Infection and Immunity in Chronic Lymphocytic Leukemia

Patients having chronic lymphocytic leukemia (CLL) are at increased risk for infectious morbidity and mortality. The predisposition to infections in CLL patients has many components, including both immunodeficiency related to the leukemia itself (humoral and cellular immune dysfunction) and the results of cumulative immunosuppression related to CLL treatment. The risk of infectious complications increases with the duration of CLL, reflecting the natural history of the disease and the cumulative immunosuppression related to its treatment. Hence, in early, untreated CLL, the infectious risk is mainly related to hypogammaglobulinemia, and infections by encapsulated bacteria are common. However, in patients having advanced CLL, par­ticularly those who receive the newer purine analogues, neutropenia and defects in cell-mediated immunity appear to be the major predisposing factors. An expanded spectrum of pathogens, including opportunistic fungi, Pneumo­cystis carinii, Listeria monocytogenes, mycobacteria, and herpesviruses, are seen in that setting. The changing spec­trum of infections in this latter group of patients mandates a newer approach to prophylaxis and therapy. Patients having chronic lymphocytic leukemia (CLL) are at increased risk for infectious morbidity and mortality. The predisposition to infections in CLL patients has many components, including both immunodeficiency related to the leukemia itself (humoral and cellular immune dysfunction) and the results of cumulative immunosuppression related to CLL treatment. The risk of infectious complications increases with the duration of CLL, reflecting the natural history of the disease and the cumulative immunosuppression related to its treatment. Hence, in early, untreated CLL, the infectious risk is mainly related to hypogammaglobulinemia, and infections by encapsulated bacteria are common. However, in patients having advanced CLL, par­ticularly those who receive the newer purine analogues, neutropenia and defects in cell-mediated immunity appear to be the major predisposing factors. An expanded spectrum of pathogens, including opportunistic fungi, Pneumo­cystis carinii, Listeria monocytogenes, mycobacteria, and herpesviruses, are seen in that setting. The changing spec­trum of infections in this latter group of patients mandates a newer approach to prophylaxis and therapy. Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, accounting for 30% of all leukemias.1Foon KA Rai KR Gale RP Chronic lymphocytic leukemia: new insights inlü biology and therapy.Ann Intern Med. 1990; 113: 525-539Crossref PubMed Google Scholar It is a malignant clonal disorder predominantly of B lymphocytes; T-cell CLL accounts for only 5% of cases. The abnormal clone replaces or inhibits growth and maturation of normal B cells (B-cell CLL), depressing immunoglobulin levels. The CLL staging systems have been proposed on the basis that the major prognostic factors are the number of involved nodal areas, the extent of hepatosplenomegaly, the pattern of marrow replacement, and the degree of anemia and thrombocytopenia. In addition, the median survival duration is more than 15 years in low-risk patients but is 2 years in high-risk patients.1Foon KA Rai KR Gale RP Chronic lymphocytic leukemia: new insights inlü biology and therapy.Ann Intern Med. 1990; 113: 525-539Crossref PubMed Google Scholar Until the early 1990s, the standard therapy consisted of alkylating agents with or without corticosteroids.1Foon KA Rai KR Gale RP Chronic lymphocytic leukemia: new insights inlü biology and therapy.Ann Intern Med. 1990; 113: 525-539Crossref PubMed Google Scholar, 2Keating MJ Chronic lymphocylic leukemia.Semin Oncol. 1999; 26: 107-114Google Scholar, 3Cheson BD Recent advances in the treatment of B-cell chronic lymphocytic leukemia.Oncology (Huntingt). 1990; 4 (83-84.): 71-78Google Scholar The introduction of new purine analogue compounds, such as fludarabine phosphate, pentostatin, and cladribine; monoclonal antibody-based strategies; and the early experience with bone marrow transplantation (BMT) (autologous, allogeneic, “mini-transplant”) in selected CLL patients have resulted in a resurgence of interest in clinical trials to treat this disease.2Keating MJ Chronic lymphocylic leukemia.Semin Oncol. 1999; 26: 107-114Google Scholar, 4Twomey JJ Infections complicating multiple myeloma and chronic lymphocytic leukemia.Arch Intern Med. 1973; 132: 562-565Crossref PubMed Google Scholar Fludarabine in particular has emerged as a very potent agent in patients having CLL refractory to alkylating agents.2Keating MJ Chronic lymphocylic leukemia.Semin Oncol. 1999; 26: 107-114Google Scholar, 3Cheson BD Recent advances in the treatment of B-cell chronic lymphocytic leukemia.Oncology (Huntingt). 1990; 4 (83-84.): 71-78Google Scholar More recently, the combination of purine analogues with alkylating agents (eg, the fludarabine-cyclophosphamide regimen) has also emerged as a promising approach.2Keating MJ Chronic lymphocylic leukemia.Semin Oncol. 1999; 26: 107-114Google Scholar Infection in CLL patients has long been recognized as a common cause of morbidity and mortality.4Twomey JJ Infections complicating multiple myeloma and chronic lymphocytic leukemia.Arch Intern Med. 1973; 132: 562-565Crossref PubMed Google Scholar Uncertainty about the pathogenesis of the increased risk of infection in these patients raises controversy regarding the management of infections. Furthermore, the encouraging new therapeutic developments have often come at the cost of serious opportunistic infections. The goal of this review is to describe the clinical characteristics and risk factors of infections in CLL as well as the abnormal host defenses in this disease. In addition, we focus on the evolving pattern of infectious complications in association with newer forms of therapy and discuss approaches to prophylaxis and treatment. Many studies have emphasized the important role of infections complicating conventional chemotherapy based on alkylating agents in the morbidity and mortality associated with CLL.4Twomey JJ Infections complicating multiple myeloma and chronic lymphocytic leukemia.Arch Intern Med. 1973; 132: 562-565Crossref PubMed Google Scholar, 5Osgood EE Seaman AJ Treatment of chronic leukemias: results of therapy by titrated, regularly spaced total body radioactive phosphorus, or roentgen irradiation.JAMA. 1952; 150: 1372-1379Crossref PubMed Google Scholar, 6Scott RB Leukaemia.Lancet. 1957; 1: 1162-1167Abstract Google Scholar, 7Pisciotta AV Hirschboeck JS Therapeutic considerations in chronic lymphocytic leukemia.Arch Intern Med. 1957; 99: 334-345Crossref Google Scholar, 8Ultmann JE Fish W Osserman E Gellhorn A The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.Ann Intern Med. 1959; 51: 501-516Crossref PubMed Google Scholar, 9Shaw RK Szwed C Boggs DR et al.Infection and immunity in chronic lymphocytic leukemia.Arch Intern Med. 1960; 106: 467-478Crossref Google Scholar, 10Hudson RP Wilson SJ Hypogammaglobulinemia and chronic lymphatic leukemia.Cancer. 1960; 13: 200-204Crossref PubMed Google Scholar, 11Shaw RK Boggs DR Silberman HR Frei III, E A study of prednisone therapy in chronic lymphocytic leukemia.Blood. 1961; 17: 182-195Google Scholar, 12Aroesty JM Furth FW Infection and chronic lymphocytic leukemia: a review of 61 cases.N Y J Med. 1962; 62: 1946-1952Google Scholar, 13Boggs DR Soffcrman SA Wintrobe MM Cartwright GE Factors influencing the duration of survival of patients with chronic lymphocylic leukemia.Am J Med. 1966; 40: 243-254Abstract Full Text PDF PubMed Google Scholar, 14Zippin C Cutler SJ Reeves Jr, WJ Lum D Survival in chronic lymphocytic leukemia.Blood. 1973; 42: 367-376PubMed Google Scholar, 15Hansen MM Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.Scand J Haematol Suppl. 1973; 18: 3-286Google Scholar, 16Revol L Creyssel R Bryon PA Coeur P Gentilhomme O Leucèmie lymphoide chronique. Encycl Med Chir. Sang, Paris, France1974: 1313-1320Google Scholar, 17Montserral-Costa E Matutes E Rozman C et al.Infections in chronic lymphocytic leukaemia [in Spanish].Sangre (Barc). 1977; 22: 968-975Google Scholar, 18Travade P Dusatt JD Cavaroc M Beytout J Rey M Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].Presse Med. 1986; 15: 1715-1718Google Scholar, 19Itala M Helenius H Nikoskelainen J Renies K Infections and serum IgG levels in patients with chronic lymphocytic leukemia.Ear J Haematol. 1992; 48: 266-270Crossref Google Scholar, 20Lee JS Dixon DO Kantarjian HM Keating MJ Talpaz M Prognosis of chronic lymphocytic leukemia: a multivariate regression analysis of 325 untreated patients.Blood. 1987; 69: 929-936PubMed Google Scholar, 21Catovsky D Fooks J Richards S MRC Working Party on Leukaemia in Adults Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survival: a report from the MRC CLL I trial.Br J Haematol. 1989; 72: 141-149Crossref PubMed Google Scholar In fact, the incidence of moderate to severe infections in CLL patients was estimated to be 0.47 per patient-year in a large study.19Itala M Helenius H Nikoskelainen J Renies K Infections and serum IgG levels in patients with chronic lymphocytic leukemia.Ear J Haematol. 1992; 48: 266-270Crossref Google Scholar However, most of these retrospective studies used different diagnostic criteria for infection and cause of death and focused on the analysis of leukemia status rather than on the infectious complications of leukemia. Moreover, these studies examined a select patient population, such as those having advanced refractory CLL, typically seen in tertiary care centers, and many of these efforts did not consider the stage of the underlying leukemia, neutrophil count, immunoglobulin level, or prior treatment using cytotoxic agents, which are all important factors for the type and severity of infections in CLL. Despite these limitations, several conclusions can be derived: (1) The incidence of infection in CLL patients was higher than that in an age-matched control group4Twomey JJ Infections complicating multiple myeloma and chronic lymphocytic leukemia.Arch Intern Med. 1973; 132: 562-565Crossref PubMed Google Scholar and not associated with the increased median age of the CLL patient population. (2) The incidence and severity of infections paralleled the stage and progression of CLL. Hence, patients having advanced refractory CLL usually die of infection.22Kempin S Lee III, BJ Thaler HT et al.Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristinc, BCNU, cyclophosphamide, melphalan, and prednisone).Blood. 1982; 60: 1110-1121PubMed Google Scholar (3) Infection may be the feature at presentation that leads to the diagnosis of CLL.15Hansen MM Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.Scand J Haematol Suppl. 1973; 18: 3-286Google Scholar (4) Fever in CLL patients usually signifies infection.13Boggs DR Soffcrman SA Wintrobe MM Cartwright GE Factors influencing the duration of survival of patients with chronic lymphocylic leukemia.Am J Med. 1966; 40: 243-254Abstract Full Text PDF PubMed Google Scholar, 15Hansen MM Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.Scand J Haematol Suppl. 1973; 18: 3-286Google Scholar (5) Finally, a subset of patients suffer from recurrent infections (mostly upper respiratory tract or soft tissue infections) usually associated with hypogammaglobulinemia. 5Osgood EE Seaman AJ Treatment of chronic leukemias: results of therapy by titrated, regularly spaced total body radioactive phosphorus, or roentgen irradiation.JAMA. 1952; 150: 1372-1379Crossref PubMed Google Scholar, 16Revol L Creyssel R Bryon PA Coeur P Gentilhomme O Leucèmie lymphoide chronique. Encycl Med Chir. Sang, Paris, France1974: 1313-1320Google Scholar, 18Travade P Dusatt JD Cavaroc M Beytout J Rey M Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].Presse Med. 1986; 15: 1715-1718Google Scholar, 19Itala M Helenius H Nikoskelainen J Renies K Infections and serum IgG levels in patients with chronic lymphocytic leukemia.Ear J Haematol. 1992; 48: 266-270Crossref Google Scholar Regarding the sites of involvement of severe infection, both pneumonia and bacteremia are common, especially in patients having profound neutropenia.4Twomey JJ Infections complicating multiple myeloma and chronic lymphocytic leukemia.Arch Intern Med. 1973; 132: 562-565Crossref PubMed Google Scholar, 5Osgood EE Seaman AJ Treatment of chronic leukemias: results of therapy by titrated, regularly spaced total body radioactive phosphorus, or roentgen irradiation.JAMA. 1952; 150: 1372-1379Crossref PubMed Google Scholar, 8Ultmann JE Fish W Osserman E Gellhorn A The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.Ann Intern Med. 1959; 51: 501-516Crossref PubMed Google Scholar, 9Shaw RK Szwed C Boggs DR et al.Infection and immunity in chronic lymphocytic leukemia.Arch Intern Med. 1960; 106: 467-478Crossref Google Scholar, 10Hudson RP Wilson SJ Hypogammaglobulinemia and chronic lymphatic leukemia.Cancer. 1960; 13: 200-204Crossref PubMed Google Scholar, 11Shaw RK Boggs DR Silberman HR Frei III, E A study of prednisone therapy in chronic lymphocytic leukemia.Blood. 1961; 17: 182-195Google Scholar, 12Aroesty JM Furth FW Infection and chronic lymphocytic leukemia: a review of 61 cases.N Y J Med. 1962; 62: 1946-1952Google Scholar, 16Revol L Creyssel R Bryon PA Coeur P Gentilhomme O Leucèmie lymphoide chronique. Encycl Med Chir. Sang, Paris, France1974: 1313-1320Google Scholar, 17Montserral-Costa E Matutes E Rozman C et al.Infections in chronic lymphocytic leukaemia [in Spanish].Sangre (Barc). 1977; 22: 968-975Google Scholar, 18Travade P Dusatt JD Cavaroc M Beytout J Rey M Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].Presse Med. 1986; 15: 1715-1718Google Scholar Also, the rate of nosocomial bloodstream infections was 9.4% in CLL patients in a prospective surveillance study in which 50% of the patients had profound neutropenia (polymorphonuclear neutrophil leukocyte count at the time of bacteremia onset <0.01 × 109/L).23Mayo JW Wenzel RP Rates of hospital-acquired bloodstream infections in patients with specific malignancy.Cancer. 1982; 50: 187-190Crossref Google Scholar Of interest is that older series5Osgood EE Seaman AJ Treatment of chronic leukemias: results of therapy by titrated, regularly spaced total body radioactive phosphorus, or roentgen irradiation.JAMA. 1952; 150: 1372-1379Crossref PubMed Google Scholar, 6Scott RB Leukaemia.Lancet. 1957; 1: 1162-1167Abstract Google Scholar, 7Pisciotta AV Hirschboeck JS Therapeutic considerations in chronic lymphocytic leukemia.Arch Intern Med. 1957; 99: 334-345Crossref Google Scholar, 8Ultmann JE Fish W Osserman E Gellhorn A The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.Ann Intern Med. 1959; 51: 501-516Crossref PubMed Google Scholar, 9Shaw RK Szwed C Boggs DR et al.Infection and immunity in chronic lymphocytic leukemia.Arch Intern Med. 1960; 106: 467-478Crossref Google Scholar, 10Hudson RP Wilson SJ Hypogammaglobulinemia and chronic lymphatic leukemia.Cancer. 1960; 13: 200-204Crossref PubMed Google Scholar, 11Shaw RK Boggs DR Silberman HR Frei III, E A study of prednisone therapy in chronic lymphocytic leukemia.Blood. 1961; 17: 182-195Google Scholar, 12Aroesty JM Furth FW Infection and chronic lymphocytic leukemia: a review of 61 cases.N Y J Med. 1962; 62: 1946-1952Google Scholar, 13Boggs DR Soffcrman SA Wintrobe MM Cartwright GE Factors influencing the duration of survival of patients with chronic lymphocylic leukemia.Am J Med. 1966; 40: 243-254Abstract Full Text PDF PubMed Google Scholar, 14Zippin C Cutler SJ Reeves Jr, WJ Lum D Survival in chronic lymphocytic leukemia.Blood. 1973; 42: 367-376PubMed Google Scholar, 15Hansen MM Chronic lymphocylic leukaemia: clinical studies based on 189 cases followed for a long time.Scand J Haematol Suppl. 1973; 18: 3-286Google Scholar, 16Revol L Creyssel R Bryon PA Coeur P Gentilhomme O Leucèmie lymphoide chronique. Encycl Med Chir. Sang, Paris, France1974: 1313-1320Google Scholar, 17Montserral-Costa E Matutes E Rozman C et al.Infections in chronic lymphocytic leukaemia [in Spanish].Sangre (Barc). 1977; 22: 968-975Google Scholar, 18Travade P Dusatt JD Cavaroc M Beytout J Rey M Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].Presse Med. 1986; 15: 1715-1718Google Scholar, 19Itala M Helenius H Nikoskelainen J Renies K Infections and serum IgG levels in patients with chronic lymphocytic leukemia.Ear J Haematol. 1992; 48: 266-270Crossref Google Scholar noted infections of the genitourinary tract, most likely due to obstruction by enlarged retroperitoneal nodes in advanced CLL. Pathogens seen frequently in CLL patients undergoing different therapeutic regimens are listed in Table 1. Bacterial infections caused by encapsulated organisms such as Streptococcus pneumoniae are common, especially in older series of patients.7Pisciotta AV Hirschboeck JS Therapeutic considerations in chronic lymphocytic leukemia.Arch Intern Med. 1957; 99: 334-345Crossref Google Scholar, 11Shaw RK Boggs DR Silberman HR Frei III, E A study of prednisone therapy in chronic lymphocytic leukemia.Blood. 1961; 17: 182-195Google Scholar, 18Travade P Dusatt JD Cavaroc M Beytout J Rey M Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].Presse Med. 1986; 15: 1715-1718Google Scholar, 19Itala M Helenius H Nikoskelainen J Renies K Infections and serum IgG levels in patients with chronic lymphocytic leukemia.Ear J Haematol. 1992; 48: 266-270Crossref Google Scholar, 24Wintrobe MM Hasenbush LL Chronic leukemia: early phase of chronic leukemia, results of treatment and effects of complicating infections: study of 86 adults.Arch Intern Med. 1939; 64: 701-718Crossref Google Scholar, 25Miller DG Karnofsky DA Immunologic factors and resistance to infection in chronic lymphatic leukemia.Am J Med. 1961; 31: 748-757Abstract Full Text PDF Google Scholar, 26Salonen J Nikoskelainen J Lethal infections in patients with hemalological malignancies.Eur J Haematol. 1993; 51: 102-108Crossref PubMed Google Scholar, 27Bernard C Mombelli G Klastersky J Pneumococcal bacteremia in patients with neoplastic diseases.Eur J Cancer Clin Oncol. 1981; 17: 1041-1046Abstract Full Text PDF Google Scholar, 28Chou MY Brown AE Blevins A Armstrong D Severe pneumococcal infection in patients with neoplastic disease.Cancer. 1983; 51: 1546-1550Crossref PubMed Google Scholar, 29Armstrong D Young LS Meyer RD Blevins AH Infectious complications of neoplastic disease.Me d Clin North Am. 1971; 55: 729-745Google ScholarStaphylococcus aureus infections were also prominent in other series.11Shaw RK Boggs DR Silberman HR Frei III, E A study of prednisone therapy in chronic lymphocytic leukemia.Blood. 1961; 17: 182-195Google Scholar, 22Kempin S Lee III, BJ Thaler HT et al.Combination chemotherapy of advanced chronic lymphocytic leukemia: the M-2 protocol (vincristinc, BCNU, cyclophosphamide, melphalan, and prednisone).Blood. 1982; 60: 1110-1121PubMed Google Scholar In contrast, an increase in gram-negative bacillary infections, particu­larly bacteremias, has been noted in recent studies.17Montserral-Costa E Matutes E Rozman C et al.Infections in chronic lymphocytic leukaemia [in Spanish].Sangre (Barc). 1977; 22: 968-975Google Scholar, 18Travade P Dusatt JD Cavaroc M Beytout J Rey M Infections associated with chronic lymphoid leukaemia: 159 infectious episodes in 60 patients [in French].Presse Med. 1986; 15: 1715-1718Google Scholar, 19Itala M Helenius H Nikoskelainen J Renies K Infections and serum IgG levels in patients with chronic lymphocytic leukemia.Ear J Haematol. 1992; 48: 266-270Crossref Google Scholar, 26Salonen J Nikoskelainen J Lethal infections in patients with hemalological malignancies.Eur J Haematol. 1993; 51: 102-108Crossref PubMed Google Scholar This increase may reflect more advanced disease and profound myelosuppression in the patients studied. In fact, cytotoxic chemotherapy for advanced refractory CLL results in infectious morbidity and mortality analogous to that seen inacute leukemia. In particular, frequent fatal bacteremias or pneumonias caused by Pseudomonas aeruginosa have been reported in that setting.29Armstrong D Young LS Meyer RD Blevins AH Infectious complications of neoplastic disease.Me d Clin North Am. 1971; 55: 729-745Google Scholar Other frequently reported pathogens include Haemophilus influenzae.12Aroesty JM Furth FW Infection and chronic lymphocytic leukemia: a review of 61 cases.N Y J Med. 1962; 62: 1946-1952Google Scholar Legionella Spp,30Kirby BD Snyder KM Meyer RD Finegold SM Legionnaires' disease: report of sixty-five nosocomially acquired cases of review of the literature.Medicine (Baltimore). 1980; 59: 188-205PubMed Google Scholar, 31Schlossberg D Bonoan J Legionella and immunosuppression.Semin Respir Infect. 1998; 13: 128-131Google Scholar, 32Jaeger TM Atkinson PP Adams BA Wright AJ Hurt RD Legionella bozemanii pneumonia in an immunocompromised patient.Mayo Clin Proc. 1988; 63: 72-76Abstract Full Text Full Text PDF Google Scholarand Salmonella Spp.33Wolfe MS Louria DB Armstrong D Blevins A Salmonellosis in patients with neoplastic disease: a review of 100 episodes at Memorial Cancer Center over a 13-year period.Arch Intern Med. 1971; 128: 546-554Crossref PubMed Google Scholar However, infections caused by Liste­ria monocytogenes, Nocardia spp, and Neisseria meningitidis are relatively infrequent in CLL patients who receive cytotoxic chemotherapy.29Armstrong D Young LS Meyer RD Blevins AH Infectious complications of neoplastic disease.Me d Clin North Am. 1971; 55: 729-745Google ScholarTable 1Frequent Pathogens in Patients Having Chronic Lymphocytic Leukemia and Receiving Different Therapeutic Regimens*CMV = cytomegalovirus; HSV = herpes simplex virus; PCP = P carinii pneumonia; VZV = varicella zoster virus.PathogenAlkylaling agents/sic roidsPurine analoguesFludarabineCladribincPcntostatinBacieriaS pneumoniaeL monocytogenesfL monocytogenesS pneumoniaeS aureusSlaphylococcus sppPseudomonas sppP aerug'mosaStreptococcus sppH influenzaeE coliLegionella sppKlebsiella sppSalmonella sppEnterobacter sppAcinetobacier sppN meningilidisC difficileFungiC neoformansCandida sppCandida sppCandida sppH capsulatumAspergiltus sppAspergitlus sppAspergillus sppCandida sppAspergitlus sppVirusesHSVvzvHSVHSVAdenovirusCMVVZVVZVCMVOtherPCP†Especially with coilicosteroids.PCPPCPMycobacteria* CMV = cytomegalovirus; HSV = herpes simplex virus; PCP = P carinii pneumonia; VZV = varicella zoster virus.† Especially with coilicosteroids. Open table in a new tab Fungal infections, particularly the endemic mycoses, have also been associated with CLL.34Kaplan MH Rosen PP Armstrong D Cryptococcosis in a cancer hospital: clinical and pathological correlates in forty-six patients.Cancer. 1977; 39: 2265-2274Crossref PubMed Google Scholar, 35Kauffman CA Israel KS Smith JW White AC Schwarz J Brooks GF Histoplasmosis in immunosuppressed patients.Am J Med. 1978; 64: 923-932Abstract Full Text PDF PubMed Google Scholar For example, CLL was reported to be the most common underlying malignancy in patients having infections caused by Cryptococ­cus neoformans34Kaplan MH Rosen PP Armstrong D Cryptococcosis in a cancer hospital: clinical and pathological correlates in forty-six patients.Cancer. 1977; 39: 2265-2274Crossref PubMed Google Scholar and the underlying malignancy in 30% of patients having infections caused by Histoplasma capsulatum from an endemic area.35Kauffman CA Israel KS Smith JW White AC Schwarz J Brooks GF Histoplasmosis in immunosuppressed patients.Am J Med. 1978; 64: 923-932Abstract Full Text PDF PubMed Google Scholar On the other hand, infections from Coccidioides immitis or Paracoccidioides spp are not commonly reported in association with CLL.36Deresinski SC Stevens DA Coccidioidomycosis in compromised hosts: experience at Stanford University Hospital.Medicine (Baltimore). 1975; 54: 377-395Crossref PubMed Google Scholar, 37Melo CR Melo IS Cerski CT lxukaemic infiltration, para-coccidioidomycosis and nodular hyperplasia of the prostate.Br J Urol. 1992; 70: 329-330Google Scholar However, an increasing incidence of opportunistic mycoses such as candidiasis or aspergillosis in patients having advanced refractory CLL has been noted.38Kontoyiannis DP Anaissie EJ Bodey GP Infection in chronic lymphocytic leukemia: a reappraisal.in: Cheson BD Chronic Lymphocylic leukemia: Scientific Advances and Clinical Developments. Marcel Dekker, New York, NY1993: 399-417Google Scholar, 39Terreni AA DiSalvo AF Baker Jr, AS Crymes WB Morris PR Dowda Jr, H Disseminated Dactylaria gallopava infection in a diabetic patient with chronic lymphocytic leukemia of the T-cell type.Am J Clin Pathol. 1990; 94: 104-107Google Scholar These mycoses are typically associated with prolonged and profound neutropenia, administration of multiple broad-spectrum antibiotics, and prior corticosteroid use, and they have emerged as a notable cause of death in patients having advanced refractory CLL.38Kontoyiannis DP Anaissie EJ Bodey GP Infection in chronic lymphocytic leukemia: a reappraisal.in: Cheson BD Chronic Lymphocylic leukemia: Scientific Advances and Clinical Developments. Marcel Dekker, New York, NY1993: 399-417Google Scholar Viral infections, particularly herpesvirus infections, occur frequently in CLL patients.4Twomey JJ Infections complicating multiple myeloma and chronic lymphocytic leukemia.Arch Intern Med. 1973; 132: 562-565Crossref PubMed Google Scholar, 8Ultmann JE Fish W Osserman E Gellhorn A The clinical implications of hypogammaglobulinemia in patients with chronic lymphocytic leukemia and lymphocytic lymphosarcoma.Ann Intern Med. 1959; 51: 501-516Crossref PubMed Google Scholar, 17Montserral-Costa E Matutes E Rozman C et al.Infections in chronic lymphocytic leukaemia [in Spanish].Sangre (Barc). 1977; 22: 968-975Google Scholar, 40Hirsch MS Herpes group virus infections in the compromised host.in: Rubin RH Young LS Clinical Approach to Infection in the Compromised Host. Plenum Medical Book Co, New York, NY1981: 389-415Google Scholar Herpesvirus infections are usually localized, although disseminated disease occurs in patients having advanced disease and severe cell-mediated immune dysfunction.41Wile UJ Holman HH Generalized herpes zoster associated with leukemia.Arch Dermatol Syph. 1940; 42: 587-592Crossref Google Scholar, 42Barton RL O'Leary PA Herpes zoster generalisatus, associated with chronic lymphatic leukemia.Arch Dermatol Syph. 1945; 51: 263-265Crossref Google Scholar Herpes simplex virus (HSV) mucositis may follow a more chronic, indolent course in some CLL patients in contrast to the more aggressive, recurrent nature of this infection in patients having acute leukemia.43Barrett AP Chronic indolent orofacial herpes simplex virus infection in chronic leukemia: a report of three cases.Oral Surg Oral Med Oral Pathol. 1988; 66: 387-390Abstract Full Text PDF PubMed Google Scholar Occasionally, severe infections caused by other viruses, such as adenovirus type 1, have been reported.44Ljungman P Ehrnst A Bjorkstrand B et al.Lethal disseminated adenovirus type 1 infection in a patient with chronic lymphocytic leukemia.Scand J Infect Dis. 1990; 22: 601-605Crossref Google Scholar On a historical note, vaccinia gangrenosa and generalized vaccinia have been reported in CLL patients after smallpox vaccination.45Ultmann JE Generalized vaccinia in a patient with chronic lymphocytic leukemia and hypogammaglobulinemia.Ann Intern Med. 1964; 61: 728-732Crossref Google Scholar However, viral infections, even though they may be associated with substantial morbidity, do not seem to cause notable mortality. Finally, other pathogens, such as mycobacteria, infrequently cause infections.46Kaplan MH Armstrong D Rosen P Tuberculosis complicating neoplastic disease: a review of 201 cases.Cancer. 1974; 33: 850-858Crossref PubMed Google Scholar Similarly, Pneumocystis carinii infections are rare in patients who receive conventional cytotoxic chemotherapy.47Reed AE Body BA Austin MB Frierson Jr, HF Cunninghamella bertholletiae and Pneumocystis carinii pneumonia as a fatal complication of chronic lymphocytic leukemia.Hum Pathol. 1988; 19: 1470-1472Abstract Full Text PDF PubMed Google Scholar The pathogenesis of infection in CLL is complex and mul­tifactorial.38Kontoyiannis DP Anaissie EJ Bodey GP Infection in chronic lymphocytic leukemia: a reappraisal.in: Cheson BD Chronic Lymphocylic leukemia: Scientific Advances and Clinical Developments. Marcel Dekker, New York, NY1993: 399-417Google Scholar, 48Molica S Infections in chronic lymphocylic leukemia: risk factors, and impact on survival, and treatment.leuk Lymphoma. 1994; 13: 203-214Crossref Google Scholar, 49Chapel HM Bunch C Mechanisms of infection in chronic lymphocytic leukemia.Semin Hematol. 1987; 24: 291-296Google Scholar The associated humoral dysfunction has traditionally been considered the most important immune defect.49Chapel HM Bunch C Mechanisms of infection in chronic lymphocytic leukemia.Semin Hematol. 1987; 24: 291-296Google Scholar However, antineopla