Coxiella burnetii (C. burnetii), the bacterium that causes Q fever, is associated with a more than 25-fold increase in the risk of developing diffuse large B-cell lymphoma (DLBCL), according to a study conducted by Cléa Melenotte, MD, of Aix-Marseilles Université in Marseilles, France, and colleagues.
“Bacterial infections play a role in the development of some B-cell non-Hodgkin lymphomas, either by inhibition of immune function or by induction of chronic inflammatory response,” Dr. Melenotte and co-authors wrote. “Several lymphoid disorders have been reported in the course of Q fever … Lymphoma, however, was previously considered to be a risk factor of persistent Q fever rather than a consequence of the infection.”
In the current study, Dr. Melenotte and researchers screened 1,468 consecutive patients who were enrolled in the French National Referral Center for Q Fever database between January 2004 and December 2014, identifying patients who had developed lymphoma after C. burnetii primary infection to assess a possible excess risk of B-cell lymphoma in Q fever patients. They then tested the presence of the bacterium in lymphoma biopsies, evaluated interleukin-10 (IL10) production in Q fever patients with lymphoma, and investigated whether patients with persistent focalized infection were more at risk for lymphoma than acute Q fever patients.
Patients were followed until as late as March 2015. Standardized incidence ratios were computed to confirm any increased risk of developing DLBCL and follicular lymphoma (FL) in patients with Q fever compared with the French general population.
Of the 1,468 patients (mean age = 50.5 years):
- 70% (1,028) had an acute Q fever without progression to persistent focalized infection
- 30% (n=440) had a persistent focalized infection – including 4.6 percent (n=68) with initial acute Q fever
Seven patients (0.48%) had a diagnosis of B-cell NHL after C. burnetii primary infection (mean age = 62.4 years), all of whom presented with mature B-cell NHL. Six patients had DLBCL (standardized infection ratio [SIR] = 25.4; 95% CI 11.4-56.4) and only one patient was diagnosed with FL (SIR=6.7; 95% CI 0.9-47.9). Using immunofluorescence and fluorescence in situ hybridization (FISH), C. burnetii was detected in CD68+ macrophages within both lymphoma and lymphadenitis tissues. However, localization in CD123+ plasmacytoid dendritic cells (pDCs) was found only in lymphoma tissues. Infection of pDCs, therefore, may represent a critical step toward the development of lymphoma.
Patients with Q fever with persistent focalized infection were at an increased risk for lymphoma compared with patients without known progression to persistent focalized infection (hazard ratio = 9.35; 95% CI 1.10-79.4). In addition, IL-10 overproduction was found in patients developing lymphoma (p=0.0003). “These results suggest that C. burnetii should be added to the list of bacteria that promote human B-cell non-Hodgkin lymphoma, possibly by the infection of pDCs and IL10 overproduction,” Dr. Melenotte and co-authors explained.
“Patients with Q fever are at significantly higher risk to develop lymphoma and should be followed to detect abnormal lymph nodes as soon as possible,” Didier Raoult, MD, PhD, corresponding author on the study, told ASH Clinical News. “Chronic infection in phagocytic cells may develop in a lymph node and may trigger lymphoma. This is probably linked to immunodepression caused by IL10 secreted during Q fever when it is persistent.”
One limitation of the study is its small sample size, and the researchers noted that larger studies are needed to confirm that the risk of lymphoma occurrence among patients with Q fever does not involve precursor lymphoid neoplasms or T-cell lymphomas.
“Although we cannot conclude that Q fever directly causes lymphoma, our results are unlikely to be due to chance since several criteria for causation are fulfilled,” the authors concluded. “Additional reports of cases treated by antibiotics alone would provide greater support for the purported association.”
The link between Q fever and lymphoma, however, “should not be neglected since early diagnosis of lymphoma could result in improved outcomes for Q fever patients [and] the management of patients with B-cell NHL could be improved by the detection of C. burnetii infection in endemic areas.”
Melenotte C, Million M, Audoly G, et al. B-cell non-Hodgkin lymphoma linked to Coxiella burnetii. Blood. 2015 October 13. [Epub ahead of print]