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Blood First Edition Paper, prepublished online June 12, 2012; DOI 10.1182/blood-2012-02-378976
How I manage pulmonary nodular lesions and nodular infiltrates in patients
with hematologic malignancies or undergoing hematopoietic cell
transplantation
John R. Wingard1
John W. Hiemenz2
Michael A. Jantz3
University of Florida College of Medicine, Divisions of Hematology/Oncology1,2 and
Pulmonary/Critical Care/Sleep Medicine3, PO Box 100277, Gainesville, FL 32610-0278.
[email protected]
Contributions: JRW wrote the paper and JWH and MAJ edited and contributed to the
text and tables.
Conflicts: The authors have no relevant conflicts.
1
Copyright © 2012 American Society of Hematology
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Abstract
Pulmonary nodules and nodular infiltrates occur frequently during treatment of
hematologic malignancies and after hematopoietic cell transplantation. In patients not receiving
active immunosuppressive therapy the most likely culprits are primary lung cancer, chronic
infectious or inactive granulomata, or even the underlying hematologic disease itself (especially
in patients with lymphoma) . In patients receiving active therapy, or who are otherwise highly
immunosuppressed, there is a wider spectrum of etiologies with infection being most likely,
especially by bacteria and fungi. Characterization of the pulmonary lesion by high resolution CT
imaging is a crucial first diagnostic step. Other non-invasive tests can often be useful but
invasive testing by bronchoscopic evaluation or acquisition of tissue by one of several biopsy
techniques should be performed for those at risk for malignancy or invasive infection unless
contraindicated. The choice of the optimal biopsy technique should be individualized, guided by
location of the lesion, suspected etiology, skill and experience of the diagnostic team, the
procedural risk of complications, and the patient status. Although presumptive therapy targeting
the most likely etiology is justified in patients suspected of serious infection while evaluation
proceeds, a structured evaluation to determine the specific etiology is recommended.
Interdisciplinary teamwork is highly desirable to optimize diagnosis and therapy.
2
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Introduction
Lung nodules and nodular infiltrates are common in patients treated for hematologic
malignancy (HM) and in patients undergoing hematopoietic cell transplantation (HCT). Various
case series suggest that 13-60% of patients develop a pulmonary infiltrate at some point in their
treatment course, with the incidence varying considerably by different diseases and treatments
(1-3). High resolution CT (HRCT) scans are the preferred method for evaluation of a lung
infiltrate over radiography because they are more sensitive in detecting infiltrates earlier and they
are more capable of better characterization of the infiltrates. In patients treated for acute
leukemia or undergoing HCT, HRCT scans have a high degree of sensitivity (>85%), high
negative predictive value (>85%) in detecting pneumonia and a gain of 5 days compared to chest
radiography (4). Clinical management is often changed because of the HRCT findings (5).
In general, pulmonary infiltrates can be categorized by their radiographic pattern broadly
into diffuse and nodular infiltrates. This distinction is useful because the differential diagnostic
possibilities are quite different (Table 1). Nodular lesions may be further characterized as
solitary micro- or macro-nodules with sharp or unsharp margins with or without halos, multiple
nodules, masses, nodular infiltrates, and focal air-space disease. In reality, many patients have
mixtures of multiple types of infiltrates simultaneously. A systematic approach to evaluation is
necessary to determine the cause and develop a sensible management strategy. This report will
address the management of pulmonary nodules and nodular infiltrates and mention diffuse
infiltrates only for comparison.
What is the differential diagnosis?
Both infectious and non-infectious etiologies can be the cause of nodules and nodular
infiltrates. The differential diagnosis varies according to the patient’s treatment and immune
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status. We will separate consideration of those receiving active chemo- or immunosuppressive
therapy who are very immunocompromised (eg, those undergoing induction chemotherapy for
acute leukemia or those within the first 6 months after allogeneic HCT or even later if still
receiving immunosuppressive therapy for chronic graft versus host disease (GVHD) from those
not receiving active chemotherapy or off immunosuppressive therapy after HCT. The latter
would also include those who present prior to treatment and after completion of their course of
anti-neoplastic and/or immunosuppressive therapy, where host defenses are more intact.
Patients not receiving active chemo- or immunotherapy. Nodular lesions may be caused
by the HM, especially in patients with Hodgkin or non-Hodgkin lymphoma, and much less so for
patients with leukemia. Pulmonary nodular lesions are occasionally seen with plasmacytomas as
extramedullary manifestations of multiple myeloma. There are case reports of acute
myelogenous leukemia (AML) causing pulmonary nodules due to leukemia but these are
infrequent. More commonly, pulmonary infiltrates in patients newly presenting with AML are
diffuse and may be due to leukostasis in those with high leukocyte counts or even frank leukemic
infiltration of tissues, pulmonary hemorrhage, and less commonly infection. Patients newly
presenting with AML occasionally present with pulmonary infections. The types of infections
that cause nodular infiltrates before start of chemotherapy have not been well described but in
our experience are mostly bacterial. Both Gram positive organisms (especially staphylococci
and streptococci) and Gram negative organisms (especially P. aeruginosa, E coli and Klebsiella
spp.) are common (6). Fungal pneumonia is infrequent in newly diagnosed AML at initial
presentation, and where seen, occurs predominantly in those with antecedent cytopenias or iron
overload (7). However, consideration should be given to the possibility for endemic mycoses in
certain high-risk geographic locations, such as coccidiomycosis in the southwest USA,
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histoplasmosis and blastomycosis principally in the Ohio and Mississippi river basins and less
commonly in other temperate zones. .
Nodules in patients not highly immun0- or myelosuppressed may also be caused by the
same types of processes that cause pulmonary nodules in non-immunosuppressed patients. In
non-compromised patients, approximately half of nodules are caused by malignancy, chiefly
primary lung cancer (usually solitary nodules) or less commonly metastases (usually multiple
nodules) (8-10). The other half are mostly due to infectious granulomata from mycobacteria or
fungi and much less commonly from other infrequent benign etiologies such as hamartomas,
sarcoidosis, or arteriovenous malformations.
The differential diagnosis of pulmonary nodules
in patients who are notimmunocompromised has been reviewed in multiple publications (8-11).
Radiographic features described below can be useful in distinguishing the likelihood of benign or
malignant etiology. If there are no manifestations of acute infection, the crucial differential
diagnosis should emphasize the exclusion of a malignant process (12) and its evaluation may
proceed in a manner similar to that for the non-compromised patient (described below).
After completion of antineoplastic therapy, pulmonary nodular lesions may represent
residua of infections that occurred earlier during active therapy. Of course, in paitents treated for
lymphoma, the principal concern is recurrent disease. In the patient undergoing allogeneic HCT,
secondary cancers must also be considered. There is a bimodal distribution of types of
secondary cancers after HCT. During the first 6-12 months, the major concern is EBVassociated post-transplant lymphoproliferative disorders (PTLD) (13). Risk factors for PTLD
include T cell depletion of the stem cell graft, use of anti-thymocyte globulin (ATG), use of a
mismatched or unrelated donor, cord blood stem cell source, and GVHD (14). The greater the
number of risk factors the greater the likelihood that PTLD will occur. Epithelial cancers of
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various types occur at a higher rate than in the general population in survivors after allogeneic
HCT and the risk begins to increase appreciably 10 years after transplant and thereafter climbs.
Recently an increased risk for lung cancer has been noted (15). Lung cancer has also been noted
to occur at increased rates in survivors of Hodgkin and non-Hodgkin lymphoma and chronic
leukemia, but this issue has been less well studied (16-19). Other potential non-infectious
causes of nodular lesions include toxicity from the antineoplastic therapy which more commonly
cause diffuse fibrosis but in some instances can cause micronodular lesions (20-21).
Patients receiving active chemo- or immunotherapy. Infections account for most nodular
infiltrates in patients receiving active chemo- or immunotherapy or have severe compromise in
immunity. Bacterial and fungal infections most commonly account for nodular infiltrates,
whereas viruses, P. jiroveci, and Legionella most commonly account for diffuse infiltrates.
Bacterial pneumonia during neutropenia can be caused by both Gram positive and Gram
negative organisms. Early after HCT staphylococcus and Gram negative pathogens are
problematic, with a spectrum of pathogens similar to that for newly diagnosed AML as noted
above. Later the likely bacterial pathogens are different: in patients with chronic GVHD after
allogeneic HCT, encapsulated bacteria are particularly problematic as causes of sinopulmonary
infections (22). Nocardia is another bacterial pathogen that causes pulmonary nodular infiltrates
late after HCT (23). Mycobacterial infections are also important but less frequent bacterial
pathogens. In advanced countries atypical mycobacteria are more common while in
underdeveloped countries, M. tuberculosis is more likely (24). However, in inner city settings in
the US and various regions elsewhere in the world, M. tuberculosis infections are becoming
more common. Accordingly, in geographic areas with high rates of M tuberculosis, strong
consideration should be given to this diagnostic possibility.
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Invasive fungal infections, especially by mold pathogens, are particularly common,
especially in patients with deep prolonged neutropenia during AML therapy. The onset is
frequently later during neutropenia, typically occurring beyond 2 weeks of neutropenia (25).
Approximately 45% of nodular infiltrates in AML treatmentare due to aspergillosis (26). In our
experience, at least half of nodular infiltrates in AML therapy and HCT are due to fungi, with
80% of the pulmonary fungal infections caused by aspergillosis, the remainder due to other
molds, such as the agents of mucormycosis, and less frequently, fusarium, and scedosporium
species.
It is also important to recognize that nodular lesions may be due to more than one
organism. Mixed mold infections (most commonly aspergillosis and mucormycosis) can occur.
Also, aspergillosis can be accompanied by coinfection by bacteria or viruses. This growing
recognition of mixed infections emphasizes the need for establishing a specific diagnosis.
Non-infectious causes must also be kept in mind, although they are less common. Noninfectious conditions include primary lung cancer, metastases from other epithelial cancers,
lymphomas, EBV-associated post-transplant lymphomas after HCT, and pulmonary
thromboembolism. Rare conditions such Wegener’s granulomatosis, sarcoidosis, and pulmonary
arteriovenous malformation, should also be considered.
Occasionally infections and non-infectious entities that usually cause diffuse infiltrates
(mentioned in Table 1) can also cause nodular infiltrates, especially micronodules, or even
consolidation. Thus, one should be mindful of these possibilities as well.
How do I make the diagnosis?
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Can Imaging distinguish various etiologies? The HRCT scan is the best imaging
technique to evaluate pulmonary infiltrates (27-29). A variety of studies in nonimmunocompromised patients have noted size, location, calcification pattern, change in size over
time, edge characteristics, internal characteristics, number of nodules, attenuation, and contrast
enhancement as features that provide important information (29). Lesions <1 cm are
infrequently due to neoplasm. Larger nodules are more likely to be malignant. Masses (lesions
>3 cm) are highly likely to be malignant. Malignant lesions are more likely to be in the upper
lobes, whereas non-malignant etiologies are more evenly distributed. Calcification is very
suggestive of a benign granulomatous etiology if it has an organized diffuse, central or laminar
pattern. Lesions stable for more than 2 years are rarely malignant. Spiculated edges are
suspicious for malignancy. Satellite nodules surrounding a central larger nodule are suggestive
of granulomatous disease. An air-bronchogram within a nodule is suggestive of malignancy.
Cavitation may be seen in both malignant and non-malignant entities. Ground glass
opacification is suggestive of malignancy such as adenocarcinoma in situ or minimally invasive
adenocarcinoma of the lung. Figure 1 offers illustrative images of nodular lesions commonly
observed.
Using such considerations, in non-compromised patients, lesions can categorized as
demonstrating low, indeterminant, or high probability of malignancy. Those lesions judged to be
high risk should undergo resection. Those at low risk (small <8 mm, benign calcification
pattern, stable over time, no smoking history) can be followed over time (30). Those judged to
be indeterminant require further evaluation.
PET scans have been shown to be quite useful in the evaluation of the solitary pulmonary
nodule (SPN) in the non-immunocompromised patient (31-33). PET scans may be of particular
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value in lesions of indeterminant significance (34), since malignancies typically have high
uptake (>2.5 SUV). PET scans have been found to be quite useful in lymphoma patients to
distinguish active disease from inactive scar (35). However, PET has not been found to be useful
for small lesions <1 cm due to false negative results. Those at high risk require resection or
biopsy. Infectious etiologies may also have high signal uptake by PET (36). Imaging using MRI
and PET technologies has been poorly studied in the evaluation of new nodules and nodular
infiltrates during active chemo- or immunotherapy in the hematologic malignancy and HCT
setting where infection is highly likely (37-38).
A number of studies have evaluated imaging findings as they relate to specific etiologies
in patients treated for HM or undergoing HCT. For bacterial pneumonias, air-space
consolidation is most common, but small centrilobular nodules and ground glass opacities are
also common; large nodules also are seen but are less common (20%) (39-41). The halo sign
appears to be the most useful radiologic sign for distinguishing aspergillosis from bacteria (40).
In patients with invasive aspergillosis (IA), one large study, in mostly HM and HCT
therapy, found that 94% had one or more macronodules (at least 1 cm in diameter) (42). In 79%
of cases, the nodules were multiple, and in 60%, there were multiple bilateral nodules. Halo
signs (dense nodules surrounded by ground glass perimeter) were found in 61%. Other findings
noted with IA were consolidation (30%), infarct-shaped nodules (27%), cavities (20%), and aircrescent signs (10%). The nodular lesions of IA are often peripherally located (43). The
presence of dense, well circumscribed nodule, air crescent sign, or cavity have been adopted as
specific radiologic criteria that along with appropriate clinical setting and with supporting
microbiology criteria establish the diagnosis of IA in consensus guidelines (44). In earlier
studies serial HRCT scans were performed in patients with IA: halo signs were most likely to be
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found early in infection, air-crescent signs much later, typically found at time of neutrophil
recovery (45-46). Although IA is the most likely cause of halo lesions in this population, it is
important to note that the halo is now known to not be specific for IA: other pathogens, such as
P. aeruginosa, the agents of mucormycosis and other less common molds can also give rise to
halo infiltrates (47). Mucormycosis can present with pulmonary nodules or nodular infiltrates
similar to IA. There may be some distinguishing findings on CT scan. Comparing IA and
mucormycosis, the presence of more than 10 nodules, pleural effusion, or sinus involvement, and
a history of prior voriconazole use (an antifungal active against aspergillus species but not
mucormycosis) were conditions more likely to be found with mucormycosis than with IA (4849). Important to note is that while pulmonary nodules are highly likely in IA, other less-specific
radiologic manifestations can also be caused by IA, including consolidation, ground-glass
infiltrates, and occasionally pleural effusion (50). The reversed halo (circular focus of ground
glass density within a ring of dense consolidation) was initially described as highly suggestive of
mucormycosis and subsequently also IA, but other infectious and non-infectious etiologies may
also present with this radiologic picture (47, 51).
In studies of patients with AML who were neutropenic and patients who underwent HCT
with lung opacities >5mm, both IA (52) and bacterial pneumonia (53) were manifest frequently
by both nodules and air-space consolidation in similar proportions (404. The halo sign was
rarely seen in bacterial pneumonia, but cavities and air crescent signs were present in both. A
recent study suggests a role for CT pulmonary angiography in the diagnosis of pulmonary mold
infections, exploiting the fact that such infections are angioinvasive (54)
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Can other non-invasive techniques be helpful? Gram stain and culture of sputum should
be performed if sputum is being expectorated; unfortunately, the patient who is neutropenic is
frequently unable to expectorate sputum. Bacterial and fungal blood cultures should be
performed; when positive, they are helpful; however, most have negative blood cultures.
Mycobacterial blood cultures should also be considered in the evaluation of nodular lesions in
non-neutropenic patients.
There are 2 commercial serum assays to assist in the diagnosis of invasive fungal
infections. The serum galactomannan (GM) and beta glucan tests are useful in detection of
invasive fungal infections. The serum GM test has been widely studied in the AML and HCT
settings. Galactomannan is a constituent of the cell wall of Aspergillus species and its presence
in serum is strongly suggestive of IA. Its sensitivity and specificity have been found to be >80%
in AML and HCT patients in the detection of IA (55). It is important to note that the test is
recommended to be performed twice weekly prospectively in patients at risk and the sensitivity
and specificity of a single test result drawn at the time of a lung infiltrate is less. There are both
false positives and negatives reported. The most common reason reported for false positive
results is the concomitant use of piperacillin-tazobactam (56). There are suggestions recently
that this may be less problematic, but more data are needed on this point. The use of anti-mold
prophylaxis attenuates the value of the galactomannan assay (57). There is also some crossreactivity with penicillium (a rare pulmonary pathogen in the US and Europe) and other endemic
fungi such as histoplasma and blastomyces, potential pathogens in certain geographic regions
(58-59).
Beta glucan is also a cell wall constituent and its presence in the blood occurs in invasive
fungal infections. The serum glucan test is highly sensitive, but less specific than the
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galactomannan test, being positive in invasive infections by candida, aspergillus, fusarium,
trichosporon, and pneumocystis species. It has been best studied in candida fungemia (60).
Neither of these fungal serologic tests can detect the agents of mucormycosis. Although
fungal PCR assays for various fungi are under study, none are commercially available.
Even given the limitations of the two commercial serum fungal assays, we recommend
their use. When positive, we launch an investigation in search of further confirmation of an
invasive fungal infection. Even when negative, if either the clinical scenario and/or imaging
suggest fungal pneumona; we recommend proceeding to invasive techniques in search of an
invasive fungal infection or to establish a specific alternative diagnosis.
Invasive techniques to establish the diagnosis. Invasive testing by bronchoscopic
evaluation or acquisition of tissue by one of several biopsy techniques is usually needed to
establish the diagnosis and should be done unless contraindicated. Studies have shown that in
highly immunosuppressed patients with HM or undergoing HCT, adjustments in antimicrobial
therapy are frequently made as a result of invasive testing (6, 12, 61, 62). The optimal type of
invasive modality should be individualized. Factors that should guide the appropriate choice of
procedure are location of the lesion, characteristics of the lesion, clinical presentation, the
suspected etiology, the skill of the diagnostic team, risk of complications, and the patient’s
ability to undergo the procedure. Several diagnostic approaches are available.
Invasive procedures for evaluation of SPN’s in the non-immunocompromised patient
include transthoracic needle aspirate (TTNA), flexible bronchoscopy (FB), or surgical resection
by video-assisted thoracoscopic surgery (VATS) or open thoracotomy. Each procedure has
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strengths and limitations and there are additional considerations for their usefulness in the HM
and HCT patient population (Table 2).
Transthoracic needle aspirate (TTNA). TTNA has a high yield for the evaluation of the
SPN in the non-compromised patient, approaching 80-90%, and thus is generally preferred for
tissue biopsy (63-64). TTNA is particularly useful in more peripherally located lesions. The
yield is high for malignancy, but much lower for benign lesions (63-65). Bleeding and
pneumothorax are the major risks. Pneumothorax occurs in 15-24% of instances and requires a
chest tube in 6-7% (65,66). Thus, TTNA would be ill advised in patients with poor lung reserve.
Studies in HM and HCT patients indicate a lower yield in the range of 50-78%, where the
likelihood of malignant etiologies is less (12, 53, 67). The complication rate is also higher, with
complications occurring in up to 38% with chest tube being required in up to 16% (Table 2) (12,
53, 67). TTNA is more likely to yield a definitive diagnosis with larger (>1 cm) and cavitary
lesions and is probably of more benefit in patients with lymphoma, where malignancy is more
likely than with AML.
Flexible bronchoscopy (FB). FB has had a more limited role in the evaluation of the SPN
in the non-compromised patient with lower yields in the range of 10-50% (63), but it can be
useful in the evaluation of central airway lesions or mediastinal adenopathy. Navigation guided
bronchoscopy techniques have been evaluated in recent years and have been found to have
higher yields, approximately 70% in a pooled analysis (68). However, FB with bronchoalveloar
lavage (BAL) is a common approach for evaluation of nodular and diffuse infiltrates in HM and
HCT patients. The reason is the low likelihood of serious complication such as hemorrhage or
pneumothorax. The presence of symptoms, location more centrally, presence of bronchus sign
on CT, and visualization during bronchoscopy are associated with higher yields (69). Major
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complication rates have been low in non-compromised patients ranging between <1% to as high
as 38% (63, 70-71), with severe complications typically 10% or less.
The yield of FB in patients with HM or undergoing HCT prior to the advent of nonculture based diagnostics varied widely in the range of 15-60% (61, 62, 72-74). The yield was
found to be substantially higher when performed promptly at the onset of pulmonary infection
rather than later (87% vs 35%) (61). Changes in therapy were made as a result of the FB in 5165% of patients (61, 62). The diagnostic yield was higher in patients with focal infiltrates
compared to diffuse infiltrates (64% vs 47%) (61).
FB is associated with low major complications in the HM and HCT setting: <2-27%
overall and <1-8% major (6, 61, 62, 74, 75). In general, FB has a lower risk for pneumothorax
compared to TTNA. Bronchoscopic transbronchial biopsy (TBBx) has the potential to increase
the yield (75), but also increases the risk of hemorrhage and pneumothorax and its utility remains
controversial in this area. TBBx should generally be avoided in patients with significant
thrombocytopenia. One study noted a yield of 55% for TBBx and 20% for BAL in patients with
HM (75). In another study of non-HIV immunosuppressed patients, of whom 46% had a HM,
the diagnostic yield of BAL was 38%, TBBx was 38%, and both combined was 78% (76). Other
studies, however, have not noted a significant improvement in diagnostic yields by including
TBBx. In one HCT study, the diagnostic yield of FB with TBBx improved in only 8% of
patients compared with BAL alone (61). Another HCT studynoted that TBBx provided
additional specific information in <10% of cases when added to BAL (77). In a study of
neutropenic patients with infiltrates, TBBx added information in only 1 of 9 patients (78). The
aforementioned studies did not include non-culture based diagnostics. It is important to note as
mentioned, there may be a higher risk of life threatening complications with FB in patients
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treated for HM or undergoing HCT in the ICU with severe respiratory complications: in one
study, 12/121 (10%) of patients had a life-threatening complication from FB (79). The high
complication rate was compounded by low diagnostic yields for infectious etiologies: only 23%
in patients with AML and 41% in patients with lymphoid malignancies.
Use of non-cultural microbial testing can also increase the yield of BAL. The use of
BAL GM testing (26, 80) has been associated with substantially increased yield in patients with
IA. In one trial BAL GM in patients with hematologic diseases had a sensitivity of 91%
compared with culture and microscopy (50-55%) (26). Other studies have also noted the utility
of BAL GM for diagnosis of IA (81). In a meta-analysis of BAL GM, summary estimates of the
BAL-GM assay for proven or probable IA were as follows: sensitivity 90%; specificity 94%;
positive likelihood ratio 14.87; and negative likelihood ratio 0.10 (82). The estimates of the
BAL-GM assay for proven IA were sensitivity 94% and specificity 79% (82). Analysis of beta
glucan in BAL specimens in diagnosing fungal pneumonia in humans has not been evaluated as
yet. Although not as yet used routinely in clinical practice, PCR-based testing of BAL
specimens for IPA is being investigated (83, 84).
Although the yield of FB in the diagnostic yield of focal lesions has been reported to be
lower than TTNA in earlier studies, the use of CT guidance and the incorporation of newer
diagnostic assays are pushing diagnostic yields of FB higher and make the need for adding a
transbronchial biopsy to BAL unnecessary in many cases. Biopsy seems to be of best use in the
diagnostic evaluation of lesions suspected to be malignancy, leukemic infiltrates, post-transplant
lymphoproliferative disorder, toxic pneumonitis, or cryptogenic organizing pneumonia (COP,
previously known as bronchiolitis obliterans organizing pneumonia, BOOP) and is likely
superior to BAL when those conditions are suspected (85). In our view, the greater safety of FB
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along with comparable yield has shifted the preference from TTNA and surgical lung biopsy to
FB in most situations in the highly immunosuppressed HM and HCT setting, particularly where
infection is most likely.
Video-assisted thoracoscopic surgery (VATS) or open thoracotomy. If the lesion cannot
be diagnosed by either FB with BAL/TBBx or TTNA, VATS and open lung biopsy are options.
Open lung biopsy offers the opportunity to examine a large piece of tissue and would be
expected to give the greatest likelihood of establishment of the diagnosis (63). It is accompanied
by considerable morbidity and occasionally mortality, and is not a good option for patients with
poor lung reserve and thrombocytopenia. Notwithstanding, the diagnostic yield in patients wtih
HM has varied considerably in different reports, generally about 60% (52, 53, 86, 87). However,
it is associated with considerable morbidity and risk for serious complications. Its morbidity and
particular danger in those with thrombocytopenia and reduced lung reserve makes it much less
appealing in most instances. VATS has supplanted the more extensive open thoracotomy lung
biopsy in many instances due to fewer complications and shorter recovery time while preserving
similar rates of yield (88, 89). VATS is not suitable for centrally located lesions or large lesions
>3 cm. Thoracotomy would be indicated for such lesions.
The choice of the diagnostic intervention must balance risk with likelihood of clearly
establishing the diagnosis. In general, the involvement of a multidisciplinary team consisting of
pulmonologist, radiologist, infectious disease specialist, and, if needed, thoracic surgeon, can
facilitate reaching the best decision as to the optimal invasive procedure.
What are sensible evaluation/treatment strategies?
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Patients not receiving active chemo- or immunotherapy. Drawing on lessons from noncompromised patients, after detection of a SPN in patients not on active therapy, there are 3
choices: 1) observe, 2) biopsy, or 3) surgical resection. The overarching principle is to
aggressively pursue diagnosis and resection if the likelihood of cancer is substantial. Consensus
guidelines have been developed to provide a structured approach in non-compromised patients
(28, 30, 63). In patients with HM, particularly patients with lymphoma, who have completed
therapy, malignancy similarly is more likely than infection (12). Figure 2 offers a diagnostic
algorithm to consider.
Patients receiving active chemotherapy or immunotherapy. Infections due to aggressive
bacteria and fungi are key concerns. Prompt initiation of antimicrobial therapy is crucial. While
evaluation is underway, presumptive therapy with broad spectrum antibiotics is warranted and
should generally follow the recommendations for healthcare associated pneumonia (90) or one of
the consensus guidelines (91-92), modified by local antibiotic susceptibility patterns. We also
recommend presumptive anti-mold therapy until the etiology is established while the evaluation
proceeds. Early diagnosis and timely initiation of therapy has been shown to improve treatment
outcomes for IA (42, 93) and mucormycosis (94). Some clinicians focus on the use of broad
spectrum antibiotics and antifungal therapy and do not pursue invasive diagnostic procedures
unless the patient does not respond to the initial therapy. The downside for this approach is the
uncertainty of the diagnosis, the need to subject the patient to therapy that he/she may not need
along with its attendant costs and toxicities, and the possibility that the empirically chosen
treatment may not target the true pathogen(s). We do not favor presumptive therapy as a
substitute for invasive procedures but rather believe that both are important.
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The development of sensitive non-cultural diagnostics has improved the yield of BAL
(26, 80, 82, 85, 95). The use of HRCT to guide the optimal site for collection of BAL specimens
has also been contributory to improved yields. Moreover, the delay in establishing a diagnosis
not covered by the presumptive therapy is likely to result in poorer treatment outcome since
delays are associated with lower responses (42, 61, 93, 94). Further, delayed investigation is
associated with lower diagnostic yields (61). A study of early (within 4 days of presentation)
versus late bronchoscopy in HCT patients found a 2.5 fold higher yield compared to later
bronchoscopy (61) and greater mortality in patients subjected to late FOB. The yield was highest
(75%) when bronchoscopy was performed within 24 hours of presentation. For these reasons,
we urge performance of an invasive procedure at presentation rather than waiting to determine
response to initial therapy, pursuing an invasive diagnostic only in those who are not responding
(Figure 1).
How should I assess the response to therapy?
The first diagnostic decision is important but it may not be the last diagnostic decision
since the results of the tests and the subsequent clinical course to therapy may dictate the need
for a second diagnostic intervention. For patients with small lesions at low risk for active
infection or malignancy in which the initial decision was to observe, additional scanning at 2-3
months is advisable.
For those who were found to have an active infection, response to therapy dictates the
type and frequency of additional subsequent testing. If clinically responding, repeat imaging
should be done periodically until the infection is resolved. It is important to note that infiltrates
may take several weeks to 1-2 months to fully resolve and thus radiology by itself should not
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dictate the need for further diagnostic interventions. It is well recognized that the infiltrates in
patients with IA worsen over the first week of therapy even though with continued therapy, the
patients respond (45). The patient with IA who is not clinically improving is the most
challenging situation (96, 97). The patient may have clinical and or radiologic deterioration even
while microbiologically responding. In large part this is related to the changing immune status
of the patient. For example, neutrophil recovery or withdrawal of immunosuppressive therapy
may exacerbate inflammatory responses leading to larger pulmonary infiltrates, persistent or
worsening fever and clinical manifestations, the so-called immune reconstitution syndrome. For
patients with IA, it has been proposed that serial GM testing can be helpful in distinguishing
those truly not responding and those who are responding in the face of clinical worsening (98).
Early data are promising for this approach but further study is needed.
If there is doubt as to whether the patient is responding or not, the diagnostic tests should
be repeated. This is important since some infections are mixed and sometimes the initial
assessment may not be conclusive. For example, in a patient who is documented to have IA at
initial assessment but is not clinically responding and the radiography is not improving,
consideration for a mixed infection by a respiratory virus, cytomegalovirus, bacteria (especially
staphylococcus and pseudomonas), or another mold, such as the agents of mucormycosis, should
be entertained and investigation to exclude these is warranted.
Summary
Lung nodules and nodular infiltrates are often caused by malignancy or aggressive
bacterial or mold infections. The principal goal of evaluation in patients not highly myelo- or
immunosuppressed is to distinguish malignant from non-malignant causes, where relapse of the
19
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HM or a new primary lung cancer are major concerns. For patients receiving active chemo- or
immunotherapy, acute infection is the chief concern. Where possible, a specific diagnosis should
be established to optimize outcomes. The choice of the diagnostic intervention must balance risk
with likelihood of clearly establishing the diagnosis. In general, the involvement of a
multidisciplinary team consisting of an oncologist, pulmonologist, radiologist, infectious disease
specialist, and, if needed, thoracic surgeon, can facilitate reaching the best decision as to the
optimal invasive procedure and treatment strategy.
20
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References
1.
1. Rossini F, Verga M, Pioltelli P, et al. Incidence and outcome of pneumonia in patients with
acute leukemia receiving first induction therapy with anthracycline-containing regimens.
Haematologica. 2000 Dec;85(12):1255-60.
2. Lehrnbecher T, Varwig D, Kaiser J, et al. Infectious complications in pediatric acute myeloid
leukemia: analysis of the prospective multi-institutional clinical trial AML-BFM 93. Leukemia.
2004 Jan;18(1):72-7
3. Soubani AO, Miller KB, Hassoun PM. Pulmonary complications of bone marrow
transplantation. Chest 1996;109:1066–1077.
4. Heussel CP, Kauczor HU, Heussel GE, et al. Pneumonia in febrile neutropenic patients and in
bone marrow and blood stem-cell transplant recipients: use of high-resolution computed
tomography. J Clin Oncol. 1999 Mar;17(3):796-805
5.Barloon TJ, Galvin JR, Mori M, et al. High-resolution ultrafast chest CT in the clinical
management of febrile bone marrow transplant patients with normal or nonspecific chest
roentgenograms. Chest. 1991 Apr;99(4):928-33
6. Hummel M, Rudert S, Hof H, et al. Diagnostic yield of bronchoscopy with bronchoalveolar
lavage in febrile patients with hematologic malignancies and pulmonary infiltrates. Ann
Hematol. 2008 Apr;87(4):291-7.
7. Kontoyiannis DP, Chamilos G, Lewis RE, et al. Increased bone marrow iron stores is an
independent risk factor for invasive aspergillosis in patients with high-risk hematologic
malignancies and recipients of allogeneic hematopoietic stem cell transplantation. Cancer. 2007
Sep 15;110(6):1303-6
8. Lillington GA. Management of solitary pulmonary nodules. Dis Mon. 1991 May;37(5):271318
9. Ost D, Fein AM, Feinsilver SH. Clinical practice. The solitary pulmonary nodule. N Engl J
Med. 2003 Jun 19;348(25):2535-42
10. Brandman S, Ko JP. Pulmonary nodule detection, characterization, and management with
multidetector computed tomography. J Thorac Imaging. 2011 May;26(2):90-105
11. Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective
experience. Radiology 2005;235(1):259–265.
12. Gupta S, Sultenfuss M, Romaguera JE, et al. CT-guided percutaneous lung biopsies in
patients with haematologic malignancies and undiagnosed pulmonary lesions. Hematol Oncol.
2010 Jun;28(2):75-81.
13. Curtis RE, Travis LB, Rowlings PA, et al. Risk of lymphoproliferative disorders after bone
marrow transplantation: a multi-institutional study. Blood. 1999 Oct 1;94(7):2208-16
14. Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after
allogeneic hematopoietic cell transplantation. Blood. 2009 May 14;113(20):4992-5001
15. Majhail NS, Brazauskas R, Rizzo JD, et al. Secondary solid cancers after allogeneic
hematopoietic cell transplantation using busulfan-cyclophosphamide conditioning. Blood. 2011
Jan 6;117(1):316-22
16. Gilbert ES, Stovall M, Gospodarowicz M, et al. Lung cancer after treatment for Hodgkin's
disease: focus on radiation effects. Radiat Res. 2003 Feb;159(2):161-73
17 Morton LM, Curtis RE, Linet MS, et al. Second malignancy risks after non-Hodgkin's
lymphoma and chronic lymphocytic leukemia: differences by lymphoma subtype. J Clin Oncol.
2010 Nov 20;28(33):4935-44
21
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
18 Dores GM, Metayer C, Curtis RE, et al. Second malignant neoplasms among long-term
survivors of Hodgkin's disease: a population-based evaluation over 25 years. J Clin Oncol. 2002
Aug 15;20(16):3484-94
19. Travis LB, Gospodarowicz M, Curtis RE et al. Lung cancer following chemotherapy and
radiotherapy for Hodgkin's disease. J Natl Cancer Inst. 2002 Feb 6;94(3):182-92
20. Rossi SE, Erasmus JJ, McAdams HP, et al. Pulmonary drug toxicity: radiologic and
pathologic manifestations. Radiographics. 2000 Sep-Oct;20(5):1245-59.
21. Cohen MB, Austin JH, Smith-Vaniz A, et al. Nodular bleomycin toxicity. Am J Clin Pathol.
1989 Jul;92(1):101-4
22. Roy V, Ochs L, Weisdorf D. Late infections following allogeneic bone marrow
transplantation: suggested strategies for prophylaxis. Leuk Lymphoma. 1997 Jun;26(1-2):1-15
23. Kumar K, Jimenez V. Pulmonary nocardiosis after bone marrow transplantation successfully
treated with doxycycline. Int J Infect Dis. 2001;5(4):222-4
24. Hughes WT. Mycobacterial infections in bone marrow transplant recipients. Biol Blood
Marrow Transplant. 2000;6(4):359-60
25. Gerson SL, Talbot GH, Hurwitz S, et al. Prolonged granulocytopenia: the major risk factor
for invasive pulmonary aspergillosis in patients with acute leukemia. Ann Intern Med. 1984
Mar;100(3):345-51.
26. Maertens J, Maertens V, Theunissen K, et al. Bronchoalveolar lavage fluid galactomannan
for the diagnosis of invasive pulmonary aspergillosis in patients with hematologic diseases. Clin
Infect Dis. 2009 Dec 1;49(11):1688-93.
27. Harders SW, Madsen HH, Rasmussen TR, et al. High resolution spiral CT for determining
the malignant potential of solitary pulmonary nodules: refining and testing the test. Acta Radiol.
2011 May 1;52(4):401-9
28. Wahidi MM, Govert JA, Goudar RK, et al. Evidence for the treatment of patients with
pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines
(2nd edition). Chest. 2007 Sep;132(3 Suppl):94S-107S
29. Soubani AO. The evaluation and management of the solitary pulmonary nodule. Postgrad
Med J. 2008 Sep;84(995):459-66
30. MacMahon H, Austin JH, Gamsu G, et al. Guidelines for management of small pulmonary
nodules detected on CT scans: a statement from the Fleischner Society. Radiology. 2005
Nov;237(2):395-400
31. Lowe VJ, Fletcher JW, Gobar L, et al. Prospective investigation of positron emission
tomography in lung nodules. J Clin Oncol. 1998 Mar;16(3):1075-84
32. Erasmus JJ, McAdams HP, Connolly JE. Solitary pulmonary nodules: Part II. Evaluation of
the indeterminate nodule. Radiographics. 2000 Jan-Feb;20(1):59-66.
33. Erasmus JJ, Connolly JE, McAdams HP, Roggli VL. Solitary pulmonary nodules: Part I.
Morphologic evaluation for differentiation of benign and malignant lesions. Radiographics.
2000 Jan-Feb;20(1):43-58.
34. Divisi D, Imbriglio G, De Vico A, Crisci R Lung nodule management: a new classification
proposal. Minerva Chir. 2011 Jun;66(3):223-34
35. Kasamon YL, Jones RJ, Wahl RL. Integrating PET and PET/CT into the risk-adapted
therapy of lymphoma. J Nucl Med. 2007 Jan;48 Suppl 1:19S-27S.
36. Chamilos G, Macapinlac HA, Kontoyiannis DP. The use of 18F-fluorodeoxyglucose
positron emission tomography for the diagnosis and management of invasive mould infections.
Med Mycol. 2008 Feb;46(1):23-9
22
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
37. Marom EM, Kontoyiannis DP. Imaging studies for diagnosing invasive fungal pneumonia in
immunocompromised patients. Curr Opin Infect Dis. 2011 Aug;24(4):309-14
38. Hot A, Maunoury C, Poiree S, et al. Diagnostic contribution of positron emission
tomography with [18F]fluorodeoxyglucose for invasive fungal infections. Clin Microbiol Infect.
2011 Mar;17(3):409-17.
39. Coelho LO, Gasparetto TD, Escuissato DL, Marchiori E. Bacterial pneumonia following
bone marrow transplantation: HRCT findings. J Bras Pneumol. 2009 May;35(5):431-5.
40. Bruno C, Minniti S, Vassanelli A, Pozzi-Mucelli R. Comparison of CT features of
Aspergillus and bacterial pneumonia in severely neutropenic patients. J Thorac Imaging. 2007
May;22(2):160-5
41. Escuissato DL, Gasparetto EL, Marchiori E, Pulmonary infections after bone marrow
transplantation: high-resolution CT findings in 111 patients. AJR Am J Roentgenol. 2005
Sep;185(3):608-15
42. Greene RE, Schlamm HT, Oestmann JW, et al. Imaging findings in acute invasive
pulmonary aspergillosis: clinical significance of the halo sign. Clin Infect Dis. 2007 Feb
1;44(3):373-9.
43. Milito MA, Kontoyiannis DP, Lewis RE et al. Influence of host immunosuppression on CT
findings in invasive pulmonary aspergillosis. Med Mycol. 2010 Sep;48(6):817-23.
44. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease
from the European Organization for Research and Treatment of Cancer/Invasive Fungal
Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases
Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis. 2008 Jun
15;46(12):1813-21
45. Caillot D, Couaillier JF, Bernard A, et al. Increasing volume and changing characteristics of
invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients
with neutropenia. J Clin Oncol. 2001 Jan 1; 19(1):253-9.
46. Caillot D, Latrabe V, Thiébaut A, et al. Computer tomography in pulmonary invasive
aspergillosis in hematological patients with neutropenia: an useful tool for diagnosis and
assessment of outcome in clinical trials. Eur J Radiol. 2010 Jun;74(3):e172-5
47. Georgiadou SP, Sipsas NV, Marom EM, Kontoyiannis DP. The diagnostic value of halo and
reversed halo signs for invasive mold infections in compromised hosts. Clin Infect Dis. 2011
May;52(9):1144-55.
48. Chamilos G, Marom EM, Lewis RE, et al. Predictors of pulmonary zygomycosis versus
invasive pulmonary aspergillosis in patients with cancer. Clin Infect Dis. 2005 Jul 1;41(1):60-6.
49. Kontoyiannis DP, Lionakis MS, Lewis RE, et al. Zygomycosis in a tertiary-care cancer
center in the era of Aspergillus-active antifungal therapy: a case-control observational study of
27 recent cases. J Infect Dis. 2005 Apr 15;191(8):1350-60.
50. Nucci M, Nouér SA, Grazziutti M, et al. Probable invasive aspergillosis without prespecified
radiologic findings: proposal for inclusion of a new category of aspergillosis and implications for
studying novel therapies. Clin Infect Dis. 2010 Dec 1;51(11):1273-80.
51. Marchiori E, Zanetti G, Irion KL et al. Reversed halo sign in active pulmonary tuberculosis:
criteria for differentiation from cryptogenic organizing pneumonia. AJR Am J Roentgenol. 2011
Dec;197(6):1324-7
52. White DA, Wong PW, Downey R. The utility of open lung biopsy in patients with
hematologic malignancies. Am J Respir Crit Care Med. 2000 Mar;161(3 Pt 1):723-9.
23
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
53. Crawford SW, Hackman RC, Clark JG. Biopsy diagnosis and clinical outcome of persistent
focal pulmonary lesions after marrow transplantation. Transplantation. 1989 Aug;48(2):266-71.
54. Stanzani M, Battista G, Sassi C, et al. Computed tomographic pulmonary angiography for
diagnosis of invasive mold diseases in patients with hematological malignancies. Clin Infect
Dis. 2012 Mar;54(5):610-6.
55. Pfeiffer CD, Fine JP, Safdar N Diagnosis of invasive aspergillosis using a galactomannan
assay: a meta-analysis. Clin Infect Dis. 2006 May 15;42(10):1417-27
56. Viscoli C, Machetti M, Cappellano P, et al. False-positive galactomannan platelia
Aspergillus test results for patients receiving piperacillin-tazobactam. Clin Infect Dis. 2004 Mar
15;38(6):913-6.
57. Marr KA, Laverdiere M, Gugel A, Leisenring W. Antifungal therapy decreases sensitivity
of the Aspergillus galactomannan enzyme immunoassay. Clin Infect Dis. 2005 Jun
15;40(12):1762-9
58. Vergidis P, Walker RC, Kaul DR, et al. False-positive Aspergillus galactomannan assay in
solid organ transplant recipients with histoplasmosis. Transpl Infect Dis. 2011 2011 Sep 26.
59. Van Der Veer J, Lewis RJ, et al. Cross-reactivity in the Platelia™ Aspergillus enzyme
immunoassay caused by blastomycosis. Med Mycol. 2011 Sep 22. [Epub ahead of print].
60. Ostrosky-Zeichner L, Alexander BD, Kett DH, et al. Multicenter clinical evaluation of the (1->3) beta-D-glucan assay as an aid to diagnosis of fungal infections in humans. Clin Infect Dis
2005; 41(5):654-659
61. Shannon VR, Andersson BS, Lei X et al. Utility of early versus late fiberoptic bronchoscopy
in the evaluation of new pulmonary infiltrates following hematopoietic stem cell transplantation.
Bone Marrow Transplant. 2010 Apr;45(4):647-55
62. Dunagan DP, Baker AM, Hurd DD, Haponik EF Bronchoscopic evaluation of pulmonary
infiltrates following bone marrow transplantation. Chest. 1997 Jan;111(1):135-41
63. Gould MK, Fletcher J, Iannettoni MD, et al. Evaluation of patients with pulmonary nodules:
when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition). Chest.
2007 Sep;132(3 Suppl):108S-130S
64. Rivera MP, Mehta AC; American College of Chest Physicians. Initial diagnosis of lung
cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest. 2007 Sep;132(3
Suppl):131S-148S
65. Lacasse Y, Wong E, Guyatt GH, Cook DJ. Transthoracic needle aspiration biopsy for the
diagnosis of localised pulmonary lesions: a meta-analysis. Thorax. 1999 Oct;54(10):884-93.
66. Wiener RS, Schwartz LM, Woloshin S, Welch HG. Population-based risk for complications
after transthoracic needle lung biopsy of a pulmonary nodule: an analysis of discharge records.
Ann Intern Med. 2011 Aug 2;155(3):137-44
67. Wong PW, Stefanec T, Brown K, White DA Role of fine-needle aspirates of focal lung
lesions in patients with hematologic malignancies. Chest. 2002 Feb;121(2):527-32.
68. Wang Memoli JS, Nietert PJ, Silvestri GA. Meta-analysis of guided bronchoscopy for the
evaluation of the pulmonary nodule. Chest. Epub Oct 6, 2011.
69. Naidich DP, Sussman R, Kutcher WL, et al. Solitary pulmonary nodules. CT-bronchoscopic
correlation. Chest. 1988 Mar;93(3):595-8.
70. Zavala DC. Diagnostic fiberoptic bronchoscopy: Techniques and results of biopsy in 600
patients. Chest. 1975 Jul;68(1):12-9
71. Bechara R, Beamis J, Simoff M et al. Practice and complications of flexible bronchoscopy
with biopsy procedures. J Bronchol 2005; 12: 139-142.
24
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
72. Huaringa AJ, Leyva FJ, Signes-Costa J, et al. Bronchoalveolar lavage in the diagnosis of
pulmonary complications of bone marrow transplant patients. Bone Marrow Transplant. 2000
May;25(9):975-9.
73. Boersma WG, Erjavec Z, van der Werf TS, et al. Bronchoscopic diagnosis of pulmonary
infiltrates in granulocytopenic patients with hematologic malignancies: BAL versus PSB and
PBAL. Respir Med. 2007 Feb;101(2):317-25.
74. Sampsonas F, Kontoyiannis DP, Dickey BF, Evans SE. Performance of a standardized
bronchoalveolar lavage protocol in a comprehensive cancer center: a prospective 2-year study.
Cancer. 2011 Aug 1;117(15):3424-33.
75. Cazzadori A, Di Perri G, Todeschini G Transbronchial biopsy in the diagnosis of pulmonary
infiltrates in immunocompromised patients. Chest. 1995 Jan;107(1):101-6
76. Jain P, Sandur S, Meli Y, et al. Role of flexible bronchoscopy in immunocompromised
patients with lung infiltrates. Chest 2004; 125:712-22.
77. 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; 127:1388-96.
78. Peikert T, Rana S, Edell ES. Safety, diagnostic yield, and therapeutic implications of flexible
bronchoscopy in patients with febrile neutropenia and pulmonary infiltrates. Mayo Clin Proc
2005; 80:1414-20.
79. Rabbat A, Chaoui D, Lefebvre A, et al. Is BAL useful in patients with acute myeloid leukemia
admitted in ICU for severe respiratory complications? Leukemia. 2008 Jul;22(7):1361-7.
80. Nguyen MH, Leather H, Clancy CJ, et al. Galactomannan testing in bronchoalveolar lavage
fluid facilitates the diagnosis of invasive pulmonary aspergillosis in patients with hematologic
malignancies and stem cell transplant recipients. Biol Blood Marrow Transplant 2011; 17(7):
1043-1050.
81. Hage CA, Knox KS, Davis TE, et al. Antigen detection in bronchoalveolar lavage fluid for
diagnosis of fungal pneumonia. Curr Opin Pulm Med 2011; 17:167-71.
82. Guo YL, Chen YQ, Wang K, et al. Accuracy of BAL galactomannan in diagnosing invasive
aspergillosis: a bivariate metaanalysis and systematic review. Chest 2010; 138:817-24.
83. Torelli R, Sanguinetti M, Moody A, et al. Diagnosis of invasive aspergillosis by a
commercial real-time PCR assay for Aspergillus DNA in bronchoalveolar lavage fluid samples
from high-risk patients compared to a galactomannan enzyme immunoassay. J Clin Microbiol
2011; 49:4273-8.
84. Tuon FF. A systematic literature review on the diagnosis of invasive aspergillosis using
polymerase chain reaction (PCR) from bronchoalveolar lavage clinical samples. Rev Iberoam
Micol 2007; 24:89-94.
85. Mulabecirovic A, Gaulhofer P, Auner HW, et al. Pulmonary infiltrates in patients with
haematologic malignancies: transbronchial lung biopsy increases the diagnostic yield with
respect to neoplastic infiltrates and toxic pneumonitis. Ann Hematol. 2004 Jul;83(7):420-2.
86. Snyder CL, Ramsay NK, McGlave PB, et al. Diagnostic open-lung biopsy after bone
marrow transplantation. J Pediatr Surg. 1990 Aug;25(8):871-6.
87. Shaikh ZH, Torres HA, Walsh GL, et al. Open lung biopsy in bone marrow transplant
recipients has a poor diagnostic yield for a specific diagnosis. Transpl Infect Dis. 2002
Jun;4(2):80-4.
88. Jiménez MF; Spanish Video-Assisted Thoracic Surgery Study Group. Prospective study on
video-assisted thoracoscopic surgery in the resection of pulmonary nodules: 209 cases from the
25
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
Spanish Video-Assisted Thoracic Surgery Study Group. Eur J Cardiothorac Surg. 2001
May;19(5):562-5.
89. Chen S, Zhou J, Zhang J, et al. Video-assisted thoracoscopic solitary pulmonary nodule
resection after CT-guided hookwire localization: 43 cases and literature review. Surg Endosc
2011; Jun; 25(6):1723-9.
90. American Thoracic Society; Infectious Diseases Society of America Guidelines for the
management of adults with hospital-acquired, ventilator-associated, and healthcare-associated
pneumonia. Am J Respir Crit Care Med. 2005 Feb 15;171(4):388-416.
91. Maschmeyer G, Beinert T, Buchheidt D, et al. Diagnosis and antimicrobial therapy of lung
infiltrates in febrile neutropenic patients: Guidelines of the infectious diseases working party of
the German Society of Haematology and Oncology. Eur J Cancer. 2009 Sep;45(14):2462-72.
92. Freifeld AG, Bow EJ, Sepkowitz KA, et al. Clinical practice guidelines for the use of
antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases
Society of America. Clin Infect Dis, 2011 Feb;52(4):427-431 and e56-93.
93. von Eiff M, Roos N, Schulten R, et al. Pulmonary aspergillosis: early diagnosis improves
survival. Respiration. 1995;62(6):341-7
94. Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy
significantly increases mortality among patients with hematologic malignancy who have
zygomycosis. Clin Infect Dis. 2008 Aug 15;47(4):503-9.
95. Hage CA, Knox KS, Davis TE, et al. Antigen detection in bronchoalveolar lavage fluid for
diagnosis of fungal pneumonia. Curr Opin Pulm Med 2011; 17:167-71.
96. Nucci M, Perfect JR. When primary antifungal therapy fails. Clin Infect Dis. 2008 May
1;46(9):1426-33
97. Wingard JR. Learning from our failures: the antifungal treatment conundrum. Clin Infect
Dis. 2008 May 1;46(9):1434-5
98. Miceli MH, Maertens J, Buvé K, et al. Immune reconstitution inflammatory syndrome in
cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle,
description, and clinical and research implications. Cancer. 2007 Jul 1;110(1):112-20
26
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Table 1. Major etiologies of pulmonary infiltrates
Noninfectious
Diffuse infiltrates
Nodules/Nodular infiltrates
Pulmonary edema
Primary lung cancer
Acute respiratory distress syndrome Lymphomas, Hodgkin lymphoma
Congestive heart failure
Post-transplant lymphoproliferative
disease
Pulmonary hemorrhage, diffuse
alveolar hemorrhage
Peri-engraftment respiratory
distress syndrome
Idiopathic pneumonia syndrome
Thromboembolism
Leukemic infiltrates
Interstitial pneumonitis, idiopathic
or toxic
Cryptogenic organizing
pneumonitis
Pulmonary alveolar proteinosis
Leukemic infiltrates
Infectious
Viruses (cytomegalovirus,
community respiratory viruses,
adenovirus, human herpesvirus VI
Pneumocystis jiroveci
Legionella
Mycoplasma
Chronic/inactive infectious
granulomata
Bacteria, Gram positive and Gram
negative
Nocardia
Aspergillus
Mucormycosis agents
Other molds
Pneumocystis jiroveci
Toxoplasmosis
Strongyloidiasis
Figure 1. Radiographs of different types of nodular lesions.
a.
Solitary nodule. b. Nodule with surrounding groundglass halo. c. masslike consolidation with
surrounding halo of ground-glass opacity. d. Peripheral pleural based nodule with pleural
effusion. e. Large central irregular speculated density with surrounding ground-glass opacity and
27
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smaller more peripheral speculated lesion. f. Cavitary nodule with sequestrum (air crescent
sign).
a.
28
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b.
c.
29
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d.
e.
30
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f.
31
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Figure 2. Diagnostic algorithm
Respiratory symptoms
HRCT
Nodular lesion
Diffuse
Patient on active treatment
Patient not on active treatment
Bacterial or fungal infection likely
Assess likelihood of malignancy
FB with BAL
including GM
Malignancy not likely
If no response, consider
repeating or another invasive
diagnostic test
[small <8 mm, benign
calcification pattern,
stable over time, no
smoking history, not
treated for lymphoma]
Observe
32
Malignancy likely
[larger, change in size,
calcification pattern not
characteristic of benign
lesion, smoking history,
receiving treatment for
lymphoma]
Perform biopsy (bronchoscopic
TBBx, TTNA , or VATS excision)
depending on size and
location)
Table 2. Invasive diagnostic techniques
Procedure
Yield
Hematologic
malignancy &
HCT
15-60% (90% for
IPA if use noncultural
diagnostics) (60,
61, 72-74)
Bronchoscopy
with BAL
10-50% (62)
Transthoracic
needle biopsy
80-90%
(62,63)
50-78% (25, 46,
66)
Open
biopsy/excision
“gold
standard” (62)
16- 60% (45, 46,
85,86)
Video-assisted
biopsy
Comparable to
open lung
biopsy (62,87)
Not adequately
studied
Risk
Noncompromised
Hematologic
malignancy & HCT
Major
complications <135%, severe 10%
(62, 70, 71)
Most complications
minor (<2-28%);
major complications
(<1-8% ) (6, 60, 61,
74, 75); 10% lifethreatening
complications if
respiratory
compromise (67)
15-38% with
6-16% requiring
chest tube (25, 46,
66)
13-21%; 30 day
mortality 2-45% (45,
46, 85,86)
Not adequately
studied
Bleeding,
pneumothorax (1524%, chest tube (67%) (64, 65)
Considerable
morbidity and
mortality
10% morbidity,
<1% mortality (87,
88)
33
Limitations and Comments
Higher yields with guided bronchoscopic
techniques
Not suitable for patients with poor lung
reserve
Lesions optimally should be peripheral
Better with larger lesions (>1 cm)
Not suitable for patients with poor lung
reserve and thrombocytopenia
Not suitable for patients with poor lung
reserve and thrombocytopenia
Not suitable for central or large (>3 cm)
lesions, lesions < 1 cm, deeper in lung
parenchyma
Ground glass lesions may require
localization procedure
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Noncompromised
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Prepublished online June 12, 2012;
doi:10.1182/blood-2012-02-378976
How I manage pulmonary nodular lesions and nodular infiltrates in patients
with hematologic malignancies or undergoing hematopoietic cell
transplantation
John R. Wingard, John W. Hiemenz and Michael A. Jantz
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