Trophyrema whipplei as causative agent in PMZL

Background: Mucosa-associated lymphatic tissue (MALT) or marginal zone lymphomas are a group of indolent B-cell lymphomas which are thought to arise with chronic antigenic stimulation of B cells, either during autoimmune diseases or by chronic infections. Little is known about potential causative pathogens in pulmonary marginal zone lymphomas (PMZL), although some data suggested a potential role of Achromobacter xylosoxidans. Methods: An index case of chronic pulmonary colonization with Tropheryma whipplei and subsequent development of PMZL was identified by T. whipplei specific PCR and metagenomics whole genome sequencing (WGS). This case prompted us to retrospectively conduct T. whipplei specific PCRs in a cohort of PMZL patients (n=22), to investigate a potential link between these bacteria and lymphomagenesis. Other pulmonary lymphomas and normal lung tissues were analyzed as controls. Positive results were confirmed by metagenomics WGS. We also searched for T. whipplei and A. xylosoxidans in our in-house metagenomics WGS dataset comprising autopsy lungs, lung biopsies and lung resection specimens (n=181). Results: A 69-year-old patient presented to our clinic with weight loss and persistent pulmonary consolidation. Subsequent metagenomics WGS analysis detected T. whipplei in the resected lung specimen. An antibiotic regimen eventually eliminated the bacteria. However, the consolidation persisted, and the diagnosis of PMZL was made in a second lung resection specimen (lobectomy). A second case of T. whipplei associated PMZL was detected, in a cohort of 22 PMZL patients. None of the samples in our in-house dataset had tested positive for T. whipplei. In contrast, A. xylosoxidans was frequently found in both autopsy lungs and lung biopsy / resection specimens (> 50% of cases). Conclusions: Our data suggests that T. whipplei colonization of lungs may trigger / promote PMZL and may be a potential driver of PMZL. Systematic analyses with larger cohorts should be conducted to further support this hypothesis. The frequent detection of A. xylosoxidans in lung tissue suggests that it is a common component of the pulmonary microbiome and therefore less likely to trigger lymphomas.