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Infectious Complications of Lung Cancer

Infectious Complications of Lung Cancer

ABSTRACT: 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 Infections
Acute 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]

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