Clinical syndromes of human listeriosis

35 Infectious Diseases Newsletter 10(5) May 1991 and review. Rev Infect Dis 12:602-610, 1990. Rogosa M, Sharpe ME: Species differentiation of human vaginal lactobacilli. J C-en Microbiol 23:197-201, 1960. Rubin LG, Vellozi E, Shapiro J, Isenberg HD: Infections with vancomycin-resis-

tant "streptococci" due to Leuconostoc species [letter] J Infect Dis 157:216, 1988. Ruoff KL, Kuritzkes DR, Wolfson JS, Ferraro MJ: Vancomycin-resistant Gram-positive bacteria isolated from

Clinical Syndromes of Human Listeriosis Charles E. Cherubin and Walid Kahyr Mercy Hospital and Medical Center, Section of Infectious Diseases, Chicago, Illinois; University of Illinois, Section of Infectious Disease, Chicago, Illinois

Human listeriosis continues to be a challenging infectious disease problem in its epidemiologic, microbiologic, and clinical aspects. Four recent major listeria outbreaks in North America (Nova Scotia, Massachusetts, Los Angeles County, and Philadelphia) were initiated by contaminated food products. This is well known in Europe where dairy regions are endemic zones for listeriosis, and listeria organisms are found in cattle both as commensals and as pathogens. Approximately 1,700 cases of listeria disease are reported annually in the United States, with an incidence of 7.1 cases per 106 population per year. However, underreporting of cases is common. Only two of 14 cases of listeriosis at the University of Illinois Hospital at Chicago (U of I) over an 8-year period, and three out of 38 cases at Rush-Presbyterian-St. Luke's Medical Center (RPSL) over 10 years were reported to the Chicago Board of Health. This low reporting rate obscures the actual incidence of listeriosis, and community outbreaks may go undetected. Because of its relative infrequency, the organism is still confused initially when detected with other Gram-positive organisms such as diphtheroids or streptococci. Furthermore, the diversity of the clinical syndromes caused by Listeria monocytogenes, and the wide range of those affected, make anticipation or recognition of the disease difficult. We will attempt here

to present some of the clinical syndromes caused by Listeria monocytogenes with special emphasis on the clinical manifestations, including those of brain stem encephalitis and brain abscess. Clinical

Syndromes

Perinatal Listeriosis In this syndrome, infection occurs in utero early in pregnancy. Fetal listeria infection is usually fatal, with up to 30% of infants being stillborn. Of infants born alive, mortality ranges between 54% and 90% during the first week of life (perhaps because of prematurity). Part of the mortality may be due to failure to consider the diagnosis in early stages when the mother presents with nonspecific symptoms, and, therefore, the failure to administer appropriate therapy. The infection is far worse for the fetus than for the mother. This clinical entity might be better termed early gestational infection and L. monocytogenes is a well-recognized cause of early gestational sepsis. Cell-mediated immunity, which is important for protection against this infection, is probably depressed during pregnancy. This syndrome usually starts with a prodrome of flu-like symptoms and progresses to acute chorioamnionitis, which results in premature labor and delivery. However, fever and premature labor may be the only presenting symptoms © 1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

human sources. J Clin Microbiol 26:2064-2068, 1988.

Address correspondence to John T. Sinnott, IV, MD, Director of Epidemiology, Tampa General Hospital, PO Box 1289, Tampa, FL 33601.

as was the case in four of our patients. These nonspecific symptoms make it difficult to modify the outcome with appropriate antibiotic intervention. Acquisition of the disease early in pregnancy usually results in spontaneous abortion, and a still birth or a nonviable fetus. Occasionally, pregnant patients may have bacteremia, but do not transmit the infection to the fetus. Such sparing of the fetus has been reported previously. The disease is usually self-limited in the mother possibly because the nidus of infection is eliminated with the birth of the infected fetus, delivery of the intrauterine contents, and termination of the pregnancy immune state. Most patients do well after delivery even without antibiotic therapy. However, cases of listeria meningitis have been reported during pregnancy. The incidence of perinatal listeriosis has been estimated to be 1:37,000 births. Although the infective source may be associated with the ingestion of foodstuffs such as dairy products, listeria can be found within the female genital and gastrointestinal tract and there is also a considerable animal reservoir. As previously noted, the first signs are those of a flu-like illness, with myalgia, fever, and headache. Gastrointestinal symptoms are variable manifestations. This prodrome, seen in the majority of cases, probably represents the bacteremic phase during which the uterine contents are invaded, and blood cultures become positive. Often associated with lower back pain, the syndrome may be mistaken for a pyelonephritis. Am-

36

Infectious Diseases Newsletter 10(5) May 1991 nionitis, premature labor, and septic abortion follow in 3-7 days. In sporadic cases of perinatal listeriosis, a high index of suspicion of the disease is required when a pregnant woman presents in this nonspecific prodromal phase of the disease. Appropriate antibiotic therapy at that point might prevent or modify the illness in the fetus or infant. Continued use of the penicillins as empiric therapy in the pregnant woman, for whatever rationale, is probably wise. During a listeria outbreak, pregnant women with fever and/or flu-like illness should be admitted to the hospital, and blood, rectal, and high vaginal cultures should be obtained. In addition, administration of intravenous ampicillin or penicillin, or perhaps vancomycin should be considered. (Erythromycin is not recommended as it is not bactericidal.) Issekutz and associates have shown that infants infected with L. monocytogenes during the perinatal period demonstrated neither a specific antibody response nor exhibited a cellmediated immunity response, which may explain the increased susceptibility of the fetus to this infection as compared with the pregnant woman. Bacteremia in the pregnant women with invasion of the fetal circulation is probably responsible for this form of perinatal listeriosis.

Neonatal Listeriosis In this later onset group, the infants are nearly full term, with the onset of symptom ranging between 9 days and 2 months after delivery. Fever and irritability are uniform, and the usual manifestations are meningitis and bacteremia. Thus, the late onset occurs in near full-term infants who may seem normal at birth, with symptoms beginning, in general, several days afterward. Infection seems to occur during the passage of the newborn through the birth canal. The mean onset of disease in this group is around 2 weeks of age, mainly because of a skewed distribution. Men-

ingitis, fever and irritability, is the predominant manifestation in this group, but sepsis is also noted. Finally, horizontal transmission of L. monocytogenes can occur, and nosocomial epidemics have been described. This adds to the argument that the late onset Iorm is acquired by partum or postpartum transmission. Because septic neonates are treated routinely with ampicillin and gentamicin, the therapy is usually appropriate and the cure rate is high. Illness in the mothers is not usually noted.

Primary Listeria Bacteremia Bacteremia is the most common clinical syndrome, along with meningitis, seen in adult patients. Fever associated with nonspecific complaints, such as fatigue, malaise, nausea, and vomiting, are the usual presenting symptoms. There are no clinical features that distinguish listeria bacteremia from other types of sepsis. L. monocytogenes can infect abnormal or prosthetic heart valves and cause endocarditis indistinguishable from any other form of endocarditis. The mortality rate associated with this syndrome is 48%. This high mortality may be related to delayed diagnosis, but more especially to the presence of predisposing factors including underlying heart disease in 60% of the endocarditis cases.

Focal Listeriosis Including Meningitis Although meningitis and primary bactermia are the most common syndromes caused by L. monocytogenes, focal listeria infections do occur, rarely. There are reported cases of brain stem encephalitis (rhomboencephalitis), brain abscess, pneumonia, empyema, peritonitis, septic bursitis, endocarditis, endophthalmitis, osteomyelitis, cholecystitis, liver abscess, and cutaneous infections. In general, these occur in immunocompromised people and are probably the result of seeding during an initial bacteremia. Thus, the finding of Gram-positive © 1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

rods, so-called "diphtheroids,'" in a supposedly sterile body compartment should raise the possibility of listeriosis, particularly in patients in high risk categories. Rhomboencephalitis is a unique syndrome of brain stem infarction (with opthalmoplegia) associated with the listeria bacteremia (usually without meningitis) and occasionally seen in the immunosuppressed patient. In this age of CAT scans and MRI, this diagnosis can be made premortum, and represents the high peak of clinical precognition reached by one of the authors. Perhaps most notable about cases of listeria meningitis is the relatively high monocytosis seen both peripherally and in the cerebrospinal fluid (CSF). In the latter specimen, this contrasts markedly with the/>90% polymorphonuclear response usually noted in a bacterial meningitis. Furthermore, the organism is seldom seen on gram stain of the CSF. Although pneumonia and/or empyema are infrequently reported manifestations of listeriosis in adults, they are in truth moderately frequent. Stamm and his associates reported listeria pneumonia to be present in seven patients among the 102 renal transplant recipients with tisteriosis that they reviewed. Listeria pteural effusion has also been reported in a patient who was apparently not immunocompromised. This form of listeriosis is probably not a rare one and may even be fairly common. This suggests the possibility that the respiratory tract can be the site of the infection, and that listeria bacteremia is a secondary feature. There is also a clear link between jaundice, alcoholic liver disease, ascites, and listeria peritonitis. Indeed, it occasionally mimics the spontaneous primary peritonitis seen in such patients. It has also been seen in cases with a variety of other forms of hepatobiliary disease. Where the organism originates from and how it penetrates to this area is a matter of conjecture. Whether it comes via the

37 Infectious Diseases Newsletter 10(5) May 1991 bowel lumen up to the portal vein and to the liver or ascitic fluid is not known but certainly seems possible. Joint or bursa involvement is rare but has been seen.

Risk Factors L. monocytogenes shows a propensity to infect individuals at the extremes of age, both the neonate and the elderly. Although listeriosis has been reported to occur in otherwise healthy individuals without clearly defined risk factors, they tend to be the older population. In our own experience, those patients with no apparent risk factors (including steriod therapy) were nearly all above 60 years of age. The high proportion of blacks and hispanics among pregnant women in most listeria series from this country suggests a socioeconomic factor in the predisposition to perinatal and neonatal listeriosis similar to what has been suggested previously. In addition to pregnancy, listeriosis has been clearly associated with leukemia/lymphoma patients. Other conditions that alter cell-mediated immunity apparently predispose to listeriosis, and L. monocytogenes is probably the most common cause of bacterial meningitis in such patients. These conditions include immunosup-

pression caused by chemotherapy and/or steroids used to treat patients with underlying malignancy, collagen-vascular disease (especially SLE, carcinoma of the GI tract, rheumatoid arthritis, organ transplantation, ulcerative colitis, or chronic obstructive lung disease), chronic diseases, such as diabetes mellitus, chronic renal disease, alcoholism and/or liver cirrhosis, and AIDS. It has been suggested by others that splenectomy may predispose to listeriosis. In addition, the earlier series on listeriosis do not include the HIVpositive patients who have now been reported from the Los Angeles area and have been seen in both Chicago and Nashville.

Bibliography Albritton W, Cochi S, Feeley J: Overview of neonatal listeriosis. Clin Invest Med 7:311-314, 1984. Carvajal A, Frederiksen W: Fatal endocarditis due to Listeria monocytogenes. Rev Infect Dis 10:616-623, 1988. Cherubin CE, Marr JS, Sierra MF, Becker S: Listeria and Gram-negative bacillary meningitis in New York City, 1972-1979. Am J Med 71:199-209, 1981. Fleming D, Cochi S, MacDonald K, et al.: Pasteurized milk as a vehicle of infection in an outbreak of listeriosis. N Engl J Med 312:404-407, 1985.

Gantz NM, Myerowitz RL, Medeiros AA, Carrera GF, Wilson RE, O'Brien TF: Listeriosis in immunosuppressed patients. A cluster of eight cases. Am J Med, May 58:637-642, 1975. Linnan M, Maseola L, Lou X, et al.: Epidemic listeriosis associated with Mexican-style cheese. N Engl J Med 319:823-828, 1988. Mascola L, Lieb L, Chiu J, Fannin SL, Linnan MJ: Listeriosis: An uncommon opportunistic infection in patients with acquired immunodeficiency syndrome. Am J Med 84:162-164, 1988. Schiech WF, Lavigne PM, Bortolusse R, et al.: Epidemic listeriosis: Evidence for transmission by food. N Engl J Med 308:203-206, 1983. Schwartz B, Hexter D, Broome C, et al.: Investigation of an outbreak of listeriosis: New hypotheses for the etiology of epidemic listeria monocytogenes infections. J Infect Dis 159:680-685, 1989. Simpson JF, Leddy JP, Hare JD: Listeriosis complicating lymphoma. Report of four cases and interpretive review of pathogenetic factors. Department of Neurology, University of Michigan Medical School, Ann Arbor, Michigan, and the Departments of Medicine and Microbiology, University of Rochester School of Medicine and Dentistry, Rochester, NY, unpublished observations, 43:39-49, July 1967. Stamm, A, Dismukes W, Simmons B, et al.: Listeriosis in renal transplant recipients: Report of an outbreak and review of 102 cases. Rev Infect Dis 4:665-668, 1982.

CASE REPORT

A 34-year-old woman beginning the 34th week of pregnancy was admitted to the hospital because of vaginal bleeding and patient-perceived decreased fetal movement for the preceding 24 h. The patient was gravida 1, para 0, and had had an uneventful pregnancy until 6 weeks prior to admission when she experienced diarrhea and a fever up to 104°F. Her husband remained well. The illness resolved without treatment in a few days, but the patient never felt entirely well. Throughout her pregnancy she took no medications other than vitamins and made an effort to

increase her consumption of dairy products. All milk and cheese products that she consumed were pasteurized and purchased at local supermarkets. She was allergic to sulfa drugs. At the time of admission the patient had a temperature of 100.4°F, respiratory rate of 22/min, pulse rate of 88/min, and blood pressure of 128/80 mmHg. Pelvic examination revealed that the cervix was 70% effaced and dilated 1-2 cm. The station was - 2 . Her hemoglobin was 12.2 g and white blood count was 11,000/mm 3. The platelet count was 134,000/mm 3. The © 1991 Elsevier Science Publishing Co., Inc. 0278-2316/91/$0.00 + 2.20

fetal heart rate was 120/min but dropped to 70/min shortly after admission, and the patient was taken to surgery for a Cesarean section as soon as this sign of fetal distress was noted. A 5-1b, 3-oz baby boy was delivered by Cesarean section with epidural anesthesia. The APGAR was 0 at 1 min and 5 at 5 min. The newborn boy had a temperature of 98.8°F, pulse rate of 172/min, and required intubation. The mother received 2 g of cefotetan intravenously during surgery. The infant was empirically started on ampicillin and gentamicin intravenously after cultures were ob-