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Pulmonary Medicine and Pulmonary Cell Research, University Hospital, Basel, Switzerland
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: mtamm{at}uhbs.ch
ABSTRACT
The number of immunocompromised patients is steadily increasing due to HIV infection, solid organ and stem cell transplantation, intensified chemotherapy, immunosuppression for autoimmune diseases, and a marked increase in the use of monoclonal antibodies. Prevention strategies for pulmonary infections and diagnostic methods have evolved and patient outcome has improved. However, therapies affecting the immune system are also given to older patients and patients with comorbidities. While the rate of pulmonary complications in HIV patients has dramatically decreased under antiretroviral therapy, we are seeing more patients with pulmonary problems after chemotherapy. Neutropenia is still the most important risk factor for bacterial and fungal infection. Flexible bronchoscopy with BAL remains an important diagnostic method with a low morbidity and high diagnostic yield in patients with pulmonary infiltrates following cancer chemotherapy.
Key Words: chemotherapy • immunocompromised hosts • neutropenia • pulmonary infections
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/µl, and the risk of infection begins to increase at an absolute neutrophil count below 1,000/µl. Chemotherapy decreases the number of neutrophils and results in chemotactic and phagocytic defects. Furthermore, breakdown of skin and mucosal barriers, which can result in bacteremia, often occurs as a result of chemotherapy, radiation, peripheral and central intravenous lines, surgery, or tumor invasion.
Immune defects related to underlying hematologic disorders further increase the risk for infections. As an example, neutrophil function before chemotherapy was examined in a study of patients with leukemia (4). The groups were divided into patients who did or did not develop subsequent infections after chemotherapy. Patients who developed severe infection or died had a significant decrease in phagocytic activity of neutrophils compared with those with only a mild infection and had a trend toward increased oxidative burst, suggesting that neutrophils 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 infiltrates in febrile neutropenic patients are associated with a particularly high risk of mortality (5).
Monoclonal Antibodies
Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. Monoclonal antibodies were recently introduced in the treatment of various neoplasms. Treatment with monoclonal antibodies also leads to a significant proportion 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
Bacterial infections
The most common infectious complications of chemotherapy are bacterial infections (Table 1). The specific pathogens isolated from infected neutropenic patients are almost exclusively pyogenic 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 by gram-negative organisms, and 12% were polymicrobial. Infection at a site other than blood alone was observed in 242 episodes, and lungs were involved in 40% (11).
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Fungal Infections
Pulmonary fungal infections are a major problem in neutropenic patients. Typically, neutropenic patients develop angioinvasive pulmonary aspergillosis (14), especially patients with hematologic malignancies that develop after treatment with high-dose chemotherapy. The risk of developing invasive pulmonary aspergillosis is directly related to the duration of the neutropenic phase. After intensive chemotherapy for hematologic malignancies, the estimated risk of developing invasive pulmonary aspergillosis 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 feature, 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 series from the Mayo Clinic evaluated 116 consecutive non–HIV-infected patients with first episodes of PCP (19). Predisposing disorders included malignant 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 (20).
Viral Infections
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 disseminated varicella-zoster virus infection can have pulmonary involvement (22).
Primary seroconversion or reactivation of other human herpes viruses (cytomegalovirus, Epstein-Barr virus, HHV-6) can occur in this patient population as a result of immunosuppression. Other common infections that occur in the neutropenic host 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, evidence-based clinical practice guidelines for the use of hematopoietic colony-stimulating factors (CSFs) in 2000 (3). The guidelines recommend that CSFs be used in the first cycle of chemotherapy only with regimens that are associated with a high incidence of febrile neutropenia of more than 40%. This recommendation was based on a trial that demonstrated lower incidence rates of febrile neutropenia in patients with small cell lung cancer who received prophylactic recombinant human granulocyte CSFs compared with placebo (26). These agents have not 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, the Infectious Diseases Society of America published guidelines for the use of antimicrobial agents in neutropenic patients with cancer (10).
NONINFECTIOUS COMPLICATIONS OF CHEMOTHERAPY
Noninfectious complications of chemotherapy include complications due to fluid overload (lung edema, pleural effusion), complications due to the application of central catheters (pneumothorax/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 toxicity in a minority of patients. Morphologic patterns of lung damage associated with chemotherapeutic agents include interstitial pneumonitis (diffuse alveolar damage, usual interstitial pneumonia, cryptogenic organizing pneumonia), adult respiratory distress syndrome, or hypersensitivity reactions (29) (Table 1).
Concomitant radiation, use of other cytotoxic agents with known lung toxicity, and exposure to high oxygen concentrations have been implicated as additional risk factors for the development of pulmonary toxicity.
DIAGNOSTIC APPROACH TO THE IMMUNOCOMPROMISED PATIENT WITH PULMONARY INFILTRATES
Early diagnosis and specific therapies are the cornerstones of successful treatment of infectious and noninfectious pulmonary complications in immunocompromised patients. Flexible fiberoptic bronchoscopy, including BAL, is an invasive diagnostic tool with low morbidity and a high diagnostic yield (16, 31–34). In a large consecutive cohort of immunocompromised patients, we compared the spectrum of infectious pulmonary complications diagnosed 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 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 increased in recent years (Figure 1).
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A large number of studies have addressed the diagnostic yield of BAL and transbronchial biopsies in immunocompromised patients. In contrast, the diagnostic approach to pleural effusions in hematologic malignancies is rarely discussed. In a recent study, 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 complications predominantly include bacterial and fungal infections associated 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 antiinfective treatment and CSFs is highly controversial.
FOOTNOTES
Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
(Received in original form August 29, 2005; accepted in final form September 6, 2005)
REFERENCES
This article has been cited by other articles:
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  C. G. Clement, S. E. Evans, C. M. Evans, D. Hawke, R. Kobayashi, P. R. Reynolds, S. J. Moghaddam, B. L. Scott, E. Melicoff, R. Adachi, et al. Stimulation of Lung Innate Immunity Protects against Lethal Pneumococcal Pneumonia in Mice Am. J. Respir. Crit. Care Med., June 15, 2008; 177(12): 1322 - 1330. [Abstract] [Full Text] [PDF]
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 M. Y. Dolina, D. C. Cornish, S. A. Merritt, L. Rai, R. Mahraj, W. E. Higgins, and R. Bascom Interbronchoscopist Variability in Endobronchial Path Selection: A Simulation Study Chest, April 1, 2008; 133(4): 897 - 905. [Abstract] [Full Text] [PDF]
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