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Airway colonisation and postoperative pulmonary complications after neoadjuvant therapy for oesophageal cancer

^a Department of Thoracic Surgery and Diseases of the Oesophagus, Sainte Marguerite University Hospital, Marseille, France
^b Department of Anaesthesiology, Sainte Marguerite University Hospital, Marseille, France
^c Department of Intensive Care Medicine, Sainte Marguerite University Hospital, Marseille, France
^d Department of Respiratory Diseases, Sainte Marguerite University Hospital, Marseille, France
^e UMR 6020-IFR 48, Faculty of Medicine, University of the Mediterranean, Marseille, France

Received 12 June 2007; received in revised form 17 September 2007; accepted 27 September 2007.

^_* Corresponding author. Address: Department of Thoracic Surgery, Sainte Marguerite University Hospital-CHU Sud, 270 Bd Ste Marguerite, 13274 Marseille Cedex 9, France. (Email: pathomas{at}ap-hm.fr).

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A References

 
Objective: To evaluate the clinical relevance of preoperative airway colonisation in patients undergoing oesophagectomy for cancer after a neoadjuvant chemoradiotherapy. Methods: From 1998 to 2005, 117 patients received neoadjuvant chemoradiotherapy for advanced stage oesophageal cancer. Among them, 45 non-randomised patients underwent a bronchoscopic bronchoalveolar lavage (BAL group) prior to surgery to assess airways colonisation. The remaining patients (n = 72) constituted the control group. The two groups were similar with respect to various clinical or pathological characteristics. Results: Thirteen of the 45 BAL patients (28%) had a preoperative bronchial colonisation by either potentially pathogenic micro-organisms (PPMs) (n = 7, 16%) or non-potentially pathogenic micro-organisms (n = 6, 13%). Cytomegalovirus (CMV) was cultured from BAL in four patients. Pre-emptive therapy was administrated in seven patients: four antiviral and three antibiotic prophylaxes. Postoperatively, 14 patients (19%) developed acute respiratory distress syndrome (ARDS) in the control group and three (7%) in the BAL group (p = 0.064). The cause of ARDS was attributed to CMV pneumonia in six control group patients on the basis of the results of open lung biopsies (n = 3) or BAL cultures (n = 3) versus none of the BAL group patients (p = 0.08). Timing for extubation was shorter in the BAL group (mean 13 ± 3 h) as compared with the control group (mean 19.5 ± 14 h; p = 0.039). In-hospital mortality was not significantly lower in BAL group patients when compared to that of control group patients (8% vs 12.5%). Conclusions: Airway colonisation by PPMs after neoadjuvant therapy is suggested as a possible cause of postoperative ARDS after oesophagectomy. Pre-emptive treatment of bacterial and viral (CMV) colonisation seems an effective option to prevent postoperative pneumonia.

Abbreviations: ARDS = acute respiratory distress syndrome • BAL = bronchoalveolar lavage • CMV = cytomegalovirus • COPD = chronic obstructive pulmonary disease • FEV = forced expiratory volume in 1 s • PPMs = potentially pathogenic micro-organisms • Non-PPMs = non-potentially pathogenic micro-organisms

Key Words: Oesophageal cancer • Oesophagectomy • Neoadjuvant therapy • Cytomegalovirus • Bronchoalveolar lavage • Bronchoscopy • Airways colonisation

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A References

 
The best treatment option for patients with locally advanced oesophageal carcinoma has not yet been determined. Although surgery remains the cornerstone, there is established evidence supporting neoadjuvant chemoradiotherapy to increase survival in those patients [1]. Whether this benefit may be sufficient to warrant the considerable risks of multimodality treatments remains unclear. Indeed, chemoradiotherapy significantly increases postoperative mortality [2]. Pneumonia and adult respiratory distress syndrome (ARDS) are the most frequent precipitating events in this setting, eventually leading to mortality [3–7].

Reasons of this pulmonary morbidity are multifaceted, and those due specifically to the neoadjuvant treatment are probably very difficult to segregate from those due to the surgical procedure, to the perioperative anaesthetic management, and to the patient himself. Nevertheless, in the pathogenesis of nosocomial pneumonia occurring in hospitalised and chronically ill individuals, chronic airway colonisation seems to be an essential first step [8]. As well, colonisation may be supposed to facilitate the development of pneumonia in the postoperative setting, when secretion clearance and cough reflex are impaired. Under immunosuppressive condition, these colonisations of the respiratory mucosal surface act in a manner that increases its ability to bind micro-organisms and lessen the risks of superimposed infections.

The aim of the present study was to identify preoperative bronchial colonisation in patients submitted to oesophagectomy after neoadjuvant chemoradiotherapy, with special emphasis on the possible benefit of a pre-emptive treatment on postoperative pulmonary complications.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A References

 
2.1 Study design
This retrospective study was conducted according to the current regulations for clinical research in France. As there was no intent of research at the time of data collection, all tests were proposed in the frame of medical care, with a presumed individual benefit for the patients. Patient charts were identified by screening a database into which data were entered prospectively for any patient undergoing surgery for thoracic malignancy at our department.

The study period ranged from January 1998 to July 2005. All patients underwent clinical examination, oesophagoscopy, full-body computerised tomography (CT), and endoscopic ultrasound (US). PET-scanning was selectively performed from 2003 when it became available at our centre in patients with equivocal results of the standard work-up. According to the guidelines of our multidisciplinary committee, all CT M0 fit patients with a locally advanced disease as defined as UST3N1 (predicted R0 resection) of the oesophagus or gastro-oesophageal junction were offered the option of a multimodal treatment.

Altogether, 117 patients with locally advanced oesophageal cancer received neoadjuvant chemoradiotherapy prior to a trans-thoracic oesophagectomy. Among them, 45 non-randomised patients accepted to have a bronchoscopic bronchoalveolar lavage (BAL group) before surgery to assess airways colonisation. The other 72 patients constituted the control group. The two groups were similar with respect to various biological, clinical or pathological characteristics (Tables 1 and 2 ).

2.2 Bronchoalveolar lavage (BAL) and microbiological analysis
Fibre optic bronchoscopy was performed approximately 4 weeks after completion of the induction therapy. The tracheobronchial tree was fully examined and special attention was paid to the trachea and main bronchi. Bronchoalveolar lavage samples were obtained at the end of the procedure: 150 ml of physiological saline were instilled separately into the left and right main bronchus and washing for microbiologic examination was obtained by suction from all lung lobes.

All samples were sent for microbiological evaluation. Blood samples were obtained simultaneously to the bronchoscopy for blood cultures, for CMV viremia, antigenemia and serology. Routine staining of BAL included Grocott's stain for Pneumocystis carinii and Papanicolaou stain. Legionella pneumoniae, atypical mycobacteria and Mycobacterium tuberculosis were investigated by conventional techniques. Immunostaining for CMV was performed using a panel of commercially available antibodies. CMV culture was performed by shell via assay, spinning the BAL fluid onto human embryonic fibroblasts and determining of CMV immediate early antigens by immunofluorescence. CMV was investigated in blood by PCR and antigenemia assay was determined by CMV light kit. CMV serologic status was achieved by fluorescent antibody and anticomplement immunofluorescence.

2.3 Pre-emptive treatment
Micro-organisms were classified according to their potential pathogenic status (PPM and non-PPM) [9,10]. Agents classically recognised as causative of respiratory infections, whether or not belonging to the oropharyngeal flora, were considered as PPM (such as gram-negative rods, i.e. Pseudomonas aeruginosa, Enterobacteriaceae and Haemophilus spp.; gram-positive cocci, i.e. Staphylococcus aureus, Streptococcus pneumoniae; and gram-negative cocci, i.e. Moraxella catarrhalis). Non-PPMs were those micro-organisms belonging to the oropharyngeal or gastrointestinal flora that are not usually involved in respiratory infections in nonimmunocompromised patients (i.e. Streptococcus viridians group, Neisseria spp., corynebacterium spp., Candida spp., and others) [9,10]. Any CMV detection was considered as a CMV infection in accordance with the dedicated literature [11]. According to the BAL results, anti infectious specific treatment was administrated for PPM. Identification of non-PPMs was considered as a contamination and, in turn, was not treated.

2.4 Surgery and postoperative course
All patients underwent a transthoracic en-bloc oesophagectomy with a 2-field lymphadenectomy. Anastomosis was performed at the top of the thorax (Ivor Lewis procedure, n = 82) or into the neck (Mac Keown procedure, n = 35). Medical and surgical complications were prospectively recorded. Respiratory complications were defined by all medical events concerning the lung parenchyma (i.e. pneumonia, sputum retention, atelectasis, acute lung injury, acute respiratory distress syndrome) in the absence of surgical complications requiring reoperation. Surgical complications included anastomotic leakage, laryngeal paralysis, chylothorax, pleural effusion, empyema and bleeding. Acute lung injury (ALI) and ARDS were defined according to the standardised ARDS criteria. ARDS was defined as PaO₂/FiO₂ less than 27 kPa. Additional criteria included the presence of bilateral infiltrations on plain chest radiograph, and a pulmonary artery occlusion pressure of less than 18 mmHg if measured or no clinical evidence of left atrial hypertension.

2.5 Statistical analysis
Statistical analysis included Student's t-test, the Mann–Whitney test, the Pearson ² test, and Fisher's exact test as appropriate. Operative mortality consisted of either 30-day or in-hospital mortalities regardless of the length of the hospital stay. Descriptive analysis was expressed in terms of mean, median, standard deviation and frequency. Statistical differences between groups were determined by Student's t-test, the Mann–Whitney test, the ² test and one-way analysis of variance (ANOVA). All statistical tests were performed using a 5% level of significance.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A References

 
3.1 General microbiological findings
Bronchoscopic BAL was positive in 13 of 45 patients (29%). Results are shown in Table 3 . There were seven PPMs (15%) and six non-PPMs (13%). BAL samples allowed to detect six cases of fungal colonisation: Candida albicans and famata were grown in BAL fluid in two cases, Aspergillus fumigatus and Niger was detected in three patients and Torulopsis glabrata was found in one patient. BAL cultures disclosed Escherichia coli in one patient and Haemophilus influenzae in 2 (>10⁵ cfu/ml). S. aureus was found in two patients but colonisation was not significant (<10³ cfu/ml). Pneumocystis carinii, Mycobacteria, Legionella pneumonia, Toxoplasmia and Amibia have not been detected in any BAL fluid.

There were no significant differences in total volumes of retrieved BAL fluid in the different patient groups submitted to comparison. Results of BAL cytology are summarised in Table 3. BAL fluid cytology showed an increased percentage of alveolar macrophages in PPM patients when compared to that of non-PPM patients, but the difference did not reach statistical significance (Table 4 ).

3.3 Postoperative mortality and morbidity
All the 117 patients underwent oesophageal resection after a mean delay between chemoradiotherapy and surgery of 45.7 ± 9 days [11–99]. Intraoperative antimicrobial prophylaxis was cephalosporin-based. Timing for extubation was shorter in the BAL group (mean 13 ± 3 h) when compared to that of the control group (mean 19.5 ± 14 h; p = 0.039). Respiratory complications occurred in 37% in the control group and 40% in the BAL group (Table 5 ). Postoperative hospital mortality rates were similar in both groups (12.5 and 8%, respectively; NS). Pneumonia and ARDS were the most common complications leading to death. Among the seven patients who received pre-emptive therapy, three (43%) experienced postoperative respiratory events, with no mortality. In one patient, the same agent was detected pre- and postoperatively on BAL samples (haemophilus). Among those patients colonised with non-PPM, none developed fungal infection.

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A References

4.2 Neoadjuvant therapy
Despite significant progress during the last decade, respiratory complications remain the major concern after oesophagectomy. Predictors of such complications include low FEV1, smoking status, advanced age, diabetes, low rate of albumin, poor performance status, use of transthoracic approaches, performance of extended lymphadenectomy, duration of one lung ventilation, timing of extubation, impaired postoperative pain management, and preoperative chemoradiotherapy [3–7]. Pathways by which neoadjuvant chemoradiation make postoperative respiratory complications happen are multiple.

Some authors have postulated that preoperative chemoradiation could lead to leucopoenia, anorexia, weight loss and interstitial pneumonitis [12]. It was shown recently that chemoradiotherapy leads to immunosuppression by severely impairing proliferative capacity of T lymphocytes [13]. Indeed, T lymphocytes play a key role in patient's defences against bacterial, viral and fungal infections. As well, it has been shown that surgery by itself could suppress cell-mediated immunity temporarily [14]. Defects in T cell proliferation and the resulting decline of IL-2 and IFN productions, expose the patients to an additional risk for sepsis [12–14]. Radiation-induced tissue damage could make the lung parenchyma more vulnerable to postoperative complications [15]. In patients treated with induction chemoradiotherapy, higher radiation doses result in increasing impairment of gas exchange by an alteration of post-cCRT Dlco [3]. Albeit the bronchial epithelium is somewhat radioresistant, radiation promotes metaplasia, alters mucus production, and results in focal necrosis and shedding of ciliated epithelial cells [12,16]. These modifications of the respiratory mucosal surface act in a manner that increases its ability to bind micro-organisms and increases the risks of superimposed infections.

4.3 Bacterial and viral airways colonisation
The lower bronchial tree is normally sterile in healthy people. A multitude of conditions may alter local defence mechanisms in the airways (e.g., impaired mucociliary clearance and expectoration), that may in itself lead to distal airway colonisation or infection. To the best of our knowledge, no data is available in the setting of oesophageal cancer. In contrast, prior airways colonisation has been suggested as a significant cause of pneumonia after neoadjuvant treatment before lung cancer resection. Patients with lung cancer often present with COPD, and consequently a roughly 40% rate of bacterial airway colonisation has been reported [9,10,16]. However, an association between previous bacterial colonisation and occurrence of postoperative respiratory infections could not be demonstrated firmly. One reason of the failure is that the process leading to infection is probably versatile.

One of the striking results of the present study is the 9% incidence of preoperative CMV detection in BAL group patients, and the 42% incidence of CMV infection in those patients who experienced ARDS postoperatively with a 66% mortality rate. CMV infection is a well-known problem in patients treated by high-dose chemotherapy for haematologic diseases [11], in HIV-infected patients, and in lung transplantation recipients [17]. Data on cancer patients are scarce, but CMV infection has been incriminated particularly if steroids were a component of the therapy. We have previously reported CMV as a possible cause of ventilator-associated pneumonia and ARDS [18]. In a prospective study, Heininger et al. [19] reported an incidence of 35.6% of active CMV infections in surgical ICU patients. These findings focus on two key points: diagnosis and treatment. In our study, we observed six cases of postoperative CMV pneumonia detected by BAL fluid cultures (n = 3) and/or open lung biopsies (n = 3). The diagnostic sensitivity of BAL using shell vial culture technique is low [20]. In contrast, OLB provides both microbiologic and pathological arguments, but is a rather invasive procedure, even if we reported recently its high benefit/risk ratio [21]. Routine blood determination of CMV pp65 antigen or PCR for the early detection CMV remains to be established in this setting. It has been demonstrated that pre-emptive Ganciclovir treatment reduces CMV end-organ disease and is accurately life-saving in bone marrow transplant recipients [22]. Ganciclovir treatment has also been associated successfully in symptomatic CMV diseases in immunocompromised patients [23]. A recent meta-analysis concluded that the use of Ganciclovir reduces the mortality of cytomegalovirus diseases in solid-organ transplant recipients [24]. These data suggest that pre-emptive antiviral therapy could prevent postoperative CMV infection or reactivation. As a matter of fact, none of the patients who received pre-emptive anti-viral therapy developed ARDS and/or CMV infection postoperatively.

4.4 Limitations
This exploratory observational study has several strong limitations. First, it was not designed as a randomised prospective trial, and possible bias may exist. The groups submitted to comparison, however, are contemporaneous, similar regarding main clinical characteristics, identical in fulfilling strict criteria for a multimodality treatment, and homogeneous regarding the invasiveness of surgery, i.e. transthoracic approach, two-field lymphadenectomy and temporary one-lung ventilation. Second, we did not assess airways colonisation in contemporaneous patients proposed to first-line oesophagectomy, thus the impact of neoadjuvant treatment remains speculative. Third, we acknowledge that we did not monitor longitudinally any inflammatory cytokine in BAL samples, which might have supported the working hypothesis of an accumulation of subsequent events in the genesis of respiratory complications (multiple hits hypothesis). Finally, our study did not include routine BAL investigations for the microbiological diagnosis of postoperative respiratory infections, and this limitation could have strongly biased the comparison between bronchoscopic perioperative colonisation and postoperative infection. However, this limitation is inherent to the clinical setting, in which the invasiveness of performing a bronchoscopy in a non-ventilated hypoxemic patient has to be weighted against the drawbacks of a probabilistic treatment.

Despite these limitations, we believe that the present study carries some new information. On the basis of our results, we elaborated the following comprehensive model. Respiratory complications are likely triggered by either a single massive insult, such as a major surgical complication, or a series of less intense insults (multiple hit hypothesis). We recently demonstrated that inadequate one-lung ventilation could be one of these insults [25]. We hypothesise that preoperative radiochemotherapy and airways colonisation at the time of surgery may represent some additional ‘hits’. Combination of these factors within a short period of time in a same patient may play a crucial role in initiating and/or propagating a compartmental inflammatory response leading to respiratory failure, then a systemic inflammatory process leading to multiple organ failure and death.

	Appendix A

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A References

 
Conference discussion

Dr J. Schirren (Wiesbaden, Germany): Thank you very much for this nice presentation. My question is: oesophageal cancer is correlated with alcoholism and smoking. How many smokers do you have in your group and did you have a sensation of smoking preoperatively?

Dr D’Journo: Smokers rate was comparable in both groups, in about 60% of cases. Before surgery we asked the patients to stop smoking three months beforehand.

Dr T. Grodzki (Szczecin, Poland): Thank you for the nice presentation. However I am a little bit confused with your data. Because you treated by antibiotics just seven patients, if I noticed properly, of more than 100. And you conclude very strong conclusions. First of all you don’t know how many of the control group were colonised by PPM and second the majority of your RDS was caused by viral infection. What is the message of your presentation? Should we do bronchoscopy preoperatively, should we give antibiotics or what?

Dr D’Journo: In departments who perform routinely oesophageal surgery for cancer and who are already experienced on ARDS after oesophagectomy, assessment of microbiological colonisation of airway must provide conclusive results to explain postoperative development of respiratory infections. We acknowledge several limitations of our results but we believe that these data could provide new information for clinicians to avoid postoperative ARDS.

Dr T. Lerut (Leuven, Belgium): I am surprised by the high incidence of CMV, of course it may be so because you are searching for it, I just wanted to know whether you see the same incidence of CMV in your pulmonary operative material? What is the overall incidence or prevalence of CMV in your hospital, in your department?

Dr D’Journo: The idea of this study was made when we observed CMV pneumonia on open lung biopsy in the ICU of our hospital. In our institution, Professor Laurent Papazian, has demonstrated that for patients with mechanical ventilation there was a very high rate of CMV pneumonia. He described it as the so-called ventilator-associated pneumonia (VAP). The VAP was related to CMV in half of the cases and might be due to a colonisation of the airway. We didn’t assess the colonisation for lung resection and we focused our results on oesophageal resection.

Dr S. Mattioli (Bologna, Italy): You didn’t randomise the study, how did you form the two groups?

Dr D’Journo: It is not a randomised study; it is just an observational prospective study. We proposed prospectively to the 117 patients who received neoadjuvant chemoradiotherapy to participate in this study with a preoperative fiberoptic BAL. Forty-five patients accepted to participate in this study and the others didn’t. We prospectively compared the two groups.

Dr D. Van Raemdonck (Leuven, Belgium): Can you elaborate on the technique of the lavage that you did in these patients? What was the volume and what was the risk in doing a lavage in a patient immediately preoperatively?

Dr D’Journo: I didn’t give the information into the slides. The pneumologist put about 100 ml of serum and retrieved some material to do microbiological studies and cytology. The most important thing is to perform a bronchial lavage into the alveoli space because otherwise you have a contamination from the main bronchus.

Dr D. Wood (Seattle, WA): Which surgery procedures underwent preoperative bronchial lavage and how long were patients treated before surgery?

Dr D’Journo: All positive patients with BAL were treated about 15 days before surgery. We accepted a delay of 1 month before surgery to do the pre-emptive treatment.

Dr Wood: Then perhaps the question is whether the results may be from actually a delay between induction therapy and surgery rather than the treatment itself.

Dr D’Journo: Yes, it is.

	Footnotes

 
Presented at the 15th European Conference on General Thoracic Surgery, Leuven, Belgium, June 3–6, 2007.

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Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion Appendix A References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Xavier Benoit D’Journo Christophe Doddoli Roger Giudicelli Pierre A. Fuentes Pascal Alexandre Thomas Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by D’Journo, X. B. Articles by Thomas, P. A. Search for Related Content PubMed PubMed Citation Articles by D’Journo, X. B. Articles by Thomas, P. A. Related Collections Lung - other Esophagus - cancer