Download Mini-review Bronchiolitis obliterans and other late onset non

Bone Marrow Transplantation (2001) 28, 425–434
 2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00
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Mini-review
Bronchiolitis obliterans and other late onset non-infectious pulmonary
complications in hematopoietic stem cell transplantation
B Afessa1, MR Litzow2 and A Tefferi2
Divisions of 1Pulmonary and Critical Care, and 2Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA
DPTS
Summary:
Pulmonary complications develop in 30–60% of hematopoietic stem cell transplants (HSCT). The main, late
onset, non-infectious complications include Bronchiolitis
obliterans (BO), Bronchiolitis obliterans organizing
pneumonia (BOOP), and idiopathic pneumonia syndrome (IPS). BO and BOOP occur almost exclusively
in allogeneic HSCT, and have 61% and 21% mortality
rates, respectively. BOOP responds favorably to corticosteroids. IPS has less than 15% 1-year survival. Bone
Marrow Transplantation (2001) 28, 425–434.
Keywords: pulmonary complications; Bronchiolitis obliterans; Bronchiolitis obliterans organizing pneumonia;
interstitial pneumonia; hematopoietic stem cell transplantation
Despite the success in treating otherwise fatal diseases,
HSCT is associated with multiple complications. Pulmonary complications develop in 30–60% of HSCT recipients.1,2 Factors that influence the development of pulmonary complications in HSCT include previous infections,
pre-transplant conditioning regimen, current or prior
immunosuppressant and radiation treatment, type of stem
cell transplant (autologous vs allogeneic), use of prophylactic antibiotics, and time elapsed since transplant. With the
use of prophylactic antibiotics, the spectrum of pulmonary
complications following HSCT has changed increasingly
from infectious to non-infectious etiologies. The times of
onset and distinguishing features of the main non-infectious
pulmonary complications are shown in Figure 1 and Table
1. This review will focus on the late-onset, non-infectious
pulmonary complications in HSCT recipients. An algorithmic approach is outlined in Figure 2. Since most of the
treatable pulmonary complications in HSCT recipients are
diagnosed non-invasively and by bronchoscopy, we rarely
subject our patients to surgical lung biopsy. However, in
patients with suspected BOOP and when bronchoscopy is
contraindicated or non-diagnostic, we occasionally resort to
video-assisted thoracoscopic surgical lung biopsy.
Correspondence: Dr B Afessa, Pulmonary and Critical Care Division,
Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA
BO
BOOP
PERDS
PCT
IPS
DAH
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Months
Figure 1 Approximate time of onset of non-infectious pulmonary complications following hematopoietic stem cell transplant. BO = Bronchiolitis obliterans; BOOP = Bronchiolitis obliterans organizing pneumonia;
DAH = diffuse alveolar hemorrhage; DPTS = delayed pulmonary toxicity
syndrome; IPS = idiopathic pneumonia syndrome; PERDS = periengraftment respiratory distress syndrome; PCT = pulmonary cytolytic
thrombi.
Abnormal lung function
Restrictive and obstructive ventilatory defects, and gas
transfer abnormalities occur frequently in HSCT recipients.3,4 In a study of 52 young, asymptomatic HSCT recipients, 38% had abnormalities in pulmonary function tests
(PFT): 23% restrictive defect with or without impaired gas
transfer and 15% isolated impaired gas transfer.3 An abnormal pulmonary function test is a risk factor for pulmonary
complications.5–9 However, the role of PFT in identifying
HSCT recipients at risk for pulmonary complications needs
further investigation. The PFT findings in BO, BOOP, and
delayed pulmonary toxicity syndrome are listed in Table 2.
Bronchiolitis obliterans (BO)
GVHD is a frequent complication of allogeneic HSCT.10
The pulmonary morphological manifestations of GVHD
include diffuse alveolar damage, lymphocytic bronchitis/
bronchiolitis with interstitial pneumonitis, BOOP, and
BO.11 BO is a nonspecific inflammatory injury affecting
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B Afessa et al
426
Table 1
The distinguishing features of the main non-infectious pulmonary complications in hematopoietic stem cell transplant recipients
Pulmonary
complication
BO
BOOP
Table 2
Pulmonary function test findings in late-onset, non-infectious
pulmonary complications of HSCT patients
Distinguishing features
Expiratory
flow
(FEV1/FVC)
Absence of fever and pulmonary infiltrates, and
presence of airway obstruction
Fever, patchy pulmonary airspace consolidation, and
typical lung histology
IPS
Mimics pneumonia of infectious etiology, and
diagnosed by exclusion of other causes
DAH
Diffuse pulmonary infiltrates, and progressively
bloodier aliquots of lavage return and/or ⭓20%
hemosiderin-laden macrophages during bronchoscopy
PERDS
Onset within 5 days of engraftment, and exclusion of
cardiac and infectious causes
DPTS
In autologous hematopoietic stem cell recipients with
breast cancer, and following high dose pre-transplant
chemotherapy; good prognosis
PCT
Fever and pulmonary nodules in children with
GVHD, and typical lung histology
Lung
volume
(TLC)
Bronchiolitis
obliterans
Decreased
Normal
Decreased
Bronchiolitis
obliterans
organizing
pneumonia
Normal
Decreased
Decreased
Delayed
pulmonary
toxicity syndrome
Normal
Decreased
Decreased
DLCO = diffusing capacity for carbon monoxide; FEV1 = forced expiratory volume in 1 s; FVC = forced vital capacity; TLC = total lung capacity.
Epidemiology
BO = Bronchiolitis obliterans; BOOP = Bronchiolitis obliterans organizing pneumonia; DAH = diffuse alveolar hemorrhage; DPTS = delayed
pulmonary toxicity syndrome; IPS = idiopathic pneumonia syndrome;
PERDS = peri-engraftment respiratory distress syndrome; PCT = pulmonary cytolytic thrombi.
primarily the small airways.12 It is recognized by the presence of airflow limitation clinically and intraluminal
fibrosis histologically. BO can be idiopathic or associated
with connective tissue disease, inhaled toxins, infections,
drugs, and chronic GVHD.12 Although almost non-existent,
two cases of fatal BO have been reported in autologous
HSCT recipients.13
The lack of precise definition and uniform diagnostic criteria has led to variations in the reported incidence of BO
in different studies. Most reported cases of BO are diagnosed by the presence of airflow limitation in the appropriate clinical setting without histological confirmation. The
incidence of BO was 8.3% among 2152 allogeneic HSCT
recipients reported in nine studies.14–22 The incidence varies
between 6% and 20% in long-term survivors with
GVHD.17,22–24
Chronic GVHD, methotrexate use, and serum immunoglobulin deficiency are risk factors for BO.14,17,21,24 In one
study of allogeneic HSCT recipients, 6% of those with
chronic GVHD developed BO compared with none of those
without chronic GVHD.17 Although pulmonary infections
Respiratory symptoms
Chest radiograph
Infiltrate
Clear
High resolution CT of the chest
Bronchoalveolar lavage
Infection or
alveolar hemorrhage
Treat
Infiltrate
Clear
Pulmonary function test
No diagnosis
No improvement
Transbronchial lung biopsy
Nondiagnostic
Video-assisted
thoracoscopic
lung biopsy
Obstruction
Normal or
restriction
Bronchoalveolar
lavage
Look for nonpulmonary cause
Improved
No infection
Infection
Bronchiolitis
obliterans
Treat
Specific diagnosis
Treat
Figure 2 An algorithmic approach to non-infectious pulmonary complications in HSCT.
Bone Marrow Transplantation
Gas
transfer
(DLCO)
Pulmonary complications after stem cell transplant
B Afessa et al
427
are common in BO, it is not clear whether they are causally
related or result from the patients’ immunodeficiency.
Pathogenesis
The pathogenesis of BO in HSCT recipients is poorly
defined. The association between BO and chronic GVHD
suggests that host bronchiolar epithelial cells serve as a
target for donor cytotoxic T-lymphocytes.25 Alternative
explanations include recurrent aspiration due to GVHDassociated esophagitis, abnormal local immunoglobulin
secretory function in the lungs, or unrecognized infection.17,25 The variations in histopathologies, bronchoalveolar lavage (BAL) cell differential, and clinical course
suggest a multifactorial pathogenesis.13,25,26
Clinical findings
Airway obstruction develops between 80 and 700 days following HSCT in BO.14,21,22,27 The respiratory symptoms
include dry cough, dyspnea, and wheezing.14,21,22 Dry
cough is present in 60–100% and dyspnea in 50–70%.14,22
Antecedent ‘cold’ symptoms develop in 20%, and another
20% are asymptomatic at the time of abnormal PFT.14
Wheezing is detected in about 40%.14 Unlike BOOP, fever
is absent in BO. Since these symptoms are nonspecific, a
complete history and physical examination focusing on
signs of chronic GVHD should be obtained.
Diagnostic evaluation
Since early diagnosis may improve outcome, HSCT recipients with suspected BO should undergo spirometry, lung
volumes, diffusing capacity for carbon monoxide (DLCO),
and arterial blood gas measurements.28 Although normal
airflow has been reported in histologically proven BO,13
airflow obstruction is its hallmark. Based on forced expiratory volume in 1 s (FEV1) expressed as percent of baseline,
BO is classified into three stages: mild (FEV1 66–80%),
moderate (FEV1 51–65%), and severe (FEV1 ⭐50%).29
In suspected BO, laboratory evaluation should be undertaken to exclude infection and other complications of
GVHD. Complete blood count with differential, blood urea
nitrogen, creatinine, total bilirubin, hepatic transaminases,
gammaglobulin levels, and urinalysis are recommended.25
Chest radiograph is usually normal or may show hyperinflation.14–16 High resolution computed tomography
(HRCT) of the chest may show hypoattenuation, bronchial
dilatation, bronchiolectasis, and expiratory air trapping
(Figure 3).15,16,18
Since there is a high prevalence of sinusitis in these
patients, radiographic assessment of the paranasal sinuses
is recommended.23,25,30,31 If gastrointestinal GVHD is
suspected, endoscopy should be performed.25,32
BAL shows neutrophilic and/or lymphocytic inflammation.26 Transbronchial lung biopsy is unlikely to add to
the diagnostic yield in BO and is contraindicated if there
is severe airway obstruction or thrombocytopenia. Because
BO involves the respiratory and membranous bronchioles,
transbronchial lung biopsy is usually nondiagnostic. Videoassisted thoracoscopic lung biopsy is required to make a
Figure 3 A computed tomography of the chest in a patient with
Bronchiolitis obliterans showing diffuse areas of parenchymal hypoattenuation, proximal bronchiectasis, and subsegmental bronchial dilatation.
definitive histological diagnosis. Lung biopsies show small
airway involvement with fibrinous obliteration of the lumen
(Figure 4).15,22,33–35 Necrotizing bronchitis and bronchiolitis
have been reported.33 Peribronchiolar inflammatory cellular
infiltrates consisting of neutrophils and lymphocytes may
be present.19
Although obstructive airways disease and BO exist as
distinct clinical entities in HSCT recipients, the diagnostic
criteria of BO have not been clearly defined. Airway
obstruction may exist without bronchiolitis and bronchiolitis without airway obstruction.25 BO should be defined by
the presence of obstructive airways with suspected
bronchiolitis due to chronic GVHD or the demonstration of
new onset airflow obstruction in a HSCT recipient without
pulmonary symptoms.25 Bronchiolitis is suspected by the
presence of cough, wheezing, dyspnea, or hypoxemia in a
HSCT recipient with a normal chest radiograph.25 Pulmonary veno-occlusive and interstitial pulmonary diseases can
have similar presentation. However, pulmonary veno-
Figure 4 Lung pathology in Bronchiolitis obliterans showing bronchiolar inflammation and luminal obliteration associated with excess fibrous
connective tissue. Alveoli and their ducts are spared. (Hematoxylin &
eosin and Verhoeff–Van Gieson elastic tissue stain.)
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428
occlusive disease is unlikely to show airways obstruction.36
Interstitial pulmonary diseases show restrictive defects on
PFT and parenchymal abnormalities on HRCT scan of
the chest.
effective treatment, routine lung biopsy is not recommended at this time unless another disease is suspected.
Because of the associated high mortality rate, prospective
studies are needed to determine the appropriate management of BO in the HSCT recipient.
Treatment
No prospective clinical trial has addressed the management
of BO. Based on anecdotal reports, corticosteroids and augmented immunosuppression are used for treatment. However, only a minority improve.4,13–16,18 Prednisone 1–1.5
mg/kg/day, not to exceed 100 mg/day, is given for 4 to 6
weeks.25 If the respiratory status remains stable, corticosteroid therapy is tapered and discontinued in 6 to 12
months. If no improvement is noted within 1 month,
immunosuppression with cyclosporine or azathioprine is
initiated.25 The dose of azathioprine is 2–3 mg/kg/day, not
to exceed 200 mg a day. Cyclosporine dose is adjusted
according to the serum level.
In addition to immunosuppression, prophylaxis for Pneumocystis carinii and Streptococcus pneumoniae should be
maintained. Although only a minority of patients respond
to bronchodilators, a trial is warranted.14,23,33 In selected
patients, lung transplant is an option.11,37
Macrolides have been shown to improve outcome in panbronchiolitis.38,39 Their beneficial effects are considered to
be due to their anti-inflammatory rather than anti-bacterial
activities.40–42 Although there has been no report of macrolide use in BO, their mechanisms of action and relatively
minor adverse effects warrant a clinical trial. Despite one
case report of BO responding to thalidomide,43 a recent
study has shown no benefit in pulmonary chronic GVHD.44
Intravenous immunoglobulin has not been shown to prevent
the development of BO.45 Cyclosporine may prevent the
development of BO.46
Prognosis
The FEV1 decline rate is widely variable in BO.14 Rapid
deterioration in FEV1 is associated with increased mortality.14 Despite treatment with bronchodilators, corticosteroids and immunosuppression, improvement in lung
function is noted in only 8% to 20%.16,22,25,28 The reported
case fatality rates vary widely, ranging from 14% to 100%
with a mean of 61%.4,11,13–15,17,19,21,22,27,28,47 In one study of
allogeneic HSCT recipients with GVHD, the 3-year mortality rate of those with BO was 65% compared to 44% of
those without BO.14
Future direction
With expanding use of allogeneic HSCT, the incidence of
BO is likely to increase. BO was first recognized in allogeneic HSCT recipients about 20 years ago. However, its
pathogenesis is unknown, the diagnostic criteria have not
been clearly defined, and prospective clinical trials of treatment are non-existent. Although serial PFTs may identify
patients earlier during their clinical course, their impact on
outcome is yet to be determined. Lung biopsy may broaden
our knowledge about BO with therapeutic and prognostic
implications for the future. However, due to the lack of
Bone Marrow Transplantation
Bronchiolitis obliterans organizing pneumonia (BOOP)
The first cases of BOOP in HSCT recipients were reported
in the early 1990s.48,49 BOOP is less common than BO.
BOOP is characterized by the presence of granulation tissue
within the alveolar ducts and alveoli. It presents more like
pneumonia than airways disease.
Incidence
Among 296 patients with BOOP reported in 63 publications, four (1.4%) were HSCT recipients.50 In our institution, the incidence of BOOP was 1.7% in allogeneic
HSCT recipients who survived for 3 months or longer.16
The publications on BOOP in HSCT recipients are limited
to case reports with a maximum number of five
patients.11,16,48–53
Pathogenesis/pathophysiology
The occurrence of BOOP almost exclusively in allogeneic
HSCT recipients with GVHD suggests that it may represent
rejection of the lung by the transplanted stem cell.
Clinical presentation
Although BOOP has been reported in the absence of
GVHD,49,54 most HSCT recipients with BOOP have
GVHD.16,50,51 The presenting symptoms include dry cough,
dyspnea, and fever,48–50 with onset between 1 and 13
months following transplant.16,48–55
Diagnostic evaluation
BOOP should be included in the differential diagnosis of
bilateral airspace disease in HSCT recipients, especially if
they do not respond to antibiotics for presumed pneumonia.
PFTs show a restrictive defect, decreased DLCO, and normal expiratory flow.48,50,56 Arterial blood gas analysis
shows hypoxemia.50 Chest radiographs and computed tomographies (CT) show peripherally distributed patchy air
space consolidation, ground-glass attenuation and nodular
opacities.48–50,57–59
Although PFT and CT scan findings, in conjunction with
the clinical features, suggest the diagnosis, definite confirmation requires surgical or transbronchial lung biopsy. Histologic confirmation of the diagnosis is particularly warranted, as long-term corticosteroid therapy is usually
needed. Surgical lung biopsy is considered the gold standard for diagnosis. The histologic hallmark of BOOP is
the presence of patchy intraluminal fibrosis, consisting of
polypoid plugs of immature fibroblasts, resembling granu-
Pulmonary complications after stem cell transplant
B Afessa et al
lation tissue (Figure 5).60 Intraluminal fibrosis is present in
the distal airways, alveolar ducts, and peribronchial
alveolar spaces.60
alveolar injury in the absence of lower respiratory tract
infection.62
429
Epidemiology
Treatment
BOOP following HSCT has a worse prognosis than idiopathic BOOP.50 Among 19 reported HSCT recipients with
BOOP, the overall case fatality was 21%.11,16,48–55
In a 1985 review of 4500 HSCT recipients, Krowka et al27
reported a 35% incidence rate of IPS. In 12 recent studies
of 4496 HSCT recipients, the overall incidence was 10%,
range between 2% and 17%.4,63–73 Differences in the patient
study populations, lack of uniform definition and diagnostic
criteria, reliance on lung biopsy in the earlier studies,
changes in the intensity of cytoreduction and immune suppression, new developments in infection prophylaxis, and
improved infection detection using newer techniques are
likely to have contributed to variations in the reported incidence rates.
Factors which predispose the HSCT recipient to IPS are
listed in Table 3. Although Kantrow et al67 did not find
that allogeneic transplantation predisposes to IPS, our
analysis of data from selected studies shows 36 of 617 autologous HSCT recipients (5.8%) developed IPS compared
to 380 of 3569 allogeneic HSCT recipients (10.6%), a significant difference.4,63–65,67–70,72,73 The probability of
developing IPS increases with the number of risk factors.65
Patients transplanted for aplastic anemia are at low risk
for IPS.64
Future direction
Pathogenesis/pathophysiology
Although BOOP responds to corticosteroid therapy, the
dose and duration of therapy need to be clarified in future
studies. The role of macrolides in the treatment of BOOP
requires further evaluation.
IPS represents a heterogeneous group of conditions that
result in interstitial pneumonitis or diffuse alveolar damage.67 Its pathogenesis has not been well defined. The
potential mechanism of IPS is parenchymal damage from
previous chemoradiation therapy and/or the conditioning
regimen, GVHD, undiagnosed infection, and excessive
recruitment and activation of inflammatory cells.
About 80% of HSCT recipients with BOOP respond favorably to treatment.16,48–53,55 The duration and dosage of
corticosteroid therapy have not been clearly defined.
Radiographic abnormalities usually clear within 1 to 3
months of initiating corticosteroid therapy.49,50,52 Based on
the experience from non-HSCT recipients with BOOP, the
initial dose of corticosteroid therapy is prednisone 0.75–1.5
mg/kg/day up to 100 mg, for 1–3 months, and this is followed with lower doses for a total duration of 6–12
months.61 We provide prophylaxis for Pneumocystis carinii
pneumonia with trimethoprim/sulfamethoxazole during
corticosteroid therapy. Erythromycin 10 mg/kg/day for 14
months was used in conjunction with corticosteroids in
one patient.53
Prognosis
Idiopathic pneumonia syndrome (IPS)
Despite aggressive diagnostic work-up, no infectious etiology is identified in many HSCT recipients with suspected
pneumonia. IPS is defined by the presence of widespread
Clinical course
Patients with IPS present with dyspnea, dry cough, hypoxemia, and radiographic infiltrates.62 The clinical spectrum
is broad, ranging from acute respiratory failure to incidental
radiographic abnormalities.62 Because IPS mimics infectious pneumonia, most patients are on antibiotics at the time
of diagnosis.67 The median time of onset of IPS is 21 to
65 days, range 0 to 1653 days, after transplant.64,67,68,74
The pneumonia resolves in about 31% of patients with
IPS.67,74 However, the patients’ clinical courses are usually
complicated by infections, predominantly viral and fungal,
Table 3
Figure 5 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 & eosin stain.)
Risk factors for idiopathic pneumonia syndrome
Transplantation for a malignancy other than leukemia
Old age
Total body irradiation
Pretransplant chemotherapy
High-dose 1-3 bis chloroethyl-1 nitrosourea (BCNU)
Graft-versus-host disease
Positive donor cytomegalovirus serology
Longer interval from diagnosis to transplant
Lower performance rating before transplant
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pneumothorax, pneumomediastinum, subcutaneous emphysema, pulmonary fibrosis, and auto-immune polyserositis
involving the pleura and pericardium.4,67,74,75
Diagnostic evaluation
The clinical presentation and radiographic findings do not
differentiate between infectious and idiopathic pneumonia.
PFT and CT of the chest are nonspecific. More than 90%
of patients with IPS have diffuse infiltrates on chest radiograph.74 The criteria for diagnosing IPS are listed in
Table 4.62
Infection needs to be excluded by BAL or lung biopsy.
In earlier studies, IPS was diagnosed histologically when
biopsy or autopsy of lung tissue showed inflammation without infection.63,64,68,74 In one recent study, 80% of IPS cases
were diagnosed by BAL, 4% required lung biopsy, and
16% were diagnosed at autopsy.67 The limitation of BAL in
providing information about the histopathological structure,
interstitial fungi and neoplasms, vascular damage, and other
abnormalities of potential therapeutic or prognostic importance is well recognized. In our diagnostic approach to
patients with suspected IPS, we perform BAL and transbronchial lung biopsy if there are no contraindications.
Lung biopsies in IPS show diffuse alveolar damage,
organizing or acute pneumonia, and interstitial lymphocytic inflammation.4,67
Treatment
Studies addressing the treatment of IPS in the HSCT recipient are non-existent. Griese et al4 reported three cases of
IPS that responded to treatment, including corticosteroids.
Studies with larger sample sizes have not shown any outcome benefit with corticosteroid treatment.67,74 Currently,
the only accepted treatment regimen is supportive care
combined with prevention and treatment of infection.
Table 4
Criteria for the diagnosis of idiopathic pneumonia syndrome
in the hematopoietic stem cell transplant recipient62
I.
Evidence of widespread alveolar injury
(a)
Multilobar infiltrate
(b)
Symptoms and signs of
pneumonia
(c)
Abnormal pulmonary
physiology with increased
alveolar to arterial oxygen
gradient and increased
restrictive defect
II.
Absence of lower respiratory tract infection after appropriate
evaluation with
(a)
Bronchoalveolar lavage negative
for bacterial and nonbacterial
pathogens
(b)
Lack of improvement with
broad spectrum antibiotics
(c)
Transbronchial lung biopsy if
tolerated
(d)
A second confirmatory test for
infection within 2–14 days
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Prognosis
In our review of six selected studies, the overall mortality
of 388 HSCT recipients with IPS was 74%, range between
60 and 86%.63–65,67,68,74 The 1-year survival is less than
15%.67,76 Infectious complications and non-pulmonary
organ failure contribute to the high mortality.67,76 For those
who require mechanical ventilation, mortality exceeds
95%.67
Future direction
IPS is a heterogenous entity of diseases of unknown etiology and pathogenesis. It has a high mortality rate and no
effective therapy. We need new studies to determine the
etiology, pathogenesis, and effective therapy of IPS.
Diffuse alveolar hemorrhage
Since DAH occurs early after transplant, we will discuss
it only briefly. DAH develops in 10% to 21% of HSCT
recipients.77,78 Despite the presence of thrombocytopenia in
most, DAH is not corrected with platelet transfusions.77 The
pathophysiology of DAH is not clearly understood. The
presence of neutrophils in the BAL of some patients with
DAH77 suggests an inflammatory mechanism. Patients with
DAH present with progressive dyspnea, hypoxemia, and
cough.77 Hemoptysis is rare.77 Chest radiograph and CT
show diffuse infiltrates that start centrally.58,77,79,80 BAL
shows progressively bloodier aliquots of lavage return.77
Lung biopsies show histologic features consistent with the
proliferative phase of diffuse alveolar damage.77 Based on
anecdotal experiences and retrospective studies, we use
corticosteroids to treat DAH.78,81–83 The reported mortality
of DAH is 70–100%.77,79,84,85 However, in our experience
of 18 HSCT recipients admitted to the intensive care unit
and treated with corticosteroids in the last 4 years, the
mortality was 33%.
Peri-engraftment respiratory distress syndrome
A study from our institution has described a periengraftment respiratory distress syndrome, defined by onset
of symptoms within 5 days of engraftment, temperature
⬎38.3°C, radiographic pulmonary infiltrates, absence of
cardiac dysfunction, arterial oxygen saturation less than
90%, and negative blood culture.86 There may be overlap
between this syndrome and DAH. Since peri-engraftment
respiratory distress syndrome occurs early in the posttransplant period, it will not be discussed here.
Delayed pulmonary toxicity syndrome
A ‘delayed pulmonary toxicity syndrome’, characterized by
interstitial pneumonitis and fibrosis, delayed for months to
years, develops in autologous BMT recipients with breast
cancer who have received high-dose chemotherapy pretransplant.87,88 The high-dose chemotherapy with cyclopho-
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B Afessa et al
sphamide, cisplatin, and bischloroethylinitrosurea (BCNU),
high incidence, low mortality, and good response to
corticosteroid treatment distinguish this syndrome from
IPS.87 It develops in about 72% of autologous HSCT recipients who have received high-dose chemotherapy for breast
cancer.88 It presents with dry cough, dyspnea and fever. It
has a better prognosis than IPS.87,88 The DLCO declines to
a nadir level in 15–18 weeks following the chemotherapy/
transplant.87 Lung function improves with corticosteroid
treatment.88 No deaths attributable to this syndrome have
been reported, and the published studies are limited to a
single institution.87,88
Pulmonary cytolytic thrombi
Pulmonary cytolytic thrombi is a non-infectious pulmonary
complication of HSCT.89 It occurs almost exclusively in
children with GVHD and is characterized by fever and pulmonary nodules. Biopsy of the nodules shows necrotic,
basophilic thromboemboli with amorphous material
suggestive of cellular breakdown products.90 Its time of
onset ranges between 8 and 343 days (median 72) after
transplant.89 Most patients improve clinically within 1–2
weeks and radiographically over weeks to months.89 In the
only published study, nine of the 13 HSCT recipients with
pulmonary cytolytic thrombi were alive at a median followup of 1.5 years.89 All received antibiotics, and nine were
treated with systemic corticosteroids.89 The published
reports on pulmonary cytolytic thrombi are limited to one
institution.
Others
Other uncommon noninfectious pulmonary complications
of HSCT include progressive pulmonary fibrosis,4 pulmonary hypertension,91 pulmonary veno-occlusive disease,36
hepatopulmonary syndrome,92 alveolar proteinosis93 and
eosinophilic pneumonia.94
Conclusions
Non-infectious pulmonary complications are common following HSCT. The pathogeneses and diagnostic criteria of
most of these complications have not been clearly defined.
Current treatment modalities, although effective in some
cases, are not based on scientific evidence. Future studies
are needed to better define the pathogeneses and clarify the
diagnostic criteria of, and determine effective therapeutic
approaches to non-infectious pulmonary complications in
the HSCT recipient.
With the wider application of peripheral blood stem cell
transplantation, neutrophil recovery time has shortened.95
This may lead to a decrease in the incidence of early infectious complications and increase in the relative frequency
of non-infectious pulmonary complications. However, since
the exact impact of peripheral blood stem cell transplantation on pulmonary complications has not been clearly
defined, we need to monitor and report the changes in
future studies.
431
Acknowledgements
We thank Dr Jeffrey L Myers for providing us with the pathology
slides and legends.
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