IPS; Varelias et al. 2015)
– MoAb anti-IL17: Brodalumab (experimental IPS; Varelias et al. 2015) |
| Evolution | Despite the diagnosis and therapeutic advances, the mortality from IPS remains high at 59–80% at ≈2 weeks of evolution (95% if mechanical ventilation is required) |
52.5. Diffuse Alveolar Hemorrhage (DAH)
Diffuse alveolar hemorrhage (DAH) is a relevant cause of acute respiratory failure that occurs in 2–14% of recipients, with similar incidence in both auto- and allo-HSCT recipients (Afessa et al. 2002a).
DAH is probably a consequence of damage to the alveolar capillary basement membrane (see Chap. 42). It is difficult to differentiate a true DAH from the alveolar hemorrhage associated with an infection (Majhail et al. 2006).
52.5.1. Clinical Aspects of DAH
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| Clinical manifestations | Usually observed within the first month after HSCT (a median of 23 days), often during the pre-engraftment phase; however, later onset is encountered in up to 42% of cases
The clinical manifestations are those of all IPS. Hemoptysis is exceptional |
| Diagnosis | Based on BAL: Same criteria as IPS plus a differential characteristic; the progressive bloodier return of BAL fluid aliquots, in at least three segmental bronchi, indicating the presence of blood in the alveoli (or 20% hemosiderin-laden macrophage, although their absence does not exclude the diagnosis as it can take 72 h to appear). Note: DAH can have infectious or noninfectious etiologies (Majhail et al. 2006) |
| Risk factors | – Higher incidence after TBI and high-dose CY
– Similar incidence among MAC and RIC
– There is no correlation with the platelet counts |
| Differential diagnosis with | – Classic IPS: Very difficult, only by means of BAL. IPS usually appears after the engraftment, predominates in allo-HSCT, does not respond to steroids, and progresses to fibrosis in 85% of cases (only 15% on DAH). Note: Noninfectious DAH falls under the “diagnostic umbrella” of IPS (Panoskaltsis-Mortari et al. 2011)
– PERDS: Almost impossible except for LBA progressively bloodier
– Pulmonary hemorrhage: By FOB, no blood is seen in DAH
– DAH associated with infection: Impossible without detection of the pathogen (Majhail et al. 2006) |
52.5.2. Treatment and Prognosis of DAH
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| Treatment | – Although systematically treated with high doses of methyl-PDN (250–500 mg q6h × 5 days, followed by tapered dosage over 2–4 weeks) and aminocaproic acid (ACA), the overall response to this treatment is disappointing (Rathi et al. 2015)
– A recent study seems to show that the best treatment is to use low steroid doses (≤250 mg/d) ± ACA (Rathi et al. 2015)
– Factor VIIa addition does not appear to improve the results obtained with PDN (Elinoff et al. 2014)
– Try to avoid mechanical ventilation by means of CPAP |
| Prognosis | – Poor: Overall mortality as high as 85% by day 100 (Rathi et al. 2015)
– Less than 15% of patients die as a direct consequence of DAH, but the frequent evolution to MOF increases mortality to >60% (30% in auto and 70% in allo-HSCT) (Afessa et al. 2002b)
– DAH that appear early after allo-HSCT (32% early vs. 70% late) or after auto-HSCT have a better prognosis (Afessa et al. 2002b; Majhail et al. 2006) |
52.6. Late-Onset Noninfectious Pulmonary Complications (LONIPC)
In addition to late-onset IPS mentioned before and some other exceptional complications (thromboembolisms, pneumomediastinum), there are two forms of chronic pulmonary dysfunction commonly observed in patients surviving more than 100 days after allo-HSCT. One is an obstructive lung disease (bronchiolitis obliterans syndrome, BOS) and the other a restrictive lung disease (cryptogenetic organizing pneumonia, COP).
A recent prospective study showed that among 198 patients included after day +100, the cumulative incidence of LONIPC is 20%, and that of BOS is 11% at 3 years among allo-HSCT recipients (Bergeron et al. 2018). Another study shows the impact of these complications on 5-year survival (28% with vs. 87% w/o LONIPC) (Nishio et al. 2009).
52.6.1. Bronchiolitis Obliterans Syndrome (BOS)
Pathogenesis, timing, incidence, clinical manifestations, diagnosis, and radiology of BOS are shown in Table .
Main clinical characteristics of BOS
Treatment and prognosis of BOS are included in Table .
Treatment and prognosis of BOS
52.6.2. Cryptogenetic Organizing Pneumonia (COP)
Formerly called BOOP (bronchiolitis obliterans with organizational pneumonia). COP is a LONIPC of that is associated with restrictive pulmonary dysfunction. Reportedly, the incidence of COP among HSCT recipients is increasing due to the use of transbronchial biopsies as diagnostic tool. The greatest diagnostic challenge is the differentiation of COP from BOS (see Table ) (Yoshihara et al. 2007; Cooke et al. 2017).
Differential diagnosis between BOS and COP
Key Points
Lung injury occurs frequently following HSCT and significantly contributes to morbidity and mortality in the immediate post transplant period and in the months and years that follow. It can be observed in 25–55% of recipients.
Noninfectious lung injury following HSCT may be mediated by either immune or nonimmune mechanisms and could represent up to the 50% of noninfectious mortality after allo-HSCT.
Most relevant noninfectious early pulmonary complications are pulmonary edema by fluid overflow, idiopathic pneumonia syndrome, and diffuse alveolar hemorrhage, a vascular endothelial syndrome.
The most relevant late-onset noninfectious pulmonary complications are bronchiolitis obliterans and cryptogenetic organizing pneumonia.
All of them have specific diagnostic criteria, management, treatment, and prognosis.
References
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. 2002a;166:1364–8. [
PubMed: 12406834] [
CrossRef]
Afessa B, Tefferi A, Litzow MR, et al. Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients. Am J Respir Crit Care Med. 2002b;166:641–5. [
PubMed: 12204858] [
CrossRef]
Bergeron A, Chevret S, Chagnon K, et al. Budesonide/formoterol for bronchiolitis obliterans after hematopoietic stem cell transplantation. Am J Respir Crit Care Med. 2015;191:1242–9. [
PubMed: 25835160] [
CrossRef]
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. [
PMC free article: PMC5817485] [
PubMed: 28787506] [
CrossRef]
Cheng GS, Edelman JD, Madtes DK, Martin PJ, Flowers ME. Outcomes of lung transplantation after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2014;20:1169–75. [
PubMed: 24727334] [
CrossRef]
Chien JW, Duncan S, Williams KM, Pavletic SZ. Bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation-an increasingly recognized manifestation of chronic graft versus-host disease. Biol Blood Marrow Transplant. 2010;16(1 Suppl):S106–14. [
PMC free article: PMC3189470] [
PubMed: 19896545] [
CrossRef]
Clark JG, Hansen JA, Hertz MI, et al. NHLBI workshop summary. Idiopathic pneumonia syndrome after bone marrow transplantation. Am Rev Respir Dis. 1993;147(6 Pt. 1):1601–6. [
PubMed: 8503576] [
CrossRef]
Cooke KR, Yanik GA. Lung injury following hematopoietic cell transplantation. In: Forman SJ, Negrin RS, Antin JH, Appelbaum FR, editors. Thomas’ hematopoietic cell transplantation. 5th ed. Hoboken: Wiley; 2016. p. 1157–70.
Cooke KR, Luznik L, Sarantopoulos S, et al. The biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-Versus-Host Disease. Biol Blood Marrow Transplant. 2017;23:211–34. [
PMC free article: PMC6020045] [
PubMed: 27713092] [
CrossRef]
Majhail NS, Parks K, Defor TE, Weisdorf DJ. Diffuse alveolar hemorrhage and infection-associated alveolar hemorrhage following hematopoietic stem cell transplantation: related and high-risk clinical syndromes. Biol Blood Marrow Transplant. 2006;12:1038–46. [
PubMed: 17067910] [
CrossRef]
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. [
PubMed: 19349954] [
CrossRef]
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. [
PMC free article: PMC3266140] [
PubMed: 21531955] [
CrossRef]
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. [
PubMed: 25531284] [
CrossRef]
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. [
PubMed: 19684637] [
CrossRef]
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. 2017;23:1955–60. [
PubMed: 28757436] [
CrossRef]
Uhlving HH, Buchvald F, Heilmann CJ, et al. Bronchiolitis obliterans after allo-SCT: clinical criteria and treatment options. Bone Marrow Transplant. 2012;47:1020–9. [
PubMed: 21874057] [
CrossRef]
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. [
PMC free article: PMC4801753] [
PubMed: 26475726] [
CrossRef]
Yanik GA, Grupp SA, Pulsipher MA, et al. TNF-receptor inhibitor therapy for the treatment of children with idiopathic pneumonia syndrome. A joint Pediatric Consortium and Children’s Oncology Group Study (ASCT0521). Biol Blood Marrow Transplant. 2015;21:67–73. [
PMC free article: PMC4286345] [
PubMed: 25270958] [
CrossRef]
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. Biol Blood Marrow Transplant. 2014;20:858–64. [
PMC free article: PMC4128626] [
PubMed: 24607553] [
CrossRef]
Yanik GA, Mineishi S, Levine JE, et al. Soluble tumor necrosis factor receptor: enbrel (etanercept) for sub-acute pulmonary dysfunction following allogeneic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18:1044–54. [
PMC free article: PMC4462521] [
PubMed: 22155140] [
CrossRef]
Yoshihara S, Yanik G, Cookee KR, Mineishi S. Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2007;13:749–79. [
PubMed: 17580252] [
CrossRef]
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