Bilateral Pneumonia in a Patient With Chronic Lymphocytic Leukemia
A 77-year-old man who had been undergoing chemotherapy for chronic lymphocytic leukemia (CLL) was admitted to the hospital for a 2-week history of intermittent fever, sweats, and progressive dyspnea.
On admission, he was hypoxic and required 6 L/min of supplemental oxygen via nasal cannula to maintain appropriate oxygenation. He was afebrile with a heart rate of 98 beats/min, blood pressure of 104/60 mm Hg, and a respiratory rate of 16 breaths/min.
Computed tomography of the chest revealed scattered lymphadenopathy consistent with his diagnosis of CLL, as well as diffuse bilateral interstitial opacities with multiple nodules (Figure).
Figure. Computed tomography of the chest with contrast revealing diffuse “ground glass” infiltrates and nodules, along with the classic lymphadenopathy of chronic lymphocytic leukemia.
Laboratory testing on admission revealed pancytopenia (white blood cell count, 3500/µL; hemoglobin, 9.0 g/dL; platelet count, 49 × 103/µL); no other significant abnormalities were disclosed on a comprehensive metabolic panel. Additional testing revealed a serum immunoglobulin G (IgG) level of 387 mg/dL (reference range, 540-1822 mg/dL) and a CD4 cell count of 57/µL (reference range, 490-1740/µL).
Because of his immunocompromised state, a broad workup for infectious diseases was undertaken, including negative serologic test results for blastomycosis, cytomegalovirus, histoplasmosis, and tuberculosis. Results of urinalysis were negative for signs of cystitis, and blood cultures drawn on admission were negative for infection. Sputum eosinophils were present, raising the question of an allergic or fungal process.
In an attempt to further understand the pulmonary process, bronchoscopy with bronchoalveolar lavage was performed. Immunostaining revealed fungal organisms consistent with Pneumocystis jirovecii infection.
Because of the patient’s significant allergy to sulfa-containing drugs, the usual therapy with trimethoprim-sulfamethoxazole was not prescribed, and second-line therapy with clindamycin (600 mg intravenously every 8 hours) and primaquine base (15 mg orally once daily) was initiated. Because primaquine use has a high risk of exacerbating glucose-6 phosphate dehydrogenase (G6PD) deficiency, a serum G6PD level was requested. Therapy was initiated while the test results were outstanding, because a delay in therapy was felt to be very risky given his immunocompromised state and tenuous clinical status.
A few days later, his G6PD level was determined to be within normal limits. The regimen of clindamycin and primaquine was continued with dramatic clinical improvement over subsequent days. Because of his low serum level of IgG, a 20-g dose of intravenous immunoglobulin (IVIG) was administered, with a subsequent increase in the IgG level to 587 mg/dL. The patient was discharged in stable condition and placed on a regimen of oral antibiotics (300 mg clindamycin every 8 hours and 15 mg primaquine base once daily) and instructions for continued follow-up with his infectious-disease physician.
CLL Background and Chemotherapy
CLL is the most common leukemia in the United States, accounting for more than 15,000 cases and 5000 deaths per year.1 It is a disorder of B cell proliferation, and it exists on a continuum that includes small lymphocytic lymphoma.2 Most patients are asymptomatic at diagnosis, but lymphadenopathy and hepatosplenomegaly are common physical examination findings.1 Laboratory findings of CLL include leukocytosis and/or lymphocytosis, which can be dramatic. The diagnosis is confirmed with flow cytometry; biopsy of bone marrow or lymph nodes is rarely necessary.1 Observation is the standard of care for patients with early asymptomatic CLL, with initiation of chemotherapy for progressive or advanced disease.2
Infectious complications in CLL are a major cause of morbidity and mortality. The predisposition to infections in CLL is multifactorial—both the disease and the drugs used to treat it can contribute to a state of immunodeficiency. Persons with CLL have underlying immune defects in humoral and cell-mediated immunity. Agents used in the management of CLL, especially the purine analogues and monoclonal antibodies (eg, alemtuzumab), contribute to the spectrum of infections seen in patients with CLL.3
Many infectious complications seen in these patients are due to the unique impact on immune function related to the specific agents used for CLL therapy. The major categories used in the management of CLL are alkylating agents, corticosteroids, purine analogues, and monoclonal antibodies.1,4 The alkylating agents chlorambucil, bendamustine, and cyclophosphamide share the same mechanism of action. They all attach to DNA bases, resulting in DNA breakage and crosslink that prevents DNA replication and transcription.5 Chlorambucil given alone or in combination with corticosteroids has been used as initial treatment for many years and is still used as monotherapy for older patients. The majority of infections with alkylating agents are bacterial.3,6
The purine analogues consist of fludarabine, pentostatin, and cladribine. They all inhibit key enzymes required for DNA synthesis.5 Of the purine analogues, fludarabine is the most studied. It causes a decrease in T cells and B cells, resulting in defects in cell-mediated immunity, and results in a wider spectrum of infectious complications compared with the alkylating agents. In addition to common bacterial infections, opportunistic infections (eg, pneumocystis) have been reported.3,6
The monoclonal antibodies are alemtuzumab, rituximab, obinutuzumab, and ofatumumab. Rituximab, ofatumumab, and obinutuzumab are anti-CD20 monoclonal antibodies that cause a reduction in the B-cell count.5,7 Severe infections and opportunistic infections are uncommon with anti-CD20 monotherapy.3,8,9 Alemtuzumab is an anti-CD52 agent. This antigen is expressed on B cells and T cells and is associated with profound defects in cell-mediated immunity, as well as neutropenia.3,6 Alemtuzumab has been associated with a wide range of infections, including bacterial, viral, fungal, and protozoal infections. Severe infections have included aspergillosis, candidiasis, pneumocystis infection, and cytomegalovirus (CMV) infection.3
Immunodeficiencies in CLL
Decreased CD4 lymphocyte levels. Patients with CLL have a reversal of the CD4 to CD8 cell ratio, resulting in a lowered CD4 cell count. This correlates with the severity of CLL and is an important component of both the pathogenesis and the risk of infection in affected patients.10 Many patients with CLL are treated with purine analogues and monoclonal antibodies, which often cause a significant and persistent T-cell immunodeficiency. As with other diseases of T cells—most notably human immunodeficiency virus (HIV)—patients with advanced CLL are at increased risk of infection with opportunistic pathogens including CMV, pneumocystis, toxoplasmosis, and others.10,11
HIV is by far the best-studied disease with depressed T lymphocytes and decreased cellular immunity. This deficiency is associated with a host of opportunistic infections and malignancies,12 and the risk of these conditions increases as CD4 cell counts decline.13 In addition to an increased risk of infection, patients with a CD4 cell count less than 200 µL-1 are vulnerable to a wide spectrum of opportunistic diseases (Table 1).11 Therefore, certain prophylactic medications are indicated at various CD4 cell count levels (Table 2).14 Opportunistic infections also occur in patients with idiopathic CD4 lymphocytopenia, a condition characterized by a CD4 T lymphocyte level less than 300 µL-1 in the absence of HIV infection. The incidence of opportunistic infections in diseases with depressed CD4 cell levels underscores the importance of these lymphocytes in normal immunity. It also supports an appropriate index of suspicion for opportunistic diseases in the setting of a low CD4 cell level such as that seen in some patients with CLL.
Hypogammaglobulinemia. One of the most widely known factors contributing to immunodeficiency and infection risk in patients with CLL is the presence of hypogammaglobulinemia. Low levels of immunoglobulins are estimated to be present in up to 85% of patients with CLL.15 The degree of hypogammaglobulinemia tends to be more pronounced with increased duration and severity of the disease.3 The most common pathogens related to low immunoglobulin levels are encapsulated bacteria such as Streptococcus pneumonia, Haemophilus influenzae, Escherichia coli, and Neisseria meningitidis.10,15,16 Like bacterial infections, hypogammaglobulinemia also increases the risk for viral infections, including herpes simplex and zoster viruses.15-17
The pathogenesis of the immunoglobulin deficiency in CLL is multifactorial and incompletely understood. It has been speculated that a combination of cytokine secretion and cell-cell interactions between normal lymphocytes and those affected by CLL contributes to the process. Several studies have proposed that B cell function is partly inhibited by the secretion of transforming growth factor β, which inhibits B cell proliferation. T helper cell function may be impaired by the secretion of interleukin-2 receptor; this leads to the downregulation of the T cells and further impairs B cell activation and function.17 While this process is impairing the patient’s normal functioning lymphocytes, the tumor cells, interestingly, are able to use the T helper cells and cytokines to further proliferate.3,10,15,17 Along with these components, several genetic factors and mutations also have been linked to the increased risk of infection associated with hypogammaglobulinemia.3,18 In addition to these factors, cases of CLL patients with recurrent infections and normal immunoglobulin levels have been reported. This suggests that a functional immunoglobulin deficiency, even in the absence of a quantitative immunoglobulin deficiency, may contribute to the immunocompromised state in CLL.10
The literature regarding infection risk based on specific immunoglobulin deficiencies and their particular levels is mixed. Immunoglobulin G4 and immunoglobulin A (IgA) are the most significant deficiencies in CLL.
Because of the prominent role of IgA in mucosal immunity, it is not surprising that the respiratory tract is the most common site of bacterial infections in patients with CLL.3 Additionally, low levels of immunoglobulin G3 may contribute to the reactivation of herpes-type viruses in persons with CLL.17 More research is needed to clarify the role of specific immunoglobulins and the associated risk of infection.
Hypogammaglobulinemia is typically not reversible regardless of the response to treatment, even if the patient is in complete remission.16 However, effective treatment has been shown to decrease the number and severity of infections regardless of the degree of hypogammaglobulinemia.17 Supplemental immunoglobulin G can be considered for patients with recurrent infections.19 While hypogammaglobulinemia certainly is not the only contributor to infection and morbidity in CLL patients, it remains a significant factor in overall risk and mortality.3,10,16,17
CLL is a common malignancy, often with an indolent course early in the disease process. Infectious complications are common in CLL as a result of both the hematologic abnormalities of the disease and the chemotherapeutic agents used to treat it. One important consideration is the increased risk of bacterial infection due to immunoglobulin deficiency in patients with CLL. Indeed, the administration of supplemental IVIG is associated with fewer bacterial infections in patients with CLL.19
As shown by the case described here, patients with CLL may have a reversal of the CD4 to CD8 cell ratio and thus may be at risk for the same opportunistic infections that affect patients with HIV/AIDS. Consideration of these risks is important when caring for individuals with CLL, particularly as they undergo treatment with immunochemotherapy that can further reduce the function of their immune systems. Indeed, it is standard in current clinical trials for patients with CLL who are undergoing chemotherapy to receive prophylaxis with trimethoprim-sulfamethoxazole for P jirovecii and antiviral prophylaxis with acyclovir during therapy.1 An appropriate suspicion should be maintained for unusual pathogens when a patient with CLL presents with symptoms of infection.
Anna Takala is a senior student in the Physician Assistant Program at Butler University in Indianapolis, Indiana.
Jamie M. S. Mulrow is a senior student in the Physician Assistant Program at Butler University.
Samuel L. Gurevitz, PharmD, CGP, is an associate professor in the Physician Assistant Program at Butler University.
Christopher Roman, MA, MMS, PA-C, is an assistant professor in the Physician Assistant Program at Butler University.
- Nabhan C, Rosen ST. Chronic lymphocytic leukemia: a clinical review. JAMA. 2014; 312(21):2265-2276.
- Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute–Working Group 1996 guidelines. Blood. 2008; 111(12): 5446-5455.
- Morrison VA. Infectious complications of chronic lymphocytic leukaemia: pathogenesis, spectrum of infection, preventive approaches. Best Pract Res Clin Haematol. 2010;23(1):145-153.
- Gupta NK, Andreadis C. New meets old: a case study and review of novel therapeutics for the treatment of CLL in older patients. J Natl Compr Canc Netw. 2014;12:1371-1375.
- Nastoupil LJ, Sinha R, Flowers CR. The role of chemotherapy in managing chronic lymphocytic leukemia: optimizing combinations with targeted therapy. Expert Rev Anticancer Ther. 2013;13(9):1089-1108.
- Young JA. Epidemiology and management of infectious complications of contemporary management of chronic leukemias. Infect Disord Drug Targets. 2011;11(1):3-10.
- Gea-Banacloche JC. Rituximab-associated infections. Semin Hematol. 2010;47(2):187-198.
- Wierda WG, Kipps TJ, Mayer J, et al. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010;28(10):1749-1755.
- Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110.
- Wadhwa PD, Morrison VA. Infectious complications of chronic lymphocytic leukemia. Semin Oncol. 2006;33(2):240-249.
- Moore RD, Chaisson RE. Natural history of opportunistic disease in an HIV-infected urban clinical cohort. Ann Intern Med. 1996;124(7):633-642.
- Crowe SM, Carlin JB, Stewart KI, Lucas CR, Hoy JF. Predictive value of CD4 lymphocyte numbers for the development of opportunistic infections and malignancies in HIV-infected persons. J Acquir Immune Defic Syndr. 1991;4(8):770-776.
- Holmes CB, Woods R, Badri M, et al. CD4 decline and incidence of opportunistic infections in Cape Town, South Africa: implications for prophylaxis and treatment. J Acquir Immune Defic Syndr. 2006;42(4):464-469.
- Opportunistic infection prophylaxis. In: Coffey S, ed. Guide for HIV/AIDS Clinical Care. Rockville, MD: Health Resources and Services Administration, HIV/AIDS Bureau, US Dept of Health and Human Services; April 2014:173-179. http://aidsetc.org/sites/default/files/resources_files/Clinical_Manual_4-30-2014_0.pdf. Accessed March 17, 2016.
- Hamblin AD, Hamblin TJ. The immunodeficiency of chronic lymphocytic leukaemia. Br Med Bull. 2008;87(1):49-62.
- Nosari A. Infectious complications in chronic lymphocytic leukemia. Mediterr J Hematol Infect Dis. 2012; 4(1):e2012070. doi:10.4084/MJHID.2012.070.
- Ravandi F, O’Brien S. Immune defects in patients with chronic lymphocytic leukemia. Cancer Immunol Immunother. 2006;55(2):197-209.
- Francis S, Karanth M, Pratt G, et al. The effect of immunoglobulin VH gene mutation status and other prognostic factors on the incidence of major infections in patients with chronic lymphocytic leukemia. Cancer. 2006;107(5):1023-1033.
- Griffiths H, Brennan V, Lea J, Bunch C, Lee M, Chapel H. Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood. 1989;73(2):366-368.