Breakdown of Pulmonary Host Defense in the
Ladina Joos and Michael Tamm
Pulmonary Medicine and Pulmonary Cell Research, University Hospital, Basel, Switzerland
The number of immunocompromised patients is steadily increasing
due to HIV infection, solid organ and stem cell transplantation,
intensified chemotherapy, immunosuppression for autoimmune
Prevention strategies for pulmonary infections and diagnostic
methods have evolved and patient outcome has improved. How-
ever, therapies affecting the immune system are also given to older
patients and patients with comorbidities. While the rate of pulmo-
antiretroviral therapy, we are seeing more patients with pulmonary
problems after chemotherapy. Neutropenia is still the most impor-
tant risk factor for bacterial and fungal infection. Flexible bronchos-
copy with BAL remains an important diagnostic method with a low
morbidity and high diagnostic yield in patients with pulmonary
infiltrates following cancer chemotherapy.
Keywords: chemotherapy; immunocompromised hosts; neutropenia;
CHEMOTHERAPEUTIC AGENTS AND THEIR EFFECT
ON PULMONARY HOST DEFENSE
Classical Chemotherapeutic Agents
Neutropenia and infection are major dose-limiting side effects
of chemotherapy. The risk of initial infection and subsequent
complications is directly related to the depth and duration of
neutropenia (1). The magnitude of neutropenia depends on the
intensity of the chemotherapy regimen and is frequently seen
with alkylating agents and purine analogs (2, 3). Neutropenia is
defined as an absolute neutrophil count of less than 1,500/?l,
and the risk of infection begins to increase at an absolute neutro-
phil count below 1,000/?l. Chemotherapy decreases the number
of neutrophils and results in chemotactic and phagocytic defects.
result in bacteremia, often occurs as a result of chemotherapy,
radiation, peripheral and central intravenous lines, surgery, or
Immune defects related to underlying hematologic disorders
function before chemotherapy was examined in a study of pa-
tients with leukemia (4). The groups were divided into patients
who did or did not develop subsequent infections after chemo-
therapy. Patients who developed severe infection or died had a
significant decrease in phagocytic activity of neutrophils com-
pared with those with only a mild infection and had a trend
toward increased oxidative burst, suggesting that neutrophils
(Received in original form August 29, 2005; accepted in final form September 6, 2005)
Correspondence and requests for reprints should be addressed to Michael Tamm,
Pulmonary Medicine and Pulmonary Cell Research, University Hospital Basel,
Petersgraben 4, CH-4031, Basel, Switzerland. E-mail: firstname.lastname@example.org
Proc Am Thorac Soc Vol 2. pp 445–448, 2005
Internet address: www.atsjournals.org
might be preactivated and might have reduced function before
the initiation of chemotherapy.
Pulmonary infiltrates emerge in 15 to 25% of patients with
profound neutropenia after intensive chemotherapy. Lung infil-
tratesinfebrile neutropenicpatients are associated with apartic-
ularly high risk of mortality (5).
Monoclonal antibodies are a new class of agents targeted at
specific receptors on cancer cells. Monoclonal antibodies were
ment with monoclonal antibodies also leads to a significant pro-
portion of neutropenic patients (6, 7) and is hence associated
with similar infectious complications as other chemotherapeutic
agents. Alemtuzumab, an antibody used in the treatment of
lymphoproliferative disorders, is associated with prolonged,
severe, multilineage cytopenias (8).
INFECTIOUS COMPLICATIONS OF CHEMOTHERAPY
The most common infectious complications of chemotherapy
from infected neutropenic patients are almost exclusively pyo-
genic or enteric bacteria. The most common gram-positive
pathogens include Staphylococcus (epidermidis and aureus),
Streptococcus (pyogenes and pneumoniae), and Enterococcus
faecalis. Escherichia coli, Pseudomonas aeruginosa, and Klebsiella
are the most common gram-negative pathogens (9, 10). One
study evaluated the distribution of organisms for 909 episodes
of bacteremia and associated outcome among 799 neutropenic
febrile patients with cancer. Among the bacteremic episodes,
46% were caused by gram-positive organisms, 42% were caused
and lungs were involved in 40% (11).
The risk for specific types of infection is also enhanced by
the underlying malignancy and its associated immune defects.
Decreased or malfunctional antibody production or clearing of
immune complexes in multiple myeloma, chronic lymphocytic
leukemia, and splenectomized patients results in an increased
patients include encapsulated bacteria such as S. pneumoniae,
Haemophilus influenzae, and Neisseria meningitidis (12). The
T-cell defects associated with Hodgkin’s disease result in an in-
creased risk of infection with intracellular pathogens, such as
Listeriamonocytogenes, Salmonellasp, Cryptococcus neoformans,
and Mycobacterium tuberculosis (Table 1)(13).
Pulmonary fungal infections are a major problem in neutropenic
patients. Typically, neutropenic patients develop angioinvasive
pulmonary aspergillosis (14), especially patients with hemato-
logic malignancies that develop after treatment with high-dose
chemotherapy. The risk of developing invasive pulmonary
446 PROCEEDINGS OF THE AMERICAN THORACIC SOCIETYVOL 2 2005
TABLE 1. INFECTIOUS AND NONINFECTIOUS COMPLICATIONS OF CHEMOTHERAPY
Infectious Complications Noninfectious Complications
Viruses (Herpes simplex, CMV, RSV, VZV)
Mycobacteria (typical, atypical)
Fungi (Aspergillus, Nocardia)
Interstitial pneumonitis (DAD, UIP, COP)
ARDS, acute lung injury
Pulmonary edema (fluid overload, heart failure)
Obstruction of upper airways by mucositis
Definitions of abbreviations: ARDS ? adult respiratory distress syndrome; CMV ? cytomegalovirus; COP ? cryptogenic organizing
pneumonia; DAD ? diffuse alveolar damage; RSV ? respiratory syncytial virus; UIP ? usual interstitial pneumonia; VZV ? varicella
aspergillosis is directlyrelated to the duration of the neutropenic
phase. After intensive chemotherapy for hematologic malignan-
cies, the estimated risk of developing invasive pulmonary asper-
gillosis is about 5%, and the reported mortality ranges from 30
to 80% (14, 15). The diagnostic yield of bronchoalveolar lavage
(BAL) to detect invasive pulmonary aspergillosis is extremely
low (16). In contrast to lung transplants and other solid organ
transplants, where tracheobronchial aspergillosis is a typical fea-
ture, aspergillus in neutropenic patients causes angioinvasion,
typically occluding pulmonary arteries, which can be detected
by multislice computed tomographic scan (17) or histology (18).
Patients with hematologic malignancies and other cancer
patients receiving highdose steroids are at increased risk of
Pneumocystis carinii pneumonia (PCP). A retrospective case
infected patients with first episodes of PCP (19). Predisposing
disorders includedmalignant hematologic diseases(30%), organ
transplant recipients (25%), inflammatory conditions (22%),
solid tumors (13%), and miscellaneous disorders (10%). Almost
all of the patients (91%) had received corticosteroid therapy
within the month before PCP. The median dose was equivalent
to 30 mg/d of prednisone, but about one quarter of patients
received as little as 16 mg/d. The median duration of prednisone
therapy was 12 wk before the onset of PCP (19). A similar
distribution was noted in a study of 103 cases over a 5-yr period
Viral infections, especially human herpesviruses, are common
in patients undergoing antineoplastic chemotherapy. Herpes
simplex viruses HSV-1 and HSV-2 are common causes of skin
eruptions. HSV can cause a wide variety of clinical syndromes,
including pneumonia (21). Immunocompromised patients with
disseminatedvaricella-zoster virusinfectioncan havepulmonary
Primary seroconversion or reactivation of other human her-
pes viruses (cytomegalovirus, Epstein-Barr virus, HHV-6) can
occur in this patient population as a result of immunosuppres-
include the community-acquired pathogens respiratory syncytial
virus (RSV) and influenza viruses (23, 24). RSV infections are
associated with a significant morbidity and mortality in patients
with cancer (25).
Prevention of Chemotherapy-induced Infections
The American Society of Clinical Oncology published updated,
poietic colony-stimulating factors (CSFs) in 2000 (3). The guide-
lines recommend that CSFs be used in the first cycle of chemo-
therapy only with regimens that are associated with a high
incidence of febrile neutropenia of more than 40%. This recom-
mendation was based on a trial that demonstrated lower inci-
dence rates of febrile neutropenia in patients with small cell
consistently and significantly reduced other measures of febrile
morbidity, including duration of fever, use of antiinfectives, or
costs of management of the febrile neutropenic episode. No
study has demonstrated a decrease in infection-related mortality
rates. Therefore, for previously untreated patients receiving
most chemotherapy regimens, primary administration of CSFs
is not recommended.
In 2002,theInfectiousDiseasesSociety ofAmericapublished
guidelines for the use of antimicrobial agents in neutropenic
patients with cancer (10).
NONINFECTIOUS COMPLICATIONS OF
Noninfectious complications ofchemotherapy include complica-
tions due to fluid overload (lung edema, pleural effusion), com-
plications due to the application of central catheters (pneumo-
thorax/hematothorax), and, most important, direct toxicity of
various agents to the lung (Table 1). Chemotherapeutic agents,
such as bleomycin (27), busulfan (28), cyclophosphamide (29),
methotrexate, and taxanes (30), cause relevant pulmonary toxic-
ity in a minority of patients. Morphologic patterns of lung dam-
age associated with chemotherapeutic agents include interstitial
pneumonitis(diffuse alveolardamage,usual interstitial pneumo-
nia, cryptogenic organizing pneumonia), adult respiratory dis-
tress syndrome, or hypersensitivity reactions (29) (Table 1).
Concomitant radiation, use of other cytotoxic agents with
have been implicated as additional risk factors for the develop-
ment of pulmonary toxicity.
DIAGNOSTIC APPROACH TO THE
IMMUNOCOMPROMISED PATIENT WITH
Early diagnosis and specific therapies are the cornerstones of
successful treatment of infectious and noninfectious pulmonary
complications in immunocompromised patients.Flexiblefiberoptic
bronchoscopy, including BAL, is aninvasive diagnostic tool with
low morbidity and a high diagnostic yield (16, 31–34). In a large
consecutive cohort of immunocompromised patients, we com-
pared the spectrum of infectious pulmonary complications diag-
nosed using BAL. The diagnostic yield of 1,066 BAL specimens
was analyzed in four different groups of immunocompromised
patients (HIV, solid organ transplants, high-dose chemotherapy
Joos and Tamm: Chemotherapeutic Agents and Their Effect on Pulmonary Host Defense447
Figure 1. Number of bronchoalveolar lavages performed in HIV and
chemotherapy patients in two time periods: 1992–1996 (white bars)
and 1997–2003 (black bars).
and/or stem cell transplants, and immunosuppressive therapy
for other diseases). The overall diagnostic yield of BAL was
34% for bacteria, 22% for cytomegalovirus (CMV), 15% for
P. jiroveci, 6% for other viruses, 6% for mycobacteria, and 2%
for aspergillus. The number of BALs performed in patients with
HIV decreased considerably in recent years despite an increase
of patients treated for HIV, whereas the number of procedures
performed in patients receiving high-dose chemotherapy in-
creased in recent years (Figure 1).
The incidence of pulmonary CMV infection, defined as a
positive CMV culture finding in BAL fluid, is a frequent finding
in all immunocompromised patients except in patients treated
with high-dose chemotherapy. However, positive CMV culture
does not necessarily imply invasive CMV disease. In contrast
to polymerase chain reaction and CMV culture, positive CMV
immunostaining in BAL fluid was shown to be a useful marker
for CMV pneumonitis (35). Although CMV is a well-known
complication in immunocompromised patients, the role of other
In a recent study in patients with cancer, RSV was recovered
in a considerable number of cultures taken from nasopharyngeal
washings. Serious complications developed in about 25% of
RSV-positive patients (25).
Alargenumber ofstudieshave addressedthediagnosticyield
of BAL and transbronchial biopsies in immunocompromised
patients. Incontrast, the diagnosticapproach topleuraleffusions
a conclusive diagnosis of pleural effusion could be made in 21%
of cases by thoracocentesis, and infection was found in one case,
suggesting that complex parapneumonic effusions occur rarely
in this cohort (36).
In summary, patients with cancer undergoing chemotherapy
often suffer from pulmonary complications.Infectious complica-
tions predominantly include bacterial and fungal infections asso-
ciated with neutropenia; however, the role of viruses may be
underestimated. The management of infectious complications is
mainly based on empiric therapy, diagnostic procedures, and
rapid therapeutic interventions. The role of prophylactic antiin-
fective treatment and CSFs is highly controversial.
Conflict of Interest Statement: Neither of the authors has a financial relationship
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