Listeriosis through “activation” of intracellular organisms
Although most outbreaks were associated with exposure to contaminated food, often additional factors must be present to cause illness due to LM. Carriage studies have recovered LM in up to 10% of stool specimens of healthy individuals , indicating that the presence of LM in the gastrointestinal tract alone (as well as in vaginal flora) does not necessarily cause illness. Another interesting study examined the refrigerator contents of patients with sporadic listeriosis. Although at least one food specimen grew LM in almost ⅔ of refrigerators of all listeriosis patients, in only ⅓ of listeriosis patients was it possible to identify the same strain as in the patient . Although this was significantly higher than expected by chance alone, it is consistent with the possibility that a proportion of patients with listeriosis become colonized with LM months or longer before disease onset, explaining why no specific food item or no food with a LM strain identical to the patient’s was identified.
An outbreak of listeriosis in Philadelphia in 1986/87 provides additional insight into the pathogenesis of listeriosis: the epidemiologic investigation was unable to confirm the same outbreak strain among case-patients or to implicate a single food. However, the investigators speculated that gastrointestinal coinfections may have precipitated invasion of commensal LM . Finally, numerous published and unpublished case reports describe the occurrence of invasive listeriosis after events that disrupt the gastrointestinal micro-environment, such as colonoscopy, shigellosis, colon cancer, or onset of ulcerative colitis. Because of its intracellular status, LM organisms survive the toxic effects of the host cells’ phagolysosomes for a prolonged period of time, until either systemic or local factors contribute to its subsequent invasion. Therefore, pinpointing an exact exposure date or food vehicle for the occurrence of sporadic LM remains problematic.
The host: risk factors for perinatal and nonperinatal listeriosis
In cases of sporadic listeriosis, risk factors play a major role, with a recognized risk found in 80% to 90% of all cases. During pregnancy, suppression of cell-mediated immunity permits the presence and growth of the genetically foreign fetus while also increasing maternal susceptibility for LM. Furthermore, LM has a predilection for the placenta; therefore, pregnant women with multiple gestations seem to be at higher risk for listeriosis than pregnant women with singletons .
Risk factors for nonperinatal listeriosis can be divided into two categories: systemic and local (Fig. 1). Systemic risks are those that suppress immunity. Listeriosis incidence directly increases with age, rising dramatically after 60 years of age . Other risk factors include steroid or other immunosuppressive therapy, malignancies and their treatment, human immunodeficiency virus infection, diabetes, renal failure, congestive heart failure, organ transplantation, liver cirrhosis, alcoholism, autoimmune diseases, status post gastrectomy or medication with antacids, histamine-2 antagonists, or proton pump inhibitors. Intravenous drug users are at increased risk if the heroin is cut and adulterated with plants or earth. Local risk factors include situations that disrupt the local gastrointestinal flora, as mentioned above.
Both systemic and local risk factors may work additively and can promote development of listeriosis in immunocompetent patients at any age. We recently noted a 15-year-old patient who presented with bloody diarrhea, with two negative sets of routine stool cultures. Further medical work-up and interventions included a colonoscopy (diagnosing ulcerative colitis) with subsequent treatment with corticosteroids and cyclosporin. One month after diarrheal onset, the patient became septic and a blood culture yielded LM.
Syndromes and presentations of perinatal and nonperinatal listeriosis
Perinatal listeriosis has various presentations. The mother, if affected at all, is usually only mildly ill, exhibiting only flu-like illness, fever, headache, and myalgia. Diagnosis of infected pregnant women is critical because appropriate antibiotic treatment for listeriosis can save the fetus. Thus, febrile pregnant women should always have blood cultures performed. Infection in the fetus or neonate is mostly severe and can result in abortion, stillbirth, and if born alive, in early-or late-onset neonatal listeriosis. Intrauterine infection of the fetus leads to early-onset listeriosis and presents either as septicemia, or less frequently as granulomatosis infantiseptica. In contrast, late-onset listeriosis develops after the neonate is exposed to LM during labor and delivery. The initially healthy newborn develops meningitis several days to weeks after delivery. In LAC, we found that among all perinatal cases with known outcome (n = 365), 71% of neonates were born alive and survived, whereas 6% resulted in abortion, 12% in stillbirth, and 11% in neonatal death. Since 1986, prognosis has not improved for the fetus. All mothers survived.
The typical presentation of nonperinatal listeriosis is either meningitis or nonspecific septicemia in an elderly or immunosuppressed patient with some significant comorbidity, such as diabetes or cancer. Prodromic symptoms, such as flu-like illness, back pain, myalgia, nausea, and diarrhea may occur. The presentation of gastrointestinal symptoms, such as diarrhea, may be part of the listerial prodromic spectrum or a gastrointestinal coinfection, such as a viral or bacterial infection, which facilitated subsequent disease.
For clinical purposes, the simultaneous infection of the meninges and brain parenchyma as well as subcortical brain abscesses should prompt strong consideration of LM as etiologic agent . Additional clinical pictures associated with listeriosis include rhombencephalitis, endocarditis, arterial infections (at susceptible sites, such as aneurysms), hepatitis and liver abscesses, peritonitis (either spontaneous or in continuous ambulatory peritoneal dialysis patients), osteomyelitis and septic arthritis, pleuropulmonary infections, and wound and skin infections (i.e., arteriovenous shunt sites of dialysis patients).
One clinical manifestation of listeriosis that has recently gained more attention is that of febrile gastrointestinal illness. The Italian listeria gastroenteritis outbreak affected 1566 persons; 292 (19%) of them were hospitalized  Almost all of the cases were immunocompetent. The most frequent symptoms were headache (88%), abdominal pain (72%), and fever (68%). The median incubation time was measured as 24 hours. National statistics show that 65% of all food-borne outbreaks reported to the Centers for Disease Control and Prevention (CDC) with an incubation period of greater than 6 hours (Michelle Young, CDC, personal communication) have unidentified etiologies. Therefore, testing of stool samples for LM in food-borne outbreaks of febrile gastroenteritis, where routine cultures fail to yield a pathogen, may substantially increase the number of identified LM gastroenteritis outbreaks. However, special transport and media requirements have to be applied when obtaining and culturing feces (see below).
In LAC, since 1986, the overall case-fatality among patients with nonperinatal listeriosis with known outcome was 30% (128/429), but case fatality has improved from 40% in 1986 to 10% in 1999.
Laboratory diagnosis of listeriosis
Typically, LM is easily diagnosed from sterile site specimens, such as blood or cerebral spinal fluid. Serologic tests are considered either insensitive or not specific enough to be useful in clinical practice. If LM is suspected in cases of gastroenteritis, it can be isolated from stool, but the specimen needs to be transported under cool conditions and should arrive in the laboratory within 4 hours of collection. If transport is delayed, it can be cooled for up to 48 hours at 4°C (Joan Sturgeon, personal communication, 2000). The stool sample also needs to be submitted either “unpreserved” or in special enrichment broths. Because selective media used for stool cultures normally suppress the growth of listeria, lithium chloride-phenylethanol-moxalactum media must be used.
Treatment of listeriosis
Because of the intracellular existence, the recommended treatment for listeriosis is a 3-week course of ampicillin (Tables 2 and 3). Although the value of the addition of an aminoglycoside, such as gentamicin, is debated, it is frequently used in addition. During epidemics of listeria, the CDC does not recommend that persons, even those in a high-risk group, obtain prophylaxis or specific laboratory testing if asymptomatic. Those individuals in a high-risk group who have eaten a known contaminated product, and who become ill with fever or signs of illness, are advised to contact their physician and inform him or her about this exposure . Recommendations for treatment of healthy patients with febrile listeria gastroenteritis are nonexistent. One reviewer recently stated that it might be prudent to consider treatment in patients with known immunocompromise to prevent invasive disease .
Reporting of cases of listeriosis to the HD and public health follow-up
In California and other states, cases of listeriosis are reportable to the HD, which receives reports by telephone, as written confidential morbidity reports, or via fax. A recent evaluation of the LAC listeria surveillance system demonstrated that completeness of reporting is approximately 80%, typically with the hospital infection-control practitioner reporting the case. However, physicians are legally responsible for disease reporting. Clinicians may under-appreciate the important role of infectious-disease reporting and the detailed chain of events that the report triggers (Fig. 1). For reported cases of listeriosis, a public health response may consist of the following: (1) interview of the patient by a public health nurse, (2) statistical case analysis, (3) outbreak investigations, and (4) molecular analysis of human isolates. The following paragraphs illustrate potential lifesaving consequences that the report of even a single case of listeriosis can have.
Interview of the patient by a public health nurse
The HD assigns the case to a public health nurse who contacts the patient and conducts an in-depth interview using a standardized investigation form. The public health nurse gathers demographic information (place of residence, age, gender), the type of listeriosis (perinatal/nonperinatal), clinical details, and risk factors (food eaten in the incubation period, medical risk factors [preexisting illnesses, prior surgeries, medications]). The listeria isolate is requested to be sent to the Public Health Laboratory.
Ongoing and periodic review and statistical evaluation of listeriosis cases
HDs often have dedicated listeriosis surveillance officers who review the data routinely to discover potential disease outbreaks. However, frequently it is the astute health care professional who is the first to notice and report a clustering of cases.
Another important function of listeriosis surveillance data may be performed by local, state, or national surveillance officers. For example, epidemiologic data presented throughout this article can only be derived from a systematic and ongoing collection of listeriosis cases and may assist in the development of preventive guidelines, clinical recommendations, and the evaluation of public health interventions, such as the FDA “zero-tolerance” policy for food.
If a cluster of listeriosis cases warrants closer investigation, an epidemiologic outbreak investigation will confirm the existence of an outbreak, ascertain cases, and develop hypotheses. The implication of a specific food usually through a case-control study ideally leads to a recall of the product and the removal of potentially contaminated products already on the shelf.
Fingerprinting of recovered LM strains
In California, LM human isolates are sent to the Public Health Laboratory for PFGE analysis. Often, successful outbreak investigations are able to match the PFGE DNA fingerprint pattern of patient isolates with those recovered from implicated food (Fig. 1; 4a) [7,8]. A comparison of these strains with a strain recovered from a food item epidemiologically implicated in the outbreak investigation (Fig. 1; 4b) may result in a recall of contaminated food. It also serves as an excellent discriminatory tool to distinguish or match LM strains with each other in non-outbreak situations.
An award-winning initiative by the CDC called PulseNet, enables an increasing number of state and selected county health laboratories to submit electronically standardized molecular fingerprinting of food-borne pathogens, such as LM, to detect similarities and discover, for example, multistate outbreaks. Molecular typing of strains of LM isolated from recalled food is also submitted routinely. The power of this new tool was demonstrated recently when the comparison of LM strains at CDC found that a single patient’s strain of LM submitted from LAC (Fig. 1; 5a), matched the strain from a recalled smoked fish product (Fig. 1; 5b) in the Eastern United States. The company had been cited previously but without actual product linkage to a human illness. A revised interview of the LAC patient revealed that she was able to remember marketing details of the fish product that matched with the recalled product.
Although the public health importance of listeriosis may seem insignificant because of its low incidence and long incubation time, this article illustrates how critical it is to take LM into account both clinically and epidemiologically. First, every pregnant woman with a febrile illness may be ill with listeriosis with potential deleterious consequences for the unborn baby. These can be avoided with prompt treatment of the mother with adequate antibiotics. Second, the high casefatality of listeriosis merits every effort to diagnose LM swiftly. Third, epidemiologists and laboratorians demonstrate how powerful the alliance of clinicians with public health professionals can be. Several outbreak investigations have shown that the prompt recognition of outbreaks can effectively reduce the number of cases. Finally, in the time of DNA fingerprinting, occasionally only a single reported case of listeriosis may suffice to identify foods with proven human hazard which can facilitate the effective regulation of contaminated food.
We thank Tina Rouse, FDA, for her assistance to make data on food recalls available to us, Joan Sturgeon, LAC Department of Health Services, for her microbiological advice, and Anchalee Chillanond for her secretarial assistance.
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