Gilles Jebrak

Survival after bilateral versus single-lung transplantation for idiopathic pulmonary fibrosis.

Context Patients with end-stage lung disease caused by idiopathic pulmonary fibrosis often have bilateral lung transplantation, but the benefits of this procedure over single-lung transplantation are unclear. Contribution In this comparison of outcomes for patients who received 1 or 2 lungs, overall survival did not differ but causes of death did. Bilateral transplantation seemed to increase mortality in the first year and decrease mortality thereafter. Caution Unmeasured variables associated with transplantation might have contributed to the studys findings. Implication Single and bilateral lung transplantation carry different short- and long-term benefits and harms for patients with idiopathic pulmonary fibrosis. The Editors Idiopathic pulmonary fibrosis (IPF) often progresses to end-stage lung disease and is the second most common reason for lung transplantation (1, 2), accounting for more than 25% of lung transplantation procedures (2). The procedure can involve single or bilateral lung transplantation (13). Single-lung transplantation was considered the procedure of choice after the first report of successful transplantation for patients with IPF by the Toronto Group (4, 5). However, patients with IPF are having bilateral lung transplantation with greater frequency, and the procedure now accounts for almost 50% of all lung transplantations in patients with IPF (2). The reason for this progressive shift toward bilateral transplantation is unclear. Because no randomized, controlled studies have addressed this issue, current evidence comes from observational studies and yields conflicting results (69). Using data from the United Network for Organ Sharing (UNOS), we aimed to compare survival rates after single and bilateral lung transplantation for patients with IPF by using multivariate model risk adjustment, propensity score risk adjustment, and propensity-based matching techniques to account for confounding factors. Methods Patients The UNOS supplied all data as a standard analysis and research file, based on Organ Procurement and Transplantation Network data as of February 2009, and included coded transplant-center identifiers. The registry contains data on all patients who had lung transplantation in the United States since the registrys inception in 1987. Before May 2005, recipients were allocated organs on the basis of wait-list times. Since May 2005, priority on the waiting list has been determined by the Lung Allocation Score, which ranks patients according to the difference between survival benefit and survival on the waiting list (10). All adult patients were eligible for the study if they had cadaveric single or bilateral lung transplantation for IPF (code 1604 of the UNOS data set) and the date of transplantation, date of last follow-up, and vital status at last follow-up were known. We collected data on donor, surgery, and recipient characteristics at the time of transplantation from the UNOS registry. We excluded variables for which data were sparse or those that described clinically uncommon or rare characteristics, and we calculated several variables from those that were available (such as donor and recipient body mass indexes and mismatches of sex and blood type). The Appendix Table lists the variables we included in the analyses. Appendix Table. Variables Tested for Association With Survival After Lung Transplantation Outcomes The primary outcome was recipient survival. We assessed cause of death of the lung recipient as a secondary end point. Statistical Analysis We adjusted for confounding factors by using multivariate model risk adjustment, propensity-score risk adjustment, and matching on the propensity score. Multivariate model risk adjustment is a conventional modeling approach that incorporates all known confounders, including interactions, into a regression model. Controlling for these confounders produces a risk-adjusted treatment effect and removes overt bias due to these factors. We used Cox proportional hazards regression models to compare mortality rates between the single and bilateral lung transplantation groups, adjusted for covariates. We used purposeful selection of covariates, as described by Hosmer and Lemeshow (11), to select the multivariate model. The first step was the inclusion of all variables significant at the 20% level in the bivariate analysis, as well as all variables known to be clinically relevant (12). The second step was to remove, one by one, variables that did not significantly contribute to the multivariate model on the basis of the Wald test P value and the change in the coefficient of the remaining variables. We assessed the scale of the continuous covariates by using residual analysis (13). We only considered first-order interactions with surgical procedure. We took transplant center effects into account by including centers in the multivariate analyses as a random effect with a Gaussian distribution. Residual plots supported a linear relation between all continuous covariates and the log hazard for death. No significant interaction was retained in the final model; interactions between age at transplantation and procedure and between systolic pulmonary artery pressure and procedure were not significant. The final model included recipient variables (age, body mass index, functional status, and mean pulmonary artery pressure), donor variables (body mass index and cytomegalovirus status), and procedure-related variables (transplantation year, surgical procedure, lung transplantation center, and lung transplantation center volume). In our analyses of cause of death, we used the cumulative incidence estimator and the proportional subdistribution hazard model described by Fine and Gray (14) to account for competing causes. Propensity scores estimate the probability that a patient with specific pretreatment characteristics will receive a treatment, in this case bilateral rather than single-lung transplantation (15, 16). Within propensity score strata, covariates in both groups tend to be similarly distributed. We computed propensity scores by using logistic regression, in which surgical procedure was the dependent variable and the variables listed in the Appendix Table were independent variables. We judged the success of the propensity score modeling by assessing balance on baseline characteristics within deciles of propensity score or after matching propensity scores for patients in the single and bilateral lung transplantation groups, and found balanced distribution of variables within deciles. We used Cox proportional hazards regression to estimate the effect of bilateral lung transplantation on survival, adjusting for the propensity score (on the linear predictor scale) and surgical procedure. In another analysis, we took only data with propensity score overlap into account and adjusted the estimates on the deciles of the propensity score. We used a 1:1 matching algorithm without replacement to match patients, with calipers defined to have a maximum width of 0.25 SD of the logit of the estimated propensity score. We used marginal Cox models, accounting for correlation within matched pairs, to compare the single and bilateral lung transplantation groups in terms of adjusted survival (17). We used several statistical methods to assess whether the effect of surgical procedure was constant over time (proportional hazards assumption), including residual plots (as described by Grambsch and Therneau [18]) and fitting of additive regression models (as described by Aalen [19]). For variables involved in the multivariate model risk adjustment and propensity score analysis, we imputed missing data by using the multiple imputations by chained equation method (20), which resulted in 20 imputed data sets. We independently analyzed each of the 20 data sets. We averaged estimates of the variables to give a single mean estimate and adjusted SEs according to the Rubin rules (2022). The Appendix lists the steps of the imputation procedure. All analyses were performed by using R, version 2.5 (R Foundation for Statistical Computing, Vienna, Austria), and Stata, version 10.2 (StataCorp, College Station, Texas), for Windows XP. Propensity-score matching was done by using the Matching package for R. Role of the Funding Source This study received no funding. The authors had full access to all data in the study and had final responsibility for the decision to submit for publication. Results The UNOS database included data for 33252 patients registered on a waiting list for lung transplantation in the United States during the study period; 18333 (55.1%) had lung transplantation. Of these, 3411 (18.6%) had received a diagnosis of IPF at the time of transplantation. We excluded 11 patients who received grafts from nonheart-beating donors, 25 patients who were younger than 18 years at the time of transplantation, and 48 patients whose survival time was unknown. The final analysis included the remaining 3327 patients who had lung transplantation in 88 U.S. centers (median, 120 lung transplantations per center [25th to 75th percentile, 22 to 323 transplantations per center]). The number of patients who had lung transplantation for IPF increased over time, from 59 in 1992 to 409 in 2008; 2146 (64.5%) had single-lung transplantation and 1181 (35.5%) had bilateral lung transplantation. The proportion of patients who had bilateral lung transplantation also increased over time, from 6 of 59 total procedures (10.2%) in 1992 to 223 of 409 procedures (54.5%) in 2008 (Appendix Figure 1). Appendix Figure 2 shows the proportion of bilateral lung transplantation by transplant-ation center volumes for IPF and all indications and suggests that high-volume centers were more likely than low-volume centers to perform bilateral lung transplantation. Appendix Figure 1. Rates of single and bilateral lung transplantation over time in patients with idiopathic pulmonary fibrosis. Data are from the United

Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status.

SummaryThe standard antitubercular regimen currently includes a combination of 3 antitubercular agents: isoniazid, rifampicin (rifampin) and pyrazinamide. Administration of a fourth agent, ethambutol, is recommended when isoniazid resistance is suspected. Two of these 4 agents (isoniazid and pyrazinamide) are major hepatotoxins. The remaining 2 agents (rifampicin and ethambutol) are rarely or not hepatotoxic. However, rifampicin, which is a powerful enzyme inducer, may enhance the hepatotoxicity of isoniazid.In patients receiving a combination of isoniazid, rifampicin and pyrazinamide, 2 patterns of fulminant liver injury can be observed. The first pattern is characterised by an increase in serum transaminase activity that occurs soon (usually within the first 15 days) after initiation of treatment. This pattern is likely to be caused by rifampicin-induced isoniazid hepatotoxicity. The prognosis is good in most cases. The second pattern is characterised by an increase in serum ransaminase activity that occurs late (usually more than 1 month) after the initiation of treatment. It has been suggested that this pattern may be related to pyrazinamide hepatotoxicity. The prognosis of this type of hepatitis is generally poor.In order to reduce the risk of severe hepatic adverse effects during antitubercular treatment, several measures are proposed. First, patients with underlying liver test abnormalities should not be given pyrazinamide. Second, isoniazid and pyrazinamide should be administered at the lowest dosage within their respective therapeutic ranges. Third, serum transaminase levels should be determined twice weekly during the first 2 weeks of treatment, every 2 weeks during the rest of the first 2 months, and every month thereafter. When serum transaminase levels increase to greater than 3 times the upper limit of normal, therapy with isoniazid, rifampicin and pyrazinamide should be stopped.After serum transaminase levels have returned to normal, isoniazid can be re-introduced at a low daily dose, without rifampicin. Pyrazinamide may not be re-introduced because of the risk of recurrence and the poor prognosis of pyrazinamide-induced hepatitis. Although it is nephrotoxic, streptomycin is an alternative in patients with liver test abnormalities during antitubercular treatment.

Preventive effect of inhaled nitric oxide and pentoxifylline on ischemia/reperfusion injury after lung transplantation.

Background. The preventive effect of inhaled nitric oxide (NO) and pentoxifylline (PTX) administered during reperfusion has been demonstrated on experimental models of lung ischemia/reperfusion (I/R) injury but this strategy is not validated in clinical lung transplantation. The aim of this study was to assess retrospectively the protective effect of inhaled NO and PTX after lung transplantation. Methods. Twenty-three consecutive patients who received inhaled NO (10 ppm) and PTX (NO-PTX group) at the time of reperfusion were compared retrospectively with (1) 23 consecutive patients transplanted just before the use of NO-PTX (control group 23); (2) 95 patients representing all the patients of the series who did not receive NO-PTX (control group 95), with respect to I/R injury related complications. In particular, the incidence of pulmonary reimplantation edema and early hemodynamic failure, the PaO2/FIO2 ratio as well as the duration of mechanical ventilation and the 2-month mortality rates were compared. Results. Reimplantation edema was observed in 6/23 patients (26%) in the NO-PTX group vs. 13/23 patients (56%) in the control group 23 (P =0.035) and 48/95 patients (50%) in the control group 95 (P =0.035). The worst PaO2/FIO2 ratio during the first three postoperative days was 240±102 mmHg in the NO-PTX group vs. 162±88 mmHg (P =0.01) and 176±107 mmHg (P =0.01) in the control group 23 and the control group 95, respectively. The duration of mechanical ventilation was 2.1±2.4 days in the NO-PTX group vs. 7±9 days in the control group 23 (P =0.02) and 6±7 days in the control group 95 (P =0.01). The 2-month mortality rate was 4.3% in the NO-PTX group vs. 26% (P =0.04) and 21% (P =0.07) in the control group 23 and the control group 95, respectively. Conclusions. The marked decrease in the incidence of allograft dysfunction compared with two historical control groups suggests that PTX and inhaled NO given before and throughout reperfusion are protective against I/R injury in the setting of clinical transplantation.

Pulmonary reimplantation response in single-lung transplantation

We studied the characteristics of the pulmonary reimplantation response (PRR) in single-lung transplantation (SLT), and detailed the occurrence, evolution, prognosis and risk factors of this complication. Forty single-lung transplant recipients were studied. Twenty four patients developed hypoxaemia and allograft infiltrates consistent with the PRR. In 40% of the cases hypoxaemia was severe, precluding weaning and requiring prolonged mechanical ventilation with high fractional inspiratory oxygen (FIO2). The mean duration of ventilation was 7 days (range 1-19 days). Clearing of the chest radiographs was progressive, with complete resolution between 6 and 21 days. In all cases, the pulmonary arterial wedge pressure was normal (6 +/- 2 mmHg) suggesting low pressure oedema. Sampling of the pulmonary oedema fluid revealed that the ratio of protein concentration in oedema fluid to that in serum exceeded 0.5. In patients with severe PRR (40% of cases) clinical, radiographic and haemodynamic abnormalities were identical to adult respiratory distress syndrome (ARDS), but the prognosis was more favourable with no death directly related to PRR in our patients. The mean duration of graft ischaemia of the oedematous grafts (241 +/- 103 min) was significantly longer than that of nonoedematous grafts (155 +/- 71 min). These date suggest that prolongation of graft ischaemia increased the incidence of PRR.

Swallowing disorders, pneumonia and respiratory tract infectious disease in the elderly

Swallowing disorders (or dysphagia) are common in the elderly and their prevalence is often underestimated. They may result in serious complications including dehydration, malnutrition, airway obstruction, aspiration pneumonia (infectious process) or pneumonitis (chemical injury caused by the inhalation of sterile gastric contents). Moreover the repercussions of dysphagia are not only physical but also emotional and social, leading to depression, altered quality of life, and social isolation. While some changes in swallowing may be a natural result of aging, dysphagia in the elderly is mainly due to central nervous system diseases such as stroke, parkinsonism, dementia, medications, local oral and oesophageal factors. To be effective, management requires a multidisciplinary team approach and a careful assessment of the patients oropharyngeal anatomy and physiology, medical and nutritional status, cognition, language and behaviour. Clinical evaluation can be completed by a videofluoroscopic study which enables observation of bolus movement and movements of the oral cavity, pharynx and larynx throughout the swallow. The treatment depends on the underlying cause, extent of dysphagia and prognosis. Various categories of treatment are available, including compensatory strategies (postural changes and dietary modification), direct or indirect therapy techniques (swallow manoeuvres, medication and surgical procedures).

Morbidity and mortality related to the native lung in single lung transplantation for emphysema

It has been advocated that a major drawback of single lung transplantation (SLT) is the risk of serious complications arising from the native lung. The morbidity and mortality related to the native lung in 46 patients who underwent SLT for pulmonary emphysema in Clichy from 1988 to 1997 were reviewed retrospectively. In particular, infectious complications and native lung hyperinflation were searched. Complications arising from the native lung are not unusual after SLT for subjects with emphysema, and it was concluded they are not responsible for a substantial mortality.

Real-life use of inhaled corticosteroids in COPD patients versus the GOLD proposals: a paradigm shift in GOLD 2011?

To the Editor: Clinical trials in chronic obstructive pulmonary disease (COPD) patients have shown that the long-term use of inhaled corticosteroids (ICS) in COPD patients reduced the number of exacerbations per patient per year and improved health status [1]. Early studies have suggested increased ICS efficacy in patients with low lung function and frequent exacerbations [2]. The efficacy was reinforced when ICS was used in conjunction with long-acting β2-agonists (LABA) [3]. In most countries, health authorities approved ICS/LABA combinations in COPD patients with severe airflow impairment and frequent exacerbations, as also recommended in the Global Initiative for Obstructive Lung Disease (GOLD) 2007 document [4]. However, several surveys found poor adherence to this proposal among primary care physicians and pulmonologists in “real life”, ICS being often prescribed at a milder stage of the disease. The GOLD 2011 document proposed a new multidimensional system for the assessment and management of patients with COPD [5]. This system classifies COPD patients into four categories (A, B, C and D) based on the level of symptoms (dyspnoea or global clinical impact) and the risk of future exacerbations, as assessed using the severity of airflow limitation and the past history …

Neural Mechanisms Underlying Breathing Complexity

Breathing is maintained and controlled by a network of automatic neurons in the brainstem that generate respiratory rhythm and receive regulatory inputs. Breathing complexity therefore arises from respiratory central pattern generators modulated by peripheral and supra-spinal inputs. Very little is known on the brainstem neural substrates underlying breathing complexity in humans. We used both experimental and theoretical approaches to decipher these mechanisms in healthy humans and patients with chronic obstructive pulmonary disease (COPD). COPD is the most frequent chronic lung disease in the general population mainly due to tobacco smoke. In patients, airflow obstruction associated with hyperinflation and respiratory muscles weakness are key factors contributing to load-capacity imbalance and hence increased respiratory drive. Unexpectedly, we found that the patients breathed with a higher level of complexity during inspiration and expiration than controls. Using functional magnetic resonance imaging (fMRI), we scanned the brain of the participants to analyze the activity of two small regions involved in respiratory rhythmogenesis, the rostral ventro-lateral (VL) medulla (pre-Bötzinger complex) and the caudal VL pons (parafacial group). fMRI revealed in controls higher activity of the VL medulla suggesting active inspiration, while in patients higher activity of the VL pons suggesting active expiration. COPD patients reactivate the parafacial to sustain ventilation. These findings may be involved in the onset of respiratory failure when the neural network becomes overwhelmed by respiratory overload We show that central neural activity correlates with airflow complexity in healthy subjects and COPD patients, at rest and during inspiratory loading. We finally used a theoretical approach of respiratory rhythmogenesis that reproduces the kernel activity of neurons involved in the automatic breathing. The model reveals how a chaotic activity in neurons can contribute to chaos in airflow and reproduces key experimental fMRI findings.

Relationship between blood eosinophils, clinical characteristics, and mortality in patients with COPD

In patients with COPD, there is controversy regarding the association of blood eosinophil (Eos) levels with 1) exacerbation frequency and 2) the effect of inhaled corticosteroids for prevention of exacerbations. To determine whether Eos define subgroups of patients exhibiting attributes of COPD clinical phenotypes, we compared clinical features and mortality rates in COPD patients from the Initiatives BPCO French cohort categorized using different thresholds of blood Eos levels. The following data were collected at inclusion: medical and smoking history, occupational exposures, dyspnea, cough and sputum production, exacerbations in the previous year, history of allergy and asthma, nasal symptoms, body mass index, St George Respiratory Questionnaire (SGRQ) total score, post-bronchodilator spirometry, comorbidities, and medications. Three-year survival between groups was compared using Kaplan–Meier analysis. Three sets of analyses were performed to compare patients with ≥2% versus <2%, ≥3% versus <3%, and ≥4% versus <4% Eos. Eos was available in 458 patients (mean age: 62 years, 72% male, mean forced expiratory volume in 1 second: 51% pred), including 235 patients with Eos ≥2% (49%), 149 with Eos ≥3% (33%), and 90 with Eos ≥4% (20%). For all cutoffs, there was no difference between Eos+ and Eos− groups in univariate analyses except for diabetes and SGRQ score (more frequent and more impaired, respectively, in lower Eos categories). In particular, there was no difference in exacerbation rate, history of asthma, or three-year survival. In conclusion, regardless of the cutoff, Eos+ COPD patients exhibited no specific characteristic in terms of symptoms, lung function, exacerbation rate, and prognosis. These findings suggest that the association of higher Eos with exacerbations reported in previous studies could be population specific, which does not support generalizing the use of Eos as a biomarker for COPD phenotyping.

Impact of gender on COPD expression in a real-life cohort

Reports regarding gender-related differences in COPD expression have provided conflicting results. In the French Initiatives BPCO real-world cohort, which contained 688 patients (146 women) when data were extracted, women were matched with men (1:3 ratio: n = 107:275) on age (5-year intervals) and FEV1 (5% predicted intervals) and comparisons were performed using univariate logistic regressions. For a given age and level of airflow obstruction, women with COPD had higher BOD scores due to more pronounced dyspnea and lower BMI, suggesting worse prognosis, and were more likely to exhibit anxiety, suggesting the need for specific assessment and care.