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Throat Cancer Causes

Study objectives: To determine the type of infections occurring in hospitalized patients with lung cancer.

Design: Prospective cohort study.

Setting: Department of internal medicine in a cancer hospital.

Patients: All patients with lung cancer who were hospitalized for any cause and who acquired infections at the time of admission or during the hospital stay between January 1997 and February 2001.

Interventions: None.

Results: Two hundred seventy-five patients with lung cancer had 435 episodes of fever and/or microbiologically or otherwise documented infection. Two hundred eighteen patients (79.3%) presented with non-small cell lung carcinoma, while 49 patients (17.8%) had small cell lung cancer. The majority of the infections occurred in the tracheobronchial tree (56%). There were 38 episodes of bacteremia or fungemia, and the primary site of infection was identified in 18 cases (47%). Microbiologically documented infections accounted for 61% of the infectious episodes, and included a total of 312 microorganisms. The most frequent pathogens were Gram-negative bacteria (64%), followed by Gram-positive bacteria (25%) and fungi (8%). The predominant Gram-negative bacteria were Haemophilus influenzae and Moraxella catarrhalis. Staphylococcus aureus, Streptococcus pneumoniae, coagulase-negative staphylococci, and Enterococcus faecalis essentially represented the Gram-positive bacteria. No multiresistant bacteria were observed. Bacteria were susceptible to most of the antibiotics classically administered for their treatment.

Conclusions: The predominant site of infection in patients with lung cancer is the tracheobronchial tree, with S pneumoniae, S aureus, H influenzae, Escherichia coli, Pseudomonas aeruginosa, and M catarrhalis as the principal pathogens.

Key words: epidemiology; infection; lung neoplasms

Abbreviations: ENT = ear, nose, and throat; FUO = fever of unknown origin; NSCLC = non-small cell lung carcinoma; OR = odds ratio; SCLC = small cell lung cancer

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During the course of their disease, patients with cancer frequently present with an infection that causes death in up to 50% of cases, before organ failure (25%) or carcinomatosis (10%). (1) In patients with lung cancer, information is currently unavailable concerning their relative frequency, both in terms of clinical presentation including the nature of the microbe and the outcome of the infection. Infections of the tracheobronchial tree and the lungs have been documented in 9.5 to 84% of these patients, (2,3) but their impact on overall survival has not been clearly established. Hansen et al (4) did not observe a statistically significant difference in survival between patients with small cell lung cancer (SCLC) presenting with or without lung abscess. Alternatively, a significant reduction in the median survival of patients with lung cancer and pulmonary infections was demonstrated by Perlin et al. (5)

Different factors can predispose patients with lung cancer to infection, and include COPD and neoplastic obstruction. Obstructive lesions favor a damming-back of secretions into the alveoli and the dilated bronchi that are filled with mucus. Subsequently, microorganisms can be isolated from bronchial secretions and lead to proliferation and infection. Occasionally, obstructive pneumonitis is observed, although the cancer has not completely obstructed the bronchus. Under these circumstances, replacement of ciliated columnar cells by carcinoma cells favors stagnation of the secretions and secondary bacterial colonization. In addition, neutropenia is also a leading cause of infection in patients with cancer. The frequency and severity of the infections has a direct relationship to the importance and duration of the neutropenia. (6) Gram-negative microorganisms are the most common pathogens and require prompt empiric therapy with broad-spectrum antibiotics. Recently, an increase in the frequency of Grampositive organisms has been observed, mainly in patients with leukemia. It is not yet clear whether this is also true for neutropenic patients with lung cancer. Lastly, the use of more hematotoxic chemotherapy regimens and implantable devices may also favor infections.

Few studies have specifically documented microbiological infections in patients with lung cancer. While Streptococcus pneumoniae remains a major potential pathogen in pulmonary infections, (3) Gramnegative bacteria such as Haemophilus influenzae, Klebsiella pneumoniae, Enterobacter cloacae, and Pseudomonas aeruginosa have also been found in up to 68% of the cases. (3) Furthermore, anaerobic bacteria have been associated with necrotizing pneumonia, obstructive pneumonitis, and abscesses. The aim of this study was to more precisely delineate the infection characteristics (sites, pathogens) in patients with lung cancer in a cancer hospital.

MATERIALS AND METHODS

All patients with lung cancer hospitalized in the Department of Medicine or in the ICUs at the Institut Jules Bordet, a cancer hospital of 154 beds, were prospectively registered in this study at the time an infection occurred. A report form was completed daily to document all the positive microbial results obtained for a given patient. The data collected by the physician in charge of the patients with lung cancer was based on results provided by the microbiology laboratory and the infectious disease consultant. Specific data on some risk factors have been included: corticosteroid treatment, neutropenia (< 1,000 granulocytes per microliter), central or peripheral venous catheters, pleural or bladder catheters, mechanical ventilation, tracheotomy, and COPD. All microbiological samples were collected according to the infection site except in the case of febrile neutropenia, where cultures of blood, sputum, and urine as well as nose, mouth, and anal swabs were systematically performed.

Microbiologically and clinically documented infections were both considered. When the patient presented with a fever that responded to empiric antibiotic therapy without locating the site of infection and no other etiology for the fever (such as drug and paraneoplastic fevers or fever related to blood products transfusions) could be demonstrated, the episode was classified as a fever of unknown origin (FUO).

Samples were obtained from the suspected site of infection. Collection of urine, sputum, and stool samples was performed according to standard procedures. Simple aspiration or BAL could be done during bronchoscopy. Protected sampling was not performed. Blood cultures were done in duplicate, using the aerobic and anaerobic BactecR systems (Becton-Dickinson; Erembodegem-Aalst, Belgium). In the case of febrile neutropenia, microbiological documentation from the blood, urine, nose, and stool was routinely obtained, in addition to sampling from the suspected infectious site. Cultures were performed according to the routine procedures of the hospital laboratory. Bacteremia or fungemia were considered positive when a potentially pathogenic organism was found in the blood culture. Coagulase-negative Staphylococcus or Corynebacterium were defined as a pathogen when they were isolated in more than one blood culture, from the blood plus a distinct clinically infected site, or from a clinically septic patient with an intravascular device. A positive urinary culture was considered as significant in the presence of local (dysuria, polyuria) or systemic signs of infection; pyuria was required in nonneutropenic patients. Tracheal secretion aspirations in intubated patients and sputum or tracheal aspirations in nonintubated patients were considered as positive if associated with clinical or radiologic signs compatible with an infection. Ear, nose, and throat (ENT) infections were considered positive when a local signs of clinical infection was detected and a potential pathogen was simultaneously isolated from the mouth, the nose, the throat or the sinuses. Every effort was made to differentiate infection from colonization. (7) Clinically documented infections, principally when affecting the tracheobronchial tree and the skin, were considered positive if clinical or radiologic signs were compatible with the diagnosis of infection as well as the evolution on empiric antibiotic therapy, and no other etiology could be identified. Superinfection was defined as a new infection that occurred during the 7 days following the completion of antibiotic therapy for the initial episode.

Binary variables were compared by [chi square] tests; p < 0.05 was considered as statistically significant. All statistical tests were performed using the StatisticaR software (Statsoft; Tulsa, OK).

RESULTS

Patient Characteristics

From January 1997 to February 2001, 275 of 442 patients with lung cancer (62.2%) managed at the Institut Jules Bordet acquired 435 episodes of fever and/or microbiologically or otherwise documented infection. Two hundred eighteen patients (79.3%) presented with non-small cell lung carcinoma (NSCLC), while 49 patients (17.8%) had SCLC. Other patients had either mixed histology (n = 2), neuroendocrine tumor (n = 2), mesothelioma (n = 3), or cancer of unknown histology (n = 1). The majority of patients with NSCLC were metastatic (n = 154), whereas seven patients had in situ carcinoma. Limited-disease NSCLC presented with stages I, II, IIIA, and IIIB in 5, 4, 11, and 37 cases, respectively. Limited-disease SCLC was observed in 16 patients, while 33 patients presented with extensive or metastatic disease. One hundred two patients had COPD. The following comorbidities and/or potentially predisposing conditions were found at the diagnosis of the infectious episode: corticosteroid therapy (n = 100), neutropenia (n = 76), peripheral venous catheter (n = 69), central (n = 21) or totally implantable venous catheters (n = 53), and bladder catheter (n = 27). Chemotherapy had been administered during the 15 days preceding 204 infectious episodes. Antibiotic therapy had been administered previously to the considered infectious episode in 31 eases. Prophylactic antibiotics was not prescribed. Fifty-five percent of the infections occurred either at home (n = 193) or were acquired within 48 h after hospital admission (n = 47). For patients hospitalized at the time of the infection, the median hospital stay was 7 days.

Types of Infection

The breakdown of the different sites of infection is reported in Table 1. The distribution of the principal types of infection was similar irrespective of the histology (NSCLC vs SCLC) or disease extent (NSCLC).

Among patients presenting with an infection, some associations between clinical characteristics were observed. Bacteremia presented more frequently during the hospital stay than in patients admitted from home (13.3% vs 6.0%; odds ratio [OR], 2.21; p = 0.02). This difference was of borderline significance when only hospitalization of > 48 h was considered (13.2% vs 7.5%; OR, 1.76; p = 0.07). Urinary infections were observed more commonly during hospital stays (13.4% vs 4.3%; OR, 3.10; p = 0.003), and skin infections were observed more frequently at home (3.3% vs 9.0%; OR, 2.70; p = 0.02). No significant relationship was found between other types of infections and the location of initial occurrence. Pulmonary infections developed more frequently in nonneutropenic patients (44.2% vs 68.4%; OR, 1.54; p = 0.0008). A slight increase in lung infections, which was of borderline statistical significance, was observed in patients with COPD (70.0% vs 61.1%; OR, 1.15; p = 0.07). Baeteremia was associated with neutropenia (25.0% vs 7.7%; OR, 3.24; p = 0.0001) and catheter use (18.8% vs 4.2%; OR, 4.84; p < 0.001), and urinary infections were associated with a bladder catheter (30.8% vs 7.7%; OR, 3.99; p = 0.0001).

Pathogens

Microbiologically documented infections accounted for 70.2% of the infectious episodes (FUO excluded) with a total of 312 microorganisms. There were 37 documented polymicrobial infections, including 32 infections with two pathogens, 3 infections with three pathogens, and 2 infections with four pathogens. The most frequent pathogens were Gram-negative bacteria (n = 201; 64%) followed by Gram-positive bacteria (n = 78; 25%) and fungi (n = 25; 8%) [Table 2]. When only pathogens documented in blood cultures were considered, Grampositive bacteria were most often observed (Table 3). In patients with COPD, the most frequently documented pathogens were H influenzae (n = 29), S pneumoniae (n = 12), Staphylococcus aureus (n = 12), Moraxella catarrhalis (n = 11), Escherichia coli (n = 9), and P aeruginosa (n = 9). The distribution of microorganisms was similar depending on the location where the infection was initiated. However, there was more S pneumoniae (15 of 21 patients) observed at home or during the first 48 h after hospital admission, and more S aureus (16 of 27 patients), Enterobacter species (10 of 13 patients), and Proteus species (8 of 10 patients) when the hospital stay was > 48 h.

Unexpected resistance to conventional antibiotics was infrequently observed. E coli strains were generally resistant to ampicillin (61%), piperacillin (56%), and cotrimoxazole (34%). Thirty percent of H influenzae strains were resistant to ampicillin, but all were sensitive to the amoxicillin/clavulanate association. M catarrhalis showed ampicillin and piperacillin resistance in 80% of the cases. All Klebsiella strains were resistant to ampicillin. None of the P aeruginosa strains were considered to be multidrug resistant. We observed only one S pneumoniae resistance to penicillin and another with reduced sensitivity. Four strains were resistant to erythromycin and three to cotrimoxazole. All of the S aureus strains were resistant to penicillin, but only three were resistant to methicillin and they had preserved susceptibility to glycopeptides. Coagulase-negative staphylococci were methicillin resistant in 56% of the cases. Only one Enterococcus (Enterococcus faecium) was resistant to ampicillin, but all group D streptococci were sensitive to vancomycin.

Fever Without Documented Infection

Fifty-nine of the 435 recorded episodes were not microbiologically or clinically documented. Except for nine cases, all of the episodes responded to empiric antibiotic therapy (n = 50). Also, FUO was more frequently observed in neutropenic patients (31.6% vs 9.7%; p < 0.001).

Evolution

Infection (FUO excluded) resolved in 305 cases (81.1%). In another 12 episodes (3.2%), the infection was controlled but was not entirely resolved after antibiotic therapy. Deterioration of the initial status was observed in 42 episodes (11.2%). They included pulmonary infection (n = 32), bacteremia (n = 4) or fungemia (n = 1), cystitis (n-1), cholecystitis (n = 1), colitis (n = 2), and sinusitis (n = 1). Thirteen episodes were not assessed for their response due to a lack of follow-up.

Fifty-eight superinfections occurred during 57 infectious episodes (15.7%). They included bacteremia (n = 6); fungemia (n = 1); pulmonary (n = 15), skin (n = 4), or mouth (n = 25) infections; colitis (n = 6); and sinusitis (n = 1). A new episode of fever without clinically or microbiologically documented infection occurred in 15 additional cases. A total of 53 pathogens were documented. Gram-positive bacteria accounted for 18.9% (two Staphylococcus epidermidis, one S aureus, one Enterococcus faecalis, one S pneumoniae, and five Clostridium difficile). Twenty-seven Gram-negative bacteria were found (50.9%): Klebsiella species (n = 5), Enterobacter species (n = 5), Stenotrophomonas maltophilia (n = 4), E coli (n = 3), Serratia species (n = 3), P aeruginosa (n = 3), H influenzae (n = 2), Morganella morganii (n = 1), and an unspecified Gram-negative bacillus (n = 1). Thirteen fungal infections were documented, mainly represented by Candida albicans and Candida glabrata. Herpesviridae type I infection occurred in three cases. Documented pathogens were considered to be resistant to the antibiotic therapy administered during the previous infectious episode for 40 cases (75.5%).

DISCUSSION

In our cohort of 275 hospitalized patients with lung cancer, 435 episodes of fever and/or infection were documented. The most prominent types of infection were tracheobronchial infections followed by bacteremia. Gram-negative bacteria accounted for the majority of documented pathogens, except in the blood where Gram-positive bacteria were mostly frequently found. H influenzae and S pneumoniae were the most frequent pathogens in lung or bronchial infections.

The aim of this study was to more precisely delineate the types of infection and nature of the responsible pathogens in patients with lung cancer. Only a few studies have been published on this topic. (2-5,8) They generally dealt only with lung infections, the frequency of which can be as high as 34.3% during the course of neoplastic disease. (5,8) Nevertheless, the relative frequency of lung and other types of infections have not yet been reported. As expected, we found that the major location for infection was the tracheobronchial tree. This can be related to concomitant COPD, as seen in our study, which is known to predispose to lung infections and neoplastic obstruction.

Few studies (2,5,8,9) have specifically addressed questions concerning the microbiological nature of infections in patients with lung cancer. S pneumoniae is a common pathogen in pulmonary infections; however, in the literature, H influenzae, K pneumoniae, E cloacae, or P aeruginosa have been documented in pulmonary infections in up to 68% of cases, and S aureus is frequently found. (2,5,8) We found the predominant pathogen in lung infections was H influenzae, followed by S pneumoniae, P aeruginosa, E coli, and M catharralis, which each accounted for approximately 10% of the documented microorganisms.

As the majority of documented pathogens occurring in lung infections are Gram-negative bacteria, empiric antibiotic therapy must adequately cover these organisms. Nevertheless, the definitive antibiotic choice needs to be adapted to the particular nature of the local environment. In our study, the majority of H influenzae, M catarrhalis, and E coli strains involved in lung infections were susceptible to a combination of amoxicillin and clavulanic acid, as has been previously reported. (10) However, suspicion of pneumococcal infection should not be forgotten in febrile patients with lung cancer with adequate early coverage, since these infections are occasionally rapidly fatal. In our study, we detected only one S pneumoniae that was resistant to penicillin, but 15% and 20% of the strains were resistant to cotrimoxazole and erythromycin, respectively. Therefore, penicillin still remains the drug of choice. Susceptibility of the most common pathogens was as anticipated for Belgium. (11,12)

The choice of empiric antibiotic therapy when there is a suspicion of bacteremia is crucial, since these infections are associated with potentially life-threatening complications, particularly in neutropenic patients. In febrile patients with cancer, especially those who are neutropenic, Gram-negative bacteria account for the majority of blood infections previously reported. Recently, an increase in the frequency of Gram-positive bacterial infections has been described. (13,14) Different theories have been proposed to explain this, including the use of totally implanted catheters, mucositis induced by chemotherapy, and prophylactic administration of fluoroquinolones leading to bacterial selection. However, it was not clear from these studies whether this is also true for patients with lung cancer. In our study, the occurrence of bacteremia was frequently associated with catheter use; therefore, it is not surprising that a majority of the bacteremia were due to Gram-positive bacteria, particularly S aureus and coagulase-negative staphylococci.

We also analyzed fevers without microbiologically or clinically documented infections, which occurred in 14% of the cases. We considered that these cases were infectious episodes after excluding the possibility of noninfectious origins, including paraneoplastic fever, drug fever, allergic reactions, immunologic diseases, thromboembolic events, or fever due to blood product transfusion. In neutropenic patients, fever can be the only symptom of infection and therefore requires empiric antibiotic therapy. (15) In this study, 40% of the patients were neutropenic, and the majority of these febrile episodes resolved after empiric antibiotic therapy.

In patients with lung cancer in whom infection is suspected, empiric antibiotic therapy must be frequently administered. In our study, 40% of the infectious episodes were not documented microbiologically but did respond to therapy. The choice of antibiotics depends on the local bacterial environment, the degree of immunosuppression (neutropenia, lymphopenia, corticotherapy, neoplastic obstruction), and previous bacterial or fungal colonization. In our study, few bacteria had unexpected resistance to conventional antibiotics. As discussed above, a combination of broad-spectrum penicillin with a [beta]-lactamase inhibitor could be used successfully for lung infections in nonneutropenic patients. The most common documented pathogens H influenzae and M catharralis (which frequently express [beta]-lactamase, 30% and 80%, respectively, in our study), and E coli and S pneumoniae are susceptible to this antibiotic combination. New fluoroquinolones such as gatifloxacin or moxifloxacin are viable alternatives in [beta]-lactam-intolerant patients, but are recommended on a large scale only in countries with a high frequency of penicillin-resistant S pneumoniae. In neutropenic patients, the risks of complications are higher and prompt empiric antibiotic therapy is necessary. Most would agree that this should include a treatment with broad-spectrum penicillin, cephalosporin, or imipenem. In demonstrated staphylococcal infections, methicillin or a glycopeptide can be added, depending on strain sensitivity to methicillin (50% in this study).

Chronic or recurrent infections, such as lung abscesses, can prevent physicians from administering chemotherapy. However, Hansen et al (4) found that patients with SCLC can have a good evolution after chemotherapy despite lung abscesses. Unfortunately, it was not possible to compare our patients with their patients. Only two of our patients had SCLC; among the 11 cases, nine patients were heavily pretreated or presented with comorbidities, which did not permit chemotherapy. Only two patients received full-dose conventional chemotherapy without any infectious complications due to lung abscess.

Our study has shown that the predominant site of infection in patients with lung cancer is the tracheobronchial tree, and the principal pathogens are S pneumoniae, S aureus, H influenzae, E coli, P aeruginosa, and M catarrhalis. A majority of these organisms were susceptible to a combination of a penicillin with a [beta]-lactamase inhibitor. We did not observe a higher rate of resistance to conventional antibiotics than expected, except for staphylococci, where methicillin resistance was found in 50% of the cases. Thus, in patients with lung cancer presenting with a tracheobronchial tree infection, empiric therapy does not automatically require broad-spectrum antibiotic treatment; however, predisposing factors to serious complications such as immunosuppression or neoplastic obstruction must be taken into consideration when deciding on the type of antibiotic therapy.

Table 1--Breakdown of the Different Sites of Infection

      Site of Infection         No.

Tracheobronchial tree (total)   244
  Bronchitis                    136
  Pneumonia                      94
  Other pulmonary infection      14
Bacteremia/fungemia              38
Genitourinary                    35
ENT, mouth, sinusitis            26
Skin                             22
Digestive system                 20
Other *                           2

* Meningitis and osteitis occurred in one case each. Fever without
microbiologically or clinically documented infection was the final
diagnosis in 59 episodes.

Table 2--Documented Pathogens Based on the Site of Infection *

           Pathogens               Pulmonary   Urinary   Bact   ENT

S pneumoniae                           21
Other Streptococcus sp                  2          1       8      1
S aureus                               17          1       7
Coagulase-negative staphylococci                   1       8
Other Gram-positive bacteria            2
H influenzae                           64                         1
E coli                                 16         21       2
P aeruginosa                           14          1              1
M catarrhalis                          15
Enterobacter sp                         8          3       1
Klebsiella sp                           7          1       1
Proteus mirabilis                       5          2              1
Other Gram-negative bacilli            23          3       3
C difficile
Mycobacterium tuberculosis              2
Chlamydia pneumoniae                    1
Mycoplasma hominis                      1
Pneumocystis carinii                    1
C albicans                                                 1     10
Other Candida sp                                                  5
Saccharomyces cerevisiae                                          1
Aspergillus sp                          1
Herpesviridae
Cytomegalovirus                         1
Total                                 201         34      31     20

           Pathogens               Skin   Other   Total

S pneumoniae                                        21
Other Streptococcus sp               1              13
S aureus                             2              27
Coagulase-negative staphylococci                     9
Other Gram-positive bacteria                         2
H influenzae                                        65
E coli                               2              41
P aeruginosa                                        16
M catarrhalis                                       15
Enterobacter sp                      1              13
Klebsiella sp                        1              10
Proteus mirabilis                    1               9
Other Gram-negative bacilli          1       2      32
C difficile                                  6       6
Mycobacterium tuberculosis                           2
Chlamydia pneumoniae                                 1
Mycoplasma hominis                                   1
Pneumocystis carinii                                 1
C albicans                           2       4      17
Other Candida sp                                     5
Saccharomyces cerevisiae                             1
Aspergillus sp                                       1
Herpesviridae                        2       1       3
Cytomegalovirus                                      1
Total                               13      13     312

* Bact = isolated bacteremia or bacteremia associated with
catheter infection.

Table 3--Documented Pathogens in Positive Blood Cultures
Findings (n = 44)

                                        Original Site of Infection

                                                             Central
                                      Pulmo-   Uri-           Venous
             Pathogens                 nary    nary   Skin   Catheter

Streptococcus sp                        2
S aureus                                2                       3
Coagulase-negative staphylococci                1               4
Clostridium perfringens                 1
Bacillus sp                             1
E coli                                  1       1      1
Klebsiella sp                           1
P aeruginosa                            1
E cloacae
Serratia marcescens
Vibrio noncholerae
Other aerobic Gram-negative bacilli
C albicans
Total                                   9       2      1        7

                                        Original Site of Infection

                                                     Not
             Pathogens                Digestive   Identified   Total

Streptococcus sp                                       8        10
S aureus                                               4         9
Coagulase-negative staphylococci                       4         9
Clostridium perfringens                                          1
Bacillus sp                                                      1
E coli                                                 2         5
Klebsiella sp                                          1         2
P aeruginosa                                                     1
E cloacae                                              1         1
Serratia marcescens                                    1         1
Vibrio noncholerae                        1                      1
Other aerobic Gram-negative bacilli                    2         2
C albicans                                             1         1
Total                                     1           24        44

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* From the Service de Medecine et Laboratoire d'Investigation Clinique H.J. Tagnon, Institut Jules Bordet, Centre des Tumeurs de l'Universite Libre de Bruxelles, Brussels, Belgium.

Manuscript received May 7, 2002; revision accepted January 15, 2003.

Correspondence to: Thierry Berghmans, MD, Institut Jules Bordet, Rue Heger-Bordet, 1, 1000 Bruxelles, Belgium; e-mail: thierry.berghmans@bordet.be

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