diseases that primarily involve the pulmonary parenchyma, such as organizing pneumonia (OP), acute interstitial pneumonitis (AIP), and acute respiratory distress syndrome (ARDS), or the vascular endothelium, including periengraftment respiratory distress syndrome (PERDS), noncardiogenic capillary leak syndrome, and diffuse alveolar hemorrhage (DAH) [17–19]. Other early complications of HSCT include secondary pulmonary alveolar proteinosis (PAP) and drug toxicity [10].

IPS is de ned as widespread alveolar injury as evidenced by multilobar airspace disease, without evidence of lower respiratory tract infection, cardiac dysfunction, acute renal failure or iatrogenic fuid overload despite thorough evaluation. The reported incidence rate of IPS ranges from 5% to 10% depending on the type of transplant (autologous or allogeneic) and the conditioning regimen used [17, 20, 21]. Retrospective data have identi ed various risk factors for IPS, including a myeloablative conditioning regimen, especially if total body irradiation is performed, high-grade acute GVHD, older recipient age, and acute leukemia or myelodysplastic syndrome, as reasons for HSCT [22]. IPS occurs at a median of 21 days, usually within the rst 3–7 weeks post-HSCT. An overall mortality rate from IPS as high as 60% has been reported and rises to 100% when mechanical ventilation must be initiated [17, 21]. Currently, the mainstay of treatment remains high-dose systemic corticosteroids, along with usual supportive care [19]. Several drugs have been studied over the years in animal models, but none have found their way into clinical practice at this time. TNF-alpha inhibitors have yielded encouraging results when added to corticosteroids in small retrospective and prospective trials [23–25]. Unfortunately, the rst randomized trial of etanercept combined with corticosteroids versus placebo ended prematurely due to slow accrual [26]. Among the 34 randomized patients, there were no differences in treatment response at 28 days. Other agents currently investigated include keratinocyte growth factor, de brotide, macrolides, N-acetylcysteine, and Th17-suppressing molecules. In light of the heterogeneous nature of IPS, the better characterization of lung involvement post-HSCT will allow for more disease-speci c treatment research.

PERDS is a well-known early HSCT complication that typically occurs within 5 days of engraftment. PERDS occurs due to massive proinfammatory cytokine release following engraftment, resulting in noncardiogenic pulmonary edema from capillary leakage, fever, and rash. PERDS can also involve the liver, kidneys, skin, or gut [19]. Early recognition of PERDS is essential since a good prognosis can be achieved with glucocorticoids. Although PERDS has a favorable initial response to steroids, it has recently been associated with lower overall 2-year survival post-HSCT [27].

Late-Onset Pulmonary Complications

Late-onset noninfectious pulmonary complications (LONIPCs) represent a heterogeneous group of conditions comprising bronchiolitis obliterans syndrome (BOS); interstitial lung diseases (ILDs), including organizing pneumonia, lymphoid interstitial pneumonia, eosinophilic pneumonia, diffuse alveolar damage, acute brinous organizing pneumonia, nonspeci c interstitial pneumonia and pleuroparenchymal broelastosis; vascular diseases (microangiopathy, thromboembolic disease, pulmonary hypertension); and pleural effusion [15]. Many of these diseases have similar presentations to their idiopathic forms [28]. Hence, when evaluating a patient with LONIPC, using a systematic approach similar to that used in any patient with interstitial lung disease (ILD) can be useful. According to a recent prospective observational single-center study called ALLOPULM, which studied more than 200 patients who underwent allogeneic HSCT, LONIPC has a cumulative incidence of 19.8% at 36 months following transplantation [29]. In the same study, the risk factors identi ed included history of chest irradiation prior to HSCT, lower respiratory tract infection within the rst 100 days following HSCT, and low mean forced expiratory fow (MFEF25–75%). The occurrence of LONIPC was associated with a doubled risk of death post-HSCT, underscoring the importance of prompt diagnosis and treatment. The most frequent LONIPC diagnosed was BOS, followed by ILD.

Bronchiolitis Obliterans (BO)

BO is the only condition that has been clearly associated with chronic GVHD. It is also the main LONIPC diagnosed following HSCT [29]. BO usually occurs from 6 months to 2 years post-HSCT but can seldom occur earlier or later [30]. The reported incidence of BO is dif cult to assess due to disparities in the diagnostic criteria used among studies. According to several retrospective data, it ranged from 2% to 26% [20, 30–32]. The incidence increases to 14% in the subpopulation of patients who develop extrathoracic chronic GVHD [33]. More recently, ALLOPULM reported a cumulative incidence of BOS at 36 months of 10.7% [29].

Pathophysiology

The pathophysiology of BO is still not fully understood. Given its correlation with chronic GVHD, it is believed to be related to immune-mediated attack of airway epithelial cells by donor T lymphocytes, as well as B cell stimulation, autoantibody synthesis, and systemic brosis [18]. When examining lung biopsies from patients diagnosed with BO, two different patterns have been observed: lymphocytic and constrictive bronchiolitis obliterans. Lymphocytic in ltration is

located in the bronchiolar wall with a variable degree of infammation and damage, whereas the constrictive pattern involves brous tissue deposition within the submucosa of the bronchium with or without minimal chronic infammation [34]. It is thought that the lymphocytic in ltrate represents the earlier stage of BO, leading to de nitive cicatricial obliteration of the airway lumen. However, the clinical presentation appears to be similar in both histologic subtypes, although the lymphocytic pattern tends to be more treatment responsive. A recent study examining 61 lung biopsies in patients with LONIPC showed a variety of histological patterns that have not been previously described, such as narrowbrous and cellular bronchiolitis or bronchiolectasis [35]. Although some patients had a diagnosis of BO, the authors did not correlate the histopathology ndings with the clinical diagnosis. However, this study suggested that BO might be associated with patterns other than the two histologic subtypes described above.

Diagnosis

A de nite diagnosis of BO is made when there is histological evidence of bronchiolar wall thickening, infammatory brosis and narrowing of the airway lumen [36] (Fig. 40.1b). That said, obtaining a lung biopsy in HSCT patients is challenging given their overall frailty [37]. Hence, in 2014, the NIH updated the previously established diagnostic criteria based on pulmonary function testing to facilitate diagnosis (Table 40.3) [38]. Based on these criteria, the term “bronchiolitis obliterans syndrome” (BOS) appeared to dissociate it from biopsy-proven BO. In the context of extrathoracic chronic GVHD in one separate organ system, a diagnosis of BOS can be made if there is evidence of airway obstruction

a

(FEV1/FVC <0.7 or < fth percentile), FEV1 < 75% of predicted with ≥10% decline over less than 2 years not correcting greater than 75% predicted with albuterol, absence of documented infection and one of the two typical changes on CT scan (air trapping, airway thickening or bronchiectasis) or evidence of air trapping on PFT (RV > 120% or predicted and elevated RV/TLC). That said, it is well known that sig-

Table 40.3  BOS diagnosis criteria NIH 2014

In the presence of a distinctive manifestation of chronic GVHD, the clinical diagnosis of BOS is suf cient to establish the diagnosis of chronic GVHD when all of the following criteria are met:

1  FEV1/vital capacity <0.7 or < the fth percentile of predicted

 (a)  Vital capacity includes forced vital capacity or slow vital capacity, whichever is greater

 (b)  The fth percentile of predicted is the lower limit of the 90% con dence interval

 (c)  For pediatric or elderly patients, use the lower limits of normal, de ned according to National Health and nutrition examination survey III calculations

2  FEV1 < 75% of predicted with ≥10% decline over less than 2 years. FEV1 should not correct to >75% of predicted with albuterol, and the absolute decline for the corrected values should still remain at ≥10% over 2 years

3  Absence of infection in the respiratory tract, documented with investigations directed by clinical symptoms, such as chest radiographs, computed tomographic (CT) scans, or microbiologic cultures (sinus aspiration, upper respiratory tract viral screen, sputum culture, and bronchoalveolar lavage)

4  One of the two supporting features of BOS:

 (a)  Evidence of air trapping by expiratory CT or small airway thickening or bronchiectasis by high-resolution chest CT or

 (b)  Evidence of air trapping by PFTs: Residual

volume > 120% of predicted or residual volume/total lung capacity elevated outside the 90% con dence interval

b

Fig. 40.1  Lung computed tomography (CT) scan (a) and lung biopsy (b) from a patient who was diagnosed with bronchiolitis obliterans 12 months after an allogeneic hematopoietic stem cell transplantation. The CT scan shows a mosaic pattern (a). The histological analysis

shows a bronchiolar wall thickened by infammatory brosis located between the epithelium and the smooth muscle. The airway lumen is narrowed (HES ×100) (b)

ni cant air trapping can lead to a relative decrease in FVC, which can translate into a normal FEV1/FVC ratio despite signi cant airfow obstruction [39, 40]. Given the predominance of small airway involvement in BO, patients develop gas trapping early in the disease process with similar reductions in FEV1 and FVC on initial spirometry, leading to a normal FEV1/FVC ratio. In fact, in the ALLOPULM cohort described above, the patients had variable lung function. Among the 22 patients diagnosed with BOS, 64% had a normal FEV1/FVC ratio at diagnosis, but 91% developed a low FEV1/FVC ratio, indicating airfow obstruction at least once over the 36-month follow-up [29]. Consequently, the NIH criteria, which mandate a ratio of FEV1/FVC <0.7 and at the same time recognize air trapping as a diagnostic criterion, seem inappropriate. In the setting of diagnosed chronic GVHD in one other organ, the presence of lung GVHD can be con rmed solely on the basis of pulmonary function test criteria. However, if there is no other systemic manifestation of chronic GVHD, a lung biopsy is required to ascertain the diagnosis of BO according to the NIH criteria, although it is very rarely performed in clinical practice. Clinically, patients with BOS can present with nonspeci c symptoms, such as progressive dyspnea on exertion, dry cough or wheezing, but they can also be asymptomatic. Computed tomography (CT) of the chest often illustrates hyperinfation with or without mosaic attenuation, bronchiectasis, bronchial thickening, and centrilobular nodules (Fig. 40.1a). Risk factors for BOS that have been identi ed in several retrospective studies include older age of recipient, acute GVHD, busulfan-based conditioning regimen, stem cell source, degree of HLA incompatibility, presence of gastroesophageal refux, gammaglobulin levels, type of GVHD prophylaxis, underlying blood disorder, and tobacco use [15, 30, 32]. In ALLOPULM, early speci c factors were identi ed as predictive of BOS. The most signi cant ones were the use of peripheral blood stem cells; bronchial abnormalities on computed tomography (CT) at 100 days post-HSCT, such as bronchial thickening and centrilobular nodules; the occurrence of lower respiratory tract infection within the rst 100 days following HSCT; and a decrease of ≥10% in FEV1 between pretransplant and day 100 posttransplant pulmonary function testing [29]. The natural history of BOS is unclear. Some studies have suggested that there is a relative stabilization in FEV1 following the initial decline [41]. Additionally, the occurrence of viral lower respiratory tract infections (LRTIs) has been identi ed as a trigger that leads to an abrupt decline in lung function [42]. A recent randomized trial of patients with BOS found an improvement in FEV1 of 200 mL and 12% in 25% of patients in the placebo group [43]. This spontaneous improvement could be related to the natural history of BOS or expected recovery following an LRTI. BOS has been associated with a 1.6-fold increase in mortality after diagnosis [30, 44, 45]. This rate worsens if BOS occurs

within the rst year post-HSCT [32, 44]. Thus, performing systematic PFT following HSCT can help to identify those at increased risk of BOS and allow for early treatment initiation. Similarly, using a handheld spirometer at home was attempted for early recognition of FEV1 decline. Although the measurements were reliable, the poor compliance of patients remained a major obstacle [46].

Management of BOS

Several treatments for BOS have been investigated, but data interpretation of these studies is challenging given their retrospective nature and the poor measurement of treatment response [47]. In fact, some studies have measured general GVHD as an endpoint or considered a stable FEV1 as a good response, although this choice probably refects the natural history of BOS. Given that BOS often occurs with concomitant extrathoracic chronic GVHD, the rst step in management should be to optimize the immunosuppressive regimen, especially if respiratory decline occurs during tapering of these drugs. Systemic steroids can be tried, but their ef cacy in BO has not been clearly established at the expense of increased mortality from infectious complications [48]. Azithromycin alone was one of the rst therapeutic agents studied in a randomized fashion for the treatment of BOS. Unfortunately, it did not show any signi cant difference in absolute FEV1 at 4 months and even a tendency toward a decreased percentage of predicted FEV1 [49]. However, combining futicasone, azithromycin, and montelukast (FAM) appeared more promising. In fact, a prospective, nonrandomized, open-label trial demonstrated a steroid-sparing effect with stabilization of FEV1 [50]. Although this approach has not been very successful in improving lung function, it is currently recommended by experts in North America despite the more signi cant bene t observed by combining inhaled budesonide/formoterol [48]. Indeed, a randomized, controlled trial of 32 highly selected patients with BOS following HSCT showed a signi cant improvement in FEV1 of 260 mL after 1 month of inhaled budesonide/formoterol, compared with 5 mL in the placebo group [43]. In an attempt to decrease BOS onset, azithromycin alone, initiated at the time of transplant, was studied in a randomized fashion. Surprisingly, the study ended prematurely due to an increased disease relapse rate in the treatment group [51]. Following this outcome, concerns arose regarding whether azithromycin initiated at the time of BOS diagnosis had similar adverse effects. Consequently, a recent large, retrospective trial showed an increased risk of solid malignancy but not hematological relapse in patients with BOS receiving azithromycin [52]. In our center, we have been more reluctant to initiate azithromycin in this patient population given the minimal bene t and potentially serious adverse events. In practice, we initiated budesonide formoterol at doses of 800 mcg and 24 mcg twice per day, based