Chronic lymphocytic leukemia (CLL) is well known for its close relationship with immune dysfunction, with around a third of patient deaths attributable to bacterial or viral infections. And while the relative risk of death due to the malignancy itself has declined over the past few decades, the risk of death from infection among those with CLL has remained constant, some research suggests.1

Infections often precede a formal diagnosis of CLL. Patients are known to suffer severe infections such as pneumonia up to 10 years prior to being diagnosed. Such findings pose a chicken-or-egg conundrum: Does the immune dysfunction occur prior to the development of CLL, potentially driving the development of the malignancy, or do CLL cells arise first, causing immune dysfunction long before the disease is diagnosed?

Shedding fresh light on this question, a group of Danish researchers undertook a retrospective analysis of nationwide Danish cancer registries and examined CLL patients’ history of antimicrobial use as a proxy for infection susceptibility. In line with previous studies, the researchers found that antimicrobial use began to rise 6 years prior to CLL diagnosis.

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But even before then, patients with leukemia had used more macrolides, antimycotics, and antivirals than healthy controls for up to 22 years before they were diagnosed. The authors wrote that this time window jibes well with the theory that immune dysfunction, and/or infections, develop prior to CLL and could potentially play a causal role in driving the disease. The findings were published last month in Leukemia.2

“I expected to see some increased usage in the last [several] years prior to diagnosis,” said Carsten U. Niemann, MD, PhD, associate professor and consultant in hematology at Rigshospitalet, Copenhagen University Hospital in Denmark, and one of the study’s coauthors. “But I had absolutely not expected to see increased use of antivirals or macrolides 20 years prior to diagnosis.”

The study drew on data from more than 8000 patients diagnosed with CLL between 1996 and 2017, according to records in the Danish Cancer Register and the Danish National Patient Register, as well as over 47,000 age-matched controls. For all subjects, the researchers obtained data on antimicrobial use through the Danish National Prescription Register. Compared with controls, overall antimicrobial use increased significantly in the 6 years leading up to disease diagnosis. This was unsurprising, as previous research has indicated that monoclonal B-cell lymphocytosis (MBL) — a premalignant state that often precedes the development of CLL — is present years prior to CLL diagnosis, and patients with MBL are known to have a higher-than-typical risk of infections.

Although overall antimicrobial use was the same between CLL patients and controls prior to this 6-year window, the researchers found that specifically macrolides, antivirals, and antimycotics had been more frequently used among the CLL cohort — up to 22 years prior to diagnosis. Notably, other research has suggested an increased risk of cellulitis, chronic rhinosinusitis, and herpes zoster more than 5 or 10 years prior to CLL diagnosis — infections that are often treated by macrolides and antivirals, the authors noted.