Worldwide, listeriosis is an important public health and food safety problem. In the
perinatal period, it is associated with pregnancy loss, premature birth, and neonatal
death. In the United States, it has been a mandatory reportable disease since 2001
and in Canada since 2006, but not in other countries, such as Brazil.[1]
[2]
[3] During pregnancy, the diagnosis of listeria infection is difficult as most cases
are asymptomatic and may lead to miscarriages and stillbirths. Furthermore, the frequent
failure to isolate the bacteria in blood and tissue cultures contributes to paucity
of confirmed diagnosis and fewer reports in the literature of neonatal listeriosis.[4] Inflammatory response is a frequent reason of premature deliveries and miscarriages,[5] so cord blood was analyzed for inflammatory cytokines.
The present study reports a case of chorioamnionitis and early neonatal sepsis caused
by Listeria monocytogenes. It reinforces the importance of clinical suspicion, careful assessment of obstetric
history, and placental histology, which confirmed the diagnosis in the present case.
Case Report
A male infant was born to a 26-year-old primigravida mother by vaginal delivery at
25 weeks' gestational age and weighed 775 g. The pregnancy was unremarkable except
for a flulike illness early in pregnancy and fever a few days prior to delivery. The
fetal membranes were ruptured just prior to delivery. The baby was floppy at birth
and required resuscitation. Apgar scores were 4 at 1 minute and 8 at 5 minutes of
age. Nonconfluent erythematous maculopapular and micropapular exanthema (1-mm diameter)
with purpuric lesions as large as 2 to 3 mm were noted at birth mostly located on
the trunk, buttocks, and thighs but absent from palms, plants, and scalp, different
from classical “blueberry muffin.”
After initial resuscitation, the patient was admitted to the neonatal intensive care
unit and intubated for respiratory distress. Surfactant replacement therapy via endotracheal
tube was given 40 minutes after birth. His clinical course continued to deteriorate,
and he died 24 hours later with septic shock that failed to respond to clinical septic
shock management, including administration of volume expanders, antibiotics, and inotropes.
Blood culture taken at birth failed to grow any organisms. The placental histology
showed acute necrotizing chorioamnionitis with funisitis, characterized by a green-yellowish
discoloration and thickening and opacity of the amnion, chorion, and fetal membranes,
associated with the presence of dense and diffuse inflammatory neutrophilic exudates,
often forming subchorionic abscesses. There was acute funisitis, with neutrophilic
exudates in the umbilical vessel walls and Warton's jelly, as well as necrosis and
presence of intracellular gram-positive bacteria in membranes and umbilical cord.
The amnion also presented necrosis and gram-positive and silver-positive intracellular
bacteria were seen (Grocott's method, [Fig. 1]), histological findings typical of L monocytogenes infection.
Figure 1 Microscopic (eight-silver; 1000 × ) amniotic epithelium, showing silver-positive
intracellular bacteria, staining by Grocott's method (silver impregnation).
Inflammatory cytokines in cord blood, collected aseptically in heparinized tubes at
birth and measured by flow cytometry using cytometric bead array (BD Cytometric Blood
Array Human Inflammatory Cytokine kit, BD Biosciences, Pharmingen, San Diago, CA),
were elevated [interleukin (IL)-8 and IL-6 (both >5000 pg/mL) and IL-10 (100 pg/mL)],
when compared with mean values of 329 (7 to 4135), 246 (50 to 1100), and 3.6 (2.2
to 7.0) pg/mL, respectively, already described in cord blood of very low-gestational-age
neonates with chorioamnionitis.[6]
Discussion
L. monocytogenes is a facultative anaerobe, intracellular gram-positive, β-hemolytic coccobacillus.
Surface proteins and enzymes allow it to invade and survive inside phagocytes and
infect other cells without exposure to antibodies and neutrophilic and complement
defenses. Factors responsible for listeria's intracellular survival, intracytosol
replication, as well as the polymerization process, which provides energy for motility
and insertion in the nearby cells, have been described in detail elsewhere.[7]
L. monocytogenes attacks mainly the central nervous system and may cross the blood-brain barrier,
causing meningoencephalitis and thromboencephalitis. The infecting dose varies according
to the strain and patient susceptibility, and in a recent study in animals, it was
found to be 107 colony forming units.[8] Thirteen serotypes have been described, according to cellular and flagellar antigens,
but serotypes 1/2a, 1/2b, and 4b are responsible for almost all human infections.
The most frequent transmission route is through the ingestion of contaminated food
(mainly milk and dairy products, poultry, uncooked meat, raw vegetables, and even
water). It is estimated that 5 to 10% of the population are carriers of L. monocytogenes in their digestive tract, cervix, or vagina, but there has not been any description
of person-to-person transmission.[4] Vertical transmission is well documented, and contamination may be ascendant, via
direct invasion or transplacentary or hematogeneous dissemination[9] and may also occur in the birth canal during labor[10] and through the breast milk.[11] Outbreaks due to the contact with contaminated equipment devices or material are
rare, but occasionally occur in neonatal intensive care units.
Recent review showed that a considerable proportion of reported listeriosis cases
(16.9%) in the United States from 2004 to 2007 consists of pregnant women, and maternal
infection resulted fetal loss in 20.3%.[12] Pregnant women are 20 times more susceptible than healthy nonpregnant adults to
be infected by this bacteria. Neonates are even more susceptible than their mothers.[1]
[2]
[3]
Clinical presentation varies according to transmission route and patient immune system
status. Incubation period ranges from 8 to 14 days (outbreaks: 3 to 70 days). Many
cases are asymptomatic, or the patient may report mild complaints (discomfort and
myalgia). Pregnant women may present with a flulike illness with fever, gastrointestinal
symptoms, low abdominal pain, skin rashes, and meningitis. The flulike illness is
always short-lived but bacteremia is always present. Skin lesions usually consist
of papules, pustules, vesicles, ulcers, and purpura.[4]
The neonate may present with early or late sepsis. In cases of intrauterine transmission,
the signs of early sepsis are apparent from birth up to 2 days of life, and eventually
can be lethal. Amniotic fluid is usually meconium-stained. Sepsis syndrome may predominate,
but respiratory symptoms are more frequent. Cyanosis, apnea, respiratory difficulties,
and pneumonia with reticulogranular pattern or diffuse infiltrates on chest X-ray
can be present. The respiratory distress is usually associated with fever and convulsion.
Cutaneous eruptions with papules, pustules, vesicles, and/or widespread ulcers usually
appear before 3 days of life. An especially severe form of neonatal listeriosis, called
“granulomatosis infantiseptica,” presents widespread microabscesses and a mortality
rate over 80%. In these cases, anatomopathological examination shows miliary granulomas
and areas of necrosis and abscess formation, with liver involvement. Other lesions
include endocarditis and widespread abscesses.
In late sepsis, when transmission has happened through the colonized birth canal,
symptoms may occur up to 2 weeks after delivery and include meningitis without associated
skin lesions.[11]
[13]
The incidence of listeriosis has been increasing in several European countries while
decreasing in the United States, possibly due to the efforts to control food quality
and disease outbreaks.[14] Neonatal listeriosis is relatively rare in Asian countries such as Taiwan and Japan,
and this difference may be due to local dietary habits compared with Western countries.[15] An Israeli report reviewed 34% of all cases of perinatal listeriosis in the world.
The incidence rate ranges from 0.1 to 1.1 for 100,000 in different periods and countries.
The mortality rate was 45% and 36% for perinatal and nonperinatal cases, respectively.
Of neonates from infected mothers, 10% did not show any evidence of infection. Most
patients presented early sepsis and in the cases of late onset, almost all presented
central nervous system involvement with increased overall mortality rate (70%).[16]
When suspected by clinical features, early infection can be easily and promptly confirmed
by cytological and gram studies of skin lesions and meconium. Definitive diagnosis
can be established through blood culture (in systemic cases) or culture of skin lesion
material or by the demonstration of microorganisms in the anatomopathological examination.[11] L. monocytogenes may be mistaken by hemolytic streptococcus, diphtheroids, or enterococcus. Serological
studies are not helpful for the diagnosis, and the white blood cell count shows leukocytosis
or leukopenia and thrombocytopenia.[4] Spinal fluid analysis is essential to rule out meningitis, and if the organism persist
for more than 2 days, despite appropriate antibiotic treatment, central nervous system
imaging may be required.[17] Unfortunately, the presence of thrombocytopenia in this case does not allow lumbar
puncture.
Many antibiotics are active against L. monocytogenes, but ampicillin is the treatment of choice even during pregnancy. During the neonatal
period, high-dose intravenous ampicillin and an aminoglycoside is recommended for
2 to 4 weeks, and up to 6 weeks in the presence of brain abscess or endocarditis.
Because L. monocytogenes is a facultative intracellular organism, the antibiotic might not be fully effective.
This explains the cure rate of only 70% despite the high susceptibility of the strains
to the antibiotics. The ideal antibiotic should have bactericidal activity superior
to that of ampicillin and be able to readily cross the blood-brain barrier and reach
high concentration inside the host cells and cytoplasm. Therefore, new quinolones
are of particular interest; however, further clinical data are still lacking. It is
uncertain whether antibiotics are sufficient to improve the prognosis by themselves.
Possibly, additional therapy with immunomodulators may improve the successful treatment
of listeriosis as a strong correlation between inflammatory cytokines and severity
of illness is evident.[18]
L. monocytogenes may even be found in the stool of preterm neonates after adequate systemic treatment.
Therefore, it is essential to take infection control measures to reduce the risk of
nosocomial infection.[10]
L. monocytogenes should be considered in the differential diagnosis of neonatal sepsis and meningitis.
Early diagnosis and prompt treatment can improve outcomes.
Placental pathology evaluation is invaluable in suspected cases. Pathological features
are remarkable. The placenta shows diffused scattered, tiny, yellowish lesions consisting
of villous microabscesses with foci of necrosis and peripheral palisaded histiocytes.
Focal villitis may be seen with the presence of neutrophils between the trophoblast
and the villous stroma. Gram-positive bacilli can be visualized in the villous inflammation.[19]
[20]
[21]
Finally, education of pregnant women about changes in their dietary habits and of
health care professional to recognize and promptly treat the pregnant woman and newborn
is critical to reduce the incidence of perinatal listeriosis.
Acknowledgments
This article is dedicated to our friend Dr. Lincoln S. Freire, who recently passed
away, for his encouragement and support in the writing of this manuscript.
