Abstract
Listeria monocytogenes infections have been described in patients with diverse types of malignancy, especially leukemia. We report the case of a 65-year-old man with previously untreated hairy cell leukemia characterized by CD5 positivity and trisomy 12 (3% of blood lymphocytes) who developed bacteremia due to L. monocytogenes serotype 1/2b. We summarize clinical features and treatment of this patient and five previously reported patients with hairy cell leukemia who also had L. monocytogenes infections. All six patients were men. Their mean age at infection diagnosis was 70 y. Three men had undergone splenectomy 4–11 y before they developed L. monocytogenes infection. The central nervous system was the primary site of infection in four men. Bacteremia alone occurred in two other men. At diagnosis of infection, one man was receiving antileukemia chemotherapy and another man was receiving treatment for Kaposi’s sarcoma. Two other patients had other comorbid conditions. All six men recovered from their infections.
1. Introduction
Hairy cell leukemia (HCL) is characterized by small mature B-lymphocytes with distinctive morphology and surface protein expression, hemocytopenias (especially neutropenia and monocytopenia), marrow fibrosis, splenomegaly, and an indolent clinical course [1]. The median age of patients with HCL is between 50 and 55 y [1]. Approximately 80% of persons with HCL are men [1]. Some persons with HCL develop autoimmune conditions unrelated to the severity of HCL [1, 2]. Cladribine therapy induces durable hematologic remissions in a high proportion of previously untreated patients [3].
We report the case of a man with previously untreated HCL who developed Listeria monocytogenes bacteremia. We summarize clinical features and treatment of this patient and five previously reported patients with HCL who were also diagnosed to have L. monocytogenes infections and discuss manifestations, management, and outcomes of L. monocytogenes infections in persons with HCL.
2. Case Report
A 64-year-old white man presented with a 10-month history of fatigue, lymphocytosis, microcytosis (elevated RDW), and subnormal platelet counts. He had bipolar disorder. Five months before presentation, he was treated as an outpatient for pneumonia not otherwise specified. Daily medications were duloxetine, lamotrigine, olanzapine, acetaminophen, fish oil, and melatonin. He tended horses and handled their silage daily. Physical examination revealed mild pallor. Lymph nodes, liver, and spleen were not enlarged.
Complete blood count revealed hemoglobin 110 g/L, erythrocytes 4.79 × 1012/L, mean corpuscular volume 73 fL, red blood cell distribution width 17.2%, leukocytes 15.6 × 109/L, neutrophils 4.4 × 109/L, lymphocytes 10.5 × 109/L, monocytes 0.5 × 109/L, and platelets 125 × 109/L. Serum iron level was 5.7 µmol/L, transferrin saturation was 7%, and serum ferritin was 23 pmol/L. Comprehensive chemistry profile values were within respective reference limits. Total immunoglobulin (Ig) G was 9.76 g/L. IgG subclass values were within respective reference limits. A HCL immunophenotype was detected in 68% of blood lymphocytes by flow cytometry (Table 1). Morphology of his leukemic blood lymphocytes is displayed in Figures 1 and 2. Fluorescent in situ hybridization revealed trisomy 12 in 3% of blood lymphocytes (reference < 1.3%). t(11;14) was not detected. He declined to undergo bone marrow evaluation or CT scanning.
(a)
(b)
Fecal occult blood testing was positive, although upper gastrointestinal tract endoscopy and colonoscopy did not reveal a site of blood loss. He was treated with four 500 mg infusions of iron as iron dextran. His fatigue resolved and his hemoglobin, erythrocytes, and mean corpuscular volume increased to 133 g/L, 4.85 × 1012/L, and 88 fL, respectively. Transferrin saturation and serum ferritin increased to 16% and 357 pmol/L, respectively.
Fifteen months after diagnosis, his physical examination revealed mild pallor. Hemoglobin was 102 g/L, neutrophil count was 6.2 × 109/L, midrange cells were 5.8 × 109/L, lymphocyte count was 36.9 × 109/L, and platelet count was 72 × 109/L. There was no evidence of recurrent iron deficiency.
At age 65 y, 16 months after diagnosis, he was admitted to hospital because he had temperature 103.1° and chills. Hemoglobin was 99 g/L, erythrocytes were 3.10 × 1012/L, mean corpuscular volume was 101 fL, leukocytes were 59.9 × 109/L, neutrophils were 3.0 × 109/L, lymphocytes were 56.9 × 109/L (88% with HCL immunophenotypes), and platelets were 83 × 109/L. The immunophenotype of his monoclonal blood lymphocytes was unchanged since diagnosis (Table 1). There was no apparent source of infection. He was treated initially with oral acetaminophen and intravenous fluids. On the second hospital day, he was treated empirically with oral levofloxacin 750 mg daily and became afebrile. He was discharged on the fourth hospital day to continue taking levofloxacin 750 mg daily (7 days total). He recovered fully. After discharge, it was reported that aerobic and anaerobic blood cultures drawn at hospital admission revealed a Gram-positive rod interpreted as Corynebacterium sp. Further study revealed that the isolate was L. monocytogenes. Neither the patient nor his wife had consumed uncooked or unpasteurized food items sometimes associated with Listeria transmission.
Subtyping of the present L. monocytogenes isolate was performed at the National Enteric Reference Laboratory (Centers for Disease Control and Prevention, Atlanta, GA) using growth phenotype on Trypticase™ Soy Agar with 5% Sheep Blood (BD Diagnostics, Sparks, MD) and nucleic acid-based analyses (average nucleotide identity and AccuProbe® culture identification testing (Hologic Inc., Marlborough, MA)). Testing detected serotype 1/2b.
In month 18 after diagnosis (Table 1), he was treated with subcutaneous cladribine therapy [1, 4] because his recurrent anemia was best explained by decreased erythropoiesis due to marrow progression of HCL [1]. In month 23 (4 months after last cladribine injection), his hemoglobin was 118 g/L, erythrocytes were 4.09 × 1012/L, mean corpuscular volume was 97 fL, leukocytes were 3.6 × 109/L, neutrophils were 2.5 × 109/L, lymphocytes were 0.8 × 109/L, and platelets were 113 × 109/L. Three percent of blood lymphocytes had a HCL immunophenotype (Table 1).
Mutation analysis to detect BRAF p.V600E (c.1799T > A) was performed for the first time in month 28 after diagnosis and 10 months after cladribine therapy (Table 1) by Genoptix (Carlsbad, CA) using the Cobas® 4800 V600 Mutation Test (Roche Molecular Systems, Inc., Branchburg, NJ). BRAF p.V600E was not detected.
3. Literature Search
We performed a computerized search of the National Library of Medicine and other sources to identify reports of patients with HCL who developed L. monocytogenes infections. We enhanced the computerized search by reviewing details of individual patients in selected case series of L. monocytogenes infections.
4. Six Patients with Hairy Cell Leukemia and L. monocytogenes Infections
We identified previous reports of L. monocytogenes infections in five patients with HCL, although their HCL immunophenotypes were not reported [5–9] (Table 2). Including the present patient, all six were men. Mean age of the six men at infection diagnosis was 70 y (standard deviation 13 y). Three men had undergone splenectomy 4–11 y before they developed L. monocytogenes infection. The central nervous system was the primary site of infection in four men. Bacteremia alone occurred in two other men. Possible sources of L. monocytogenes were reported in two men. At diagnosis of infection, one man was receiving antileukemia chemotherapy and another man was receiving treatment for Kaposi’s sarcoma. Two other patients also had other comorbid conditions. Antibiotic therapy was reported in five men, four of whom were treated with ampicillin in combination with other agents. All six men recovered from their infections (Table 2). L. monocytogenes serotyping and detailed flow cytometry and fluorescent in situ hybridization analyses were not described in the previous five reports [5–9].
5. Discussion
L. monocytogenes infection in patients with HCL has been reported infrequently [5–9]. The mean age and sex of the five previously reported cases and the present patient were typical of patients with HCL [1]. Splenectomy, current chemotherapy, and other comorbid conditions were common among these six patients. Four men had infections of the central nervous system, and the other two had bacteremia alone. Each patient recovered from his infection.
Persons with normal immunity who ingest L. monocytogenes in contaminated food typically have no manifestations or self-limited fever and diarrhea [10]. Those with persistent fever and positive stool cultures may benefit from antibiotic treatment [10]. Persons who have compromised defenses against L. monocytogenes include pregnant women; neonates; those with malignancy, diabetes mellitus, or chronic renal disease; those with acquired immunodeficiency syndrome; those who take glucocorticosteroid medications; and those > 50 years of age [10, 10–14]. Presenting symptoms of listeriosis in these persons include fever, myalgias, headache, confusion, loss of balance, and seizures. Most persons with compromised defenses who develop listeriosis require hospitalization, antibiotic therapy, and supportive care [10]. Serious complications include miscarriage and premature delivery; infection of neonates; and bacteremia, meningitis, and death [10–14].
Bacteremia without an evident focus is the most common manifestation of L. monocytogenes infections in compromised hosts [12]. In a 2004 review of 118 patients with malignancy and L. monocytogenes infections, the most common site of infection was also blood alone (53%) [13], consistent with the present case. Fifty-three percent of the 118 patients had leukemia (chronic lymphocytic leukemia, 21%; acute lymphoblastic leukemia and variants, 15%; acute myelogenous leukemia, 7%; chronic myelogenous leukemia, 6%; HCL, 3% [7, 8, 15]; and other leukemia, 2%) [13]. There were strong associations of L. monocytogenes infection with recent corticosteroid therapy (50%), recent chemotherapy (43%), or previous stem cell transplantation (17%). Mortality among patients with L. monocytogenes bacteremia alone was 18% [13].
BRAF p.V600E was detected at diagnosis in each of 48 patients with HCL reported by Tiacci et al. [16]. BRAF p.V600E was not detected in the present patient ten months after cladribine therapy. At that time, flow cytometry detected a hairy cell immunophenotype in only 0.9% of blood lymphocytes. The limit of detection of the assay used is 5% mutant alleles in a background of 95% wild-type alleles [17]. Thus, one cannot conclude that HCL in the present patient is not associated with BRAF p.V600E.
Features of the present case that distinguish it from variant HCL include lack of prominent nucleoli (Figure 1); positivity for CD11c, CD25, and CD103 (Table 1); and excellent response to cladribine [18]. Leukocyte counts were reported in 47 of 48 patients with HCL and BRAF p.V600E, among whom 12 (25.5%) had leukocyte counts at diagnosis > 11.0 × 109/L (range 11.4–55.0 × 109/L) [16]. Thus, we do not interpret leukocytes 15.6 × 109/L (lymphocytes 10.5 × 109/L) at diagnosis of the present patient as evidence that he has variant HCL.
Leukemic lymphocytes in the present patient were positive for CD5. Although CD5 positivity is not typical of HCL [19], this phenotype has been described in a small proportion of HCL cases [20]. Whether CD5 positivity represents a distinctive subtype of lymphoid malignancy is unknown [20]. Trisomy 12 occurred in three percent of blood lymphocytes in the present case. Trisomy 12 is not typical of HCL [3, 21] but has been described in a small proportion of patients [22, 23]. In such cases, the proportion of cells that display trisomy 12 is small [22, 23], like the present case. Except the appearance of dim CD23 positivity in leukemic lymphocytes in month 18, the leukemia cell immunophenotype in the present patient did not change.
Limitations of the present study include the possibility that we overlooked other reports of L. monocytogenes infections in patients with HCL in our manual literature review. Cases of other patients with HCL who developed L. monocytogenes infections may be unreported. Foodborne L. monocytogenes sometimes causes epidemic acute, febrile gastroenteritis that lasts two days [24]. Some patients with HCL and L. monocytogenes gastroenteritis may have been mistakenly diagnosed to have non-Listeria gastroenteritis.
Authors’ Contributions
James C. Barton conceived the study, treated the patient, tabulated data, and drafted the manuscript. Hayward S. Edmunds performed flow cytometry, interpreted hematologic data, performed photomicrography, and contributed to the manuscript.
Conflicts of Interest
The authors have no conflicts of interest to report.
Acknowledgments
This work was supported in part by Southern Iron Disorders Center. The National Enteric Reference Laboratory (Centers for Disease Control and Prevention, Atlanta, GA) identified the serotype of the present L. monocytogenes isolate.