Listeriosis is a food-borne disease caused by Listeria monocytogenes or Listeria ivanovii, often due to ingestion of unpasteurized milk and dairy products as well as contaminated undercooked meat, ice-cream, salads, and other ready-to-eat items. However, in a significant proportion of patients, the contaminated food source may not be obvious. In immunocompetent hosts, listeriosis usually manifests as a self-limiting febrile gastroenteritis. Nevertheless, in patients of extreme age, pregnant women, and other immunodeficiency states, it may lead to systemic sepsis with bacteremia, disseminated abscesses in multiple organs especially liver and spleen, and most severely central nervous system infections including meningitis, rhombencephalitis, cerebritis and brain abscess. As L. monocytogenes and L. ivanovii are intracellular pathogens, the immunocompromised patients with listeriosis are often those with cell-mediated immunity defects, such as patients receiving corticosteroids, transplant recipients, and HIV carriers.

Targeted therapies are widely used for treatment of various kinds of autoimmune diseases as well as solid organ and hematological malignancies. Since the targets of such therapies are usually major players of immunological pathways, they are often associated with infectious diseases that require the particular type of immune response for control. Various opportunistic infections have been described to be associated with different targeted therapies, the commonest reported ones being tuberculosis and invasive fungal infections (1–4). Although case reports or a few case series of listeriosis have been reported to be associated with targeted therapy, most of the cases were related to anti-tumor necrosis factor-α (anti-TNFα) monoclonal antibody (5–36). Recently, we described the first report of L. monocytogenes bacteremia and severe sepsis complicating carfilzomib (proteosome inhibitor) and daratumumab (anti-CD38 monoclonal antibody) treatment for multiple myeloma (37). In this study, we describe the epidemiology and clinical course of listeria infections in a tertiary hospital in Shenzhen, a Southern Chinese metropolitan city with a large immigrant population from other parts of China. The importance of targeted therapy as a risk factor of listeriosis is also discussed.

During the last decade or so, there has been a marked increase in the success in the elucidation of the molecular mechanisms behind primary immunodeficiency syndromes that result in opportunistic infections. Some of these syndromes include anti-interferon gamma autoantibody (an immunological defect typically associated with infections caused by intracellular pathogens) and mutations in genes that encode key players of various cellular and immunological pathways (e.g., STAT3, TSC2) (41). In the same period of time, the surge in the use of targeted therapies, such as kinase inhibitors and antibodies against various targets in the cellular and immunological pathways, has led to secondary immunodeficiency; which in turn has resulted in opportunistic infections (2). In the present cohort, all the five cases with listeriosis in our hospital had predisposing factors, some of the well-known ones being pregnancy (case 3 and 4) and corticosteroid therapy (case 1, 2 and 3). On the other hand, it is of note that 60% of the cases had either the above-mentioned primary immunodeficiency syndrome (case 5) or secondary immunodeficiency induced by targeted therapy (case 1 and 2). In fact, the case of listeria bacteremic meningitis (case 5) was the first report of listeriosis in a patient with anti-interferon gamma autoantibody in the literature (40). For the two patients who had targeted therapy (case 1 and 2), both of them received inhibitors of the EGFR/HER2 pathway during their course of lung and breast cancer therapy, respectively. Gefitinib and osimertinib are EGFR tyrosine kinase inhibitors, lapatinib is a dual tyrosine kinase inhibitor on the EGFR/HER2 pathway, afatinib is a tyrosine kinase inhibitor that can bind to EGFR, HER2 and HER4, and trastuzumab is an anti-HER2 monoclonal antibody. Although it has been shown in various studies and meta-analysis that inhibitors of the EGFR/HER2 pathway were associated with higher risks and severity of infections (42–44), the relative contribution of them is often difficult to quantify, as these patients are usually prescribed with other medications, such as corticosteroids, with immunosuppressive effects. In fact, both case 1 and 2 have also been given corticosteroid and chemotherapy for their underlying malignancies in addition to the EGFR/HER2 pathway inhibitors.

Targeted therapy is an important predisposing factor for listeriosis. The first patient reported to have listeria infection complicating targeted therapy was a patient with Crohn's disease on infliximab, an anti-TNFα monoclonal antibody (5). Since then, including the two cases in the present cohort, a total of 82 cases of listeriosis complicating targeted therapy have been reported in the scientific literature (5–37, 45–57). For 69 out of the 82 patients, gender, age, and clinical information were reported (5–11, 13–26, 28–32, 34–37, 45–57). The most common underlying diseases in these patients were autoimmune diseases (Figure 1A), whereas the commonest targeted therapy used was anti-TNFα monoclonal antibody (Figure 1B). In fact, the only case of listeriosis associated with inhibitors of the EGFR/HER2 pathway in the literature was a patient with metastatic breast cancer who received trastuzumab and lapatinib (47). The two patients in the present cohort who received gefitinib/osimertinib/afatinib and trastuzumab/lapatinib, respectively represent the second and third cases of patients with listeria infections related to inhibitors of the EGFR/HER2 pathway. For the listeria infection, the majority had bacteremia (Figure 2), in line with the present cohort where all five patients were blood culture positive. Central nervous system infection, present in one of our patients, was also commonly observed (Figure 2). Interestingly, around 80% of the listeria cases complicating targeted therapy were reported from the western world (Figure 1C). We speculate that this is at least partially due to the dietary habits and culinary traditions in these countries. It is important to note, but many clinicians may not be aware of, that listeria bacteria are resistant to cephalosporins, therefore in suspected cases ampicillin or penicillin should be added. As shown in the present cohort, two out of the five patients with listeriosis were on targeted therapy, which made it an important risk factor to consider. Therefore, listeriosis is an important differential diagnosis in patients on targeted therapy who present with sepsis and/or central nervous system infection and the use of antibiotic regimens that cover listeria is crucial for empirical treatment. Furthermore, avoidance of high-risk food items in these patients is important for the prevention of listeriosis.

The incidence of listeriosis could be underestimated. One of the most important causes of culture-negative infections is partially treated pyogenic bacterial infections. In the present cohort, although L. monocytogenes was isolated from the blood culture of case 5, it could not be recovered from the cerebrospinal fluid, despite the fact that there was increased white cell count and protein in the cerebrospinal fluid. Subsequently, the cerebrospinal fluid was sent for next-generation sequencing which confirmed the diagnosis of listeria meningitis. In 2020, we encountered a 26-year-old previously healthy woman who presented with recent onset of fever, severe headache and altered mental function. She had diarrhea for 4 days and has been treated with antibiotics. On admission, her temperature was 40.1°C. She also had neck rigidity, delirium and nystagmus. Examination of the cerebrospinal fluid revealed elevated white cell count with predominant neutrophils, increased protein and decreased glucose levels. Although Gram-smear revealed abundant Gram-positive rods, no bacteria could be isolated. All other microbiological investigations were negative. We speculate that this patient also had listeria meningoencephalitis, although it could not be confirmed microbiologically, as the patient had received antibiotics for a few days before lumbar puncture. She was treated as such accordingly and then recovered. These two cases illustrated that listeria infections could have been underestimated. A high index of suspicion is important and the use of next-generation sequencing would be useful for identifying more cases of partially treated listeriosis (40, 58).

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by the Institutional Review Board of The University of Hong Kong - Shenzhen Hospital. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

FX and PW conceptualized the study and wrote the manuscript. FX reviewed the clinical data. SKFL supervised the microbiological investigations. All authors have read and approved the final version of the manuscript.

This study was partly supported by Sanming Project of Medicine in Shenzhen, China (SZSM201911014) and the seed fund of The University of Hong Kong-Shenzhen Hospital (HKUSZH201901036). The funders had no role in study design, data collection or analysis, decision to publish, or preparation of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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