Infection in chronic lymphocytic leukemia: parsimony has its limits

Occam's razor is often quoted in medicine, as physicians are taught diagnostic parsimony. The counterpoint to this principle is Hickam's dictum, stating that a patient “can have as many diseases as he damn well pleases” [1]. Infection, which is a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) [2], provides many examples of Hickam's dictum. In patients with CLL, the progressive accumulation of dysfunctional malignant B-lymphocytes leads to a number of quantitative and qualitative defects in adaptive and innate immunity. The earliest clinical manifestation of defective adaptive immunity is usually hypogammaglobulinemia and the associated increased risk of serious infections by encapsulated bacteria [2]. Abnormalities in T cell function can also be detected early in the course of this disease, and are manifest by changes in T cell subtypes and T cell receptor repertoire resulting in both immune compromise and an increased risk of autoimmune complications [3,4]. The innate immune system defects in patients with CLL include decreased complement levels, altered monocyte subtypes and impaired dendritic cell, neutrophil and natural killer cell function [2]. All of these immune defects generally progress over time after the diagnosis of CLL, and are often considerably exacerbated by immunosuppressive therapies, resulting in a further increase in the risk of serious infections.

The case report by Lim et al. in this issue of the journal is an example of the limitations of a parsimonious approach to the management of infections in patients with CLL [5]. Their patient had long-standing untreated intermediate-stage CLL with hypogammaglobulinemia. He presented with cellulitis initially responsive to antibiotic therapy. He then developed bacterial and fungal pneumonia, and had Epstein–Barr virus (EBV) viremia and fatal hemophagocytic lymphohistiocytosis (HLH). The authors’ exhaustive ante- and post-mortem evaluations provide conclusive documentation of all these complications, and thus provide the opportunity to demonstrate several important points about the management of infections in patients with CLL. Infections by encapsulated bacteria causing cellulitis are common in patients with CLL and require aggressive antibiotic therapy and careful follow-up. Exacerbation of the infection is not unusual in these patients and requires both intensification of the therapy (e.g. intravenous antibiotics) and investigation of additional etiologies and complications. Further investigation requires consideration of the spectrum of infections and immune pathologies that can occur in the immune-compromised host. This case report shows that infections in patients with CLL can have multiple discrete etiologies and complications, and that accurate diagnosis is required for appropriate therapy even though it unfortunately does not guarantee a good therapeutic outcome.

In patients with lymphoid malignancies including CLL, HLH is a rare idiopathic inflammatory syndrome that can be precipitated by infections [6]. Despite the availability of published diagnostic criteria [7], the diagnosis of HLH can be difficult. HLH should be considered in the differential diagnosis of patients with CLL who have infections that do not respond to treatment or have persistent fevers and progressive cytopenias [6,8]. Early diagnosis could result in better responses to treatment, but the outcome is generally guarded. However, prevention or early detection and effective therapy of infections in patients with CLL could decrease the risk of HLH.

Previously used therapies for CLL have usually exacerbated disease-associated immunodeficiency. However, potentially less toxic and more effective targeted therapies such as the kinase inhibitors and anti-CD20 monoclonal antibodies could have the potential to improve immune function in patients with CLL. Initial results from studies of the Bruton's tyrosine kinase inhibitor ibrutinib in CLL suggest that this drug could reverse T cell abnormalities in patients with CLL and decrease the rate of infectious complications [9,10]. If substantiated by additional data, these findings could provide support for considering clinical trials of earlier treatment of CLL in selected patients with higher risk. In the interim, physicians caring for patients with CLL need to continue to use appropriate patient education, vaccinations, intravenous immunoglobulin, antibiotic prophylaxis and granulocyte colony-stimulating factors to prevent infections.

As noted by Lim et al., HLH is truly a rare occurrence in CLL. In contrast, multiple concurrent infectious complications are not uncommon in patients with CLL. While parsimony may be a useful guiding principle in most medical disciplines, an exhaustive work-up of patients with multiple immune defects remains critically important. Treating physicians need to have a high index of suspicion for complex infectious complications in patients with CLL at all clinical stages of their disease. In addition, patients with CLL with an identified infection who are not responding adequately to therapy need to be actively investigated for additional infections and immune pathology that may be exacerbating their condition.

Potential conflict of interest

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