# Increased delay to lung transplantation for women candidates: gender-based disparity matters in the lung transplant trajectory

Adrien Tissot, Anne-Sophie Coatanea, Olivia Rousseau, Antoine Roux, Benjamin Coiffard, Xavier Demant, Benjamin Renaud-Picard, Jérôme Le Pavec, Antoine Magnan, Jean-françois Mornex, et al.

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## To cite this version:

Adrien Tissot, Anne-Sophie Coatanea, Olivia Rousseau, Antoine Roux, Benjamin Coiffard, et al. Increased delay to lung transplantation for women candidates: gender-based disparity matters in the lung transplant trajectory. ERJ Open Research, 2025, pp.00623-2024. 10.1183/23120541.00623-2024. inserm-04880240

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https://inserm.hal.science/inserm-04880240v1

Submitted on 10 Jan 2025

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Original Research Article

**Increased delay to lung transplantation for
women candidates: gender-based disparity
matters in the lung transplant trajectory**

Adrien Tissot, Anne-Sophie Coatanea, Olivia Rousseau, Antoine Roux, Benjamin Coiffard, Xavier Demant, Benjamin Renaud-Picard, Jérôme Le Pavec, Antoine Magnan, Jean-François Mornex, Thomas Villeneuve, Loïc Falque, Mathilde Salpin, Véronique Boussaud, Christiane Knoop, Martine Reynaud-Gaubert, Romain Kessler, Gaëlle Dauriat, David Lair, Aurore Foureau, François-Xavier Blanc, Mathilde Karakachoff, Patricia Lemarchand,

Please cite this article as: Tissot A, Coatanea A-S, Rousseau O, et al. Increased delay to lung transplantation for women candidates: gender-based disparity matters in the lung transplant trajectory. *ERJ Open Res* 2025; in press (https://doi.org/10.1183/23120541.00623-2024).

This manuscript has recently been accepted for publication in the *ERJ Open Research*. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online.

Copyright ©The authors 2025. This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.
Word count abstract: 244

Word count manuscript: 2970

Increased delay to lung transplantation for women candidates:
gender-based disparity matters in the lung transplant trajectory

Adrien Tissot, MD¹, Anne-Sophie Coatanea, MD², Olivia Rousseau, MSc³, Antoine Roux, MD ⁴,⁵, Benjamin Coiffard, MD⁶, Xavier Demant, MD⁷, Benjamin Renaud-Picard, MD⁸, Jérôme Le Pavec, MD⁹, Antoine Magnan, MD⁴, Jean-François Mornex, MD¹⁰, Thomas Villeneuve MD¹¹, Loïc Falque, MD¹², Mathilde Salpin, MD⁵,¹³, Véronique Boussaud, MD¹⁴, Christiane Knoop, MD¹⁵, Martine Reynaud-Gaubert, MD⁶, Romain Kessler, MD⁸, Gaëlle Dauriat, MD⁹, David Lair, PhD¹, Aurore Foureau, MSc ¹, François-Xavier Blanc, MD¹⁶, Mathilde Karakachoff, Msc³, Patricia Lemarchand, MD¹⁶ and the COLT consortium*

## Affiliations

¹ Nantes Université, CHU Nantes, INSERM, Service de Pneumologie, l'institut du thorax, Center for Research in Transplantation and Translational Immunology, UMR 1064, F-44000 Nantes, France

² Nantes Université, CHU Nantes, Service de Pneumologie, l'institut du thorax, F-44000 Nantes, France

³ Nantes Université, CHU Nantes, Pôle Hospitalo-Universitaire 11 : Santé Publique, Clinique des données, INSERM, CIC 1413, F-44000 Nantes, France

⁴ Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department, Hôpital Foch, Suresnes, Université de Versailles Saint Quentin Paris-Saclay, INRAE UMR 0892, France

⁵ Paris Transplant Group, Paris, France
⁶ Aix Marseille Univ, Department of Respiratory Medicine and Lung Transplantation, APHM, Hôpital Nord, Marseille, France

⁷ Service de Pneumologie, Centre Hospitalier Universitaire de Bordeaux, Pessac, France

⁸ Service de pneumologie, Hôpitaux universitaires de Strasbourg, Strasbourg, France

⁹ Service de Pneumologie et Transplantation Pulmonaire, Groupe hospitalier Marie-Lannelongue -Saint Joseph, Le Plessis-Robinson, Université Paris-Saclay, Le Kremlin Bicêtre, UMR_S 999, Université Paris-Sud, INSERM France

¹⁰ Université de Lyon, université Lyon 1, PSL, EPHE, INRAE, IVPC, hospices civils de Lyon, groupement hospitalier est, service de pneumologie, orphalung, RESPIFIL Lyon, France

¹¹ Service de Pneumologie, Centre de compétence des maladies pulmonaires rares Hôpital Larrey CHU Toulouse, Toulouse, France, France

¹² Service Hospitalier Universitaire de Pneumologie et Physiologie, Pôle Thorax et Vaisseaux, CHU Grenoble Alpes, France

¹³ APHP Nord-Université Paris Cité, Hôpital Bichat, Service de Pneumologie B et Transplantation Pulmonaire, Université Paris Cité, PHERE UMRS 1152, F-75018, Paris, France

¹⁴ Service de Pneumologie, Hôpital Cochin, F-75679 Paris, France

¹⁵ CHU Erasme, Department of Chest Medicine, Route de Lennik 808, B-1070 Bruxelles, Belgium

¹⁶ Nantes Université, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000 Nantes, France
* the COLT consortium composition

Elodie Blanchard1; Xavier Demant1; Virginie Hulo1; Maria Ruiz-Patino2; Maarten Vander Kuylen2; Youri Sokolow2; Constantin Stefanidis2; Isabelle Huybrechts2; Laurent Perrin2; Fabio Taccone2; Isabelle Etienne2; Christiane Knoop2; Anna Roussoulières2; Maya Hites2; Agnes Lambert2; Axelle Hemelsoet2; Pierrick Bedouch3; Amandine Briault3; Loic Falque3; Quentin Perrier3; Christel Saint Raymond3; Samarmar Chacaroun3; Yoann Gioria3; Joane Quentin3; Renaud Grima4; Gabrielle Drevet4; Jean-Michel Maury4; François Tronc4; Philippe Portan4; Jean-François Mornex4; Claire Merveilleux Du Vignaud4; Eva Chatron4; Jean Charles Glérant4; Ségolène Turquier4; Salim Si Mohamed4; Vincent Cottin4; Lara Chalabresse4; Chantal Dubois4; Aurélie Rea4; Médéric Reignier4; Julia Canterini4; Nicolas Carlier5; Véronique Boussaud5; Romain Guillemain5; Xavier-Benoit D'Journo6; Pascale-Alexandre Thomas6; Delphine Trousse6; Geoffrey Brioude6; David Boulate6; Alex Fourdrain6; Fabienne Bregeon6; Stéphane Delliaux6; Martine Reynaud-Gaubert6; Bérengère Coltey6; Nadine Dufeu6; Benjamin Coiffard6; Julien Bermudez6; Ana Nieves6; Hervé Dutau6; Julie Tronchetti6; Jean-Yves Gaubert6; Paul Habert6; Mathieu Di Biscéglie6; Agnes Basire6; Pascal Pedini6; Florence Daviet6; Christophe Guervilly6; Sami Hraiech6; Jean Marie Forel6; Louis Delamarre6; Aude Charvet6; Ines Gragueb-Chatti6; Pierre Mora6; Daniel Laurent6; Sophie Giusiano6; Jean-Philippe Dales6; Mélanie Gaubert6; Marc Laine6; Philippe Lacoste7; Christian Perigaud7; Jean-Christian Roussel7; Thomas Senage7; Antoine Mugnot7; Isabelle Danner7; Adrien Tissot7; Charlotte Bry7; Morgane Penhouet7; Emmanuelle Eschapasse7; Delphine Horeau-Langlard7; François-Xavier Blanc7; Thierry Lepoivre7; Mickael Vourch7; Sophie Brouard7; Richard Danger7; Megguy Bernard7; Elodie Godard7; Régine Valéro7; Karine Maugendre7; Eugénie Durand7; Nataliya Yeremenko7; Aurore Foureau7; David Lair7; Géraldine Gallot7; Mathilde Berthome7; Jérôme Le Pavec8; Gaëlle Dauriat8; Pauline Pradere8; Séverine Feuillet8; Samuel Dolidon8; Chahine Medraoui8; Pierre Gazengel8; Adrian Crutu8; Amir Hanna8; Elie Fabre9; Olaf Mercier9; Delphine Mitilian9; Justin Issard9; Dominique Fabre9; Yves Castier10; Pierre Mordant10; Pierre Cerceau10; Antoine Girault10; Arnaud Roussel10; Enora Atchade-Thierry10; Sylvain Jean-Baptiste10; Sandrine Boudinet10; Sébastien Tanaka10; Aurélie Gouel10; Philippe Montravers10; Nathalie Zappella10; Aurélie Snauwaert10; Parvine Tashk10; Brice Lortat-Jacob10; Tiphaine Goletto10; Domitille Mouren10; Lise Morer10; Mathilde Salpin10; Hervé Mal10; Armelle Marceau10; Gaëlle Weisenburger10; Vincent Bunel10; Adèle Sandot10; Kinan El Husseini10; Pierre Halitim10; Lucie Genet10; Sabrina Trigueiros10; Alice Savary10; Hakima Rabia10; Pierre-Emmanuel Falcoz11; Anne Olland11; Charlotte Ponte11; Charles Tacquard11; Garib Ajob11; Olivier Collange11; Antoine Pons11; Xavier Delabranche11; Olivier Helms11; Anne Roche11; Benjamin Renaud-Picard11; Romain Kessler11; Tristan Degot11; Sandrine Hirschi11; Armelle Schuller11; Anne Dory11; Florence Toti11; Nadia Benkirane-Jessel11; Laurence Kessler11; Julien Stauder11; Edouard Sage12; Francois Parquin12; Sandra De Miranda12; Clément Picard12; Antoine Roux12; Olivier Brugière12; Béatrice D'Urso12; Marc Stern12; Akounach Mbarka12; Antoine Magnan12; Quentin Marquant12; Isabelle Schwartz12; Helene Salvator12; Tiffany Pascreau12; Thomas Villeneuve13; Marion Dupuis13; Marlène Murris-Espin13; Pierre Rabinel13; Laurent
Brouchet13 ; Laure Crognier13 ; Olivier Mathe13 ; Frédérique Legenne13 ; Myriam Barthes13 ; Blandine Vilquin13 ; Anne-Laure Costes13 ; Isabelle Recoche13 ; Anne Bergeron15 ; Gregory Berra15 ; Angela Koutsokera15 ;

1 Service de Pneumologie, Centre Hospitalier Universitaire de Bordeaux, Pessac, France,

2 Département médico-chirurgical des pathologies thoraciques, Hôpital Universitaire de Bruxelles, Bruxelles, Belgium

3 Service Hospitalier Universitaire de Pneumologie et Physiologie, CHU Grenoble Alpes, Pôle Thorax et Vaisseaux, Grenoble, France

4 Université Claude Bernard Lyon 1, EPHE, INRAE, IVPC, Lyon F-69007, Hospices civils de Lyon, Lyon F-69007, Inserm, Hospices civils de Lyon, CIC1407, Lyon F-69007

5 APHP, Service de Pneumologie, Hôpital Cochin, Paris, France

6 APHM, Department of Respiratory Medicine and Lung Transplantation, Hôpital Nord, Marseille, France ; Aix Marseille Université, France

7 Nantes Université, CHU Nantes, INSERM, Service de Pneumologie, l'institut du thorax, Center for Research in Transplantation and Translational Immunology (CR2TI), UMR 1064, Nantes, France

8 Service de Pneumologie et Transplantation Pulmonaire, Groupe hospitalier Marie-Lannelongue -Saint Joseph, Le Plessis-Robinson, Université Paris-Saclay, Le Kremlin Bicêtre, UMR_S 999, Université Paris-Sud, INSERM France

9 Service de Chirurgie thoracique et Transplantation Pulmonaire, Groupe hospitalier Marie-Lannelongue -Saint Joseph, Le Plessis-Robinson, Université Paris-Saclay, Le Kremlin Bicêtre, UMR_S 999, Université Paris-Sud, INSERM France

10 APHP Nord-Université Paris Cité, Hôpital Bichat, Service de Pneumologie B et Transplantation Pulmonaire, Université Paris Cité, PHERE UMRS 1152, Paris, France

11 Department of Respiratory Medicine and Strasbourg Lung Transplant Program, Hôpitaux Universitaires de Strasbourg, Strasbourg, France ; Université de Strasbourg, Inserm UMR 1260, Strasbourg, France

12 Pneumology, Adult Cystic Fibrosis Center and Lung Transplantation Department Hôpital Foch, Suresnes, Université de Versailles Saint Quentin Paris-Saclay, INRAe UMR 0892, Paris Transplant Group, Paris, France

13 CHU Toulouse, Service de Pneumologie, Université Toulouse III-Paul Sabatier, Toulouse, France

14 Service de Pneumologie, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1211 Genève
**Corresponding author**

Adrien Tissot, adrien.tissot@chu-nantes.fr

Service de Pneumologie, CHU de Nantes, 44093 Nantes Cedex

N° ORCID : 0000-0002-3259-6430

**Trial registration**

ClinicalTrials.gov NCT00980967
**Author Contribution**

A. Tissot had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Tissot, Lemarchand, Coatanea, Rousseau, Blanc and Karakachoff

Acquisition, analysis, and interpretation of data: Coatanea, Tissot, Lair, Roux, Coiffard, Demant, Renaud-Picard, Le Pavec, Magnan, Mornex, Villeneuve, Falque, Salpin, Boussaud, Knoop, Reynaud-Gaubert, Kessler, Dauriat and Foureau

Drafting of the manuscript: Rousseau, Lemarchand and Tissot.

Critical revision of the manuscript for important intellectual content: Lemarchand, Karakachoff, Blanc.

Statistical analysis: Rousseau and Karakachoff

Study supervision: Lemarchand, Blanc and Tissot

**Disclosure:** All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare no financial relationships with any organization that might have had an interest in the submitted work in the previous three years or no other relationships or activities that could appear to have influenced the submitted work.

**Funding:** Cohort in Lung Transplantation was funded by Vaincre La Mucoviscidose and l'Association Grégory Lemarchal, the French Research Ministry (Agence Nationale de la Recherche grant), the French Government (Programme Hospitalier de Recherche Clinique - DGOS 20-11), the European Union (FP7 collaborative project
HEALTH.2012.2.1.2-1 grant agreement number: 305457), Nantes Metropole, and the
Institut de Recherche en Santé Respiratoire des Pays de Loire. The study sponsor or
funder had no role in the study design; collection, analysis, and interpretation of data;
writing of the report; and decision to submit the article for publication. Researchers
were independent from funders, and all authors, external and internal, had full access
to all of the data (including statistical reports and tables) in the study and can take
responsibility for the integrity of the data and the accuracy of the data analysis.
ACR: acute cellular rejection

BMI: body mass index

BOS: bronchiolitis obliterans syndrome

CF: cystic fibrosis

CI: confidence interval

CLAD: chronic lung allograft dysfunction

CMV: cytomegalovirus

COLT: cohort in lung transplantation

COPD: chronic obstructive pulmonary disease

D: Donor

DLCO: diffusing capacity for carbon monoxide

DSA: donor-specific antibodies

EBV: Epstein-Barr virus

ILD: interstitial lung disease

FEV1: forced expiratory volume in one second;

FVC: forced vital capacity

HBP: high blood pressure

HLA: human leukocyte antigen

HR: hazard ratio

ILD: interstitial lung disease

IPF: idiopathic pulmonary fibrosis

IQR: interquartile range

LT: lung transplantation

PAH: pulmonary arterial hypertension

PFTs: pulmonary function tests

PGD: primary graft dysfunction

pTLC: predicted total lung capacity
R: Recipient

RAS: restrictive allograft syndrome

TLC: total lung capacity
**Abstract**

**Background**

Lung transplantation (LT) is a highly dynamic segment of solid organ transplantation in which gender plays a central role. Our objective was to investigate the causes of outcome differences between women and men all along the LT pathway.

**Methods**

We used data from the COhort in Lung Transplantation (COLT) study (12 participating LT centers). Analyses were performed in three phases: baseline clinical characteristics, peri-transplantation period, and post-transplantation follow-up.

**Results**

Overall, 1710 participants (802 women and 908 men) were included in this study. Women were less likely than men to undergo transplantation (91.6% vs. 95.6%, p=0.001) and waited longer before transplantation (115 vs. 73 days, p<0.001). Female gender and pre-transplant class I anti-HLA antibodies were identified as independent factors associated with longer waiting time duration. Female LT recipients commonly received lungs from height- and sex-matched donors, despite higher female waiting-list mortality and a higher proportion of male donors. Importantly, women with oversized lung transplantation (defined by predicted TLC ratio and weight mismatch) did not have worse survival. The overall post-transplant survival of female recipients was significantly higher than that of male recipients (65.6% vs 57.3%, p<0.001), although the prevalence of specific major LT outcomes did not differ according to gender.

**Conclusion**

Women waited longer and were less likely to undergo transplant. Women transplanted with an oversized lung did not have worse survival after transplantation, suggesting that size matching criteria based on pTLC ratio and weight mismatch may be less stringent in this context.
Introduction

The number of lung transplantations performed each year has almost constantly risen
since the 1990's, and to date nearly 70,000 adult procedures have been reported
worldwide ¹. The field of lung transplantation has made significant advances over the
last decades with improvement of donor lung utilization and allocation ²⁻⁵, surgical
techniques and intensive care management ⁶. It is the fastest growing segment of
organ transplant, but despite those favorable trends, lung transplantation remains
fraught with a high mortality risk and morbidity ⁷. Understanding factors associated to
the natural history of lung transplantation, from waiting list to short- and long-term
survival, is important for predicting and potentially improving outcomes.

Gender as a critical intrinsic and extrinsic factor plays a pivotal role in the field of
transplantation ⁸. Recent studies have pointed out gender differences and disparities
all along the transplantation path, from the access to the waiting list to post-
transplantation outcomes ⁹. Lung transplantation data from the United States of
America demonstrated that women had a lower chance of being transplanted than men
(83.9% vs. 88.7%) and that women waited longer before transplant ¹⁰,¹¹. As for survival
after lung transplantation, there seems to be an advantage for female recipients which
has not been fully explained ¹²,¹³. These studies have mostly been performed using
the United Network of Organ Sharing (UNOS) registry and more studies from different
countries in other regions of the world are needed to confirm their results. Furthermore,
no study has attempted to specifically evaluate the potential differences between men
and women both before and after transplantation in the same cohort, and to investigate
the potential causes for these differences.

We performed a retrospective study of French participants extracted from the Cohort
in lung transplantation (COLT) database, in order to carry out a comparative analysis
between women and men at three different periods of the lung transplantation process:
waiting list, lung transplantation itself, and post-transplantation periods.
# Materials and Methods

## Patients

Patients were selected among those enrolled in COLT (NCT00980967) ¹⁴. COLT cohort was a prospective study that included French patients between September 2009 and December 2018. The ethics committee (Comité de Protection des Personnes Ouest 1-Tours, 2009-A00036-51) approved the study and all participants provided written informed consent. To obtain a complete donor data set, we selected patients who were also included in the French Biomedical Agency database ¹⁵. Consequently, patients on the transplant waiting list of 12 French COLT partner centers were included. Patients with previous history of lung transplantation were excluded. This study complied with the International Society for Heart and Lung Transplantation statement on Transplant Ethics.

## Collected data

Patients were enrolled at the time of registration on the waiting list before lung transplantation and then followed up to 10-year post-transplant. Clinical data were collected from a dedicated database approved by the Commission Nationale Informatique et Libertés (CNIL, Authorization number: 911142). Collected data included baseline characteristics such as demographics, medical history, pulmonary function tests (PFTs), transplantation data (surgery, per-and post-operative complications), and follow-up outcomes (rejections, infections, treatment, and PFT results). Gender was self-reported. The 6 minute walking test was performed according to ATS guidelines¹⁶. The following classifications were used to describe the underlying diseases: cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD)/emphysema, pulmonary arterial hypertension (PAH), interstitial lung disease
(ILD) (including idiopathic pulmonary fibrosis (IPF)), and other (including scleroderma, sarcoidosis, lymphangioleiomyomatosis, and other connective tissue diseases).

Chronic lung allograft dysfunction (CLAD) phenotype was assessed for every patient at 3 and 5-years post-transplantation or at death/retransplantation by an adjudication committee. Classification was initially made according to the proposition of Verleden et al. and updated from the 2019 ISHLT consensus report¹⁷,¹⁸.

The French lung allocation policy is detailed in Supplemental 1. The choice of a lung donor and the matching with a recipient, including lung volume matching, was the responsibility of the local lung transplantation team with no written common policy. Weight mismatch was calculated as (donor weight – recipient weight). For the donor-to-recipient predicted total lung capacity (pTLC) ratio, we used donor and recipient pTLCs calculated according to the Global Lung Function Initiative references values ¹⁹,²⁰. To address the non-linear association between pTLC ratio and overall survival, a spline was used to separate transplanted individuals into 3 relevant categories (supplemental figure 3) ²¹.

## Statistical analysis

Analysis were performed in three phases according to transplantation process. The first set of results analyzed the socio-demographic, medical history, and baseline clinical characteristics. The second one analyzed peri-transplantation period variables, including recipient-donor and mismatch characteristics. The third set of analyses involved the post-transplantation follow-up and graft rejection features.

The characteristics of women and men included in the study were expressed as numbers, medians, and proportions, according to the type of variable. Continuous variables were reported as mean [± SD] or median [± IQR], as indicated in tables, and comparisons between groups were computed using Student's t test in case of variables normally distributed and Wilcoxon's test otherwise. Categorical variables were
reported as counts and percentages, comparisons were computed through Pearson χ²
test or Fisher test. Censored time-dependent variables, including living status, delay to
transplantation, CLAD occurrence, high-emergency transplantation, and related time-
to-event curves, were analyzed using the Kaplan-Meier method. Log-rank tests were
used to compare curves between genders, weight mismatch, gender-related
mismatch, age class, and other relevant groups.

Survival curve adjustment and the influence of predictor variables were investigated using Cox proportional hazards regression models after validation of the proportional hazard assumption. Hazard ratios, 95% confidence intervals, and p-values were computed at univariable, gender-adjusted and multivariable levels. In gender-adjusted analysis, p-values were corrected following the Benjamini-Hochberg method. Variables presenting a p-value < 0.2 in the univariable analysis were selected to perform a multivariable model using a stepwise forward variable selection with Akaike information criterion threshold.

Missing values were reported for each variable if applicable and were not included when performing comparison tests. No imputation was applied to missing data, excepted for medical history variables, considered as “not having the disease”, when missing. A p < 0.05 was considered as statistically significant. All analyses were performed using R, version 4.0.4.

## Results

### Pre-transplant characteristics

A total number of 1710 patients were included in the present study, in which 802 were women (47%) and 908 were men (53%) (Figure 1). In both genders, the main underlying disease was COPD/emphysema, followed by CF and ILD (Figure 2). At the time of registration on lung transplant waiting list, women were younger (47 vs 54 years; p<0.001) (Table 1) and displayed fewer comorbidities than men, including
ischemic heart disease (2.7 vs 6.8%, p<0.001) and cardiovascular risk factors (dyslipidemia, high blood pressure, and smoking history) (Table 1). Mean height and weight were higher in men (67 vs. 53 kg, p<0.001 and 173 vs. 160 cm, p<0.001). Pre-transplant anti-HLA antibodies were more prevalent in women than in men (46 vs. 26%, p<0.001) for both class I and II. Regarding respiratory failure severity, women were less likely to be on long-term oxygen therapy (81 vs 86%; p=0.03) and performed a slightly higher predicted distance in the 6-minute walk test (45 vs. 43% of predicted, p=0.03). PFTs according to underlying disease are shown in Supplemental table 1.

## Peri-transplantation phase

Lung transplantation was less often performed in women (735/802, 91.7%) than in men (868/908, 95.6%, p=0.001). Reasons for removal from waiting list were not significantly different according to gender (Supplemental table 2). Time duration on waiting list before lung transplantation differed markedly in women and men: women waited significantly longer before transplantation, with a median of 115 days (34-295) versus 73 days (28-184 for men (p<0.001) (Table II and Figure 3A). As for the procedure itself, women had less single lung transplantation (9.4 vs. 15.8%; p<0.001) but more volume reduction than men (16.6% vs 7.8%; p<0.001) (Table II). We observed on univariable analysis that gender, age, height, underlying disease, positive anti-HLA antibodies pre-transplant, specific listing on the high emergency program, smoking history, CMV positive serology and the 6-minute walk test performance had a significant impact on waiting time duration before transplantation (Supplemental table 3). Independent factors associated with a shorter waiting time duration before transplantation, identified in multivariable analysis, were the followings: male gender, age and listing on the high emergency lung transplantation program. In contrast, the number of pre-transplant class I anti-HLA antibodies was associated with an increased waiting time duration
before transplantation, together with underlying diagnosis of COPD and other
underlying diseases (Figure 3C and Supplemental table 4).

Donor clinical characteristics are presented in Supplemental table 5. A minority of
recipients underwent gender-mismatched transplants, and women were more
frequently transplanted with a male donor than men with a female donor (38 vs. 27.9%;
p <0.001, Table II). More women than men had a high donor-to-recipient predicted TLC
ratio (pTLC ratio > 1.41: 10.1 vs. 0.1%, p<0.001). Additionally, more transplantations
with lungs from a donor weighing more than 15 kg than the recipient were performed
in women than in men (41.2% in women vs. 30.6% in men, p<0.001). Similar findings
were also observed using height and body surface area (data not shown). In summary,
women waited longer to get a lung transplantation and gender was an independent
factor associated with the waiting list duration time. Lung volume mismatch with donor
of larger stature than recipient was more frequently observed in women.

## Post-transplant outcomes

The median follow-up post-transplantation for the entire cohort was 5.7 [1.9;7.9] /*-
years. After lung transplantation, survival was higher in women than in men, with death
occurring in 34.4% female recipients and in 42.7% male recipients (p<0.001, Table III).
In female recipients, survival at 1 year, 3 years and 5-years post-transplantation was
83%, 73%, and 70%, whereas in male recipients, the figures were 79%, 69%, and
61%, respectively (Figure 4A). Main causes of death in both groups were infection and
graft failure, with no significant gender difference (Supplemental table 6). There was
no significant gender difference in CLAD prevalence (14.7% female and 15.7% male
recipients, p=0.9), and time to CLAD did not differ significantly between both genders
(Figure 4B, Table III). Women and men also exhibited similar rates of acute cellular
rejection (40.3 vs 39%, p=0.3) and antibody-mediated rejection (19.5 vs. 17.9%,
p=0.18). Finally, there was no difference in bacterial, fungal, or viral infection
occurrence, but cancer occurred more frequently after transplantation in men (12.3 vs. 8.7%, p=0.02) (Table III).

Univariable analysis identified multiple variables as significantly associated with post-transplantation survival, including gender, age, donor age, and pTLC ratio between donor and recipient (Supplemental table 7). Multivariable analysis identified that variables associated with a lower survival were the followings: male gender, single lung transplantation, heart and lung transplantation, volume reduction, history of ischemic heart disease, COPD, ILD, other underlying diseases, EBV mismatch, donor age and recipient age (Figure 4C, Supplemental table 8).

Regarding gender matching combinations between donors and recipients, survival was not significantly different according to donor gender, in contrast with recipient gender, with a higher survival in female recipients even in case of gender mismatch (p=0.01, Figure 5A). For the whole population, weight-negative mismatch (defined as donor weight - recipient weight ≤ -15 kg) had a negative impact on survival, whereas weight-positive mismatch (defined as donor weight - recipient weight ≥ 15 kg) did not impact survival (Figure 5B). Similar results were observed when separating female and male recipients (Supplemental figure 2). Survival rate according to pTLC ratio was similar between the 3 pTLC ratio categories as defined above (Figure 5C). To question a possible role of menopause on survival in female recipients, we analyzed survival according to age and did not find a statistical difference between female recipients ≤ 50 and > 50 years (p=0.4) (Figure 5D). Overall, stature mismatch with high pTLC ratio or lower recipient weight as compared to donor did not have consequence on survival. Finally, we performed a survival analysis between female and male recipients according to the underlying disease, showing a significant lower survival for male recipients with COPD. No difference in survival according to gender was observed for other underlying diseases (Supplemental figure 2).
Discussion

Our study identified striking differences between men and women along their lung
transplantation trajectory. Time duration on waiting list before transplantation was on
average 6 weeks longer for women, and fewer women were transplanted than men.
The multivariable analysis identified, among other factors, female gender as an
independent factor associated with a longer waiting time duration before
transplantation. After transplantation, female recipient survival was significantly higher
than that of male recipients, while the prevalence of specific lung transplantation
outcomes including PGD, CLAD, ACR, and infection, were not different according to
gender.

One strength of our study lies in the multicentric, nationwide nature of the cohort,
associating all existing centers in France and from a European setting which presents
differences with the north American context, notably in terms of recipient and donor
characteristics²²,²³. The specific reasons for which women waited longer before
transplantation are complex to decipher but beyond the already known role of HLA
sensitization, we hypothesized that lung volume played an important role for delayed
lung transplantation due to the lack of compatible donors. Gender disparities on lung
transplant waiting list have already been analyzed in previous studies. The most recent
and largest one also showed a longer median waiting list duration time for women²⁴,
and another study by Wille et al. showed that women were more likely than men to
worsen or die within 3 years of registering on the waiting list in the USA (16 vs 11%,
odds ratio = 1.58, p <0.001) and they were indeed less likely than men to be
transplanted (83.9% vs 88.7%, odds ratio = 0.63, p <0.001)¹⁰. Sell et al. also observed
that short stature was associated with a lower rate of lung transplantation and higher
rates of death and respiratory failure while awaiting transplantation, and that female
patients were being disproportionately affected by this disparity¹¹. A transplantation
with a lung volume mismatch may be more complex, and it has been shown that
transplantation with undersized lung (based on donor-recipient's height ratio) was associated with worse post-transplantation outcomes¹,²,¹,²,⁵⁻²⁷. Importantly, oversized transplanted lungs are not deleterious, except for candidates with ILD¹,²⁰,²¹.

We observed that despite the fact that donors were mostly men (56%), taller by 16 cms and heavier by 22 kgs as compared to the average height and weight of female recipients, a majority of recipients were size-matched to their donor and most transplants were performed with gender matching. However, when considering LT with lung volume mismatch, there were more female recipients than male transplanted with a pTLC ratio > 1.41, and in consequence more volume reduction in this group. Importantly, women overall who did receive an oversized lung did not have worse survival after transplantation than those who did not. Historically, size matching in France has relied upon height and sex only. This study may support a more widespread use of pTLC for size matching, which may be more accurate and may decrease the volume reduction number, as volume reduction was associated with reduced overall survival. As a result, it may possibly allow a higher proportion of female recipients to receive male donor transplants in a safe way and thus, addressing some of the gender inequalities on waiting list.

The other major known factor affecting waiting time duration before transplantation is pre-transplant HLA immunization. As pregnancy is an important trigger for immunization, anti-HLA antibodies are mostly found in women. Several studies have highlighted this issue²⁸,²⁹. Our work confirms these data and this result is a strength of our study, as in the study discussed above, in which gender was associated with longer waiting time, this variable was not specifically assessed¹¹,²⁴.

The main limitation of our study, besides the retrospective nature of the analysis, lies in the cohort size which is smaller as compared to UNOS-based studies on this topic. Furthermore, some items presented a high rate of missing data such as volume
reduction or the 6 minutes walking test data, and the unknown reason for waiting list
removal, which could not be retrieved.

Finally, increased late survival in female lung transplant recipients has been observed
in several studies with different cohorts¹,¹⁵,²⁷. However, the reason for poorer overall
survival in male recipients is equivocal and probably multifactorial. Indeed, men are
significantly older than women at the time of lung transplantation and have more
cardiovascular comorbidities. This is especially true for patients with COPD, in which
even without lung transplantation, differences in survival between men and women are
observed to the advantage of the latter³². This difference may also be partly related to
factors that could also be gender-related, including resumption of smoking after
transplantation, poorer compliance or risk-taking more frequently observed among
men than women³³. The fact that in our study gender difference in survival was only
significant in COPD recipients, the only behavioral disease of concern here, supports
this hypothesis. Another interesting result is that less women were listed for LT than
men, which raises the question of unequal access to LT program. However, although
women were younger, had less cardiovascular risk factors and were less frequently on
long term oxygen, we did not have information available to support the fact that listing
criteria differed in the way that marginal men candidates were accepted for listing
whereas women candidates were declined. Interestingly, we bring new evidence that
CLAD incidence does not seem to be influenced by gender. Finally, Bonner et al.
recently analyzed from UNOS data the intersection of race/ethnicity, gender and
primary diagnosis on 1-year mortality and adjusted 5-year survival, identifying a clear
impact of social factors²².

Conclusion

Women were less likely to be transplanted and waited significantly longer than men to
get a lung transplant and this longer duration for women may be related to shorter
stature and the presence of pre-transplant anti-HLA antibodies. This discrepancy was
observed despite a higher number of volume reduction, to overcome more frequent
oversizing in female recipients.
Acknowledgments

We thank the participating patients and their families whose trust, support, and cooperation were essential for collecting the data used in this study. We also thank all the participating centers (CHU de Nantes, Hospices Civils de Lyon, Assistance publique – Hôpitaux de Marseille, Hôpital Foch, Assistance publique - Hôpitaux de Paris - Hôpital Européen Georges Pompidou, CHU de Grenoble, CHRU de Strasbourg, CHU de Bordeaux, Assistance publique - Hôpitaux de Paris - Hôpital Bichat, Hôpital Marie Lannelongue and CHU de Toulouse) and the COLT Consortium for their organizational achievements. The authors thank the Centre de Ressources Biologiques du CHU De Nantes, the LUNG innOvatiOn (LUNG O2) cluster, and the GENDER cluster for their logistic support.
References

1. Chambers DC, Cherikh WS, Harhay MO, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult lung and heart-lung transplantation Report—2019; Focus theme: Donor and recipient size match. *J Heart Lung Transplant*. 2019;38(10):1042-1055.

2. Krutsinger D, Reed RM, Blevins A, et al. Lung transplantation from donation after cardiocirculatory death: a systematic review and meta-analysis. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant*. 2015;34(5):675-684.

3. Gottlieb J. Lung allocation. *J Thorac Dis*. 2017;9(8):2670-2674.

4. Cypel M, Yeung JC, Liu M, et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. *N Engl J Med*. 2011;364(15):1431-1440.

5. Sommer W, Kühn C, Tudorache I, et al. Extended criteria donor lungs and clinical outcome: results of an alternative allocation algorithm. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant*. 2013;32(11):1065-1072.

6. Fuehner T, Kuehn C, Hadem J, et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation. *Am J Respir Crit Care Med*. 2012;185(7):763-768.

7. Young KA, Dilling DF. The Future of Lung Transplantation. *Chest*. 2019;155(3):465-473.

8. Ge F, Huang T, Yuan S, Zhou Y, Gong W. Gender issues in solid organ donation and transplantation. *Ann Transplant*. 2013;18:508-514.

9. Melk A, Babitsch B, Borchert-Mörlins B, et al. Equally Interchangeable? How Sex and Gender Affect Transplantation. *Transplantation*. 2019;103(6):1094-1110.

10. Wille KM, Harrington KF, deAndrade JA, Vishin S, Oster RA, Kaslow RA. Disparities in lung transplantation before and after introduction of the lung allocation score. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant*. 2013;32(7):684-692.

11. Sell JL, Bacchetta M, Goldfarb SB, et al. Short Stature and Access to Lung Transplantation in the United States. A Cohort Study. *Am J Respir Crit Care Med*. 2016;193(6):681-688.

12. Chacon-Alberty L, Ye S, Daoud D, et al. Analysis of sex-based differences in clinical and molecular responses to ischemia reperfusion after lung transplantation. *Respir Res*. 2021;22(1):318.

13. Erp JMK van, Smits JM, Verplancke V, et al. Outcomes of Donor-Recipient Gender Mismatched Lung Transplantation in the Eurotransplant Area. *J Heart Lung Transplant*. 2019;38(4):S417.
14. Koutsokera A, Royer PJ, Antonietti JP, et al. Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation. *Front Med.* 2017;4:109.

15. Demande d'accès aux données individuelles issues des (&hellip;) - Agence de la biomédecine.

16. ATS Statement. Am J Respir Crit Care Med. 2002;166(1):111-117.

17. Verleden GM, Raghu G, Meyer KC, Glanville AR, Corris P. A new classification system for chronic lung allograft dysfunction. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant.* 2014;33(2):127-133.

18. Verleden GM, Glanville AR, Lease ED, et al. Chronic lung allograft dysfunction: Definition, diagnostic criteria, and approaches to treatment-A consensus report from the Pulmonary Council of the ISHLT. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant.* 2019;38(5):493-503.

19. Hall GL, Filipow N, Ruppel G, et al. Official ERS technical standard: Global Lung Function Initiative reference values for static lung volumes in individuals of European ancestry. *Eur Respir J.* 2021;57(3):2000289.

20. Riddell P, Ma J, Dunne B, et al. A simplified strategy for donor-recipient size-matching in lung transplant for interstitial lung disease. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant.* 2021;40(11):1422-1430.

21. Eberlein M, Reed RM, Maidaa M, et al. Donor-recipient size matching and survival after lung transplantation. A cohort study. *Ann Am Thorac Soc.* 2013;10(5):418-425.

22. Bonner SN, Thumma JR, Valbuena VSM, et al. The intersection of race and ethnicity, gender, and primary diagnosis on lung transplantation outcomes. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant.* 2023;42(7):985-992.

23. Chambers DC, Zuckermann A, Cherikh WS, et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: 37th adult lung transplantation report — 2020; focus on deceased donor characteristics. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant.* 2020;39(10):1016-1027.

24. Riley LE, Lascano J. Gender and racial disparities in lung transplantation in the United States. *J Heart Lung Transplant.* 2021;40(9):963-969.

25. Eberlein M, Reed RM, Bolukbas S, et al. Lung size mismatch and primary graft dysfunction after bilateral lung transplantation. *J Heart Lung Transplant Off Publ Int Soc Heart Transplant.* 2015;34(2):233-240.

26. Mason DP, Batizy LH, Wu J, et al. Matching donor to recipient in lung transplantation: How much does size matter? *J Thorac Cardiovasc Surg.* 2009;137(5):1234-1240.e1.

27. Eberlein M, Reed RM, Permutt S, et al. Parameters of donor-recipient size mismatch and survival after bilateral lung transplantation. *J Heart Lung Transplant.* 2012;31(11):1207-1213.e7.
28. Aversa M, Benvenuto L, Kim H, et al. Effect of Calculated Panel Reactive Antibody Value on Waitlist Outcomes for Lung Transplant Candidates. *Ann Transplant*. 2019;24:383-392.

29. Tague LK, Witt CA, Byers DE, et al. Association between Allosensitization and Waiting List Outcomes among Adult Lung Transplant Candidates in the United States. *Ann Am Thorac Soc*. 2019;16(7):846-852.

30. Agence de la biomédecine.

31. Loor G, Brown R, Kelly RF, et al. Gender differences in long-term survival post-transplant: A single-institution analysis in the lung allocation score era. *Clin Transplant*. 2017;31(3):e12889.

32. de Torres JP, Cote CG, López MV, et al. Sex differences in mortality in patients with COPD. *Eur Respir J*. 2009;33(3):528-535.

33. Courtenay WH. Constructions of masculinity and their influence on men's well-being: a theory of gender and health. *Soc Sci Med* 1982. 2000;50(10):1385-1401.
# Tables

<table><caption>Table I. Demographic and clinical characteristics in women and men listed for lung transplantation.</caption><thead><tr><th>Variables</th><th>Women (n = 802)</th><th>Men (n = 908)</th><th>p-value<sup>a</sup></th></tr></thead><tbody><tr><td>Age, years</td><td>47 [32 ; 57]</td><td>54 [39 ; 60]</td><td>&lt;0.001</td></tr><tr><td>Medical history</td><td></td><td></td><td></td></tr><tr><td>Ischemic heart disease</td><td>22 (2.7)</td><td>62 (6.8)</td><td>&lt;0.001</td></tr><tr><td>Dyslipidemia</td><td>36 (4.5)</td><td>64 (7.0)</td><td>0.032</td></tr><tr><td>High blood pressure</td><td>76 (9.5)</td><td>117 (12.9)</td><td>0.032</td></tr><tr><td>Diabetes</td><td>113 (14.1)</td><td>147 (16.2)</td><td>0.25</td></tr><tr><td>Heart failure</td><td>9 (1.1)</td><td>12 (1.3)</td><td>0.88</td></tr><tr><td>PH group III</td><td>89 (11.1)</td><td>105 (11.6)</td><td>0.82</td></tr><tr><td>Kidney failure</td><td>0 (0.0)</td><td>5 (0.6)</td><td>0.1</td></tr><tr><td>Osteoporosis</td><td>58 (7.2)</td><td>45 (5.0)</td><td>0.06</td></tr><tr><td>Cancer</td><td>46 (5.7)</td><td>37 (4.1)</td><td>0.14</td></tr><tr><td>Gastroesophageal reflux disease</td><td>82 (10.2)</td><td>88 (9.7)</td><td>0.77</td></tr><tr><td>Smoking history</td><td>339 (42.3)</td><td>539 (59.4)</td><td>&lt;0.001</td></tr><tr><td>Missing data (%)<sup>b</sup></td><td>166 (20.7)</td><td>142 (15.6)</td><td></td></tr><tr><td>Weight, kg</td><td>53 (± 12)</td><td>67 (± 15)</td><td>&lt;0.001</td></tr><tr><td>Missing data (%)</td><td>124 (15.5)</td><td>90 (9.9)</td><td></td></tr><tr><td>Height, cm</td><td>160 (± 7)</td><td>173 (± 7)</td><td>&lt;0.001</td></tr><tr><td>Missing data (%)</td><td>122 (15.2)</td><td>90 (9.9)</td><td></td></tr><tr><td>BMI, kg/m<sup>2</sup></td><td>20.6 (± 4.1)</td><td>22.6 (± 4.6)</td><td>&lt;0.001</td></tr><tr><td>Missing data (%)</td><td>126 (15.7)</td><td>94 (10.4)</td><td></td></tr><tr><td>Pre-transplant anti-HLA antibodies</td><td>366 (45.6)</td><td>232 (25.6)</td><td>&lt;0.001</td></tr><tr><td>Pre-transplant anti-HLA class I antibodies</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>None</td><td>518 (64.6)</td><td>739 (81.4)</td><td></td></tr><tr><td>[1-10]</td><td>219 (27.3)</td><td>162 (17.8)</td><td></td></tr><tr><td>[11-20]</td><td>33 (4.1)</td><td>3 (0.3)</td><td></td></tr><tr><td>[21-30]</td><td>22 (2.7)</td><td>4 (0.4)</td><td></td></tr><tr><td>&gt;30</td><td>10 (1.2)</td><td>0 (0.0)</td><td></td></tr><tr><td>Pre-transplant anti-HLA class II antibodies</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>None</td><td>571 (71.2)</td><td>775 (85.4)</td><td></td></tr><tr><td>[1-10]</td><td>199 (24.8)</td><td>127 (14.0)</td><td></td></tr><tr><td>[11-20]</td><td>31 (3.9)</td><td>5 (0.6)</td><td></td></tr><tr><td>[21-30]</td><td>1 (0.1)</td><td>1 (0.1)</td><td></td></tr><tr><td>Bacterial colonization</td><td>375 (46.8)</td><td>491 (54.1)</td><td>0.01</td></tr><tr><td>Missing data (%)</td><td>24 (3.0)</td><td>23 (2.5)</td><td></td></tr><tr><td>Fungal colonization</td><td>437 (54.5)</td><td>545 (60.0)</td><td>0.07</td></tr><tr><td>Missing data (%)</td><td>24 (3.0)</td><td>23 (2.5)</td><td></td></tr><tr><td>6-minute walk test, % of predicted</td><td>45.3 (± 16.4)</td><td>43.1 (± 17.0)</td><td>0.026</td></tr><tr><td>Missing data (%)</td><td>289 (36.0)</td><td>293 (32.3)</td><td></td></tr><tr><td>Non-invasive ventilation</td><td>314 (39.2)</td><td>340 (37.4)</td><td>0.18</td></tr><tr><td>Missing data (%)</td><td>77 (9.6)</td><td>69 (7.6)</td><td></td></tr></tbody></table>
<table><tr><td>Long-term oxygen</td><td>651 (81.2)</td><td>779 (85.8)</td><td>0.035</td></tr><tr><td>Missing data (%)</td><td>69 (8.6)</td><td>57 (6.3)</td><td></td></tr></table>

Data are expressed as numbers (%), means (± standard deviations), or medians [IQR].

<footnote>a Estimated with $\chi^2$, Student's, or Wilcoxon tests. b There were no missing data in variables where there is no corresponding line. PH: pulmonary hypertension, BMI: body mass index, HLA: human leukocyte antigen.</footnote>
<table><caption>Table II. Per-transplant outcomes in female versus male lung transplant recipients.</caption><thead><tr><th>Variables</th><th>Women (n = 735)</th><th>Men (n = 868)</th><th>p-value<sup>a</sup></th></tr></thead><tbody><tr><td>Waiting time duration before transplantation, days</td><td>115 [34 ; 295]</td><td>73 [28 ; 184]</td><td>&lt;0.001</td></tr><tr><td>High emergency</td><td>124 (16.9)</td><td>117 (13.5)</td><td>0.07</td></tr><tr><td>Procedure</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Double lung</td><td>579 (78.8)</td><td>662 (76.3)</td><td></td></tr><tr><td>Single lung</td><td>69 (9.4)</td><td>137 (15.8)</td><td></td></tr><tr><td>Heart and lung</td><td>24 (3.3)</td><td>22 (2.5)</td><td></td></tr><tr><td>Missing data (%)<sup>b</sup></td><td>63 (8.6)</td><td>47 (5.4)</td><td></td></tr><tr><td>Volume reduction</td><td>122 (16.6)</td><td>68 (7.8)</td><td>&lt;0.001</td></tr><tr><td>Missing data (%)</td><td>143 (19.5)</td><td>139 (16.0)</td><td></td></tr><tr><td>Total graft ischemic time, minutes</td><td>603 (± 165)</td><td>609 (± 168)</td><td>0.51</td></tr><tr><td>Gender mismatch</td><td>279 (38.0)</td><td>242 (27.9)</td><td>&lt;0.001</td></tr><tr><td>Blood type mismatch</td><td>42 (5.7)</td><td>51 (5.9)</td><td>0.94</td></tr><tr><td>Missing data (%)</td><td>131 (17.8)</td><td>149 (17.2)</td><td></td></tr><tr><td>Weight mismatch (donor weight – recipient weight, in absolute value)</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>[-15 ; +15] kg difference between donor and recipient</td><td>344 (46.8)</td><td>437 (50.3)</td><td></td></tr><tr><td>Donor weight > +15 kg recipient weight</td><td>303 (41.2)</td><td>266 (30.6)</td><td></td></tr><tr><td>Donor weight < -15 kg recipient weight</td><td>31 (4.2)</td><td>115 (13.2)</td><td></td></tr><tr><td>Missing data (%)</td><td>57 (7.8)</td><td>50 (5.8)</td><td></td></tr><tr><td>pTLC ratio between donor and recipient</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>[0.92 ; 1.41]</td><td>523 (71.2)</td><td>542 (62.4)</td><td></td></tr><tr><td>&lt; 0.92</td><td>73 (9.9)</td><td>263 (30.3)</td><td></td></tr><tr><td>&gt; 1.41</td><td>74 (10.1)</td><td>1 (0.1)</td><td></td></tr><tr><td>Missing data (%)</td><td>65 (8.8)</td><td>62 (7.1)</td><td></td></tr><tr><td>CMV mismatch</td><td>140 (19.0)</td><td>181 (20.9)</td><td>0.55</td></tr><tr><td>Missing data (%)</td><td>36 (4.9)</td><td>36 (4.1)</td><td></td></tr><tr><td>EBV mismatch</td><td>48 (6.5)</td><td>52 (6.0)</td><td>0.54</td></tr><tr><td>Missing data (%)</td><td>40 (5.4)</td><td>38 (4.4)</td><td></td></tr><tr><td>Number of HLA incompatibilities</td><td>6 [5 ; 6]</td><td>6 [5 ; 7]</td><td>0.35</td></tr><tr><td>Missing data (%)</td><td>72 (9.8)</td><td>77 (8.9)</td><td></td></tr><tr><td>Primary graft dysfunction</td><td>184 (25.0)</td><td>185 (21.3)</td><td>0.2</td></tr><tr><td>Missing data (%)</td><td>130 (17.7)</td><td>166 (19.1)</td><td></td></tr></tbody></table>

Data are expressed as counts (%), means (± standard deviation), or medians [IQR].

<footnote>a Estimated with $\chi^2$, Student's, or Wilcoxon tests. b There were no missing data in variables where there is no corresponding row. pTLC: predicted total lung capacity, CMV, cytomegalovirus; EBV, Epstein-Barr virus; HLA, human leukocyte antigen.</footnote>
<table><caption>Table III. Post-transplant outcomes in female versus male transplant recipients.</caption><thead><tr><th>Variables</th><th>Women (n = 735)</th><th>Men (n = 868)</th><th>p-value<sup>a</sup></th></tr></thead><tbody><tr><td>Death</td><td>253 (34.4)</td><td>371 (42.7)</td><td>&lt;0.001</td></tr><tr><td>Follow-up, years</td><td>6.1 [2.3; 8.2]</td><td>5.3 [1.6; 7.8]</td><td>0.001</td></tr><tr><td>Patients with k acute cellular rejection episode &gt; grade A1 (per year)</td><td></td><td></td><td>0.34</td></tr><tr><td>k = 0</td><td>409 (55.6)</td><td>506 (58.3)</td><td></td></tr><tr><td>k in ]0 - 1]</td><td>268 (36.5)</td><td>311 (35.8)</td><td></td></tr><tr><td>k &gt; 1</td><td>28 (3.8)</td><td>28 (3.2)</td><td></td></tr><tr><td>Missing data (%)<sup>b</sup></td><td>30 (4.1)</td><td>23 (2.6)</td><td></td></tr><tr><td>Antibody-mediated rejection</td><td>143 (19.5)</td><td>155 (17.9)</td><td>0.18</td></tr><tr><td>Missing data (%)</td><td>30 (4.1)</td><td>23 (2.6)</td><td></td></tr><tr><td>Chronic lung allograft dysfunction</td><td></td><td></td><td>0.88</td></tr><tr><td>No chronic lung allograft dysfunction</td><td>415 (56.5)</td><td>471 (54.3)</td><td></td></tr><tr><td>Bronchiolitis obliterans syndrome</td><td>87 (11.8)</td><td>106 (12.2)</td><td></td></tr><tr><td>Restrictive allograft syndrome</td><td>13 (1.8)</td><td>17 (2.0)</td><td></td></tr><tr><td>Mixed</td><td>8 (1.1)</td><td>13 (1.5)</td><td></td></tr><tr><td>Missing data (%)</td><td>212 (28.8)</td><td>261 (30.1)</td><td></td></tr><tr><td>Cancer</td><td>64 (8.7)</td><td>107 (12.3)</td><td>0.023</td></tr><tr><td>Missing data (%)</td><td>30 (4.1)</td><td>23 (2.6)</td><td></td></tr><tr><td>Dialysis</td><td>68 (9.3)</td><td>67 (7.7)</td><td>0.12</td></tr><tr><td>Missing data (%)</td><td>85 (11.6)</td><td>79 (9.1)</td><td></td></tr><tr><td>Kidney transplantation</td><td>10 (1.4)</td><td>10 (1.2)</td><td>0.26</td></tr><tr><td>Missing data (%)</td><td>30 (4.1)</td><td>23 (2.6)</td><td></td></tr><tr><td>Post-transplant anti-HLA Donor specific antibodies</td><td>180 (24.5)</td><td>172 (19.8)</td><td>0.015</td></tr><tr><td>Missing data (%)</td><td>30 (4.1)</td><td>23 (2.6)</td><td></td></tr><tr><td>Number of patients with k bacterial infection episode (per year)</td><td></td><td></td><td>0.06</td></tr><tr><td>k = 0</td><td>158 (21.5)</td><td>207 (23.8)</td><td></td></tr><tr><td>k in ]0 - 1]</td><td>448 (61.0)</td><td>495 (57.0)</td><td></td></tr><tr><td>k in ]1 - 2]</td><td>55 (7.5)</td><td>66 (7.6)</td><td></td></tr><tr><td>k &gt; 2</td><td>44 (6.0)</td><td>77 (8.9)</td><td></td></tr><tr><td>Missing data (%)</td><td>30 (4.1)</td><td>23 (2.6)</td><td></td></tr><tr><td>Number of patients with k fungal infection episode (per year)</td><td></td><td></td><td>0.2</td></tr><tr><td>k = 0</td><td>383 (52.1)</td><td>454 (52.3)</td><td></td></tr><tr><td>k in ]0 - 1]</td><td>283 (38.5)</td><td>329 (37.9)</td><td></td></tr><tr><td>k &gt; 1</td><td>39 (5.3)</td><td>62 (7.1)</td><td></td></tr><tr><td>Missing data (%)</td><td>30 (4.1)</td><td>23 (2.6)</td><td></td></tr><tr><td>Number of patients with k viral infection episode (per year)</td><td></td><td></td><td>0.22</td></tr><tr><td>k = 0</td><td>374 (50.9)</td><td>422 (48.6)</td><td></td></tr><tr><td>k in ]0 - 1]</td><td>297 (40.4)</td><td>385 (44.4)</td><td></td></tr><tr><td>k in &gt; 1</td><td>34 (4.6)</td><td>38 (4.4)</td><td></td></tr><tr><td>Missing data (%)</td><td>30 (4.1)</td><td>23 (2.6)</td><td></td></tr><tr><td>Re-transplant(s) during follow-up = Yes</td><td>27 (3.7)</td><td>22 (2.5)</td><td>0.24</td></tr></tbody></table>
Data are expressed as counts (%), means (± standard deviation), or medians [IQR].

<footnote>a Estimated with χ², Student's, or Wilcoxon tests. b There were no missing data in variables where there is no corresponding row. HLA: human leukocyte antigen.</footnote>
## Figures

<figure><img src="image_4.png" /><figcaption>**Figure 1. Flowchart.** COLT: COhort in Lung Transplantation, CRISTAL: French biomedical agency database, W: women, M: men.</figcaption></figure>
<figure><img src="image_5.png" /><figcaption>**Figure 2.** Underlying diagnosis in women and men awaiting lung transplantation,

χ² tests used. ILD: Interstitial lung disease, PAH: Pulmonary arterial hypertension, COPD: Chronic obstructive pulmonary disease.</figcaption></figure>
<figure><img src="image_6.png" /></figure>

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /><figcaption>Figure 3. Waiting time duration before lung transplantation according to gender.</figcaption></figure>

(A) Boxplot representation of waiting time duration (log10 applied, Wilcoxon test). (B) Kaplan-Meier transplantation curves in men and women over 24 months, log-rank test used. (C) Multivariable Cox proportional hazards model showing factors associated with a shorter (HR > 1) or longer (HR < 1) waiting time duration before lung transplantation. Variables with a p-value < 0.2 in the univariable analysis were selected, and a forward stepwise selection using Akaike information criterion was used for the final multivariable Cox model. ILD: Interstitial lung disease, PAH: Pulmonary arterial hypertension, COPD: Chronic obstructive pulmonary disease, HLA: human leucocyte antigen, CMV: cytomegalovirus.
<figure><img src="image_9.png" /></figure>

<table><thead><tr><th></th><th>Patient number</th></tr></thead><tbody><tr><td>Men</td><td>868</td></tr><tr><td>Women</td><td>735</td></tr></tbody></table>

<figure><img src="image_10.png" /></figure>

<table><thead><tr><th></th><th>Patient number</th></tr></thead><tbody><tr><td>Men</td><td>607</td></tr><tr><td>Women</td><td>523</td></tr></tbody></table>

C

Gender
Women
Men (p = 0.003)

▲ Reference ◦ p ≤ 0.05 • p > 0.05

Underlying diagnosis
Cystic fibrosis
PAH (p = 0.5)

COPD/emphysema (p < 0.001)

Other (p < 0.001)

ILD (p < 0.001)

Type of transplantation
Double lung
Single lung (p = 0.001)
Heart and lung (p = 0.004)

Ischemic heart disease
No
Yes (p = 0.007)

Volume reduction
No
Yes (p = 0.01)

Recipient age
(p = 0.03)

Donor age
(p = 0.01)

EBV mismatch
No
Yes (p = 0.02)

Graft ischemia
(p = 0.08)

Cancer
No
Yes (p = 0.05)

High emergency
No
Yes (p = 0.10)

Hazard ratio

<caption>**Figure 4.** Overall survival and CLAD occurrence following lung transplantation according to recipient gender. (A) Kaplan-Meier survival curves over 8 years between women and men, log-rank test used. (B) Comparison of CLAD occurrence between women and men over 8 years, log-rank test used. (C) Multivariable Cox proportional hazards model showing factors associated with a shorter (HR < 1) or longer (HR > 1) survival. Variables with a p-value < 0.2 in the univariable analysis were selected and a forward stepwise selection using Akaike information criterion was used for the final multivariable Cox model. ILD: Interstitial lung disease, PAH: Pulmonary arterial hypertension, COPD: Chronic obstructive pulmonary disease, EBV: Epstein-Barr virus.</caption>
<figure><img src="image_11.png" /></figure>

<table><thead><tr><th></th><th colspan="5">Patient number</th></tr></thead><tbody><tr><th scope="row">D<sub>M</sub>R<sub>M</sub></th><td>625</td><td>455</td><td>373</td><td>264</td><td>132</td></tr><tr><th scope="row">D<sub>W</sub>R<sub>M</sub></th><td>242</td><td>170</td><td>139</td><td>106</td><td>67</td></tr><tr><th scope="row">D<sub>M</sub>R<sub>W</sub></th><td>279</td><td>214</td><td>178</td><td>142</td><td>81</td></tr><tr><th scope="row">D<sub>W</sub>R<sub>W</sub></th><td>457</td><td>354</td><td>300</td><td>237</td><td>120</td></tr></tbody></table>

<figure><img src="image_12.png" /></figure>

<table><thead><tr><th></th><th colspan="5">Patient number</th></tr></thead><tbody><tr><th scope="row">&lt; -15</th><td>146</td><td>87</td><td>68</td><td>49</td><td>22</td></tr><tr><th scope="row">no</th><td>781</td><td>578</td><td>488</td><td>369</td><td>212</td></tr><tr><th scope="row">&gt; 15</th><td>569</td><td>450</td><td>386</td><td>315</td><td>164</td></tr></tbody></table>

<figure><img src="image_13.png" /></figure>

<table><thead><tr><th></th><th colspan="5">Patient number</th></tr></thead><tbody><tr><th scope="row">&lt; 0.92</th><td>336</td><td>240</td><td>194</td><td>148</td><td>93</td></tr><tr><th scope="row">Inside</th><td>1065</td><td>810</td><td>700</td><td>542</td><td>284</td></tr><tr><th scope="row">&gt; 1.41</th><td>75</td><td>54</td><td>43</td><td>37</td><td>20</td></tr></tbody></table>

<figure><img src="image_14.png" /></figure>

<table><thead><tr><th></th><th colspan="5">Women patient number</th></tr></thead><tbody><tr><th scope="row">&lt; 50</th><td>396</td><td>304</td><td>270</td><td>236</td><td>130</td></tr><tr><th scope="row">&ge; 50</th><td>286</td><td>224</td><td>186</td><td>138</td><td>69</td></tr></tbody></table>

**Figure 5.** Factors influencing survival after lung transplantation according to recipient gender. (A) $(\frac{|\text{donor height} - \text{recipient height}|}{\text{recipient height}} \times 100) \chi^2$ Kaplan-Meier survival curves according to donor vs recipient gender combinations over 8 years, log-rank test used. $D_M$: men donor, $D_W$: women donor, $R_M$: men recipient, $R_W$: women recipient. Kaplan-Meier survival over 8 years, log-rank tests used. (B) Survival according to weight mismatch (donor weight - recipient weight), No: [-15, 15]. (C) Survival according to pTLC ratios between donor and recipient. (D) Survival according to age, in female recipients only.
Supplementary Appendix

<table><tr><td>Supplemental 1. French lung allocation policy</td><td>2</td></tr><tr><td>Supplemental table 1. Pulmonary function tests at registration on waiting list in female versus male patients with cystic fibrosis, ILD, COPD and pulmonary arterial hypertension.</td><td>3</td></tr><tr><td>Supplemental table 2. Causes of removal from waiting list.</td><td>4</td></tr><tr><td>Supplemental table 3. Univariate Cox regression analysis for waiting time duration before lung transplantation and gender-adjusted analysis.</td><td>5</td></tr><tr><td>Supplemental table 4. Multivariable Cox regression analysis for waiting time duration before lung transplantation.</td><td>8</td></tr><tr><td>Supplemental table 5. Clinical characteristics of female and male donors</td><td>9</td></tr><tr><td>Supplemental table 6. Cause of death after transplantation.</td><td>10</td></tr><tr><td>Supplemental table 7. Univariate Cox regression for overall survival, and gender-adjusted analysis</td><td>11</td></tr><tr><td>Supplemental table 8. Multivariable Cox regression for overall survival.</td><td>16</td></tr><tr><td>Supplemental figure 1. Comparison of survival between women and men over 8 years according to underlying diagnosis.</td><td>17</td></tr><tr><td>Supplemental figure 2. Comparison of survival according to weight mismatch (donor weight - recipient weight) over 8 years.</td><td>18</td></tr><tr><td>Supplemental figure 3. pTLC ratio nonlinear association with declining risk of death.</td><td>19</td></tr></table>
**Supplemental 1. French lung allocation policy**

Lung transplant candidates whose life is threatened in the very short term are given a priority access at the national level, according to procedures and terms defined by the Agence de la Biomédecine which includes a referral to a college of experts. If several recipients are registered in the lung high-emergency category, the graft is offered to the earliest candidate registered in this category. Priority is granted for 8 days and may be extended to another 8 days.

The next level of allocation is local, in which the donor lung is proposed to the nearest lung transplantation centre from the donor site.

The final level of allocation is a national round where the donor lung is proposed successively to the lung transplantation teams.

Apart from the high-emergency procedure, the choice of the recipient within its waiting list is the responsibility of the lung transplantation team.

Overall, donor proposition is made for a candidate of similar blood group. Special access for a different compatible group can be asked to the agency with expert review (e.g. B candidate for O donor).
Supplemental table 1. Pulmonary function tests at registration on waiting list in female versus male patients with cystic fibrosis, ILD, COPD and pulmonary arterial hypertension.

<table><thead><tr><th>Variables</th><th>Women</th><th>Men</th><th>p-value<sup>a</sup></th></tr></thead><tbody><tr><td><strong>Cystic fibrosis</strong></td><td><strong>n = 242</strong></td><td><strong>n = 214</strong></td><td></td></tr><tr><td>FEV1 as % of predicted</td><td>24.0 [19.9 ; 29.0]</td><td>22.0 [19.0 ; 27.2]</td><td>0.014</td></tr><tr><td>Missing data (%)</td><td>9 (3.7)</td><td>5 (2.3)</td><td></td></tr><tr><td>FVC as % of predicted</td><td>41.0 [33.0 ; 50.0]</td><td>41.0 [33.0 ; 48.1]</td><td>0.26</td></tr><tr><td>Missing data (%)</td><td>14 (5.8)</td><td>10 (4.7)</td><td></td></tr><tr><td>DLCO as % of predicted</td><td>46.0 [37.5 ; 53.4]</td><td>46 [38 ; 56]</td><td>0.73</td></tr><tr><td>Missing data (%)</td><td>199 (82.2)</td><td>170 (79.4)</td><td></td></tr><tr><td>TLC as % of predicted</td><td>105 [95 ; 117]</td><td>102 [87 ; 114]</td><td>0.08</td></tr><tr><td>Missing data (%)</td><td>112 (46.3)</td><td>97 (45.3)</td><td></td></tr><tr><td><strong>Interstitial lung disease</strong></td><td><strong>n = 96</strong></td><td><strong>n = 209</strong></td><td></td></tr><tr><td>FEV1 as % of predicted</td><td>42.5 [33.8 ; 54.0]</td><td>51.0 [38.1 ; 61.0]</td><td>0.001</td></tr><tr><td>Missing data (%)</td><td>12 (12.5)</td><td>11 (5.3)</td><td></td></tr><tr><td>FVC as % of predicted</td><td>40 [33 ; 50]</td><td>46 [36 ; 58]</td><td>0.002</td></tr><tr><td>Missing data (%)</td><td>11 (11.5)</td><td>14 (6.7)</td><td></td></tr><tr><td>DLCO as % of predicted</td><td>25.6 [18.4 ; 34.8]</td><td>22.0 [17.0 ; 30.0]</td><td>0.14</td></tr><tr><td>Missing data (%)</td><td>70 (72.9)</td><td>89 (42.6)</td><td></td></tr><tr><td>TLC as % of predicted</td><td>47 [41 ; 61]</td><td>50 [43 ; 62]</td><td>0.32</td></tr><tr><td>Missing data (%)</td><td>39 (40.6)</td><td>51 (24.4)</td><td></td></tr><tr><td><strong>COPD/emphysema</strong></td><td><strong>n = 279</strong></td><td><strong>n = 358</strong></td><td></td></tr><tr><td>FEV1 as % of predicted</td><td>22.0 [18.0 ; 27.0]</td><td>20.5 [17.0 ; 27.0]</td><td>0.12</td></tr><tr><td>Missing data (%)</td><td>12 (4.3)</td><td>17 (4.7)</td><td></td></tr><tr><td>FVC as % of predicted</td><td>56.4 [43.0 ; 70.0]</td><td>54.0 [44.0 ; 69.0]</td><td>0.59</td></tr><tr><td>Missing data (%)</td><td>16 (5.7)</td><td>26 (7.3)</td><td></td></tr><tr><td>DLCO as % of predicted</td><td>20.0 [13.4 ; 27.6]</td><td>22.0 [16.0 ; 29.9]</td><td>0.17</td></tr><tr><td>Missing data (%)</td><td>161 (57.7)</td><td>184 (51.4)</td><td></td></tr><tr><td>TLC as % of predicted</td><td>139 [126 ; 155]</td><td>125 [110 ; 140]</td><td>&lt;0.001</td></tr><tr><td>Missing data (%)</td><td>80 (28.7)</td><td>94 (26.3)</td><td></td></tr><tr><td><strong>Pulmonary arterial hypertension</strong></td><td><strong>n = 67</strong></td><td><strong>n = 34</strong></td><td></td></tr><tr><td>FEV1 as % of predicted</td><td>78 [65 ; 89]</td><td>83.0 [62.3 ; 97.2]</td><td>0.55</td></tr><tr><td>Missing data (%)</td><td>14 (20.9)</td><td>6 (17.6)</td><td></td></tr><tr><td>FVC as % of predicted</td><td>94 [76 ; 104]</td><td>94 [70 ; 102]</td><td>0.6</td></tr><tr><td>Missing data (%)</td><td>17 (25.4)</td><td>8 (23.5)</td><td></td></tr><tr><td>DLCO as % of predicted</td><td>58.0 [40.2 ; 66.3]</td><td>35.0 [27.8 ; 57.6]</td><td>0.016</td></tr><tr><td>Missing data (%)</td><td>35 (52.2)</td><td>12 (35.3)</td><td></td></tr><tr><td>TLC as % of predicted</td><td>94 [84 ; 108]</td><td>93 [82 ; 100]</td><td>0.47</td></tr><tr><td>Missing data (%)</td><td>23 (34.3)</td><td>9 (26.5)</td><td></td></tr></tbody></table>

Data are expressed as median [interquartile range] and missing data as number (%).

<footnote>a Estimated using the Wilcoxon test. FEV1: forced expiratory volume in one second. FVC, forced vital capacity; DLCO, diffusing capacity for carbon monoxide; TLC, total lung capacity; COPD, chronic obstructive pulmonary disease.</footnote>
<table><caption>Supplemental table 2. Causes of removal from waiting list</caption><thead><tr><th></th><th>Women<br>(n = 66)</th><th>Men<br>(n = 41)</th><th>p-value</th></tr></thead><tbody><tr><td>Cause (%)</td><td></td><td></td><td>0.07</td></tr><tr><td>Improvement</td><td>5 (7.7)</td><td>0 (0.0)</td><td></td></tr><tr><td>Contra indication</td><td>4 (6.2)</td><td>5 (12.2)</td><td></td></tr><tr><td>Death</td><td>34 (52.3)</td><td>28 (68.3)</td><td></td></tr><tr><td>Undetermined</td><td>23 (33.8)</td><td>8 (19.5)</td><td></td></tr></tbody></table>
<table><caption>Supplemental table 3. Univariate Cox regression analysis for waiting time duration before lung transplantation and gender-adjusted analysis.</caption><thead><tr><th rowspan="2">Variables</th><th colspan="2">Univariate analysis</th><th colspan="4">Gender adjusted analysis<br>(Surv(delay, transplantation) ~ gender + variable)<sup>a</sup></th></tr><tr><th>HR (95% CI)</th><th>P-value</th><th>Gender adjusted HR<br>(95% CI)</th><th>Gender adjusted p-value</th><th>Variable adjusted HR<br>(95% CI)</th><th>Variable adjusted p-value</th></tr></thead><tbody><tr><td>Male gender</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001</td><td></td><td></td><td></td><td></td></tr><tr><td>Age</td><td>1.01 (1.00-1.01)</td><td>0.001</td><td>1.26 (1.14-1.39)</td><td>&lt;0.001 ***</td><td>1.00 (1.00-1.01)</td><td>0.006 *</td></tr><tr><td>Underlying diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Interstitial lung disease</td><td>Ref.</td><td>-</td><td>1.25 (1.13-1.38)</td><td>&lt;0.001 ***</td><td>Ref.</td><td>-</td></tr><tr><td>Cystic fibrosis</td><td>0.76 (0.66-0.88)</td><td>&lt;0.001</td><td>-</td><td>-</td><td>0.78 (0.67-0.91)</td><td>0.001 *</td></tr><tr><td>Pulmonary arterial hypertension</td><td>0.77 (0.61-0.97)</td><td>0.029</td><td>-</td><td>-</td><td>0.81 (0.64-1.02)</td><td>0.075</td></tr><tr><td>COPD/emphysema</td><td>0.83 (0.72-0.95)</td><td>0.008</td><td>-</td><td>-</td><td>0.83 (0.72-0.96)</td><td>0.012</td></tr><tr><td>Other</td><td>0.68 (0.55-0.83)</td><td>&lt;0.001</td><td>-</td><td>-</td><td>0.69 (0.57-0.85)</td><td>&lt;0.001 *</td></tr><tr><td>CMV positive serology</td><td>1.12 (1.01-1.24)</td><td>0.026</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>1.13 (1.02-1.25)</td><td>0.016</td></tr><tr><td>EBV positive serology</td><td>0.99 (0.82-1.21)</td><td>0.942</td><td>1.29 (1.16-1.43)</td><td>&lt;0.001 ***</td><td>0.98 (0.81-1.19)</td><td>0.838</td></tr><tr><td>Bacterial colonization</td><td>1.01 (0.91-1.11)</td><td>0.903</td><td>1.28 (1.16-1.41)</td><td>&lt;0.001 ***</td><td>0.99 (0.90-1.10)</td><td>0.921</td></tr><tr><td>Fungal colonization</td><td>1.10 (1.00-1.22)</td><td>0.058</td><td>1.27 (1.15-1.41)</td><td>&lt;0.001 ***</td><td>1.09 (0.98-1.20)</td><td>0.103</td></tr><tr><td>6-minute walk test, % of predicted</td><td>1.00 (0.99-1.00)</td><td>0.005</td><td>1.31 (1.16-1.47)</td><td>&lt;0.001 ***</td><td>1.00 (0.99-1.00)</td><td>0.026</td></tr></tbody></table>
<table><tbody><tr><td>Non-invasive ventilation</td><td>0.98 (0.88-1.09)</td><td>0.692</td><td>1.26 (1.13-1.39)</td><td>&lt;0.001 ***</td><td>0.98 (0.88-1.09)</td><td>0.711</td></tr><tr><td>Long-term oxygen</td><td>1.14 (0.96-1.36)</td><td>0.14</td><td>1.27 (1.14-1.40)</td><td>&lt;0.001 ***</td><td>1.14 (0.96-1.35)</td><td>0.149</td></tr><tr><td>Ischemic heart disease</td><td>1.11 (0.88-1.39)</td><td>0.391</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>1.05 (0.83-1.32)</td><td>0.698</td></tr><tr><td>High blood pressure</td><td>1.10 (0.94-1.29)</td><td>0.218</td><td>1.28 (1.16-1.41)</td><td>&lt;0.001 ***</td><td>1.06 (0.91-1.24)</td><td>0.448</td></tr><tr><td>Pulmonary hypertension group III</td><td>0.86 (0.73-1.01)</td><td>0.06</td><td>1.29 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>0.86 (0.73-1.00)</td><td>0.054</td></tr><tr><td>Dyslipidemia</td><td>1.10 (0.90-1.36)</td><td>0.35</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>1.06 (0.86-1.31)</td><td>0.58</td></tr><tr><td>Diabetes</td><td>0.94 (0.82-1.07)</td><td>0.349</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>0.94 (0.82-1.08)</td><td>0.393</td></tr><tr><td>Heart failure</td><td>0.86 (0.54-1.36)</td><td>0.516</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>0.84 (0.53-1.34)</td><td>0.476</td></tr><tr><td>Gastroesophageal reflux</td><td>0.98 (0.83-1.15)</td><td>0.786</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>0.97 (0.82-1.14)</td><td>0.713</td></tr><tr><td>Kidney failure</td><td>1.76 (0.56-5.45)</td><td>0.331</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>1.57 (0.50-4.88)</td><td>0.436</td></tr><tr><td>Cancer</td><td>1.00 (0.80-1.26)</td><td>0.996</td><td>1.28 (1.16-1.42)</td><td>&lt;0.001 ***</td><td>1.00 (0.80-1.26)</td><td>0.993</td></tr><tr><td>Number of pre-transplant anti-HLA class I antibodies</td><td>0.98 (0.97-0.99)</td><td>&lt;0.001</td><td>1.25 (1.13-1.38)</td><td>&lt;0.001 ***</td><td>0.99 (0.98-1.00)</td><td>0.005 *</td></tr><tr><td>Number of pre-transplant anti-HLA class II antibodies</td><td>0.98 (0.96-0.99)</td><td>0.01</td><td>1.26 (1.14-1.40)</td><td>&lt;0.001 ***</td><td>0.98 (0.96-1.00)</td><td>0.072</td></tr><tr><td>Height, cm</td><td>1.01 (1.01-1.02)</td><td>&lt;0.001</td><td>1.26 (1.10-1.45)</td><td>0.001 **</td><td>1.00 (1.00-1.01)</td><td>0.505</td></tr><tr><td>Recipient's blood type</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>A</td><td>Ref.</td><td>-</td><td>1.32 (1.19-1.48)</td><td>&lt;0.001 ***</td><td>Ref.</td><td>-</td></tr><tr><td>AB</td><td>1.08 (0.81-1.45)</td><td>0.586</td><td>-</td><td>-</td><td>1.06 (0.79-1.43)</td><td>0.674</td></tr></tbody></table>
<table><tr><td></td><td>1.10 (0.92-1.32)</td><td>0.308</td><td>-</td><td>-</td><td>1.09 (0.91-1.30)</td><td>0.371</td></tr><tr><td>B</td><td>0.94 (0.84-1.06)</td><td>0.296</td><td>-</td><td>-</td><td>0.91 (0.81-1.03)</td><td>0.131</td></tr><tr><td>O</td><td>0.90 (0.80-1.01)</td><td>0.061</td><td>1.27 (1.14-1.42)</td><td>&lt;0.001 ***</td><td>0.87 (0.78-0.97)</td><td>0.016</td></tr><tr><td>Smoking history</td><td>1.14 (1.00-1.31)</td><td>0.057</td><td>1.30 (1.18-1.43)</td><td>&lt;0.001 ***</td><td>1.18 (1.03-1.36)</td><td>0.018</td></tr><tr><td>High emergency</td><td></td><td></td><td></td><td></td><td></td><td></td></tr></table>

<footnote>ª Where Surv() is the survival function; delay is the time between the day of registration on the waiting list and transplantation (or the day of data extraction for non-transplanted patients), transplantation is the event of the survival analysis, gender is present in all the adjusted bivariable analysis, and variable corresponds to the other explanatory variables. Results with significant p-values corrected by Benjamini-Hochberg are indicated as follows: * p < 0.05, ** p < 0.01, and *** p < 0.001. HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CMV, Cytomegalovirus; EBV, Epstein-Barr Virus; HLA, human leukocyte antigen.</footnote>
Supplemental table 4. Multivariable Cox regression analysis for waiting time duration before lung transplantation.

<table><thead><tr><th>Variables (n = 1,529)</th><th>HR (95% CI)</th><th>P-value</th></tr></thead><tbody><tr><td>Male gender</td><td>1.21 [1.09-1.34]</td><td>&lt;0.001</td></tr><tr><td>Underlying diagnosis</td><td></td><td></td></tr><tr><td>Interstitial lung disease</td><td>Ref.</td><td>-</td></tr><tr><td>Cystic fibrosis</td><td>0.94 [0.77-1.15]</td><td>0.52</td></tr><tr><td>Pulmonary arterial hypertension</td><td>0.82 [0.64-1.05]</td><td>0.12</td></tr><tr><td>COPD/emphysema</td><td>0.85 [0.73-0.99]</td><td>0.03</td></tr><tr><td>Other</td><td>0.69 [0.56-0.85]</td><td>&lt;0.001</td></tr><tr><td>Number of pre-transplant anti-HLA class I antibodies</td><td>0.98 [0.97-1.00]</td><td>&lt;0.001</td></tr><tr><td>CMV positive serology</td><td>1.10 [0.99-1.22]</td><td>0.08</td></tr><tr><td>High-emergency</td><td>1.23 [1.06-1.42]</td><td>0.01</td></tr><tr><td>Recipient age</td><td>1.01 [1.00-1.01]</td><td>0.03</td></tr><tr><td>Fungal colonization</td><td>1.09 [0.97-1.22]</td><td>0.13</td></tr></tbody></table>

HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; HLA, human leukocyte antigen; CMV, Cytomegalovirus.
<table><caption>Supplemental table 5. Clinical characteristics of female and male donors</caption><thead><tr><th>Variables</th><th>Women<br>(n = 699)</th><th>Men<br>(n = 904)</th><th>p-value<sup>a</sup></th></tr></thead><tbody><tr><td>Age, years</td><td>51.0 [40.0 ; 59.0]</td><td>44.5 [30.0 ; 56.0]</td><td>&lt;0.001</td></tr><tr><td>Missing data (%)<sup>b</sup></td><td>55 (7.9)</td><td>56 (6.2)</td><td></td></tr><tr><td>Weight, kg</td><td>65 (± 13)</td><td>75 (± 13)</td><td>&lt;0.001</td></tr><tr><td>Height, cm</td><td>163 (± 7)</td><td>176 (± 7)</td><td>&lt;0.001</td></tr><tr><td>Body mass index, kg/m2</td><td>24.3 (± 4.7)</td><td>24.2 (± 3.6)</td><td>0.69</td></tr><tr><td>Cause of death</td><td></td><td></td><td>&lt;0.001</td></tr><tr><td>Vascular</td><td>453 (64.8)</td><td>390 (43.1)</td><td></td></tr><tr><td>Traumatic, public road accident</td><td>59 (8.4)</td><td>154 (17.0)</td><td></td></tr><tr><td>Traumatic, non-road accident</td><td>61 (8.7)</td><td>184 (20.4)</td><td></td></tr><tr><td>Anoxia</td><td>98 (14.0)</td><td>139 (15.4)</td><td></td></tr><tr><td>Meningitis</td><td>11 (1.6)</td><td>11 (1.2)</td><td></td></tr><tr><td>Tumor</td><td>8 (1.1)</td><td>2 (0.2)</td><td></td></tr><tr><td>Intoxication</td><td>3 (0.4)</td><td>5 (0.6)</td><td></td></tr><tr><td>Other</td><td>6 (0.9)</td><td>18 (2.0)</td><td></td></tr><tr><td>Missing data (%)</td><td>0 (0.0)</td><td>1 (0.1)</td><td></td></tr><tr><td>Smoking history</td><td>244 (34.9)</td><td>377 (41.7)</td><td>0.007</td></tr><tr><td>Blood type</td><td></td><td></td><td>0.41</td></tr><tr><td>A</td><td>273 (39.1)</td><td>329 (36.4)</td><td></td></tr><tr><td>AB</td><td>12 (1.7)</td><td>20 (2.2)</td><td></td></tr><tr><td>B</td><td>60 (8.6)</td><td>82 (9.1)</td><td></td></tr><tr><td>O</td><td>298 (42.6)</td><td>416 (46.0)</td><td></td></tr><tr><td>Missing data (%)</td><td>56 (8.0)</td><td>57 (6.3)</td><td></td></tr><tr><td>CMV positive serology</td><td>369 (52.8)</td><td>420 (46.5)</td><td>0.014</td></tr><tr><td>EBV positive serology</td><td>678 (97.0)</td><td>852 (94.2)</td><td>0.027</td></tr><tr><td>Missing data (%)</td><td>0 (0.0)</td><td>1 (0.1)</td><td></td></tr><tr><td>Toxoplasmosis positive serology</td><td>355 (50.8)</td><td>495 (54.8)</td><td>0.27</td></tr><tr><td>Missing data (%)</td><td>98 (14.0)</td><td>112 (12.4)</td><td></td></tr></tbody></table>

Data are expressed as numbers (%), means (± standard deviations), or medians [interquartile ranges].

<footnote><sup>a</sup>Estimated with χ2, Student's, or Wilcoxon tests. <sup>b</sup> There are no missing data for variables for which there is no corresponding line. CMV, Cytomegalovirus; EBV, Epstein-Barr Virus.</footnote>
<table><caption>Supplemental table 6. Cause of death after transplantation</caption><thead><tr><th></th><th>Women<br>(n = 253)</th><th>Men<br>(n = 371)</th><th>p-value</th></tr></thead><tbody><tr><td>Cause of death (%)</td><td></td><td></td><td>0.51</td></tr><tr><td>Cancer</td><td>15 (5.9)</td><td>28 (7.5)</td><td></td></tr><tr><td>Cardiovascular</td><td>19 (7.5)</td><td>23 (6.2)</td><td></td></tr><tr><td>Cerebrovascular</td><td>4 (1.6)</td><td>8 (2.2)</td><td></td></tr><tr><td>Digestive</td><td>0 (0.0)</td><td>1 (0.3)</td><td></td></tr><tr><td>Graft failure</td><td>91 (36.0)</td><td>116 (31.3)</td><td></td></tr><tr><td>Hemorrhage</td><td>23 (9.1)</td><td>23 (6.2)</td><td></td></tr><tr><td>Infection</td><td>58 (22.9)</td><td>95 (25.6)</td><td></td></tr><tr><td>MOF</td><td>14 (5.5)</td><td>29 (7.8)</td><td></td></tr><tr><td>Other</td><td>13 (5.1)</td><td>15 (4.0)</td><td></td></tr><tr><td>Traumatic</td><td>0 (0.0)</td><td>3 (0.8)</td><td></td></tr><tr><td>Unknown</td><td>16 (6.3)</td><td>30 (8.1)</td><td></td></tr></tbody></table>
<table><caption>Supplemental table 7. Univariate Cox regression for overall survival, and gender-adjusted analysis</caption><thead><tr><th rowspan="2">Variables</th><th colspan="2">Univariate analysis</th><th colspan="4">Gender adjusted analysis<br>(Surv(time, rejection) ~ gender + variable)<sup>a</sup></th></tr><tr><th>HR (95% CI)</th><th>P-value</th><th>Gender adjusted<br>HR<br>(95% CI)</th><th>Gender<br>adjusted<br>p-value</th><th>Variable adjusted<br>HR<br>(95% CI)</th><th>Variable<br>adjusted<br>p-value</th></tr></thead><tbody><tr><td>Male gender</td><td>1.32 (1.12-1.55)</td><td>0.001</td><td></td><td></td><td></td><td></td></tr><tr><td>Age</td><td>1.01 (1.01-1.02)</td><td>&lt;0.001</td><td>1.26 (1.07-1.48)</td><td>0.006 **</td><td>1.01 (1.01-1.02)</td><td>&lt;0.001 ***</td></tr><tr><td>Underlying diagnosis</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Cystic fibrosis</td><td>Ref.</td><td>-</td><td>1.19 (1.01-1.41)</td><td>0.035 *</td><td>Ref.</td><td>-</td></tr><tr><td>Pulmonary arterial hypertension</td><td>1.32 (0.88-1.98)</td><td>0.177</td><td>-</td><td>-</td><td>1.35 (0.90-2.03)</td><td>0.147</td></tr><tr><td>COPD/emphysema</td><td>1.82 (1.46-2.26)</td><td>&lt;0.001</td><td>-</td><td>-</td><td>1.80 (1.45-2.24)</td><td>&lt;0.001 ***</td></tr><tr><td>Other</td><td>2.04 (1.50-2.78)</td><td>&lt;0.001</td><td>-</td><td>-</td><td>2.08 (1.52-2.83)</td><td>&lt;0.001 ***</td></tr><tr><td>Interstitial lung disease</td><td>2.82 (2.23-3.58)</td><td>&lt;0.001</td><td>-</td><td>-</td><td>2.72 (2.14-3.46)</td><td>&lt;0.001 ***</td></tr><tr><td>CMV positive serology</td><td>1.07 (0.91-1.25)</td><td>0.431</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>1.08 (0.92-1.26)</td><td>0.362</td></tr><tr><td>EBV positive serology</td><td>0.84 (0.63-1.13)</td><td>0.254</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>0.84 (0.63-1.12)</td><td>0.235</td></tr><tr><td>Bacterial colonization</td><td>1.40 (1.20-1.65)</td><td>&lt;0.001</td><td>1.28 (1.09-1.51)</td><td>0.002 **</td><td>1.39 (1.18-1.62)</td><td>&lt;0.001 **</td></tr><tr><td>Fungal colonization</td><td>1.11 (0.94-1.30)</td><td>0.209</td><td>1.30 (1.11-1.53)</td><td>0.001 **</td><td>1.10 (0.94-1.29)</td><td>0.248</td></tr><tr><td>6-minute walk test, % of predicted</td><td>1.00 (0.99-1.00)</td><td>0.096</td><td>1.40 (1.15-1.70)</td><td>0.001 **</td><td>1.00 (0.99-1.00)</td><td>0.147</td></tr><tr><td>On noninvasive ventilation before transplantation</td><td>0.75 (0.63-0.88)</td><td>0.001</td><td>1.31 (1.11-1.55)</td><td>0.001 *</td><td>0.74 (0.63-0.88)</td><td>0.001 **</td></tr></tbody></table>
<table><tr><td>Long term oxygen supplementation</td><td>1.07 (0.80-1.41)</td><td>0.657</td><td>1.32 (1.12-1.56)</td><td>0.001 **</td><td>1.04 (0.78-1.37)</td><td>0.808</td></tr><tr><td>Ischemic heart disease</td><td>1.87 (1.39-2.52)</td><td>&lt;0.001</td><td>1.29 (1.10-1.52)</td><td>0.002 **</td><td>1.80 (1.34-2.43)</td><td>&lt;0.001 **</td></tr><tr><td>High blood pressure</td><td>1.12 (0.88-1.42)</td><td>0.367</td><td>1.31 (1.12-1.54)</td><td>0.001 **</td><td>1.09 (0.86-1.39)</td><td>0.483</td></tr><tr><td>Secondary pulmonary arterial hypertension</td><td>0.95 (0.73-1.22)</td><td>0.669</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>0.94 (0.73-1.21)</td><td>0.642</td></tr><tr><td>Dyslipidemia</td><td>1.51 (1.13-2.02)</td><td>0.006</td><td>1.30 (1.11-1.53)</td><td>0.001 **</td><td>1.46 (1.09-1.96)</td><td>0.011 *</td></tr><tr><td>Diabetes</td><td>0.78 (0.62-0.98)</td><td>0.033</td><td>1.32 (1.13-1.55)</td><td>0.001 **</td><td>0.77 (0.61-0.97)</td><td>0.025</td></tr><tr><td>Heart failure</td><td>1.15 (0.57-2.30)</td><td>0.701</td><td>1.32 (1.12-1.54)</td><td>0.001 **</td><td>1.13 (0.56-2.27)</td><td>0.735</td></tr><tr><td>Gastroesophageal reflux</td><td>0.77 (0.58-1.03)</td><td>0.075</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>0.77 (0.58-1.02)</td><td>0.073</td></tr><tr><td>Kidney failure</td><td>0.00 (0.00-Inf)</td><td>0.988</td><td>1.32 (1.13-1.55)</td><td>0.001 **</td><td>0.00 (0.00-Inf)</td><td>0.988</td></tr><tr><td>Osteoporosis</td><td>0.96 (0.69-1.34)</td><td>0.827</td><td>1.32 (1.12-1.54)</td><td>0.001 **</td><td>0.98 (0.70-1.37)</td><td>0.906</td></tr><tr><td>Cancer</td><td>1.60 (1.17-2.19)</td><td>0.003</td><td>1.33 (1.13-1.56)</td><td>0.001 **</td><td>1.63 (1.19-2.23)</td><td>0.002 *</td></tr><tr><td>Pre-transplant anti-HLA antibodies</td><td>0.88 (0.75-1.05)</td><td>0.149</td><td>1.30 (1.10-1.53)</td><td>0.002 **</td><td>0.93 (0.78-1.10)</td><td>0.413</td></tr><tr><td>Height, cm</td><td>1.01 (1.00-1.02)</td><td>0.085</td><td>1.36 (1.10-1.68)</td><td>0.005 **</td><td>1.00 (0.99-1.01)</td><td>0.59</td></tr><tr><td>pTLC ratio between donor and recipient</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>[0.92 ; 1.41]</td><td>Ref.</td><td>-</td><td>1.30 (1.09-1.55)</td><td>0.003 **</td><td>Ref.</td><td>-</td></tr><tr><td>&lt; 0.92</td><td>1.25 (1.04-1.51)</td><td>0.02</td><td>-</td><td>-</td><td>1.17 (0.96-1.41)</td><td>0.116</td></tr><tr><td>&gt; 1.41</td><td>1.19 (0.83-1.70)</td><td>0.346</td><td>-</td><td>-</td><td>1.36 (0.94-1.98)</td><td>0.104</td></tr></table>
<table><thead><tr><th>Recipient's blood type</th><th>Ref.</th><th></th><th></th><th></th><th>Ref.</th><th></th></tr></thead><tbody><tr><td>A</td><td></td><td>-</td><td>1.31 (1.10-1.55)</td><td>0.002 **</td><td></td><td>-</td></tr><tr><td>AB</td><td>0.93 (0.58-1.49)</td><td>0.768</td><td>-</td><td>-</td><td>0.92 (0.58-1.47)</td><td>0.729</td></tr><tr><td>B</td><td>0.91 (0.68-1.21)</td><td>0.517</td><td>-</td><td>-</td><td>0.92 (0.69-1.23)</td><td>0.578</td></tr><tr><td>O</td><td>0.96 (0.80-1.15)</td><td>0.661</td><td>-</td><td>-</td><td>0.96 (0.80-1.15)</td><td>0.636</td></tr><tr><td>Smoking history</td><td>1.53 (1.26-1.85)</td><td>&lt;0.001</td><td>1.33 (1.11-1.61)</td><td>0.002 **</td><td>1.46 (1.20-1.77)</td><td>&lt;0.001 **</td></tr><tr><td>High emergency</td><td>1.47 (1.21-1.80)</td><td>&lt;0.001</td><td>1.33 (1.13-1.56)</td><td>0.001 **</td><td>1.49 (1.22-1.82)</td><td>&lt;0.001 **</td></tr><tr><td>Type of transplantation</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Double lung transplant</td><td>Ref.</td><td>-</td><td>1.28 (1.08-1.51)</td><td>0.004 **</td><td>Ref.</td><td>-</td></tr><tr><td>Single lung transplant</td><td>1.72 (1.14-2.60)</td><td>0.01</td><td>-</td><td>-</td><td>1.76 (1.16-2.65)</td><td>0.007 *</td></tr><tr><td>Heart and lung transplant</td><td>1.87 (1.53-2.29)</td><td>&lt;0.001</td><td>-</td><td>-</td><td>1.81 (1.48-2.21)</td><td>&lt;0.001 ***</td></tr><tr><td>Volume reduction</td><td>1.24 (0.98-1.57)</td><td>0.068</td><td>1.45 (1.21-1.73)</td><td>&lt;0.001 **</td><td>1.35 (1.07-1.71)</td><td>0.013 *</td></tr><tr><td>Graft ischemia, hours</td><td>1.04 (1.01-1.07)</td><td>0.012</td><td>1.31 (1.12-1.54)</td><td>0.001 **</td><td>1.04 (1.01-1.07)</td><td>0.016</td></tr><tr><td>Gender mismatch</td><td>0.97 (0.82-1.15)</td><td>0.745</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>1.00 (0.85-1.19)</td><td>0.962</td></tr><tr><td>Blood type mismatch</td><td>0.95 (0.68-1.33)</td><td>0.755</td><td>1.31 (1.10-1.55)</td><td>0.002 **</td><td>0.95 (0.68-1.33)</td><td>0.757</td></tr><tr><td>Weight mismatch (D-R)</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>No weight mismatch</td><td>Ref.</td><td>-</td><td>1.23 (1.04-1.45)</td><td>0.016 *</td><td>Ref.</td><td>-</td></tr><tr><td>Donor weight &lt; -15 kg recipient weight</td><td>1.57 (1.22-2.01)</td><td>&lt;0.001</td><td>-</td><td>-</td><td>1.50 (1.17-1.92)</td><td>0.002 **</td></tr></tbody></table>
<table><tbody><tr><td>Donor weight > +15 kg recipient weight</td><td>0.83 (0.70-0.99)</td><td>0.038</td><td>-</td><td>-</td><td>0.84 (0.71-1.01)</td><td>0.061</td></tr><tr><td>CMV mismatch</td><td>1.08 (0.89-1.31)</td><td>0.418</td><td>1.31 (1.12-1.54)</td><td>0.001 **</td><td>1.08 (0.89-1.31)</td><td>0.432</td></tr><tr><td>EBV mismatch</td><td>1.26 (0.94-1.70)</td><td>0.122</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>1.27 (0.94-1.70)</td><td>0.114</td></tr><tr><td>Count of HLA incompatibilities</td><td>1.00 (0.94-1.06)</td><td>0.963</td><td>1.30 (1.10-1.54)</td><td>0.002 **</td><td>1.00 (0.94-1.06)</td><td>0.936</td></tr><tr><td>Primary graft dysfunction</td><td>1.56 (1.29-1.89)</td><td>&lt;0.001</td><td>1.38 (1.15-1.65)</td><td>0.001 **</td><td>1.60 (1.32-1.93)</td><td>&lt;0.001 ***</td></tr><tr><td>Donor age, years</td><td>1.01 (1.00-1.01)</td><td>0.002</td><td>1.32 (1.12-1.56)</td><td>0.001 **</td><td>1.01 (1.00-1.01)</td><td>0.001 **</td></tr><tr><td>Weight, kg</td><td>1.00 (0.99-1.00)</td><td>0.648</td><td>1.35 (1.15-1.60)</td><td>&lt;0.001 **</td><td>1.00 (0.99-1.00)</td><td>0.179</td></tr><tr><td>Height, cm</td><td>1.00 (0.99-1.01)</td><td>0.707</td><td>1.40 (1.18-1.66)</td><td>&lt;0.001 **</td><td>0.99 (0.98-1.00)</td><td>0.073</td></tr><tr><td>Body mass index, kg/m2</td><td>1.00 (0.98-1.02)</td><td>0.818</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>1.00 (0.98-1.02)</td><td>0.707</td></tr><tr><td>Cause of death</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Vascular</td><td>Ref.</td><td>-</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>Ref.</td><td>-</td></tr><tr><td>Traumatic, public road accident</td><td>0.89 (0.70-1.14)</td><td>0.354</td><td>-</td><td>-</td><td>0.88 (0.69-1.13)</td><td>0.307</td></tr><tr><td>Traumatic, non-road accident</td><td>1.07 (0.85-1.33)</td><td>0.58</td><td>-</td><td>-</td><td>1.04 (0.83-1.31)</td><td>0.717</td></tr><tr><td>Anoxia</td><td>0.99 (0.79-1.25)</td><td>0.951</td><td>-</td><td>-</td><td>0.98 (0.78-1.24)</td><td>0.886</td></tr><tr><td>Meningitis</td><td>1.57 (0.88-2.80)</td><td>0.124</td><td>-</td><td>-</td><td>1.58 (0.89-2.82)</td><td>0.117</td></tr><tr><td>Tumor</td><td>0.66 (0.21-2.07)</td><td>0.478</td><td>-</td><td>-</td><td>0.62 (0.20-1.95)</td><td>0.416</td></tr><tr><td>Intoxication</td><td>2.07 (0.86-5.01)</td><td>0.106</td><td>-</td><td>-</td><td>1.92 (0.79-4.65)</td><td>0.149</td></tr></tbody></table>
<table><tbody><tr><td>Other</td><td>0.89 (0.46-1.72)</td><td>0.728</td><td>-</td><td>-</td><td>0.84 (0.43-1.63)</td><td>0.608</td></tr><tr><td>Smoking history</td><td>1.02 (0.87-1.20)</td><td>0.801</td><td>1.32 (1.12-1.54)</td><td>0.001 **</td><td>1.01 (0.86-1.18)</td><td>0.936</td></tr><tr><td>Blood type</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>A</td><td>Ref.</td><td>-</td><td>1.30 (1.10-1.53)</td><td>0.002 **</td><td>Ref.</td><td>-</td></tr><tr><td>AB</td><td>0.88 (0.48-1.61)</td><td>0.671</td><td>-</td><td>-</td><td>0.86 (0.47-1.57)</td><td>0.62</td></tr><tr><td>B</td><td>1.06 (0.80-1.42)</td><td>0.667</td><td>-</td><td>-</td><td>1.08 (0.81-1.44)</td><td>0.594</td></tr><tr><td>O</td><td>1.00 (0.84-1.19)</td><td>0.989</td><td>-</td><td>-</td><td>1.00 (0.84-1.19)</td><td>0.996</td></tr><tr><td>Anti-CMV antibodies</td><td>1.08 (0.92-1.26)</td><td>0.363</td><td>1.32 (1.13-1.55)</td><td>0.001 **</td><td>1.09 (0.93-1.27)</td><td>0.293</td></tr><tr><td>Anti-EBV antibodies</td><td>1.09 (0.74-1.60)</td><td>0.662</td><td>1.32 (1.12-1.55)</td><td>0.001 **</td><td>1.11 (0.75-1.63)</td><td>0.609</td></tr><tr><td>Anti-toxoplasmosis antibodies</td><td>1.03 (0.87-1.23)</td><td>0.734</td><td>1.33 (1.12-1.58)</td><td>0.001 **</td><td>1.03 (0.87-1.23)</td><td>0.724</td></tr></tbody></table>

ª Where *Surv()* is the survival function, *time* is the time between the transplantation day and the rejection or the day of the last follow-up, *rejection* is the event of the survival analysis, *gender* is present in all the adjusted bivariable analyses, *variable* corresponds to the other explanatory variables.

Results with significant p-values corrected by Benjamini-Hochberg are indicated as follows: \* p < 0.05, \*\* p < 0.01, and \*\*\* p < 0.001. HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; CMV, Cytomegalovirus; EBV, Epstein-Barr Virus; pTLC, predicted total lung capacity; HLA, human leukocyte antigen; D: Donor, DSA, donor-specific antibodies; R: Recipient.
<table><caption>Supplemental table 8. Multivariable Cox regression for overall survival</caption><thead><tr><th>Variables (n = 1,256)</th><th>HR (95% CI)</th><th>P-value</th></tr></thead><tbody><tr><td>Male gender</td><td>1.34 [1.11-1.62]</td><td>&lt;0.001</td></tr><tr><td>Underlying diagnosis</td><td></td><td></td></tr><tr><td>Cystic fibrosis</td><td>Ref.</td><td>-</td></tr><tr><td>Pulmonary arterial hypertension</td><td>1.23 [0.71-2.12]</td><td>0.47</td></tr><tr><td>COPD/emphysema</td><td>2.46 [1.74-3.48]</td><td>&lt;0.001</td></tr><tr><td>Other</td><td>2.21 [1.45-3.35]</td><td>&lt;0.001</td></tr><tr><td>Interstitial lung disease</td><td>3.09 [2.14-4.45]</td><td>&lt;0.001</td></tr><tr><td>Type of transplantation</td><td></td><td></td></tr><tr><td>Double lung transplant</td><td>Ref.</td><td>-</td></tr><tr><td>Single lung transplant</td><td>1.48 [1.16-1.89]</td><td>&lt;0.001</td></tr><tr><td>Heart and lung transplant</td><td>2.18 [1.28-3.69]</td><td>&lt;0.001</td></tr><tr><td>Ischemic heart disease</td><td>1.57 [1.13-2.17]</td><td>0.01</td></tr><tr><td>Volume reduction</td><td>1.39 [1.07-1.81]</td><td>0.01</td></tr><tr><td>Recipient age</td><td>0.99 [0.98-1.00]</td><td>0.03</td></tr><tr><td>Donor age</td><td>1.01 [1.00-1.01]</td><td>0.01</td></tr><tr><td>EBV mismatch</td><td>1.54 [1.09-2.17]</td><td>0.02</td></tr><tr><td>Graft ischemia, hours</td><td>1.03 [1.00-1.07]</td><td>0.08</td></tr><tr><td>Cancer</td><td>1.44 [1.00-2.09]</td><td>0.05</td></tr><tr><td>High emergency</td><td>1.24 [0.96-1.59]</td><td>0.1</td></tr></tbody></table>

After the pre-selection of variables with a p-value < 0.2 in the univariate analysis, a stepwise forward selection was applied with the Akaike information criterion to create a multivariate model with the recipient's gender. HR, hazard ratio; CI, confidence interval; COPD, chronic obstructive pulmonary disease; EBV, Epstein-Barr Virus.
<figure><img src="image_15.png" /><figcaption>Supplemental figure 1. Comparison of survival between women and men over 8 years according to underlying diagnosis.</figcaption></figure>

Log-rank tests used. (A) COPD/emphysema. COPD: Chronic obstructive pulmonary disease. (B) Cystic fibrosis. (C) ILD: Interstitial lung disease. (D) PAH: Pulmonary arterial hypertension.
<figure><img src="image_16.png" /><figcaption>Supplemental figure 2. Comparison of survival according to weight mismatch (donor weight – recipient weight) over 8 years.</figcaption></figure>

Log-rank tests used. No corresponds to no mismatch (with a weight difference between -15 and 15kg). (A) Only female recipients and (B) only male recipients are considered.
<figure><img src="image_17.png" /><figcaption>Supplemental figure 3. pTLC ratio nonlinear association with declining risk of death.</figcaption></figure>

The impact of pTLC ratio values on recipient survival was computed with a Cox model. pTLC ratios were modelized with a spline to deal with the nonlinear relationship between those variables. The intersection points between pTLC ratio spline with the hazard ratio value 1 served as cutoff points to categorize pTLC ratio values.