[
Original Research Disorders of the Pleura
]
Survival in Patients With Malignant Pleural Effusions Who Developed Pleural Infection A Retrospective Case Review From Six UK Centers Anna C. Bibby, MBChB; Amelia O. Clive, MBBS; Gerry C. Slade, RGN, FCCP; Anna J. Morley, RGN; Janet Fallon, MBBS; Ioannis Psallidas, PhD; Justin C. T. Pepperell, BMBCh; Mark G. Slade, MBBS; Andrew E. Stanton, MBChB; Najib M. Rahman, BMBCh; and Nick A. Maskell, BMBS, FCCP
Malignant pleural effusion (MPE) incidence is increasing, and prognosis remains poor. Indwelling pleural catheters (IPCs) relieve symptoms but increase the risk of pleural infection. We reviewed cases of pleural infection in patients with IPCs for MPE from six UK centers between January 1, 2005, and January 31, 2014.
OBJECTIVE:
Survival in patients with pleural infection was compared with 788 patients with MPE (known as the LENT [pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type] cohort) and with national statistics. METHODS:
Of 672 IPCs inserted, 25 (3.7%) became infected. Most patients (20 of 25) had mesothelioma or lung cancer. Median survival in the pleural infection cohort appeared longer than in the LENT cohort, although this result did not achieve significance (386 days vs 132 days; hazard ratio, 0.67; P 5 .07). Median survival with mesothelioma and pleural infection was twice as long as national estimates for mesothelioma survival (753 days vs , 365 days) and double the median survival of patients with mesothelioma in the LENT cohort (339 days; 95% CI, nonoverlapping). Survival with lung and breast cancer did not differ significantly between the groups. Sixty-one percent of patients experienced early infection. There was no survival difference between patients with early and late infection (P 5 .6).
RESULTS:
This small series of patients with IPCs for MPE suggests pleural infection may be associated with longer survival, particularly in patients with mesothelioma. Results did not achieve significance, and a larger study is needed to explore this relationship further and investigate whether the local immune response, triggered by infection, is able to modulate mesotheCHEST 2015; 148(1):235-241 lioma progression.
CONCLUSIONS:
Manuscript received September 5, 2014; revision accepted November 3, 2014; originally published Online First November 27, 2014. ABBREVIATIONS: HR 5 hazard ratio; IPC 5 indwelling pleural catheter; LENT 5 pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type; MPE 5 malignant pleural effusion AFFILIATIONS: From the Royal United Hospital NHS Trust (Dr Bibby), Combe Park, Bath; the North Bristol Lung Centre (Drs Clive and Maskell and Ms Morley), Southmead Hospital, North Bristol NHS Trust, Bristol; Papworth Hospital NHS Foundation Trust (Ms Slade and Dr Slade), Papworth Everard, Cambridge; Musgrove Park Hospital (Drs Fallon and Pepperell), Taunton, Somerset; the Oxford Centre for Respiratory Medicine (Drs Psallidas and Rahman), Churchill Hospital, Oxfordshire; Great Western Hospital NHS Trust (Dr Stanton), Swindon, Wiltshire; and the
journal.publications.chestnet.org
Academic Respiratory Unit (Dr Maskell), University of Bristol School of Clinical Sciences, Bristol, England. This research was presented in abstract form (S117) at the British Thoracic Society Winter Meeting, December 5, 2014, London, England. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Nick A. Maskell, BMBS, FCCP, Academic Respiratory Unit, Second Floor, Learning and Research Bldg, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, England; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-2199
235
Malignant pleural effusions (MPEs) are common, affecting up to 200,000 people in the United States and United Kingdom each year.1 Their presence often signifies advanced or metastatic disease, and consequently they are associated with poor prognosis. Median survival ranges from 3 to 15 months, depending on underlying tumor type and stage. Lung cancer is the most common underlying pathology and is associated with the worst outcome.1 Predicting prognosis with MPEs is difficult, but recently a prognostic scoring system, the LENT (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type) score, has been developed and validated as a tool to stratify patients into prognostic groups and predict life expectancy.2
Indwelling pleural catheters (IPCs) are increasingly used to relieve symptoms of MPEs. They are as effective at relieving symptoms as tube drainage and talc pleurodesis, and they improve quality of life.3 IPCs can be inserted as a day case procedure, leading to shorter inpatient stays. However, IPCs are associated with a higher risk of pleural infection, particularly if they remain in situ for long periods of time.3
Materials and Methods
Baseline data on patient demographics, oncologic diagnosis and treatment, and details of pleural infection were gathered retrospectively. The data collection sheet is shown in e-Table 2.
Basic descriptive statistics were used to summarize patient characteristics and factors relating to pleural infection. The primary outcome measure was survival time, calculated from date of diagnosis with MPE and censored at date of death or final follow-up. Survival times were compared with results from a database of 788 patients with MPE, prospectively collected from three international pleural centers (LENT cohort) 2 and to national US6 and UK7-9 statistics. Kaplan-Meier curves were drawn to visually compare the two cohorts and Cox proportional hazards model used to calculate the hazard ratio (HR). Individual LENT scores were calculated at diagnosis, and LENT-predicted median life expectancy compared with actual survival (see e-Table 3 for LENT score calculation).
Local ethics approval was obtained for the LENT cohort and individual consent obtained from participants (UK Research Ethics Committee reference 08/H0102/11, Central Bristol). Data for the pleural infection cohort was collected as a retrospective audit of practice, in keeping with local ethics committee guidance.
Univariable Cox regression modeling was undertaken to establish whether there was any association of age, performance status, duration of antibiotic treatment, oncologic treatment received, or timing of pleural infection with survival. All analyses were undertaken using Stata version 11 (StataCorp LP).
Results
The times between IPC insertion and pleural infection are shown in Figure 3. Sixteen of 25 patients (64%) developed early infection (within 90 days of IPC insertion). Thirteen of 25 patients (52%) received IV antibiotics, and ten of 13 (77%) received additional oral antibiotics. Mean antibiotic duration was 24 days (range, 3-70 days). Fifteen of 25 patients (60%) were treated as inpatients, with an average length of stay of 10.5 days (range, 2-34 days).
All IPCs inserted for MPE between January 1, 2005, and January 31, 2014, in six UK centers were reviewed and cases of pleural infection identified. Recruitment periods differed between centers according to when services were established. Details are shown in e-Table 1. Pleural infection was defined as clinical symptoms and signs consistent with pleural infection, necessitating antibiotic treatment, with or without positive pleural fluid microscopy or culture. Superficial wound infections at IPC insertion site were not included.
Six hundred seventy-two IPCs were inserted during the study period. Twenty-five patients (3.7%) were identified as having experienced pleural infection. Each patient had a single episode of pleural infection, affecting a unilateral IPC. One individual with pleural infection also appeared in the LENT cohort. This patient was removed from the LENT group prior to analysis. Baseline characteristics of patients with pleural infection are summarized in Table 1, and a patient flow diagram is shown in Figure 1. Baseline information on the LENT cohort is available in e-Table 4.
There has been anecdotal evidence for decades that patients with pleural malignancy who survive iatrogenic pleural infection tend to have slower progression of their malignancy in the subsequent months.4,5 We wanted to explore this hypothesis and, hence, undertook a retrospective review of MPE cases from six UK centers who developed pleural infection in conjunction with an IPC. The aim was to determine whether these patients’ survival differed from their predicted life expectancy.
Factors Relating to Infection
No patients required surgery. Three of 25 IPCs (12%) were removed because of pleural infection. Information on pleurodesis was available for 19 patients. Eleven of 19 (58%) achieved pleurodesis, including the three patients who had their IPCs removed.
Microbiologic culture was positive in 22 of 25 cases (88%). Organisms are shown in Figure 2.
Three of 25 (12%) died within 30 days of being diagnosed with pleural infection. Although specific cause of death
236 Original Research
[
1 4 8 # 1 C H E S T J U LY 2 0 1 5
]
TABLE 1
] Baseline Characteristics of Patients With Pleural Infection
Characteristic
No. (%)
Sex Male Female Age, median (range), y
19 (76) 6 (24) 69 (35-79)
WHO PS 0
5 (20)
1
13 (52)
2
3 (12)
3
2 (8)
Not recorded
2 (8)
Tumor Mesothelioma
12 (48)
NSCLC
8 (32)
Breast
3 (12)
Lymphoma
1 (4)
Thyroid
1 (4)
Oncologic treatment Chemotherapy
7 (28)
Radiotherapy
7 (28)
Both
5 (20)
Neither
5 (20)
Not known
1 (4)
NSCLC 5 non-small cell lung cancer; WHO PS 5 World Health Organization performance status.
was unknown, it is assumed that pleural infection was a contributing factor. Survival Times
Twenty-one patients were followed up until death, two patients were censored at the time of data collection (at 223 days and 317 days, respectively), and two patients were excluded from survival analysis because of
missing data on mortality status. Median survival for patients with IPCs and pleural infection was 386 days (95% CI, 302-684) (Table 2). This compares with a median survival of 132 days in the LENT cohort (mean, 270 days; 95% CI, 246-293 days).2 Kaplan-Meier curves comparing survival for the two cohorts showed enhanced survival in the pleural infection cohort but did not reach statistical significance (HR, 0.67; 95% CI, 0.43-1.03; P 5 .07) (Fig 4). Survival With Mesothelioma: Eleven patients had mesothelioma (64% epithelial, 9% sarcomatoid, 27% not specified, compared with the LENT cohort of 45% epithelial, 11% sarcomatoid, 8% biphasic, and 36% unspecified). Median survival in the mesothelioma group exceeded the LENT cohort (753 days vs 339 days) and exceeded nationally reported US and UK survival rates. US National Cancer Statistics on Mesothelioma predict a median life expectancy of 242 days in patients aged between 65 and 74 years and 112 days in patients diagnosed over the age of 75 years.6 In this series, the six patients with mesothelioma aged 65 to 74 years had a median survival of 766 days (95% CI, 310-1,067 days), and the four patients aged . 75 years had a median survival of 526 days (95% CI, 0-1,881 days). In the United Kingdom, median life expectancy with mesothelioma is reported between 9 and 12 months.7-9 The median survival of patients with mesothelioma and pleural infection in this study was . 2 years. US and UK 1-year survival rates are , 40%,6,8 compared with 82% in this series. Survival With Lung Cancer: There were no patients with small cell lung cancer in the pleural infection cohort. Patients with pleural infection and non-small cell lung cancer had longer median survival than patients with non-small cell lung cancer in the LENT cohort, but CIs overlapped (Table 2). The pleural infection cohort had
Figure 1 – Flowchart of participants with pleural infection. IPC 5 indwelling pleural catheter; LENT 5 pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type.
journal.publications.chestnet.org
237
when stratified by timing of infection in 3-month blocks (HR 5 0.97; 95% CI, 0.71-1.30; P 5 .83).
Discussion
Figure 2 – Microbiologic organisms cultured from pleural fluid. MRSA 5 methicillin-resistant Staphylococcus aureus.
higher 1-year survival rates than US rates for stage IV non-small cell lung cancer (29% vs 19%).10 Survival With Breast Cancer: Survival times with breast cancer were similar in the pleural infection group and the LENT cohort. CIs for the two cohorts were also similar. Survival According to LENT Scores: Data were available to calculate individual LENT scores for 13 patients. Nine of 13 (69%) exceeded the LENT score-predicted median life expectancy (e-Table 5). Factors Affecting Survival: Univariable Cox regression was performed and did not show any association between the following variables and survival: age (HR 5 0.96, P 5 .04), performance status (HR 5 1.41, P 5 .26), duration of antibiotic treatment (HR 5 1.00, P 5 .74), and whether the patient received chemotherapy (HR 5 0.63, P 5 .35) or radiotherapy (HR 5 0.74, P 5 .56). Multivariate modeling was not possible due to small numbers. There was no difference in survival between patients who developed infection within 90 days of IPC insertion and patients with later infection (median, 209 days; 95% CI, 196-779 days vs 504 days; 95% CI, 291-760; HR 5 1.06; P 5 .91). There was no difference in survival
Figure 3 – Timing of pleural infection. See Figure 1 legend for expansion of abbreviation.
238 Original Research
This retrospective review of practice from six UK hospitals suggests that patients who develop pleural infection with an IPC in situ for MPE may live longer than those without infection. Hazard modeling in this small sample did not achieve significance (P 5 .07); however, the trend toward significance, the appearance of the Kaplan-Meier survival curves, and the CIs that do not overlap (for the overall population and mesothelioma) raise the possibility of a genuine effect. Further research in warranted to investigate this potential relationship in greater depth. Causality cannot be determined from this observational study, but our results support the hypothesis that pleural infection may stimulate antitumor activity. Bacteria in the pleural space can generate local immune activation, causing proliferation and migration of T-cell populations, which can act against tumor.11 In mesothelioma, cytotoxic T lymphocytes that normally inhibit tumor growth are suppressed, allowing the tumor to be locally aggressive.12 The ability to maintain T lymphocyte activity is associated with better outcomes with mesothelioma,13 and pleural infection may assist in preserving this response. This theory is supported by mouse models of mesothelioma in which intratumor delivery of a Staphylococcus toxin generated local T-cell activation, induced tumor necrosis, and inhibited tumor growth.14 Bacterial agents such as OK-432 and Staphylococcus superantigen have demonstrated survival benefits when used to treat patients with non-small cell cancer and MPE.15,16 Our results did not show this, but the small number of patients with lung cancer in this study prevent this from being a convincing negative. Our results also support previous observations that IPC-related infections can be managed conservatively in the majority of cases. In our study, 48% of patients were treated with oral therapy alone, and 40% did not require admission to hospital. This mimics the findings from the largest cohort of patients with IPC to date, wherein almost 40% of patients with pleural infection were treated with oral antibiotics, and one-fourth were managed as outpatients.17 This should reassure clinicians who have ongoing concerns about the risk of IPC-related infection in patients with MPE. The spectrum of bacterial organisms in this series mirrored previous studies. Staphylococci and gram-positive organisms contributed to 69% of IPC-related infections,
[
1 4 8 # 1 C H E S T J U LY 2 0 1 5
]
TABLE 2
] Median Survival for Patients With Indwelling Pleural Catheter LENT Cohort
Tumor Type
Pleural Infection Cohort
Median Survival, d (95% CI)
No.
All
133 (246-293)
788
386 (302-684)
23
Mesothelioma
339 (267-442)
170
753 (446-1,089)
11
75 (138-205)
215
138 (62-479)
7
Breast
192 (133-271)
140
167 (0-360)
3
Thyroid
N/A
Non-small cell lung cancer
Lymphoma
218 (160-484)
35
Median Survival, d (95% CI)
No.
148
1
449
1
The LENT cohort was a prospectively collected international cohort of 788 patients with malignant pleural effusions. LENT 5 pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type; N/A 5 not applicable.
compared with 62% in another IPC series17 and 63% in the general population.18 Bacterial infection has long been associated with high rates of pleurodesis, and bacterial agents are used as pleurodesis agents in some countries.15-17 Pleurodesis rates in this study were at the low end of the 60% to 80% reported in other trials,16,17 but this is likely to be a reflection of missing data, an accepted limitation of the study design. There are limitations to this study, which, alongside the small sample size, are likely to have contributed to the lack of statistical significance. Retrospective identification of cases is the first limitation, as, although this was as rigorous as possible, it relied on comprehensive record keeping for IPC insertion and pleural infection. If this were not the case, recall bias may have occurred. Similarly,
case mix was outside of our control. The predominance of epithelial subtype mesothelioma in the study group may have positively skewed survival times, although the LENT cohort had a similar distribution of mesothelioma subtypes. Prospective data collection would reduce these limitations, but the low incidence of pleural infection in patients with IPCs would make this a lengthy undertaking. This study was not a formal case control study. Limited resources meant that data could not be collected on patients with IPCs without pleural infection. Consequently, there was no control group available within the cohort being studied. The LENT cohort was chosen as a comparator instead, as it is the largest published cohort of patients with MPEs and was prospectively collected over the same time period as the pleural infection cohort. Potential differences between the two groups may have
Figure 4 – Kaplan-Meier survival curves for LENT cohort and pleural infection cohort. See Figure 1 legend for expansion of abbreviation.
journal.publications.chestnet.org
239
introduced bias; however, by comparing cases of pleural infection to a large cohort with comprehensive baseline data and robust follow-up, bias from missing data was minimized. The presence of pleural infection within the LENT cohort was not known, and this is a limitation. However, pleural infection rates are likely to have been very low in the LENT cohort, as IPCs were present in just 15% of this group. The presence of incidental pleural infection in LENT cohort subjects would act to weaken the effect size demonstrated, and this may have contributed to the failure to achieve overall statistical significance. The authors acknowledge that this series is vulnerable to confounding. When IPC services were in their infancy, IPCs were offered to patients most expected to benefit from them (ie, those with the longest anticipated life expectancy). Consequently, the longer survival times seen in this series may reflect confounding by indication based on the presence of an IPC, particularly when compared with the LENT cohort, in which only 15% of people had an IPC. However, the publication of data showing equivalence between IPCs and chest tube drainage in 20123 may have led to increased IPC use, so confounding is likely to have diminished over the study period. Nonetheless, to avoid this issue, future work in this area should include patients matched for the presence or absence of an IPC.
240 Original Research
Another area of potential confounding is the increase in infection risk the longer an IPC remains in situ. Could the findings of this study simply represent patients who lived longer with an IPC in situ and developed infection as a consequence of prolonged IPC presence? The fact that 61% of patients developed infection within 3 months of IPC insertion would dispute this. The population was too small to undertake reliable regression analysis, but subgroup analysis showed no difference in survival between patients with early and late infection. This suggests that the observed association between pleural infection and longer survival is not just an effect of having an IPC in situ for a longer period of time.
Conclusions In summary, this review of 25 cases of pleural infection in patients with IPC for MPE suggests enhanced survival, particularly in patients with mesothelioma. Similarities between our population and previously published series indicate that this cohort is representative and support the possibility that this observation represents a genuine effect. The study has limitations, and statistical significance is not achieved; however, despite this, the Kaplan-Meier survival curves suggest a possible effect. This requires confirmation in a larger dataset with greater statistical power but if confirmed would be of great clinical significance.
[
1 4 8 # 1 C H E S T J U LY 2 0 1 5
]
Acknowledgments Author contributions: A. C. B. and N. A. M. are the guarantors of the article and take responsibility for the manuscript, the data, and the analysis. A. C. B. and N. A. M. contributed to conceiving the article, collated and analyzed the data, and wrote the manuscript; A. O. C. contributed to providing data from the LENT cohort and contributed significantly to data analysis and manuscript writing; G. C. S., A. J. M., J. F., I. P., J. C. T. P., M. G. S., A. E. S., and N. M. R. contributed to providing data on cases and reviewed the final manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Clive has received conference travel costs from CareFusion Corporation. Dr Maskell has sat on the advisory board for CareFusion Corporation and received unrestricted research grants from CareFusion Corporation. Drs Bibby, Fallon, Psallidas, Pepperell, Slade, Stanton, and Rahman and Mss Slade and Morley have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.
References 1. American Thoracic Society. Management of malignant pleural effusions. Am J Respir Crit Care Med. 2000;162(5): 1987-2001. 2. Clive AO, Kahan BC, Hooper CE, et al. Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score. Thorax. 2014;69(12):1098-1104.
journal.publications.chestnet.org
3. Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA. 2012;307(22):2383-2389. 4. Takita H. Effect of postoperative empyema on survival of patients with bronchogenic carcinoma. J Thorac Cardiovasc Surg. 1970;59(5):642-644. 5. Ruckdeschel JC, Codish SD, Stranahan A, McKneally MF. Postoperative empyema improves survival in lung cancer. Documentation and analysis of a natural experiment. N Engl J Med. 1972;287(20): 1013-1017. 6. Malignant mesothelioma. US National Cancer Institute at the National Institute of Health website. http://www.cancer.gov/ cancertopics/types/malignantmesothelioma. Accessed April 24, 2014. 7. Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest. 1998; 113(3):723-731. 8. Ribak J, Selikoff IJ. Survival of asbestos insulation workers with mesothelioma. Br J Ind Med. 1992;49(10):732-735. 9. Yates DH, Corrin B, Stidolph PN, Browne K. Malignant mesothelioma in south east England: clinicopathological experience of 272 cases. Thorax. 1997; 52(6):507-512. 10. Cetin K, Ettinger DS, Hei YJ, O’Malley CD. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. Clin Epidemiol. 2011;3:139-148. 11. Anraku M, Cunningham KS, Yun Z, et al. Impact of tumor-infiltrating T cells on
12.
13.
14.
15.
16.
17.
18.
survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2008;135(4):823-829. Hegmans JP, Hemmes A, Hammad H, Boon L, Hoogsteden HC, Lambrecht BN. Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J. 2006;27(6):1086-1095. Suzuki K, Kadota K, Sima CS, et al. Chronic inflammation in tumor stroma is an independent predictor of prolonged survival in epithelioid malignant pleural mesothelioma patients. Cancer Immunol Immunother. 2011;60(12):1721-1728. Lansley SM, Varano Della Vergiliana JF, Cleaver AL, et al. A commercially available preparation of Staphylococcus aureus bio-products potently inhibits tumour growth in a murine model of mesothelioma. Respirology. 2014; 19(7):1025-1033. Sakamoto J, Teramukai S, Watanabe Y, et al. Meta-analysis of adjuvant immunochemotherapy using OK-432 in patients with resected non-small cell lung cancer. J Immunother. 2001;24(3):250-256. Ren S, Terman DS, Bohach G, et al. Intrapleural staphylococcal superantigen induces resolution of malignant pleural effusions and a survival benefit in non-small cell lung cancer. Chest. 2004;126(5):1529-1539. Fysh ET, Tremblay A, Feller-Kopman D, et al. Clinical outcomes of indwelling pleural catheter-related pleural infections: an international multicenter study. Chest. 2013;144(5):1597-1602. Maskell NA, Batt S, Hedley EL, Davies CW, Gillespie SH, Davies RJ. The bacteriology of pleural infection by genetic and standard methods and its mortality significance. Am J Respir Crit Care Med. 2006;174(7):817-823.
241
Original Research Disorders of the Pleura
]
Survival in Patients With Malignant Pleural Effusions Who Developed Pleural Infection A Retrospective Case Review From Six UK Centers Anna C. Bibby, MBChB; Amelia O. Clive, MBBS; Gerry C. Slade, RGN, FCCP; Anna J. Morley, RGN; Janet Fallon, MBBS; Ioannis Psallidas, PhD; Justin C. T. Pepperell, BMBCh; Mark G. Slade, MBBS; Andrew E. Stanton, MBChB; Najib M. Rahman, BMBCh; and Nick A. Maskell, BMBS, FCCP
Malignant pleural effusion (MPE) incidence is increasing, and prognosis remains poor. Indwelling pleural catheters (IPCs) relieve symptoms but increase the risk of pleural infection. We reviewed cases of pleural infection in patients with IPCs for MPE from six UK centers between January 1, 2005, and January 31, 2014.
OBJECTIVE:
Survival in patients with pleural infection was compared with 788 patients with MPE (known as the LENT [pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type] cohort) and with national statistics. METHODS:
Of 672 IPCs inserted, 25 (3.7%) became infected. Most patients (20 of 25) had mesothelioma or lung cancer. Median survival in the pleural infection cohort appeared longer than in the LENT cohort, although this result did not achieve significance (386 days vs 132 days; hazard ratio, 0.67; P 5 .07). Median survival with mesothelioma and pleural infection was twice as long as national estimates for mesothelioma survival (753 days vs , 365 days) and double the median survival of patients with mesothelioma in the LENT cohort (339 days; 95% CI, nonoverlapping). Survival with lung and breast cancer did not differ significantly between the groups. Sixty-one percent of patients experienced early infection. There was no survival difference between patients with early and late infection (P 5 .6).
RESULTS:
This small series of patients with IPCs for MPE suggests pleural infection may be associated with longer survival, particularly in patients with mesothelioma. Results did not achieve significance, and a larger study is needed to explore this relationship further and investigate whether the local immune response, triggered by infection, is able to modulate mesotheCHEST 2015; 148(1):235-241 lioma progression.
CONCLUSIONS:
Manuscript received September 5, 2014; revision accepted November 3, 2014; originally published Online First November 27, 2014. ABBREVIATIONS: HR 5 hazard ratio; IPC 5 indwelling pleural catheter; LENT 5 pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type; MPE 5 malignant pleural effusion AFFILIATIONS: From the Royal United Hospital NHS Trust (Dr Bibby), Combe Park, Bath; the North Bristol Lung Centre (Drs Clive and Maskell and Ms Morley), Southmead Hospital, North Bristol NHS Trust, Bristol; Papworth Hospital NHS Foundation Trust (Ms Slade and Dr Slade), Papworth Everard, Cambridge; Musgrove Park Hospital (Drs Fallon and Pepperell), Taunton, Somerset; the Oxford Centre for Respiratory Medicine (Drs Psallidas and Rahman), Churchill Hospital, Oxfordshire; Great Western Hospital NHS Trust (Dr Stanton), Swindon, Wiltshire; and the
journal.publications.chestnet.org
Academic Respiratory Unit (Dr Maskell), University of Bristol School of Clinical Sciences, Bristol, England. This research was presented in abstract form (S117) at the British Thoracic Society Winter Meeting, December 5, 2014, London, England. FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study. CORRESPONDENCE TO: Nick A. Maskell, BMBS, FCCP, Academic Respiratory Unit, Second Floor, Learning and Research Bldg, Southmead Hospital, University of Bristol, Bristol, BS10 5NB, England; e-mail: [email protected] © 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details. DOI: 10.1378/chest.14-2199
235
Malignant pleural effusions (MPEs) are common, affecting up to 200,000 people in the United States and United Kingdom each year.1 Their presence often signifies advanced or metastatic disease, and consequently they are associated with poor prognosis. Median survival ranges from 3 to 15 months, depending on underlying tumor type and stage. Lung cancer is the most common underlying pathology and is associated with the worst outcome.1 Predicting prognosis with MPEs is difficult, but recently a prognostic scoring system, the LENT (pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type) score, has been developed and validated as a tool to stratify patients into prognostic groups and predict life expectancy.2
Indwelling pleural catheters (IPCs) are increasingly used to relieve symptoms of MPEs. They are as effective at relieving symptoms as tube drainage and talc pleurodesis, and they improve quality of life.3 IPCs can be inserted as a day case procedure, leading to shorter inpatient stays. However, IPCs are associated with a higher risk of pleural infection, particularly if they remain in situ for long periods of time.3
Materials and Methods
Baseline data on patient demographics, oncologic diagnosis and treatment, and details of pleural infection were gathered retrospectively. The data collection sheet is shown in e-Table 2.
Basic descriptive statistics were used to summarize patient characteristics and factors relating to pleural infection. The primary outcome measure was survival time, calculated from date of diagnosis with MPE and censored at date of death or final follow-up. Survival times were compared with results from a database of 788 patients with MPE, prospectively collected from three international pleural centers (LENT cohort) 2 and to national US6 and UK7-9 statistics. Kaplan-Meier curves were drawn to visually compare the two cohorts and Cox proportional hazards model used to calculate the hazard ratio (HR). Individual LENT scores were calculated at diagnosis, and LENT-predicted median life expectancy compared with actual survival (see e-Table 3 for LENT score calculation).
Local ethics approval was obtained for the LENT cohort and individual consent obtained from participants (UK Research Ethics Committee reference 08/H0102/11, Central Bristol). Data for the pleural infection cohort was collected as a retrospective audit of practice, in keeping with local ethics committee guidance.
Univariable Cox regression modeling was undertaken to establish whether there was any association of age, performance status, duration of antibiotic treatment, oncologic treatment received, or timing of pleural infection with survival. All analyses were undertaken using Stata version 11 (StataCorp LP).
Results
The times between IPC insertion and pleural infection are shown in Figure 3. Sixteen of 25 patients (64%) developed early infection (within 90 days of IPC insertion). Thirteen of 25 patients (52%) received IV antibiotics, and ten of 13 (77%) received additional oral antibiotics. Mean antibiotic duration was 24 days (range, 3-70 days). Fifteen of 25 patients (60%) were treated as inpatients, with an average length of stay of 10.5 days (range, 2-34 days).
All IPCs inserted for MPE between January 1, 2005, and January 31, 2014, in six UK centers were reviewed and cases of pleural infection identified. Recruitment periods differed between centers according to when services were established. Details are shown in e-Table 1. Pleural infection was defined as clinical symptoms and signs consistent with pleural infection, necessitating antibiotic treatment, with or without positive pleural fluid microscopy or culture. Superficial wound infections at IPC insertion site were not included.
Six hundred seventy-two IPCs were inserted during the study period. Twenty-five patients (3.7%) were identified as having experienced pleural infection. Each patient had a single episode of pleural infection, affecting a unilateral IPC. One individual with pleural infection also appeared in the LENT cohort. This patient was removed from the LENT group prior to analysis. Baseline characteristics of patients with pleural infection are summarized in Table 1, and a patient flow diagram is shown in Figure 1. Baseline information on the LENT cohort is available in e-Table 4.
There has been anecdotal evidence for decades that patients with pleural malignancy who survive iatrogenic pleural infection tend to have slower progression of their malignancy in the subsequent months.4,5 We wanted to explore this hypothesis and, hence, undertook a retrospective review of MPE cases from six UK centers who developed pleural infection in conjunction with an IPC. The aim was to determine whether these patients’ survival differed from their predicted life expectancy.
Factors Relating to Infection
No patients required surgery. Three of 25 IPCs (12%) were removed because of pleural infection. Information on pleurodesis was available for 19 patients. Eleven of 19 (58%) achieved pleurodesis, including the three patients who had their IPCs removed.
Microbiologic culture was positive in 22 of 25 cases (88%). Organisms are shown in Figure 2.
Three of 25 (12%) died within 30 days of being diagnosed with pleural infection. Although specific cause of death
236 Original Research
[
1 4 8 # 1 C H E S T J U LY 2 0 1 5
]
TABLE 1
] Baseline Characteristics of Patients With Pleural Infection
Characteristic
No. (%)
Sex Male Female Age, median (range), y
19 (76) 6 (24) 69 (35-79)
WHO PS 0
5 (20)
1
13 (52)
2
3 (12)
3
2 (8)
Not recorded
2 (8)
Tumor Mesothelioma
12 (48)
NSCLC
8 (32)
Breast
3 (12)
Lymphoma
1 (4)
Thyroid
1 (4)
Oncologic treatment Chemotherapy
7 (28)
Radiotherapy
7 (28)
Both
5 (20)
Neither
5 (20)
Not known
1 (4)
NSCLC 5 non-small cell lung cancer; WHO PS 5 World Health Organization performance status.
was unknown, it is assumed that pleural infection was a contributing factor. Survival Times
Twenty-one patients were followed up until death, two patients were censored at the time of data collection (at 223 days and 317 days, respectively), and two patients were excluded from survival analysis because of
missing data on mortality status. Median survival for patients with IPCs and pleural infection was 386 days (95% CI, 302-684) (Table 2). This compares with a median survival of 132 days in the LENT cohort (mean, 270 days; 95% CI, 246-293 days).2 Kaplan-Meier curves comparing survival for the two cohorts showed enhanced survival in the pleural infection cohort but did not reach statistical significance (HR, 0.67; 95% CI, 0.43-1.03; P 5 .07) (Fig 4). Survival With Mesothelioma: Eleven patients had mesothelioma (64% epithelial, 9% sarcomatoid, 27% not specified, compared with the LENT cohort of 45% epithelial, 11% sarcomatoid, 8% biphasic, and 36% unspecified). Median survival in the mesothelioma group exceeded the LENT cohort (753 days vs 339 days) and exceeded nationally reported US and UK survival rates. US National Cancer Statistics on Mesothelioma predict a median life expectancy of 242 days in patients aged between 65 and 74 years and 112 days in patients diagnosed over the age of 75 years.6 In this series, the six patients with mesothelioma aged 65 to 74 years had a median survival of 766 days (95% CI, 310-1,067 days), and the four patients aged . 75 years had a median survival of 526 days (95% CI, 0-1,881 days). In the United Kingdom, median life expectancy with mesothelioma is reported between 9 and 12 months.7-9 The median survival of patients with mesothelioma and pleural infection in this study was . 2 years. US and UK 1-year survival rates are , 40%,6,8 compared with 82% in this series. Survival With Lung Cancer: There were no patients with small cell lung cancer in the pleural infection cohort. Patients with pleural infection and non-small cell lung cancer had longer median survival than patients with non-small cell lung cancer in the LENT cohort, but CIs overlapped (Table 2). The pleural infection cohort had
Figure 1 – Flowchart of participants with pleural infection. IPC 5 indwelling pleural catheter; LENT 5 pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type.
journal.publications.chestnet.org
237
when stratified by timing of infection in 3-month blocks (HR 5 0.97; 95% CI, 0.71-1.30; P 5 .83).
Discussion
Figure 2 – Microbiologic organisms cultured from pleural fluid. MRSA 5 methicillin-resistant Staphylococcus aureus.
higher 1-year survival rates than US rates for stage IV non-small cell lung cancer (29% vs 19%).10 Survival With Breast Cancer: Survival times with breast cancer were similar in the pleural infection group and the LENT cohort. CIs for the two cohorts were also similar. Survival According to LENT Scores: Data were available to calculate individual LENT scores for 13 patients. Nine of 13 (69%) exceeded the LENT score-predicted median life expectancy (e-Table 5). Factors Affecting Survival: Univariable Cox regression was performed and did not show any association between the following variables and survival: age (HR 5 0.96, P 5 .04), performance status (HR 5 1.41, P 5 .26), duration of antibiotic treatment (HR 5 1.00, P 5 .74), and whether the patient received chemotherapy (HR 5 0.63, P 5 .35) or radiotherapy (HR 5 0.74, P 5 .56). Multivariate modeling was not possible due to small numbers. There was no difference in survival between patients who developed infection within 90 days of IPC insertion and patients with later infection (median, 209 days; 95% CI, 196-779 days vs 504 days; 95% CI, 291-760; HR 5 1.06; P 5 .91). There was no difference in survival
Figure 3 – Timing of pleural infection. See Figure 1 legend for expansion of abbreviation.
238 Original Research
This retrospective review of practice from six UK hospitals suggests that patients who develop pleural infection with an IPC in situ for MPE may live longer than those without infection. Hazard modeling in this small sample did not achieve significance (P 5 .07); however, the trend toward significance, the appearance of the Kaplan-Meier survival curves, and the CIs that do not overlap (for the overall population and mesothelioma) raise the possibility of a genuine effect. Further research in warranted to investigate this potential relationship in greater depth. Causality cannot be determined from this observational study, but our results support the hypothesis that pleural infection may stimulate antitumor activity. Bacteria in the pleural space can generate local immune activation, causing proliferation and migration of T-cell populations, which can act against tumor.11 In mesothelioma, cytotoxic T lymphocytes that normally inhibit tumor growth are suppressed, allowing the tumor to be locally aggressive.12 The ability to maintain T lymphocyte activity is associated with better outcomes with mesothelioma,13 and pleural infection may assist in preserving this response. This theory is supported by mouse models of mesothelioma in which intratumor delivery of a Staphylococcus toxin generated local T-cell activation, induced tumor necrosis, and inhibited tumor growth.14 Bacterial agents such as OK-432 and Staphylococcus superantigen have demonstrated survival benefits when used to treat patients with non-small cell cancer and MPE.15,16 Our results did not show this, but the small number of patients with lung cancer in this study prevent this from being a convincing negative. Our results also support previous observations that IPC-related infections can be managed conservatively in the majority of cases. In our study, 48% of patients were treated with oral therapy alone, and 40% did not require admission to hospital. This mimics the findings from the largest cohort of patients with IPC to date, wherein almost 40% of patients with pleural infection were treated with oral antibiotics, and one-fourth were managed as outpatients.17 This should reassure clinicians who have ongoing concerns about the risk of IPC-related infection in patients with MPE. The spectrum of bacterial organisms in this series mirrored previous studies. Staphylococci and gram-positive organisms contributed to 69% of IPC-related infections,
[
1 4 8 # 1 C H E S T J U LY 2 0 1 5
]
TABLE 2
] Median Survival for Patients With Indwelling Pleural Catheter LENT Cohort
Tumor Type
Pleural Infection Cohort
Median Survival, d (95% CI)
No.
All
133 (246-293)
788
386 (302-684)
23
Mesothelioma
339 (267-442)
170
753 (446-1,089)
11
75 (138-205)
215
138 (62-479)
7
Breast
192 (133-271)
140
167 (0-360)
3
Thyroid
N/A
Non-small cell lung cancer
Lymphoma
218 (160-484)
35
Median Survival, d (95% CI)
No.
148
1
449
1
The LENT cohort was a prospectively collected international cohort of 788 patients with malignant pleural effusions. LENT 5 pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, serum neutrophil to lymphocyte ratio, and tumor type; N/A 5 not applicable.
compared with 62% in another IPC series17 and 63% in the general population.18 Bacterial infection has long been associated with high rates of pleurodesis, and bacterial agents are used as pleurodesis agents in some countries.15-17 Pleurodesis rates in this study were at the low end of the 60% to 80% reported in other trials,16,17 but this is likely to be a reflection of missing data, an accepted limitation of the study design. There are limitations to this study, which, alongside the small sample size, are likely to have contributed to the lack of statistical significance. Retrospective identification of cases is the first limitation, as, although this was as rigorous as possible, it relied on comprehensive record keeping for IPC insertion and pleural infection. If this were not the case, recall bias may have occurred. Similarly,
case mix was outside of our control. The predominance of epithelial subtype mesothelioma in the study group may have positively skewed survival times, although the LENT cohort had a similar distribution of mesothelioma subtypes. Prospective data collection would reduce these limitations, but the low incidence of pleural infection in patients with IPCs would make this a lengthy undertaking. This study was not a formal case control study. Limited resources meant that data could not be collected on patients with IPCs without pleural infection. Consequently, there was no control group available within the cohort being studied. The LENT cohort was chosen as a comparator instead, as it is the largest published cohort of patients with MPEs and was prospectively collected over the same time period as the pleural infection cohort. Potential differences between the two groups may have
Figure 4 – Kaplan-Meier survival curves for LENT cohort and pleural infection cohort. See Figure 1 legend for expansion of abbreviation.
journal.publications.chestnet.org
239
introduced bias; however, by comparing cases of pleural infection to a large cohort with comprehensive baseline data and robust follow-up, bias from missing data was minimized. The presence of pleural infection within the LENT cohort was not known, and this is a limitation. However, pleural infection rates are likely to have been very low in the LENT cohort, as IPCs were present in just 15% of this group. The presence of incidental pleural infection in LENT cohort subjects would act to weaken the effect size demonstrated, and this may have contributed to the failure to achieve overall statistical significance. The authors acknowledge that this series is vulnerable to confounding. When IPC services were in their infancy, IPCs were offered to patients most expected to benefit from them (ie, those with the longest anticipated life expectancy). Consequently, the longer survival times seen in this series may reflect confounding by indication based on the presence of an IPC, particularly when compared with the LENT cohort, in which only 15% of people had an IPC. However, the publication of data showing equivalence between IPCs and chest tube drainage in 20123 may have led to increased IPC use, so confounding is likely to have diminished over the study period. Nonetheless, to avoid this issue, future work in this area should include patients matched for the presence or absence of an IPC.
240 Original Research
Another area of potential confounding is the increase in infection risk the longer an IPC remains in situ. Could the findings of this study simply represent patients who lived longer with an IPC in situ and developed infection as a consequence of prolonged IPC presence? The fact that 61% of patients developed infection within 3 months of IPC insertion would dispute this. The population was too small to undertake reliable regression analysis, but subgroup analysis showed no difference in survival between patients with early and late infection. This suggests that the observed association between pleural infection and longer survival is not just an effect of having an IPC in situ for a longer period of time.
Conclusions In summary, this review of 25 cases of pleural infection in patients with IPC for MPE suggests enhanced survival, particularly in patients with mesothelioma. Similarities between our population and previously published series indicate that this cohort is representative and support the possibility that this observation represents a genuine effect. The study has limitations, and statistical significance is not achieved; however, despite this, the Kaplan-Meier survival curves suggest a possible effect. This requires confirmation in a larger dataset with greater statistical power but if confirmed would be of great clinical significance.
[
1 4 8 # 1 C H E S T J U LY 2 0 1 5
]
Acknowledgments Author contributions: A. C. B. and N. A. M. are the guarantors of the article and take responsibility for the manuscript, the data, and the analysis. A. C. B. and N. A. M. contributed to conceiving the article, collated and analyzed the data, and wrote the manuscript; A. O. C. contributed to providing data from the LENT cohort and contributed significantly to data analysis and manuscript writing; G. C. S., A. J. M., J. F., I. P., J. C. T. P., M. G. S., A. E. S., and N. M. R. contributed to providing data on cases and reviewed the final manuscript. Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr Clive has received conference travel costs from CareFusion Corporation. Dr Maskell has sat on the advisory board for CareFusion Corporation and received unrestricted research grants from CareFusion Corporation. Drs Bibby, Fallon, Psallidas, Pepperell, Slade, Stanton, and Rahman and Mss Slade and Morley have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.
References 1. American Thoracic Society. Management of malignant pleural effusions. Am J Respir Crit Care Med. 2000;162(5): 1987-2001. 2. Clive AO, Kahan BC, Hooper CE, et al. Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score. Thorax. 2014;69(12):1098-1104.
journal.publications.chestnet.org
3. Davies HE, Mishra EK, Kahan BC, et al. Effect of an indwelling pleural catheter vs chest tube and talc pleurodesis for relieving dyspnea in patients with malignant pleural effusion: the TIME2 randomized controlled trial. JAMA. 2012;307(22):2383-2389. 4. Takita H. Effect of postoperative empyema on survival of patients with bronchogenic carcinoma. J Thorac Cardiovasc Surg. 1970;59(5):642-644. 5. Ruckdeschel JC, Codish SD, Stranahan A, McKneally MF. Postoperative empyema improves survival in lung cancer. Documentation and analysis of a natural experiment. N Engl J Med. 1972;287(20): 1013-1017. 6. Malignant mesothelioma. US National Cancer Institute at the National Institute of Health website. http://www.cancer.gov/ cancertopics/types/malignantmesothelioma. Accessed April 24, 2014. 7. Herndon JE, Green MR, Chahinian AP, Corson JM, Suzuki Y, Vogelzang NJ. Factors predictive of survival among 337 patients with mesothelioma treated between 1984 and 1994 by the Cancer and Leukemia Group B. Chest. 1998; 113(3):723-731. 8. Ribak J, Selikoff IJ. Survival of asbestos insulation workers with mesothelioma. Br J Ind Med. 1992;49(10):732-735. 9. Yates DH, Corrin B, Stidolph PN, Browne K. Malignant mesothelioma in south east England: clinicopathological experience of 272 cases. Thorax. 1997; 52(6):507-512. 10. Cetin K, Ettinger DS, Hei YJ, O’Malley CD. Survival by histologic subtype in stage IV nonsmall cell lung cancer based on data from the Surveillance, Epidemiology and End Results Program. Clin Epidemiol. 2011;3:139-148. 11. Anraku M, Cunningham KS, Yun Z, et al. Impact of tumor-infiltrating T cells on
12.
13.
14.
15.
16.
17.
18.
survival in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg. 2008;135(4):823-829. Hegmans JP, Hemmes A, Hammad H, Boon L, Hoogsteden HC, Lambrecht BN. Mesothelioma environment comprises cytokines and T-regulatory cells that suppress immune responses. Eur Respir J. 2006;27(6):1086-1095. Suzuki K, Kadota K, Sima CS, et al. Chronic inflammation in tumor stroma is an independent predictor of prolonged survival in epithelioid malignant pleural mesothelioma patients. Cancer Immunol Immunother. 2011;60(12):1721-1728. Lansley SM, Varano Della Vergiliana JF, Cleaver AL, et al. A commercially available preparation of Staphylococcus aureus bio-products potently inhibits tumour growth in a murine model of mesothelioma. Respirology. 2014; 19(7):1025-1033. Sakamoto J, Teramukai S, Watanabe Y, et al. Meta-analysis of adjuvant immunochemotherapy using OK-432 in patients with resected non-small cell lung cancer. J Immunother. 2001;24(3):250-256. Ren S, Terman DS, Bohach G, et al. Intrapleural staphylococcal superantigen induces resolution of malignant pleural effusions and a survival benefit in non-small cell lung cancer. Chest. 2004;126(5):1529-1539. Fysh ET, Tremblay A, Feller-Kopman D, et al. Clinical outcomes of indwelling pleural catheter-related pleural infections: an international multicenter study. Chest. 2013;144(5):1597-1602. Maskell NA, Batt S, Hedley EL, Davies CW, Gillespie SH, Davies RJ. The bacteriology of pleural infection by genetic and standard methods and its mortality significance. Am J Respir Crit Care Med. 2006;174(7):817-823.
241
