Noninfectious pneumonitis after blood and marrow transplant
Bekele Afessa and Steve G. Peters
Division of Pulmonary and Critical Care Medicine,
Department of Medicine, Mayo Clinic College of
Medicine, Rochester, Minnesota, USA
Correspondence to Bekele Afessa, MD, Division of
Pulmonary and Critical Care Medicine, Mayo Clinic
College of Medicine, 200 First Street, SW, Rochester,
MN 55905, USA
Tel: +1 507 284 2494; fax: +1 507 266 4372;
e-mail: afessa.bekele@mayo.edu
Current Opinion in Oncology 2008, 20:227–233
Introduction
Thousands of patients undergo blood and marrow trans-
plant (BMT) annually [1]. The pretransplant condition-
ing regimen virtually eliminates preexisting immunity
[2]. Pulmonary complications develop in 30–60% of
BMT recipients [3] and are the immediate cause of death
in approximately 61% [4,5]. Recent data suggest that
noninfectious pulmonary complications may be more
common than infections [6]. This review will summarize
recent developments in noninfectious complications that
manifest as pulmonary infiltrates in BMT recipients
(Tables 1 and 2).
Approach to pulmonary complications in
blood and marrow transplant recipients
When BMT recipients present with pulmonary manifes-
tations, plain chest radiographs are usually obtained.
Pulmonary function testing is part of the evaluation when
bronchiolitis obliterans is suspected. If chest radiograph
1040-8746 ! 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Purpose of review
Blood and marrow transplant recipients are predisposed to infectious and noninfectious
pulmonary complications. Such complications can develop in 30–60% of blood and
marrow transplant recipients and are the immediate cause of death in approximately
61%. This review will summarize recent developments in noninfectious complications
that manifest as pulmonary infiltrates.
Recent findings
Recent data in blood and marrow transplant recipients suggest that noninfectious
pulmonary diseases may be more common than infectious complications. The main
noninfectious pulmonary complications that present as pulmonary infiltrates include
idiopathic pneumonia syndrome, peri-engraftment respiratory distress syndrome and
diffuse alveolar hemorrhage. Bronchoalveolar lavage fluid shows progressively bloodier
return and/or over 20% hemosiderin-laden macrophages in diffuse alveolar
hemorrhage. Peri-engraftment respiratory distress syndrome differs from idiopathic
pneumonia syndrome by its occurrence during the neutrophil peri-engraftment period
and favorable response to corticosteroid therapy. The treatment of noninfectious
pulmonary complications is not based on randomized clinical trials.
Summary
Noninfectious pulmonary complications develop frequently in blood and marrow
transplant recipients. The clinical presentations of idiopathic pneumonia syndrome,
Peri-engraftment respiratory distress syndrome and diffuse alveolar hemorrhage may
mimic pneumonia of infectious etiology. The therapeutic and prognostic implications
mean that accurate diagnosis of these conditions is important.
Keywords
bronchiolitis obliterans organizing pneumonia, diffuse alveolar hemorrhage,
hematopoietic stem-cell transplantation, idiopathic pneumonia syndrome
Curr Opin Oncol 20:227–233
! 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins
1040-8746
is nonspecific, high-resolution computed tomography
may suggest specific diagnoses [7]. When initial
evaluation reveals no specific etiology and empiric
therapy fails, bronchoalveolar lavage (BAL) with or with-
out transbronchial lung biopsy, fluoroscopy or computed
tomography guided transthoracic fine-needle aspiration,
or video-assisted thoracoscopic lung biopsy may be
needed (Fig. 1) [7,8].
Idiopathic pneumonia syndrome
The term ‘idiopathic pneumonia’ is used to describe
pneumonia without infectious etiology in BMT recipi-
ents. A 1985 review reported a 35% incidence rate of
idiopathic pneumonia [9]. A more recent study has shown
this incidence rate to be 7.3% [10]. The 1993 workshop
sponsored by the National Heart, Lung, and Blood Insti-
tute defined idiopathic pneumonia syndrome (IPS) as the
presence of widespread alveolar injury in the absence of
lower respiratory tract infection or heart failure (Table 3)
[11]. Although diffuse alveolar hemorrhage (DAH) and
 228 Transplantation

Table 1 Noninfectious complications that present with pulmon- Figure 1 Diagnostic approach to blood and marrow transplant
ary infiltrates in blood and marrow transplant recipients recipients with pulmonary infiltrates
Idiopathic pneumonia syndrome
Diffuse alveolar hemorrhage
Peri-engraftment respiratory distress syndrome
Pulmonary infiltrate
Bronchiolitis obliterans organizing pneumonia
Delayed pulmonary toxicity syndrome
Pulmonary cytolytic thrombi
FOB
Organizing pneumonia
Transfusion-related acute lung injury
Acute pulmonary edema
Pulmonary alveolar proteinosis Specific diagnosis No diagnosis
Eosinophilic pneumonia
Posttransplant lymphoproliferative disorders
Sarcoidosis Treat No improvement Improved

peri-engraftment respiratory distress syndrome (PERDS)

VATS
also fulfill the diagnostic criteria of IPS, their response to
treatment and clinical course are different [12,13].
Specific diagnosis

Epidemiology
The overall incidence of IPS is 10% [14,15]. The median Treat
time of onset of IPS is between 21 and 87 days after
transplant. Risk factors for the development of IPS include
FOB, fiberoptic bronchoscopy; VATS, video-assisted thoracoscopic
old age, transplant for malignancy other than leukemia, surgery.
pretransplant chemotherapy, total body irradiation, graft-
versus-host disease (GVHD) and positive donor cytome-
galovirus serology [14,16].
Diagnostic evaluation
More than 90% of patients with IPS have diffuse infiltrate
Pathogenesis
on chest radiograph [21]. In our diagnostic approach to
The pathogenesis of IPS is not well defined. Lung tissue
patients with suspected IPS, we perform BAL and, if
injury, inflammation and cytokine release are implicated.
there are no contraindications, transbronchial lung
Pretransplant radiation and chemotherapy, and undocu-
biopsy. We resort to video-assisted thoracoscopic lung
mented infections may be responsible for the initial injury.
biopsy if transbronchial lung biopsy is contraindicated or
The increased levels of interleukin-6, interleukin-8 and
the transbronchial lung biopsy specimen is inadequate.
tumor necrosis factor (TNF)-a in the serum and BAL of
Lung biopsies of patients with IPS show diffuse alveolar
BMT recipients with IPS, and the clinical improvement
damage, organizing or acute pneumonia, and interstitial
following the administration of etanercept, suggest the role
lymphocytic inflammation.
of these cytokines in the pathogenesis [17–20].

Clinical findings Treatment

The clinical presentation of IPS includes dyspnea, dry
cough, hypoxemia and nonlobar radiographic infiltrates
[11]. The clinical spectrum is broad, ranging from acute
respiratory failure to incidental radiographic abnormalities
[11].
Despite case reports of patients with IPS responding to
corticosteroids, larger studies have not shown any outcome
benefit [10,22]. Currently, the only accepted approaches
are supportive care, and prevention and treatment of
infection. There are three case reports with lung function

Table 2 The features of the main noninfectious complications that present with pulmonary infiltrates in blood and marrow transplant
recipients
Pulmonary complication Main features

IPS Diffuse pulmonary infiltrates, and exclusion of infectious pneumonia and other causes
DAH Diffuse pulmonary infiltrates, and bronchoalveolar lavage with progressively bloodier
return and/or over 20% hemosiderin-laden macrophages
PERDS Diffuse pulmonary infiltrates, onset within 5 days of neutrophil engraftment, and exclusion
of cardiac and infectious causes
BOOP Fever, patchy pulmonary airspace consolidation and typical lung histology
DPTS Ground-glass opacities in autologous blood and marrow recipients with breast cancer, and
following high-dose pretransplant chemotherapy; good prognosis
PCT Fever and pulmonary nodules in children with GVHD, and typical lung histology
BOOP, bronchiolitis obliterans organizing pneumonia; DAH, diffuse alveolar hemorrhage; DPTS, delayed pulmonary toxicity syndrome; GVHD, graft-
versus-host disease; IPS, idiopathic pneumonia syndrome; PERDS, peri-engraftment respiratory distress syndrome; PCT, pulmonary cytolytic thrombi.

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Table 3 Criteria for the diagnosis of idiopathic pneumonia
syndrome in hematopoietic stem cell transplant recipients [11]
Evidence of widespread alveolar injury
Multilobar infiltrate
Symptoms and signs of pneumonia
Abnormal pulmonary physiology with increased alveolar
to arterial oxygen gradient and increased restrictive defect.
Absence of lower respiratory tract infection after appropriate
evaluation with
Bronchoalveolar lavage negative for bacterial and nonbacterial
pathogens
Lack of improvement with broad spectrum antibiotics
Transbronchial lung biopsy if tolerated
A second confirmatory test for infection within 2–14 days
improving following etanercept administration [20].
Randomized clinical trials sponsored by the National
Institutes of Health are currently ongoing to evaluate
the role of etanercept in children and adult allogeneic
BMT recipients. Lung transplantation may play a role in
selected patients [23].
Clinical course and prognosis
Although the pneumonitis resolves in about 31% of
patients with IPS [10,22], the clinical course is often
complicated by infections, pneumothorax, pneumome-
diastinum, subcutaneous emphysema, pulmonary fibrosis
and autoimmune polyserositis [14,15]. The case fatality
of IPS is about 74% [14]. Although more recent studies
show a higher survival rate [24,25], mortality may exceed
95% for those who require mechanical ventilation [10].
Diffuse alveolar hemorrhage
DAH occurs in approximately 5% of BMT recipients
[12,26]. Risk factors for DAH include older age, total
body irradiation, myeloablative conditioning regimen,
allogeneic donor source, and severe acute GVHD
[12,26]. Reducing the intensity of conditioning regimen
in allogeneic BMT recipients does not protect against
DAH [27]. There are no associations between DAH and
pretransplant pulmonary function testing, or prolonged
prothrombin or partial thromboplastin time or low plate-
lets [12]. Evidence of pretransplant airway inflammation
has been associated with subsequent DAH [28]. The
pathogenesis of DAH in the BMT recipient has not been
clearly established. Lung tissue injury, inflammation and
cytokine release are implicated [12].
Clinical findings
Symptoms of DAH typically include dyspnea, fever and
cough [29]. Hemoptysis is reported in less than 20%
[12,30]. The onset of DAH is usually within the first
30 days after transplant.
Diagnostic evaluation
Arterial blood gas studies show hypoxemia. Chest radio-
graphs usually show alveolar and interstitial infiltrates
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Pulmonary complications after transplant Afessa and Peters 229
involving middle and lower lung zones [31]. The most
common computed tomography findings in DAH are
bilateral areas of ground-glass attenuation or consolida-
tion. The criteria for the diagnosis of DAH include
progressively bloodier return or more than 20% hemosi-
derin-laden macrophages in BAL fluid, in the absence of
infection [30]. Lung tissues in DAH show diffuse alveolar
damage [4,29].
Treatment
BMT recipients with DAH are treated with systemic
corticosteroids [12,30]. A recent observational study, how-
ever, has not confirmed the survival benefit of high-dose
corticosteroids [26]. Although a recent retrospective study
showed no outcome benefit [32!!], there are case reports of
allogeneic BMT recipients with DAH successfully treated
with recombinant factor VIIa [33,34].
Clinical course and prognosis
The majority of BMT recipients with DAH require mech-
anical ventilation for respiratory failure [12,30,32!!]. The
reported mortality rate of DAH ranges between 48% and
100% [12,26,30,32!!]. Although multiple organ failure and
sepsis had been reported to be the most common causes of
death [35,36], respiratory failure was more common in two
recent studies [30,32!!].
Peri-engraftment respiratory distress
syndrome
Engraftment syndrome is characterized by skin rash,
noninfectious pulmonary infiltrates, fever, diarrhea and
capillary leak occurring during the peri-engraftment
period. PERDS refers to the pulmonary component of
the engraftment syndrome. It responds to treatment and
has low case fatality rate [13]. About one-third of DAH
occurs during the peri-engraftment period and about one-
third of patients with PERDS have DAH [13,30]. The
incidence of PERDS is about 5% in autologous BMT
recipients [13]. The pathogenesis of PERDS is believed
to be complex interaction between the conditioning-
related endothelial damage and the cytokine release
associated with the neutrophil and lymphocyte recovery
[13].
Clinical findings and diagnostic evaluation
The diagnostic criteria of PERDS include fever
(>38.38C) and pulmonary injury evidenced by hypoxia
(arterial oxygen saturation below 90%) and/or pulmonary
infiltrates, in the absence of cardiac dysfunction and
infection, within 5 days of neutrophil engraftment [13].
The median time to onset is 11 days after transplant [13].
Dyspnea is present in all and fever in approximately 63%
at the onset of symptoms. Bilateral pulmonary infiltrates
may not be present on plain chest radiograph at the
onset of symptoms [13]. BAL may show neutrophilic
 230 Transplantation
inflammation [13]. Transbronchial lung biopsy is usually
contraindicated because of thrombocytopenia. Surgical
lung biopsy may show diffuse alveolar damage, but is
rarely necessary.
Treatment, prevention and prognosis
Corticosteroid therapy usually leads to rapid clinical
improvement [13]. A short course of corticosteroid
therapy has been used effectively to reduce engraftment
syndrome [37]. Unlike DAH and IPS, only about one-
third of BMT recipients with PERDS require intensive
care unit admission and mechanical ventilation [13]. The
reported mortality rate of PERDS is about 26%.
Bronchiolitis obliterans organizing
pneumonia
Bronchiolitis obliterans organizing pneumonia (BOOP) is
characterized by the presence of granulation tissue within
the alveolar ducts and alveoli. The published medical
literature on BOOP in BMT recipients mostly is limited
to isolated case reports [3,14,38]. The occurrence of
BOOP in allogeneic BMT recipients with GVHD sug-
gests that it may represent a form of allo-immune injury
by the transplanted stem cell. It has also been reported in
autologous BMT recipients, however, suggesting addi-
tional mechanisms [39]. Human leukocyte antigen B35
may be a risk factor for the development of BOOP [40].
T-cell depletion may prevent BOOP in allogeneic reci-
pients [38].
Clinical findings and diagnostic evaluation
The onset of BOOP is 1 month to 2 years after transplant
[14]. Presenting symptoms include dry cough, dyspnea and
fever. Pulmonary function testing shows a restrictive
defect, decreased diffusing capacity for carbon monoxide
(DLCO), normal airflow and hypoxemia [3,14]. Chest
radiographs show patchy airspace consolidation, ground-
glass attenuation and nodular opacities [41]. Although
usually bilateral, the radiographic abnormalities can also
be unilateral [39,42]. Exhaled nitric oxide concentration
may be increased in active disease and decline as response
to treatment [43]. The definitive diagnosis of BOOP
requires transbronchial, or, more commonly, surgical lung
biopsy. Typical findings include patchy intraluminal fibro-
sis, with polypoid plugs of immature fibroblasts resembling
granulation tissue obliterating the distal airways, alveolar
ducts and peribronchial alveolar space (Fig. 2).
Treatment and prognosis
About 80% of BMT recipients with BOOP respond
favorably to corticosteroids [3,14]. Radiographic abnorm-
alities usually clear within 1–3 months of initiating
therapy. Erythromycin has been used in conjunction with
corticosteroid in one case with favorable outcome [44].
The case fatality rate of BOOP is about 19% [3,14].
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Figure 2 Lung pathology in bronchiolitis obliterans organizing
pneumonia showing the presence of intraluminal granulation
tissue in bronchioli, alveolar ducts and alveoli
There is also interstitial infiltration with mononuclear cells and foamy
macrophages (hematoxylin and eosin stains).
Organizing pneumonia
Organizing pneumonia with no infectious etiology has
been described in three BMT recipients [45]. Chest
radiograph showed patchy consolidation or diffuse
ground-glass opacities. The disease responded to corti-
costeroid therapy.
Delayed pulmonary toxicity syndrome
Delayed pulmonary toxicity syndrome (DPTS) devel-
ops in up to 72% of autologous BMT recipients who
have received high-dose chemotherapy with cyclopho-
sphamide, cisplatin and bischloroethylinitrosurea for
breast cancer [3]. The relatively high frequency, low
mortality and good response to corticosteroids dis-
tinguish DPTS from IPS. The pathogenesis of DPTS
is not known. The depletion of reduced glutathione
and impaired antioxidant defenses caused by cyclopho-
sphamide and bischloroethylinitrosurea have been
implicated [46].
Clinical and diagnostic evaluation
Patients with DPTS present with cough, dyspnea and
fever [3]. The onset of symptoms ranges from 2 weeks to
4 months following transplantation. In the context of
prior breast cancer treated with high-dose chemother-
apy and autologous BMT, DPTS is diagnosed by a
decline in DLCO and exclusion of infectious causes
[3]. The median absolute DLCO decrement is 26% and
a nadir is reached in 15–18 weeks following transplant.
The most common findings on computed tomography
of the chest are ground-glass opacities [47]. Invasive
procedures are not usually required due to the typical
clinical presentation and response to therapy.

Prevention, treatment and prognosis
Corticosteroid therapy for DPTS usually results in
resolution of symptoms and improvement in DLCO
without long-term pulmonary sequelae [3]. One case of
DPTS refractory to steroid was treated successfully with
interferon-g [48]. Prophylactic inhaled corticosteroids
may reduce the frequency of DPTS [49]. No deaths
attributable to DPTS have been reported [3].
Pulmonary cytolytic thrombi
Pulmonary cytolytic thrombi (PCT) occur exclusively
after allogeneic transplant, typically in the setting of
GVHD. All but one of the 17 BMT recipients with
PCT reported in the medical literature are from a single
institution [50–52]. Sixteen of the 17 patients were under
18 years of age at the time of diagnosis. The pathogenesis
of PCT is not known. Although the hemorrhagic infarcts
in PCT are similar to those seen in angioinvasive fungal
infections, none of the lung biopsies in the reported cases
had evidence of infection [50,51]. The development of
PCT exclusively in allogeneic BMT recipients, chiefly in
those with GVHD, suggests that it may be a manifes-
tation of GVHD targeting the endothelium of the lungs
[50].
Clinical findings and diagnostic evaluation
Most BMT recipients with PCT have active GVHD. The
onset of PCT is at a median of 72 days after transplan-
tation. All patients are febrile and some have cough at
presentation, but dyspnea has not been noted. Chest
radiographs may be normal in 25% of patients [53].
Abnormal chest radiographic findings include nodules,
interstitial prominence and atelectasis. Computed
tomography of the chest shows multiple peripheral
pulmonary nodules, ranging from a few mm to 4 cm in
size. Bronchoscopy with BAL is used to exclude infec-
tion. Transbronchial lung biopsy is unlikely to yield a
diagnosis due to the peripheral and intravascular location
of the nodules. Histological demonstration of PCT
requires surgical lung biopsy or necropsy [51–53].
Features of PCT include occlusive vascular lesions and
hemorrhagic infarcts due to thrombi that consist of
intensely basophilic, amorphous material that may
extend into the adjacent tissue through the vascular wall
[50]. The amorphous material suggests cellular break-
down products. Immunohistochemical studies show a
discontinuous endothelial cell layer. The cells that make
up PCT are exclusively monocytes [52].
Treatment and prognosis
Most patients with PCT improve clinically within 1–2
weeks and radiographically over weeks to months [53].
No deaths attributed to PCT have been reported. Of the
15 BMT recipients with PCT reported from the Univer-
sity of Minnesota, 10 were still alive at an average of
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Pulmonary complications after transplant Afessa and Peters 231
13 months after diagnosis and five had died (one from
GVHD and four from infectious complications) [50].
Other noninfectious pulmonary complications
Few case reports of transfusion-related acute lung injury
have been reported following allogeneic stem-cell infu-
sion [54–56].
Acute pulmonary edema is common during the neutrope-
nic phase and likely represents a combination of both
cardiogenic and noncardiogenic (capillary leak) factors
[57,58]. Chest radiographic findings are typical of pulmon-
ary edema [41]. Pulmonary edema can be prevented by
fluid restriction and diuretic therapy [58].
Pulmonary alveolar proteinosis is characterized by exces-
sive accumulation of surfactant lipoprotein in the alveoli.
Cordonnier et al. [59] described three BMT recipients with
pulmonary alveolar proteinosis. All three had received
allogeneic BMT. Chest radiographs showed diffuse infil-
trates. Only one of the three survived. The roles of
BAL and aerosolized granulocyte-macrophage colony-
stimulating factor in BMT recipients with pulmonary
alveolar proteinosis are unknown due to the small number
of cases reported in the literature.
Three cases of chronic eosinophilic pneumonia have
been reported in BMT recipients (one autologous and
two allogeneic) [60–62]. Despite initial response to
steroid therapy, one patient had a fatal course [60].
Posttransplant lymphoproliferative disorder is an uncom-
mon complication of BMT, occurring in less than 1% of
patients. There is one case report of the disorder in a
BMT recipient who presented as interstitial pneumonia
and was successfully treated with rituximab [63].
Sarcoidosis is uncommon in BMT recipients [64,65].
Until recently, the reported cases of sarcoidosis were
donor-acquired. Bhagat et al. [66] reported four cases of
de-novo pulmonary sarcoidosis in BMT recipients (three
autologous and one allogeneic).
Conclusion
The most common noninfectious pulmonary compli-
cations in BMT recipients are IPS, DAH and PERDS.
The clinical course of IPS is different from that of DAH
and PERDS; however, the National Heart, Lung, and
Blood Institute criteria subsume all of them as IPS. In the
absence of uniform criteria, heterogeneous definitions in
the medical literature have resulted in wide variations
in the reported frequency and clinical course of nonin-
fectious pulmonary complications. Further analysis and
consensus are needed to create unique criteria for these
 232 Transplantation
three syndromes. Once such criteria are developed,
multicenter studies are needed to better describe the
frequency and clinical course of each syndrome, to study
pathogenesis, and to identify appropriate diagnostic and
therapeutic approaches.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
! of special interest
!! of outstanding interest
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