Non-infectious pulmonary complications after haematopoietic progenitor transplantation: a diagnostic approach

Introduction

Over the last few years, an average of 28,000 haematopoietic stem cell transplantations (HCTs) have been performed in developed countries. HCT are increasing exponentially each year and consequently the associated complications (1). Post-HCT pulmonary complications are classified as non-infectious and infectious and represent an increasingly important clinical scenario, with a prevalence of around 30–40% and a non-negligible mortality risk (2). Infectious complications are of course becoming less frequent and less severe due to prophylaxis. However, non-infectious complications have been progressively increasing in recent years, becoming one of the most important causes of post-HCT morbidity and mortality.

Traditionally, these complications have been classified according to their time of onset in relation to the graft as follows: (I) neutropenic or pre-engraftment phase (first 30 post-HCT); (II) early or early post-engraftment phase (days +30 to +100 post-HCT); and (III) late or late post-engraftment phase (days +100 or later post-HCT). Figure 1 shows chronologically the timing of the most frequent post-HCT non-infectious pulmonary complications.

Figure 1 Evolutionary timeline of onset of non-infectious pulmonary complications post-HCT. HCT, haematopoietic stem cell transplantation; PERDS, peri-engraftment respiratory distress syndrome; DAH, diffuse alveolar hemorrhage; PE, pleural effusion; IPS, idiopathic pneumonia syndrome; PVOD, pulmonary veno-occlusive disease; BO, bronchiolitis obliterans; OP, organizing pneumonia; PPFE, pleuroparenchymal fibroelastosis; AL, air leak; PTLD, post-transplantation lymphoproliferative disorder; d, days; m, month; y, years.

There is a growing awareness that the assessment of the patient undergoing HCT should start before the transplantation itself. Thus, it is known that total body irradiation dose, the source of HCT, myeloablative regimens or lower baseline lung function are key risk factors in the development of pulmonary complications (3). However, it is important to keep in mind that alterations in pre-transplant lung function tests alone do not exclude transplantation, but should be used to establish baseline lung function and alert us to a possible increased risk of future respiratory complications.

Therefore, despite advances in the understanding of their pathophysiology and treatment, many aspects are still unknown, which highlights the need for further research into the understanding and treatment of these entities (4).

Specific entities

As previously mentioned, frequency, morbidity and mortality of post-HCT non-infectious pulmonary complications have increased discreetly over the last few years, in contrast to the decrease in infectious complications. This group of non-infectious respiratory complications has a variable incidence for each specific entity but often common risk factors (Table 1). The various complications are described below, grouped according to their stage of onset. They are also listed in Table 2.

Neutropenic phase or pre-graft

Peri-engraftment respiratory distress syndrome (PERDS)

PERDS is a clinically diagnosed syndrome characterised by the presence of bilateral pulmonary infiltrates, hypoxaemia and non-specific respiratory symptoms in the first 5–11 days post-HCT (both autologous and allogeneic) (5). This lung damage has been associated with pulmonary release of neutrophils and various pro-inflammatory cytokines. Bilateral ground-glass opacities, consolidation, septal thickening and even pleural effusion (PE) are frequently observed on thoracic computed tomography (CT) (6). Bronchoalveolar lavage (BAL) is predominantly polymorphonuclear and transbronchial biopsy, when performed, can show diffuse alveolar damage and other non-specific findings.

Treatment of this entity consists of administration of corticosteroids, which, unlike other post-HCT complications, usually have a very favourable response rate (>90%). This good prognosis has been related to a more neutrophilic cellular release profile at the pulmonary level, as previously mentioned, as opposed to a T-cell pathway that is usually characteristic of other pulmonary complications that will be described later (7).

Diffuse alveolar haemorrhage (DAH)

DAH has an incidence of around 5% and is defined by the presence of a haematic BAL fluid (≥ 20% haemosiderophages) of unknown origin (8). Myeloablative regimens, cord HCT, engraftment failure and other findings are known to be major risk factors (9). Other aspects that may contribute to the development of DAH are thrombocytopenia and coagulopathy.

Radiologically, multilobar ground-glass opacities are frequently observed, which, together with a clinical picture of haemoptysis and the features described in BAL fluid (haematic cellularity and negative microbiology), help to establish the diagnosis (10).

Treatment of DAH is supportive with corticosteroids, therapies aimed at controlling coagulopathy (such as aminocaproic acid or recombinant factor VIIa) and cytokine antagonists (such as etanercept or cyclophosphamide) (11,12). Despite early diagnosis and treatment, DAH has a poor prognosis with a reported mortality >70% (9).

Early phase or early post-engraftment phase

Idiopathic pneumonia syndrome (IPS)

IPS is a diagnosis of exclusion defined by the American Thoracic Society as a pneumopathy of unknown cause occurring in a patient undergoing both autologous and allogeneic HCT (13). Its estimated incidence is around 3–15% (14). Known risk factors for the development of IPS are older age, total body irradiation, graft-versus-host disease (GVHD) and/or certain previous haematological diagnoses such as acute leukaemia. As the name implies, it is an entity whose cause is not exactly known, but it is hypothesised that certain lung damage results in cell-mediated immune injury. IPS actually encompasses a variety of clinical syndromes resulting from acute lung injury.

Therefore, the diagnosis involves combining a series of criteria (multilobar involvement in imaging tests, respiratory symptoms and/or restrictive functional pattern) in the absence of another cause for these findings (documented infection, volume overload or organ dysfunction). Therefore, it is understandable that a BAL is necessary for the diagnosis in order to exclude infection (13). Based on the fact that pro-inflammatory cytokines and tumor necrosis factor (TNF)-α have been found in BAL fluid, it has been postulated that etanercept, in addition to corticosteroids, could be a useful treatment (15).

Pulmonary veno-occlusive disease (PVOD)

PVOD and pulmonary thromboembolism are included in the term venous thromboembolic disease (VTD), which has an incidence of 3–7% between 1–4 years post-HCT, being more frequent in the allogeneic transplants (16). Known risk factors for the development of PVOD are: aggressive myeloablative treatments, lymphoma or multiple myeloma, thrombocytopenia, total body irradiation, immobility, history of previous venous thromboembolism (VTE), GVHD and/or the presence of indwelling central venous catheters (17,18). It is known that most cases of PVOD occur within 6–12 months after HCT and only 1–4% are symptomatic (19).

Despite the known increased risk of DVT in the post-HCT period, thromboembolic prophylaxis is not frequently performed (used in only 15% of cases), due to the increased risk of thrombocytopenia and/or haemorrhage in these patients (20).

Treatment of PVOD is based on the administration of corticosteroids and anticoagulants, although there is no robust scientific evidence to support their use (21). There is a novel therapy for hepatic veno-occlusive disease (defibrotide) which, due to pathophysiological similarities, could be useful in PVOD (22). Despite these therapies, it is an entity with a high mortality, which can reach 70% (23).

PE

In the post-HCT period, there are multiple causes that could lead to PE, both transudate (due to water overload, among others) and exudate (parapneumonic effusions, empyema, neoplasms, etc.). For a correct differential diagnosis between entities, it is necessary to perform a diagnostic thoracentesis. Resolution of PE will depend on adequate treatment of the underlying cause (24).

Late phase or late post-engraftment phase

Bronchiolitis obliterans syndrome (BOS)

BOS is characterised by previously not present airflow obstruction resulting from end-stage bronchial involvement that occurs in 6–7% of patients undergoing allogeneic HCT (between day +100 and up to the first 2 years) (25). BOS is commonly known to be associated with chronic GVHD and it is therefore recommended that at diagnosis of GVHD, BOS screening should be performed quarterly for at least the first 2 years (26,27). A definitive diagnosis of BOS requires surgical lung biopsy, which is not usually performed in routine clinical practice due to the associated risks. Thus, the diagnosis is usually made clinically by summing up the following functional and radiological findings (28):

• Forced expiratory volume in the first second/forced vital capacity (FEV₁/FVC) <0.7 or <5^th percentile.
• FEV₁ <75% of predicted with ≥10% decline in less than 2 years (FEV₁ cannot correct to >75% of predicted with bronchodilators).
• Absence of respiratory infection.
• One or more of the following criteria indicative of air trapping:
  • Thoracic CT evidence of air trapping, bronchiectasis or small airway thickening.
  • Functional test evidence of air trapping [residual volume (RV) >120% of predicted or RV/total lung capacity (TLC) >90%].

The most commonly used treatment is the classic triple therapy consisting of azithromycin, montelukast and inhaled corticosteroids (FAM regimen), which has been shown to improve FEV₁ in some series (29). However, Bergeron et al. reported increased relapse prevalence when azithromycin (250 mg three times a week) was used as prophylaxis, compared with placebo. The additional immunosuppressive prophylaxis medication appeared to increased relapse prevalence in high-risk patients. These findings teach us to be cautious when prescribing the FAM prophylactic regimen and the panel believes that these data should not lead to the omission of FAM in patients with clinically overt BOS (30).

On the other hand, systemic corticosteroids and immunosuppressants are used in acute exacerbations of the disease with variable results. If the outcome is not favourable, lung transplantation may be an option in these cases. Anti-thymocyte globulin administration, umbilical cord transplantation and a reduced toxicity regimen could be considered as preventive measures, as these factors have been associated with a lower risk of BOS (28). In this way, the European Respiratory Society/European Society for Blood and Marrow Transplantation task force recommend the use of inhaled corticosteroid and long-acting beta-agonist (ICS/LABA) and FAM (together comprising ICS/LABA, azithromycin and montelukast) in BOS patients along with extracorporeal photopheresis in progressive disease and lung transplantation for end-stage pulmonary GVHD (31).

Organizing pneumonia (OP)

OP is histologically defined by the deposition of granulation tissue, connective tissue and myofibroblasts in the intra-alveolar area together with recruitment and activation of alloreactive T and B cells. It usually occurs after day +100 post-HCT, with an incidence of around 10% (5). It is more common in female donors to male recipients, with the presence of GVHD and/or previous upper respiratory tract infection (32).

Radiologically, the most characteristic features are bilateral pulmonary consolidations and ground-glass opacities (33), and functionally there may be obstructive, restrictive or mixed impairment. It should be noted that definitive diagnosis requires anatomo-pathological confirmation, where transbronchial biopsy has an adequate diagnostic yield (26).

OP, unlike other entities, usually has an appropriate response to treatment with high-dose corticosteroids for a minimum of 4–8 weeks (0.5–1/mg/kg body weight) (32). In contrast, relapses are common when corticosteroid treatment is reduced or withdrawn, but these do not affect the final prognosis and respond adequately to re-institution of therapy (34). In refractory cases, other drugs such as rituximab, cyclophosphamide, immunoglobulins and antifibrotics have been tried (35-38).

Pleuroparenchymal fibroelastosis (PPFE)

PPFE is defined by proliferation of elastic fibres with pleural and subpleural lung parenchymal thickening predominantly in the upper lobes. It is more common after allogeneic HCT (39). PPFE has a delayed time of onset, with a median debut at 8.9 years after HCT (40).

As reflected by histological changes, upper predominant fibrosis, pleural thickening, subpleural retraction, volume reduction and traction bronchiectasis are seen on chest CT (41,42). It has been postulated, although with limited evidence, that antifibrotic treatment may halt disease progression (43). Despite this, it is an entity with a poor prognosis, where lung transplantation is an option reserved for a very limited number of patients (44).

Air leak syndrome (ALS)

ALS is an overarching term that encompasses different entities that include any type of air leakage at the pulmonary level, such as pneumothorax, pneumomediastinum or subcutaneous emphysema. It has an estimated incidence of 3% of cases, is more common in patients with GVHD or previous invasive fungal lung infection, and usually occurs after day +200 of HCT (45).

From a pathophysiological point of view, ALS is characterised by alveolar rupture resulting from increased intrathoracic pressure due to an anoxia affecting the respiratory tract. Treatment is supportive along with drainage measures (such as chest tube placement).

Post-transplant lymphoproliferative disorder (PTLD)

PTLD is a spectrum of lymphoid proliferation resulting from immunosuppression after HCT, and is more common in allogeneic HCT (46). It includes various entities ranging from reactive plasmacytic hyperplasia to lymphoma. PTLD is characterised by the expansion of B lymphocytes produced by the Epstein-Barr virus in the host with compromised T cells, which is why it is most frequent in the first 6 months after HCT, the time with the highest level of immunosuppression (47).

The lung is the most frequently affected organ in PTLD, where lymphadenopathy is more common than parenchymal involvement (nodules, masses and infiltrates) (48). Therefore, lymph node biopsy by bronchoscopic ultrasound should be a priority for diagnosis, which may be risky depending on the clinical status of the patient. In this way, a diagnosis of suspicion can be assumed, with the results of thoracic CT, BAL cellularity and quantitative Epstein-Barr virus titres (49). For management, an early approach is needed to reduce the level of immunosuppression and administer a drug such as rituximab (50).

Other less common pulmonary complications

Interstitial lung disease (ILD)

ILD, as a post-HCT complication, has an incidence of 2.4% and the median time of onset is 11.3 months after transplantation (more frequent if peripheral stem cell transplantation and with a history of GVHD).

Diagnosis requires a high-resolution chest CT scan (which can show various patterns: diffuse alveolar damage, organised pneumonia, non-specific interstitial pneumonia, lymphoid interstitial pneumonia, among others), complete diffusion functional tests (which usually show low-diffusion restriction) and fibrobronchoscopy with BAL (which rules out infection and shows lymphocyte-predominant cellularity).

There is a lack of clinical trials that provide robust evidence for the management of post-HCT ILD. In general, management is based on the administration of corticosteroids with poor response and a reported 2-year mortality of around 40% (51).

Transfusion reactions

Transfusion-related pulmonary complications are called transfusion-related acute lung injury (TRALI) and transfusion-associated circulatory overload (TACO). Of course, these are not specific post-HCT complications, but can occur regardless of patient’s underlying diagnosis.

TRALI is defined as acute-onset lung injury (within 6 hours of transfusion) characterised by pulmonary oedema and respiratory failure, with no other underlying causes. It has a low incidence of around 0.1%. It is more frequent in patients who are alcoholics, smokers, with a positive fluid balance prior to therapy and with the administration of blood products with a high plasma volume. Treatment consists of supportive measures (52).

TACO also involves pulmonary oedema, respiratory distress due to fluid overload and elevated B-type natriuretic peptide within 6 hours of transfusion. It has a slightly higher incidence: 1–5% of cases. It is more common in patients with pre-existing cardiac, pulmonary or renal disease, older than 70 years and with previous positive balance. Therapies for this entity are supportive measures and diuretics in selected cases (53).

Treatment-related toxicities after HCT

HCT outcomes are limited by significant complications including pulmonary toxicity, which are a major driver of non-relapse mortality. However, limited data have been reported on the prevention and management of pulmonary toxicity and despite advances in supportive care, pulmonary complications still develop in 30–60% of cases. Reported risk factors include pulmonary toxicity of chemotherapies, total body irradiation and comorbidities such as restrictive lung disease and smoking history (54).

Delayed pulmonary toxicity syndrome (DPTS) is primarily seen in autologous stem cell transplant populations who received conditioning regimens containing bleomycin, bortezomib, thalidomide, cyclophosphamide, bischloroethyl nitrosourea, cisplatin and etoposide. DPTS has an incidence between 29% and 64% with a median time of onset of 45 days after HCT (13). Patients usually present with nonspecific symptoms (fever, dyspnoea, cough and hypoxaemia) and have patchy or diffuse reticular infiltrates on the chest CT. Lung biopsy shows diffuse alveolar damage, interstitial pneumonitis and early fibrosis. Treatment with high-dose steroids leads to resolution in >90% cases (55).

Therefore, strategies to mitigate early post-transplantation pulmonary toxicities must include careful consideration of the appropriate conditioning regimen and intensity in patients considered at high risk (older cases with comorbidities, patients with prior chest irradiation, and those undergoing transplantation for such malignancies).

Assessment and diagnosis of the patient with suspected post-HCT non-infectious pulmonary complications

From the above-mentioned aspects, it follows that in order to reduce pulmonary complications, a pre-HCT assessment including a complete medical history, physical examination, chest X-ray and pulmonary function is necessary to serve as a baseline assessment of the patient’s condition (56).

In the post-HCT phase, clinicians need to be alert to the presence of respiratory symptoms in patients, which should be interpreted in relation to the post-transplant period and immune status. In this regard, thoracic CT and BAL bronchoscopy findings help to guide the diagnosis (Figure 2).

Figure 2 Algorithm for the diagnosis of non-infectious pulmonary complications of haematopoietic stem cell transplantation. HCT, haematopoietic stem cell transplantation; BAL, bronchoalveolar lavage; CT, computed tomography; PH, pulmonary hypertension; DAH, diffuse alveolar hemorrhage; AIP, acute interstitial pneumonitis; PERDS, peri-engraftment respiratory distress syndrome; PVOD, pulmonary veno-occlusive disease; PFT, pulmonary function tests; BO, bronchiolitis obliterans; GVHD, graft versus host disease; OP, organizing pneumonia; LIP, late interstitial pneumonia.

Therefore, it is recommended that patients be carefully monitored after HCT with regular outpatient visits including assessment of symptomatology and lung function every 3–6 months (between day +100 and up to a minimum of 2 years) (57).

Thus, the detection of a restrictive pattern during follow-up would suggest ILD, while an obstructive pattern would be consistent with a possible BOS. The next step would be to perform a thoracic CT scan to assess for radiological changes consistent with a specific entity. Due to the limited therapeutic options, it is not usually necessary to perform a lung biopsy in these patients, which is also usually risky; rather, the diagnosis is clinical and exclusion is made by adding the results of pulmonary function, radiology and symptomatology.

Conclusions

Thanks to antibiotic prophylaxis and post-HCT support measures, infectious pulmonary complications have been decreasing in recent years. In contrast, non-infectious respiratory complications have been increasing, making them a major cause of morbidity and mortality in these patients. The pathophysiology and aetiopathogenesis of these complications are poorly understood, which in many cases makes it impossible to fine-tune their treatment. Therefore, corticosteroids continue to be the main therapy administered with variable response rates, which highlights the need for research into new and more specific targets. In view of the limited therapeutic response mentioned above, preventive measures for patients undergoing HCT, such as conditioning of less ablative regimens or pre-selection of high-risk cases, are of paramount importance. Thus, due to therapeutic limitations and preventive measures, clinicians need to be made aware of the importance of early detection and management in order to mitigate the severity of these devastating pulmonary complications.

Acknowledgments

Funding: None.

Footnote

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