Cyclophosphamide for interstitial lung disease-associated acute respiratory failure: mortality, clinical response and radiological characteristics

Abstract

Background: Treatment for interstitial lung disease (ILD) patients with acute respiratory failure (ARF) is challenging, and literature to guide such treatment is scarce. The reported in-hospital mortality rates of ILD patients with ARF are high (62-66%). Cyclophosphamide is considered a second-line treatment in steroid-refractory ILD-associated ARF. The first aim of this study was to evaluate the in-hospital mortality in patients with ILD-associated ARF treated with cyclophosphamide. The second aim was to compare computed tomographic (CT) patterns and physiological and ventilator parameters between survivors and non-survivors.

Methods: Retrospective analysis of patients with ILD-associated ARF treated with cyclophosphamide between February 2016 and October 2017. Patients were categorized into three subgroups: connective tissue disease (CTD)-associated ILD, other ILD or vasculitis. In-hospital mortality was evaluated in the whole cohort and in these subgroups. Clinical response was determined using physiological and ventilator parameters: Sequential Organ Failure Assessment Score (SOFA), PaO2/FiO2 (P/F) ratio and dynamic compliance (Cdyn) before and after cyclophosphamide treatment. The following CT features were quantified: ground-glass opacification (GGO) proportion, reticulation proportion, overall extent of parenchymal disease and fibrosis coarseness score.

Results: Fifteen patients were included. The overall in-hospital mortality rate was 40%. In-hospital mortality rates for CTD-associated ILD, other ILD and vasculitis were 20, 57, and 33%, respectively. The GGO proportion (71% vs 45%) was higher in non-survivors. There were no significant differences in the SOFA score, P/F ratio or Cdyn between survivors and non-survivors. However, in survivors the P/F ratio increased from 129 to 220 mmHg and Cdyn from 75 to 92 mL/cmH2O 3 days after cyclophosphamide treatment. In non-survivors the P/F ratio hardly changed (113-114 mmHg) and Cdyn even decreased (27-20 mL/cmH2O).

Conclusion: In this study, we found a mortality rate of 40% in patients treated with cyclophosphamide for ILD-associated ARF. Connective tissue disease-associated ILD and vasculitis were associated with a lower risk of death. In non-survivors, the CT GGO proportion was significantly higher. The P/F ratio and Cdyn in survivors increased after 3 days of cyclophosphamide treatment.

Keywords: Acute respiratory failure; Cyclophosphamide; Ground-glass opacification; Interstitial lung disease.

Fig. 1

Examples of CT coarseness sore. a Coarseness score 1 (fine intralobular fibrosis); b coarseness score 2 (microcystic reticular pattern comprising air spaces smaller than or equal to 4 mm in diameter); c coarseness score 3 (macrocystic reticular pattern comprising air spaces larger than 4 mm in diameter)

Fig. 2

CT scans of two patients before cyclophosphamide treatment and after cyclophosphamide treatment. Coronal CT scan: case 8 (SLE-like disease) before cyclophosphamide treatment (a) and after cyclophosphamide treatment (b). Axial CT scan: case 10 (MCTD-ILD) before cyclophosphamide treatment (c) and after cyclophosphamide treatment (d)

Fig. 3

P/F ratio and dynamic compliance before and after cyclophosphamide therapy. o survivors; x non-survivors. a Case 7 was not shown: ECMO, therefore no realistic P/F ratio. b Case 9 was not shown: patient was extubated after cyclophosphamide treatment; therefore, Cdyn after cyclophosphamide was not available. cdyn: dynamic compliance; CYC: cyclophosphamide; P/F ratio: PaO2/FiO2-ratio