B acte rial Pneumon ia in

P a t i e n t s wi t h C a n c e r
Novel Risk Factors and Management
Justin L. Wong, MDa, Scott E. Evans, MDb,*

KEYWORDS
 Bacterial pneumonia  Cancer  Neutropenia  Hematologic malignancy  Stem cell transplant
 Immunocompromised host pneumonia

KEY POINTS
 Bacterial pneumonias in patients with cancer cause significant morbidity and mortality, particularly
among those with treatment-induced cytopenias.
 Cancer-related and cancer treatment-related derangements of lung architecture, mucositis, and
impaired airway protection/swallow function all contribute to pneumonia risks.
 Neutropenia, cytotoxic chemotherapy, graft-versus host disease and other factors increase the risk
of developing life-threatening bacterial pneumonia.
 Chest imaging is often nonspecific, but may aid in diagnosis. Bronchoscopy with bronchoalveolar
lavage is recommended for patients with suspected bacterial pneumonia with new infiltrates on
chest imaging.
 Early initiation of antibiotic therapy is recommended for those suspected of having bacterial pneu-
monia, ensuring coverage of pathogens commonly encountered in the health care setting.

INTRODUCTION many as 80% hematopoietic stem cell transplant

(HSCT) recipients will experience at least 1
Bacterial pneumonias cause disproportionate episode of pneumonia, and pneumonia is the
morbidity and mortality in patients with cancer, proximate cause of death in 20% of HSCT pa-
despite the current aggressive use of prophylactic tients.11–13 Patients with cancer demonstrate
antibiotics and environmental hygiene measures in unique susceptibility to bacterial pneumonias
this population.1–5 Pneumonias are estimated to owing to the complex immune dysfunction caused
cause or complicate nearly 10% of hospital admis- by the disease and its treatment, reflecting such
sions among patients with cancer, notably disparate mechanisms as neutropenia, lung archi-
including patients with hematologic malignancies tectural derangements, and malnutrition.5,14–17
whose estimated risk of pneumonia during the Further, frequent exposure to uncommon or
course of treatment exceeds 30%.3,5–8 In fact, in antibiotic-resistant organisms occurs through
the transfusion era, pneumonia is the leading repeated encounters with the health care sys-
cause of death among patients with acute leuke- tem.15,18,19 In addition to lethality attributable to
mias.3,9,10 Some investigations suggest that as

Disclosures: Dr J.L. Wong declares no relevant conflicts of interest. S.E. Evans is an author on United States
chestmed.theclinics.com

patent 8,883,174 entitled ‘Stimulation of Innate Resistance of the Lungs to Infection with Synthetic Ligands.
’ S.E. Evans owns stock in Pulmotect, Inc, which holds the commercial options on these patent disclosures.
a
Division of Internal Medicine, Department of Pulmonary, Critical Care and Sleep Medicine, The University of
Texas Health Sciences Center, 6431 Fannin Street, MSB 1.434, Houston, TX 77030, USA; b Division of Internal
Medicine, Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, 1515
Holcombe Boulevard, Unit 1100, Houston, TX 77030, USA
* Corresponding author.
E-mail address: seevans@mdanderson.org

Clin Chest Med 38 (2017) 263–277

http://dx.doi.org/10.1016/j.ccm.2016.12.005
0272-5231/17/Ó 2016 Elsevier Inc. All rights reserved.
264 Wong & Evans

the infection, a diagnosis of bacterial pneumonia is successfully establishes infection.32,33 In fact,

associated with poorer overall outcomes in pa- many of the classical clinical signs that charac-
tients with cancer.7,20,21 In some cases, worsened terize the syndrome of pneumonia are predomi-
outcomes result from cancer progression when nantly manifestations of these host responses.
cytotoxic treatments are deferred in patients sus- These include radiographic pulmonary infiltrates
pected of having pneumonia. However, indepen- that reflect airspace filling by edema fluid, leuko-
dent of effects on anticancer treatment, a single cytes, and debris; systemic signs such as fever
episode of bacterial pneumonia is associated and leukocytosis; and mucopurulent cough.16,34
with an increased frequency and complexity of Both cancer and its treatment cause derange-
hospitalization.22 This review addresses the pre- ments of innate and adaptive responses to bacte-
vention, diagnosis, and management of bacterial ria in the lungs. As summarized in Fig. 1, leukocyte
pneumonia in patients with cancer, with an depletion, dysregulated inflammation, mucosal
emphasis on the host factors that contribute to disruptions, impaired pathogen recognition,
susceptibility. tumor-related anatomic abnormalities, and graft-
versus-host responses all contribute to the
PATHOGENESIS OF CANCER-ASSOCIATED tremendous susceptibility of patients with cancer
PNEUMONIA to lower respiratory tract infections.5,35 Functional
and anatomic defects frequently coexist in pa-
In both healthy and immunocompromised patients, tients with cancer. Further, recurrent health care
bacteria reach the peripheral lung via inhalation, encounters that are typical among patients with
aspiration, hematogenous spread, or locoregional cancer promote exposure to nosocomial and
progression of proximal airway infections. The drug-resistant pathogens.15
overwhelming majority of inhaled or aspirated Thus, not only are patients with cancer uniquely
pathogens are expelled via mucociliary escalator susceptible to bacterial infections, but their
function before reaching the alveolar level, with dysfunctional immune responses make the diag-
particulates and microbes impacted in the visco- nosis of bacterial pneumonia challenging. In the
elastic airway lining fluid by turbulent air flow.23 absence of a brisk inflammatory response, many
Those bacteria that reach the peripheral lung of the cardinal features of clinical pneumonia
must breach the barrier defenses that exclude may not be present. This diagnosis may be made
pathogens from the lower respiratory tract.24,25 even more difficult when the patient has an already
The barrier defenses of the lower respiratory abnormal chest radiograph due to the disease or
tract are often thought of as passive barricades its treatment, or when a patient has competing
to pathogen translocation. However, the lungs causes for fever or cough.
are protected by a complex array of dynamic
defenses that include both structural impediments HOST SUSCEPTIBILITY FACTORS IN THE
to pathogen entry and active antimicrobial effec- CANCER PATIENT
tors. Epithelial cells express effectors such as
cationic antimicrobial peptides, reactive oxygen Patients with cancer encounter myriad homeostat-
species, and surfactant proteins into the airway ic derangements, and susceptibility to bacterial
lining fluid, reducing pathogen burden through pneumonia among patients with cancer varies ac-
direct microbiocidal effects, activation of cording to the type of malignancy, treatment
leukocyte-mediated immunity, and enhanced types, and timing and comorbidities.15
pathogen opsonization.26–28 Alveolar macro- General debility, as suggested in individual pa-
phages engulf invading pathogens and promote tients by Eastern Cooperative Oncology Group
host response via the complement system and in- Performance Status scores of 2 or greater, has
flammatory mediators.29–31 Ligation of local been identified as a risk factor among patients
epithelial and macrophage pattern recognition re- with lung cancer for the development of bacterial
ceptors by pathogen-associated molecular pat- pneumonia.36 It has been suggested that this
terns promotes recruitment and activation of may reflect, in part, the catabolic and malnour-
neutrophil responses and sculpts the adaptive ished states that are common among patients
response in the lung.26–28 with cancer. In particular, malignancy-related defi-
In the intact host, these responses are usually ciencies of essential fatty acids and polyribonucle-
successful in eliminating pathogen threats. otides, have been noted to cause important
However, the immunopathology resulting from (but reversible) impairments of inflammatory and
the robust expression of antimicrobial mediators cytotoxic responses that contribute to pneumonia
may result in local tissue injury and systemic susceptibility.37 Preexisting lung disease,
inflammation, particularly when the pathogen including emphysema or bronchiectasis, are also
 Bacterial Pneumonia in Patients with Cancer 265

Fig. 1. Host factors that promote bacterial pneumonia susceptibility in patients with cancer. Although the med-
ical encounters that patients with cancer require expose them to uncommon, virulent, and drug-resistant path-
ogens, much of the increased risk of pneumonia in this population derives from complex and often concurrent
impairments of the host defense. Shown are frequent defects in the pneumonia defenses of patients with cancer,
caused by insults both in and outside the lungs. CNS, central nervous system.

associated with increased risk of cancer-related causes of aspiration of orogastric contents,

bacterial pneumonia and mortality.38,39 placing patients at increased risk for pneu-
monia.40,41 Similarly, pneumonia risks are
increased among patients with esophageal can-
Aspiration Events
cers owing to excessive gastric reflux and trache-
Poorly coordinated swallow function and impair- oesophageal fistulae.42,43 Unfortunately, these
ments of airway protection are frequently risks may persist after completion of cancer treat-
observed among patients with cancer. Structural ment in each of these conditions owing to persis-
lesions associated with head and neck cancer tent neuropraxias or permanent anatomic
and neurologic defects associated with central derangements caused by radiation fibrosis, laryn-
nervous system lesions are well-recognized gectomy, or esophagectomy.44–46
266 Wong & Evans

Mass lesions are not the only causes of therapy to the head and neck, mediastinum,
aspiration-related lower respiratory tract infections esophagus, and to a lesser extent among any pa-
in patients with cancer. Oral mucositis and esoph- tient receiving thoracoabdominal radiation.62–64
agitis commonly affect patients with hematologic
malignancies or those receiving stem cell trans- Anatomic Derangements
plantation, also causing impairments of swallow As in patients without cancer, distorted lung anat-
function that result in bacterial pneumonias. Inter- omy owing to preexisting lung disease or prior in-
estingly, although the oral microbial diversity of fections predisposes to colonization and infection
patients with cancer does not much differ from with bacterial pathogens.65–67 Further, architec-
the general population, the incidence of peri- tural changes specific to cancer and its treatment
odontal disease is significantly greater in those un- also place patients at increased risk for bacterial
dergoing cancer chemotherapy.47–49 It has been pneumonia. Airway obstruction caused by endolu-
suggested subsequently that optimized dental minal disease or extrinsic compression may
care in patients receiving chemotherapy may impede normal mucociliary clearance and pro-
reduce the incidence of aspiration events and mote postobstructive pneumonias.68–70 Lymphan-
reduce the frequency of fever, productive cough, gitic disease may obstruct airways and may impair
and positive blood cultures.50 Relatedly, whereas leukocyte responses to infected lung segments.
gut dysbiosis has been associated with such Similarly, airway distortion caused by prior radio-
HSCT complications as bloodstream infections therapy or surgical intervention may lead to more
and graft-versus-host disease (GVHD), it has bacterial infections.
been reported recently that altered gut microbiota
may also be predictive of pulmonary complica- Neutropenia
tions of HSCT, including bacterial pneumonias.51
In 1977, Bodey and colleagues71 described the
inverse association of absolute neutrophil count
Mucositis and Bacterial Translocation and risk of infection. Since then, chemotherapy-
In addition to the aspiration risk, cancer-related induced neutropenia has become the most widely
mucositis also facilitates pneumonia caused by recognized risk factor for cancer-associated bac-
hematogenous spread of pathogens that translo- terial pneumonias. Neutrophils are particularly
cate from the upper and lower gastrointestinal sensitive to nucleoside analogues and alkylating
tract. Owing to the profound effects on rapidly agents, both causing dose-dependent decreases
replicating gastrointestinal epithelial cells, in circulating neutrophil levels. Severe neutropenia
chemotherapy-related mucositis represents a (<500 cells/mL) is especially associated with
serious threat to mucosal integrity. This has been serious lung infections and poor outcomes.
long observed with the use of drugs that alter Underscoring the relevance of this risk factor,
DNA synthesis, and has been classically Vento and colleagues72 estimate that nearly
described with such agents as methotrexate, 60% of patients with cancer experiencing
5-fluoruracil, and cytosine arabinoside. However, chemotherapy-induced neutropenia will develop
the chemotherapeutic agents known to cause pulmonary infiltrates on radiographic examination.
mucositis are many and varied in mechanism of The rapidity of onset, duration, severity, and
action, including melphalan-based regimens,52–55 underlying physiologic process all further impact
cyclophosphamide,52 docetaxel, and vinorelbine susceptibility to neutropenic pneu-
to note a few.56,57 Repetitive treatment cycles monia.18,30,35–39,73 Moreover, impairments of
are associated with an increasing risk and severity neutrophil phagocytosis and chemotaxis follow
of mucositis.58 Even when clinical mucositis common cancer-related insults such as radiation,
scores are low, even the modest degrees of muco- corticosteroids, hypovolemia, acidosis, and hy-
sitis still represent potentially important break- perglycemia.5,40 Thus, functional neutropenia can
downs in the host innate defense barriers.59 also contribute to cancer-related pneumonia risk.3
Unfortunately, although targeted therapies Although chemotherapy-induced neutropenia is
generally have fewer off-target effects than do associated most commonly with treatment of he-
conventional cytotoxic therapies, mucositis is still matologic malignancies and conditioning regi-
widely reported with many tyrosine kinase, mens for HSCT, a number of regimens to treat
mammalian target of rapamycin, epidermal growth solid tumors also cause neutropenia.74–77
factor receptor, and vascular endothelial growth
Nonneutropenic Defects
factor receptor inhibitors.60,61
Pneumonia-relevant mucositis is also extremely Chemotherapy regimens also cause a wide array
common among patients receiving radiation of nonneutropenic leukocyte defects that
 Bacterial Pneumonia in Patients with Cancer 267

predispose patients to bacterial pneumonias. For patients with cancer. Periodontal disease after ra-
example, alkylating agents also cause immune diation, chemotherapy, or malignancy-related im-
dysfunction through disproportionate depletion of mune dysfunction can all be associated with
CD41 T cells, relative to CD81 T cells.78–80 Tyro- increased risk of preventable pneumonia.
sine kinase inhibitors increase risks for bacterial The role of vaccinations in patients with cancer
pneumonia through both neutropenia-dependent has been an issue of intensive investigation, given
and -independent mechanisms, possibly including the complex immunologic consequences of malig-
effects on antibody class switching.81,82 Anthracy- nant diseases, chemotherapy and immunosup-
clines, taxanes, topoisomerase inhibitors, and pression. The only vaccinations approved by the
vinca alkaloids all seem to be capable of US Food and Drug Administration available
increasing risk of bacterial pneumonia via nonneu- against bacterial pneumonia both target Strepto-
tropenic mechanisms during treatment.83 coccus pneumoniae. The 23-valent polysaccha-
There are also a number of nonneutropenic de- ride vaccine (PSV23), principally activates mature
fects that predispose patients to bacterial pneu- B-cells, which may be deficient or dysfunctional
monia, even after treatment has been completed. in patients with cancers such as lymphomas or
For example, agents such as fludarabine and myelomas. Interestingly, in this population, anti-
alemtuzumab can cause long-term lymphocyte body responses to PSV23 positively correlate
dysfunction, in some cases lasting years beyond with hematologic response to chemotherapy.85
the treatment interval. The conjugated 13-valent pneumococcal vaccina-
In recipients of allogeneic stem cell transplants, tion (PCV13) depends more heavily on T-cell
GVHD can predispose to bacterial pneumonias responses, and remains more immunogenic
both through episodes of mucositis and chronic in many immunocompromised cancer
defects of cell-mediated immunity.13,84 Moreover, populations.86–88
intensification of immunosuppressive therapies in Two cancer populations of particular note when
response to GVHD flares notably enhances sus- considering vaccination are those with asplenia
ceptibility to bacterial pneumonia. and those receiving anti-CD20 therapy, because
Finally, hematologic malignancies can cause both generate poor humoral responses to vac-
intrinsic immune defects that predispose patients cines. Some patients with cancer require thera-
to bacterial pneumonia. Specific defects depend peutic splenectomy whereas others, including
on the cells affected by the malignancy. For many patients with Hodgkin lymphoma, develop
example, excessive expansion of clonal leukemia functional asplenia that results in both increased
populations can result in deficiencies of functional frequency and severity of pneumococcal dis-
leukocytes, resulting in immune dysfunction ease.89 These patients may generate reduced
through cytopenias. In contrast, nonmalignant leu- initial antibody titers to PCV13 vaccination, espe-
kocytes may be present at near normal levels in cially if given during cytoreductive therapy, and
multiple myeloma, but immune defects may exist even apparently normal initial levels may decline
due to deficiencies of functional immunoglobulins below expected titers years after vaccination.90
and immunoglobulin class switching. Anti-CD20 therapy such as rituximab disrupts
B-cell–mediated antibody production, increasing
PREVENTION OF BACTERIAL PNEUMONIA IN the risk of invasive pneumococcal disease impair-
PATIENTS WITH CANCER ing responses to both PCV13 and PSV23.87,91
The current recommendation from the Centers
Minimizing pathogen exposures is foundational for Disease Control and Prevention is that immu-
to preventing bacterial pneumonia in patients nocompromised patients with cancer receive
with cancer. Optimized hand hygiene is central both the PCV13 followed by PSV23 at least
to nosocomial spread of pneumonia-causing 8 weeks later.92 Where feasible, patients typically
organisms as well as avoidance of community- initiate vaccination before the initiation of chemo-
acquired pathogens, and no other single interven- therapy, particularly if rituximab is anticipated. In
tion has been demonstrated to be more effective.3 those not vaccinated before receiving cytotoxic
The past 4 decades have also seen reduced path- therapy, some experts recommend delaying
ogen transmission to neutropenic patients through vaccination up to 6 months after chemotherapy
development of protected hospital environments is completed to ensure greater efficacy. The effec-
using laminar airflow, ultraviolet light decontami- tiveness of the current recommendations in
nation, and specialized personal protective reducing disease burden remains unclear, poten-
equipment. tially owing to the underuse of vaccines in the can-
Given the relevance of oropharyngeal aspiration cer population resulting from confusion about the
to pneumonia, regular dental care is important in usefulness of vaccination in patients who are
268 Wong & Evans

receiving myeloablative treatments, even in ter- between typical patterns suggestive of bacterial
tiary cancer centers.93 infection than radiographic imaging.95 In another
The optimized strategy to best protect HSCT pa- study of adults with febrile neutropenia, 48% of
tients remains an area of intensive investigation. patients with a CT scan suggestive of pneumonia
Multisociety guidelines from 200911 recognize that were found to have a radiograph that was inter-
PSV23 elicits inadequately immunogenic responses preted as normal.96 Offsetting enthusiasm for early
in the first year after HSCT, so 3 doses of the more and frequent CT in patients with cancer is the fact
immunogenic, but less broad, PCV are recommen- that radiographic studies subject patients to radia-
ded in that interval. A fourth vaccination with PSV23 tion exposures, potentially to organs that also
may provide enhanced breadth of coverage, receive therapeutic radiation. Ultra–low-dose CT
although PCV may be preferred for the fourth dose scanning has been investigated as a tool to main-
in patients with chronic GVHD. The timing of the tain adequate image quality while reducing radia-
vaccination also remains controversial, because tion dose to patients with cancer. A recent study
initiation of pneumococcal vaccination 3 months af- in patients with febrile neutropenia suggests that
ter HSCT may provide confer early protection, but this approach may preserve reasonable diagnostic
may not provide similarly durable antibody re- accuracy.97
sponses or reliable PSV23 boost compared with Certain CT patterns, such as lobar consolidation
vaccination started 9 months after HSCT. or peribronchial nodules, have been described as
characteristic of bacterial pneumonias98
DIAGNOSIS OF BACTERIAL PNEUMONIA IN (Fig. 2A–C). However, CT patterns are frequently
THE PATIENT WITH CANCER nonspecific, particularly in patients with impaired
immune function, and cannot be relied on for a
Although the clinical syndrome of pneumonia is microbiologic diagnosis.98,99 Moreover, the pat-
well-characterized in the general population, this terns observed in patients with cancer with bacte-
diagnosis may be challenging in the patients with rial pneumonia overlap substantially with
cancer. Most of the cardinal clinical features of competing noninfectious diagnoses, as suggested
pneumonia represent host response elements by the CT patterns shown in Fig. 2D–F.
that may be impaired or absent in immunocompro- PET using fluorine-18 fluorodeoxyglucose has
mised patients with cancer. Conversely, when pre- been proposed as a means to predict infection in
sent, cough, fever, and radiographic infiltrates may patients with cancer with infiltrates, although no
be manifestations of the malignancy itself or com- study has defined clearly the standard uptake
plications of therapy. Nevertheless, the correct values that are confirmatory of infection or
diagnosis of pneumonia and identification of an changed management.100–102
infecting pathogen are both associated with better
outcomes. Thus, a high clinical suspicion and
appropriate testing are essential. Further, given Diagnostic Bronchoscopy
the severe immune impairment and frequent Although CT scanning lacks specificity, it is
health care exposures experienced by patients frequently helpful in directing bronchoscopic in-
with cancer, it important to consider the possibility vestigations. In patients with cancer with sus-
that pneumonias may be caused by uncommon, pected pneumonia and from whom high-quality
atypical, or opportunistic organisms. sputum samples cannot be obtained, flexible
bronchoscopy with bronchoalveolar lavage (BAL)
Imaging Studies
is the diagnostic tool of choice. Depending on
Although plain chest radiographs are often rapidly the patient population investigated and the tech-
available and can reveal some lower respiratory nique used, the diagnostic yield for a pathogen
tract infections, they are nonspecific and have a or noninfectious cause of infiltrates (eg, malignant
poor negative predictive value, particularly in he- cytology) is reported between 15% and
matologic malignancy and HSCT patients. In 1 55%.103–106 Diagnostic yield may be enhanced
recent study, radiologist-interpreted radiographs by rigorous adherence to BAL protocol.106 Further,
predicted the correct type of infection in immuno- performance of BAL in the first 4 days of symp-
compromised patients with pneumonia only 34% toms in HSCT patients with suspected pneumonia
of the time.94 Computed tomography (CT) scan- is associated with improved diagnostic yield and
ning is more sensitive than radiography in the mortality.107 The role for bronchial washings re-
detection and characterization of pneumonia. mains unclear, and the addition of protected spec-
When performed with high-resolution formatting, imen brushing and protected BAL has not been
in particular, CT scanning is better able to discern shown to improve the diagnosis of pneumonia in
bilateral and apical disease, and to discriminate patients with hematologic malignancies.108
 Bacterial Pneumonia in Patients with Cancer 269

Fig. 2. Radiographic presentations of bacterial pneumonia in patients with cancer. Computed tomography im-
ages of patients with cancer with documented bacterial pneumonias. (A) Multifocal lobar consolidation in a pa-
tient with acute myelogenous leukemia and Legionella micdadei pneumonia. (B) Diffuse ground-glass infiltrates
in a patient with chronic myelomonocytic leukemia and Raoultella planticola pneumonia. (C) Peribronchial nod-
ules (and small, chronic pleural effusions) in a patient with myelodysplastic syndrome and Stenotrophomonas
maltophilia pneumonia. (D) Multidrug-resistant Klebsiella pneumoniae pneumonia presenting as a single mass
in a patient with aplastic anemia. (E) Diffuse, mixed alveolar and interstitial infiltrates in a patient with myelodys-
plastic syndrome and Pseudomonas aeruginosa pneumonia. (F) Methicillin-resistant Staphylococcus aureus pneu-
monia presenting as new nodules on a background of preexisting nodules in a patient with renal cell carcinoma
metastatic to the lungs.

Transbronchial biopsy is beneficial principally in material even from nonviable bacteria.110 Further,
aiding the diagnosis of neoplasms or noninfectious multiplex detection of resistance cassettes can
pneumonitis.109 Not only is this procedure often allow prediction of antibiotic susceptibility and
precluded in patients with cancer by thrombocyto- may allow detection of difficult to culture patho-
penia, but convincing evidence is lacking that cul- gens, including anaerobes.111 However, the use
ture of biopsy tissue results in reliable culture of standalone PCR detection for bacteria is
information. Thus, this intervention is recommen- impeded currently by local laboratory capability
ded in only select patients with cancer and sus- and practical challenges of testing sufficiently
pected pneumonia. comprehensive PCR probe sets.
Serial dilution culture remains the standard clin-
ical practice for bacterial pathogen detection,
Nonbronchoscopic Diagnostics
owing to the breadth of organisms that can be
identified by this strategy, the ability to quantify Data from general (noncancer) populations indi-
pathogen burden, and the ability to subculture cate that urine antigen testing for bacterial patho-
for antimicrobial susceptibility testing. Box 1 iden- gens including S pneumoniae and Legionella spp.
tifies select bacterial pathogens that are frequently provides enhanced sensitivity for the diagnosis of
detected in patients with chemotherapy-induced bacterial pneumonias over culture-only strategies.
neutropenia by this technique. However, polymer- Moreover, like PCR testing on respiratory secre-
ase chain reaction (PCR)-based pathogen detec- tions, urinary antigen testing can be performed in
tion has the potential to supplement and, minutes, potentially improving time to diagnosis
theoretically, supplant culture-based methods in and time to correct antibiotics.112,113 Notably,
patients with cancer. PCR-based strategies there seems to be a strong correlation between
obviate the obligate delays for pathogen growth, urine antigen levels and markers of host response,
potentially improving the time to correct antibi- including procalcitonin levels, C-reactive protein
otics. Because patients with cancer are typically levels, and lobar infiltrates on radiographic imag-
receiving empiric antimicrobials by the time of ing. Thus, there may be some dependency of urine
BAL, standard growth techniques may be antigen levels on the host responses, so further
impaired, but PCR assays can detect genomic testing is required to confirm that the sensitivity
270 Wong & Evans

Box 1
MANAGEMENT OF BACTERIAL PNEUMONIA
Bacterial pneumonia pathogens commonly IN THE CANCER PATIENT
associated with chemotherapy-induced Antibiotic Therapy
neutropenia
The value of these diagnostic tests is contingent
Gram-positive bacteria upon the availability of effective therapies.
Because of the broad range of potential pathogens
Nocardia spp.
and innumerable host factors, therapeutic strate-
Rhodococcus equi gies must be directed by the patient’s immune sta-
Streptococcus pneumoniaea tus and exposure history, both to pathogens and
Streptococcus pyogenes antimicrobials.
Treatment should generally not be withheld
Staphylococcus aureusa,b while diagnostic interventions are undertaken. De-
Gram-negative bacteria lays in appropriate antimicrobial therapy increase
Acinetobacter baumannii complex
the risk of secondary complications and
infection-associated deaths in immunocompro-
Alcaligenes/Achromobacter spp. mised patients with cancer; thus, it is common
Burkholderia spp. practice to initiate empiric or preemptive antibiotic
Citrobacter spp.b therapy when pneumonia is suspected.3,18,117,118
No consensus exists for the optimal time to first
Enterobacter cloacaeaa
antibiotic dose, although a recent study suggests
Escherichia colib that neutropenic fever outcomes are better when
Klebsiella pneumonia antibiotics are delivered within 104 minutes of pre-
Moraxella catarrhalis sentation.119 Although the earliest possible anti-
biotic dosing is generally recommended,
Neisseria meningitides
possible exceptions include when bronchoscopic
Nontypeable Haemophilus influenzaa evaluation is available immediately.3 In that case,
Proteus spp.b it may be reasonable to hold empiric antibiotic
Pseudomonas spp.a,b
therapy until completion of the brief procedure,
potentially enhancing the diagnostic yield of the
Stenotrophomonas maltophiliab collected microbiologic cultures. This delay should
Serretia marcescensa generally be no longer than 2 hours. Antibiotics
should not be held for multiple hours or days in
Atypical bacteria
anticipation of bronchoscopy, because the harm
Chlamydophyla pneumoniae from delaying therapy outweighs the benefits of
Legionella spp. improved test performance.120–122
Mycoplasma pneumoniae Initial antimicrobial therapy for febrile patients
with cancer with pulmonary infiltrates should
a
Routinely consider in initial selection of antibiotics. ensure coverage of multidrug-resistant strains of
b
Increased risk for antimicrobial resistance.
Staphylococcus aureus and Pseudomonas aeru-
ginosa.15,123–126 Coverage for atypical organisms
is comparable in immunocompromised cancer is also appropriate in patients with cancer
populations. admitted with community-acquired pneumonia,
Biomarkers to aid in the diagnosis of bacterial with the selection of macrolide, fluoroquinolone,
pneumonia in immunocompromised patients with or doxycycline therapy largely dependent on the
cancer have been long sought. Serum concentra- agent(s) chosen for drug-resistant pathogens
tions of procalcitonin, interleukin-6, C-reactive and on prior prophylactic regimens.127,128 All anti-
protein, serum amyloid proteins, and others have biotic choices should consider culture data, pneu-
been investigated for their usefulness in the diag- monia severity, local antibiotic sensitivity profiles,
nosis of fevers of unknown origin.114 Although in- prior antibiotic exposures, and patient immune
creases in these markers have been observed in status.129 Empiric antibiotics for early hospital-
critically ill patients, none has demonstrated acquired pneumonia (within 7 days of admission)
discriminatory capacity for bacterial pathogens in should include coverage of S pneumoniae,
this population.115 Procalcitonin levels in pleural methicillin-resistant S aureus, Haemophilus influ-
fluid may offer some advantage in distinguishing enzae, and Enterobacteriaceae. Initial regimens
parapneumonic or tuberculous effusions from ma- for patients with late hospital-acquired pneu-
lignant effusions.114,116 monia, health care-associated pneumonia, or
 Bacterial Pneumonia in Patients with Cancer 271

ventilator-associated pneumonia should ensure populations and protocols.138 However, some au-
enhanced coverage for multidrug resistant thors argue that severely ill neutropenic patients
Gram-negative bacilli.117,120,125,130 Secondary may benefit from granulocyte transfusion.137
antibiotic selections for patients with refractory In addition to efforts to increase the absolute
hospital-acquired pneumonia, health care- number of leukocytes in cytopenic patients, multi-
associated pneumonia, or ventilator-associated ple groups have investigated the manipulation of
pneumonia should be determined by institutional existing leukocytes through the administration of
pathogen susceptibility profiles and on prior pa- recombinant cytokines. Exogenous interferon-
tient antimicrobial exposures.124,125,130,131 gamma has demonstrated success in reducing
Early deescalation of broad empiric therapy may some bacterial infections in patients with congen-
be considered in patients who demonstrate ital neutropenia, and more recent studies suggest
prompt clinical response and in whom granulocyte efficacy in patients with opportunistic infections
recovery has occurred, especially if a susceptible after HSCT.139 Postulated mechanisms for this ef-
pathogen has been identified.132,133 Deescalation fect include induction of surface molecules such
should be undertaken with caution in patients as major histocompatibility complex class II, Fc re-
with poor clinical response to antimicrobial ther- ceptor gamma and integrins, increased phagoly-
apy, persistent neutropenia, or ongoing immuno- sosomal superoxide production, and prolonged
suppressive therapy.134 half-life of granulocytes. Administration of
interleukin-12 has also been proposed as a means
to protect against lung infections,140 potentially via
Therapies to Augment Host Defenses
interferon-gamma–dependent and tumor necrosis
Despite broad-spectrum antibiotic strategies, factor–dependent mechanisms.
mortality rates remain unacceptably high in pa- Induction of innate antimicrobial responses
tients with cancer who also have bacterial pneu- directly from lung epithelial cells offers a novel
monia, particularly among neutropenic patients. alternate strategy to prevent, and possibly treat,
Often, antibiotic failures arise, at least in part, pneumonias in patients with cancer. Lung epithe-
from the continuing immune defects associated lial cells are long lived and relatively resistant to
with the primary disease. Consequently, the chemotherapy.141,142 Beyond their well-known
means to mitigate immune defects of patients barrier function, these cells also demonstrate a
with cancer and improve pathogen clearance substantial capacity to detect pathogens, modu-
have become an area of intensive investigation. late local immune responses, and generate
A major research focus has been correction of directly bactericidal responses through the pro-
granulocytopenia. Preparations of granulocyte duction of antimicrobial peptides and reactive
colony stimulating factor (filgrastim, lenograstim, species.26,143 Advances in the understanding of
and pegfilgrastim) and granulocyte macrophage the molecular mechanisms involved in recognition
colony stimulating factor (sargramostim and mol- and signal transduction have allowed develop-
gramostim) are available commercially. Both clas- ment of inhaled therapeutics that induce protec-
ses demonstrate efficacy in reducing the duration tive innate immune responses from the lung
of neutropenia, although a less favorable side ef- epithelium in animals. In animal models of pneu-
fect profile of granulocyte macrophage colony monia, this provides protection from lethal patho-
stimulating factor limits its use primarily to post- gens, even when there is concurrent
HSCT immune reconstitution.135,136 Although the neutropenia.142,144,145 Preclinical animal studies
evidence suggests that colony-stimulating factors of one such treatment, PUL-042, demonstrate
may be used safely to prevent some bacterial protection against gram-positive, gram-negative,
pneumonias in cancer populations,137 they are fungal, and viral pneumonias, and clinical trials
not recommended generally as a treatment of are ongoing.142,145,146 Augmentation of innate im-
established bacterial infections. Current guidelines mune responses offer several hypothetical advan-
recommend the administration of granulocyte col- tages in terms of rapidity of effect, breadth of
ony stimulating factor if the risk of developing pathogen specificity, and lack of known antimicro-
febrile neutropenia is greater than 20% based on bial resistance, but efficacy has not been estab-
patient-specific risk factors.136 lished in humans.
Infusion of donor granulocytes has also been
proposed as an adjunct therapy in patients with SUMMARY
cancer with febrile neutropenia. Although this
strategy holds promise, it remains investigational Bacterial pneumonias remain a frequent and chal-
and interpretation of the associated studies is lenging complication in patients with cancer. The
challenging owing to heterogeneity of the clinical approach requires integration of traditional
272 Wong & Evans

microbiologic techniques as well as targeted mo- 11. Center for International Blood and Marrow Trans-
lecular diagnostics. Successful management stra- plant Research, National Marrow Donor Program,
tegies depend on early recognition, consideration European Blood and Marrow Transplant Group, Eu-
of numerous cancer-related host factors, and ropean Blood and Marrow Transplant Group
prompt initiation of broad-spectrum antibacterial (EBMT), et al. Guidelines for preventing infectious
agents. Newer host-directed therapies that help complications among hematopoietic cell transplant
to reconstitute or augment the immune system recipients: a global perspective. Bone Marrow
are under active investigation in clinical trials. Transplant 2009;44(8):453–558.
These modalities may serve to supplement more 12. Lossos IS, Breuer R, Or R, et al. Bacterial pneu-
traditional approaches in the future. monia in recipients of bone marrow transplantation.
A five-year prospective study. Transplantation
1995;60(7):672–8.
ACKNOWLEDGMENTS
13. Aguilar-Guisado M, Jiménez-Jambrina M,
The authors thank Dr Ahmed Salahudeen for Espigado I, et al. Pneumonia in allogeneic stem
contributing the original art included in this article. cell transplantation recipients: a multicenter pro-
spective study. Clin Transplant 2011;25(6):E629–38.
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