Idiopathic Pneumonia Syndrome after HCT: Evidence of Occult Infectious Etiologies

Background: Idiopathic pneumonia syndrome (IPS) is diagnosed by clinical/radiographic presentation and the exclusion of infection. However, molecular diagnostic methods may allow cases previously classified as idiopathic to be linked to an infectious agent.  We applied a broad panel of currently available molecular tests and pathogen discovery methods to patients with IPS and correlated pathogen detection with outcome.

Methods:  Frozen bronchoalveolar lavage (BAL) samples from 69 HCT patients with IPS diagnosed from 1992 to 2006 were tested by Q-PCR for Legionella, M. pneumoniae, C. pneumoniae, HSV, VZV, EBV, CMV, HHV-6, polyomavirus (BK, JC, WU, KI), parvovirus B19, RSV, PIV, Influenza, HMPV, ADV, HRV, CoVs, HBoV, Enterovirus and Parechovirus, and for aspergillus GM (aGM). Research BALs obtained between day 35 and 50 from 21 asymptomatic HCT patients served as controls. Pathogens were categorized by quantity and known/unknown pathogenicity; the association with overall mortality was analyzed using Cox regression models.

Results: Among 69 HCT patients with IPS (time from HCT to BAL: median 22 days, range 4–119), 39 (57%) had a pathogen detected, compared to 11 out of 21 controls (52%); high pathogen load was detected in 19% and 5%, respectively (Table). The most frequent pathogens were HHV-6 and HRV; CMV low-level shedding was also detected. Among the patients with IPS, the presence of a pathogen was associated with higher mortality in multivariate models (HR, 1.92; p=0.03; adjusted for donor type, steroid use, and diffuse alveolar hemorrhage); neither pathogenicity category (Figure) nor pathogen load were significantly associated with mortality.

Conclusions: A significant number of pathogens were detected in patients with IPS, and pathogen detection was associated with increased mortality. The increased mortality could be due to lack of specific treatment and/or use of corticosteroids. Known pathogens (aspergillus, RSV, PIV, HMPV) can now be readily detected by multiplex PCR and the aGM assay. The interpretation of the detection of pathogens of unknown significance (HHV-6, HRV) is more difficult, but mortality was similar to that of known pathogens. Overall, our data suggest that expanded infection detection panels may re-classify a significant number of IPS cases as infectious pneumonia.  

 

 

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