Infectious Complications of Lung Cancer

Although patients with lung cancer have benefited from advances in diagnostic techniques, surgery, chemotherapy, and radiation, infection frequently complicates the course of cancer treatment. Infection may be caused by the tumor itself, by antineoplastic therapy, or by supportive care measures. Recognition of risk factors for infection is critical. The relationship between an underlying immune defect and certain infections is well documented. Diagnosis may be complicated by the paucity of signs and symptoms or by an atypical presentation. Prompt institution of empiric antimicrobial therapy is usually warranted, particularly in life-threatening infections. This review will focus on the epidemiology, diagnosis, and management of particular infections that can occur in patients with lung cancer.

In the United States, lung cancer is a frequently diagnosed malignancy, second only to prostate cancer in men and breast cancer in women. It is also the leading cause of cancer mortality in both sexes.[1] The American Lung Association estimates that lung cancer was responsible for 164,400 deaths in the United States in 2004.[2] When death occurs, it is usually attributed to local or metastatic progression of disease. Other problems such as paraneoplastic syndromes may contribute. Patients with lung cancer are also susceptible to infection, which can be present at the time of cancer diagnosis, complicate the treatment course, and result in death. Causes of infection include bronchial obstruction, aspiration, immunosuppression from radiation and/or chemotherapy, disruption of local host defenses due to tumor invasion, and necrosis of both normal and tumor tissue.[3] Other factors such as the presence of invasive devices, steroids, and nutritional status further influence the risk for infectious complications.[4-6] This article aims to review the epidemiology of infections occurring in lung cancer patients and the infectious complications that can arise from lung cancer treatment. A focus on pulmonary infections, which are the most common infectious type to occur in this particular population, as well as the impact of these infections on survival, will follow.

Epidemiology
Few reports have been published regarding the infectious morbidity and mortality in patients with lung cancer (Table 1). One group in Ferrara, Italy, performed diagnostic bronchoscopy in 96 consecutive patients with visible endobronchial tumor and studied quantitative cultures of fluid obtained from bronchoalveolar lavage (BAL).[7] None of the patients had received prior radiotherapy, chemotherapy, or immunosuppressive treatment. A colony count of equal to or greater than 105 colony forming units per milliliter (cfu/mL) was considered indicative of bacterial pulmonary infection. Specimens were also subjected to acid-fast smear examination after Ziehl-Neelsen staining, as well as culturing for mycobacteria. Chlamydia trachomatis was identified through DNA probes, and Pneumocystis jiroveci was detected via immunofluorescence technique. A total of 42 microorganisms were isolated from BAL of 33 patients, in which 50% were gram-negative bacteria, 33.3% were gram-positive species, and 16.7% were other organisms (3 with C trachomatis and 4 with P jiroveci). Eight patients had polymicrobial cultures. The calculated prevalence at the time of cancer diagnosis alence at the time of cancer diagnosis (34%) was felt to be an underestimation, as 30 of 96 patients were receiving antimicrobial treatment at the time of bronchoscopy. No statistically significant relationship between the presence of pulmonary infection and histology, stage, Karnofsky performance status, total lymphocyte count, or T-lymphocyte subsets was found.[7] Other studies have estimated the incidence of pulmonary infections at any point along the cancer course to range from 24% to 70%.[3,8] One potential reason for the variability may be that each group used different criteria to define infections of the upper and lower respiratory tract.

The three studies cited above also attempted to delineate the microbiologic profile of documented pulmonary infections. Infections were typically defined as productive cough associated with fever and/or infiltrate seen on chest radiograph.[3,8] One or more organisms were isolated from sputum or BAL specimens in 34% to 75% of infectious episodes. Bacterial species accounted for ≥ 90%. Gram-negative bacteria, including Haemophilus species, members of Enterobacteriaceae, and Pseudomonas aeruginosa, predominated. Notable gram-positive pathogens were viridans streptococci, Staphylococcus aureus, and Streptococcus pneumoniae.[3,7,8] Information derived from these reports suggests that broad-spectrum antibiotics are indicated in treating pulmonary infections associated with lung cancer. Patients with lung cancer can acquire other infections that are unrelated to the respiratory tract. Not much is known regarding their frequency relative to pulmonary infections. In a recent review, the group at the Institut Jules Bordet, a cancer hospital in Brussels, prospectively tracked 275 patients with lung cancer who were hospitalized between January 1997 and February 2001. The investigators reported 435 episodes of fever and/or infection occurring in these 275 patients. Only 76 patients were neutropenic. The majority of infections involved the upper and lower respiratory tract (n = 244; 56%), followed by infections involving the blood (n = 38), urinary tract (n = 35), head and neck (n = 26), skin (n = 22), gastrointestinal tract (n = 20), and 1 case each of meningitis and osteitis. The remaining episodes were fever without documented infection. Pulmonary infections developed more frequently in nonneutropenic patients, compared to those with neutropenia (68.4% vs 44.2%, P = .0008).[9] However, the type and frequency of infection may change with the presence of neutropenia. Fuks et al followed 65 consecutive patients with non-small-cell lung carcinoma (NSCLC) treated with intensive induction chemotherapy at the University of Maryland Cancer Center from May 1979 to February 1981. Fortyfour infections were observed for 30 (46%) of 65 neutropenic patients. The majority of infections involved the gastrointestinal tract (n = 20) and were probably related to mucosal damage associated with cytotoxic chemotherapy. Remaining episodes included infections of the respiratory tract (n = 9), blood (n = 3), skin (n = 3), and urinary tract (n = 2), as well as 7 cases of fever of unknown origin. All infections presented with white blood cell (WBC) counts of less than 1,000/μL, and 34 of the 44 infectious episodes occurred while WBC counts were less than 500/μL.[10]

Infections Due to Lung Cancer Treatment
The approach to management of lung cancer has been detailed in recent reviews.[11-13] Surgery, radiation, and chemotherapy are the three modalities used to treat lung cancer, either singly or in combination. Their application depends on the histology and stage of the neoplastic disease. Each has its own toxicity profile.

Surgery
With improved surgical technique, anesthesia, and perioperative care, the operative mortality for surgical resections has decreased significantly. Today, pneumonectomy can be performed with a mortality rate of less than 6%; lobectomy, less than 3%; and smaller resections with 1% mortality or less.[1] However, patients undergoing surgery for lung cancer have a high likelihood of developing postoperative cardiopulmonary problems. Age, preoperative pulmonary function, cardiovascular comorbidity, and smoking status are frequently cited risk factors.[14] The most common postoperative infection is nosocomial pneumonia, with incidence ranging from 6.4% to 22%.[14-17] One series found that postoperative pneumonia occurred after a week of hospitalization, whereas mechanical complications (eg, air leak) typically happened within days of surgery.[14] The impact of nosocomial pneumonia can be seen with longer hospital stays, increased costs, and significant mortality.[14-16] Empyema with or without bronchopleural fistula (0.4%-5%) and wound infections (2.4%-5%) occur much less frequently.[14-17]

Radiation Therapy
Standard thoracic radiotherapy for lung cancer can give rise to various types of toxicity, including esophagitis, pneumonitis, skin desquamation, myelopathies, and cardiac abnormalities. Refinements in radiation technique such as altered fractionation schedules and three-dimensional computed tomography (CT) have been tested with the aims of improving response rates and sparing normal tissue. Concurrent administration of chemotherapy augments the radiosensitivity of the tumor, but the likelihood of adverse effects, particularly mucosal injury and myelosuppression, also increases.[12,18]

Chemotherapy
Many chemotherapeutic agents are effective against lung cancer, including cisplatin, carboplatin, etoposide, irinotecan (Camptosar), cyclophosphamide (Cytoxan, Neosar), doxorubicin, vincristine, paclitaxel, docetaxel (Taxotere), vinorelbine, gemcitabine (Gemzar), and ifosfamide. Because these agents are used in combination, it can be difficult to sort out individual drug toxicities. Major side effects include nausea, vomiting, alopecia, myelosuppression, nephrotoxicity, neuropathy, high-pitch hearing loss, and electrolyte depletion.[12] One important and potentially fatal consequence is the development of infection, which is often secondary to myelosuppression. Combining chemotherapy with radiation seems to potentiate the risk for infectious complications.[18]

Specific Infectious Complications
The following is a discussion of certain infections that can occur as a result of radiation and/or chemotherapy and thus are not unique to the lung cancer patient.

• Fever and Neutropenia-Patients with lung cancer have mild and relatively short periods of neutropenia in comparison to those with hematologic malignancies or patients undergoing hematopoietic stem cell transplantation. Yet lung cancer patients are just as susceptible to developing infections while neutropenic, as shown by Fuks and colleagues.[10] These authors noted that the type and incidence of infectious complications were similar to other studies examining infections in cancer patients with depressed WBC counts. Of note, patients with WBC counts ≤ 500/μL were more likely to develop infection than those with WBC nadirs between 501 and 1,000/μL (P < .0001). The management of fever and neutropenia in the lung cancer patient is the same as for any other oncologic patient.[19]

•Therapy-Induced Mucosal Injury and Superinfection-Radiation therapy to the thorax induces mucosal injury, particularly to the esophagus. The incidence of severe acute esophagitis (grade 3 or higher) in patients treated for lung cancer is 1.3% with standard radiotherapy alone, 6% to 14% with the addition of concurrent chemotherapy, and 24% to 34% when hyperfractionated irradiation is used in conjunction with chemotherapy.[ 20] Tissue injury is characterized by the absence of mitosis in the basal epithelial layer and submucosal edema.[ 21] During the second or third week of radiotherapy, patients may notice swallowing difficulties. This may progress to odynophagia and later to constant pain unrelated to swallowing. If the pain on swallowing is severe, patients may require intravenous hydration, feeding through percutaneous gastrostomy or jejunostomy, or parenteral nutrition. In addition, the cancer treatment course may have to be halted temporarily to allow for esophageal healing. Symptoms of acute esophagitis can persist for 1 to 3 weeks after completion of radiation therapy.[20] Mucosal injury is frequently accompanied by candidal superinfection. Under normal circumstances, gastrointestinal flora keeps the growth of Candida in check. Exposure to radiation and/or chemotherapy disrupts this balance by causing local tissue trauma and depressing host immunity. The presence of other factors such as diabetes mellitus and corticosteroid use may enhance the likelihood of oropharyngeal and esophageal candidiasis in lung cancer patients.[22] Esophagitis may arise as an extension of oropharyngeal candidiasis, although the esophagus can also be the only site involved. Diagnosis is usually made clinically, and empiric antifungal therapy is prescribed. Candida albicans accounts for the majority of cases. Upper endoscopy with brushing and biopsy is performed to confirm the diagnosis of esophageal candidiasis and to rule out infection due to herpes simplex virus (HSV) or cytomegalovirus (CMV). The typical endoscopic appearance is characterized by yellow-white plaques on an erythematous background, with varying degrees of ulceration. Differential diagnosis includes radiation esophagitis, reflux esophagitis, or viral infection due to CMV or HSV.[22] For mild to moderate oropharyngeal thrush, topical nystatin (suspension of 100,000 U/mL: 4-6 mL four times daily) or clotrimazole troches (one 10-mg troche five times daily) may be used.[22] Fluconazole tablets (100-200 mg once daily) or itraconazole solution (200 mg once daily) may be used for moderate to severe cases and for those with esophageal involvement. Clinical response rates of 90% and good tolerability have been reported for both azoles.[23] Intravenous azole therapy may be initiated in patients who cannot swallow due to pain. With symptomatic improvement, azoles can be easily converted to an oral formulation for the remainder of the course. Particularly severe cases or those with decreased susceptibility to azoles may require intravenous amphotericin B (0.3-0.7 mg/kg once daily) or caspofungin (50 mg once daily).[24,25] Duration of therapy for oropharyngeal candidiasis is 7 to 14 days; the duration for esophagitis is 14 to 21 days. Mucosal injury can also be accompanied by reactivation of latent HSV. The frequency of HSV reactivation in solid tumor treatment regimens is not well established. HSV-induced mucositis may be clinically indistinguishable from direct mucosal injury caused by radiation and/or chemotherapy. Lesions are often ulcerative and may extend along the mucosal surface to involve the esophagus, trachea, or lungs.[21] Diagnosis is presumptively made by the finding of multinucleated giant cells or by positive fluorescent-antibody reaction, and may be confirmed by rapid shell vial or conventional tube culture.[ 26,27] Acyclovir reduces the duration of viral shedding and shortens the time to healing. Mild to moderate cases may be treated orally (400 mg three times daily or 200 mg five times daily) for 7 days. Severe cases may require intravenous acyclovir (5 mg/kg every 8 hours).[21,26] Finally, the disruption of the mucosal barrier may predispose to bacteremia. Streptococci are the most frequent bacterial pathogens associated with mucosal injury. In particular, viridans streptococci are increasingly recognized for their virulence in neutropenic patients.[ 21] Although the frequency of such bloodstream infections may not be as high as for those undergoing intensive chemotherapy for hematologic malignancies, vigilance should be maintained.

• Herpes Zoster Infection-Herpes zoster results from recrudescence of latent varicella-zoster virus from dorsal root ganglia. Risks for viral reactivation include the normal age-related decrease in cellular immunity as well as exposure to steroids, chemotherapy, and radiation.[28] In general, herpes zoster is relatively uncommon among patients with solid tumors (0.5%-2.7%). However, the frequency of herpes zoster in patients with small-cell lung carcinoma (SCLC) treated with combination chemotherapy has been reported to be as high as 12%.[29] Another series documented a rate of 8.1% in patients receiving combined-modality treatment for SCLC.[30] Not much is known about the incidence in patients with NSCLC. Herpes zoster seems to develop late in the course of cancer treatment, ranging from 22 days to 24 months after initiation of therapy. The thorax appears to be the most commonly affected site, regardless of whether the patient is exposed to radiation.[29,30] Patients typically present with a prodrome of hyperesthesia, paresthesias, or a burning sensation along the affected dermatome, followed by the appearance of vesicular lesions. Disseminated infection has occurred in patients with SCLC, although infrequently.[ 29,30] Diagnosis on the basis of clinical appearance may be sufficient. In cases where the location or the appearance of the lesions may be atypical, direct immunofluorescence assay or shell vial culture may be used.[28] Oral acyclovir (800 mg five times daily) can reduce the duration of viral shedding, stop formation of new lesions, and hasten rate of healing. Newer agents (valacyclovir [Valtrex], 1,000 mg every 8 hours; famciclovir [Famvir], 500 mg every 8 hours) are more bioavailable and offer less frequent dosing. Acyclovir can be given intravenously (10 mg/kg every 8 hours) for moderate to severe cases, including disseminated infection, and for patients who cannot take medications orally. The duration of therapy ranges from 7 to 14 days. Concomitant corticosteroids have not been shown to reduce the incidence or duration of postherpetic neuralgia, although acute pain may be alleviated.[28]

Spectrum of Pulmonary InfectionsAcute Exacerbations of Chronic Bronchitis
Many patients with lung cancer will likely have underlying chronic obstructive pulmonary disease (COPD), as smoking is a major risk factor for both diseases. It is estimated that 80% of patients with COPD either smoke or have smoked and that 87% of patients with lung cancer have a smoking history.[2,31] One component of COPD is chronic bronchitis, which is typified by periodic attacks of airway obstruction due to inflammation and clogging with mucus, often in response to environmental stimuli or viral tracheobronchitis. Acute exacerbations of chronic bronchitis (AECB) are characterized by an increase in cough and sputum production, dyspnea, and a variable decrease in pulmonary function. Symptoms may worsen with bacterial superinfection. Bacterial agents appear to be particularly associated with AECB in patients with low lung function and those with frequent episodes. Non-typeable Haemophilus influenzae, Moraxella catarrhalis, and S pneumoniae are estimated to account for > 50% of all episodes of AECB. Haemophilus parainfluenzae, P aeruginosa, and members of the Enterobacteriaceae family can be recovered in patients with more severe lung disease.[31,32] Diagnosis is supported by the patient's self-reported symptoms as well as clinical assessment. Physical exam may reveal rales and expiratory rhonchi. Spirometry or peak flow measurement often shows obstruction. A chest x-ray may be normal or may show increased bronchovascular markings. Although it is common practice to culture expectorated sputum, recovery of organisms may simply reflect chronic colonization. Some pathogens such as H influenzae are difficult to isolate in sputum and, thus, are the reason for false-negative cultures. Many experts therefore advocate initiating empiric antibiotic therapy without bacteriologic evaluation.[31] Treatment for AECB includes supportive care and antibiotics directed against H influenzae, M catarrhalis, and S pneumoniae. Antibiotic therapy shortens the duration of illness and is cost-effective for patients with moderate to severe symptoms. Traditional oral agents include amoxicillin, doxycycline, and trimethoprim-sulfamethoxazole. However, the emergence of penicillin-resistant S pneumoniae as well as beta-lactamase-producing Haemophilus and Moraxella strains has complicated antibiotic selection in recent years. Depending on a community's susceptibility patterns, alternate choices include amoxicillinclavulanate, expanded-spectrum cephalosporins, newer macrolides, and the fluoroquinolones (Table 2). Duration of therapy is usually 5 to 7 days.[31,32] Additionally, patients should receive the influenza vaccine annually and the pneumococcal vaccine at least once. If more than 5 years has elapsed since receipt of the first dose, then a one-time pneumococcal revaccination is appropriate for this patient population. Although the pneumococcal vaccine does not decrease the frequency or severity of AECB, the reduction in the frequency of pneumococcal pneumonia has been demonstrated in studies.[33]

Infections of the Lower Respiratory Tract

•Differential Diagnosis-Patients with lung cancer frequently present with lower respiratory tract pathology. In addition to infection, patients can have pulmonary dysfunction from tumor progression, treatment-related toxicity, edema, thromboembolic disease, and hemorrhage.[34,35] Distinguishing between infectious and noninfectious conditions is difficult. Common processes present atypically, and more than one process can occur simultaneously. A practical approach is to categorize patients according to the distribution of pulmonary infiltrates (localized or diffuse) and the immune status of the host. Factors to consider when assessing the immune status include the presence of neutropenia and its duration, recent exposure to chemotherapeutic agents and radiation, concurrent medications (eg, steroids), recent hospitalizations, and comorbid conditions. Recognizing the type, severity, and duration of an existing immune deficiency helps to predict the most likely causative organisms.[ 34,36] To establish an appropriate diagnosis, a high index of suspicion and specialized diagnostic evaluations often are required.

• Diagnostic Approach-The initial evaluation consists of a detailed history and physical exam, pulse oximetry reading (or arterial blood gas, if critically ill), a chest x-ray, laboratory tests that include a complete blood cell count, and cultures. A serum antigen test for Cryptococcus, urinary antigen tests for Histoplasma and Legionella serotype 1, and collection of nasopharyngeal specimens for detection of respiratory viruses may be helpful in the appropriate clinical setting. Chest CT provides additional information regarding the pattern and extent of pulmonary infiltrates, atelectasis, hilar or mediastinal lymphadenopathy, and pleural effusions. Spiral CT technology allows for the evaluation of pulmonary arteries in patients with suspected pulmonary embolus.[35]

Depending on the clinical setting, respiratory samples can be examined for bacterial, mycobacterial, fungal, viral, or parasitic organisms. Analysis of properly collected sputum can help establish an etiologic diagnosis for pneumonia. Adequate sputum for microbiologic evaluation should contain few epithelial cells and numerous polymorphonuclear neutrophils if the patient is not neutropenic. However, obtaining a good specimen, particularly in critically ill and/or neutropenic patients, might be difficult. The diagnostic yield can vary, although recovery of Legionella, Nocardia, Mycobacterium tuberculosis, dimorphic fungi, Pneumocystis jiroveci (formerly Pneumocystis carinii), or influenza virus is indicative of disease.[ 33,37] Sputum cannot distinguish infection from treatment-related toxicity, and the yield for malignancy is low.[35] Flexible bronchoscopy with bronchoalveolar lavage (BAL) can be used to evaluate the lower airways. BAL is the preferred primary approach, considering its low complication rate of less than 2% and a diagnostic yield ranging from 30% to 90%.[37] In the setting of diffuse pulmonary infiltrates, the diagnostic yield of BAL for pulmonary hemorrhage and for certain nonbacterial infections including P jiroveci, respiratory viruses, Mycobacterium species, and Histoplasma capsulatum is greater than 80%.[34-36] The utility of BAL in the evaluation of focal infiltrates is variable, and other sampling techniques such as protected specimen brush or transbronchial biopsy may be needed. Transbronchial biopsy is superior to BAL in diagnosing malignancy and other noninfectious processes such as drug toxicity and bronchiolitis obliterans organizing pneumonia.[34,35] However, this technique is not routinely performed, especially in critically ill patients, due to concerns of pneumothorax, bleeding, and respiratory failure. Tissue biopsy remains the gold standard and should be considered when other techniques fail to provide a diagnosis. The most predictive factor in determining a specific diagnosis with biopsy is the presence of a focal radiographic abnormality.[38] Complications include pneumothorax, bleeding, and wound infection. Biopsy results often lead to alterations in therapy although the overall survival outcome may not be changed.[36]

• Community-Acquired Pneumonia- Because smoking and COPD are predisposing factors for communityacquired pneumonia, this illness is frequently suspected in the lung cancer patient who presents with a focal infiltrate and a compatible clinical syndrome. S pneumoniae accounts for the majority of cases in which an etiologic diagnosis is made. In some areas of the United States, more than 30% of isolates are intermediately resistant or highly resistant to penicillin. There are also reports of increasing resistance to cephalosporins, macrolides, and fluoroquinolones. Other implicated pathogens include H influenzae, M catarrhalis, Klebsiella pneumoniae and other gram-negative bacilli, S aureus, and the "atypical" pathogens (Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila). The goal of therapy is to provide optimal coverage for S pneumoniae and L pneumophila since both can be potentially fatal. Hospitalized patients with normal renal function can be treated with intravenous cefotaxime (Claforan, 2 g every 6-8 hours) or ceftriaxone (Rocephin, 1-2 g every 24 hours) in combination with a macrolide (eg, azithromycin [Zithromax], 500 mg once daily). Alternatively, a fluoroquinolone with antipneumococcal activity (levofloxacin [Levaquin], 500 mg once daily; gatifloxacin [Tequin], 400 mg once daily, or moxifloxacin [Avelox], 400 mg once daily) can be given. The excellent bioavailability of the fluoroquinolones allows for easy intravenous to oral conversion. Clinical improvement typically occurs after 48 to 72 hours. Duration of therapy and switch to oral antimicrobials should be individualized according to the infecting organism(s) and overall condition of the patient. Treatment of bacterial pneumonia ranges from 7 to 10 days, whereas atypical pneumonia may require treatment for up to 21 days.[33]

• Postobstructive Pneumonia- Postobstructive pneumonitis develops distal to the obstructing endobronchial lesion or site of external compression. This clinical entity is a combination of atelectasis, bronchiectasis, and parenchymal inflammation. Pneumonia occurs when colonizing flora become trapped in the affected lung by tumor and is frequently polymicrobial.[ 39] Progression to empyema or lung abscess formation is possible. Antibiotic regimens should include activity against anaerobes. Potential therapeutic options include, but are not limited to, clindamycin monotherapy or in combination with other agents, a beta-lactam/beta-lactamase inhibitor, or a carbapenem (Table 3). If patients have had extensive hospitalizations or prior antibiotic use, involvement of highly resistant organisms is likely, and antibiotic selection should take this into account. Effective treatment requires removal of the obstructing lesion by surgery, chemotherapy, or irradiation to aid in adequate drainage of the affected lung.[40]

• Aspiration Pneumonia-Malignant invasion of either the vagus or recurrent laryngeal nerve can occur in some patients with lung cancer. Vocal cord paralysis results in dysphonia, dysphagia, and weak cough due to glottal incompetence.[41] Ciliary dysfunction due to radiotherapy further increases the likelihood of aspiration pneumonia.[40] Colonizing bacteria gain entrance to the lung via aspirated oropharyngeal secretions. Diagnosis is suspected when a person at risk for aspiration has radiographic evidence of an infiltrate in the dependent lung segments (posterior segments of the upper lobes, apical segments of the lower lobes). Infections are usually of a mixed aerobic and anaerobic etiology, and antimicrobial therapy is similar to that for postobstructive pneumonia. Complications of untreated aspiration pneumonia include abscess formation, necrotizing pneumonia, and empyema. Management should also include minimizing the risk of aspiration.[42]

• Lung Abscess-The association between lung abscess and underlying lung cancer-particularly squamous cell carcinoma-has been long recognized, with the incidence of in situ infection reported to be as high as 27%. Tumor necrosis, either due to size or as a result of cancer treatment, can lead to cavitation, which in turn may become infected and produce an abscess. Ipsilateral hilar and mediastinal lymphadenopathy may be due to malignancy, but may also be related to active infection. Often patients presenting with lung abscess secondary to an undiagnosed lung cancer may be treated for repeated bouts of pneumonia before the malignancy is discovered. This frequently leads to a delay in diagnosis and work-up such that the percentage of patients with resectable tumor is relatively low.[43] Radiographic imaging may not reliably distinguish between a cavitary tumor, carcinomatous abscess, and a benign abscess. Cavitary lesions with a maximum wall thickness of < 1 mm generally suggest a benign process, whereas those with a cavity wall > 15 mm are more frequently malignant. Fine-needle aspiration via fluoroscopic, ultrasound, or CT guidance is an effective method for diagnosis. Samples should be sent for both microbiology and cytology.[43,44] Patients with infected lung tumors respond clinically and radiographically to antibiotic treatment. Because infecting flora can include aerobic gram-negative and gram-positive species as well as anaerobes, broad-spectrum antimicrobial therapy is warranted, as for postobstructive and aspiration pneumonias, but the duration is typically prolonged (weeks to months).[44] Upon completion of antibiotic therapy, restaging may be required if the tumor shrinks in size and/or the lymphadenopathy resolves.[43]

• Pneumonia During Fever and Neutropenia-The duration of neutropenia, if it occurs in the lung cancer patient, generally lasts less than 14 days. Bacterial pneumonias predominate in this setting. Infecting organisms include the Enterobacteriaceae, P aeruginosa, and S aureus. Empiric broad-spectrum antibiotic therapy should be promptly initiated. Delay in treatment, particularly for a gram-negative pneumonia, may lead to sepsis.[34,36] Depending on the institution, monotherapy or combination therapy for the treatment of fever and neutropenia is employed. Appropriate choices for monotherapy include ceftazidime (2 g intravenously every 8 hours), cefepime (Maxipime, 2 g intravenously every 8 hours), or a carbapenem (eg, imipenemcilastatin [Primaxin], 500 mg intravenously every 6 hours; meropenem [Merrem], 1 g intravenously every 8 hours). Combination therapy for febrile, neutropenic patients typically consists of a beta-lactam with antipseudomonal activity (eg, piperacillin/ tazobactam [Zosyn], ceftazidime, cefepime) plus an aminoglycoside.[19] If patients improve within 48 to 72 hours, a course of 10 to 14 days is recommended. The lack of clinical response within 48 to 72 hours of empiric antibiotic therapy should prompt a reevaluation. Therapy should be modified if there is concern about resistant organisms that may not be covered by the initial antimicrobial regimen or if the pneumonia is due to less common etiologic agents such as L pneumophila. A diagnostic procedure such as flexible bronchoscopy may be appropriate in this setting.[36]

• Opportunistic Pulmonary Infections- Patients with lung cancer may take corticosteroids for any number of reasons, including management of COPD. Chronic steroid use can impair cellular immunity, and the possibility of opportunistic pathogens should be considered in such patients with a pulmonary infiltrate. Of these, invasive pulmonary aspergillosis and pneumonia due to P jiroveci deserve special mention. In general, invasive aspergillosis occurs more frequently in patients with hematologic malignancies, whereas the incidence ranges from 1% to 8% in patients with solid tumors. An autopsy survey of 845 consecutive patients treated for SCLC in Warsaw, Poland, identified only eight deaths (0.9%) due to invasive aspergillosis. Risk factors for invasive aspergillosis were neutropenia and significant corticosteroid exposure.[45] Invasive pulmonary aspergillosis is generally characterized by a localized, nodular infiltrate. The differential diagnosis should include Trichosporon, Fusarium, and Rhizopus. Depending on travel history or environmental exposures, H capsulatum, Coccidioides immitis, and Cryptococcus neoformans should also be considered. Definitive diagnosis depends on microbiologic or histopathologic confirmation in biopsy specimens, although isolation of a fungal pathogen from the respiratory tract usually correlates with infection. The treatment of invasive aspergillosis has been aided by the introduction of new antifungal agents. A recent study showed that patients treated with intravenous voriconazole (6 mg/kg every 12 hours for 1 day, followed by 4 mg/kg every 12 hours) produced better responses and improved survival with fewer serious side effects compared to those treated with conventional amphotericin B.[46] Amphotericin B (deoxycholate or the lipid preparations) and itraconazole (200 mg intravenously every 12 hours for 2 days, followed by 200 mg intravenously every 24 hours) remain as alternatives. The usual dose of conventional amphotericin B is 1 to 1.5 mg/kg once daily, whereas the dose of the lipid formulations is 5 mg/kg once daily. Intravenous caspofungin (a load of 70 mg, followed by 50 mg once daily) is licensed for the treatment of invasive aspergillosis in patients who are intolerant of, or refractory to, other antifungals.[47] Oral formulations of voriconazole and itraconazole allow for easy conversion to step-down therapy, facilitating outpatient care. Patients with Pneumocystis pneumonia can present with fever, a nonproductive cough, tachypnea, and hypoxemia. The time course of symptoms can range from a chronic, indolent course to an acute presentation. Abrupt onset of symptoms is more typical in cancer patients. Auscultation of the lungs may reveal fine rales or may be unremarkable. The chest xray typically shows diffuse interstitial infiltrates, although other patterns ranging from normal to a lobar infiltrate can be seen. An elevated lactate dehydrogenase may be present. Definitive diagnosis requires demonstration of cysts or trophozoites in respiratory specimens, either via sputum induction or bronchoalveolar lavage.[48] The treatment of choice is trimethoprim- sulfamethoxazole (Table 4). Moderately and severely ill patients should receive intravenous trimethoprimsulfamethoxazole (15-20 mg/kg/d of trimethoprim in four divided doses) for up to 21 days. Those with mild illness may take the combination orally. Patients who cannot tolerate or who fail to respond to trimethoprimsulfamethoxazole may be treated with intravenous pentamidine (4 mg/kg once daily). Other options include trimetrexate (Neutrexin, 45 mg/m² intravenously once daily) plus leucovorin; atovaquone (Mepron, 750 mg orally three times a day); dapsone (100 mg orally once daily) plus trimethoprim (5 mg/kg orally every 8 hours); or clindamycin (300-450 mg orally every 6 hours) plus primaquine (15-30 mg base orally once daily). Corticosteroids may be administered to patients with a PaO₂ of 70 mm Hg or less.[34,48] Patients who recover from Pneumocystis pneumonia but remain at risk for recurring infection will require secondary prophylaxis.

Impact of Pulmonary Infections on Outcomes
There appears to be some evidence that the presence of pulmonary infections may adversely affect overall survival in patients with lung cancer. According to a report from Taiwan, coexisting pulmonary tuberculosis seems to shorten survival when compared to outcomes in lung cancer patients without tuberculosis.[49] The timing of its diagnosis in relation to that of lung cancer may also matter. Tamura et al analyzed 25 cases with both lung cancer and pulmonary tuberculosis encountered at Tokyo National Chest Hospital between 1991 and 1998. In patients with concurrent illness (n = 14), treatment for tuberculosis was successful except for one case. In comparison, those diagnosed with tuberculosis prior to lung cancer (n = 11) had more extensive and severe disease. In fact, 5 of the 11 patients died within 3 months.[50] Corticosteroid administration appears to be a risk factor for the reactivation of M tuberculosis. In a review of autopsy data of 304 patients with lung cancer at Kyushu University Hospital in Japan between 1976 and 1990, the incidence of mycobacterial infection in those receiving cancer treatment and corticosteroids was significantly higher than in those receiving antineoplastic therapy alone (10.5% vs 2.6%, P = .028).[51] Bacterial pneumonia also seems to adversely impact survival. In Japan, Kohno and colleagues found that deceased patients had significantly higher rates of pneumonia compared to survivors of lung cancer, regardless of the stage. This finding implied that infection could be contributing to the cause of death.[8] The impact of pulmonary infections on survival was more clearly seen in the following study: Perlin et al conducted a retrospective review of 121 lung cancer patients treated at Howard University Hospital in Washington, DC, between January 21, 1984, and December 31, 1986. A total of 37 patients had single episodes of pneumonia, and 48 had more than one. Median survival of patients with one or more infections (4.2 months) was significantly shorter than that of uninfected patients, who had a median survival of 12.9 months (P < .05).[3] The implication of these reports is that clinicians treating lung cancer patients should maintain a high index of suspicion for infection and orient management toward rapid diagnosis and appropriate antimicrobial treatment.

Conclusions
Although progress has been made in the diagnosis and treatment of lung cancer, patients are prone to developing infectious complications. Pulmonary infections remain an important cause of morbidity and mortality in this population. Recognition of risk factors should guide the clinician in performing the appropriate diagnostics and in selecting antimicrobial therapy.

Disclosures:

The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Feld R, Ginsberg RJ, Payne DG, et al: Lung, in Abeloff MD, Armitage JO, Lichter AS, et al (eds): Clinical Oncology, 2nd ed, pp 1398- 1477. New York, Churchill Livingstone, 2000.
2. American Lung Association: Trends in lung cancer morbidity and mortality. Available at: http://www.lungusa.org/atf/cf/{7A8D42C2- FCCA-4604-8ADE-7F5D5E762256}/lc1.pdf. Accessed on November 11, 2004.
3. Perlin E, Bang KM, Shah A, et al: The impact of pulmonary infections on the survival of lung cancer patients. Cancer 66:593-596, 1990.
4. Greene JN: Catheter-related complications of cancer therapy. Infect Dis Clin North Am 10:255-295, 1996.
5. Dale DC, Petersdorf RG: Corticosteroids and infectious diseases. Med Clin North Am 57:1277-1287, 1973.
6. Phair JP, Riesing KS, Metzger E: Bacteremic infection and malnutrition in patients with solid tumors: Investigation of host defense mechanisms. Cancer 45:2702-2706, 1980.
7. Putinati S, Trevisani L, Gualandi M, et al: Pulmonary infections in lung cancer patients at diagnosis. Lung Cancer 11:243-249, 1994.
8. Kohno S, Koga H, Oka M, et al: The pattern of respiratory infection in patients with lung cancer. Tohoku J Exp Med 173:405-411, 1994.
9. Berghmans T, Sculier JP, Klastersky J: A prospective study of infections in lung cancer patients admitted to the hospital. Chest 124:114- 120, 2003.
10. Fuks JZ, Patel H, Hornedo J, et al: Infections in patients with non-small-cell lung cancer treated with intensive induction chemotherapy. Med Pediatr Oncol 14:255-261, 1986.
11. Gridelli C, Rossi A, Maione P: Treatment of non-small-cell lung cancer: State of the art and development of new biologic agents. Oncogene 22:6629-6638, 2003.
12. Spira A, Ettinger DS: Multidisciplinary management of lung cancer. N Engl J Med 350:379-392, 2004.
13. Stupp R, Monnerat C, Turrisi AT 3rd, et al: Small cell lung cancer: State of the art and future perspectives. Lung Cancer 45:105-117, 2004.
14. Stephan F, Boucheseiche S, Hollande J, et al: Pulmonary complications following lung resection: A comprehensive analysis of incidence and possible risk factors. Chest 118:1263- 1270, 2000.
15. Patel RL, Townsend ER, Fountain SW: Elective pneumonectomy: factors associated with morbidity and operative mortality. Ann Thorac Surg 54:84-88, 1992.
16. Busch E, Verazin G, Antkowiak JG, et al: Pulmonary complications in patients undergoing thoracotomy for lung carcinoma. Chest 105:760-766, 1994.
17. Deslauriers J, Ginsberg RJ, Piantadosi S, et al: Prospective assessment of 30-day operative morbidity for surgical resections in lung cancer. Chest 106:329S-330S, 1994.
18. Feld R: Complications in the treatment of small cell carcinoma of the lung. Cancer Treat Rev 8:5-25, 1981.
19. Hughes WT, Armstrong D, Bodey GP, et al: 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730-751, 2002.
20. Werner-Wasik M, Yu X, Marks LB, et al: Normal-tissue toxicities of thoracic radiation therapy: Esophagus, lung, and spinal cord as organs at risk. Hematol Oncol Clin North Am 18:131-160, x-xi, 2004.
21. Khan SA, Wingard JR: Infection and mucosal injury in cancer treatment. J Natl Cancer Inst Monogr 29:31-36, 2001.
22. Vazquez JA, Sobel JD: Mucosal candidiasis.Infect Dis Clin North Am 16:793-820, 2002.
23. Phillips P, De Beule K, Frechette G, et al: A double-blind comparison of itraconazole oral solution and fluconazole capsules for the treatment of oropharyngeal candidiasis in patients with AIDS. Clin Infect Dis 26:1368-1373, 1998.
24. Rex JH, Walsh TJ, Sobel JD, et al: Practice guidelines for the treatment of candidiasis. Infectious Diseases Society of America. Clin Infect Dis 30:662-678, 2000.
25. Villanueva A, Gotuzzo E, Arathoon EG, et al: A randomized double-blind study of caspofungin versus fluconazole for the treatment of esophageal candidiasis. Am J Med 113:294-299, 2002.
26. Saral R: Oral complications of cancer therapies. Management of acute viral infections. NCI Monogr 9:107-110, 1990.
27. Smith TF, Wold AD, Espy MJ, et al: New developments in the diagnosis of viral diseases. Infect Dis Clin North Am 7:183-201, 1993.
28. Gnann JW Jr, Whitley RJ: Clinical practice. Herpes zoster. N Engl J Med 347:340-346, 2002.
29. Huberman M, Fossieck BE Jr, Bunn PA Jr, et al: Herpes zoster and small cell bronchogenic carcinoma. Am J Med 68:214-218, 1980.
30. Feld R, Evans WK, DeBoer G: Herpes zoster in patients with small-cell carcinoma of the lung receiving combined modality treatment. Ann Intern Med 93:282-283, 1980.
31. Sethi S: Infectious exacerbations of chronic bronchitis: diagnosis and management. J Antimicrob Chemother 43(suppl A):97-105, 1999.
32. Wilson R: The role of infection in COPD. Chest 113:242S-248S, 1998.
33. Bartlett JG, Dowell SF, Mandell LA, et al: Practice guidelines for the management of community-acquired pneumonia in adults. Infectious Diseases Society of America. Clin Infect Dis 31:347-382, 2000.
34. Shelhamer JH, Toews GB, Masur H, et al: NIH conference. Respiratory disease in the immunosuppressed patient. Ann Intern Med 117:415-431, 1992.
35. White P: Evaluation of pulmonary infiltrates in critically ill patients with cancer and marrow transplant. Crit Care Clin 17:647-670, 2001.
36. Dichter JR, Levine SJ, Shelhamer JH: Approach to the immunocompromised host with pulmonary symptoms. Hematol Oncol Clin North Am 7:887-912, 1993.
37. Collin BA, Ramphal R: Pneumonia in the compromised host including cancer patients and transplant patients. Infect Dis Clin North Am 12:781-805, 1998.
38. White DA, Wong PW, Downey R: The utility of open lung biopsy in patients with hematologic malignancies. Am J Respir Crit Care Med 161:723-729, 2000.
39. Liaw YS, Yang PC, Wu ZG, et al: The bacteriology of obstructive pneumonitis. A prospective study using ultrasound-guided transthoracic needle aspiration. Am J Respir Crit Care Med 149:1648-1653, 1994.
40. Rolston KV: The spectrum of pulmonary infections in cancer patients. Curr Opin Oncol 13:218-223, 2001.
41. Filaire M, Mom T, Laurent S, et al: Vocal cord dysfunction after left lung resection for cancer. Eur J Cardiothorac Surg 20:705-711, 2001.
42. Marik PE: Aspiration pneumonitis and aspiration pneumonia. N Engl J Med 344:665- 671, 2001.
43. Stewart CE, Winer-Muram HT, Jennings SG, et al: Necrotic mass-like upper lobe opacity. Chest 123:277-279, 2003.
44. Liao WY, Liaw YS, Wang HC, et al: Bacteriology of infected cavitating lung tumor. Am J Respir Crit Care Med 161:1750-1753, 2000.
45. Remiszewski P, Slodkowska J, Wiatr E, et al: Fatal infection in patients treated for small cell lung cancer in the Institute of Tuberculosis and Chest Diseases in the years 1980-1994. Lung Cancer 31:101-110, 2001.
46. Herbrecht R, Denning DW, Patterson TF, et al: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 347:408-415, 2002.
47. Groll AH, Walsh TJ: Caspofungin: pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Investig Drugs 10:1545-1558, 2001.
48. Wilkin A, Feinberg J: Pneumocystis carinii pneumonia: A clinical review. Am Fam Physician 60:1699-1708, 1713-1714, 1999.
49. Chen YM, Chao JY, Tsai CM, et al: Shortened survival of lung cancer patients initially presenting with pulmonary tuberculosis. Jpn J Clin Oncol 26:322-327, 1996.
50. Tamura A, Hebisawa A, Tanaka G, et al: [Active pulmonary tuberculosis in patients with lung cancer]. Kekkaku 74:797-802, 1999.
51. Nagata N, Nikaido Y, Kido M, et al: Terminal pulmonary infections in patients with lung cancer. Chest 103:1739-1742, 1993.