Pulmonary Complications After Allogeneic Hematopoietic Cell Transplantation - UpToDate

12/10/2020 Pulmonary complications after allogeneic hematopoietic cell transplantation - UpToDate
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Pulmonary complications after allogeneic hematopoietic

cell transplantation
Authors: Robert J Kaner, MD, Dana Zappetti, MD
Section Editors: Talmadge E King, Jr, MD, Robert S Negrin, MD
Deputy Editor: Helen Hollingsworth, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2020. | This topic last updated: Aug 08, 2018.
INTRODUCTION
Allogeneic hematopoietic cell transplantation (HCT) is the treatment of choice for many
hematologic disorders. Pulmonary complications are a common cause of morbidity and
occasionally mortality following this procedure [1-4].
Certain aspects of the transplant procedure influence the later development of pulmonary
disease; the pretransplant conditioning regimen and posttransplant immunosuppression
contribute to direct lung toxicity and increase the risk of opportunistic infections.
The pulmonary complications of allogeneic HCT will be reviewed here. The determination of
eligibility for HCT, infectious complications of HCT, supportive care following HCT, and pulmonary
complications of autologous HCT are discussed separately. (See "Determining eligibility for
allogeneic hematopoietic cell transplantation" and "Overview of infections following
hematopoietic cell transplantation" and "Early complications of hematopoietic cell
transplantation" and "Pulmonary complications after autologous hematopoietic cell
transplantation".)
OVERVIEW AND DEFINITIONS
Hematopoietic cell transplantation (HCT) is a general term for a variety of procedures in which the
patient is treated with chemotherapy and/or irradiation (ie, the "preparative regimen") followed by
the infusion of hematopoietic progenitor cells. Progenitor cells can come from a variety of sources
(eg, bone marrow, peripheral blood, cord blood). (See "Sources of hematopoietic stem cells".)
Allogeneic versus autologous HCT — Allogeneic HCT refers to the use of hematopoietic

progenitor cells collected from a relative (which can be human leukocyte antigen [HLA] identical,
haploidentical, or mismatched) or an unrelated donor (volunteer or umbilical cord donor).
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Autologous HCT refers to collection of hematopoietic progenitor cells from the patient prior to the
administration of high dose chemotherapy designed to target an underlying malignancy, followed
by reinfusion of these cells.
Many of the pulmonary complications of allogeneic HCT also occur with autologous HCT, but
there are some important differences. Prevention of graft rejection and graft-versus-host disease
(GVHD) in allogeneic HCT necessitates more intense immunosuppression than that required for
autologous HCT, which does not have these complications. Allogeneic grafts may be associated
with development of potentially detrimental GVHD. On the other hand, some allogeneic HCT
patients may benefit from a graft-versus-tumor effect. (See "Biology of the graft-versus-tumor
effect following hematopoietic cell transplantation".)
Autologous HCT is discussed separately. (See "Multiple myeloma: Use of autologous

hematopoietic cell transplantation" and "Pulmonary complications after autologous
hematopoietic cell transplantation" and "Determining eligibility for autologous hematopoietic cell
transplantation".)
Preparative conditioning regimen — Preparative conditioning regimens are designed to ablate

or suppress the host bone marrow and thereby prevent graft rejection, but have the potential to
cause pulmonary toxicity. Preparative regimens for HCT have been termed myeloablative (eg,
total body irradiation ≥5 Gy, high dose busulfan), nonmyeloablative (fludarabine,
cyclophosphamide, antithymocyte globulin, irradiation ≤2 Gy), and reduced intensity (eg, low dose
busulfan, melphalan). The various preparative conditioning regimens are discussed in greater
detail separately. (See "Preparative regimens for hematopoietic cell transplantation".)
Engraftment — Engraftment after HCT is defined as the attainment of an absolute neutrophil

count (ANC) of 1000/microL, or three consecutive days with a count greater than 500. Time to
engraftment is variable, and dependent on multiple variables, including cell source, graft
composition, and type of conditioning.
At the time of engraftment of donor hematopoietic cells, patients may develop a cytokine-driven
engraftment syndrome. (See 'Engraftment syndrome' below.)
Maintenance immunosuppression — After allogeneic HCT, maintenance immunosuppression is

administered to prevent graft rejection and GVHD. A commonly used regimen is the combination
of methotrexate and a calcineurin inhibitor such as cyclosporine or tacrolimus; alternative or
additional agents include glucocorticoids, sirolimus, mycophenolate mofetil, and also agents
targeting T cell depletion. These agents contribute to the risk of pulmonary toxicity and
opportunistic infections. (See "Prevention of acute graft-versus-host disease".)
Graft-versus-host disease — Graft-versus-host disease (GVHD) occurs when immune cells

transplanted from a non-identical donor (the graft) recognize the transplant recipient (the host) as
foreign, thereby initiating an immune reaction that causes disease in the transplant recipient.
Hyperacute GVHD, which is rare with current HLA typing, occurs in the first 14 days post HCT,
acute GVHD in the first 100 days, and chronic GVHD after the first 100 days, although the specific

timing is approximate. Despite preconditioning and maintenance immunosuppression to prevent

GVHD, a substantial proportion of allogeneic HCT recipients are affected by GVHD. GVHD in turn
may increase the risk of certain pulmonary complications, such as the idiopathic pneumonia
syndrome, diffuse alveolar hemorrhage, bronchiolitis obliterans, and late-occurring infections.
CAUSES AND CLINICAL MANIFESTATIONS
The types of pulmonary complications that occur following allogeneic hematopoietic cell
transplantation (HCT) vary based on the time since the transplant occurred, although some
complications can occur both early and late (table 1 and table 2).
Pre-engraftment period — In the pre-engraftment period from HCT up to engraftment (eg,

about 0 to 30 days post HCT), the differential diagnosis of pulmonary complications includes
infection, pulmonary edema due to cardiac and noncardiac causes such as sepsis syndrome or
aspiration, and the engraftment syndrome (table 1). Symptoms and signs are nonspecific and
include fever, dyspnea, cough, and hypoxemia.
Pulmonary infections — Infections due to aerobic gram positive and gram negative bacteria,
fungi, and certain viruses occur in up to 10 percent of HCT recipients in the pre-engraftment
phase (figure 1) [5-7]. In addition to the effects of neutropenia, mucositis from the conditioning
regimen contributes to the risk of infection via swallowing difficulties, aspiration, and possibly
impaired mucociliary clearance [8-10]. Distinguishing clinical, radiographic, and other diagnostic
features of these infections are shown in the table (table 1). A general approach to lung infection
in immunocompromised patients and the spectrum of infections that complicate HCT is provided
separately. (See "Approach to the immunocompromised patient with fever and pulmonary
infiltrates" and "Overview of infections following hematopoietic cell transplantation", section on
'Pneumonia'.)
Among 427 consecutive allogeneic recipients, bacterial pneumonia developed in the first post-
HCT month in 4 percent; fungal pneumonia in 9 percent, and viral pneumonia in 2 percent; 4
percent had suspected pneumonia without a specific organism being identified [6]. Pneumonia
was a major contributor to mortality [6]. The most common bacterial causes of pneumonia were
Escherichia coli, Pseudomonas aeruginosa, and Streptococcus pneumoniae.
HCT recipients are at risk for serious lung infection due to respiratory virus infections, such as
influenza A and B, parainfluenza viruses (PIV) especially PIV 3, respiratory syncytial virus (RSV),
and human metapneumovirus (hMPV). Lymphopenia appears to be an important risk factor for
respiratory virus infection.
Aspergillus pneumonia in neutropenic patients may present with the classic triad of fever, pleuritic
chest pain, and hemoptysis, although this triad is frequently not present. The radiographic
appearance is varied and includes single or multiple nodules with or without cavitation, patchy or
segmental consolidation, or peribronchial opacities (image 1). A characteristic feature of
Aspergillus nodules in the neutropenic patient is a surrounding ground glass opacity (the halo
sign) that reflects angioinvasion and hemorrhage into the surrounding tissue (image 2). However,
the halo sign is not specific to Aspergillus and can be seen with other fungi, such as Fusarium spp,
agents of Mucormycosis, and Scedosporium spp.
Candida pneumonitis is rare due to the frequent use of prophylaxis with antifungal azole
derivatives. In a case series of Candida pneumonitis in HCT recipients, the typical presentation
was fever unresponsive to board-spectrum antibiotics [11]. CT findings included multiple nodules
ranging from 3 to 30 mm in diameter in 15 patients [11]. Air-space consolidation was present in
11 patients and in five, nodules were surrounded by discrete areas of ground-glass opacity (CT
halo sign). In those patients with acute lung injury due to Candida pneumonitis, the CT scan
showed extensive ground glass opacities in addition to a focal area of consolidation. The
bronchoalveolar lavage grew Candida in all patients.
Pulmonary edema — Pulmonary edema of cardiogenic or noncardiogenic origin can occur in

the first month after HCT, sometimes complicating other processes such as pneumonia, sepsis,
the engraftment syndrome, or hyperacute graft-versus-host-disease (GVHD). (See 'Engraftment
syndrome' below and 'Hyperacute and acute graft-versus-host disease' below.)
Cardiac dysfunction can result from previous therapy for the primary disease with
cyclophosphamide, anthracyclines, or external beam chest irradiation. Among patients with mild
cardiac dysfunction, the administration of large volumes of intravenous fluids because of
mucositis or antibiotic treatment for neutropenic fever can lead to pulmonary edema. The
radiographic manifestations of cardiogenic pulmonary edema include interlobular septal
thickening, cephalad vascular distribution, ground glass opacification (sometimes in a perihilar
"butterfly" distribution) (image 3), pleural effusions, and sometimes cardiomegaly. The plasma
brain natriuretic peptide (BNP) is usually elevated and the echocardiogram shows left ventricular
dysfunction. The evaluation of cardiogenic pulmonary edema is discussed separately. (See
"Approach to diagnosis and evaluation of acute decompensated heart failure in adults".)
On the other hand, noncardiogenic pulmonary edema can be induced by sepsis, aspiration
pneumonia, viral infection (eg, influenza) [12], toxic effects of the conditioning regimen, or
hyperacute GVHD. The evaluation of noncardiogenic pulmonary edema is discussed separately.
(See "Noncardiogenic pulmonary edema" and "Clinical manifestations, diagnosis, and grading of
acute graft-versus-host disease", section on 'Timing and organ involvement'.)
Patients with severe hepatic veno-occlusive disease (another complication of HCT) can present
with either cardiogenic or noncardiogenic pulmonary edema with pleural effusions. (See
"Diagnosis of hepatic sinusoidal obstruction syndrome (veno-occlusive disease) following
hematopoietic cell transplantation", section on 'Clinical features'.)
Engraftment syndrome — The engraftment syndrome is a noninfectious complication that is

reported in 7 to 10 percent of autologous HCT, but only rarely following allogeneic HCT [13]. It
develops around 7 to 11 days following HCT during the time of neutrophil recovery [14]. The
engraftment syndrome usually causes only mild symptoms, but can result in dyspnea, fever

≥38.3˚C, an erythematous maculo-papular rash (not attributable to a drug), weight gain,

hypoxemia, and diffuse pulmonary opacities consistent with noncardiogenic pulmonary edema
[15-21].
The pulmonary manifestations of the engraftment syndrome are felt to be due to diffuse capillary
leakage. Findings on chest computed tomography include bilateral ground-glass opacification,
hilar or peribronchial consolidation, and thickening of interlobular septa [13,22,23]. Pleural
effusions were common in one series [14,24]. Bronchoalveolar lavage may show neutrophilia [14].
In two patients who underwent lung biopsy, diffuse alveolar damage was noted.
The presence of a skin rash raises the possibility that the engraftment syndrome is a
manifestation of hyperacute GVHD. However, the exact findings on skin biopsy in patients with
engraftment syndrome include mild edematous changes of the epidermal-dermal junction,
absence of lymphocytic infiltration, presence of neutrophils in the lumen of small venules and
capillaries [20]. In contrast, skin biopsy in acute GVHD typically shows interface dermatitis
(vacuolization of the basal layer of the epidermis and a lymphocytic infiltrate in the superficial
dermis) and epidermal apoptotic keratinocytes. However, the accuracy of differentiation of these
processes by skin biopsy is unclear. (See "Cutaneous manifestations of graft-versus-host disease
(GVHD)", section on 'Skin biopsy'.)
The evaluation and management of the engraftment syndrome are discussed separately. (See
"Pulmonary complications after autologous hematopoietic cell transplantation", section on
'Engraftment syndrome and PERDS'.)
Hyperacute and acute graft-versus-host disease — Hyperacute and acute GVHD are the
consequence of HLA mismatch between the donor and recipient. With accurate HLA typing using
molecular methods, hyperacute GVHD is very rare.
Hyperacute GVHD occurs in the first 14 days post-transplant and is frequently (88 percent)
associated with both skin involvement and noncardiogenic pulmonary edema. (See "Clinical
manifestations, diagnosis, and grading of acute graft-versus-host disease", section on 'Clinical
and histological manifestations'.)
Acute graft-versus-host disease (GVHD) develops in the first 100 days following allogeneic HCT,
although it is recognized that signs and symptoms can occur later in some patients' acute GVHD.
It rarely affects the lung directly, although it can be a risk factor for noncardiogenic pulmonary
edema, diffuse alveolar hemorrhage, and later development of airflow obstruction. (See 'Diffuse
alveolar hemorrhage' below and 'Pulmonary edema' above and 'Airflow obstruction and
bronchiolitis obliterans' below and "Clinical manifestations, diagnosis, and grading of acute graft-
versus-host disease".)
Post hematopoietic cell engraftment — The spectrum of pulmonary complications changes in

the period after engraftment. Infections continue to be a significant cause of morbidity and
mortality, although the specific organisms differ (figure 1). The idiopathic pneumonia syndrome,
diffuse alveolar hemorrhage, and pulmonary alveolar proteinosis are infrequent, but can cause

substantial pulmonary morbidity (table 2). Noncardiogenic and cardiogenic pulmonary edema are
more common pre-engraftment, but also occur postengraftment. Pulmonary thromboembolism
has not specifically been associated with allogeneic HCT, but is a potential complication of
hospitalization and severe medical illness.
Pulmonary infections — In the postengraftment period (ie, three weeks to three months),
impaired cellular and humoral immunity are the main factors contributing to pulmonary infection.
In the late postengraftment period (ie, more than three months after HCT), infectious
complications are less common; the major risk factors for infection in this phase are chronic
GVHD and its therapy. The organisms that cause lung infection in the postengraftment period are
shown in the figure (figure 1) and are discussed in detail separately. (See "Overview of infections
following hematopoietic cell transplantation".)
The features related to postengraftment pulmonary infection are reviewed here:
● Bacteria – Lung infection due to S. pneumoniae and H. influenzae, although less frequent than
pre-engraftment, continues to occur in the first year post-HCT, largely associated with defects
in cellular and humoral immunity. During this period, numerous other bacteria can cause
infection, including Legionella, Nocardia, and Actinomyces. (See "Overview of infections
following hematopoietic cell transplantation".)
● Mycobacteria – Mycobacterial and atypical mycobacterial infections are occasionally

reported after HCT [25]. The overall incidence of M. tuberculosis infections in allogeneic bone
marrow transplant patients is 1 to 3 percent, except in Hong Kong where the incidence is
reported to be >5 percent [26]. Total body irradiation and chronic GVHD (requiring enhanced
immunosuppressive therapy) are associated with an increased risk of tuberculosis. Allogeneic
HCT is associated with depressed delayed-type hypersensitivity reactions, so skin testing with
purified protein derivative (PPD) is not likely to be helpful. Sputum samples are usually
diagnostic. (See "Overview of infections following hematopoietic cell transplantation", section
on 'Pneumonia'.)
M. haemophilum and M. avium complex can be important pulmonary pathogens after HCT
[25,27,28]. The diagnosis of M. haemophilum should be suspected in patients who have skin
nodules or joint inflammation with or without pulmonary infiltrates. Confirmation of the
diagnosis requires special culture conditions for isolation; thus, close communication with the
microbiology laboratory is essential. Failure to recognize this treatable pathogen in a timely
fashion can lead to a fatal outcome.
The treatment of mycobacterial infections is discussed separately. (See "Treatment of drug-

susceptible pulmonary tuberculosis in HIV-uninfected adults" and "Treatment of
Mycobacterium avium complex pulmonary infection in adults".)
● Cytomegalovirus – Cytomegalovirus (CMV) pneumonitis rarely occurs during the pre-

engraftment period as the major risk involves cellular immunity. However, once engraftment
occurs, it should be included in the differential diagnosis of cough, fever, or dyspnea, even in

the absence of radiographic abnormalities. The risk is highest in seropositive recipients who
receive marrow from a seronegative donor. Preemptive and prophylactic antiviral therapy has
markedly reduced the incidence and severity of CMV disease and delayed its onset, although
CMV must be considered in any allogeneic HCT recipient who is CMV seropositive or received
hematopoietic cells from a seropositive donor [29]. Chest radiographs typically show patchy
areas of ground glass or consolidation (image 4). High resolution computed tomography
(HRCT) may show ground glass attenuation, parenchymal opacification, or innumerable small
(<5 mm) nodules [30,31].
CMV pneumonitis is discussed separately. (See "Overview of infections following

hematopoietic cell transplantation", section on 'Pneumonia' and "Overview of diagnostic tests
for cytomegalovirus infection".)
● Respiratory viruses – Community-acquired infections with influenza, parainfluenza,

respiratory syncytial virus, adenoviruses, and human metapneumovirus can occur during the
postengraftment period (figure 1 and table 2). Some specific details that pertain to
postengraftment lung infection in HCT recipients are provided below. Viral infections
following HCT are discussed in greater detail separately. (See "Overview of infections
following hematopoietic cell transplantation" and "Diagnostic approach to community-
acquired pneumonia in adults", section on 'Viral infections'.)
Influenza virus has the potential to cause serious lung infection and respiratory failure
among HCT recipients [32]. This was noted in particular with the 2009 pandemic influenza
A/H1N1 [33]. Infections with influenza tend to be seasonal, predominantly between
November and April in North America. Progression to pneumonia is more likely among
lymphopenic patients and thus is more common pre-engraftment than postengraftment [32].
(See "Diagnosis of seasonal influenza in adults", section on 'Choice of diagnostic test'.)
Parainfluenza virus, a recognized cause of both upper and lower respiratory tract disease
after HCT, affects 2 to 7 percent of HCT recipients and is seasonal. There are four serotypes,
with type 3 being the most common cause of lung infection after HCT; the incubation period
is one to four days. Upper respiratory tract symptoms may precede lower tract disease by
several days, although pneumonia may occur without upper respiratory symptoms.
Parainfluenza virus is also associated with asymptomatic shedding in HCT recipients.
The HRCT findings in parainfluenza virus pneumonia include small peribronchial nodular
opacities, ground glass opacities, and/or air space consolidation (image 5). The evaluation
and treatment of parainfluenza virus are discussed separately. (See "Parainfluenza viruses in
adults", section on 'Clinical manifestations'.)
Pneumonia due to RSV affects adult patients as well as children and has a high mortality after
HCT [34]. There is a marked seasonal variation in incidence, with the peak between January
and March. In addition, RSV can occur as a nosocomial outbreak [35]. The presence of
concomitant otitis media or sinusitis should raise the suspicion for RSV infection. Diffuse

ground glass opacities are the most common radiographic pattern associated with RSV
pneumonitis. The diagnosis can be established by culture or rapid immunofluorescence of
respiratory secretions, throat swabs, or nasopharyngeal washes. (See "Respiratory syncytial
virus infection: Clinical features and diagnosis" and "Respiratory syncytial virus infection:
Treatment".)
Adenoviruses, which can be isolated in 3 to 5 percent of patients after HCT, should be

considered in the differential diagnosis of pulmonary infection [36]. Affected patients present
with pharyngitis, tracheitis, bronchitis, pneumonitis, enteritis, hemorrhagic cystitis, or
disseminated disease and may progress to fatal pneumonia. The specific pattern of
symptoms depends at least in part on the particular serotype and on the age of the recipient.
Younger HCT recipients appear to be at risk for more severe infection. Asymptomatic
shedding of adenovirus can often be detected in cultures from the pharynx, respiratory
secretions, stool, or urine two to three months post-HCT [37]. The clinical manifestations,
diagnosis, and management of adenovirus lung infection are discussed in detail separately.
(See "Pathogenesis, epidemiology, and clinical manifestations of adenovirus infection" and
"Diagnosis, treatment, and prevention of adenovirus infection", section on 'Treatment'.)
Human metapneumovirus is emerging as a pathogen affecting HCT recipients and is

discussed separately. (See "Human metapneumovirus infections".)
● Human herpesvirus 6 – Pneumonia due to human herpesvirus-6 (HHV-6) has been reported
after HCT, although active pneumonitis due to this virus appears uncommon [38,39]. HHV-6
reactivation occurs in approximately half of allogeneic HCT recipients and may account for
some cases of pneumonitis previously considered to be idiopathic [40,41]. (See 'Idiopathic
pneumonia syndrome' below.) The clinical manifestations of HHV-6 infection are poorly
described, and the prevalence of HHV-6 as a cause of interstitial pneumonia post-HCT
remains to be determined. The diagnosis of HHV6 as a cause of pneumonitis has been drawn
into question given that this virus is latent in lymphocytes, which complicates the
interpretation of histopathology. (See "Clinical manifestations, diagnosis, and treatment of
human herpesvirus 6 infection in adults", section on 'Pneumonitis' and "Human herpesvirus 6
infection in hematopoietic cell transplant recipients", section on 'Other possible associations'.)
● Fungal infection – During the postengraftment period, patients are at risk for infection with
aspergillosis, other invasive molds, and Pneumocystis jirovecii (formerly P. carinii) pneumonia
(PCP) (table 2). The median time of onset of Aspergillus infection is 100 days post-HCT; risk
factors include older age, the presence and severity of GVHD, glucocorticoid therapy, and
leukopenias. The radiographic features of Aspergillus infection are described above. (See
'Pulmonary infections' above and "Overview of infections following hematopoietic cell
transplantation" and "Epidemiology and clinical manifestations of invasive aspergillosis",
section on 'Pulmonary aspergillosis' and "Diagnosis of invasive aspergillosis", section on
'Diagnostic modalities' and "Clinical manifestations and diagnosis of Fusarium infection",
section on 'Pneumonia'.)

Pneumocystis prophylaxis has reduced the risk of Pneumocystis pneumonia, which is a rare
infection in patients who receive prophylaxis and take their medications. PCP is usually
associated with diffuse radiographic opacities, but can occasionally present with focal
opacities, cavitations, or a normal initial chest radiograph. Rarely, the conventional chest
radiograph is normal in PCP, but high resolution computed tomography of the chest shows
ground glass opacities. PCP is described in greater detail separately. (See "Overview of
infections following hematopoietic cell transplantation" and "Epidemiology, clinical
manifestations, and diagnosis of Pneumocystis pneumonia in HIV-uninfected patients" and
"Treatment and prevention of Pneumocystis pneumonia in HIV-uninfected patients".).
● Toxoplasmosis – Reactivation of toxoplasmosis causing lung infection is rare following

allogeneic HCT, particularly because most HCT candidates are tested for IgG and IgM
antibodies to toxoplasmosis and, if positive, offered a course of therapy prior to HCT. The
infection typically develops in the second month after transplantation in patients with a
positive pretransplant serology who have not received preemptive treatment. The presence
of neurologic toxoplasmosis should prompt assessment for disseminated disease. The
radiographic presentation of toxoplasmosis is similar to that of Pneumocystis; Toxoplasma
tachyzoites can be identified in bronchoalveolar lavage (BAL) fluid. The clinical manifestations
and diagnosis of toxoplasmosis are discussed separately. (See "Toxoplasmosis in HIV-infected
patients", section on 'Clinical presentation' and "Overview of infections following
hematopoietic cell transplantation", section on 'Pneumonia' and "Diagnostic testing for
toxoplasmosis infection".)
Idiopathic pneumonia syndrome — The idiopathic pneumonia syndrome (IPS) is an

important complication that develops in up to 10 percent of patients and generally occurs within
four months after HCT, with a median time of onset of 19 days [13,42-46]. IPS may represent a
heterogeneous group of disorders that result in the common pathologic findings of interstitial
pneumonitis and/or diffuse alveolar damage.
A consensus conference defined IPS as a clinical syndrome that fulfills the following criteria [47]:
● Widespread alveolar injury, defined as multilobar opacities on chest radiograph or computed

tomography (CT) scan PLUS signs and symptoms of pneumonia PLUS evidence of abnormal
pulmonary physiology manifested by an increased alveolar-arterial oxygen gradient or the
need for supplemental oxygen.
● Absence of lower respiratory tract infection, as determined by a negative bronchoalveolar

lavage or lung biopsy, ideally followed by a second negative invasive test within two weeks. A
broad array of microbiologic tests are used to exclude infection. Appropriate tests depend on
the clinical features; examples are included in the table (table 2). Newer methods of
quantitative polymerase chain reaction (PCR) for a broad spectrum of pathogens may identify
additional potential culprits, although the etiologic importance of such agents is not entirely
clear. Nonetheless, it is possible that certain viruses (eg, HHV-6) may account for some cases
of pneumonitis previously considered to be idiopathic [41]. (See 'Pulmonary infections' above

and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on

'Other possible associations'.)
The exact pathogenesis of IPS is not known, but the intensity of the preparative conditioning
regimen has been implicated as a contributing factor (see 'Preparative conditioning regimen'
above). One retrospective study of 1100 patients found a lower incidence of IPS in patients
treated with a nonmyeloablative versus a myeloablative regimen (2 versus 8 percent) [43]. A
systematic analysis of 20 studies (1090 patients) found an association between the incidence of
IPS and the use of high dose radiotherapy, high dose cyclophosphamide, and busulfan [48].
Murine models suggest that these conditioning agents produce pulmonary epithelial injury
followed by recruitment and activation of pulmonary macrophages and T-lymphocytes [46,49-51].
The clinical manifestations include dyspnea, dry cough, hypoxemia, and diffuse radiographic
opacities [47]. The evaluation includes bronchoscopy with bronchoalveolar lavage and, if the
patient will tolerate it, transbronchial biopsy. Surgical lung biopsy is occasionally performed if the
transbronchial biopsy is contraindicated or inadequate [52]. (See 'Evaluation' below.)
Optimal therapy of IPS in HCT recipients is uncertain but typically involves high dose
glucocorticoids of 1 mg/kg or more, and the prognosis is poor. In a series of approximately 81
patients who developed IPS after HCT, the disease progressed rapidly and the mortality rate was
approximately 75 percent within 30 days of hospital discharge despite the use of high-dose
glucocorticoid therapy in the majority of patients [43]. Similar findings were noted in another
study in which the mortality rate at one year was more than 85 percent [42].
The observation that certain cytokines (eg, interleukin [IL]-6, IL-8, tumor necrosis factor
alpha[TNF-alpha]) are increased in the BAL fluid of patients with IPS has led to studies of the
combination of systemic glucocorticoids plus a TNF-alpha inhibitor, such as etanercept or
infliximab [46,52-57]. As examples:
● In a series of 15 patients with IPS who were treated with glucocorticoids plus etanercept (0.4
mg/kg [maximum 25 mg]) twice weekly with a maximum of eight doses, 10 patients had a
complete response within 3 to 18 days and the survival rate at 28 days was 73 percent [53].
However, survival was only 20 percent at six months, a rate that persisted out to four years.
● Similar results were reported for a series of 11 patients with IPS; six received high-dose
glucocorticoids alone and five also received etanercept or infliximab [54]. The overall initial
response rate was 81 percent; however, survival was only 30 percent at one year.
● In a series of 22 patients with IPS treated with glucocorticoids and etanercept, 28 day and 2
year survivals of 88.2 percent (95% CI 61-97 percent) and 18 percent (95% CI 4-38 percent)
were reported [56].
The safety and efficacy of TNF-alpha inhibitors for IPS are under investigation. Information about
clinical trials for IPS is available on the NIH clinical trials web site
(http://clinicaltrials.gov/ct2/results?term=idiopathic+pneumonia+syndrome).
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Diffuse alveolar hemorrhage — Diffuse alveolar hemorrhage (DAH) occurs in less than 1

percent of HCT and is less common following allogeneic than autologous HCT (image 6 and image
7) [58]. However, among patients who undergo allogeneic HCT for an inherited metabolic storage
disease, the risk of DAH is increased among those with mucopolysaccharidosis (19 percent), but
not leukodystrophies [59]. Onset can be within the first 30 days or later [60]. (See "Pulmonary
complications after autologous hematopoietic cell transplantation", section on 'Diffuse alveolar
hemorrhage'.)
DAH following HCT is of unclear pathogenesis, but may be a consequence of factors such as
infection, acute GVHD, or diffuse alveolar damage [61]. Mortality is high (>80 percent) whether
DAH is associated with infection or not [58].
Patients with DAH typically have patchy or diffuse opacities with air bronchograms on HRCT. The
diagnosis is typically made by BAL, which shows progressively hemorrhagic returns on sequential
lavages in the same subsegment and hemosiderin-laden macrophages on cytologic analysis. The
diagnostic evaluation of DAH is discussed in greater detail separately. (See "The diffuse alveolar
hemorrhage syndromes".)
Treatment of DAH in the setting of allogeneic HCT depends on the underlying cause of DAH.
● For patients with infection-associated DAH, management includes treatment of the infection
and general supportive care (eg, supplemental oxygen, mechanical ventilation). (See
appropriate topic reviews.)
● For patients with DAH in the setting of acute GVHD, treatment is aimed at the acute GVHD
with supportive care (eg, supplemental oxygen, mechanical ventilation) as necessary. Empiric
antibiotics are often administered simultaneously. (See "Treatment of acute graft-versus-host
disease", section on 'Initial management' and "Prevention of acute graft-versus-host
disease".)
● For patients without evidence of infection or acute GVHD, systemic glucocorticoids are
typically administered, despite the absence of formal data. In one report, four patients with
DAH following allogeneic stem cell transplantation rapidly responded to glucocorticoids,
although two of the patients ultimately died of multiple organ dysfunction [62]. Conversely,
no significant response to glucocorticoids was noted in a small retrospective study of children
who developed DAH following allogeneic stem cell transplantation [63]. Similarly, in a larger
retrospective series, there was no obvious survival benefit with glucocorticoid treatment [64].
Use of recombinant human Factor VII for refractory alveolar hemorrhage has been reported [65-
68]; the risks of fatal thrombotic events must be weighed if this therapy is considered.
Connective tissue disease — A small number of patients have developed pulmonary

involvement with autoimmune disease (eg, scleroderma, polymyositis, Sjögren syndrome,
antineutrophil cytoplasmic antibody-positive vasculitis) following allogeneic HCT; the mean onset

is late, 31 months after HCT [69]. The majority of these patients received a myeloablative
conditioning regimen. A history of prior or current GVHD was common.
In a case series and literature review, the pulmonary manifestations of autoimmune disease
included nonspecific interstitial pneumonia, lymphocytic pneumonia, diffuse alveolar damage,
and bronchiolitis obliterans [69]. Autoantibodies, such as antinuclear antibody, anti-Scl70,
antineutrophil cytoplasmic antibody (ANCA), anti-smooth muscle, and rheumatoid factor, were
frequently noted. The patients described have had a poor prognosis, despite treatment with
systemic glucocorticoids [69]. (See "Clinical manifestations, diagnosis, and grading of chronic
graft-versus-host disease", section on 'Autoantibodies' and "Lymphoid interstitial pneumonia in
adults" and "Treatment and prognosis of nonspecific interstitial pneumonia" and "Acute
interstitial pneumonia (Hamman-Rich syndrome)".)
Organizing pneumonia — Organizing pneumonia (OP, also known as bronchiolitis obliterans

organizing pneumonia or BOOP) is reported following allogeneic HCT [70,71] and may be
cryptogenic or related to lung irradiation, GVHD, or successful treatment of CMV pneumonitis [72-
74], or chronic GVHD [75,76]. CT scans from patients with OP often reveal more extensive lung
disease than expected from review of the plain chest radiograph. Radiographic patterns include
patchy air-space consolidation, ground-glass opacities, small nodular opacities, and bronchial wall
thickening with dilation. Patchy opacities occur most frequently in the periphery of the lung and
at the lung bases. The diagnosis of OP is based upon the characteristic histopathologic pattern
seen on surgical lung biopsy; treatment with systemic glucocorticoids is usually beneficial. The
evaluation and management of organizing pneumonia is discussed separately. (See "Cryptogenic
organizing pneumonia".)
Malignancy — The lungs can be the site of relapse of the underlying malignancy, development
of a second cancer years after HCT, and secondary lymphoproliferative disease. Recurrence of the
underlying malignancy in the lung is seen most commonly after allogeneic HCT for lymphoma.
(See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B
cell lymphoma" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and
"Hodgkin lymphoma: Epidemiology and risk factors" and "Clinical manifestations, pathologic
features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid
tissue (MALT)".)
Posttransplant lymphoproliferative disease (PTLD) developing after allogeneic HCT is thought to

be a consequence of immunosuppression, which causes a deficiency in Epstein-Barr virus (EBV)
specific cytotoxic T lymphocytes [77,78]. The typical appearance of PTLD on chest CT is multiple
pulmonary nodules with a peripheral or basal predominance; other patterns include patchy
consolidation, mediastinal and hilar lymphadenopathy, pleural or chest wall masses and pleural
effusion [79]. Biopsy and histopathologic analysis are needed for diagnosis, which typically
reveals EBV. While refractory to standard chemotherapy, post-HCT lymphoproliferative disease
may respond to other treatment protocols, including rituximab and reduced immunosuppression
[80]. The diagnosis and management of secondary lymphoproliferative disorders are discussed
separately. (See "Treatment and prevention of post-transplant lymphoproliferative disorders".)
Pulmonary alveolar proteinosis — Pulmonary alveolar proteinosis (PAP) has been reported as

a reversible cause of respiratory failure after allogeneic HCT for acute leukemia [81,82]. PAP
presents with dyspnea and perihilar opacities in a "bat-wing" distribution on chest radiograph
(image 8 and image 9). The diagnosis is made by BAL; the BAL fluid has a characteristic milky
appearance and stains positively for lipoproteins. (See "Causes, clinical manifestations, and
diagnosis of pulmonary alveolar proteinosis in adults" and 'Bronchoscopy' below and
"Mucopolysaccharidoses: Clinical features and diagnosis".)
Pulmonary cytolytic thrombi — Pulmonary cytolytic thrombi (PCT) are an unusual

complication of allogeneic HCT; PCT is without known etiology, although it may be a
manifestation of acute and chronic GVHD [83,84]. PCT is more common in children [52,84]. The
clinical presentation is fever, cough and dyspnea; conventional chest radiographs are usually
clear, but HRCT shows numerous peripheral tiny pulmonary nodules. Peripheral nodular lesions
have a broad differential in allogeneic HCT recipients, including aspergillus infection, OP,
metastatic malignancy, or idiopathic interstitial pneumonia [84]. As these processes require very
different treatment, a definitive diagnosis is essential.
A surgical lung biopsy is usually necessary to make the diagnosis of PCT and is performed after
the usual blood and BAL studies to exclude infection fail to identify an infection. The
histopathology of PCT reveals basophilic cytolytic thrombi in the small to medium distal
pulmonary vessels with entrapped monocytes [85]. Hemorrhagic infarcts are present, similar to
those seen in invasive aspergillus infection, but stains and cultures for aspergillus are negative.
The optimal treatment for PCT is not known, although systemic glucocorticoid therapy has been
associated with successful outcomes [84,86].
Pulmonary veno-occlusive disease — Pulmonary veno-occlusive disease (PVOD) occurs rarely

after allogeneic HCT and may be a consequence of pretransplant chemotherapy for the
underlying malignancy [87]. It generally occurs late in the course, after the first 100 days, and
should be suspected in patients with dyspnea, reduced diffusing capacity (DLCO), mild restriction
on pulmonary function tests, and no evidence of infection, particularly if there is evidence of
pulmonary venous congestion on imaging studies and pulmonary arterial hypertension in the
absence of left-sided heart disease on right heart catheterization.
Chest radiographs often reveal a pleural effusion and Kerley B lines may be noted. CT may reveal
septal thickening, diffuse or mosaic ground glass opacities with a centrilobular distribution,
multiple small nodules, or alveolar consolidation. CT pulmonary angiography shows no evidence
of pulmonary emboli. Doppler echocardiography shows pulmonary hypertension. Right-sided
heart catheterization is necessary to document the combination of pulmonary hypertension and a
normal pulmonary artery occlusion pressure. Occult alveolar hemorrhage may be found on BAL
[88]. A presumptive diagnosis of PVOD is based on an integrated assessment of these findings;
however, lung biopsy is required for definitive confirmation of the diagnosis.

The diagnosis and treatment of PVOD are discussed separately. (See "Epidemiology,
pathogenesis, clinical evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary
capillary hemangiomatosis in adults".)
Drug toxicity and radiation pneumonitis — Allogeneic HCT recipients are at risk for lung
toxicity due to the chemotherapeutic agents (eg, busulfan, cyclophosphamide, carmustine,
sirolimus) and radiation therapy used for preparative conditioning, or for treatment of the
underlying disease prior to HCT. (See "Busulfan-induced pulmonary injury" and
"Cyclophosphamide pulmonary toxicity" and "Nitrosourea-induced pulmonary injury" and
"Methotrexate-induced lung injury" and "Pharmacology of mammalian (mechanistic) target of
rapamycin (mTOR) inhibitors", section on 'Respiratory system'.)
Acute radiation pneumonitis usually develops 4 to 12 weeks after irradiation, whereas symptoms
of late or fibrotic radiation pneumonitis develop after 6 to 12 months. (See "Radiation-induced
lung injury".)
Both drug toxicity and radiation pneumonitis usually present with dyspnea and a nonproductive
cough; fever may also be present. Chest radiographs can show patchy or diffuse opacities with
ground glass or consolidative attenuation. The evaluation and treatment of cytotoxic
antineoplastic agent and irradiation-induced lung injury are discussed separately. (See
"Cyclophosphamide pulmonary toxicity" and "Busulfan-induced pulmonary injury" and
"Methotrexate-induced lung injury" and "Radiation-induced lung injury".)
Airflow obstruction and bronchiolitis obliterans — Airflow obstruction developing after

allogeneic HCT may be a consequence of HCT or may be due to bronchiolitis obliterans (BO). BO is
manifest pathologically by development of small airways inflammation and narrowing due to
fibrous scar. These changes are associated with the clinical finding of airflow limitation. The term
bronchiolitis obliterans syndrome (BOS) is used when a patient has airflow limitation in the
absence of other etiologies, but histopathology to document BO is not available. (See "Overview
of pulmonary function testing in adults".)
● Mild airflow limitation – Mild decrements in lung function are frequent following HCT, but
are rarely symptomatic and chest radiographs are usually normal [89-91]. As an example, one
study of 52 patients who received allogeneic or autologous bone marrow transplants during
childhood found that spirometry, lung volume, and diffusing capacity measurements were
within normal limits in only 62 percent [92]. However, none reported chronic respiratory
symptoms. In a second study, airflow obstruction was present in 26 percent of patients after
allogeneic HCT [89]. Risk factors for the development of airflow obstruction included older
age, a history of acute or chronic GVHD, and respiratory viral infections in the early post-
transplant period. The pathophysiology of this mild airways obstruction is not well
understood, but does not appear to be related to airway hyperresponsiveness [93-95].
● Bronchiolitis obliterans risk factors – Moderate-to-severe airflow obstruction is usually a

manifestation of bronchiolitis obliterans, which is thought to be similar to BOS that is a

manifestation of chronic rejection in lung transplant recipients (picture 1A-B) [96,97]. The
cause of bronchiolitis obliterans after HCT is unknown, although risk factors such as chronic
GVHD, ABO blood group incompatibility, use of peripheral blood stem cells, and certain viral
infections have been identified [98-100].
● Clinical presentation – Chronic GVHD is a late (>100 days) complication of allogeneic HCT.
Initially, patients with bronchiolitis obliterans often have a normal lung examination and a
clear chest radiograph. As the disease progresses, the chest CT may show bronchiectasis and
a mosaic pattern of ground glass opacities [101]. (See "Chronic lung transplant rejection:
Bronchiolitis obliterans", section on 'Diagnosis'.)
● Diagnosis – BOS is suspected clinically when new airflow obstruction is found in the absence
of infection (especially viral infection) and when the exam and high resolution CT chest with
expiratory images are both suggestive of bronchiolitis. Care must be taken to exclude the
infectious causes of bronchiolitis.
● Initial treatment – Treatment of BOS following HCT is based on clinical experience and
observational data. Some experts (including us) initiate treatment with high-dose inhaled
glucocorticoids (eg, budesonide >720 mcg/day, fluticasone propionate >440 mcg/day) at the
onset of mild airflow limitation (forced expiratory volume in one second [FEV1] ≥70 percent
predicted, but <80 percent) and administer systemic immunosuppressive therapy as indicated
for extrapulmonary manifestations of GVHD (table 3) [102,103].
An inhaled long-acting beta-agonist (LABA) may be used in combination, particularly if the

patient is symptomatic [103-105]. The inhaled glucocorticoid is continued until airflow
obstruction worsens or until six months after systemic immunosuppressive therapy for GVHD
has been successfully discontinued.
● Continued symptoms despite inhaled glucocorticoids – Many experts will expand the
regimen to “FAM” therapy (ie, inhaled fluticasone 440 mcg twice daily, azithromycin 250 mg
three times weekly, and montelukast 10 mg daily) for those patients who continue to have
FEV1 decline and symptoms on inhaled glucocorticoids/LABA. This is based only upon small
studies that demonstrate low risk and some evidence of FEV1 stability [106,107].
● Progressive worsening of airflow limitation – If airflow limitation progresses (FEV1 <70

percent predicted) with or without significant airtrapping on HRCT, infection is carefully
excluded (see 'Pulmonary infections' above), and systemic glucocorticoids are initiated or
increased to the equivalent of prednisone 1 mg/kg per day (table 3). For patients with
worsening airflow limitation and requiring systemic glucocorticoids, additional agents may
include azithromycin (250 mg) three times weekly and montelukast 10 mg/day, although
supportive evidence is limited [106]. The dose of prednisone is tapered within two weeks of
objective improvement in lung function with further tapering at two week intervals as
tolerated.

● Refractory bronchiolitis obliterans – Some patients with refractory BOS due to chronic
GVHD respond to glucocorticoids and increased immune suppression, but often BOS is
irreversible. Other patients respond poorly to treatment and progress to hypercapnia and
respiratory failure [96,97,108-110]. In two small case series of patients with refractory
disease, lung transplantation was successful [111,112]. In one series, 13 patients underwent
lung transplantation and 11 survived (median follow-up 4.2 years), although 4 subsequently
developed BOS in the lung allograft. (See "Lung transplantation: An overview" and "Lung
transplantation: General guidelines for recipient selection".)
● Prevention – Prophylactic azithromycin improves BOS-free survival after lung

transplantation, but a multicenter, randomized trial found that azithromycin had a
deleterious effect after HCT [113]. A total of 480 patients were assigned to receive
azithromycin 250 mg or placebo, three times per week, starting at the time of the
conditioning regimen. The trial was stopped early because of increased hematologic relapse
in the azithromycin group. In addition, the azithromycin group experienced a decrease in
airflow decline-free survival. Based on this information, the US Food and Drug Administration
has issued a safety alert recommending that long-term azithromycin not be prescribed for
prophylaxis of BOS after HCT pending further review [114].
APPROACH TO THE PATIENT WITH RESPIRATORY SYMPTOMS OR SIGNS
The approach to evaluating pulmonary complications that occur after allogeneic hematopoietic
cell transplantation (HCT) begins with considering the timing of onset of the pulmonary disease
(eg, before or after engraftment), the appearance of the chest radiograph (eg, clear, focal
opacities, diffuse opacities), and the following features (table 1 and table 2):
● The risk for certain infections can be predicted based on pretransplant serostatus (eg,
cytomegalovirus, herpes simplex virus, HIV, varicella-zoster virus, Epstein-Barr virus,
toxoplasmosis), prior exposures (eg, cats, birds, mycobacteria, endemic fungi) of the recipient
and donor, and also the history of prophylaxis for infectious agents. (See "Overview of
infections following hematopoietic cell transplantation", section on 'Risk of infection'.)
● History of timing, dose, and field of radiation therapy delivered to the chest to treat the
underlying malignancy or as part of the conditioning regimen, as radiation pneumonitis is a
potential cause of respiratory symptoms and signs. (See "Radiation-induced lung injury".)
● Exposure to drugs that cause pulmonary or cardiac toxicity during the pretransplant
treatment of the primary disease. (See "Pulmonary toxicity associated with systemic
antineoplastic therapy: Clinical presentation, diagnosis, and treatment" and "Pulmonary
toxicity associated with antineoplastic therapy: Cytotoxic agents" and "Cardiotoxicity of non-
anthracycline cancer chemotherapy agents" and "Clinical manifestations, monitoring, and
diagnosis of anthracycline-induced cardiotoxicity" and "Prevention and management of
anthracycline cardiotoxicity".)

● Knowledge of the current and previous immunosuppressive and chemotherapeutic agents

(eg, methotrexate, cyclophosphamide, busulfan, glucocorticoids) helps in assessing the risk
of opportunistic infection and the likelihood of lung toxicity due to the agents given. (See
"Pulmonary toxicity associated with systemic antineoplastic therapy: Clinical presentation,
diagnosis, and treatment".)
The acuity of illness (eg, fever, tachypnea, hypoxemia, leukocyte counts) should guide the rapidity
of the evaluation and the need for empiric antibiotics. Almost all febrile HCT recipients are treated
empirically with broad-spectrum antibiotics, until a causative organism is identified or an
alternate diagnosis is confirmed. The choice of empiric therapy should depend upon the risk for
specific infections, the potential sites of infection and the susceptibility patterns at a given
institution (figure 1). (See "Overview of infections following hematopoietic cell transplantation".)
EVALUATION
The initial evaluation of pulmonary complications of allogeneic hematopoietic cell transplantation

(HCT) typically includes laboratory testing (eg, complete blood counts, blood cultures, peripheral
blood and urine tests for bacterial, viral, and fungal antigens) and imaging studies. Additional
testing is based on the timing of symptom onset, acuity of illness, and the appearance of the
chest radiograph.
Laboratory testing — Laboratory testing generally includes assessment of complete blood

counts and differential to assess the severity of neutropenia and lymphocytopenia, and also the
possibility that anemia is contributing to dyspnea. D-dimer and brain natriuretic peptide levels are
sent when thromboembolism or cardiogenic pulmonary edema are suspected.
Cytomegalovirus (CMV) pneumonitis is common in the post-engraftment phase, so blood is tested

for CMV replication (eg, viral load by PCR) in most patients with fever and radiographic opacities
after engraftment. Serum assays for aspergillus galactomannan, beta-D-glucan, and cryptococcus
antigen are obtained as well as urinary Legionella antigen. Blood cultures are obtained for
bacteria and fungi. A more detailed discussion of the evaluation for infection following HCT is
provided separately. (See "Overview of infections following hematopoietic cell transplantation"
and "Approach to the immunocompromised patient with fever and pulmonary infiltrates" and
"Diagnostic approach to the adult cancer patient with neutropenic fever" and "Diagnosis of
invasive aspergillosis" and "Clinical manifestations and diagnosis of candidemia and invasive
candidiasis in adults", section on 'Non-culture methods'.)
Nasopharyngeal washings or swabs are sent for immunofluorescence antibody or multiplex

polymerase chain reaction (PCR) testing for respiratory viruses and culture. (See "Parainfluenza
viruses in adults", section on 'Diagnosis' and "Diagnosis of seasonal influenza in adults", section
on 'Laboratory tests'.)
Imaging — A conventional chest radiograph is obtained in virtually all HCT recipients with fever
and/or pulmonary symptoms or signs, as the radiographic appearance can help guide the
evaluation of pulmonary complications of HCT (table 1 and table 2).
In addition, most patients undergo computed tomography (CT), which is more sensitive than a
conventional chest radiograph and may identify subtle abnormalities missed on the conventional
chest radiograph [115,116]. Chest CT is also used to characterize the patterns of abnormalities
(eg, ground glass versus reticular, nodular versus diffuse) and the exact location [117]. However,
the specific radiographic pattern is rarely diagnostic and many of the pulmonary diseases that
follow allogeneic HCT can have multiple radiographic appearances.
● Diffuse pulmonary opacities – After allogeneic HCT, diffuse pulmonary opacities can be
caused by a broad spectrum of disease processes, including bacterial, viral (eg, CMV,
influenza), or fungal (eg, Pneumocystis) infection, the engraftment syndrome, the idiopathic
pneumonia syndrome, diffuse alveolar hemorrhage, interstitial pneumonia due to connective
tissue disease, and pulmonary alveolar proteinosis (table 2) [52,118]. Many of these disorders
are associated with diffuse ground glass opacities, although CMV, Aspergillus, Pneumocystis,
organizing pneumonia, and pulmonary cytolytic thrombi can present with diffuse small
nodular opacities.
● Focal pulmonary opacities – Focal or lobar opacities in febrile, allogeneic HCT recipients are
often caused by bacterial or fungal infection, but can also be caused by pulmonary
thromboembolism or organizing pneumonia. Invasive pulmonary fungal infection should be
particularly suspected when there are nodular abnormalities on chest radiograph or CT scan
[117,119]. Less common causes of focal radiographic opacities include organizing
pneumonia, irradiation pneumonitis (localized to a field of treatment), and recurrent
lymphoma.
Nodular opacities without associated fever can be caused by processes such as recurrent
lymphoma, posttransplant lymphoproliferative disease, and lung cancer [117]. (See
'Malignancy' above.)
● Clear chest radiograph – Following allogeneic HCT, the disease processes that cause
dyspnea and a clear conventional chest radiograph include anemia, early Pneumocystis
pneumonia, thromboembolic disease, cardiac dysfunction, and airways disease such as
bronchiolitis obliterans (BO) [120,121]. Pneumocystis pneumonia and pulmonary veno-
occlusive disease may present with a normal chest radiograph, but the chest CT is not
normal. Pulmonary thromboembolism can present with a clear chest radiograph, but the
presence of hypoxemia and/or or a positive D-dimer should lead to additional imaging
studies. (See "Epidemiology, clinical manifestations, and diagnosis of Pneumocystis
pneumonia in HIV-uninfected patients", section on 'Radiographic findings' and 'Pulmonary
veno-occlusive disease' above.)
● Additional imaging studies – When pulmonary thromboembolic disease or pulmonary

veno-occlusive disease is suspected (eg, due to a positive D-dimer test, a characteristic
pulmonary function test or radiographic pattern, or a degree of hypoxemia out of proportion

to the radiographic opacities), either a computed tomography pulmonary angiogram (CTPA)

or conventional pulmonary angiogram is obtained. (See "Epidemiology, pathogenesis, clinical
evaluation, and diagnosis of pulmonary veno-occlusive disease/pulmonary capillary
hemangiomatosis in adults", section on 'Venous congestion on chest imaging' and "Clinical
presentation, evaluation, and diagnosis of the nonpregnant adult with suspected acute
pulmonary embolism" and "Clinical presentation, evaluation, and diagnosis of the
nonpregnant adult with suspected acute pulmonary embolism", section on 'Catheter-based
pulmonary angiography'.)
Pulmonary function testing — The evaluation of dyspnea in stable allogeneic HCT recipients

without significant hypoxemia or radiographic opacities usually includes full pulmonary function
testing with exercise oximetry and/or arterial blood gas analysis [122]. (See "Overview of
pulmonary function testing in adults" and "Diffusing capacity for carbon monoxide" and "Pulse
oximetry".)
The combination of a restrictive pattern with a gas transfer abnormality on pulmonary function
testing suggests that interstitial lung disease may be present but too subtle to identify on a
conventional chest radiograph. (See 'Imaging' above.)
The findings of normal lung volumes, but a pulse oxygen saturation and diffusing capacity (DLCO)
that are lower than expected on the basis of the HRCT findings, suggest idiopathic pneumonitis,
thromboembolic disease, or veno-occlusive disease.
An obstructive pattern may be a nonspecific finding following HCT or may be a manifestation of

BO. For patients with suspected BO, spirometry is monitored at one to three month intervals; if
spirometry is stable for a year, the frequency can be decreased to 6 to 12 month intervals (table 3)
[102]. (See 'Airflow obstruction and bronchiolitis obliterans' above.)
Echocardiography — An echocardiogram is obtained when cardiac dysfunction is suspected (eg,

diffuse opacities consistent with pulmonary edema) or to assess pulmonary artery pressures
when pulmonary veno-occlusive disease is suspected. (See 'Pulmonary veno-occlusive disease'
above and "Transthoracic echocardiography: Normal cardiac anatomy and tomographic views"
and "Tissue Doppler echocardiography".)
Skin biopsy — The accuracy and predictive value of skin biopsy in the differentiation of
engraftment versus GVHD is unclear. (See "Cutaneous manifestations of graft-versus-host disease
(GVHD)", section on 'Skin biopsy'.)
Bronchoscopy
Patients with diffuse pulmonary opacities — Bronchoscopy with bronchoalveolar lavage

(BAL) and bronchial brushing is usually performed when the patient has diffuse or widespread
lung disease based on imaging studies, unless cardiogenic pulmonary edema is strongly
suspected [123].

At the time of bronchoscopy, endobronchial brushing samples are obtained to look for the
cytologic changes typical of viral infections (eg, inclusion bodies in CMV), in addition to routine
cytology.
Bronchoalveolar lavage is performed in an area that appears involved based on the radiographic
evaluation. To detect alveolar hemorrhage, three sequential lavages (30 to 60 mL aliquots) are
obtained to look for progressively more hemorrhagic returns. Samples of BAL fluid and bronchial
brushings are sent for immunofluorescence studies (eg, Pneumocystis, parainfluenza, influenza),
stains (eg, gram, acid-fast), culture (eg, bacterial, mycobacterial, viral, fungal), a rapid shell-vial
culture for CMV, Aspergillus galactomannan antigen, multiplex polymerase chain reaction (PCR)
for respiratory viruses, and cytologic evaluation. (See "Basic principles and technique of
bronchoalveolar lavage".)
With the shell-vial culture technique, the pellet from centrifuged BAL fluid is added to fibroblast
monolayers, which are then immunohistochemically stained for expression of immediate-early
viral antigens. Direct staining of BAL macrophages with monoclonal antibodies can also give
results the same day with both high sensitivity and specificity for CMV pneumonitis.
Polymerase chain reaction (PCR) testing of BAL fluid is another highly sensitive technique for
identifying CMV, but may not be specific for active disease. However, combining PCR with
immunostaining of alveolar cells using monoclonal antibodies to CMV may improve both
specificity and positive predictive value (picture 2) [124]. (See "Overview of infections following
hematopoietic cell transplantation", section on 'Pneumonia'.)
The additional diagnostic value of transbronchial lung biopsy (TBLB) in conjunction with BAL is
controversial [125,126]. We base the decision to obtain a TBLB on how well the patient is
tolerating the bronchoscopy, whether they have risk factors for bleeding from a TBLB, and how
well they would tolerate iatrogenic pneumothorax. Often, TBLB cannot be performed due to
thrombocytopenia.
Focal opacities — For stable patients with focal opacities on lung imaging, bronchoscopic
evaluation may be delayed pending the results of noninvasive cultures, laboratory tests, and
empiric antibiotics directed at the most likely infection(s) based on the patient's post HCT phase
(figure 1). If the initial cultures and other tests are negative and the patient hasn’t responded to
empiric therapy, bronchoscopy is usually performed to obtain BAL and brushing samples from the
affected area for cultures, cytology, and possibly flow cytometry. The studies performed on the
BAL fluid and endobronchial brushing samples are described above. (See 'Patients with diffuse
pulmonary opacities' above.)
Lung biopsy — If the above blood, imaging, and bronchoscopic studies do not yield an
explanation for diffuse pulmonary opacities and the patient is a surgical candidate, a surgical lung
biopsy may be needed to secure a diagnosis [118,123]. Lung biopsy may be performed via video-
assisted thoracoscopic surgery (VATS) or open thoracotomy. Samples are obtained from an area of
disease activity, as determined by computed tomography and sent for histopathologic analysis

and bacterial, mycobacterial, fungal, and viral culture. Special stains for mycobacteria and fungi
are performed, and also in situ hybridization and/or immunohistochemistry to identify viral
pathogens (picture 2) [127]. (See "Role of lung biopsy in the diagnosis of interstitial lung disease",
section on 'Surgical lung biopsy'.)
In a case series of 35 bone marrow recipients with diffuse pulmonary opacities who underwent
open lung biopsy, the most common causes were idiopathic interstitial pneumonia (40 percent),
cytomegalovirus pneumonia (20 percent), and organizing pneumonia (14 percent) [118]. Drug
reactions were diagnosed in 30 percent, some of whom had organizing pneumonia. The
idiopathic interstitial pneumonias found in these patients were diffuse alveolar damage (ie, acute
interstitial pneumonia) or nonspecific interstitial pneumonia. (See "Acute interstitial pneumonia
(Hamman-Rich syndrome)" and "Treatment and prognosis of nonspecific interstitial pneumonia".)
For patients with lung toxicity due to chemotherapeutic agents or radiation therapy, biopsy
findings are nonspecific and include diffuse alveolar damage, type II alveolar epithelial cell atypia
and hyperplasia, interstitial pneumonitis, and thickening of the interstitium with early fibrosis.
There is usually minimal acute inflammation.
SUMMARY AND RECOMMENDATIONS
● Several aspects of allogeneic hematopoietic cell transplantation (HCT) contribute to the

development of pulmonary disease, including previous treatment of the underlying disease,
the pretransplant conditioning regimen, engraftment of donor cells, graft-versus-host
disease (GVHD), and ongoing immunosuppression. (See 'Introduction' above and 'Overview
and definitions' above.)
● A prompt and thorough diagnostic approach is justified in the evaluation of pulmonary

symptoms and signs after allogeneic HCT, because opportunistic infections are common and
specific treatments are available. (See 'Approach to the patient with respiratory symptoms or
signs' above.)
● The pulmonary complications of allogeneic HCT include a broad spectrum of infectious,

inflammatory, and neoplastic disorders (table 1 and table 2). The approach to evaluating
these complications begins with considering the timing of onset of the pulmonary disease
(eg, before or after engraftment), the appearance of the chest radiograph (eg, clear, focal
opacities, diffuse opacities), and certain patient and donor specific features such as CMV
serologic status, exposures to animals and endemic fungi, exposure to pneumotoxic drugs
and radiation therapy, the underlying disease, and degree of immunosuppression. (See
'Approach to the patient with respiratory symptoms or signs' above and 'Causes and clinical
manifestations' above.)
● The initial evaluation of pulmonary complications of allogeneic HCT typically includes

laboratory testing (eg, complete blood counts, brain natriuretic protein [BNP], blood cultures,
and also peripheral blood and urine tests for viral, fungal, and Legionella infection) and a
chest radiograph. Additional testing is based on the timing of symptom onset, acuity of
illness, and the appearance of the chest radiograph. (See 'Evaluation' above.)
● For patients with focal opacities on lung imaging, the most likely diagnosis is infection,
although organizing pneumonia, radiation pneumonitis, and recurrent lymphoma are
included in the differential. After noninvasive cultures and laboratory tests are obtained,
empiric antibiotics are initiated based on the infections considered likely for that patient's
post HCT phase (figure 1). If the initial cultures and other tests are negative and the patient
hasn't responded to empiric therapy, bronchoscopy is usually performed to obtain cultures,
cytology, and possibly flow cytometry from the affected area. (See 'Bronchoscopy' above.)
● For patients who have received cardiotoxic medications as therapy for their underlying
disease, cardiac dysfunction can be a cause of dyspnea and diffuse radiographic opacities.
Cardiac dysfunction may be suspected in the absence of fever, chills, or night sweats, but it
can present concomitantly with infection. The evaluation typically includes measurement of
BNP and echocardiography. (See 'Pulmonary edema' above.)
● For HCT recipients with diffuse radiographic opacities on lung imaging, bronchoscopy with
bronchoalveolar lavage (BAL) is usually performed, preferably in an area of radiographic
abnormality. Samples are obtained to look for alveolar hemorrhage, to identify potential
infectious agents, and for cytologic analysis. Endobronchial brushing is also performed and
samples sent for cytologic analysis. The additional diagnostic value of transbronchial biopsy
in conjunction with BAL is controversial. (See 'Bronchoscopy' above.)
● For patients with focal or diffuse radiographic opacities, if the diagnosis remains unclear after
the above testing and the patient is not responding to empiric antimicrobial therapy, a
surgical lung biopsy may be needed to secure a diagnosis. (See 'Lung biopsy' above.)
● Patients with dyspnea and normal chest radiographs following allogeneic HCT may have
anemia, pulmonary thromboembolic disease, bronchiolitis obliterans, pulmonary veno-
occlusive disease, or cardiac dysfunction. Full pulmonary function testing with arterial blood
gas analysis or exercise oximetry is helpful in guiding the evaluation. High resolution
computed tomography of the chest is more sensitive than the plain chest radiograph and
may detect subtle interstitial disease. Echocardiography is often performed to assess for
cardiac dysfunction or evidence of pulmonary veno-occlusive disease. (See 'Airflow
obstruction and bronchiolitis obliterans' above and 'Pulmonary veno-occlusive disease'
above.)
● Allogeneic HCT recipients who develop fever and radiographic lung opacities usually require
empiric antibiotics, especially in the presence of neutropenia. Empiric antibiotics are chosen
based on the patient's risk for specific infections, the potential sites of infection, the
susceptibility patterns at a given institution, and the cost of the various regimens (figure 1).
(See 'Approach to the patient with respiratory symptoms or signs' above.)

● The treatment of pulmonary complications of allogeneic HCT depends on the specific cause.
An approach to management of airflow limitation following HCT is provided in the table (table
3). Respiratory failure requiring prolonged mechanical ventilation after allogeneic HCT is
generally associated with a very poor prognosis. (See "Prognosis of cancer patients in the
intensive care unit", section on 'Predictors of prognosis'.)
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REFERENCES
1. Yen KT, Lee AS, Krowka MJ, Burger CD. Pulmonary complications in bone marrow
transplantation: a practical approach to diagnosis and treatment. Clin Chest Med 2004;
25:189.
2. Roychowdhury M, Pambuccian SE, Aslan DL, et al. Pulmonary complications after bone
marrow transplantation: an autopsy study from a large transplantation center. Arch Pathol
Lab Med 2005; 129:366.
3. Bhatia S, Francisco L, Carter A, et al. Late mortality after allogeneic hematopoietic cell
transplantation and functional status of long-term survivors: report from the Bone Marrow
Transplant Survivor Study. Blood 2007; 110:3784.
4. Lucena CM, Torres A, Rovira M, et al. Pulmonary complications in hematopoietic SCT: a

prospective study. Bone Marrow Transplant 2014; 49:1293.
5. Kotloff RM, Ahya VN, Crawford SW. Pulmonary complications of solid organ and
hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2004; 170:22.
6. Aguilar-Guisado M, Jiménez-Jambrina M, Espigado I, et al. Pneumonia in allogeneic stem cell

transplantation recipients: a multicenter prospective study. Clin Transplant 2011; 25:E629.
7. Dettenkofer M, Wenzler-Röttele S, Babikir R, et al. Surveillance of nosocomial sepsis and

pneumonia in patients with a bone marrow or peripheral blood stem cell transplant: a
multicenter project. Clin Infect Dis 2005; 40:926.
8. Sisson JH, Reed EC, Robbins RA, et al. Impairment of nasal mucociliary clearance during
bone marrow transplantation. University of Nebraska Medical Center bone Marrow
Transplantation Pulmonary Study Group. Bone Marrow Transplant 1994; 13:631.
9. Facchini L, Martino R, Ferrari A, et al. Degree of mucositis and duration of neutropenia are
the major risk factors for early post-transplant febrile neutropenia and severe bacterial
infections after reduced-intensity conditioning. Eur J Haematol 2012; 88:46.
10. De Neve NY, Benoit DD, Depuydt PO, et al. Aspiration pneumonia: an underestimated cause
of severe respiratory failure in patients with haematological malignancies and severe oral
mucositis? Acta Clin Belg 2010; 65:416.
11. Franquet T, Müller NL, Lee KS, et al. Pulmonary candidiasis after hematopoietic stem cell
transplantation: thin-section CT findings. Radiology 2005; 236:332.
12. Cost C, Brock E, Adams-Huet B, et al. 2009 pandemic influenza A (H1N1) virus infection in
pediatric oncology and hematopoietic stem cell transplantation patients. Pediatr Blood
Cancer 2011; 56:127.
13. Franquet T, Müller NL, Lee KS, et al. High-resolution CT and pathologic findings of
noninfectious pulmonary complications after hematopoietic stem cell transplantation. AJR
Am J Roentgenol 2005; 184:629.
14. Capizzi SA, Kumar S, Huneke NE, et al. Peri-engraftment respiratory distress syndrome
during autologous hematopoietic stem cell transplantation. Bone Marrow Transplant 2001;
27:1299.
15. Mossad S, Kalaycio M, Sobecks R, et al. Steroids prevent engraftment syndrome after
autologous hematopoietic stem cell transplantation without increasing the risk of infection.
Bone Marrow Transplant 2005; 35:375.
16. Schmid I, Stachel D, Pagel P, Albert MH. Incidence, predisposing factors, and outcome of
engraftment syndrome in pediatric allogeneic stem cell transplant recipients. Biol Blood
Marrow Transplant 2008; 14:438.
17. Foncillas MA, Diaz MA, Sevilla J, et al. Engraftment syndrome emerges as the main cause of
transplant-related mortality in pediatric patients receiving autologous peripheral blood
progenitor cell transplantation. J Pediatr Hematol Oncol 2004; 26:492.
18. Dispenzieri A, Lacy MQ, Hayman SR, et al. Peripheral blood stem cell transplant for POEMS
syndrome is associated with high rates of engraftment syndrome. Eur J Haematol 2008;
80:397.
19. Akasheh M, Eastwood D, Vesole DH. Engraftment syndrome after autologous hematopoietic
stem cell transplant supported by granulocyte-colony-stimulating factor (G-CSF) versus
granulocyte-macrophage colony-stimulating factor (GM-CSF). Bone Marrow Transplant 2003;
31:113.
20. Nishio N, Yagasaki H, Takahashi Y, et al. Engraftment syndrome following allogeneic

hematopoietic stem cell transplantation in children. Pediatr Transplant 2009; 13:831.
21. Spitzer TR. Engraftment syndrome following hematopoietic stem cell transplantation. Bone
22. Evans A, Steward CG, Lyburn ID, Grier DJ. Imaging in haematopoietic stem cell
transplantation. Clin Radiol 2003; 58:201.

23. Tanaka N, Kunihiro Y, Yujiri T, et al. High-resolution computed tomography of chest

complications in patients treated with hematopoietic stem cell transplantation. Jpn J Radiol
2011; 29:229.
24. Ravenel JG, Scalzetti EM, Zamkoff KW. Chest radiographic features of engraftment syndrome.
J Thorac Imaging 2000; 15:56.
25. Weinstock DM, Feinstein MB, Sepkowitz KA, Jakubowski A. High rates of infection and
colonization by nontuberculous mycobacteria after allogeneic hematopoietic stem cell
transplantation. Bone Marrow Transplant 2003; 31:1015.
26. Ip MS, Yuen KY, Woo PC, et al. Risk factors for pulmonary tuberculosis in bone marrow
transplant recipients. Am J Respir Crit Care Med 1998; 158:1173.
27. Kiehn TE, White M, Pursell KJ, et al. A cluster of four cases of Mycobacterium haemophilum
infection. Eur J Clin Microbiol Infect Dis 1993; 12:114.
28. Kiehn TE, White M. Mycobacterium haemophilum: an emerging pathogen. Eur J Clin
Microbiol Infect Dis 1994; 13:925.
29. de Medeiros CR, Moreira VA, Pasquini R. Cytomegalovirus as a cause of very late interstitial
pneumonia after bone marrow transplantation. Bone Marrow Transplant 2000; 26:443.
30. Abe K, Suzuki K, Kamata N, et al. [High-resolution CT findings in cytomegalovirus

pneumonitis after bone marrow transplantation]. Nihon Igaku Hoshasen Gakkai Zasshi
1998; 58:7.
31. Leung AN, Gosselin MV, Napper CH, et al. Pulmonary infections after bone marrow
transplantation: clinical and radiographic findings. Radiology 1999; 210:699.
32. Chemaly RF, Ghosh S, Bodey GP, et al. Respiratory viral infections in adults with hematologic
malignancies and human stem cell transplantation recipients: a retrospective study at a
major cancer center. Medicine (Baltimore) 2006; 85:278.
33. Renaud C, Campbell AP. Changing epidemiology of respiratory viral infections in

hematopoietic cell transplant recipients and solid organ transplant recipients. Curr Opin
Infect Dis 2011; 24:333.
34. Englund JA, Sullivan CJ, Jordan MC, et al. Respiratory syncytial virus infection in
immunocompromised adults. Ann Intern Med 1988; 109:203.
35. Harrington RD, Hooton TM, Hackman RC, et al. An outbreak of respiratory syncytial virus in a
bone marrow transplant center. J Infect Dis 1992; 165:987.
36. La Rosa AM, Champlin RE, Mirza N, et al. Adenovirus infections in adult recipients of blood
and marrow transplants. Clin Infect Dis 2001; 32:871.

37. Morris DJ, Corbitt G, Bailey AS, et al. Fatal disseminated adenovirus type 2 infection following
bone marrow transplantation for Hurler's syndrome: a primary infection. J Infect 1993;
26:181.
38. Carrigan DR, Drobyski WR, Russler SK, et al. Interstitial pneumonitis associated with human
herpesvirus-6 infection after marrow transplantation. Lancet 1991; 338:147.
39. Cone RW, Hackman RC, Huang ML, et al. Human herpesvirus 6 in lung tissue from patients
with pneumonitis after bone marrow transplantation. N Engl J Med 1993; 329:156.
40. Buchbinder S, Elmaagacli AH, Schaefer UW, Roggendorf M. Human herpesvirus 6 is an

important pathogen in infectious lung disease after allogeneic bone marrow
transplantation. Bone Marrow Transplant 2000; 26:639.
41. Seo S, Renaud C, Kuypers JM, et al. Idiopathic pneumonia syndrome after hematopoietic cell
transplantation: evidence of occult infectious etiologies. Blood 2015; 125:3789.
42. Afessa B, Litzow MR, Tefferi A. Bronchiolitis obliterans and other late onset non-infectious
pulmonary complications in hematopoietic stem cell transplantation. Bone Marrow
Transplant 2001; 28:425.
43. Fukuda T, Hackman RC, Guthrie KA, et al. Risks and outcomes of idiopathic pneumonia
syndrome after nonmyeloablative and conventional conditioning regimens for allogeneic
hematopoietic stem cell transplantation. Blood 2003; 102:2777.
44. Crawford SW, Longton G, Storb R. Acute graft-versus-host disease and the risks for idiopathic
pneumonia after marrow transplantation for severe aplastic anemia. Bone Marrow
45. Crawford SW, Hackman RC. Clinical course of idiopathic pneumonia after bone marrow
transplantation. Am Rev Respir Dis 1993; 147:1393.
46. 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; 183:1262.
47. Clark JG, Hansen JA, Hertz MI, et al. NHLBI workshop summary. Idiopathic pneumonia
syndrome after bone marrow transplantation. Am Rev Respir Dis 1993; 147:1601.
48. Sampath S, Schultheiss TE, Wong J. Dose response and factors related to interstitial
pneumonitis after bone marrow transplant. Int J Radiat Oncol Biol Phys 2005; 63:876.
49. Panoskaltsis-Mortari A, Taylor PA, Yaeger TM, et al. The critical early proinflammatory events
associated with idiopathic pneumonia syndrome in irradiated murine allogeneic recipients
are due to donor T cell infusion and potentiated by cyclophosphamide. J Clin Invest 1997;
100:1015.

50. Cooke KR, Krenger W, Hill G, et al. Host reactive donor T cells are associated with lung injury
after experimental allogeneic bone marrow transplantation. Blood 1998; 92:2571.
51. Hildebrandt GC, Olkiewicz KM, Corrion LA, et al. Donor-derived TNF-alpha regulates
pulmonary chemokine expression and the development of idiopathic pneumonia syndrome
after allogeneic bone marrow transplantation. Blood 2004; 104:586.
52. Afessa B, Peters SG. Noninfectious pneumonitis after blood and marrow transplant. Curr
Opin Oncol 2008; 20:227.
53. Yanik GA, Ho VT, Levine JE, et al. The impact of soluble tumor necrosis factor receptor
etanercept on the treatment of idiopathic pneumonia syndrome after allogeneic
hematopoietic stem cell transplantation. Blood 2008; 112:3073.
54. Keates-Baleeiro J, Moore P, Koyama T, et al. Incidence and outcome of idiopathic pneumonia
syndrome in pediatric stem cell transplant recipients. Bone Marrow Transplant 2006; 38:285.
55. Gonzalez-Vicent M, Diaz MA, Sevilla J, Madero L. Cerebral toxoplasmosis following etanercept
treatment for idiophatic pneumonia syndrome after autologous peripheral blood progenitor
cell transplantation (PBPCT). Ann Hematol 2003; 82:649.
56. Tizon R, Frey N, Heitjan DF, et al. High-dose corticosteroids with or without etanercept for
the treatment of idiopathic pneumonia syndrome after allo-SCT. Bone Marrow Transplant
2012; 47:1332.
57. Thompson J, Yin Z, D'Souza A, et al. Etanercept and Corticosteroid Therapy for the Treatment
of Late-Onset Idiopathic Pneumonia Syndrome. Biol Blood Marrow Transplant 2017; 23:1955.
58. Majhail NS, Parks K, Defor TE, Weisdorf DJ. Diffuse alveolar hemorrhage and infection-
associated alveolar hemorrhage following hematopoietic stem cell transplantation: related
and high-risk clinical syndromes. Biol Blood Marrow Transplant 2006; 12:1038.
59. Kharbanda S, Panoskaltsis-Mortari A, Haddad IY, et al. Inflammatory cytokines and the
development of pulmonary complications after allogeneic hematopoietic cell transplantation
in patients with inherited metabolic storage disorders. Biol Blood Marrow Transplant 2006;
12:430.
60. Gupta S, Jain A, Warneke CL, et al. Outcome of alveolar hemorrhage in hematopoietic stem
cell transplant recipients. Bone Marrow Transplant 2007; 40:71.
61. Agustí C, Ramirez J, Picado C, et al. Diffuse alveolar hemorrhage in allogeneic bone marrow
transplantation. A postmortem study. Am J Respir Crit Care Med 1995; 151:1006.
62. Raptis A, Mavroudis D, Suffredini A, et al. High-dose corticosteroid therapy for diffuse
alveolar hemorrhage in allogeneic bone marrow stem cell transplant recipients. Bone

63. Ben-Abraham R, Paret G, Cohen R, et al. Diffuse alveolar hemorrhage following allogeneic
bone marrow transplantation in children. Chest 2003; 124:660.
64. Wanko SO, Broadwater G, Folz RJ, Chao NJ. Diffuse alveolar hemorrhage: retrospective
review of clinical outcome in allogeneic transplant recipients treated with aminocaproic acid.
Biol Blood Marrow Transplant 2006; 12:949.
65. Pastores SM, Papadopoulos E, Voigt L, Halpern NA. Diffuse alveolar hemorrhage after
allogeneic hematopoietic stem-cell transplantation: treatment with recombinant factor VIIa.
Chest 2003; 124:2400.
66. Hicks K, Peng D, Gajewski JL. Treatment of diffuse alveolar hemorrhage after allogeneic bone
marrow transplant with recombinant factor VIIa. Bone Marrow Transplant 2002; 30:975.
67. Pihusch M, Bacigalupo A, Szer J, et al. Recombinant activated factor VII in treatment of
bleeding complications following hematopoietic stem cell transplantation. J Thromb
Haemost 2005; 3:1935.
68. Blatt J, Gold SH, Wiley JM, et al. Off-label use of recombinant factor VIIa in patients following
bone marrow transplantation. Bone Marrow Transplant 2001; 28:405.
69. Bergeron A, Bengoufa D, Feuillet S, et al. The spectrum of lung involvement in collagen
vascular-like diseases following allogeneic hematopoietic stem cell transplantation: report of
6 cases and review of the literature. Medicine (Baltimore) 2011; 90:146.
70. Daniels CE, Myers JL, Utz JP, et al. Organizing pneumonia in patients with hematologic
malignancies: a steroid-responsive lesion. Respir Med 2007; 101:162.
71. Nakasone H, Onizuka M, Suzuki N, et al. Pre-transplant risk factors for cryptogenic
organizing pneumonia/bronchiolitis obliterans organizing pneumonia after hematopoietic
cell transplantation. Bone Marrow Transplant 2013; 48:1317.
72. Mathew P, Bozeman P, Krance RA, et al. Bronchiolitis obliterans organizing pneumonia
(BOOP) in children after allogeneic bone marrow transplantation. Bone Marrow Transplant
1994; 13:221.
73. Palmas A, Tefferi A, Myers JL, et al. Late-onset noninfectious pulmonary complications after
allogeneic bone marrow transplantation. Br J Haematol 1998; 100:680.
74. Jinta M, Ohashi K, Ohta T, et al. Clinical features of allogeneic hematopoietic stem cell
transplantation-associated organizing pneumonia. Bone Marrow Transplant 2007; 40:465.
75. Freudenberger TD, Madtes DK, Curtis JR, et al. Association between acute and chronic graft-
versus-host disease and bronchiolitis obliterans organizing pneumonia in recipients of
hematopoietic stem cell transplants. Blood 2003; 102:3822.

76. Thirman MJ, Devine SM, O'Toole K, et al. Bronchiolitis obliterans organizing pneumonia as a
complication of allogeneic bone marrow transplantation. Bone Marrow Transplant 1992;
10:307.
77. Micallef IN, Chhanabhai M, Gascoyne RD, et al. Lymphoproliferative disorders following
allogeneic bone marrow transplantation: the Vancouver experience. Bone Marrow
78. Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone
marrow transplantation: a multi-institutional study. Blood 1999; 94:2208.
79. Scarsbrook AF, Warakaulle DR, Dattani M, Traill Z. Post-transplantation lymphoproliferative

disorder: the spectrum of imaging appearances. Clin Radiol 2005; 60:47.
80. Styczynski J, Einsele H, Gil L, Ljungman P. Outcome of treatment of Epstein-Barr virus-related

post-transplant lymphoproliferative disorder in hematopoietic stem cell recipients: a
comprehensive review of reported cases. Transpl Infect Dis 2009; 11:383.
81. Cordonnier C, Fleury-Feith J, Escudier E, et al. Secondary alveolar proteinosis is a reversible

cause of respiratory failure in leukemic patients. Am J Respir Crit Care Med 1994; 149:788.
82. Ansari M, Rougemont AL, Le Deist F, et al. Secondary pulmonary alveolar proteinosis after
unrelated cord blood hematopoietic cell transplantation. Pediatr Transplant 2012; 16:E146.
83. Morales IJ, Anderson PM, Tazelaar HD, Wylam ME. Pulmonary cytolytic thrombi: unusual
complication of hematopoietic stem cell transplantation. J Pediatr Hematol Oncol 2003;
25:89.
84. Gulbahce HE, Pambuccian SE, Jessurun J, et al. Pulmonary nodular lesions in bone marrow
transplant recipients: impact of histologic diagnosis on patient management and prognosis.
Am J Clin Pathol 2004; 121:205.
85. Peters A, Manivel JC, Dolan M, et al. Pulmonary cytolytic thrombi after allogeneic
hematopoietic cell transplantation: a further histologic description. Biol Blood Marrow
86. Woodard JP, Gulbahce E, Shreve M, et al. Pulmonary cytolytic thrombi: a newly recognized
complication of stem cell transplantation. Bone Marrow Transplant 2000; 25:293.
87. Mandel J, Mark EJ, Hales CA. Pulmonary veno-occlusive disease. Am J Respir Crit Care Med
2000; 162:1964.
88. Seguchi M, Hirabayashi N, Fujii Y, et al. Pulmonary hypertension associated with pulmonary
occlusive vasculopathy after allogeneic bone marrow transplantation. Transplantation 2000;
69:177.

89. Chien JW, Martin PJ, Gooley TA, et al. Airflow obstruction after myeloablative allogeneic
hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2003; 168:208.
90. Clark JG, Crawford SW, Madtes DK, Sullivan KM. Obstructive lung disease after allogeneic
marrow transplantation. Clinical presentation and course. Ann Intern Med 1989; 111:368.
91. Kaplan EB, Wodell RA, Wilmott RW, et al. Chronic graft-versus-host disease and pulmonary
function. Pediatr Pulmonol 1992; 14:141.
92. Cerveri I, Zoia MC, Fulgoni P, et al. Late pulmonary sequelae after childhood bone marrow
transplantation. Thorax 1999; 54:131.
93. St John RC, Gadek JE, Tutschka PJ, et al. Analysis of airflow obstruction by bronchoalveolar
lavage following bone marrow transplantation. Implications for pathogenesis and
treatment. Chest 1990; 98:600.
94. Barisione G, Bacigalupo A, Crimi E, et al. Changes in lung volumes and airway
responsiveness following haematopoietic stem cell transplantation. Eur Respir J 2008;
32:1576.
95. Barisione G, Bacigalupo A, Crimi E, Brusasco V. Acute bronchodilator responsiveness in

bronchiolitis obliterans syndrome following hematopoietic stem cell transplantation. Chest
2011; 139:633.
96. Williams KM, Chien JW, Gladwin MT, Pavletic SZ. Bronchiolitis obliterans after allogeneic
hematopoietic stem cell transplantation. JAMA 2009; 302:306.
97. Bacigalupo A, Chien J, Barisione G, Pavletic S. Late pulmonary complications after allogeneic
hematopoietic stem cell transplantation: diagnosis, monitoring, prevention, and treatment.
Semin Hematol 2012; 49:15.
98. Gassas A, Craig-Barnes H, Dell S, et al. Chest health surveillance utility in the early detection
of bronchiolitis obliterans syndrome in children after allo-SCT. Bone Marrow Transplant
2013; 48:814.
99. Bergeron A, Godet C, Chevret S, et al. Bronchiolitis obliterans syndrome after allogeneic
hematopoietic SCT: phenotypes and prognosis. Bone Marrow Transplant 2013; 48:819.
100. Ditschkowski M, Elmaagacli AH, Koldehoff M, et al. Bronchiolitis obliterans after allogeneic
hematopoietic SCT: further insight--new perspectives? Bone Marrow Transplant 2013;
48:1224.
101. Song I, Yi CA, Han J, et al. CT findings of late-onset noninfectious pulmonary complications in
patients with pathologically proven graft-versus-host disease after allogeneic stem cell
transplant. AJR Am J Roentgenol 2012; 199:581.
102. Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease. Blood 2015; 125:606.
103. Bergeron A, Belle A, Chevret S, et al. Combined inhaled steroids and bronchodilatators in
obstructive airway disease after allogeneic stem cell transplantation. Bone Marrow
104. Bergeron A, Chagnon K, Feuillet S, et al. [Prospective evaluation of the efficacy of the
combination of budesonide/formoterol in obstructive airway disease after allogeneic
hematopoietic stem cell transplantation]. Rev Mal Respir 2009; 26:794.
105. Bergeron A, Chevret S, Chagnon K, et al. Budesonide/Formoterol for bronchiolitis obliterans

after hematopoietic stem cell transplantation. Am J Respir Crit Care Med 2015; 191:1242.
106. Norman BC, Jacobsohn DA, Williams KM, et al. Fluticasone, azithromycin and montelukast
therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after
allogeneic hematopoietic SCT: a case series of eight patients. Bone Marrow Transplant 2011;
46:1369.
107. Williams KM, Cheng GS, Pusic I, et al. Fluticasone, Azithromycin, and Montelukast Treatment
for New-Onset Bronchiolitis Obliterans Syndrome after Hematopoietic Cell Transplantation.
Biol Blood Marrow Transplant 2016; 22:710.
108. Boas SR, Noyes BE, Kurland G, et al. Pediatric lung transplantation for graft-versus-host
disease following bone marrow transplantation. Chest 1994; 105:1584.
109. Rabitsch W, Deviatko E, Keil F, et al. Successful lung transplantation for bronchiolitis
obliterans after allogeneic marrow transplantation. Transplantation 2001; 71:1341.
110. Pechet TV, de le Morena M, Mendeloff EN, et al. Lung transplantation in children following
treatment for malignancy. J Heart Lung Transplant 2003; 22:154.
111. Holm AM, Riise GC, Hansson L, et al. Lung transplantation for bronchiolitis obliterans
syndrome after allo-SCT. Bone Marrow Transplant 2013; 48:703.
112. Vogl UM, Nagayama K, Bojic M, et al. Lung transplantation for bronchiolitis obliterans after
allogeneic hematopoietic stem cell transplantation: a single-center experience.
Transplantation 2013; 95:623.
113. Bergeron A, Chevret S, Granata A, et al. Effect of Azithromycin on Airflow Decline-Free

Survival After Allogeneic Hematopoietic Stem Cell Transplant: The ALLOZITHRO Randomized
Clinical Trial. JAMA 2017; 318:557.
114. U.S. Food and Drug Administration. FDA warns about increased risk of cancer relapse with lo
ng-term use of azithromycin (Zithromax, Zmax) antibiotic after donor stem cell transplant htt
ps://www.fda.gov/Drugs/DrugSafety/ucm614085.htm (Accessed on August 06, 2018).
115. Graham NJ, Müller NL, Miller RR, Shepherd JD. Intrathoracic complications following
allogeneic bone marrow transplantation: CT findings. Radiology 1991; 181:153.

116. Versluys AB, Bierings MB, Beek FJ, et al. High-resolution CT can differentiate between
alloimmune and nonalloimmune lung disease early after hematopoietic cell transplantation.
AJR Am J Roentgenol 2014; 203:656.
117. Wingard JR, Hiemenz JW, Jantz MA. How I manage pulmonary nodular lesions and nodular
infiltrates in patients with hematologic malignancies or undergoing hematopoietic cell
transplantation. Blood 2012; 120:1791.
118. Wang JY, Chang YL, Lee LN, et al. Diffuse pulmonary infiltrates after bone marrow
transplantation: the role of open lung biopsy. Ann Thorac Surg 2004; 78:267.
119. Mori M, Galvin JR, Barloon TJ, et al. Fungal pulmonary infections after bone marrow
transplantation: evaluation with radiography and CT. Radiology 1991; 178:721.
120. Sharma S, Nadrous HF, Peters SG, et al. Pulmonary complications in adult blood and marrow
transplant recipients: autopsy findings. Chest 2005; 128:1385.
121. Worthy SA, Flint JD, Müller NL. Pulmonary complications after bone marrow transplantation:
high-resolution CT and pathologic findings. Radiographics 1997; 17:1359.
122. Milburn HJ, Prentice HG, du Bois RM. Can lung function measurements be used to predict
which patients will be at risk of developing interstitial pneumonitis after bone marrow
transplantation? Thorax 1992; 47:421.
123. Chellapandian D, Lehrnbecher T, Phillips B, et al. Bronchoalveolar lavage and lung biopsy in
patients with cancer and hematopoietic stem-cell transplantation recipients: a systematic
review and meta-analysis. J Clin Oncol 2015; 33:501.
124. Cathomas G, Morris P, Pekle K, et al. Rapid diagnosis of cytomegalovirus pneumonia in

marrow transplant recipients by bronchoalveolar lavage using the polymerase chain
reaction, virus culture, and the direct immunostaining of alveolar cells. Blood 1993; 81:1909.
125. Patel NR, Lee PS, Kim JH, et al. The influence of diagnostic bronchoscopy on clinical
outcomes comparing adult autologous and allogeneic bone marrow transplant patients.
Chest 2005; 127:1388.
126. Jain P, Sandur S, Meli Y, et al. Role of flexible bronchoscopy in immunocompromised patients
with lung infiltrates. Chest 2004; 125:712.
127. Barberà JA, Martín-Campos JM, Ribalta T, et al. Undetected viral infection in diffuse alveolar
damage associated with bone marrow transplantation. Eur Respir J 1996; 9:1195.
Topic 4339 Version 30.0

GRAPHICS
Pulmonary complications of allogeneic hematopoietic cell transplantation: Preengraftment
Disease Associated Radiographic Lung biopsy

Risk factors Useful diagnostic tests
process manifestations findings needed
Bacterial Mucositis, Fever, cough, Usually focal Broad microbiologic testing; Generally not
pneumonia neutropenia sputum consolidation; response to empiric antibiotics
becomes diffuse in
acute lung injury
Fungal Prolonged Fever Focal nodular and Broad microbiologic Sometimes

pneumonia neutropenia; consolidative testing including BAL; β-D-
exposure to opacities, "halo glucan of the blood; Aspergillus
endemic fungi; sign," "reverse halo galactomannan EIA of the
prior treatment sign" blood and BAL fluid; response
for invasive to empiric antifungal therapy
fungus
Aspiration Impaired Fever, dyspnea Diffuse or focal Cultures are often negative No
pneumonia swallowing due ground glass or
to mucositis; consolidative
opiate therapy opacities
Permeability Aspiration, Fever, dyspnea Diffuse ground glass Normal BNP, normal LV No
pulmonary engraftment opacities function on echocardiogram
edema syndrome,
hyperacute
GVHD, sepsis
syndrome
Cardiogenic Cardiotoxic Dyspnea, weight Perihilar opacities in Elevated BNP; echocardiogram No

pulmonary medications; gain, peripheral butterfly showing reduced LV function
edema copious edema distribution, septal
intravenous fluid thickening, pleural
administration effusion,
cardiomegaly
Engraftment Erythematous CT: bilateral ground- Skin biopsy; BAL to exclude Sometimes to
syndrome maculo-papular glass opacification, infection exclude other
rash, fever >38.3°C, hilar or treatable
weight gain peribronchial causes, lung
consolidation, and biopsy shows
thickening of diffuse alveolar
interlobular septa damage
Hyperacute HLA mismatch Rash, abdominal Diffuse ground glass Skin biopsy; BAL to exclude Sometimes to
GVHD* cramps, diarrhea, consistent with infection exclude other
elevated bilirubin acute lung injury processes
Diffuse CT: patchy or diffuse BAL to exclude infection and to No

alveolar opacities, may have identify increasingly bloody
hemorrhage air bronchograms return in sequential lavages
and >20 percent hemosiderin-
laden macrophages
BAL: bronchoalveolar lavage; EIA: enzyme immunoassay; BNP: brain natriuretic protein; LV: left ventricular; CT: computed tomography;
GVHD: graft-versus-host-disease; HLA: human leukocyte antigens; CTPA: computed tomography pulmonary angiogram.
* Hyperacute GVHD is very rare preengraftment, but may rarely occur at the time of engraftment and overlaps clinically with engraftment
syndrome.
Graphic 83194 Version 2.0

Pulmonary complications of allogeneic hematopoietic cell transplantation: Postengraftment
Lung
Associated Radiographic Useful diagnostic
Disease process Risk factors biopsy
manifestations findings tests
needed
Bacterial pneumonia Focal or patchy Blood cultures, Legionella Rarely

consolidation, and pneumococcal urinary
may be antigens, BAL for Gram
peribronchial stain and aerobic and
Occasionally anaerobic cultures,
mass-like "round- Legionella culture,
pneumonia" Mycoplasma PCR, and
modified AFB stain and
culture for Nocardia
Mycobacterial Total body irradiation, M. haemophilum is Miliary pattern TST after HCT not helpful; Rarely
pneumonia chronic GVHD associated with AFB staining and cultures
skin nodules and/or of induced sputum and
joint inflammation BAL are helpful
CMV pneumonitis Seropositive recipient CT: patchy or Serology, blood test for Rarely
with seronegative diffuse ground- pp65 antigen or CMV PCR,
donor; delayed glass opacities, BAL and endobronchial
reconstitution, prior patchy brush for cytologic
treatment for CMV consolidation, examination for inclusion
small nodular bodies and BAL shell vial
opacities; rarely cultures for CMV
tree-in-bud
pattern
Respiratory viruses Exposure to someone URI symptoms Diffuse ground PCR, culture, or rapid Sometimes to
with active viral prior to onset of glass opacities immunofluorescence of completely
infection lower respiratory are the most nasopharyngeal lavage or exclude other
tract symptoms common swab and BAL fluid possibilities
Fungal infection (eg, Presence and severity Focal nodular Broad microbiologic Sometimes
invasive aspergillosis, GVHD, older patient and consolidative testing of blood and BAL; when cultures
Fusarium, agents of age, cytopenia, CMV opacities, "halo blood tests for β-D-glucan are negative
mucormycosis, infection sign," "reverse and Aspergillus and no
Candida, halo galactomannan EIA; BAL response to
Scedosporium, sign," sometimes for initial therapy
Pneumocystis) subpleural Aspergillus galactomannan
wedge-shaped EIA; and induced sputum
densities and BAL for Pneumocystis
staining
Idiopathic pneumonia Busulfan, high dose Extensive Negative stains, cultures, Yes, either
syndrome cyclophosphamide, opacities antigen testing, and PCR of transbronchial
radiation, blood, sputum, urine, and or surgical
nonmyeloablative BAL
conditioning regimen
Diffuse alveolar Underlying CT: patchy or BAL showing increasingly Not usually
hemorrhage mucopolysaccharidosis diffuse opacities, bloody return in sequential
may have air lavages and >20 percent
bronchograms hemosiderin-laden
macrophages
Connective tissue Myeloablative Extrapulmonary CT: subpleural, Autoantibody tests positive Often to
disease conditioning regimen manifestations ground-glass identify
such as dry opacities; septal specific type
mouth/dry eyes, thickening of interstitial
joint pain/swelling, pneumonitis
muscle weakness
Cryptogenic Irradiation, CMV CT: patchy air- Lung biopsy Yes

organizing infection, HCT space
pneumonia/organizing associated connective consolidation,
pneumonia (formerly tissue disease, chronic ground-glass
known as bronchiolitis GVHD opacities, small

obliterans organizing nodular
pneumonia) opacities,
"reverse halo
sign"
Bronchiolitis Chronic GVHD, CT initially clear; Spirometry showing airflow Sometimes, if

obliterans postviral as progresses, CT limitation diagnosis
may show Skin biopsy for GVHD uncertain
mosaic ground
glass opacities
and
bronchiectasis
Malignancy Underlying lymphoma, Nodular BAL cytology and flow Biopsy usually
EBV infection in opacities, cytometry, biopsy needed
posttransplant lymphangitic
lymphoproliferative pattern
disorder
Pulmonary alveolar HCT for myeloid Perihilar Bronchoalveolar lavage Not usually
proteinosis disorder opacities in a showing characteristic
"bat-wing" milky appearance and
distribution often positive stain for
with air lipoproteins
bronchograms
Pulmonary cytolytic Chronic GVHD is a risk Low grade fever, CT: peripheral BAL to rule out infection; Yes, findings
thrombi factor cough nodules lung biopsy are basophilic
cytolytic
thrombi in the
small to
medium distal
pulmonary
vessels with
entrapped
monocytes
Pulmonary veno- Onset after first 100 Reduced DLCO CXR: pleural Right heart catheterization; For definitive
occlusive disease days, chronic GVHD effusion and BAL showing occult diagnosis
Kerley B lines; CT hemorrhage
chest:
centrilobular
ground glass
opacities; no
emboli on CTPA
Drug toxicity History of May be associated Varied Increased BAL eosinophils Sometimes to
pneumotoxic drug use with rash, may be seen; other completely
(eg, busulfan, peripheral processes excluded by exclude other
cyclophosphamide) eosinophilia negative blood and BAL possibilities
stains and cultures,
negative fungal studies
Radiation pneumonitis History of radiation Acute: onset Acute CT: Other processes excluded Sometimes to
therapy involving usually 4 to 12 ground-glass by negative blood and BAL completely
lungs weeks following attenuation stains and cultures, exclude other
irradiation within the area of negative fungal studies possibilities
Late: onset after 6 irradiated lung
to 12 months Late CT: linear
opacities
(scarring) or an
area of dense
consolidation
and volume loss
Selection of specific diagnostic tests is based on clinical features and results of prior testing.
BAL: bronchoalveolar lavage; PCR: polymerase chain reaction; AFB: acid-fast bacillus; GVHD: graft-versus-host disease; TST: tuberculin skin
test; HCT: hematopoietic cell transplantation; CMV: cytomegalovirus; CT: computed tomography; URI: upper respiratory infection; EIA:
enzyme immunoassay; EBV: Epstein-Barr virus; DLCO: diffusing capacity for carbon monoxide; CXR: chest radiograph; CTPA: computed
tomography pulmonary angiography.


Phases of opportunistic infections among allogeneic hematopoietic cell transplant

recipients
EBV: Epstein-Barr virus; HHV6: human herpesvirus 6; PTLD: posttransplant lymphoproliferative disease.
Reproduced from: Tomblyn M, Chiller T, Hermann E, et al. Guidelines for preventing infectious complications among hematopoietic cell
transplantation recipients: A global perspective. Biol Blood Marrow Transplant 2009; 15:1143. Illustration used with the permission of
Elsevier Inc. All rights reserved.

Aspergillus bronchiolitis and bronchopneumonia
High-resolution computed tomography images (1.0 mm collimation) at the level of the right middle
lobe bronchus (A) and liver dome (B) show patchy peribronchial consolidation, centrilobular nodules,
and branching linear structures (arrows). Cavity formation is seen in both lower lobes.
Reproduced with permission from: Müller NL, Fraser RS, Lee KS, Johkoh T. Pulmonary infections. In: Diseases of the
Lung, Lippincott Williams & Wilkins, Philadelphia 2002. Copyright © 2002 Lippincott Williams & Wilkins.
www.lww.com.

Computed tomography (CT) pulmonary aspergillosis
Halo sign (A) converting to an air-crescent sign (B) after neutrophil recovery.
Reproduced with permission from: Maertens J, Meersseman W, Van Bleyenbergh P. New therapies
for fungal pneumonia. Curr Opin Infect Dis 2009; 22:183. Copyright © 2009 Lippincott Williams &
Wilkins.

Hydrostatic pulmonary edema
Pulmonary edema in a "butterfly distribution" due to left ventricular failure. Chest

radiograph shows large perihilar opacities in patient with enlarged cardiac silhouette.
Courtesy of Paul Stark, MD.

CMV pneumonia
Chest radiograph showing multifocal patchy pneumonia due to cytomegalovirus

infection.
Normal chest radiograph
Posteroanterior view of a normal chest radiograph.
Courtesy of Carol M Black, MD.

Chest CT findings in hematopoietic cell transplant recipients

with parainfluenza pneumonia
(A) High-resolution CT scan of the lungs of patient 1 that show peribronchial nodules
<5 mm, 5 to 10 mm, and >10 mm in diameter. (B) High-resolution CT scan of the lungs
of patient 1 that show nodules with associated consolidation. (C) High-resolution CT
scan of the lungs of patient 3 that shows very small (<5 mm) peribronchial nodules in
the left upper lobe. (D) High-resolution CT scan of the lungs of patient 5 that show
multiple small (≤5 mm) peribronchial nodules and the appearance of ground-glass
consolidation.
CT: computed tomography.
Reproduced with permission from: Ferguson PE, Sorrell TC, Bradstock KF, et al. Parainfluenza virus
type 3 pneumonia in bone marrow transplant recipients: Multiple small nodules in high-resolution
lung computed tomography scans provide a radiological clue to diagnosis. Clin Infect Dis 2009;
48:905. Copyright ©2009 University of Chicago Press.

Diffuse alveolar hemorrhage
Widespread alveolar filling representing diffuse alveolar hemorrhage following bone

marrow transplantation.
Normal chest radiograph
Posteroanterior view of a normal chest radiograph.
Courtesy of Carol M Black, MD.

Diffuse alveolar hemorrhage CT

Pulmonary alveolar proteinosis chest radiograph
Chest radiograph shows large perihilar and lower lobe opacities with normal cardiac
silhouette.

Pulmonary alveolar proteinosis chest CT scan
Ground-glass opacification and thickened intralobular structures and interlobular

septa, in typical polygonal shapes referred to as "crazy-paving."
Courtesy of Talmadge E King, Jr, MD.

Bronchiolitis obliterans following allogeneic bone marrow

transplantation
Photomicrographs of a partially obliterated bronchiole in a patient who has received

an allogeneic bone marrow transplant. Left: Hematoxylin and eosin stained section
shows a largely obliterated bronchiole with peribronchiolar fibrosis and an associated
infiltrate of mononuclear inflammatory cells. Right: An elastic tissue stain outlines the
elastic layer of the same bronchiole pictured on the left and shows a compressed but
patent lumen (arrow).
Courtesy of Jeffrey L Myers, MD.

Bronchiolitis obliterans following bone marrow transplantation
Photomicrographs of a completely obliterated bronchiole in a patient who has

received an allogeneic bone marrow transplant. Left: Hematoxylin and eosin stained
section shows complete replacement of a bronchiole by a collagenous scar associated
with a scant inflammatory infiltrate and so-called cholesterol clefts, a nonspecific
finding. Right: An elastic tissue stain is helpful in outlining the elastic layer of the same
bronchiole pictured on the left and shows complete replacement of the bronchiole
lumen by scar tissue.

General guidelines for monitoring and management of new airflow obstruction after
hematopoietic stem cell transplantation
Guidelines
A. Significant new airflow obstruction with a % predicted FEV 1 ≥70%
1. Initiate inhaled glucocorticoid therapy. Add inhaled long-acting beta agonist, if patient symptomatic. Treatment should
continue until either FEV 1 becomes <70% (see B below) or until GVHD resolves (ie, resolution of all reversible manifestations
of GVHD without exacerbation for at least 6 months after discontinuation of all systemic immunosuppressive treatment)
2. Other immunosuppressive treatment as indicated to control GVHD in other organs
Treatment should continue until either FEV 1 becomes <70% (see B below), or until GVHD resolves (ie, resolution of all
reversible manifestation of GVHD without exacerbation for at least 12 months after discontinuation of all systemic
treatments)
3. Monitor PFTs or spirometry monthly for at least 3 months
If FEV 1 stabilizes, obtain PFTs or spirometry every 3 months for 1 year, then continue at 6 month intervals for 1 year and
at 6 to 12 month intervals thereafter
If FEV 1 continues to decrease, go to B below
B. Significant airflow obstruction with a FEV 1 <70% with/without significant airtrapping by high resolution chest CT
1. Consider bronchoscopy to rule out an undetected infectious etiology for airflow obstruction, even if no radiographic
opacity is apparent
2. After infection has been ruled out, evaluate the patient's eligibility for clinical trial for treatment of BOS and initiate (or
increase) prednisone dose to 1 mg/kg per day
Start standard chronic GVHD taper at 2 weeks
Consider continuing inhaled glucocorticoids throughout prednisone therapy
3. If FEV 1 decreases further to <70% during treatment, discuss changes of immunosuppressive treatment with transplant
physician
4. CMV monitoring in blood per standard practice
5. Monitor PFTs or spirometry monthly for at least 3 months
If FEV 1 stabilizes, continue PFTs or spirometry every 3 months for 1 year
If FEV 1 continues to decrease, go to C below
C. Glucocorticoid-resistant airflow obstruction defined as progressive decline of FEV 1 by ≥10% despite treatment with 1 mg/kg per
day of prednisone (or similar glucocorticoids)
1. May consider increasing the dose of prednisone to 2 mg/kg per day for a maximum of 2 weeks, followed by a taper to reach
a dose of 1 mg/kg per day by 2 to 4 weeks
2. Another treatment must be considered and discussed with the transplant team
3. Monitor CMV in blood per standard practice
4. Monitor PFTs monthly for at least 3 months
If FEV 1 stabilizes, monitor PFTs every 3 months for 1 year
D. Additional considerations
1. Consider changing prophylaxis for encapsulated bacterial infection to azithromycin 250 mg on Mondays-Wednesdays-
Fridays
Assure patient is receiving adequate prophylaxis for Pneumocystis, varicella virus, and herpes simplex virus infections
Fungal prophylaxis per standard practice
2. Monitor CMV in blood per standard practice
3. May continue inhaled glucocorticoids throughout prednisone therapy
4. Discontinuation of inhaled glucocorticoid treatment can be considered 12 months after treatment with prednisone has
been discontinued
Before considering treatment, all potential infectious etiologies of airflow obstruction must be investigated and treated if present.
Investigations that should be considered (directed by clinical symptoms), include sinus CT scan, nasal washes, sinus aspiration,
high-resolution chest CT scan, sputum culture, bronchoalveolar lavage, and lung biopsy.
FEV 1 : forced expiratory volume in one second; GVHD: graft-versus-host disease; PFT: pulmonary function test; CT: computed tomography;
CMV: cytomegalovirus.
Reproduced with permission of the American Society of Hematology, from Flowers ME, Martin PJ. How we treat chronic graft-versus-host disease.
Blood 2015; 125:606; permission conveyed through Copyright Clearance Center, Inc.

CMV pneumonitis
Photomicrograph shows an infected pneumocyte in a patient with cytomegalovirus

pneumonitis. The infected cell (arrow) is enlarged and contains an eosinophilic
intranuclear inclusion and coarse basophilic cytoplasmic inclusions.
Normal lung
High power photomicrograph shows alveoli containing capillaries within a narrow

interstitium. The alveoli are lined with thin, elongated type I pneumocytes (arrow)
and smaller numbers of cuboidal type II pneumocytes (dashed arrow).
Courtesy of Steven E Weinberger, MD.

Pulmonary Complications After Allogeneic Hematopoietic Cell Transplantation - UpToDate

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12/10/2020 Pulmonary complications after allogeneic hematopoietic cell transplantation - UpToDate

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Pulmonary complications after allogeneic hematopoietic

OVERVIEW AND DEFINITIONS

Allogeneic versus autologous HCT — Allogeneic HCT refers to the use of hematopoietic

Autologous HCT is discussed separately. (See "Multiple myeloma: Use of autologous

Preparative conditioning regimen — Preparative conditioning regimens are designed to ablate

Engraftment — Engraftment after HCT is defined as the attainment of an absolute neutrophil

Maintenance immunosuppression — After allogeneic HCT, maintenance immunosuppression is

Graft-versus-host disease — Graft-versus-host disease (GVHD) occurs when immune cells

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timing is approximate. Despite preconditioning and maintenance immunosuppression to prevent

CAUSES AND CLINICAL MANIFESTATIONS

Pre-engraftment period — In the pre-engraftment period from HCT up to engraftment (eg,

Pulmonary edema — Pulmonary edema of cardiogenic or noncardiogenic origin can occur in

Engraftment syndrome — The engraftment syndrome is a noninfectious complication that is

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≥38.3˚C, an erythematous maculo-papular rash (not attributable to a drug), weight gain,

Post hematopoietic cell engraftment — The spectrum of pulmonary complications changes in

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The features related to postengraftment pulmonary infection are reviewed here:

● Mycobacteria – Mycobacterial and atypical mycobacterial infections are occasionally

The treatment of mycobacterial infections is discussed separately. (See "Treatment of drug-

● Cytomegalovirus – Cytomegalovirus (CMV) pneumonitis rarely occurs during the pre-

https://www.uptodate.com/contents/pulmonary-complications-after-allogeneic-hematopoietic-cell-transplantation/print?search=graft versus host desease&topic… 6/50

CMV pneumonitis is discussed separately. (See "Overview of infections following

● Respiratory viruses – Community-acquired infections with influenza, parainfluenza,

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Adenoviruses, which can be isolated in 3 to 5 percent of patients after HCT, should be

Human metapneumovirus is emerging as a pathogen affecting HCT recipients and is

https://www.uptodate.com/contents/pulmonary-complications-after-allogeneic-hematopoietic-cell-transplantation/print?search=graft versus host desease&topic… 8/50

● Toxoplasmosis – Reactivation of toxoplasmosis causing lung infection is rare following

Idiopathic pneumonia syndrome — The idiopathic pneumonia syndrome (IPS) is an

● Widespread alveolar injury, defined as multilobar opacities on chest radiograph or computed

● Absence of lower respiratory tract infection, as determined by a negative bronchoalveolar

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and "Human herpesvirus 6 infection in hematopoietic cell transplant recipients", section on

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Diffuse alveolar hemorrhage — Diffuse alveolar hemorrhage (DAH) occurs in less than 1

Connective tissue disease — A small number of patients have developed pulmonary

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Organizing pneumonia — Organizing pneumonia (OP, also known as bronchiolitis obliterans

Posttransplant lymphoproliferative disease (PTLD) developing after allogeneic HCT is thought to

Pulmonary alveolar proteinosis — Pulmonary alveolar proteinosis (PAP) has been reported as

Pulmonary cytolytic thrombi — Pulmonary cytolytic thrombi (PCT) are an unusual

Pulmonary veno-occlusive disease — Pulmonary veno-occlusive disease (PVOD) occurs rarely

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Airflow obstruction and bronchiolitis obliterans — Airflow obstruction developing after

● Bronchiolitis obliterans risk factors – Moderate-to-severe airflow obstruction is usually a

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An inhaled long-acting beta-agonist (LABA) may be used in combination, particularly if the

● Progressive worsening of airflow limitation – If airflow limitation progresses (FEV1 <70

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● Prevention – Prophylactic azithromycin improves BOS-free survival after lung

APPROACH TO THE PATIENT WITH RESPIRATORY SYMPTOMS OR SIGNS

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● Knowledge of the current and previous immunosuppressive and chemotherapeutic agents

The initial evaluation of pulmonary complications of allogeneic hematopoietic cell transplantation

Laboratory testing — Laboratory testing generally includes assessment of complete blood

Cytomegalovirus (CMV) pneumonitis is common in the post-engraftment phase, so blood is tested

Nasopharyngeal washings or swabs are sent for immunofluorescence antibody or multiplex

evaluation of pulmonary complications of HCT (table 1 and table 2).

● Additional imaging studies – When pulmonary thromboembolic disease or pulmonary