Incidence of pulmonary damage is high after allogeneic stem cell transplantation (allo-SCT) and accounts for one of the main causes of non-relapse mortality (NRM) and intensive care unit admission. Pre-transplant alteration of lung function is considered to be the most important parameter to take into account to predict pulmonary complications and outcomes.1 As a consequence, pre-transplant pulmonary function testing (PFT) is required in all patients eligible for an allo-SCT. Diffusion lung capacity for carbon monoxide measured after a 10-s single breath-hold technique (DLCO10s, thereafter DLCO), which reflects the alveolar capillary interface, is considered to be one of the key parameters to cancel the allograft. Indeed, reduction of the diffusion capacity has been shown to predict NRM, overall survival (OS) and early respiratory failure after allo-SCT.1, 2 Thus, current guidelines suggest that patients with a pre-transplant DLCO <60% of predicted normal value (PNV) are not ideal candidates for allo-SCT. However, this recommendation is currently debated, especially since the predominant use of less toxic reduced-intensity conditioning regimens.3, 4, 5
Other pulmonary parameters may help to discriminate patients at high risk of severe lung complications. In 1987, Guénard et al.,6 demonstrated that nitric oxide (NO), together with CO, can be used to measure the diffusion pathway from the alveoli to capillary plasma in the lung. The lung diffusing capacity for NO (DLNO) is considered to be a measure of membrane conductance, which is less affected by any diffusive resistance associated with capillary erythrocytes, except the presence of free hemoglobin. In fact, DLNO reflects the distance between the alveoli and the capillaries mainly related to the alveolar–capillary membrane and the thickness of the alveolar blood barrier, while DLCO rather reflects the capillary blood vessels function.7 Also, DLNO/DLCO ratio represents a new index of gas exchange and an alternative way of investigating the alveolar membrane and the blood reacting with the gas.8 Although explored in many lung diseases,9, 10, 11, 12 the impact of DLNO and DLNO/DLCO ratio has not been yet established in the setting of allo-SCT. It is of particular interest as radiotherapy and chemotherapy used to treat patients with hematological diseases affect mostly the alveolar–capillary membrane, destruction of which is better appreciated by DLNO than DLCO measure. In our study, DLNO and DLNO/DLCO ratio seem more appropriate to predict pulmonary complications than DLCO after allo-SCT and, therefore, should be rather considered to define eligibility for transplant.
Between March 2012 and January 2014, 153 adults performed a pre-transplant PFT in our department. Fifty patients were excluded from the study because: (1) no DLNO measure was performed during the pre-transplant PFT (n=30); (2) an unevaluated pre-transplant diffusion lung capacity (n=10); (3) allograft was contra-indicated due to abnormal PFT (n=1), uncontrolled infection (n=4), psychiatric illness (n=1), relapse before transplant (n=3) or death during the conditioning regimen (n=1). Thus, overall, the full PFT data required for the study for each case were available in 103 patients. Characteristics of patients are summarized in Table 1. The study was approved by the Institutional Review Board of the French learned society for respiratory medicine—Société de Pneumologie de Langue Française (ref. number CEPRO 2015-025)—and patients gave their consents for anonymous use of their data.
All PFT were performed routinely at the CHU of Nantes in the same laboratory. Because of faster diffusion, DLNO is measured after a 5 s (and not 10 s) single breath-hold technique (DLNO5s, thereafter DLNO). DLCO can be measured simultaneously (DLCO5s) for a double diffusion measure, allowing calculation of a DLNO5s/DLCO5s ratio (thereafter DLNO/DLCO). Normal DLCO and DLNO percentage of PNV (>80%) were documented in 48 and 44 patients, respectively, but median percentages for the all cohort were below the normal at transplant: DLCO: 78.9%, DLNO: 78.1%. Median DLNO/DLCO ratio was 5.3 (range: 2.7–8.6). Only six patients had a pejorative high-risk lung function score (between 6 and 9).13 Median DLCO was significantly decreased in older patients (>58 years, 75.4% of PNV vs 81.0%, P=0.05), patients with previous documented respiratory events (72.3 vs 81.5%, P=0.001) or previous administration of drugs with cardiac or pulmonary toxicities (74.2 vs 80.6%, P=0.02). Median DLNO was also significantly decreased in patients with previous documented respiratory events (74.3 vs 80.9%, P=0.03) and patients with active or history of smoking (75.3 vs 81.8%, P=0.03). Finally, younger patients (⩽58 years) had a significant lower median DLNO/DLCO ratio (5.2 vs 5.5, P=0.04).
Median follow-up was 21.5 months (range: 3.8–34.7). Two years OS, disease-free survival, relapse incidence and NRM were 65.4% (55.2–73.6), 52.5% (42.7–62.2), 31.8% (22.3–41.7) and 15.8% (9.4–23.5), respectively. Cumulative incidence (CI) of acute GvHD grade II–IV and grade III–V were 34% (25–43.2) and 19.4% (12.4–27.6), while CI of overall and extensive chronic GvHD were 25.5% (17.5–34.3) and 14.7% (8.6–22.3), respectively.
After transplant, any type of pulmonary event was retrieved retrospectively from clinical and radiologic data available in medical records. Thus, 77 respiratory events were documented in 53 patients: 27 bronchitis, 22 pneumonia, 14 invasive fungal infection, 4 bronchiolitis obliterans syndrome, 2 idiopathic pulmonary fibrosis, 2 pneumothorax, 1 tuberculosis, 1 sinusoidal obstruction syndrome, 1 mediastinal lymphoma, 1 acute pulmonary edema, 1 pulmonary embolus and 1 case with multiple pulmonary nodules of undetermined significance. The median number of pulmonary events per patient after transplant was 1 (range: 0–7). Two year CI of severe pulmonary complication (SPC; defined as any pulmonary complication responsible for hospitalization), acute respiratory distress syndrome (ARDS) and pulmonary related mortality (PRM) were 25.4% (17–34), 7.8% (4–14), and 4.9% (1.8–10.4), respectively. Overall, five patients died of a respiratory complication (one invasive aspergillosis; one CMV pneumonia; three bacterial pneumonia in patients with severe acute or refractory chronic GvHD: pseudomonas aeruginosa n=2, pseudomonas aeruginosa+acinetobacter baumanii n=1).
In univariate analysis, when considering various cutoffs (⩾80%, 60–80% and <60%), DLCO was not predictive of any outcomes considered for the analysis: ARDS, SPC, PRM and NRM (Table 2). Conversely, a DLNO value <60% was associated with significant higher incidences of SPC (⩾80%: 20.5% vs 60–80%: 24% vs <60%: 59.3%, P=0.02) and ARDS (⩾80%: 9.1% vs 60–80%: 2% vs <60%: 35.6%, P<0.005). When considering DLCO and DLNO as continuous variables, lower percentage were associated with higher risk of SPC for both parameters (P=0.048 and P=0.026, respectively). Also, lower DLNO/DLCO ratio (considered as a continuous variable) was associated with higher PRM (P=0.04). Previous history of pulmonary events was associated with higher risk of ARDS (no: 3.1% vs yes: 15.8%, P<0.01). Among factors related to patient, disease or transplant, only the type of disease impacted on pulmonary outcomes as lymphoid patients were associated with higher risk of ARDS (P=0.04), SPC (P=0.03) and PRM (P=0.02).
In multivariate analysis, there was a trend for a significant association between lower value of pre-transplant DLNO (<60%) and higher risk of ARDS (hazards ratio (HR): 3.34, 95% confidence interval (CI): 0.99–11.2, P=0.05) and of SPC (HR: 2.5, 95% CI: 0.93–7.12, P=0.06).
At our knowledge, this is the first series reporting on the impact of pre-transplant DLNO percentage and DLNO/DLCO ratio after allo-SCT. In univariate analysis, lower value of DLNO (<60% of PNV) was associated with higher incidence of ARDS and SPC, while lower DLNO/DLCO ratio was associated with an increased risk of PRM. Significance was not reached by multivariate analysis probably because of the relative small number of patients of our cohort.
Currently, lower pre-transplant DLCO percentage remains generally an exclusion criterion when considering the eligibility of a patient for allo-SCT. Guidelines suggest that patients with pre-transplant DLCO <60% of PNV should not proceed with the transplant because of an inacceptable increased risk of pulmonary complication and mortality. Here, we found no impact of lower pre-transplant DLCO value, confirming recent results observed in adults as well as in children.3, 4, 5 In fact, DLCO is the most variable parameter in a PFT, particularly when a restrictive or obstructive ventilatory impairment is present, suggesting that a lower value in one patient may be equivalent to a normal value in another. Thus, DLCO should not be retained anymore as unique criteria to decide or not to perform the graft in patient.
In the literature, DLNO/DLCO ratio has been observed between 4.3 and 5.3,8 which is in accordance with the median value (4.9±0.6) observed in a cohort of healthy subjects who performed PFT, including both DLNO and DLCO measures, in our department. If the median ratio was higher for hematological patients included in this study, it is difficult to define it as abnormal, as no normal values have been clearly reported currently. Higher median ratio may be the fact of older age of our cohort or higher concentration of free hemoglobin in this population, as it is highly reactive with NO.14
As a conclusion, DLNO and DLNO/DLCO ratio seem more appropriate to predict pulmonary complications than DLCO after allo-SCT and, therefore, should be rather considered to define eligibility for transplant. However, the number of patients is low in our study and many variables may be involved explaining the results. Then multivariable analysis with a larger patient-group and clear exclusion criteria of transplant patients, who are considered not eligible because of preceding pulmonary problems, should be proposed in the future.
Parimon T, Madtes DK, Au DH, Clark JG, Chien JW . Pretransplant lung function, respiratory failure, and mortality after stem cell transplantation. Am J Respir Crit Care Med 2005; 172: 384–390.
Sorror ML, Maris MB, Storb MR, Baron F, Sandmanier BM, Maloney DG et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood 2005; 106: 2912–2919.
Chien JW, Sullivan KM . Carbon monoxide diffusion capacity: how low can you go for hematopoietic cell transplantation eligibility? Biol Blood Marrow Transplant 2009; 15: 447–453.
Ho VT, Weller E, Lee SJ, Alyea EP, Antin JH, Soiffier RJ . Prognostic factors for early severe pulmonary complications after hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 2001; 7: 223–229.
Kaya Z, Weiner DJ, Yilmaz D, Rowan J, Goyal RK . Lung function, pulmonary complications, and mortality after allogeneic blood and marrow transplantation in children. Biol Blood Marrow Transplant 2009; 15: 817–826.
Guénard H, Varene N, Vaida P . Determination of lung capillary blood volume and membrane diffusing capacity in man by the measurements of NO and CO transfer. Respir Physiol 1987; 70: 113–120.
Glenet SN, De Bisschop C, Vargas F, Guénard HJ . Deciphering the nitric oxide to carbon monoxide lung transfer ratio: physiological implications. J Physiol 2007; 582 (Pt 2): 767–775.
Hughes JM, van der Lee I . The TL,NO/TL,CO ratio in pulmonary function test interpretation. Eur Respir J 2013; 41: 453–461.
van der Lee I, Gietema HA, Zanen P, van Klaveren RJ, Prokop M, Lammers JW et al. Nitric oxide diffusing capacity versus spirometry in the early diagnosis of emphysema in smokers. Respir Med 2009; 103: 1892–1897.
Werneau-Stervinou L, Perez T, Murphy C, Polge AS, Wallaert B . Lung capillary blood volume and membrane diffusion in idiopathic interstitial pneumonia. Respir Med 2012; 106: 564–570.
Degano B, Mittaine M, Guenard H, Rami J, Kamar N, Bureau C et al. Nitric oxide and carbon monoxide lung transfer in patients with advanced liver cirrhosis. J Appl Physiol 2009; 107: 139–143.
Farha S, Laskowski D, George D, Park MM, Tang WH, Dweik RA et al. Loss of alveolar membrane diffusing capacity and pulmonary capillary blood volume in pulmonary arterial hypertension. Respir Res 2013; 14: 6.
Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R et al. Interpretative strategies for lung function tests. Eur Respir J 2005; 26: 948–968.
Sakari H, Okuda N, Sato A, Yamanue T, Takeoka S, Tsuchida E . Hemoglobin encapsulation in vesicles retards NO and CO binding and O2 release when perfused through narrow gas-permeable tubes. Am J Physiol Heart Circ Physiol 2010; 298: H956–H965.
Armand P, Kim HT, Logan BR, Wang Z, Alyea EP, Kalaycio ME et al. Validation and refinement of the Disease Risk Index for allogeneic stem cell transplantation. Blood 2014; 123: 3664–3671.
The authors declare no conflict of interest.
About this article
Cite this article
Le Bourgeois, A., Malard, F., Chevallier, P. et al. Impact of pre-transplant diffusion lung capacity for nitric oxide (DLNO) and of DLNO/pre-transplant diffusion lung capacity for carbon monoxide (DLNO/DLCO) ratio on pulmonary outcomes in adults receiving allogeneic stem cell transplantation for hematological diseases. Bone Marrow Transplant 51, 589–592 (2016). https://doi.org/10.1038/bmt.2015.284