Case Study: Host and Pathogen Response to Bacteriophage Engineered Against Mycobacterium abscessus Lung Infection. Nick et al.
Description
Summary: Two engineered mycobacteriophages were administered intravenously with antibiotics to a male with treatment-refractory M. abscessus pulmonary infection and severe cystic fibrosis lung disease. Evidence of phage-induced lysis was observed using molecular and metabolic assays within days of phage treatment initiation, computerized tomography (CT) assessment, and airway cultures. Anti-phage neutralizing antibody titers to one phage increased with time. The subject received lung transplantation on day 379, and systematic cultures of the explanted lung did not detect M. abscessus. This study describes the course and associated markers of successful phage treatment of M. abscessus in the context of advanced lung disease. CT scans: Video files incorporating a complete set of axial, coronal and sagittal reconstructions of high-resolution CT scans pre- and post-phage. Scans demonstrate severe diffuse varicose upper-lobe cystic bronchiectasis with a left apical cavity. Multifocal mucoid impaction, widespread mosaic attenuation, and scattered poorly defined nodules were present. Focal tree-in-bud pattern was most marked in the right lower lobe. Areas of improvement were seen post-phage day 81 that were further improved by day 229. H& E: Gross and microscopic pathological photographs of the explanted lungs at time of lung transplant (day 379 of phage). The left and right lungs showed similar changes and are described together. Gross appearance of the pleural surface was tan-purple, wrinkled and dull displaying moderate cobblestoning and induration, with no grossly discernable masses or lesions. H&E-stained sections showed extensive bronchiectasis with dilation of both bronchi and bronchioles frequently associated with acute bronchopneumonia consisting of neutrophils, mucin and cellular debris within the airway lumens. Master data: Raw data from Figures 1A, 1F, 4A, 4B, 4C, 4D, 6A and Supplemental Table 1. Airway culture results (Figures 1A, 1F and 4A) from day -3519 days pre- phage, through day 469. CF cultures are tabulated as positive or negative for P. aeruginosa and/or MRSA. NTM cultures are tabulated as positive or negative for either M. abscessus or M. avium. Cultures prior to transplant (day 379) were obtained from expectorated sputum, and post-transplant from BAL. qPCR analysis of M. abscessus DNA over time (Figure 4B). M. abscessus DNA concentrations (pg/ul) were extrapolated from a standard curve (Sup. Fig. 2). The participant was unable to produce sputum post-transplant (day 379). Urine LAM components D-ara and TBSA (ng/ml) over time (Figure 4C). Levels of both peaked 47 days after initiation of phage, and by day 152 were both below LOD, continuing post-transplant. Serum anti-M. abscessus IgA and IgG over time (Figure 4D). Half maximal titers of IgG antibodies over various time points pre- and post-phage for phages BPs∆33HTH_HRM10 and D29_HRMGD40 (depicted in Figure 6A).
Files
Institutions
- National Jewish Health Department of Medicine