Emergence of sporadic non-clustered cases of hospital-associated listeriosis among immunocompromised adults in southern Taiwan from 1992 to 2013: effect of precipitating immunosuppressive agents

Listeria monocytogenes is an important cause of disease in humans, particularly in patients with impaired cellular immunity [1]. The common manifestations include listeriosis during pregnancy, sepsis and meningitis in newborns, acute febrile gastroenteritis, invasive disease in food-borne outbreaks, and fatal disseminated infection in immunocompromised hosts [1, 2]. Unusual localized infections such as pneumonia, hepatitis, arthritis and endophthalmitis have also been reported [2]. The clinical presentation of non-perinatal listeriosis depends on predisposing factors. Patients with a severe immunocompromised status tend to have bacteremia without a focus, localized infection, and central nervous system (CNS) infection with coma or encephalitis [1].

L. monocytogenes is a common colonizer of the human gastrointestinal tract with the asymptomatic carrier rate in the general population reported to be 1–10% [3]. The occurrence of invasive listeriosis depends on the integrity of the immune system of the host, and the number of bacteria delivered to the intestinal tract [4, 5]. After entering a susceptible host, L. monocytogenes adheres to the host receptor E-cadherin [6], is transcytosed across the intestinal epithelium barrier, and then released into the lamina propria by exocytosis [7]. Most of the bacteria become trapped in the liver and spleen by macrophages. In innate immunity, macrophages play an important role in initial control of infection because replication of L. monocytogenes occurs primarily within the macrophages that mediate clearance of bacteria. After specific recognition of pathogen-derived products by Toll-like receptors on macrophages, dendritic cells are activated and initiate CD4 and CD8 T cell responses that result in a stable population of L. monocytogenes-specific memory T cells [8]. The microorganism can escape immune clearance and re-enter the bloodstream to cause potentially fatal disease unless their replication is controlled by a functional host immune response. Precipitating immunosuppressive agents may lead to the development of invasive disease from latent or subclinical infection.

Listeriosis is mainly transmitted through consumption of contaminated food in the community [9], and vertical transmission from mother to child [10]. Hospital-associated infections usually occur as clustered outbreaks from environmental contact [11–17] or contaminated food [18–25]. Sporadic non-clustered hospital-associated listeriosis is an emerging infectious disease. It has been reported in many countries including the United States [26, 27], Europe [1, 28, 29], Australia [30], Israel [2] and more recently China [31]. It may be triggered from latent or sub-clinical infection by immunosuppressive agents, but the exact pathogenesis and source still needs to be identified. In view of the relatively high rate of asymptomatic carriers of L. monocytogenes in the general population [3] and the increasing numbers of patients receiving potent immunosuppressive agents, listeriosis needs to be considered in the differential diagnosis of sepsis in immunocompromised patients.

The current retrospective study of cases at a large teaching medical center in southern Taiwan during a 21-year period was designed to better understand the impact of immunosuppressive agents and underlying diseases in triggering listeriosis, and to compare the clinical features and outcomes of hospital-associated and community-associated listeriosis.

Sporadic, non-clustered, hospital-associated listeriosis is a relatively rare, but life-threatening disease. We identified 12 cases in adults at a large medical center in southern Taiwan over a period of 21 years, or 0.34 cases per year. In a similar study conducted at a large tertiary care hospital in China, Yang et al. found nine non-clustered hospital-associated cases over a period of 12 years, or 0.75 cases per year [31]. We also identified 23 community-associated cases. In the present study, 32 of the 35 cases (91.4%) were immunocompromised. This is similar to previous reports [1, 28, 30, 33]. The listeriosis-related mortality rate of 34.3% observed in the current study is similar to other reports (24–52%) [2]. The 60-day mortality rate was significantly higher in patients with hospital-associated than community-associated listeriosis (66.7% vs. 17.4%, p = 0.007). Other reports showed a mortality rate of hospital-associated listeriosis of 27.2–53% [30, 31].

Although it may be argued that a hospital-associated case defined by symptoms developing ≥48 hours after admission could be a case of community-associated listeriosis with a protracted course and delayed diagnosis, detailed analysis of the cause of admission and initiation of a precipitating immunosuppressive agent in these 12 hospital-associated cases suggests these were truly hospital-associated cases rather than community-associated with a subacute course.

Reactivation of latent or subclinical infection by immunosuppressive agents provides an attractive explanation for the mechanism of sporadic non-clustered hospital-associated listeriosis in immunocompromised hosts. In the present study, almost all of the non-clustered hospital-associated cases (n = 11, 91.7%) received a new or more intensive precipitating immunosuppressive agent within 4 weeks prior to the onset of listeriosis compared with only 4.3% (n = 1) of the community-associated cases (p < 0.001). Other investigators have reported the occurrence of listeriosis within 4 weeks after receiving chemotherapy or corticosteroids in patients with underlying malignancies [2, 33]. Listeriosis has also been reported among patients undergoing therapy with biological agents such as infliximab [26, 27, 29] and etanercept [34]. This concept that immunosuppressive agents trigger latent listeriosis is further supported by the relatively short time interval (median 12 days; range, 4–27 days) from the order for a precipitating immunosuppressive agent to onset of severe, life-threatening hospital-associated listeriosis.

In the current study, only four of the 35 (11.4%) cases were treated with an appropriate antibiotic within 24 hours after the onset of listeriosis. The rate was low for both community-associated and hospital-associated cases (4.3% and 25%, p = 0.16). This may arise because of the non-specific manifestations and rare occurrence of listeriosis, combined with the primary physician being unfamiliar with the disease. Education of physicians about the presentation of listeriosis, especially sepsis and meningitis in the elderly and immunocompromised patients, and in the setting of new or increased treatment with immunosuppressive agents in hospital may improve the rate of appropriate prescribing of antimicrobial agents.

Mortality rates from listeriosis tend to be higher in severely immunocompromised patients, such as those with AIDS, or who receive immunosuppressive therapy for organ transplantation, than in less immunocompromised patients or apparently healthy hosts [1]. In the multivariable analysis of mortality we found that an APACHE II score > 21 and receipt of precipitating immunosuppressive agents within 4 weeks prior to the onset of listeriosis were indicators of poor prognosis. Other factors reported in the literature for poor prognosis include hepatic decompensation [33], renal failure, and age >65 years [35].

Prophylaxis with trimethoprim-sulfamethoxazole (TMP-SMZ) for Pneumocystis jiroveci and Toxoplasma gondii is given in patients with advanced human immunodeficiency virus (HIV) infection and organ transplant recipients [36–38]. In the current study, no patients had HIV infection or organ transplantation and they didn’t receive TMP-SMZ prophylaxis at the onset of listeriosis. Mark et al. revealed that prescription of TMP-SMZ for Pneumocystis jiroveci prophylaxis in persons with HIV infection also significantly decrease risk for other infections, including Haemophilus, Salmonella, and S. aureus disease, but not listeriosis [39]. However, estimation of TMP-SMZ prophylaxis for listeriosis in HIV-infected patient and other hosts with a severe immunocompromised status needs further studies.

The strengths of the current study are the relatively large number of cases of a rare disease and our ability to determine the key role of precipitating immunosuppressive agents as the major risk factor for life-threatening sporadic non-clustered hospital-associated listeriosis. The current study was conducted in a single institution in Taiwan, but the findings are consistent with reports from many other countries. The weakness is the retrospective nature of this long-term study. However, this approach was the only way we could collect a sufficient number of cases for detailed analysis. It prevented us from being able to identify the potential source(s) of infection, detect carriers, preserve the bacterial isolates for molecular epidemiological studies and to evaluate the efficacy of antimicrobial therapy. Listeriosis is not a notifiable disease in Taiwan. Therefore relevant data about the epidemiology and clinical manifestations are limited [33, 40–43].

Sporadic non-clustered hospital-associated listeriosis is an emerging infectious disease in immunocompromised hosts. It should be included in the differential diagnosis of sepsis, particularly in those receiving new or increased doses of immunosuppressive agents, such as corticosteroids or chemotherapy within the previous 4 weeks. Whether the incidence of this disease will increase in association with the development and widespread use of new and more focused immunosuppressive agents needs further study.