Listeriosis: Epidemiology and Clinical Aspects

The causative agent of listeriosis, Listeria monocytogenes, is an intracellular Gram-positive bacillus capable of surviving under particularly extreme conditions (low temperatures, high acidity and high salt concentration).1 Its placental tropism makes it responsible for severe fetal and neonatal infections. The clinical spectrum ranges from mild self-limiting gastroenteritis to severe invasive manifestations. Invasive listeriosis primarily affects at-risk populations such as the elderly, immunocompromised individuals, pregnant women and neonates. It is characterized by 3 distinct clinical syndromes: bacteremia, meningitis and maternal–neonatal listeriosis.1 Maternal–neonatal listeriosis is defined by the identification of Listeria in a maternal, fetal or neonatal sample.2 EPIDEMIOLOGY The number of reported human listeriosis cases has increased over recent decades. In 2023, 2952 cases of invasive listeriosis were reported in Europe, corresponding to an incidence of 0.66 cases per 100,000 inhabitants—the highest since surveillance began in 2007.3 Pregnancy, linked to relative immunosuppression, increases the risk of listeriosis more than 100-fold compared to nonpregnant women of the same age group.1 The incidence of maternal–neonatal listeriosis is estimated to be between 4 and 10 cases per 100,000 pregnant women in Europe and the United States.3 Interestingly, the proportion of listeriosis among neonatal meningitis cases has declined: although it was reported as the second most common cause of meningitis in the United States in the 1980s, it now accounts for 1%–5% of neonatal meningitis cases, based on data from France, Canada and the United Kingdom.1 Listeriosis is rare in older children. Charlier et al. recently analyzed confirmed cases of listeriosis in children aged 1 month to 18 years in the MONALISA cohort, which tracked all reported listeriosis cases in France between 2009 and 2023. Among 1646 cases, only 61 occurred in this age group (preprint manuscript).4 Outbreaks are regularly reported, usually linked to the consumption of dairy products or ready-to-eat food. The 2017–2018 outbreak in South Africa, with 1024 documented cases, remains the largest to date1; 39% of cases were neonates.5,6 This outbreak was due to the consumption of ready-to-eat processed meat.6 CLINICAL PRESENTATION IN CHILDREN Maternal–Neonatal Listeriosis Maternal–neonatal listeriosis’ incubation period typically ranges from 19 to 27 days, and infection most often occurs during the third trimester of pregnancy.2 In pregnant women, clinical signs are often mild and nonspecific; fever may be absent, making diagnosis difficult. Neurolisteriosis is exceptional in this population. However, the vast majority of infected women present with obstetric complications such as fetal loss and premature delivery.5 Neonatal listeriosis generally results from direct transplacental transmission but can also be secondary to intrapartum transmission. It may manifest as early-onset sepsis (EOS; <7 days) or late-onset sepsis (LOS; ≥7 days).7 Bacteremia is documented in most cases, particularly in EOS. Meningitis (9%–13%) and pneumonia (9%–23%) are less common. Mortality is estimated to be around 10%–20% ranging from 3% in 1 study in France to 73% in a study in Chinese neonates,8–10 and neurological sequelae are common. In the MONALISA cohort, 189 children born to infected mothers were analyzed. Of these, 70% (132/189) presented with EOS, and 6% (12/189) with LOS with meningitis. All cases of LOS occurred between 7 and 21 days after birth.10 More than half (57%; 108/189) were born prematurely, including 22% (42/189) before 32 weeks of gestation. The mortality rate was 3% (5/189), and 6% (12/189) had severe cerebral lesions.10 In the same cohort, long-term neurological outcomes were assessed 5 years after neonatal infection in a series of 53 children. Among those, 31 (58%) were born prematurely. Developmental scores were obtained for 44 children, with nearly two-thirds having at least 1 disability (29/44, 66%), and 18% (8 children) suffering from severe disability. However, their outcomes did not differ from those of a gestational age-matched uninfected control group, suggesting that prematurity is the primary driver impacting the long-term prognosis of children affected by neonatal listeriosis.11 A retrospective study by Ntuli et al., including 42 neonates hospitalized during the South African outbreak (2017–2018), reported a prematurity rate of 81% (34/42): all but 1 presented with sepsis within the first 72 hours of life. Meningitis was documented in 40% (14/42) of cases, and 11% of the neonates died.5 Listeriosis Beyond the Neonatal Period Pediatric cases of listeriosis beyond the neonatal period are rare and remain poorly characterized. Among the 1646 listeriosis cases reported in the MONALISA cohort, 61 occurred in this age group. Of these, 48 cases (3%) were included in the study. The median age was 4 years (interquartile 25–75, range 1–10).4 In contrast to adults, in whom bacteremia is the predominant presentation, neurolisteriosis (meningitis or meningoencephalitis) is the most frequent manifestation in children. In this cohort, 60% (29/48) of pediatric cases presented with neurolisteriosis. Additionally, 25% (12/48) of children had isolated bacteremia, 6 had gastrointestinal involvement (gastroenteritis or appendicitis) and 1 had a cutaneous infection.4 Underlying immunosuppression was present in 67% (8/12) of children with bacteremia but only in 21% (6/29) of those with neurolisteriosis. This highlights that, unlike bacteremia, neurolisteriosis in children occurs predominantly in the absence of apparent immunosuppression. Lower frequency of bacteremia in children compared to adults may be related to the lower rate of immunosuppression among children.4 DIAGNOSIS Microbiologic Diagnosis Historically, pediatric listeriosis has always been diagnosed by cerebrospinal fluid (CSF), blood or peripheral samples culture from the infant/child or maternal samples (blood or placental swab). In the neonatal MONALISA cohort, the samples with the highest microbiological sensitivity were placental smear (78%) and gastric fluid (78%) cultures. In 98% of the cases, diagnosis was confirmed on the p*lacenta and/or maternal blood culture.10 CSF cultures (systematic samples) are rarely positive in newborns with EOS (2% and 16% in the South African and MONALISA cohorts, respectively).6,10 However, in newborns who presented with LOS, a positive CSF culture or Polymerase Chain Reaction (PCR) was reported more frequently (12/12).10 Among older children, aged 1 month to 15 years, in the South African cohort, 59% of cases had positive blood cultures, 2% had positive CSF cultures and 39% had another positive peripheral sample (eg, stool, urine, synovial fluid, pus).6 Currently, cultures remain the gold standard, but the use of multiplex PCR panels containing L. monocytogenes for CSF analysis provides faster results (turnaround time 1 hour). The first meningitis/encephalitis multiplex PCR was approved by the FDA in October 2015.12 Nonspecific Biologic Indicators CSF Cytochemistry Markers In newborns with proven meningitis (either EOS or LOS), the median protein concentration (2.6 g/L; 2.5 g/L) and median polymorphonuclear to nucleated cell ratio (0.52; 0.55) were almost identical. However, the median nucleated cell count was very different between newborns with EOS meningitis, 125 cells/mm3 (min 40–max 945 cells/mm3) and newborns with LOS meningitis 3350 cells/mm3 (min 1040–max 5055 cells/mm3).10 There are currently very few data available on the characteristics of lumbar puncture in children older than 1 month with Listeria meningitis. Two small studies (n = 8 and n = 7) both reported hypoglycorrhachia and hyperproteinorrachia but reported discordant results regarding the predominant cell type (monocytes vs. polymorphonuclear cells).13,14 In all patients combined (>1 month and adults), CSF leukocyte counts in Listeria meningitis are elevated but less than those seen in meningitis due to other bacteria. Radiologic Signs Few studies describe imaging performed in these newborns or children with neuromeningeal listeriosis. In adults, rhombencephalitis is highly suggestive of Listeria infection on brain imaging, even if this presentation is uncommon.15 In the pediatric case series, these radiological findings were not observed. The neuroimaging findings included intraventricular hemorrhages in prematurely born infants, hydrocephalus, hemorrhage, meningoencephalitis, leukoencephalopathy and ischemic lesions in older children.11,16,17 Listeria Treatment Rapid administration of adequate intravenous antibiotics is the cornerstone of Listeria treatment and is key to avoiding complications (sequelae, death), even though neither the optimal drug(s) nor its/their duration has been established in controlled trials.1 First-line Agents Listeria is intrinsically resistant to cephalosporins. To date, penicillin and aminopenicillins, such as amoxicillin or ampicillin, remain the cornerstone of treatment.1,18,19 A combined treatment with aminoglycosides is often suggested.18–20 Even though several observational studies suggested a benefit of combination therapy,21,22 controlled studies proving its superiority compared to monotherapy are lacking. Second-line Agents In case of beta-lactam allergy, co-trimoxazole and to some extent quinolones can be used as an alternative.18–20 Use of alternative second-line agents that are active intracellulary (trimethoprim/sulfamethoxazole, quinolones, linezolid and/or rifampicin) is supported by case reports in adults.20 Empirical Listeria Treatment In mother-to-child transmission, even if Listeria is mostly transmitted transplacentally and is responsible for EOS, it can also be transmitted by ascending vaginal colonization and cause LOS.18 Consequently, and despite rare occurrences of Listeria infection in children >4 weeks old,10 some experts recommend aminopenicillins as part of empirical antibiotic treatment in febrile children up to 8 weeks of age.19,23 The recent American Academy of Pediatrics (AAP) guidelines do not recommend empirical Listeria in children >21 days old with fever without source; however, if meningitis is suspected, empirical Listeria coverage remains recommended until 28 days of age.24 Regarding meningitis, European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines do not recommend empirical Listeria coverage in healthy children with meningitis beyond the neonatal period because of the very low incidence of Listeria infection in this group. Resistance to Antibiotics Even though some countries reported an increasing resistance to antibiotics amongst Listeria isolates,25 this has not been confirmed in large European datasets,26,27 where no resistance to aminopenicillins has been documented to date. Caution is therefore advised in case of an atypical resistance profile in an isolate, and using an alternative susceptibility testing method (ie, broth microdilution if initial resistance testing was performed using the disk diffusion method) should be considered to confirm findings. For second-line agents, the choice of antimicrobials should be based on the susceptibility profile of the isolate.20 Treatment Duration and Administration Route For listeriosis in the first month of life (mother-to-child transmission), aminopenicillins for 14–21 days, in combination with gentamicin for 7 days, are recommended. As the likelihood of associated meningitis increases with age in neonates with Listeria bacteremia,10,18 some experts recommend 21 days of treatment in neonates >7 days old with bacteremia without documented meningitis, compared with 14 days in neonates 0–7 days old.1,28 For documented meningitis, a course of at least 21 days is recommended in case of central nervous system involvement. For Listeria in older children, bacteremia without meningitis is usually treated for 14 days,18–20,29 but some experts recommend longer courses in immunocompromised patients. For Listeria endocarditis, a rare entity, a course of 4–6 weeks is usually recommended.18,20,29 For meningitis, a course of at least 3 weeks is recommended;18–20,29 some experts recommend performing brain imaging near the end of treatment to document the absence of complications that might warrant longer treatment.20 Indeed, brain abscesses, cerebritis and rhombencephalitis are usually treated for at least 6 weeks.18,29 Regarding Listeria gastroenteritis, which is commonly self-limited, there is a lack of data regarding treatment efficacy, and hence, antibiotics are not routinely recommended.18 As the evidence for oral stepdown is limited to case reports, intravenous antibiotics are used for the entire treatment course in most patients. Adjunctive Treatment In patients with Listeria meningitis, some data have suggested an increase in mortality in patients receiving steroids.22 Therefore, if Listeria is suspected in a patient with meningitis, the use of steroids should be reconsidered. Similarly, if Listeria is identified in a patient with meningitis, steroids should be discontinued.30 In neonatal meningitis, steroids are not empirically recommended.30 Other Treatment Considerations As iron may enhance the pathogenicity of L. monocytogenes, iron supplementation should be withheld until treatment completion.19,20 Listeria Prevention Primary Prevention The main animal reservoir of Listeria is ruminant animals (cattle, sheep and goat). Listeria is a foodborne infection whose prevention relies on the control of food chain contamination. Consequently, the education of vulnerable persons or their caretakers (parents) is the cornerstone of Listeria prevention. Prevention relies primarily on the avoidance of potentially contaminated food, such as unpasteurized dairy, raw fish/seafood, smoked fish, undercooked meat, unheated deli (meat, cold cuts, hot dog, sausages, pâté, meat spread), premade deli salad and raw sprouts.31,32 Crust should be removed from cheese, animal food cooked thoroughly, and vegetables/aromatics washed thoroughly. Refrigerators should be regularly cleaned and set at the right temperature, and ready-to-eat refrigerated food must be eaten quickly.31,32 A review of recent outbreaks identified unpasteurized dairy and ready-to-eat products as responsible for >75% of recent outbreaks.1 Prevention of Mother-to-Child Transmission In case of presumptive exposure to Listeria in symptomatic pregnant women, an expectative attitude is often suggested if the woman is afebrile. In case of fever, empirical treatment with intravenous aminopenicillins is started to prevent transmission of Listeria (among other bacteria such as Streptococcus agalactiae) from infected mothers to neonates. Blood cultures are obtained and, in case of delivery, placental cultures.33 In pregnant women with documented Listeria infection, aminopenicillins in combination with gentamicin are commonly given.1,33 Practical Recommendations Listeriosis is exceptionally rare in children over 1 month of age. It remains a rare but serious cause of EOS and meningitis in newborns. EOS typically presents as bacteremia, whereas LOS is almost always associated with meningitis. Maternal–fetal infections can be diagnosed through cultures of placental smears, and maternal and neonatal blood. Cultures from other peripheral sites may also contribute to diagnosis (gastric aspirates). The standard treatment combines an aminopenicillin with gentamicin. Duration is 14 days for EOS, and 21 days for LOS or confirmed meningitis, with gentamycin administered for the first 7 days. Prevention is crucial. Primary prevention targets at-risk populations, while secondary prevention includes screening and treating pregnant women with suggestive symptoms—both approaches help to reduce neonatal mortality.

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