In this study, we derived two conclusions on the efficacy of PLEX on life-threatening AAV.
Firstly, in terms of the rate of and the predictor for all-cause mortality in AAV patients receiving PLEX, the rate of all-cause mortality was assessed as 44.4%, but no significant predictor for all-cause mortality was determined. In the MEPEX trial, the rates of all-cause mortality at 3 and 12 months were 16% and 27% in the PLEX group, which was reflective of renal involvement as the serious manifestation in combination with a high risk of infection due to immunosuppressive therapy [5]. Meanwhile, the PEXIVAS trial included two groups: 352 patients in the PLEX group and 352 in the no PLEX group based on glucocorticoid therapy. The rate of all-cause mortality and end-stage renal disease (ESRD) occurrence was 28.4% in the PLEX groups and 31.0% in the no PLEX groups. The HR of PLEX on all-cause mortality compared to no PLEX was 0.87 (95% confidence interval 0.58-1.29). Therefore, PLEX did not have any influence on the rate of all-cause mortality or ESRD occurrence in AAV patients [8]. It could be assumed that the very high mortality rate might interfere and offset the statistical significance of the predictor of all-cause mortality after performing PLEX. Also, this may have two clinical meanings: first, the therapeutic efficacy of PLEX might not be as high as was expected. Second, the severity of AAV might exceed the therapeutic potential of PLEX on AAV.
Secondly, we compared the survival-benefit of PLEX for DAH between patients with DAH receiving PLEX and those not receiving. Most previous studies on the efficacy of PLEX have been conducted in patients with kidney involvement of AAV. Two representative clinical trials, such as MEPEX and PEXIVAS, reported the conflicting efficacy of PLEX on RPGN [5, 8]. As for AAV patients with reduced kidney function due to RPGN, there are alternative treatment-modalities in addition to PLEX: transient renal replacement together with combination therapy of high dose glucocorticoid and either cyclophosphamide or rituximab may improve RPGN [3, 4]. However, as for patients with DAH, there is no alternative treatment-modality in addition to PLEX because DAH is more rapidly progressive and fatal than RPGN. For this reason, it seems to be impossible to design and conduct randomised case-controlled clinical trials in AAV patients with urgent DAH, unlike RPGN.
There was the observational case series regarding the efficacy of PLEX on DAH in 12 AAV patients who were admitted to an intensive care unit. The authors demonstrated that PLEX together with a combination of glucocorticoid and immunosuppressive drugs might have a benefit to improve both the respiratory dysfunction and AAV-related DAH in AAV patients, although one patient died. In this study, 10 AAV patients with DAH, of whom 6 patients received PLEX, were retrospectively analysed [10]. However, unlike the previous study, this study could not find any efficacy of PLEX on DAH to improve all-cause mortality. At last, in the Kaplan survival analysis, PLEX did not increase the cumulative patients' survival rate in AAV patients with DAH. In addition, when only 6 AAV patients with DAH receiving PLEX in this study were compared with 12 patients in the previous study, the rate of all-cause mortality was significantly different, 50% vs. 10% [10].
We considered the reason for this discrepancy as the follow-up period. The previous study evaluated the SpO2/FiO2 ratio and assessed the mechanical ventilation mode hourly for 7 days. However, they did not evaluate all-cause mortality after extubation and during follow-up [10]. Thus, it could not be easily accepted that PLEX is beneficial for the improvement of prognosis of AAV-related DAH. Whereas, the median follow-up duration of our study is significantly longer than that of the previous study (1145.5 days for 4 patients not receiving PLEX and 130.0 days for 6 patients receiving PLEX). Of 4 AAV deceased patients with DAH, three patients died of sepsis due to secondary pneumonia one patient died of the rapid progression of DAH due to ineffectiveness of PLEX (Table 3).
Taken together with the results of both our and the previous studies, we would suggest the therapeutic strategies depending on the time-course. Firstly, within one or two weeks from DAH development, PLEX along with a combination of glucocorticoid with CYC or RTX should be promptly initiated under close observation in the intensive care unit. This strategy is expected to reduce the rate of all-cause mortality at a rate from 8.3% to 10.0%. Next, after two weeks from DAH development, the most common reason for death was secondary pneumonia and sepsis. Therefore, the monitoring of pneumonia occurrence, the use of preventive antibiotics and the choice of dose or type of immunosuppressive drugs should be carefully considered.
Our study has several limitations. Firstly, we provided a narrative report rather than an analytic one, as the number of patients who received PLEX was too small to conduct a subgroup analysis. In particular, for this reason, the comparison of variables between patients with DAH and without DAH treated with PLEX was not allowed. Secondly, we could not obtain all sufficient information from the medical record such as PLEX technique, ventilator modes and lung-involvement pattern due to the limitation of a retrospective study design. Thirdly, this study analysed the data which had been accumulated over 8 years. During this period, the overall prognosis of AAV patients had been improved along with the development of the accuracy of ANCA tests and the efficacy of immunosuppressive drugs. Therefore, this might impact on the results of the retrospective and observational study. Despite these limitations, however, we believe that our study, which is based on the biggest cohort in Korea, could provide valuable information on PLEX in Korean patients with AAV. Therefore, this study has a clinical significance as a pilot study.