French Researchers Warn That HMPV Infections Could Possibly Cause Chronic Lymphocytic Leukemia-Like Lymphocytosis

Medical News: French researchers from the Geriatrics Internal Medicine Department at the University Hospital of Dijon have sounded an alarm about a potentially concerning link between infections caused by the human metapneumovirus (HMPV) and the onset of a condition resembling chronic lymphocytic leukemia (CLL). Their groundbreaking study, recently published, delves into the case of a 91-year-old man whose HMPV infection coincided with the sudden emergence of lymphocytosis, a hallmark of CLL. This News Medical report explores their findings and the implications for future research and medical practice.

Hypothesis for virus involvement in CLL pathophysiology. Some subsets of B cells acquire CD5+ expression. Without SHM (high-frequency point mutations in Ig heavy and light chains that occur in germinal center B cells in response to signals from T follicular helper cells. Mutations that result in increased affinity of antibodies for antigen impart a selective survival advantage to the B cells producing those antibodies and lead to affinity maturation of the humoral immune response), a subset of these CD5+ B cells which do not penetrate the GC could lead to unmutated IGHV CLL, a condition with a poor prognosis. For the other subset of CD5+ B cells, they penetrate the GC where SHM occurs with IGHV mutations and, for certain, CSR. The recognition of a viral antigen by the M-IGHV BcR Ig of CD5+ cells may occur some immunogenetic changes in the cell and acquire pathological clonal expansion called MBL. After some additional immunogenetic changes, like after exposure to a new virus, the most severe form of MBL, HC-MBL (LC-MBL is not represented), could transform into CLL. BcR: B cell Receptor, CLL: Chronic lymphocytic leukemia, CSR: Class switch recombination, GC: germinal center, HC or LC—MBL: High-count or Low-count monoclonal B-cell lymphocytosis, M/U IGHV: mutated/unmutated immunoglobulin heavy-chain variable region gene, SHM: Somatic hypermutation.

Hypothesis for virus involvement in CLL pathophysiology. Some subsets of B cells acquire CD5+ expression. Without SHM (high-frequency point mutations in Ig heavy and light chains that occur in germinal center B cells in response to signals from T follicular helper cells. Mutations that result in increased affinity of antibodies for antigen impart a selective survival advantage to the B cells producing those antibodies and lead to affinity maturation of the humoral immune response), a subset of these CD5+ B cells which do not penetrate the GC could lead to unmutated IGHV CLL, a condition with a poor prognosis. For the other subset of CD5+ B cells, they penetrate the GC where SHM occurs with IGHV mutations and, for certain, CSR. The recognition of a viral antigen by the M-IGHV BcR Ig of CD5+ cells may occur some immunogenetic changes in the cell and acquire pathological clonal expansion called MBL. After some additional immunogenetic changes, like after exposure to a new virus, the most severe form of MBL, HC-MBL (LC-MBL is not represented), could transform into CLL. BcR: B cell Receptor, CLL: Chronic lymphocytic leukemia, CSR: Class switch recombination, GC: germinal center, HC or LC—MBL: High-count or Low -count monoclonal B-cell lymphocytosis, M/U IGHV: mutated/unmutated immunoglobulin heavy-chain variable region gene, SHM: Somatic hypermutation.

The Case That Raised Concerns
The patient - admitted to the hospital for delirium - had a medical history marked by peripheral neuropathy and cognitive decline. Upon examination, he exhibited symptoms of a respiratory infection, including fever and rhinorrhea. Laboratory tests confirmed the presence of HMPV using molecular RT-PCR assays. Initial treatment focused on symptomatic relief, but a startling development occurred five days later: the patient’s lymphocyte count spiked dramatically.
 
This case study examines the intriguing discovery that this sudden hyperlymphocytosis was linked to the emergence of CLL. Further tests, including immunophenotyping, confirmed markers consistent with B-cell CLL, such as CD5+ and CD23+. In tandem, the researchers identified type-1 cryoglobulinemia, another rare hematological condition associated with B-cell proliferation.
 
How HMPV Could Be Implicated
HMPV, a relatively recent discovery in the realm of virology, primarily affects the respiratory tract, often causing mild to severe symptoms in both the young and elderly. However, its role in triggering hematological abnormalities remains largely unexplored. In this case, the patient’s lymphocyte count soared to dangerous levels - a phenomenon the researchers suspect may be due to the virus’s ability to dysregulate immune function.
 
The study’s authors - Jérémy Barben, Alain Putot, Anca-Maria Mihai, Jérémie Vovelle, and Patrick Manckoundia - hypothesize that viral antigens could activate certain B-cells, causing them to proliferate uncontrollably. This cascade could mirror the immune dysregulation seen in CLL and other B-cell malignancies, though more research is needed to solidify this link.
 
Understanding Chronic Lymphocytic Leukemia-Like Lymphocytosis
Chronic lymphocytic leukemia (CLL) is a slow-progressing cancer characterized by the accumulation of abnormal B-lymphocytes in the blood, bone marrow, and lymphoid tissues. The researchers noted that in the aftermath of the HMPV infection, the patient’s clinical and immunological profile bore striking similarities to early-stage CLL, raising critical questions about the virus’s role in its development.
 
Interestingly, the patient’s peripheral neuropathy, previously unexplained, was attributed to cryoglobulinemia. This condition - marked by the presence of abnormal proteins that precipitate in cold conditions - has long been associated with lymphoproliferative disorders, including CLL. The researchers propose that HMPV may have acted as a catalyst, pushing an undiagnosed precursor state, known as monoclonal B-cell lymphocytosis (MBL), into full-blown CLL.
 
Wider Implications for Medical Science
The role of viruses in oncogenesis has been a topic of scientific interest for decades. Epstein-Barr virus (EBV) and hepatitis B and C viruses are well-established contributors to malignancies such as Burkitt’s lymphoma and hepatocellular carcinoma. This study adds HMPV to the growing list of viruses that might influence cancer pathways. The researchers emphasize the importance of studying the molecular mechanisms through which HMPV interacts with the immune system, particularly its impact on B-cell proliferation.
 
"The temporal association between the HMPV infection and the onset of CLL-like symptoms cannot be ignored," said Dr. Barben. "While causality has not been proven, the evidence strongly supports the need for further investigation."
 
Key Study Findings
The study’s findings hinge on the following observations:
 
-Sudden Lymphocytosis: The patient’s lymphocyte count rose sharply within days of the HMPV diagnosis, indicating a direct or indirect link.
 
-Immunophenotyping Results: Flow cytometry confirmed the presence of B-cell markers characteristic of CLL.
 
-Cryoglobulinemia Discovery: The type-1 cryoglobulinemia diagnosis added another layer of complexity, as this condition is rare and closely linked to lymphoproliferative disorders.
 
-Clinical Course: Despite the absence of aggressive symptoms or organ involvement, the patient exhibited hallmark signs of CLL.
 
Conclusions
This case highlights the potential role of HMPV in triggering or exacerbating lymphoproliferative disorders such as CLL. By providing a detailed clinical timeline and diagnostic insights, the study opens the door for broader research into viral oncogenesis. It underscores the importance of vigilance in managing respiratory infections, particularly in elderly patients with unexplained hematological abnormalities.
 
While this is the first documented case of its kind, the findings suggest that other viruses may similarly interact with precursor conditions like MBL to promote malignancy. The researchers urge the scientific community to explore these pathways, leveraging advancements in molecular biology to unravel the intricate relationships between infections and cancer.
 
The study findings were published in the peer-reviewed journal: Viruses.
https://www.mdpi.com/1999-4915/13/1/115
 
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