Middle-aged Man With Fever and Neurologic Signs

A 52-year-old man is admitted to the hospital for altered mental status and fever of 2 days’ duration.

HISTORY

He has a several-year history of chronic lymphocytic leukemia (CLL), currently stage IV, and has over the years received aggressive therapy with cyclophosphamide, prednisone, rituximab and, most recently, fludarabine and dexamethasone several weeks ago. His wife noticed intermittent confusion and delirium-like episodes over the past week, but until today she could arouse him to a near-normal cognitive state. When the fever manifested, she brought him for medical evaluation. He has not traveled away from home in recent months, but he did attend a family picnic 2 weeks earlier, where a variety of meats and prepared salads were served.

PHYSICAL EXAMINATION

Temperature is 38.5°C (101.3°F); heart rate, 108 beats per minute; respiration rate, 20 breaths per minute; and blood pressure, 105/60 mm Hg. Pallor of the mucous membranes is noted. There is no nuchal rigidity. Diffuse 1- to 3-cm lymphadenopathy is evident in the neck and supraclavicular and axillary regions. Heart and lungs are normal, but the spleen is palpable 3 cm below the left costal margin. His mental status waxes and wanes from relative alertness to obtundation throughout the course of the initial day. Myoclonus is elicited in both ankles.

LABORATORY AND IMAGING RESULTS

White blood cell count is 42,000/µL with 90% lymphocytes and 10% polymorphonuclear (PMN) forms; “smudge” cells are seen on the smear. Hemoglobin level is 9.7 g/dL, and platelet count is 89,000/µL. Albumin level is 2.9 g/dL, and blood glucose level is 210 mg/dL.

A CT scan of the brain is negative for hemorrhage and masses. Thickening and inflammatory changes are noted in the meninges, particularly in the brainstem area.

Analysis of a cerebrospinal fluid (CSF) specimen shows a protein level of 190 mg/dL, a glucose level of 110 mg/dL, and a cell count of 480/µL with an equal mixture of PMN and mononuclear forms. The next morning, the microbiology laboratory reports that both blood and CSF cultures grew a short, gram-positive rod.

Which of the following is the most significant epidemiological risk factor predisposing this patient to his infection?

A. The presence of neutropenia.

B. The presence and therapeutics of a hematologic malignancy.

C. His age.

D. Ingestion of home jarred foods.

(Answer on Next Page)

Correct Answer: B

This patient manifests a wide variety of clinical features strongly suggestive of meningitis caused by Listeria monocytogenes. His febrile illness and CSF findings are essentially diagnostic of meningitis.¹ Further, the ancillary findings of movement disorder, some focality to his neurological examination, fluctuating mental status, and the presence of positive blood cultures are all far more typical of Listeria meningitis than other relatively common bacterial forms such as Haemophilus influenzae, Streptococcus pneumoniae, or the meningococcus.^1-3

EPIDEMIOLOGY

An appropriate discussion begins with the epidemiology of Listeria infection. L monocytogenes is a short, non–spore-forming gram-positive rod able to survive in aerobic or anaerobic conditions. An outstanding discriminant factor is its cold tolerance such that Listeria growth is enriched in a cold environment unlike the growth of most other human pathogens. This results in the finding of significant contamination by Listeria in refrigerated foods. The classic factoid is its presence in soft cheeses, but contamination of sausage and especially chicken is even more common, as shown by isolate studies and human epidemic studies.⁴ It is this route whereby humans are exposed to Listeria most commonly.

CLINICAL FEATURES

Once a patient is infected, a variety of clinical syndromes may ensue: these include a febrile gastroenteritis, neonatal sepsis and meningitis, primary bacteremia, and CNS infection as occurred in this case. Listeria infections are quite serious. For example, compared with other bacterial meningitides (including that caused by the very noxious pneumococcus), Listeria meningitis is associated with the highest mortality (22%), although the overall incidence is much lower (3.2% of meningitis cases).^1-3

Some of this may be related to risk factors that seem to predispose to Listeria infection. Surprisingly, listeriosis is not a common infection in neutropenic patients or in those with diminished immunoglobulin production—two very typical defense mechanisms against bacterial infection (choice A). In fact, one of Listeria’s pathogenetic ploys is its ability to enter, survive within, and even use human leukocytes for protection and transportation.¹ In addition, age is not a particularly strong risk factor (choice C). Listeria infections occur with sustained frequency across all decades of life, although there is increased risk in the elderly (older than 65 years). This patient is 52, so his age, per se, is not a strong risk factor.

What is, however, is his CLL diagnosis and therapy with rituximab and fludarabine. Conditions that affect cellular immunity do indeed vary significantly and logarithmically enhance the risk of Listeria infection. These include, in order of decreasing risk³:

•Organ transplantation (with its attendant profound immune suppression).

•Hematologic malignancies (especially lymphomas and CLL, even more so with aggressive therapies).

•AIDS.

•Pregnancy.

Thus, choice B, the hematologic malignancy and the profound cellular immunity related to it and its therapy, is the correct answer here. This patient manifests a meningitis syndrome with a variety of aspects very typical of Listeria as the cause. And, he is in an extremely high epidemiologic risk group for this infection.

DIFFERENTIAL DIAGNOSIS

Botulism, caused by the anaerobic spore-forming organism Clostridium botulinum, is another gram-positive rod infection that certainly produces a neurological syndrome. However, unlike Listeria infection, botulism is less a disease found in the refrigerator and more a disease related to improper canning and jarring of foods. Bacteremia is not typical, and the findings on gram staining are quite different morphologically. Thus, choice D is not most likely here.

OUTCOME OF THIS CASE

An empiric regimen of ceftriaxone and gentamicin was started. Once the gram stain findings and positive blood cultures for a small gram-positive rod became known, this regimen was changed to ampicillin and gentamicin. At 48 hours, L monocytogenes infection was confirmed on culture of blood and CSF specimens. There was gradual improvement, although the clinical course was stormy. Antibiotics were continued for 4 weeks, and the patient recovered from his infection. n