Primary graft dysfunction following lung transplantation: From pathogenesis to future frontiers

Table 1 The International Society for Heart and Lung Transplantation primary graft dysfunction definition and severity grading 2005 and 2016

PGD stage	PaO2/FiO2 ratio (mmHg)	Chest X-ray findings	2016 update
0	> 300	Normal	Any P/F ratio
1	> 300	Diffuse allograft infiltration/pulmonary oedema	No changes
2	200-300	Diffuse allograft infiltration/pulmonary oedema	No changes
3	< 200	Diffuse allograft infiltration/pulmonary oedema	No changes

PGD: Primary graft dysfunction.

Table 2 Basic phenotypes of chronic lung allograft dysfunction

Phenotypes	Spirometry changes	CT opacities
CLAD	Persistent ≥ 20% decline in FEV1 (based on 2 FEV1 values ≥3 wk apart) compared to baseline
BOS	CLAD and obstruction (FEV1/FVC < 0.7)	No
RAS	CLAD and restriction (≥ 10% decline in TLC from baseline)	Yes
Mixed phenotype	CLAD with obstruction and restriction	Yes
Undefined phenotype	CLAD with obstruction and/or restriction	Yes/No

Adapted from the 2019 Consensus Definition. FVC: Forced vital capacity; BOS: Bronchiolitis obliterans syndrome; RAS: Restrictive allograft syndrome; CLAD: Chronic lung allograft dysfunction; CT: Computed tomography.

Table 3 2019 chronic lung allograft dysfunction staging from the 2019 consensus definition

CLAD stage	Spirometric values
CLAD 0	Current FEV1 > 80% baseline
CLAD 1	Current FEV1 > 65%-80% baseline
CLAD 2	Current FEV1 > 50%-65% baseline
CLAD 3	Current FEV1> 35%-50% baseline
CLAD 4	Current FEV1 ≤ 35% baseline

CLAD: Chronic lung allograft dysfunction; FEV₁: Forced expiratory volume in one second.

Table 4 Oxyhemoglobin saturation and positive end-expiratory pressure combinations for low tidal volume ventilation in managing acute respiratory distress syndrome by the Acute Respiratory Distress Syndrome Network[124]

Arterial oxygenation and PEEP
Target Oxygenation PaO2 = 55-80 mmHg (7.35-10.7 kPa)or O2 saturations (SpO2) = 88%-95%
FiO2/PEEP combinations
FiO2 (%)	PEEP (H2O)
30	5
40	5-8
50	8-10
60	10
70	10-14
80	14
90	14-18
100	18-24

PaO₂: Arterial oxygen tension; SpO₂: Oxyhemoglobin saturation; PEEP: Positive end-expiratory pressure; FiO₂: Fraction of inspired oxygen.

Table 5 Differences between the ex-vivo lung perfusion protocols

Description	Lund	OCS	Toronto
Year	2001[176]	2011[222]	2008[177]
Perfusion parameters
Perfusate	CellularSteen solution + RBCs	CellularOCS proprietary solution + RBCs	AcellularSteen solution
Target haematocrit	14%	15%-25%	N/A
Target flow	100% cardiac output	2.0-2.5 L/min	40% cardiac output
PA pressure	≤ 20 mmHg	≤ 20 mmHg	Flow dictated (usually < 15 mmHg)
Left atrium	Open	Open	Closed
Flow type	Continuous	Pulsatile	Continuous
Ventilation
Initial temperature	32 oC	34 oC	32 oC
Tidal volume	5-7 mL/kg	6 mL/kg	7 mL/kg
Respiratory rate	20/min	10/min	7/min
FiO2	50%	12%	21%
PEEP	5 cmH2O	5-7 cmH2O	5 cmH2O

FiO2: Fraction of inspired oxygen; RBCs: Red blood cells; PEEP: Positive end-expiratory pressure; OCS: Organ Care System.

Table 6 List of biomarkers that have been used in primary graft dysfunction

Biomarker	Donor/recipient	Timing	Type
RAGE[179]	Donor	Retrieval	Alveolar epithelium
	Recipient	Intraoperative, post-transplant
PAI-1[175]	Recipient	Post-transplant	Vascular endothelium
Protein C[179]	Recipient	Post-transplant	Vascular endothelium
IL-8[176]	Donor	EVLP	Inflammatory marker
	Recipient	Pre-transplant
		Post-transplant
ET-1[171]	Donor	EVLP	Inflammatory marker
ICAM-1[27]	Recipient	Post-transplant	Vascular endothelium
IL-6[135]	Recipient	Pre-transplant	Inflammatory marker
		Post-transplant
IL-10[135]	Recipient	Pre-transplant	Inflammatory marker
		Post-transplant
proADM[178]	Recipient	Post-transplant	Vascular endothelium
TNF-α[139]	Recipient	Post-transplant	Inflammatory marker
P-selectin[26]	Recipient	Post-transplant	Vascular endothelium
SP-D[179]	Recipient	Post-transplant	Alveolar epithelium

EVLP: Ex-vivo lung perfusion; proADM: Proadrenomedullin; RAGE: Receptor for advanced glycation endproducts; PAI-1: Plasminogen activator inhibitor-1; ET-1: Endothelin-1; ICAM-1: Intercellular adhesion molecule-1; TNF-α: Tumor necrosis factor-alpha; SP-D: Surfactant protein-D.