INTRODUCTION
Since the early 1960s, hematopoietic stem cell transplan-
tation (HSCT) has been used with increasing frequency for
the treatment of malignant and nonmalignant diseases. How-
ever, overall pulmonary complications, including infectious
and non-infectious, was reported to occur in 40 to 60% of
all HSCT recipients, which accounted for considerable mor-
bidity and mortality (1). Moreover, mortality rates for HSCT
recipients with pulmonary infiltrates requiring mechanical
ventilation approach 90% (2). Conditioning regimen, recon-
stitution of the immune system, and prophylactic strategy
for infection influence the incidence of pulmonary complica-
tions following HSCT (3). Infectious complications are more
common in allogeneic HSCT recipients because of graft-ver-
sus-host disease (GVHD) itself and the prophylactic or thera-
peutic immunosuppressive therapy for GVHD (4, 5). As the
incidence of infectious pulmonary complications has dimin-
ished as a result of effective prophylactic therapy, noninfec-
tious pulmonary complications have emerged as a major cause
of post-HSCT morbidity and mortality (6). The purpose of
our study was to describe 1) the causes, incidence and mor-
tality rates of pulmonary complications, and 2) the risk factors
associated with pulmonary complications following HSCT.
MATERIALS AND METHODS
We reviewed the medical records of patients, who under-
went HSCT for hematologic disorders from February 1996
to October 2003 at Samsung Medical Center. A total of 287
patients were enrolled. Table 1 summarizes the characteris-
tics of these patients.
Autologous transplantation was performed in 134 patients
and allogeneic transplantation in 153 patients (114 matched
sibling donors, 37 matched unrelated donors, and 2 mismat-
ched cord blood). Acute and chronic leukemias, malignant
lymphomas, and multiple myeloma were the common under-
lying diseases. The conditioning regimens employed are sum-
marized in Table 2. In matched sibling donor allogeneic trans-
plantation (n=114), a combination of cyclosporine (CSP) and
methotrexate (MTX) was most commonly used for GVHD
Do Hyoung Lim1, Jeeyun Lee1,
Hong Ghi Lee�, Byeong-Bae Park,
Kyong Ran Peck*, Won Sup Oh*,
Sang Hoon Ji, Se-Hoon Lee,
Joon Oh Park, Kihyun Kim,
Won Seog Kim, Chul Won Jung,
Young Suk Park, Young-Hyuck Im,
Won Ki Kang, Keunchil Park
Division of Hematology/Oncology & Division of
Infectious Disease*, Department of Medicine,
Samsung Medical Center, Sungkyunkwan University
School of Medicine; Division of Hematology-Oncology�,
Department of Internal Medicine, Konkuk University
Hospital, Seoul, Korea
1These authors contributed equally to the work
presented here.
Address for correspondence
Hong Ghi Lee, M.D.
Division of Hematology-Oncology, Department of
Internal Medicine, Konkuk University Hospital, 4-12
Hwayang-dong, Gwangjin-gu, Seoul 143-914, Korea
Tel : +82.2-2030-7538, Fax : +82.2-2030-7748
E-mail : mlee@kuh.ac.kr
406
J Korean Med Sci 2006; 21: 406-11
ISSN 1011-8934
Copyright � The Korean Academy
of Medical Sciences
Pulmonary Complications After Hematopoietic Stem Cell Transplantation
Despite advanced effective prophylaxes, pulmonary complications still occur in a
high proportion of all hematopoietic stem cell recipients, accounting for considerable
morbidity and mortality. The aim of our study was to describe the causes, incidences
and mortality rates secondary to pulmonary complications and risk factors of such
complications following hematopoietic stem cell transplantation (HSCT). We reviewed
the medical records of 287 patients who underwent either autologous or allogeneic
HSCT for hematologic disorders from February 1996 to October 2003 at Samsung
Medical Center (134 autografts, 153 allografts). The timing of pulmonary complica-
tions was divided into pre-engraftment, early and late period. The spectrum of pul-
monary complications included infectious and non-infectious conditions. 73 of the
287 patients (25.4%) developed pulmonary complications. Among these patients,
40 (54.8%) and 29 (39.7%) had infectious and non-infectious conditions, respectively.
The overall mortality rate from pulmonary complications was 28.8%. Allogeneic trans-
plant, grade II-IV acute graft-versus-host disease (GVHD) and extensive chronic
GVHD were the risk factors with statistical significance for pulmonary complications
after HSCT. The mortality rates from pulmonary complications following HSCT were
high, especially those of viral and fungal pneumonia, diffuse alveolar hemorrhage
and idiopathic pneumonia syndrome.
Key Words : Infection; Hematopoietic Stem Cell Transplantation; Graft vs. Host Disease
Received : 16 June 2005
Accepted : 1 November 2005

Pulmonary Complications after HSCT 407
prophylaxis (n=79). CSP alone was applied for patients at the
age of 20 yr or less (n=8), and a combination of CSP, MTX
and methylprednisolone (MP) was applied for patients at the
age of 45 yr or more (n=10). In allogeneic transplantation
with matched unrelated donor (n=37), a combination of CSP
and MTX (n=17) and a combination of CSP, MTX and MP
(n=9) were the most common GVHD prophylaxis regimens.
The timing of pulmonary complications was divided into
three categories: 1) pre-engraftment period, defined as less
than 30 days after HSCT; 2) early period, defined as 30 to
100 days after HSCT; 3) late period, defined as over 100 days
after HSCT. Pulmonary complications were divided into in-
fectious and non-infectious categories. Infectious complica-
tions included not only microbiologically defined pneumo-
nia, but also clinically defined bacterial pneumonia. A “clini-
cally defined bacterial pneumonia” was defined as the pres-
ence of respiratory and infectious signs and symptoms, with
pulmonary infiltrates on imaging studies, and the definite
response of pneumonia to broad-spectrum antibiotics, but
clinically significant microorganisms were not identified from
blood and sputum cultures. To identify the cause of a pulmo-
nary complication, invasive procedures such as bronchoscopy
with bronchoalveolar lavage (BAL), transbronchial lung biop-
sy, or open lung biopsy were performed if possible. Idiopath-
ic pneumonia syndrome was defined as the presence of mul-
tilobar pulmonary infiltrates on imaging studies with no mi-
croorganism identified despite of invasive procedures. “Un-
known etiology” was defined as the presence of respiratory and
infectious signs and symptoms, with pulmonary infiltrates
on imaging studies, but clinically significant microorganisms
were not identified from blood and routine sputum cultures
and pneumonia did not respond to anti-bacterial, anti-fungal,
anti-viral and anti-Pneumocystis carinii agents. Patients whose
disease was categorized as “unknown etiology” were unable
to undergo invasive procedures due to poor physical condi-
tion or refusal to undergo such a procedure.
Prophylactic antimicrobials
Antibiotics for bacterial prophylaxis were not routinely pro-
vided. Amoxicillin/clavulanate was administered for prevent-
ing infection with encapsulated organisms among allogeneic
recipients with chronic GVHD for as long as active chronic
GVHD treatment was administered. Nystatin or clotrimazole
was given to prevent fungal colonization in the upper diges-
tive mucosa during neutropenia; if patient did not tolerate
them well, fluconazole was administered orally or intravenous-
ly. Weekly blood sampling for cytomegalovirus (CMV) shell
vial culture and CMV antigenemia assay started at engraft-
ment (absolute neutrophil count >0.5×103/ L) following
allogeneic HSCT and continued until any immunosuppres-
sive agent for the prevention or treatment of GVHD had been
AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; CML,
chronic myeloid leukemia; ABL, acute biphenotypic leukemia; NHL, non-
Hodgkin’s lymphoma; MM, multiple myeloma; SAA, severe aplastic ane-
mia; TBI, total body irradiation.
*Others, myelodysplastic syndromes, neuroblastoma, chronic EBV syn-
drome, idiopathic myelofibrosis, chronic myelomonocytic leukemia, pri-
mary amyloidosis, paroxysmal nocturnal hemoglobinuria.
Median age (range, yr) 38 (15-67)
Sex
Male/Female 166 (57.8%)/121 (42.2%)
Underlying disease
AML 83 (28.9%)
ALL 18 (6.3%)
CML 44 (15.3%)
ABL 9 (3.1%)
NHL 60 (20.9%)
MM 37 (12.9%)
SAA 21 (7.3%)
*Others 15 (5.2%)
Type of transplantation
Autologous 134 (46.7%)
Allogeneic 153 (53.3%)
Matched sibling 114 (39.7%)
Matched unrelated 37 (12.9%)
Mismatched cord blood 2 (0.7%)
Conditioning regimen
TBI-based 120 (41.8%)
Non-TBI-based 167 (58.2%)
Table 1. Patient characteristics
CML, chronic myeloid leukemia; NHL, non-Hodgkin’s lymphoma; MM,
multiple myeloma; SAA, severe aplastic anemia; TBI, total body irradia-
tion; VCT, VP-16 (etoposide), cyclophosphamide and total body irradi-
ation; CY, cyclophosphamide; BU/CY, busulfan and cyclophosphamide;
BEAM, BCNU, etoposide, cytarabine and melphalan; ATG, anti-thymo-
cyte globulin; MEL, melphalan.
Acute leukemias*, acute myeloid leukemia, acute lymphoblastic leuke-
mia, acute biphenotypic leukemia. Others�, BU/TBI, busulphan and total
body irradiation; TT/TBI, thiotepa and total body irradiation; MEL/TBI, mel-
phalan and total body irradiation; VACT, etoposide, cytarabine, cyclo-
phophamide and total body irradiation. Others�, CBV, cyclophosphami-
de, BCNU and etoposide; TT/Carbo, thiotepa and carboplatin; TT/CY,
thiotepa and cyclophosphamide; ARA-C/CY/ATG, cytarabine, cyclophos-
phamide and anti-thymocyte globulin. Others�, myelodysplastic syndro-
mes, neuroblastoma, chronic EBV syndrome, idiopathic. myelofibrosis,
chronic myelomonocytic leukemia, primary amyloidosis, paroxysmal noc-
turnal hemoglobinuria.
Acute 42 33 2 21 1 0 0 11
leukemias*
CML 3 1 1 36 0 0 0 3
MM 0 0 0 0 1 0 35 1
NHL 5 1 3 4 43 0 1 3
SAA 0 0 0 0 0 18 0 3
Others� 1 5 0 4 2 0 0 3
Table 2. Conditioning regimens
VCT CY/ Others�BU/ BEAM CY/ MEL Others�
TBI CY ATG
Conditioning regimen
TBI-based Non-TBI-basedUnderlying
disease

408 D.H. Lim, J. Lee, H.G. Lee, et al.
completed. Allogeneic recipients began preemptive treatment
with ganciclovir, if CMV viremia or antigenemia was detect-
ed. Acyclovir prophylaxis was offered to all herpes simplex
virus (HSV)-seropositive HSCT recipients to prevent HSV
reactivation during the early posttransplant period. Pneumo-
cystis carinii pneumonia prophylaxis with oral trimethoprim-
sulfamethoxazole or aerosolized pentamidine was adminis-
tered from engraftment until 6 months after HSCT for allo-
geneic recipients.
Treatment of infectious complications
Each infectious complication during neutropenic period was
treated according to the guidelines for the use of antimicrobial
agents prepared by the Infectious Diseases Society of Ameri-
ca (7, 8). Antimicrobial agents were scrupulously chosen based
on the cultures and serology tests for microorganisms and the
clinical manifestations.
Statistical analyses
Clinical data were analyzed to determine whether the inci-
dence of pulmonary complications was correlated with previ-
ously known risk factors such as age, sex, underlying disease
type, transplant type, GVHD, and total body irradiation
(TBI) using Student t-test, chi-square test, and a linear by
linear association as univariate analysis. Binary logistic regres-
sion was used in multivariate analysis. A p value of <0.05 was
considered statistically significant.
RESULTS
Pulmonary complications developed in 73 out of a total of
287 patients (25.4%). Among these 73 patients, 40 (54.8%)
had infectious complications and 29 (39.7%) had non-infec-
tious complications.
Infectious complications
Table 3 shows the causes and mortality rates of infectious
pulmonary complications. Bacterial pneumonia was the most
common type of infection in all periods (45.0%) but was mi-
crobiologically documented from the blood or BAL fluid in
only 4 patients. Pseudomonas aeruginosa was identified from the
blood culture of 2 patients, Staphylococcus aureus from the blood
culture of 1 patient, and Escherichia coli from the blood and
BAL fluid culture of 1 patient. We failed to identify clinical-
ly significant microorganisms from blood, sputum or BAL
fluid in the remaining 14 patients. Viral pneumonia devel-
oped in 7 patients. Five patients had CMV pneumonia and
2 had adenovirus pneumonia. The diagnosis of viral pneumo-
nia was made with BAL (n=2), transbronchial biopy (n=2),
or open lung biopsy (n=3). Only two patients with viral pne-
umonia were alive at the time of analysis. One patient with
viral pneumonia died of a non-pneumonic event. Fungal pne-
umonia developed in 6 patients, all of who were diagnosed
with invasive pulmonary aspergillosis. Five of the six patients
with invasive pulmonary aspergillosis underwent open lung
biopsy for definitive diagnosis. Despite intensive treatment
with anti-fungal agents, two patients died. All patients with
pulmonary tuberculosis were diagnosed by positive acid-fast
bacilli stain or culture of either sputum or BAL fluid. All of
the pulmonary tuberculosis patients survived. Compared to
that of bacterial pneumonia, the mortality rates for viral and
fungal pneumonia were very high (Table 3).
Non-infectious complications
Table 3 shows the causes and mortality rates of non-infec-
tious pulmonary complications. In the pre-engraftment peri-
od, pulmonary edema (n=9) and pleural effusion (n=5) were
the most common non-infectious complications. These were
the result of fluid overload related to the conditioning ther-
apy. Diffuse alveolar hemorrhage (n=6) and idiopathic pneu-
monia syndrome (n=4) were also important causes of non-in-
fectious complications. Nine out of the 10 patients succum-
bed to either diffuse alveolar hemorrhage or idiopathic pneu-
monia syndrome.
Complications caused by unknown etiology
Three (75%) of the 4 patients with infection of unknown
etiology died despite of aggressive treatment with anti-bac-
terial, anti-fungal, anti-viral and anti-Pneumocystis carinii agents.
DAH, diffuse alveolar hemorrhage; IPS, idiopathic pneumonia syndrome;
GVHD, graft-versus-host disease; BOOP, bronchiolitis obliterans with
organizing pneumonia. *Others, Bronchial stenosis.
Infectious
Bacterium 6 7 5 18 (45) 3 (16.7)
Virus 2 3 2 7 (17.5) 4 (57.1)
Fungus 1 3 2 6 (15) 2 (33.3)
Tuberculosis 1 3 5 9 (22.5) 0 (0)
Total 10 16 14 40 (100) 9 (22.5)
Non-infectious
Pulmonary edema 9 0 0 9 (31.0) 0 (0)
Pleural effusion 5 0 0 5 (17.2) 0 (0)
DAH 3 1 2 6 (20.7) 5 (83.3)
IPS 0 2 2 4 (13.8) 4 (100)
Radiation pneumonitis 0 0 1 1 (3.4) 0 (0)
GVHD 0 0 1 1 (3.4) 0 (0)
BOOP 0 0 2 2 (6.9) 0 (0)
*Others 0 1 0 1 (3.4) 0 (0)
Total 17 4 8 29 (100) 9 (31.0)
Unknown etiology 1 0 3 4 (100) 3 (75)
Total 28 20 25 73 21 (28.8)
Pre-E Early Late Total Death (%) (mortality)
Table 3. Causes and mortalities of pulmonary complications

Pulmonary Complications after HSCT 409
Mechanical ventilatory support
Thirty-four (47%) out of the 73 patients with pulmonary
complications following HSCT required intensive care unit
care (20 infectious, 11 non-infectious and 3 unknown etiol-
ogy). Mechanical ventilation was provided for respiratory
support in 23 patients (13 infectious, 7 non-infectious and
3 unknown etiology), but 21 patients died during mechani-
cal ventilation support.
Risk factors
Table 4 outlines the risk factors associated with pulmonary
complications following HSCT. Allogeneic transplant, the
development of grade II-IV acute GVHD, and extensive
chronic GVHD were the significant risk factors for the devel-
opment of pulmonary complications following HSCT in uni-
variate analysis (all p<0.001). In multivariate analysis, allo-
geneic transplant and extensive chronic GVHD were signifi-
cant influential factors for pulmonary complications (p=0.003
and 0.010, respectively); however, grade II-IV acute GVHD
revealed a trend for development of pulmonary complications
without statistical significance (p=0.055).
DISCUSSION
We confirmed the positive correlations between the type
of transplant, the development of GVHD and the incidence
of pulmonary complications following HSCT. As far as the
relationship between underlying primary disease and the inci-
dence of pulmonary complications was concerned, acute and
chronic leukemias were more closely related to the develop-
ment of pulmonary complications than multiple myeloma
and non-Hodgkin’s lymphoma though this was not found to
be statistically significant. This result might be due to the
small number of patients in each disease category. In contrast
to the results of other studies (9, 10), TBI-based condition-
ing regimen was not a significant risk factor for the develop-
ment of pulmonary complications after HSCT in our study.
The majority of episodes of clinical radiation pneumonitis
have been described in association with therapeutic radiation
for solid tumors or lymphomas, but a few episodes were report-
ed with low-radiation dose used in TBI (11). The develop-
ment of clinical illness was uncommon as a direct result of
TBI and fatal pulmonary complications after HSCT were not
significantly different between TBI-based and non-TBI-based
regimens (12). However, a direct or permissive role of radia-
tion has been suggested in the development of infectious pne-
umonia or idiopathic pneumonitis.
Clinically significant microorganisms were isolated from
the blood in only 4 out of the 18 patients (22.2%) with bac-
terial pneumonia in our study. Blood culture positive bacte-
rial pneumonia constituted a small proportion of bacterial
pneumonia in the setting of HSCT. Moreover, in our study,
the etiology could not be evaluated in 4 patients with un-
known etiology due to poor clinical conditions of the patients.
No compound infectious complication was identified, which
might be attributed to prophylactic administration of antimi-
crobials for HSCT recipients. The detailed pathophysiologies
of diffuse alveolar hemorrhage (13-17) and idiopathic pneu-
monia syndrome (18-21) have not been clarified yet, and the
treatment options of these diseases are limited. In general, dif-
fuse alveolar hemorrhage during the pre-engraftment period
after HSCT results mainly from idiopathic etiologies and
rarely from infections (13-17).
The incidences of pulmonary complications after HSCT
have been well established in previous studies (1). Compared
CML, chronic myeloid leukemia; MM, multiple myeloma; NHL, non-Ho-
dgkin’s lymphoma; GVHD, graft-versus-host disease; TBI, total body
irradiation.
A*, presence of complication, B*, absence of complication; Acute leu-
kemia�, acute myeloid leukemia, acute lymphoblastic leukemia, acute
biphenotypic leukemia; Others�, severe aplastic anemia, myelodysplas-
tic syndromes, neuroblastoma, chronic EBV syndrome, idiopathic myelo-
fibrosis, chronic myelomonocytic leukemia, primary amyloidosis, parox-
ysmal nocturnal hemoglobinuria; Chronic GVHD�, classified by Revised
Seattle classification.
Median age (yr) 37.6 35.7 38.2 0.890 0.344
Sex 0.063 0.063
Male 166 49 117
Female 121 24 97
Type of disease 0.197 0.966
Acute leukemia� 110 31 79
CML 44 17 27
NHL 60 10 50
MM 37 4 33
Others� 36 11 25
Type of transplant <0.001 0.003
Autologous 134 17 117
Allogeneic
Matched sibling 114 32 82
Matched unrelated 37 22 15
Mismatched 2 2
cord blood
GVHD
Acute GVHD <0.001 0.055
No GVHD and 268 61 207
Grade 1
Grade 2-4 19 12 7
Chronic GVHD� <0.001 0.010
No GVHD 265 60 205
and Limited
Extensive 22 13 9
Conditioning regimen 0.132 0.292
TBI-based 120 36 84
Non-TBI-based 167 37 130
A* B* Univariate Multi-
(n=73) (n=214) variate
Table 4. Risk factors for pulmonary complications
Complication p value
Total
(n=287)

410 D.H. Lim, J. Lee, H.G. Lee, et al.
to previous reports, the incidence and mortality of pulmonary
complications after HSCT were lower in our study (40 to 60
% vs. 25.4% and over 30% vs. 28.8%, respectively), which
may be due to the large proportion (46.7%) of autologous
HSCT patients in our study.
In our study, the incidence of pulmonary complications was
significantly lower in recipients of autologous HSCT com-
pared to that of allogeneic HSCT recipients. Severe pulmonary
complications occurred in 24% of allogeneic transplant pa-
tients and 2.9% of autologous transplant patients (p<0.001)
(22). Recipients of autologous transplants had a lower prob-
ability of developing opportunistic pulmonary infections than
did the recipients of allogeneic transplants (p<0.001) (23).
It is believed that the low incidence of pulmonary complica-
tions in autologous transplant recipients result from the mul-
tiple factors such as the faster immunologic recovery, absence
of GVHD or other alloreactive mechanisms, no use of immu-
nosuppressive agents for GVHD prophylaxis or treatment.
In the pre-antiviral era, CMV pneumonia developed at the
rate of 40 to 50% among bone marrow transplantation pa-
tients and its mortality exceeded 90% (1, 10). With the intro-
duction of preemptive and prophylactic treatments for CMV
following HSCT, the incidence of CMV pneumonia has dro-
pped to 10.6% (24). A combination of ganciclovir and intra-
venous immunoglobulin for the treatment of CMV pneumo-
nia contributed to the improvement of survival rate at 3 mon-
ths to between 48% and 85% (25-27). However, the survival
rates have decreased further with time. Viral pneumonia was
one of the most fatal pulmonary complications after HSCT
even with antiviral therapies following aggressive interven-
tions in our study. Among the 73 patients with pulmonary
complications following HSCT, 34 patients required inten-
sive care and 21 patients died despite mechanical ventilation
support in our series. In general, viral and fungal infections,
diffuse alveolar hemorrhage and idiopathic pneumonia syn-
drome were associated with high mortality.
HSCT is an effective and promising therapeutic tool for a
number of malignant and non-malignant conditions. Its suc-
cess, however, is occasionally limited by the high incidence
of complications, especially those related to the pulmonary
system. An early broncoscopy with BAL and transbronchial
biopsy has been recommended for diffuse interstitial lung
diseases (28-30) and a percutaneous fine-needle aspiration for
focal lung lesions with excellent yield (31). However, prog-
nosis is grave despite of early detection of the pathogen of
pulmonary complications by invasive procedures. Consider-
ing the rapid clinical deterioration in these patients, an early
aggressive diagnostic work-up should be pursued. Effective
prophylaxis and empirical treatment are very important for
high-risk group of HSCT recipients to prevent viral or fun-
gal pneumonia.
It was confirmed in our study that allogeneic transplant,
acute and chronic GVHD requiring treatment were impor-
tant risk factors for pulmonary complications after HSCT.
Therefore, a deliberate selection of transplant type and pro-
phylaxis and timely treatment of GVHD are critical to min-
imize the mortality and morbidity from pulmonary compli-
cations after HSCT.
ACKNOWLEDGMENTS
We thank Debra Phillips, Pharm.D. for critical reading of
the manuscript and editorial assistance.
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