In this study, we report the in-hospital mortality, clinical response and radiologic characteristics of cyclophosphamide-treated mechanically ventilated patients with ILD-associated ARF. We found an overall in-hospital mortality rate of 40%. This is in line with the recent case series of Schulze et al. on 14 patients with ILD-associated ARF treated with cyclophosphamide. In this study, cyclophosphamide therapy was associated with a favourable outcome. However, only the minority of patients had non-vasculitis ILD . Compared to previous reports on mixed ILD-associated ARF not treated with cyclophosphamide, we found lower mortality rates (40% vs 62–67%) [1,2,3]. A systematic review, including 50 studies on patients admitted to the intensive care unit (ICU) with ILD-associated ARF, showed overall in-hospital mortality rates in mechanically ventilated patients of 67% in mixed-ILD and 77% in IPF . Consistent with previous studies, we found that CTD-associated ILD and vasculitis were associated with a lower risk of death than other ILDs (20% and 33% vs 57%) [1, 2, 5]. For life-threatening vasculitis, the following treatment strategies are well known and in accordance with current guidelines: glucocorticoids and either cyclophosphamide or rituximab . Reported ICU survival rates amongst patients with vasculitis-associated ARF range from 25 to 50% . For non-vasculitis, ILD data are scarce, and given the poor prognosis, add-on treatments are needed. Our findings might contribute to the awareness of cyclophosphamide as a treatment option for patients with ARF requiring ICU care, particularly in patients with vasculitis-associated ILD and MCTD-ILD.
Patients with IPF were not included in the study since in the participating hospitals, patients with IPF are rarely admitted to the ICU and generally treated with intravenous corticosteroids alone.
Radiologic evaluation through computed tomography (CT) is essential for the characterization and classification of ILD. In a retrospective analysis of 160 patients with ILD admitted to an ICU, analysis of the 76 with CT scans revealed a higher percent of fibrosing ILD among those who did not survive their ICU stay . However, only 12 of the 160 patients were intubated. The CT scan analysis in our study might be used to predict the prognosis in ILD patients with more severe respiratory failure requiring invasive ventilation. Nevertheless, a larger confirmatory study is needed.
One of the most compelling observations of this study is the significantly higher ground-glass opacification (GGO) proportion in non-survivors than in survivors (71% vs 45%, respectively). The greater proportion of GGOs might be associated with more widespread impairment of alveolar and interstitial space and more prominent reduction of the surface for gas exchange. Therefore, the amount of GGO may be useful in predicting severe disease and the need for aggressive therapy. Furthermore, non-survivors had higher reticulation and fibrosis coarseness scores (26 vs 8; 7 vs 1, respectively). This might imply that a poor prognosis in ILD-associated ARF is associated with the initiation of the fibrotic process. The overall extent of disease may not be that significant, since it is partly determined by consolidation, which may be reversible.
The P/F ratio might be used to predict mortality in ARDS . In our study, non-survivors have overall lower P/F ratio and Cdyn levels at baseline and 3 days after cyclophosphamide treatment. Given the small sample size, this difference did not reach statistical significance. There was a marked increase in the P/F ratio and Cdyn in survivors after 3 days of cyclophosphamide therapy. In non-survivors, the P/F ratio remained virtually unchanged, and Cdyn actually decreased (Table 3, Fig. 2). As such the P/F ratio and Cdyn could potentially be used to monitor the response to cyclophosphamide. Although P/F ratio and Cdyn seem to improve after methylprednisolone initially (Table 3), these patients were not able to wean from the ventilator or make further improvements after steroid therapy. Furthermore, the median time to respond to cyclophosphamide, defined as extubation or a successful weaning course, was 9 days. This may be useful for clinicians seeking to estimate time to treatment effect.
Cyclophosphamide is a highly potent immunosuppressant that comes with potential toxicities, including haemorrhagic cystitis, bone marrow suppression, increased risk of opportunistic infections, and malignancies . However, the level of toxicity is related to the cumulative dose. In this study, only one cycle of cyclophosphamide was given. No severe adverse events were observed. Given the poor prognosis of ILD-associated ARF, the adverse event profile of cyclophosphamide is considered acceptable .
There are a number of limitations to our study that should be considered when interpreting our findings. First, as our study did not include a control group of untreated patients. Therefore, we cannot determine the impact of cyclophosphamide treatment on mortality in ILD-associated ARF. However, in our study the mortality of patients with ILD related ARF treated with cyclophosphamide was lower than the mortality in historical reports in patients not treated with cyclophosphamide. Second, the small size of our series limits the reliability of the results. Unfortunately, the low prevalence of ILD-associated ARF limits patient studies and data collection. Future studies in larger populations, each including a control group, are needed to confirm our findings.