Clinical Impact of Respiratory Viruses in Haematopoietic Stemcell Transplantation; a Firm Association with Bronchiolitis Obliterans.
Authors: Versluys Birgitta , Bierings M. , Schuurman R. , Ewijk B. , Boelens J.J. 
Published: April 2020

Abstract
In lung transplants respiratory viruses (RV) are associated with bronchiolitis obliterans (BO). Also in HSCT patients RV may progress to pneumonia and may trigger immunological mediated effects on lungfunction.We prospectively studied the clinical impact of RV in pediatric HSCT patients.
Between 1/2004 and 7/2005 46 patient underwent 51 allo-HSCTs in our center. In all patients with respiratory symptoms viral PCRs (adeno-, human metapneumo-, influenza-, corona-, parainfluenza-, rhino- and RS-virus) were done on a nasopharyngeal washing, in addition to standard diagnostics. The severity and course of the respiratory symptoms was monitored. BO was defined as abnormalities in pulmonary function tests (&gt; 20% decrease in FEV1) and/or on specific changes on HR-CT scan such as bronchial wall thickening, air trapping and mosaic parenchymal attenuation.
33 HLA-identical and 18 HLA-mismatched grafts were used from 11 sibs, 25 UDs, 12 cordbloods and 3 mismatched FDs. 8 grafts were T-cell depleted. Follow up was 9mths (range 1–18 mth). Overall survival is 67%. Acute-GvHD (&gt; grade II) occured in 11/51 (21%) and cGVHD in 7/39 (18%; 4 extensive, including 3 BO, and 3 limited). Respiratory symptoms were seen in 25/51 HSCTs. In 6/25 patients a non-viral etiology was found: ARDS(2), VOD(2), IPS/DAH(2). The other 19 patients had viral disease; based on a positive PCR (16) or by clinical symptoms and exclusion of other causes (3). The onset of symptoms was within the 1st mth after HSCT (16), before HSCT (1) or after discharge (2). Rhinovirus (9), parainfluenza (3), influenza A (1) and multiple viruses (3; rhino/parainfluenza, adeno/parainfluenza, human metapneumo/rhino) were detected. 6/19 had upper respiratory tract infection (URTI) symptoms only, 11 were oxygen dependent, and 2 patients were ventilated. The patient with influenza-A was treated with a neuraminidase inhibitor. All others showed spontaneous recovery within 4–8 weeks. After resolution of symptoms and after tapering the immunosuppresion 3/19 patients developed BO (range: 3–8mth postHSCT). None of the other children in this cohort have developed BO. All BO patients underwent their first HSCT with a HLA-identical graft (2 sib, 1 UD). They were succesfully engrafted and had no signs of aGvHD. The severity of the initial respiratory symptoms, caused by rhinovirus (2) and para-influenza, was comparable to the other patients with RV infection. One patient died, the others are still receiving therapy. Respiratory problems are frequently seen in pediatric HSCT. RV were the most common cause in this cohort. The acute clinical course is usually mild, but in the longer term RV are firmly associated with BO. Our results might be an underestimate, due to short follow up of some patients. Monitoring viral infections with PCR of nasopharyngeal washing warrants early detection of a viral cause of the clinical syndrome. In such a case it might - paradoxically- be important to increase or prolong immunosuppressive treatment on a positive PCR only, or as soon as signs of BO develop.