Listeriosis at a Tertiary Care Hospital in Beijing, China: High Prevalence of Nonclustered Healthcare-Associated Cases Among Adult Patients

Thirty-eight cases of listeriosis over a 12-year period from inpatients at a tertiary care hospital in China were reviewed. We found a high prevalence of healthcare-associated cases that did not cluster in time and space.

Listeriosis is a relatively uncommon but serious infection caused by Listeria monocytogenes. This organism is ubiquitous in the environment and can survive at temperatures ranging from −7°C to body temperature [1]. The main route of transmission is believed to be through the consumption of contaminated food ( processed meats, unpasteurized milk, soft cheeses, and cantaloupes) [2][3][4][5][6][7] and vertical transmission from mother to child [8,9]. However, healthcare-associated transmission has also been reported through patient-topatient transmission, mineral bathing oil, contaminated resuscitation equipment, and the contaminated hands of medical personnel [10][11][12][13][14]. Most of the healthcareassociated infections are clustered and related to food processing [11][12][13].
Gastroenteritis, bacteremia, and meningitis are the most common manifestations of listeriosis. Because L. monocytogenes has a strong predilection for elderly and immunocompromised persons [15][16][17][18], results in poor fetal outcomes [19][20][21], exhibits poor response to third-generation cephalosporins, and is associated with a high mortality rate, it has become an increasingly important emerging infectious disease [22].
In the United States, L. monocytogenes is the fourth causative microorganism of bacterial meningitis [23]. Among persons aged >65 years, L. monocytogenes is the third leading pathogen [24,25]. Most listeriosis cases have been reported from industrialized Western countries. Reports from East Asia and developing countries are scarce [26,27].
Our goal was to retrospectively review all culture-proven cases of listeriosis at Peking Union Medical College Hospital (PUMCH) since 1999 and describe the clinical characteristics and outcomes of the infected patients.

METHODS
PUMCH is an 1800-bed tertiary care hospital in Beijing, China. Founded in 1921 by the Rockefeller Foundation, PUMCH is the national medical technical support center for the diagnosis and treatment of severe and complicated diseases. In 2002, another hospital in Beijing merged with PUMCH and was renamed the Western campus of PUMCH. The latter housed several departments (general medicine, rheumatology, oncology, and breast surgery), and both campuses shared other departments (hematology, gastroenterology). PUMCH provides medical services to patients from surrounding areas (Beijing, and Hebei province) and to patients being referred from various outside institutions throughout China.
We retrospectively identified all patients with L. monocytogenes infections based on a list generated from an electronic database in the clinical microbiology laboratory at PUMCH. All positive culture results for L. monocytogenes diagnosed at PUMCH since 1999 are stored in the database. We included all cases from January 1999 to October 2011. Clinical data from the identified cases were abstracted from the medical records. These data included demographic characteristics, comorbidities, known risk factors (immunosuppressive therapy, dietary history, travel, and exposures), the sites from which the organism was isolated, clinical presentation, laboratory data, type of antimicrobial therapy, duration of hospitalization, and outcomes.
The diagnosis of listeriosis was based on one of the following: isolation of L. monocytogenes from normally sterile clinical specimens (eg, cerebrospinal fluid [CSF], blood, amniotic fluid, uterine swab); isolation of L. monocytogenes from nonsterile specimens (eg, rectal swab, tracheal swab); and histopathology compatible with listeriosis [22]. Cases were categorized as neonatal, maternal, or nonmaternal infections. All maternal cases were in pregnant women who had L. monocytogenes isolated from cultures of normal sterile body sites or vaginal swab [19]. Healthcare-associated cases were defined as onset of listeriosis symptoms >48 hours after admission for medical conditions other than listeriosis.
We used descriptive statistics. Where appropriate, we present point estimates with 95% confidence intervals (CIs). This study was reviewed and approved by the Institutional Review Board at PUMCH.

RESULTS
We identified 38 patients (cases) of listeriosis diagnosed between 1999 and 2011. The demographic characteristics of these cases are summarized in Table 1. There were 5 neonatal, 8 maternal, and 25 nonmaternal infections with L. monocytogenes.

Neonatal Listeriosis
Of 26 221 deliveries during this time period, there were 5 cases of neonatal listeriosis identified. Four of 5 cases of neonatal listeriosis were male. All 5 neonatal listeriosis cases were born to symptomatic mothers. All had positive cultures and presented with fetal distress (n = 5), sepsis (n = 4), meningitis (n = 4), Apgar score <5 (n = 3), low birth weight (n = 2), and meconium aspiration (n = 1), suggestive of intrauterine infection. The clinical characteristics and outcomes of these 5 cases are summarized in Table 2.

Maternal Listeriosis
There were 8 maternal cases of listeriosis identified. Six cases were confirmed by culture. Two other cases were suspected based on symptoms and positive cultures in their infants at the time of delivery. The median age was 30 years (range, 26-33 years). The median gestation was 29 weeks (range, 18.9-39.9 weeks). Maternal cases presented with a sudden onset (<1 week from presentation) of symptoms (n = 7), which included high fevers with a maximal temperature >39°C (n = 6), gastrointestinal symptoms (diarrhea, abdominal pain; n = 5), and various obstetrical manifestations (decreased fetal movement in 2 cases, intrauterine fetal death, vaginal bleeding, and acute pyelonephritis) ( Table 3). Two maternal cases had L. monocytogenes cultured from blood; all 3 cases whose L. monocytogenes was detected on uterine swabs had histopathologic evidence of either acute chorioamnionitis or intrauterine fetal infection. In one case, L. monocytogenes was cultured from the vaginal swab, placental histopathology demonstrated chorioamnionitis, and the infant had culture-proven listeriosis. The other 2 cases had symptoms consistent with listeriosis, positive listeria cultures in the newborns, and pathologic findings of acute chorioamnionitis ( Table 2). None of the mothers had central nervous system (CNS) involvement and all recovered fully after delivery.
Obstetrical outcomes included 5 cases of listeriosis in the infants postpartum. All 5 cases were the result of listeria infections during the third trimester of gestation, and a single one of these cases was fatal. There were 2 induced/late abortions as a result of listeria infections during the second trimester of gestation, and a normal pregnancy outcome for a single second-trimester infection.

Nonmaternal Listeriosis
Among the 25 nonmaternal cases, the median age was 47 years (range, 18-79 years), and 72% (95% CI, 52.5%-85.7%) were female. Twenty-three (92%; 95% CI, 75.03%-97.78%) infections occurred in patients with significant comorbidities (Table 4). Ten (40%) patients had concurrent neoplasms: 2 cases each of leukemia, multiple myeloma, liver cancer, and rectal cancer, and 1 case each of breast cancer and abdominal malignant metastases from an unknown primary. Ten nonmaternal infections occurred in patients with autoimmune diseases: 6 cases in patients with systemic lupus erythematosus (SLE), 2 cases in patients with dermatomyositis, 1 case in a patient with Still's disease, and 1 in a patient with mixed connective tissue disease. Other comorbidities included diabetes mellitus and polycystic kidney disease with chronic renal failure. Ten (40%) nonmaternal adult listeriosis cases were receiving chronic corticosteroids at the onset of symptoms, and 6 (24%) had received chemotherapy within 2 months before the onset of listeriosis.
The 2 cases of L. monocytogenes that occurred in otherwise healthy hosts had early CNS involvement, manifested by coma. The first, a 20-year-old patient, experienced sudden onset of diarrhea, fever, and headache and deteriorated rapidly.     He was intubated and treated at a local outside hospital first (where no L. monocytogenes was isolated from his cultures), and L. monocytogenes was isolated from sputum and CSF 4 weeks after the onset of gastrointestinal symptoms (Table 4, patient 4). The second, a 69-year-old previously healthy man, developed sudden fever and convulsions (Table 4, patient 17) rapidly progressing to coma complicated by acute renal failure and pneumonia. His condition improved after an extensive hospital stay and he was transferred to an outside institution for further rehabilitation. No long-term follow-up was available. Seventy-two percent of adults were treated empirically with cephalosporins and all were switched to ampicillin after the positive culture results became known. Among the 9 (36%; 95% CI, 20.25%-55.48%) fatal cases, 8 had severe underlying diseases and developed complications after being infected with L. monocytogenes. All died of multiple severe complications within 30 days after the onset of infection. The fatal cases were more likely to have sepsis (n = 9), rapid onset of coma (n = 6), and multiorgan failure (n = 3).
These infections were first detected in 2006, and there were 1, 3, 3, 1, and 3 infections detected per year from 2006 to 2010, consecutively. These infections were scattered in 6 different wards, both in the eastern and western campuses of PUMCH. There were 3 cases each in the rheumatologic and hematologic wards and 2 cases in the general medicine ward. Only 2 cases appeared to be clustered in space and time. Nine of these 11 cases did not appear to be clustered. There was no consistent pattern (location, seasonality, and timing) that emerged for the 9 nonclustered cases. The source of their infection could not be determined.

DISCUSSION
The most striking finding from this case series is the prevalence of nonclustered healthcare-associated cases of listeriosis. Eleven of 25 nonmaternal listeriosis cases were healthcareassociated. These infections did not appear to be clustered in time and space. There are rare reports of healthcare-associated transmission of L. monocytogenes via contaminated foods, healthcare workers, and infected patients, but most of these were clustered in time and space. For example, a recent study reported a cluster of 6 L. monocytogenes infections in hospitalized adults during a 10-month period in Brazil [28]. The median age of these patients was 80 years and all had underlying severe comorbidities. Four isolates belonged to a single pulsed-field gel electrophoresis (PFGE) genotype, suggesting a common source. The epidemiological investigation pointed to the hospital kitchen as the possible source of contamination. It is intriguing to speculate whether these healthcareassociated cases were the result of in-hospital acquisition, or whether this was the result of colonization. Until this retrospective case series was conducted, we had absolutely no insight about the frequency of these healthcare-associated cases. The cases were not clustered in time or space so they did not elicit additional surveillance. Although we could not perform PFGE on the specimens from our study, the majority did not cluster in time or space, suggesting that a common source was unlikely. Investigators have recognized for >20 years that L. monocytogenes can be carried in the gastrointestinal tract [29][30][31]. Listeria monocytogenes can be isolated in the stool of 1%-10% of the population, where it can persist without causing symptoms [32]. Using repeated sampling, Listeria can be detected in the feces of nearly 70% of healthy nonpregnant individuals and 44% of pregnant women [21,31]. MacGowan et al found that Listeria was isolated from 5.6% (10/177) of renal transplant recipients on 1 or more occasions over the period of a year; moreover, >1 species or serovar of listeria can be isolated from 40% of fecal carriers, and no cases of clinical infection occurred in any fecal carriers [33]. Fecal, cervicovaginal, and oropharyngeal carriage of L. monocytogenes has been reported as a possible predisposing factor for perinatal listeriosis [34,35]. In one study conducted by Schuchat et al [36], asymptomatic carriage of the illnessassociated strain of L. monocytogenes was identified in nearly one-fifth of household contacts of patients with sporadic listeriosis, and no cases of secondary disease were detected within households in this study. Their findings suggest that gastrointestinal carriage of pathogenic strains of L. monocytogenes is not uncommon in contacts of cases, underscoring the critical role that host susceptibility plays in determining whether illness occurs following exposure to this organism. All of our cases of healthcare-associated listeriosis had severe underlying immunosuppression. Besides immunosuppression, many of our patients had underlying diseases involving the gastrointestinal tract, or their therapy could impact the integrity of the intestinal mucosa. So, the role that gastrointestinal colonization of Listeria played in the pathogenesis of these healthcareassociated infections warrants further study.
After the discovery of these nonclustered healthcareassociated cases, we have implemented a more aggressive approach: all healthcare-associated cases will be thoroughly investigated for both prehospital and in-hospital exposures. We are also saving all bacterial isolates for DNA fingerprinting. This more aggressive approach may help us better define the source of these infections.
Forty percent of our cases had underlying rheumatologic diseases. This proportion is higher than what was previously reported in the literature [38]. Although PUMCH does not specifically specialize in the treatment of rheumatic diseases, we do have a large population of such patients. Persons of Asian descent have a higher incidence of SLE, compared with other races [44][45][46]. Given the paucity of published reports on L. monocytogenes from East Asia, this may explain the higher incidence among patients with rheumatic diseases in our report. This may also have impacted the sex distribution of cases. Traditionally, L. monocytogenes has been reported more often among men than women. The male to female ratio in our study was 1:1.8. This may reflect the increased predisposition of rheumatic diseases among women [47][48][49].
Comorbidity plays a very important role in the prognosis of listeriosis [18]. Eighty-one percent of 225 patients with listeriosis studied in France had a predisposing immunocompromising condition, whose severity was the major prognostic factor [17]. In our population, 92% of nonmaternal listeriosis cases were immunosuppressed.
Our cases of infant listeriosis mirrored the cases reported in the literature, as did their outcomes. We did not observe any late-onset cases of infant listeriosis, as reported by other authors [9,22,[50][51][52]. Similarly, the characteristics of our maternal listeriosis were similar to those reported in the literature.
This study has several limitations. First, it is a retrospective assessment over a protracted timespan. As such, we were unable to obtain specimens for molecular testing, and we were unable to clarify additional issues relating to certain in-hospital epidemiological exposures. Second, it consists of a relatively small sample size, and our findings may not be necessarily generalizable to other populations or settings. Third, cases of listeriosis in China are not routinely reported to public health authorities. As such, the epidemiology of listeria is not well defined. Our case series reflects a selection bias toward hospitalized (ie, sicker) patients and may not reflect the overall epidemiology of listeria.
Nonclustered healthcare-associated cases of L. monocytogenes occurred at a large tertiary care hospital in Beijing, China. The source of these infections is unclear. Although rare, in the setting of immunosuppression, Listeria should be considered in the differential diagnosis of healthcare-associated infections-even in the absence of a point-source outbreak.