Neonatal listeriosis: Uncommon or misdiagnosed?

1 Introduction

Listeriosis is a relatively uncommon and potentially fatal foodborne infection caused by the Listeria species - Listeria monocytogenes and less frequently Listeria ivanovii. These gram positive bacilli are motile, microaerophilic, and beta hemolytic [1]. Until recently, the incidence of listeriosis in the United States was decreasing, but over the last few years there has been an increase in outbreaks [2, 3]. Infection is more prevalent in pregnant women, neonates, elderly, and immunocompromised hosts [4]. There are 2-13 reported neonatal infections per 100,000 live births with mortality ranging from 20% to 60% [2, 5–7]. Significant morbidities including hydrocephalus, developmental delay and other neurologic sequelae can be seen in survivors [1]. We present a case of neonatal listeriosis (NL) in a preterm infant to highlight the continued challenges encountered in the neonate.

2 Case summary

A female infant was born at 28 weeks by spontaneous breech vaginal delivery to a gravida 4 para 3, 27-year-old Hispanic woman. The pregnancy was complicated by premature onset of labor and precipitous delivery preceded by one day of maternal fever. Maternal GBS status was unknown, and the mother received one dose of ampicillin just before delivery. At birth the patient was apneic and bradycardic requiring intubation and surfactant administration. Subsequently, she was admitted to the intensive care and required ventilator support. Her weight (860 g), length (33 cm), and head circumference (24 cm) were between the 10th and 25th percentile. In addition to respiratory distress, admission physical exam was significant for generalized bruising and petechiae (Fig. 1). Initial laboratory evaluation revealed pancytopenia (white blood count: 3600, platelet count: 120,000, and hematocrit: 33%). Empirical antibiotics consisting of ampicillin and gentamicin were started under the impression of sepsis. Blood culture grew Listeria monocytogenes at 48 hours. Chest X-ray showed diffuse infiltrates. Cerebrospinal fluid culture (CSF) was sterile. CSF studies (white blood cell count: 11, red blood cell count: 18,380, glucose 58 mg/dl, protein 160 mg/dl) were not suggestive of meningitis. Ampicillin 200 mg/kg/day initially and then 300 mg/kg/day was administered for 14 days. Retrospective questioning of the mother revealed that she consumed unpasteurized soft cheese during pregnancy. She developed fever and cold-like symptoms one week prior to delivery. Cranial US on the second day of life revealed grade 4 (left) and grade 3 (right) intraventricular hemorrhages and bilateral cerebellar hemorrhages (Fig. 2). The patient was treated and discharged home at a corrected gestational age of 38 weeks. She was last seen at 14 months of age in the neurodevelopment clinic, and was diagnosed with global developmental delay with a developmental age of 10 months. Magnetic resonance Imaging of the brain at term and at corrected age of 14 months showed hemosiderin staining of the lateral ventricles and superior cerebellar cistern and Pontocerebellar hypoplasia with normal myelination (Fig. 3).

3 Discussion

NL is a relatively rare but serious disease with a high mortality rate. The recent localized outbreaks raise the question if further preventative measures can be taken [2, 9]. Numerous reasons have been cited for underreporting and misdiagnosis of listeriosis. Listeria is morphologically similar to many organisms like Corynebacterium, clostridium and bacillus [10]. Listeria can decolorize readily during the Gram-staining procedure and has been mistakenly identified as a gram-negative organism, like Haemophilus. L monocytogenes meningitis yields a positive Gram stain in only about 33% of cases [10, 11]. A positive blood or CSF culture in a septic neonate for a diphtheroid or Haemophilus should alert the physician to a possible NL infection as Listeria has morphological similarities (short, Gram-positive bacillus) and therefore can be mistaken for a contaminant if cultures are not examined carefully [10]. The variable nature of Listeria infections suggests that many illnesses and some deaths may go undiagnosed and unreported. The perinatal incidence could also be higher due to undiagnosed spontaneous abortions and stillbirths [1, 6].

Fever and clinical presentation described as a flu-like syndrome are the most common symptoms in pregnant women [12]. Fetal infection can occur via transplacental transmission. Vertical Transmission can also occur via passage through an infected birth canal or ascending infection through ruptured amniotic membranes. As in other types of neonatal sepsis the presentation can be early or late onset [1]. Early - onset NL most often presents as pneumonia and/or sepsis and less commonly as meningitis [12]. In our case, beside prematurity, the initial impression was sepsis. Blood culture confirmed the diagnosis of NL. The infiltrates on chest radiography, can be attributed to respiratory distress syndrome from surfactant deficiency but similar findings have been ascribed to NL. The characteristic NL rash, granulomatosis infantisepticum, described in the literature as small, pale, granulomatous nodules or pustules was not seen in our patient [1, 13]. Instead the skin showed areas of erythematous, confluent petechial rash, and bruising (Fig. 1). The non-specificity of chest radiography and skin rash adds to the challenge of timely diagnosis in the absence of high suspicion. The presence of bilateral intraventricular and cerebellar hemorrhage is not uncommon in premature infants with sepsis. The severity of pontocerebellar hypoplasia in our patient without any disruption to the myelination and migration processes poses the question if such finding is specifically related to NL infection as similar finding are seen in some congenital infections.

The immune responses to Listeria are primarily cell mediated, which explains the greater frequency in pregnancy, AIDS, organ transplantation and the newborn [10]. Due to pregnancy-induced immunosuppression, pregnant women are 13 times more likely to become infected [7]. A better understanding of the fetal and neonatal immune system has shown that deficient synthesis of IL-12, IFN-gamma, IL-4, TNF-alpha and MyD88 results in poor modulation of immune responses like macrophage and NK cell activation. This contributes to the increased susceptibility of neonates to Listeria [1, 10]. The serotypes from neonates with early-onset NL are type Ia, Ib and occasionally IVb. Late-onset disease is more frequently associated with serotype IVb. In our case serotyping was not done as it is useful in epidemiologic studies, but is not of clinical importance.

Ampicillin is the drug of choice for the treatment of NL as first-line drug for the treatment of NL [14]. Due to the likelihood of progression to the central nervous system (CNS) and the possibility that Ampicillin is bacteriostatic or having delayed bactericidal activity against Listeria, adding an aminoglycoside for synergistic activity is recommended [14]. Meningitic dosing should be used regardless of CNS involvement [14]. With appropriate clinical response, Ampicillin alone can be continued for 14 days and for more severe infections or meningitis, treatment for 21 days will be needed [1, 14]. Cephalosporins have poor activity against Listeria and using Cefotaxime as a single agent for suspected sepsis in the neonatal period will not treat NL.

The awareness of NL as a major neonatal infection has been highlighted in isolated reports from around the world [15, 16]. Currently there are public health preventative measures including advice on preventing the exposure of pregnant women to listeria infection in place [17, 18]. Preventive measures for all food-borne illnesses including Listeriosis include general food handling advice on cooking animal source food, and avoiding unpasteurized milk. Specific preventative measures in pregnant women are to avoid soft cheeses like feta, brie, camembert, blue cheese, blue-veined, and Mexican-style cheese such as “queso fresco”. As there is a resurgence of health consciousness with tendency toward eating non processed fresh foods, there needs to be ongoing education and information about associated risk of infections. Effective surveillance and management of pregnant women is also needed [19, 20]. The incidence of pregnancy associated listeriosis is markedly higher among the Hispanic population (8.9 per 100,000) compared with non-Hispanic women (2.3 per 100,000) [21]. Additional vigilance and education to targeted populations with specific advice like avoiding queso fresco is needed. This is highlighted in our case as the mother of the patient admitted to consuming a soft Mexican cheese. The American College of Obstetricians has recently recognized the re-emergence of this deadly illness in the pregnant women and has guidelines to facilitate care of pregnant women with a likelihood of exposure to listeria [22]. Listeriosis is not a notifiable communicable disease in many areas of the world. Mandating a reportable status in cases of Listeria infection can improve the needed awareness [23].

For detection of listeriosis outbreaks, the CDC has established PulseNet, a network of laboratories that employ pulsed-field gel electrophoresis to subtype foodborne pathogens in order to detect disease clusters that may have a common source [24]. Other target specific measures like the introduction of routine Polymerase Chain Reaction testing in the agriculture and food industry makes a more rapid and accurate diagnosis and helps in early control of localized epidemics [25]. This has yet to make an impact as seen by newer food sources as in hummus, Bluebell ice cream, cantaloupe and other soft cheeses [26–28].

In conclusion, NL continues to be a cause of serious mortality and morbidity in the neonatal period as shown in our case. High index of suspicion and careful interpretation of blood culture results are required for early diagnosis and appropriate treatment. Preventive measures in pregnant women as outlined above are crucial to decrease the frequency of NL.

Disclosures

None.

Conflicts of interest

None.