Patients with chronic lymphocytic leukaemia (CLL) are all to a degree immunodeficient. The most obvious and well-known abnormality is hypogammaglobulinaemia which is present in up to 85% of patients . Serum immunoglobulin levels are suppressed in other lymphoid malignancies but in CLL the suppression is to a far greater degree. Profound defects of cell mediated immunity also occur though these are most obvious in patients who have been treated with purine analogues. However, even untreated patients have defects of T cell numbers and function. This review will seek to explore the extent of the immune defect in CLL, its causes, clinical significance and possible remedies.
The extent of the immune defect
Infections are the major cause of death in between a quarter and a half of patients with CLL . Bacterial infection of the respiratory tract, skin or urinary tract is the commonest problem and before the use of purine analogues for treatment, the usual organisms were Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Escherichia coli. Protection against these organisms is provided principally by antibody, but only 15% of patients with CLL have completely normal serum immunoglobulins . It is likely that the only patients with CLL who do not have hypogammaglobulinaemia are those in whom it will occur in the future.
The extent of hypogammaglobulinaemia depends on the stage and duration of the disease. Older papers described serum IgA as the first immunoglobulin to be reduced followed by IgM and IgG , but this is by no means invariable and most patients have depression of all classes of immunoglobulin. It should be stressed that the hypogammaglobulinaemia is not confined to patients who have been treated. In one study of an untreated patient with stage B disease without a detectable paraprotein, the hypogammaglobulinaemia was so profound that over 90% of the detectable immunoglobulin in the serum was idiotypic, and thus derived from the tumour .
Despite the low levels of serum immunoglobulins, most patients suffer no clinical consequences from this, and in one study 65% of bacterial infections occurred with serum IgG levels below 300 mg/dL . It is recommended that patients with primary immunodeficiency begin immunoglobulin replacement therapy when the serum IgG falls below this level.
The non-malignant B-cell population in CLL is not well characterized . The proportion and overall number of non-malignant B cells is often significantly reduced, and clearly their function is impaired since the normal immunoglobulins are suppressed. What is not clear is whether they are directly suppressed by the tumour or indirectly as a consequence of inhibitory effects elsewhere in the immune response.
Apart from bacterial infections, patients with CLL also suffer from the reactivation of herpes viruses. Most commonly this involves herpes zoster. In one series from before the era of treatment with purine analogue, the incidence of herpes zoster was given as 28.6%, with 3.5% having recurrent attacks . Particularly important is the observation that attacks of shingles frequently precede the clinical diagnosis of CLL , suggesting that the underlying immune defect does not depend on either hypogammaglobulinaemia or the physical overwhelming of immune organs by infiltrating tumour cells.
Recurrent attacks of herpes simplex also occur in some untreated patients. Both HSV1 and HSV2 may be involved. The recent recognition that herpes simplex is implicated in many cases of Bell’s palsy  may explain the association of Bell’s palsy, including recurrent attacks, in patients with CLL .
Treatment greatly increases the risk of the reactivation of herpes viruses. Reactivation of cytomegalovirus (CMV) is of course particularly associated with treatment with alemtuzumab, symptomatic infections occurring in 15% of patients treated in one clinical trial and asymptomatic reactivation in more than half (7], but symptomatic reactivation may occur after treatment with fludarabine (D Oscier, personal communication) and asymptomatic reactivation even after treatment with chlorambucil .
The Epstein-Bar virus (EBV) has recently been associated with the increase in the incidence of Richter’s syndrome in patients who have been treated with fludarabine 
Human herpes virus 8 (HHV8) is the cause of Kaposi’s sarcoma in immunodeficient individuals. The first reported case in CLL occurred in an untreated patient  and the second in a patient treated with fludarabine . An American SEER report noted 9 cases between 1973 and 1996 among 16,367 patients observed, a statistically significant hazard ration of 5.09 .
Human herpes virus 6 causes the childhood exanthem, roseola, but in adults has it has been suggested as an initiating agent in chronic fatigue syndrome and multiple sclerosis [12, 13]. Fatigue is a common symptom in CLL often dismissed by physicians yet much discussed on patient websites. Multiple sclerosis has been reported as occasionally coexisting with CLL . HHV6 has also been associated with giant cell hepatitis in adults  and I have recently been consulted by a patient with CLL and obscure giant cell hepatitis.
A systematic study of herpes viral copy number in haematological diseases has been carried out using real-time quantitative polymerase chain reaction (RQ-PCR). Occasional patients with CLL had high copy numbers of EBV, CMV and HHV6A, but not HHV6b, HHV7 and HHV8 . Although interesting, the use of leukaemic B cells as a source of DNA means that T-cell lymphotropic viruses would be missed, and no indication was given as to the stage of the patients or the degree of immunosuppression.
1. Hamblin TJ. Chronic lymphocytic leukaemia. Balliere's Clinical Haematology 1987; 1: 449 491.
2. Foa R, Catovsky D, Brozovic M, Ooyirilangkumaran T, Cherchi M, Galton DAG. Clinical staging and immunological findings in chronic lymphocytic leukaemia. Cancer 1979; 44:483-487.
3. Stevenson FK, Hamblin TJ, Stevenson GT, Tutt Al. Extracellular idiotypic immunoglobulin arising from human leukemic B lymphocytes. J Exp Med 1980; 152:1484-1496.
4. Boughton BJ, Jackson N, Lim S, Smith N. Randomized trial of intravenous immunoglobulin prophylaxis for patients with chronic lymphocytic leukaemia and secondary hypogammaglobulinaemia. Clin Lab Haematol 1995; 17:75-80.
5. Johnston PB, Kay NE. Pathogenesis of impaired cellular immune function in CLL. In Chronic Lymphocytic Leukemia: Molecular Genetics, Biology, Diagnosis and Management. Ed GB Faguet. Humana Press: Totowa, New Jersey. 2004. p 109-121.
6. Steiner I, Mattan Y, Bell's palsy and herpes viruses: to (acyclo)vir or not to (acyclo)vir? J Neurol Sci. 1999;170:19-23.
7. Hillmen P, Skotnicki AB, Robak T, Jaksic B, Dmoszynska A, Wu J, Sirard C, Mayer J. Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol. 2007;25:5616-23
8. Thornton PD, bellas C, Santon A. Shah G, Pocock C, Wotherspoon AC, matutes E, Catovsky D. Richter’s transformation of chronic lymphocytic leukemia. The possible role of fludarabine and Epstein-Barr virus in its pathogenesis. Leuk Res 2005; 29:389-95.
9. Contu L, Carcassi C, La Nasa G, Zurrida SM, Sirigu F, Del Giacco S, Cerimele D, Longinotti M, Pitzus F. A case of classical Kaposi's sarcoma in B-cell chronic lymphocytic leukemia (B-CLL). Tumori. 1986;72:365-74.
10. Wijermans PW, van Groningen K, van Royen EA, Bruijn JA.Kaposi's sarcoma in an HIV-negative CLL patient as the cause of thrombocytopenia. Ann Hematol. 1994;68:307-10.
11. Hisada M, Biggar RJ, Greene MH, Fraumeni JF Jr, Travis LB. Solid tumors after chronic lymphocytic leukemia. Blood. 2001;98:1979-81.
12. Vojdani A, Lapp CW.Interferon-induced proteins are elevated in blood samples of patients with chemically or virally induced chronic fatigue syndrome. Immunopharmacol Immunotoxicol. 1999;21:175-202.
13. Knox KK, Brewer JH, Henry JM, Harrington DJ, Carrigan DR.Human herpesvirus 6 and multiple sclerosis: systemic active infections in patients with early disease. Clin Infect Dis. 2000;31:894-903.
14. Kuntzen T, Friedrichs N, Fischer HP, Eis-Hübinger AM, Sauerbruch T, Spengler U.Postinfantile giant cell hepatitis with autoimmune features following a human herpesvirus 6-induced adverse drug reaction. Eur J Gastroenterol Hepatol. 2005;17:1131-4.