Circulating blood lymphocytes include populations of T cells, B cells, and natural killer cells. Levels of blood lymphocytes are higher in neonates and young children (within 12 years) with an absolute lymphocyte count as high as 8,000 cells/μL. In subjects older than 12 years, lymphocytosis is defined as an absolute count greater than 4,000 cells/μL.

Lymphocytosis can be due to a reactive proliferation or to a clonal expansion. The most common cause is infection. Reactive lymphocytosis is a physiologic or pathophysiologic response to infection, toxins, cytokines, or unknown factors. Normally it is characterized by polyclonal populations of lymphocytes with a pleomorphic morphology. Infectious mononucleosis (EBV) is the most common reactive cause. In this case, infected B cells stimulate the proliferation of atypical polyclonal T or NK cells which are observed peripherally. Pertussis infection, which is most often seen in pediatric populations, is an important exception. In fact, it is characterized by monomorphic lymphocytes. Nonclonal lymphocytes proliferation rarely exceeds 30,000 cell/ μL.

Lymphoproliferative disorders are also associated with peripheral lymphocytosis and in early phases it may be difficult to distinguish them from a reactive lymphocytosis. The morphologic appearance of lymphocytes may help in this way. In fact, a monomorphic lymphocytosis favors a neoplastic proliferation. Major causes of lymphocytosis are summarized in Tables 5.3 and 5.4 [1–5].