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F. Keklik et al.
between lower infused cell dose and DAH was even more evident.
Most cases of DAH occurred within 2 weeks of neu- trophil engraftment. This suggests that a sudden neu- trophil influx may contribute to lung injury.1,7,15,37-39 This phenomenon can even occur in a periengraftment period when patients still have neutropenia.15,38,40
Older age (>40 years),3,5,15 severe acute GvHD,3,7,41 and compromised renal function15,41 have each been reported as risk factors for DAH. In our study, neither age nor acute GvHD was recognized as a risk factor. Kidney dysfunction was observed in one-third of the patients with DAH. Clinically apparent coagulopathy, as determined by stan- dard tests, was uncommon in our DAH patients, as in ear- lier studies.42 Pretransplant respiratory infections have also been described as risk factors for DAH after HCT.10 Although there is no study specifically evaluating the association between smoking and pulmonary complica- tions among HCT recipients, tobacco use and prior lung disease have not been reported as risk factors for DAH.43 Likewise, no correlation was found between smoking sta- tus, bronchiolitis index determined by bronchoscopy, or inflammatory cell fractions, and the likelihood of develop- ing DAH in autologous HCT recipients.44 We observed that almost half of the patients with DAH had a history of smoking but were rarely diagnosed with a specific lung
disease prior to their allogeneic HCT.
The therapy of DAH remains empirical and thus inade-
quate, due in part to the unknown pathogenesis of the condition. Because the immune response and inflamma- tion are suggested to contribute to the pathogenesis of DAH, steroid treatment and mechanical ventilator support for acute respiratory failure are used commonly, although often unsuccessfully, for therapy.21,25,38,45 Etanercept or other anti-cytokine agents,46 drugs targeting coagulopathy such as aminocaproic acid and recombinant factor VIIa,47-49 and prophylactic use of an interleukin-1 receptor antagonist to prevent GvHD50 have also been used. All led to poor out- comes in patients with DAH and the mortality rates for this syndrome remain very high3,9,37,38,51-53 due to respiratory failure, sepsis and multi-organ failure.38,54
Our study confirms that the pathogenesis of DAH is complex, affected by conditioning regimen, graft source, and engraftment kinetics and that the outcome remains poor, particularly for patients requiring intubation/mechanical ventilation. Improved manage- ment of DAH awaits better understanding of the complex relationship of these multiple risk factors and the defini- tion of the best strategy to expedite engraftment and limit lung injury. Formal testing in comparative trials of thera- peutic strategies is needed to validate approaches and limit the high mortality of this devastating syndrome.
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