Listeriosis overview

# Overview
Listeriosis is a heterogeneous group of infectious diseases caused by Listeria spp. (commonly Listeria monocytogenes), a flagellated, catalase-positive, facultatively intracellular, anaerobic, gram-positive bacillus. Listeriosis is a relatively uncommon infection with an annual incidence of listeriosis in the United States ranging between 0.2 to 0.3 cases per 100,000 individuals. Listeria is commonly transmitted via contaminated food or via vertical transmission from mother to fetus. Following transmission, Listeria encodes thermoregulated virulence factor in the human host, invades the intestinal epithelium, and multiplies intracellularly within phagocytic phagolysosomes. Following transmission, Listeria may cause any the following syndromes: neonatal listeriosis, genitourinary infection, gastroenteritis, central nervous system infection, endocarditis, bacteremia, and localized infection. Risk factors in the development of listeriosis include ingestion of uncooked meats and vegetables, unpasteurized (raw) milk and cheeses, processed (or ready-to-eat) meats and smoked seafood.  Populations at higher risk of developing listeriosis include immunosuppressed patients (e.g. transplant recipients, patients with history of splenectomy, patients receiving immunosuppressive therapy, or patients with advanced diabetes, kidney/ liver disease, or active malignancy),  neonates, pregnant women, and elderly patients. The majority of healthy patients do not develop clinical manifestations or may develop a mild, transient bacteremia. Early clinical manifestations (usually fever) typically develop early within 24 hours of transmission. If left untreated, patients typically progress within 1-90 days to develop Listeria-associated complications, including bacteremia, abscess formation, pneumonia, ARDS, acute kidney injury, and CNS impairment. Among healthy children and young adults, the prognosis of listeriosis is generally good. Prognosis is poorer among high-risk populations, who are more likely to develop complications and death even with prompt management. For symptomatic patients, diagnosis of listeriosis is confirmed following the isolation of Listeria monocytogenes from a normally sterile site, such as blood, spinal fluid (in the setting of nervous system involvement), or amniotic fluid/placenta (in the setting of pregnancy). Nonetheless, the diagnosis of listeriosis requires a high pre-test probability, given the organism's morphological similarity to other organisms, variability in clinical manifestations, and low rates of Gram-staining. All patients with listeriosis require antibiotic therapy. Ampicillin, with or without gentamicin, is the antibiotic of choice for the treatment of listeriosis. Patients intolerant to penicillins may be managed with trimethoprim-sulfamethoxazole. Duration of therapy depends on the clinical syndrome and may range from several days in non-complicated gastroenteritis to 6 weeks in endocarditis or encephalitis. Listerial gastroenteritis is frequently self-limited among healthy adults, but a short course of oral ampicillin may be considered among immunocompromised or pregnant individuals or those who have ingested food implicated in outbreaks. Non-gastroenteritis listeriosis often requires hospitalization and intravenous (IV) antibiotic therapy. Surgery may be required among patients who develop complications, such as abscess formation or advanced endocarditis. General recommendations for the primary prevention of infection with Listeria include appropriately washing and handling of food, maintaining a clean and safe kitchen and environment, cooking meat and poultry thoroughly, safely storing foods, and choosing safe foods. There are no vaccines against listeriosis, and pharmacologic prophylaxis is not recommended.

# Historical Perspective
Listeria monocytogenes (formerly Bacterium monocytogenes) was first isolated in 1926 by Everitt Murray. The organism was renamed Listeria monocytogenes in 1940 in honor of Joseph Lister. Initially described as a bacteria of laboratory animals, the first human cases were described in 1929 by Nyfeldt in Denmark.

# Classification
Listeriosis may be classified according to the clinical syndrome into the following: neonatal listeriosis, genitourinary infection, gastroenteritis, central nervous system infection, endocarditis, bacteremia, and localized infection.

# Pathophysiology
Listeria is commonly transmitted via contaminated food or via vertical transmission from mother to fetus. Following transmission, Listeria encodes thermoregulated virulence factor in the human host, invades the intestinal epithelium, and multiplies intracellularly within phagocytic phagolysosomes. It is able to escape lysosomal destruction by secreting phospholipases and listeriolysin O, a hemolysin that is responsible for lysis the vacuole's membrane. Listeria then migrates between cells by forming protrusions called filopods or "rockets" using polymerized actin and Gelsolin, an actin-binding protein. Microscopically, tissue infected with Listeria monocytogenes often demonstrates microscopic features of inflammation, exudate formation, and neutrophilia. In prolonged infections, macrophages may be abundantly present in tissue specimens, and granuloma formation may occur.

# Causes
Listeriosis is caused by the bacterium Listeria monocytogenes, a flagellated, catalase-positive, facultative intracellular, anaerobic, nonsporulating, Gram-positive bacillus. Listeria is commonly found in soil, water, vegetation and fecal material.

# Differential Diagnosis
Listeriosis is associated with more than one clinical syndrome. It must be differentiated from other infections that cause fever and systemic/localized symptoms (either CNS disease, gastroenteritis, genitourinary disease, endocarditis, or bacteremia), such as E. coli, Neisseria spp., Streptococcus spp., Staphylococcus spp., Shigella, Salmonella, Campylobacter, Serratia spp., or Haemophilus spp., mononucleosis, or tuberculosis. Listeria monocytogenes must also be differentiated from other organisms that are morphologically similar, such as pneumococci, diphtheroids, or Haemophilus spp. Differential diagnosis of listeriosis additionally includes hematologic malignancies (such as leukemia or lymphoma), thyroid disease, drug fever, vasculitides, or rheumatologic diseases.

# Epidemiology and Demographics
The annual incidence of listeriosis in the United States is approximately 0.2-0.3 cases per 100,000 individuals. The incidence of listeriosis is higher among females (especially pregnant women), neonates, elderly individuals, and Hispanic individuals. Listeriosis has a worldwide distribution in both developed and developing countries.

# Risk Factors
Risk factors in the development of listeriosis include ingestion of uncooked meats and vegetables, unpasteurized (raw) milk and cheeses, processed (or ready-to-eat) meats, and smoked seafood.  Populations at higher risk of developing listeriosis include immunosuppressed patients (e.g. transplant recipients, patients with history of splenectomy, patients receiving immunosuppressive therapy, or patients with advanced diabetes, kidney/ liver disease, or active malignancy),  neonates, pregnant women, and elderly patients.

# Natural History, Complications and Prognosis
Following transmission, the majority of healthy patients do not develop clinical manifestations or may develop a mild, transient bacteremia. Early clinical manifestations (usually fever) typically develop early within 24 hours of transmission. If left untreated, patients typically progress within 1-90 days to develop Listeria-associated complications, including bacteremia, abscess formation, pneumonia, ARDS, acute kidney injury, and CNS impairment. Among healthy children and young adults, the prognosis of listeriosis is generally good. Prognosis is poorer among high-risk populations, who are more likely to develop complications and death even with prompt management.

# Diagnosis

## History and Symptoms
Fever is the most common symptom of listeriosis. Other symptoms develop on location of the infection: Patients with gastroenteritis may develop watery diarrhea, abdominal pain, vomiting, and headache. Patients with CNS infection may develop symptoms of meningitis, encephalitis, cerebritis, rhombencephalitis, or spinal cord infection, such as headache, back pain, neck pain, photophobia, phonophobia, deafness, confusion, ataxia, seizures, and neurological impairment.

## Physical Examination
The findings on the physical examination depend on the clinical manifestation of listeriosis. Common findings include fever, tachycardia, pallor, and abdominal tenderness.  Signs of neurological involvement may include altered mental state, paralysis, respiratory failure, and coma.

## Laboratory Findings
For symptomatic patients, diagnosis of listeriosis is confirmed following the isolation of Listeria monocytogenes from a normally sterile site, such as blood, spinal fluid (in the setting of nervous system involvement), or amniotic fluid/placenta (in the setting of pregnancy). Cultures from non-sterile sites, such as stool samples, are not recommended (1-15% carriage rate) but may still be useful in gastroenteritis with high suspicion of listeriosis. Listeria monocytogenes may be isolated readily on routine media. Since Listeria is an intracellular organism, only 1/3 of cultures yield positive Gram-stains. Selective enrichment media improve rates of isolation from contaminated specimens. The cultures typically require 1-2 days for growth. A negative culture does not rule out infection in the presence of strong clinical suspicion. Cerebrospinal fluid (CSF) analysis may confirm the diagnosis among patients with CNS listeriosis. Serological tests (e.g. listeriolysin O titers) have been used, but their use remains controversial and are currently not recommended. Polymerase chain reaction for the detection of the HLY gene may be diagnostic, but it is not yet widely available for commercial use. Laboratory testing on asymptomatic patients (including high-risk asymptomatic patients) is not recommended.

## MRI
Brain MRI may be helpful in the diagnosis of Listeria monocytogenes brain lesions. Findings on MRI suggestive of listeriosis include lesions in the cerebellum, brainstem, and cortex.  High-signal lesions on T2-weighted images and enhancing lesions on T1-weighted images can be identified in the cerebral parenchyma on MRI following administration of IV contrast. With a high pre-test probability, brainstem involvement on MRI is strongly suggestive of listeriosis. Contrast MRI is recommended among all patients presenting with listerial meningitis, listerial bacteremia, suggestive CNS signs and symptoms or upon suspicion of intracranial listeriosis.

## Other Diagnostic Studies
Additional studies for the diagnosis of listeriosis are not recommended.

# Treatment

## Medical Therapy
All patients with listeriosis require antibiotic therapy. Ampicillin, with or without gentamicin, is the antibiotic of choice for the treatment of listeriosis. Patients intolerant to penicillins may be managed with trimethoprim-sulfamethoxazole. Duration of therapy depends on the clinical syndrome and may range from several days in non-complicated gastroenteritis to 6 weeks in endocarditis or encephalitis. Listerial gastroenteritis is frequently self-limited among healthy adults, but a short course of oral ampicillin may be considered among immunocompromised or pregnant individuals or those who have ingested food implicated in outbreaks. Non-gastroenteritis listeriosis often requires hospitalization and intravenous (IV) antibiotic therapy.

## Surgery
Surgery is not usually recommended among patients with listeriosis. Surgery may be indicated in cases of Listeria-associated complications, such as abscess formation requiring abscess drainage or advanced endocarditis require valve repair.

## Primary Prevention
General recommendations for the primary prevention of infection with Listeria include appropriately washing and handling of food, maintaining a clean and safe kitchen and environment, cooking meat and poultry thoroughly, safely storing foods, and choosing safe foods.  In addition to the general recommendations on how to prevent an infection with Listeria, there are additional recommendations specifically for persons who are at higher risk, such as pregnant women, elderly, and individuals with compromised immune status. There is no vaccine against listeriosis. Pharmacologic prophylactic measures against listeriosis are not helpful.