Pulmonary Complications Of Hematopoietic Stem Cell Transplant

Front 1

Principle and types of HSCT

Back 1

Front 2

Pulmonary complications are common, affecting approximately _______% of recipients, and contribute significantly to morbidity and mortality.

Back 2

40-60%

According to some studies, pulmonary complications account for 50% of all deaths in this population

Source: Radiographics 2014

Front 3

Allogeneic vs. Autologous HSCT:

In which type, are infectious complications more common? Noninfectious complications?

Back 3

Although infectious complications are more common in patients with ALLOGENEIC HSCT because of the need for posttransplant immunosuppressant therapy to prevent or treat graft versus host disease (GVHD), noninfectious complications occur with a SIMILAR overall frequency in allogeneic and autologous HSCT

Source: Tyndall A. Successes and failures of stem cell transplantation in autoimmune diseases. Hematology Am Soc Hematol Educ Program 2011;2011(1):280–284

Front 4

Timeline of infectious and noninfectious pulmonary complications after HSCT

Back 4

Source: RadioGraphics 2014; 34:663–683

Front 5

What are the complications in the first 30 days after transplant?

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The neutropenic period includes the first 30 days after transplant, when the transplanted marrow is not yet functioning and the patient remains neutropenic. During this period, the frequency of infectious and noninfectious pulmonary complications is similar. Idiopathic pneumonia syndrome (IPS) is a frequent early noninfectious complication with a complex definition and complex manifestations. Other noninfectious entities that may occur during this period include pulmonary edema, diffuse alveolar hemorrhage (DAH), and engraftment syndrome (periengraftment respiratory distress syndrome [PERDS]).

Source: RadioGraphics 2014; 34:663–683

Front 6

A post-HSCT clinical syndrome that manifests with widespread alveolar injury and acute pulmonary dysfunction in the absence of infection, cardiac or renal disease, or an iatrogenic cause such as fluid overload. Imaging findings of parenchymal opacities in a patient with rapidly progressive respiratory symptoms after recent HSCT in the absence of infection (confirmed with BAL) suggest this diagnosis?

Other clues:
Incidence is higher in allogeneic HSCT who undergo myeloablative regimens (3-15% of these patients). Although it may also affect autologous HSCT recipients, the incidence is lower in these patients, the onset is later, and the overall prognosis is better

Median time of onset is 20–42 days after transplant (range, 4–106 days)

Mortality is high (60%–80%) and usually occurs shortly after diagnosis.

Back 6

Idiopathic Pneumonia Syndrome
- A severe complication of HSCT
- clinical and imaging manifestations of IPS are nonspecific. However, patients invariably present with signs of rapidly progressive acute respiratory dysfunction often associated with cough and fever
- Because the definition of IPS is clinical, there is no definite histopathologic diagnosis.
- Tx is supportive and with IV steroids


Source: 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(9):1262–1279

Front 7

____________ is the most common noninfectious complication in the first weeks after HSCT, with a peak incidence in the 2nd to 3rd week after transplant.

Back 7

Pulmonary edema is the most common noninfectious complication in the first weeks after HSCT, with a peak incidence in the 2nd to 3rd week after transplant. Pulmonary edema affects autologous and allogeneic transplant recipients equally. The etiology is multifactorial, and pulmonary edema may be either hydrostatic or due to increased permeability.

Figure: Pulmonary edema in a 56-year-old woman with shortness of breath 7 days after allogeneic HSCT for aplastic anemia. Coronal HRCT image shows enlarged pulmonary vessels (arrow), smooth interlobular septal thickening (arrowhead), and bilateral ground-glass opacities.

Source: RadioGraphics 2014; 34:663–683

Front 8

Multilobar pulmonary opacities seen at imaging and a progressively bloodier return at BAL in the absence of infection very early post-HSCT (median 12-15 days)

A finding of >20% of hemosiderin-laden macrophages can be suggestive (BUT NOT SPECIFIC) of this diagnosis.

Back 8

Diffuse Alveolar Hemorrhage
- Incidence: 5-30%
- Allo = Auto
- Mortality is invariably high (60%–100% of cases within 3 weeks of diagnosis) despite treatment
- Pathogenesis unknown; similar to IPS, DAH is part of the spectrum of post-HSCT acute lung injuries, with capillary bleeding induced by conditioning chemotherapy and radiation and possibly by occult infection

Exclusion of associated infection with BAL is crucial because treatment of DAH involves steroid administration.

Source: RadioGraphics 2014; 34:663–683

Figure: DAH in a 58-year-old man who developed respiratory failure 2 weeks after allogeneic HSCT for hairy cell leukemia. Axial HRCT image shows a diffuse crazy-paving pattern (white arrowheads), areas of consolidation, and a small right pleural effusion (black arrowhead). Note the typical subpleural sparing (arrow). The patient died within 1 week. Autopsy revealed severe diffuse alveolar damage in the proliferative phase, with intra-alveolar hemorrhage.

Front 9

Are platelet transfusions helpful in DAH?

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Although thrombocytopenia is common, the platelet count of patients with DAH is not lower than that of patients without DAH, and platelet transfusion is not helpful.

Source: Tyndall A. Successes and failures of stem cell transplantation in autoimmune diseases. Hematology Am Soc Hematol Educ Program 2011;2011(1):280–284.; RadioGraphics 2014; 34:663–683

Front 10

How often does hemoptysis occur in patients s/p HSCT who are diagnosed with DAH?

Back 10

Hemoptysis should suggest the diagnosis of DAH but occurs in only 66% of cases, and frank hemoptysis is rare.

The absence of hemoptysis does not exclude DAH.

Source: 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(9):1262–1279.

Front 11

Characterized by diffuse capillary leak, cutaneous rash, and fever that occur during the engraftment of hematopoietic stem cells and neutrophil recovery (usually, within 5 days of engraftment, or 7–21 days after transplant).

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Engraftment Syndrome or PERDS [periengraftment respiratory distress syndrome]

Although the pathogenesis of engraftment syndrome is not completely understood, it appears to result from the release of proinflammatory cytokines during engraftment.

Prognosis is generally good - may either resolve spontaneously or respond promptly to steroid treatment

However, if MV is required there is high mortality.

Source: RadioGraphics 2014; 34:663–683

Front 12

Is engraftment syndrome more common in autologous or allogeneic transplants?

Back 12

More common in patients with autologous HSCT.

Front 13

30-year-old man 9 days after autologous HSCT for Hodgkin lymphoma. What's the likely diagnosis?

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The imaging appearance of PERDS may be indistinguishable from that of pulmonary edema and may mimic that of acute respiratory distress syndrome when there are extensive ground-glass opacities. The absence of cardiac enlargement or other clinical findings of pulmonary edema and the presence of a skin rash and fever may be helpful for differentiation.

Figure: Axial HRCT image shows diffuse bilateral ground-glass opacities and peribronchial consolidation in the right upper lobe. The pulmonary arteries are not enlarged, a finding that helps distinguish engraftment syndrome from pulmonary edema

Source: RadioGraphics 2014; 34:663–683

Front 14

________ is the most common noninfectious complication in the early posttransplant period and the most common cause of multilobar infiltrates 30–180 days after transplant

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Idiopathic Pulmonary Syndrome

Front 15

_________ is a major cause of morbidity and mortality in patients after allogeneic HSCT and is caused by an immune reaction of the donor cells to the host tissues.

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GVHD

GVHD has been reported in 20%–75% of allogeneic HSCT recipients and affects primarily the skin, liver, and gastrointestinal system. Although the lungs are not considered a classic target, a histologic spectrum of pulmonary GVHD has been described that ranges from acute injury to chronic irreversible damage.

Acute pulmonary GVHD is rare. HRCT findings are nonspecific and may include diffuse interstitial and alveolar opacities that resemble pulmonary edema.

Source: RadioGraphics 2014; 34:663–683

Front 16

A 67-year-old woman who initially presented with fever and acute respiratory failure after HSCT for diffuse large B-cell non-Hodgkin lymphoma. This resolved after steroids given and BAL negative revealing above image. What's the likely diagnosis?

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Radiation pneumonitis

Front 17

________________ is a rare pulmonary complication that exclusively affects allogeneic HSCT recipients with acute or chronic GVHD.

It has been reported primarily in children, with a median onset of 72 days after HSCT.

Back 17

Pulmonary cytolytic thrombi is a rare pulmonary complication that exclusively affects allogeneic HSCT recipients with acute or chronic GVHD. Although its pathogenesis is unknown, pulmonary cytolytic thrombi may be a manifestation of GVHD. It has been reported primarily in children, with a median onset of 72 days after HSCT.

Pulmonary cytolytic thrombi consists of intravascular thromboemboli associated with the infiltration of monocytes of donor and recipient origins in small and medium pulmonary vessels, surrounded by an area of alveolar hemorrhage or infarct. The thromboemboli are composed of necrotic basophilic debris, with an amorphous material suggestive of the products of cellular breakdown.

The main differential diagnosis in these patients is infection, particularly invasive fungal infection, and infection must be excluded before treatment is instituted. Patients with pulmonary cytolytic thrombi usually respond well to an increase in immunosuppressive therapy.

Front 18

_____________ is the most common and most relevant complication in long-term survivors after HSCT.

It occurs exclusively in patients with allogeneic HSCT.

Back 18

Chronic GVHD is the most common and most relevant complication in long-term survivors after HSCT.

It occurs exclusively in patients with allogeneic HSCT as the result of an immune-mediated reaction of the donor T lymphocytes against the host tissues.

In contrast to the acute form of GVHD, chronic GVHD is relatively common in the lungs and may manifest as organizing pneumonia or bronchiolitis obliterans.

Front 19

9 mo s/p HSCT trasnplant. The patient has an insidious dry cough. What's the dx?

Back 19

Bronchiolitis Obliterans

Most cases manifest within 6–12 months after transplant, although presentation as early as 3 months and as late as 10 years after transplant has been reported.

Bronchiolitis obliterans is considered a manifestation of chronic GVHD in the lungs and therefore is a complication of allogeneic HSCT.

Photomicrograph (original magnification, ×100; H-E stain) shows a bronchiole with subepithelial organizing fibrosis (arrow), a finding consistent with bronchiolitis obliterans.

Source: RadioGraphics 2014; 34:663–683

Front 20

The term __________________ describes a clinical syndrome characterized by an irreversible decline in forced expiratory volume in 1 second (FEV1) of at least 20% from the baseline

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The term bronchiolitis obliterans syndrome describes a clinical syndrome characterized by an irreversible decline in forced expiratory volume in 1 second (FEV1) of at least 20% from the baseline.

Patients with biopsy-proved bronchiolitis obliterans may not fulfill the clinical criteria for bronchiolitis obliterans syndrome on the basis of pulmonary function test results, whereas patients with a clinical diagnosis of bronchiolitis obliterans syndrome may not demonstrate the classic pathologic features. Nevertheless, these two terms are often used interchangeably in clinical practice.

Front 21

In which type of HSCT transplant does BOS occur?

Back 21

Bronchiolitis obliterans is considered a manifestation of chronic GVHD in the lungs and therefore is a complication of allogeneic HSCT

Front 22

30 yo F s/o 6 mo from allogeneic HSCT. What is the dx?

Back 22

The most characteristic HRCT manifestation of bronchiolitis obliterans is the mosaic perfusion pattern, a finding of areas of decreased attenuation and vascularity interspaced with areas of normal or increased attenuation.

The mosaic perfusion pattern is highly suggestive of bronchiolitis obliterans in this population, with 74%–91% sensitivity and 67%–94% specificity. The areas of decreased attenuation are accentuated on expiratory-phase images because of airtrapping.

Source: RadioGraphics 2014; 34:663–683

Front 23

The overall mortality rate in post-HSCT bronchiolitis obliterans is____% at 5 years, and most patients die of a superimposed pulmonary infection

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12%–27%

Treatment includes corticosteroid and immunosuppressant therapies, but the overall response is poor. Early recognition and treatment of superimposed infection is crucial to treatment.

Front 24

43 yo M 9 m s/o allogeneic HSCT for AML. BAL ruled out infection. What is the dx?

Back 24

Organizing Pneumonia
- It is a well-known late complication of HSCT, but its incidence is low (2%–10%)
- Allo>Auto

Although pathology is the standard of reference for diagnosis, characteristic HRCT features in the appropriate clinical setting should allow confident presumptive diagnosis and preclude the need for biopsy.

Figure: Axial HRCT image shows patchy bilateral peribronchial and peripheral consolidation. Focal consolidation in the right lower lobe with central ground-glass attenuation (“reversed-halo” sign) (black arrows) is highly suggestive of organizing pneumonia. The elongated consolidation in a perilobular distribution seen in the right upper lobe (white arrows) is also very suggestive of this diagnosis.

Most patients respond favorably to steroid treatment, and in about 80% of patients, the findings resolve or remain stable. Radiographic resolution may take 1–3 months after the initiation of therapy.

Source: RadioGraphics 2014; 34:663–683

Front 25

_____ refers to spontaneous pneumothorax, pneumomediastinum, subcutaneous emphysema, or pulmonary interstitial emphysema in HSCT recipients.

Typically, occurs as a late complication of allogeneic transplant in patients with chronic GVHD and bronchiolitis obliterans syndrome

Back 25

Air Leak Syndrome

Other potential causes of air leak must be excluded, such as cough, vomiting, underlying emphysema, and infectious causes (ie, Pneumocystis jiroveci pneumonia [PCP] and aspergillosis).

Front 26

Enlarging nodes in a post-HSCT patient....dx?

CLUE:
B-cell non-Hodgkin lymphoma is the most common type of lymphoma associated.

Back 26

Post-trasnplant lymphoproliferative disorder

Comprises a heterogeneous group of lymphoproliferative disorders that result from the abnormal proliferation of lymphocytes infected with Epstein-Barr virus originating from the donor.

This uncontrolled proliferation is possible because of the impaired cytotoxic function of the host as the result of immunosuppression (allo>>auto).

Histologic subtypes vary from hyperplastic and indolent disease to aggressive lymphoma.

Pulmonary involvement occurs in ~20%; most commonly spleen, liver, and lymph nodes are affected. Overall incidence ~1%.

Front 27

Pulmonary HTN + Pulmonary Edema on Imaging + normal pulmonary artery occlusion pressure. What's the dx?

Clue:
- Typically, manifests 2-6 mo after HSCT trasnplant.
- HRCT findings include dilatation of the main pulmonary artery, right-sided cardiac chamber enlargement, centrilobular ground-glass opacities, and smooth interlobular septal thickening. Mediastinal lymph node enlargement is often seen
- use of vasodilators is dangerous because it can precipitate severe pulmonary edema and death

Back 27

Pulmonary Veno-occlusive Disease

Characterized by intimal proliferation and fibrous occlusion of venules and small veins that leads to vascular congestion, increased pulmonary capillary pressure, pulmonary arterial hypertension, and right-sided heart failure

Front 28

A rare described entity characterized by fibrotic thickening of the pleura and fibroelastosis of the subpleural parenchyma that affects predominantly the upper lobes. Often 2-16 years after transplant.

Coronal HRCT image shows smooth thickening of the visceral pleura of the right lung and tiny subpleural blebs in the right apex (arrowhead). Also note the thickened pleura adjacent to the left upper lobe (arrow) and low lung volumes.

Back 28

Pleuroparenchymal fibroelastosis

Source: RadioGraphics 2014; 34:663–683

Front 29

Differential Diagnosis of Noninfectious Causes of the Crazy-Paving Pattern after HSCT

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Source: RadioGraphics 2014; 34:663–683

Front 30

Diagnostic Approach to Noninfectious Causes of Diffuse Infiltrates in the Early Phase (<100 Days) after HSCT

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Front 31

Diagnostic Approach to the Most Common Causes of Noninfectious Pulmonary Complications in the Late Phase (>100 Days) after HSCT

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