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PubMed2002

Clinical implications of endotoxin concentrations in vaccines.

BACKGROUND: A previous study suggested that high concentrations of endotoxin may be present in whole-cell diphtheria/tetanus/pertussis (DTP) vaccine, and the scientific literature contains many studies examining the reactivity of whole-cell DTP vaccine. The medical and scientific communities have previously reported that the presence of endotoxin in commercial vaccines may have negative effects on vaccine recipients. OBJECTIVE: To determine the endotoxin concentrations in whole-cell DTP, acellular DTP(DTaP), and DT vaccines and determine the clinical experience with each vaccine. METHODS: To study the endotoxin concentrations in vaccines, the Limulus amebocyte lysate (LAL) assay was used. The vaccines analyzed with the LAL assay were whole-cell DTP vaccine lots manufactured by Connaught, Lederle, the Michigan and Massachusetts Departments of Health, and Wyeth; DTaP vaccine lots manufactured by Merieux and Takeda; and DT vaccine lots manufactured by Wyeth and Lederle. The incidence of adverse reactions following whole-cell DTP, DTaP, and DT vaccines were determined based on analysis of the Vaccine Adverse Events Reporting System (VAERS) database. RESULTS: The results of the LAL assay showed that whole-cell DTP vaccines contained considerably more endotoxin than either DTaP or DT vaccines. The VAERS showed that statistically significantly more adverse reactions were associated with whole-cell DTP vaccine than DTaP or DT vaccines. CONCLUSIONS: This analysis confirmed higher concentrations of endotoxin in whole-cell DTP vaccines compared with DTaP or DT vaccines. As high concentrations of endotoxin may be correlated with a higher incidence of adverse events, the switch from whole-cell DTP to DTaP for routine vaccinations in the US seems well justified.

Adolescent↗
PubMed1997

A rapid qualitative assay to detect circulating endotoxin can predict the development of multiorgan dysfunction.

OBJECTIVE: To determine whether a rapid qualitative assay for the detection of circulating endotoxin (SimpliRED Endotoxin Test [SRE]; AGEN, Inc; Brisbane, Australia) can predict the occurrence of multiorgan dysfunction and hospital mortality. To compare the SRE to the limulus amebocyte lysate (LAL) assay as a predictor of clinical outcomes. DESIGN: Prospective, blinded, single-center study. SETTING: Medical ICU of Barnes-Jewish Hospital, St. Louis, a university-affiliated teaching hospital. PATIENTS: Included in the study were 265 adult patients requiring medical ICU admission. INTERVENTIONS: Daily collection of blood samples. MEASUREMENTS AND RESULTS: Daily detection for the presence of endotoxin in blood during intensive care and assessment for the development of multiorgan dysfunction (ie, an organ system failure index >2) or death. On ICU day 1, 55 (20.8%) patients had circulating endotoxin detected by the SRE. On ICU day 2, 29 of the 143 (20.3%) patients remaining in the ICU had a positive SRE. The development of multiorgan dysfunction was significantly greater among SRE-positive patients (44.8%) compared to SRE-negative patients (21.9%) on ICU day 2 (p=0.013). Multiple logistic regression analysis identified a positive SRE on ICU day 2 (adjusted odds ratio, 4.1; 95% confidence interval, 2.5 to 6.8; p=0.006) as being independently associated with the development of multiorgan dysfunction. A positive SRE test was not predictive of hospital mortality. Direct quantitative measurement of the concentration of circulating endotoxin using the LAL assay was not associated with either the development of multiorgan dysfunction or hospital mortality (p>0.1). CONCLUSIONS: Our preliminary data suggest that a bedside assay to qualitatively detect circulating endotoxin is predictive of the development of multiorgan dysfunction among patients admitted to a medical ICU. The rapid detection of circulating endotoxin could be useful for stratifying patients into various risk categories for the development of multiorgan dysfunction.

Agglutination Tests↗
PubMed1986

Endotoxin-induced ATP depletion in thyrotoxic rats.

Effect of endotoxin from E. coli on the ATP content in heart muscle, the liver and the kidney of thyrotoxic rats was studied. When endotoxin (200-400 micrograms) was intravenously injected to rats taking drinking water containing 2-7.5 micrograms T3 per ml, body temperature rose and the heart rate increased. At the same time, a marked decrease in the ATP content in heart muscle and the kidney was observed together with an increase in Na+-K+-ATPase activity. Such changes were not observed or seen only to a small extent in euthyroid rats after endotoxin administration. Endotoxin-induced ATP depletion in T3-treated rats was prevented by administration of 5 mg hydrocortisone just prior to endotoxin injection. These findings indicate that endotoxin easily causes ATP depletion in some tissue or organs in thyrotoxicosis, even if the dose of endotoxin is not enough to produce such an effect in the euthyroid. These observations are of interest in relation to thyroid storm associated with bacterial infection.

Adenosine Triphosphatases↗
PubMed1979

The effect of heparinized blood exchange transfusion on endotoxin induced disseminated intravascular coagulation (DIC).

Sepsis of the newborn induced by gram negative bacteria, especially E. coli is often accompanied by a severe coagulation disorder. It can be treated by blood exchange transfusion (ET) with heparinized blood. In this study the hematological effect obtained by the exchange transfusion was investigated in rabbits after induction of a generalized Shwartzman reaction by two spaced injections of endotoxin (75 microgram/kg) 24 hrs. apart. Three groups of 6 animals each were investigated: group I: without endotoxin but with ET (controls); group II: endotoxin without ET; group III: endotoxin with ET. Fibrinogen, soluble fibrin monomer complexes (SFMC), fibrin(ogen) degradation products (FDP), platelet- and leukocyte counts and urine volume (ml/hr) were estimated. In group II a decline in the fibrinogen level, and in platelet and leukocyte count, as well as an increase in SFMC and FDP could be observed from 6 hrs. on after the second endotoxin injection. In group III 6 hrs. after the second endotoxin injection, exchange transfusion with heparinized blood was performed. Variance analysis showed significant differences in all parameters, except in the urine volumes after exchange transfusion between group III and group II. By exchange transfusion an approach of the values towards the values of the controls could be recognized. The findings indicate, that by blood exchange transfusion the hematological consequences of the endotoxin induced DIC can be corrected, while the dysfunction of the kidneys can be improved only slightly.

Animals↗
PubMed1997

Differential distribution of ecNOS and iNOS mRNA in rat heart after endotoxin administration.

To evaluate the relationship between cardiovascular injury and the pathological significance of endothelial constitutive nitric oxide synthase (ecNOS) and inducible nitric oxide synthase (iNOS) in endotoxic shock, Wistar rats were injected intraperitoneally with 10 mg/kg Escherichia coli endotoxin and the resulting cardiovascular changes observed using immunohistochemistry, immunoelectron microscopy, the reverse transcription polymerase chain reaction (RT-PCR) and in situ hybridization at 4, 6, 8 and 10 h after endotoxin administration. Immunohistochemical and electron microscopic observations showed that ecNOS was localized in the cytoplasmic vesicles and rough endoplasmic reticulum of the endothelium of coronary arteries and intermyocardial capillaries in both control and endotoxin-treated rats. iNOS was localized in the cytoplasmic vesicles and endoplasmic reticulum of vascular endothelial cells, vascular smooth muscle cells and cardiomyocytes after endotoxin administration. The RT-PCR study confirmed the expression of ecNOS and iNOS mRNA in the heart tissues of all animals including controls. In situ hybridization showed that ecNOS mRNA was expressed in the cytoplasm of vascular endothelial cells in control and endotoxin-treated rats. After endotoxin administration, iNOS mRNA was strongly expressed in vascular endothelial cells, vascular smooth muscle cells, cardiomyocytes and a small number of macrophages. Bacterial lipopoly-saccharide induces rapid release of nitric oxide in the microvasculature and cardiomyocytes resulting in the depression of cardiomyocyte contraction. These findings may describe the cardiac response after endotoxin treatment.

Animals↗
PubMed1987

Induction of metallothionein synthesis in cultured cells by substances released from endotoxin-activated macrophages.

The involvement of macrophages in the induction of metallothionein (MT) synthesis by bacterial endotoxin was studied in vitro. Rat peritoneal macrophages were incubated with endotoxin. The incubation medium from endotoxin-activated macrophages accelerated MT synthesis by human hepatic Chang cells. However, the incubation medium from non-activated macrophages did not. Endotoxin added to the culture medium of Chang cells was ineffective in inducing MT synthesis. The contents of zinc, copper and cadmium, which are primary inducers of MT, in the incubation medium of macrophages in the presence of endotoxin were not different from those in the absence of endotoxin. These results suggest that MT synthesis is induced by endotoxin-treated macrophages.

Animals↗
PubMed1980

Development changes in the febrile response to endotoxin in rabbit.

The pyrogenicity of E. coli endotoxin (lipopolysaccharide, LPS) was measured at both 25 degrees C and neutral temperatures (Tn) in day -1 to adult rabbits. Intravenous injection of endotoxin (0.5 micrograms/kg) produced febrile response at Tn in day -1 rabbits, but not at 25 degrees C. A similar response was observed when endotoxin was injected s.c. (1.0 micrograms/kg) or intracisternally (0.0001 micrograms/kg). The mean magnitude of the rise of rectal temperature increased with the advance of age. Propranolol abolished the endotoxin-fever in day 3 rabbits. The inhibitory effect of propranolol was incomplete in day 14 rabbits and was not seen in day 28 rabbits. The inhibitory effect of phentolamine was not observed in day 3 and day 28 rabbits, but the blocker reduced the febrile response in day 14 rabbits. No shivering activity was evident in day 3 rabbits after injection of endotoxin. In the day 7 and 14 rabbits, shivering was less significant and of shorter duration than in the case of day 28 rabbits. The endotoxin caused no significant decrease in ear skin temperature in day 3 rabbits. A decrease in ear skin temperature was observed in rabbits older than 14 days. Thus, pyrogenic sensitivity is apparent even in day -1 rabbits. The mechanism of the heat production underlying endotoxin-fever gradually shifted from the nonshivering thermogenesis mediated by catecholamines to shivering thermogenesis during the first month of life.

Animals↗
PubMed1994

The inhibitory effect of endotoxins on growth of human cell lines.

A study was conducted to examine the effect of endotoxin present in periodontal pockets on the proliferation and attachment of human cell lines on the culture plates (Ca9-22 and gingival fibroblasts). The endotoxin was collected from periodontal pockets of anterior teeth in patients with periodontal disease by subgingival irrigation with sterilized distilled water. The solutions obtained were then subjected to hot phenol-water extraction. The collected endotoxin from periodontal pocket and four other kinds of endotoxin obtained commercially as positive controls were added to cell cultures and the numbers of viable cells on the culture plates were counted. Among the commercially available endotoxins used in this study, only 500 micrograms/ml of endotoxin derived from Escherichia coli 0111:B4 significantly decreased the number of attachment cells of Ca9-22 and gingival fibroblasts on the culture plates. Endotoxin from periodontal pockets at 5 micrograms/ml also significantly decreased the numbers of attachment cells of both cell lines.

Adult↗
PubMed1992

Permeability of the normal round window membrane to Haemophilus influenzae type b endotoxin.

Sensorineural hearing loss associated with otitis media may be due to passage of ototoxic substances such as bacterial toxins and antibiotics, from the middle ear into the inner ear. The round window membrane is the most likely route for such transport. The aim of this study was to analyze the extent of endotoxin passage through the normal round window membrane. The round window membranes of 19 chinchillas were exposed in vivo to Gelfoam soaked in purified Haemophilus influenzae type b endotoxin at a concentration of 45,000 endotoxin units per ml (EU/ml) during 3 to 24 h. Endotoxin levels in the perilymph were measured with Limulus Amaebocyte Lysate or Quantitative Chromogenic Limulus Amaebocyte Lysate. Endotoxin was detected in half of the inner ears at concentrations close to the detection limit (approximately 4 EU/ml). The results suggest that the normal round window membrane efficiently protects the inner ear against the passage of bacterial endotoxins from the middle ear cavity. It is unlikely that endotoxin at concentrations found in the middle ear secretion during otitis media can traverse the round window membrane in sufficient amount to cause inner ear deterioration.

Animals↗
PubMed1997

Prognostic value of plasma endotoxin levels in patients with cirrhosis.

BACKGROUND: Endotoxemia has frequently been observed in patients with cirrhosis. Previous studies have shown that cirrhotic patients with endotoxemia have a higher mortality than those without. We evaluated the clinical value of plasma endotoxin level in predicting short-term (3 months) and long-term (2 years) survival among cirrhotic patients and compared it with the Child-Pugh score. METHODS: Plasma endotoxin levels were determined in 102 cirrhotic patients without clinical evidence of infection by a quantitative Limulus assay. The patients were followed up for 3 months to assess short-term survival and for 2 years for long-term survival. RESULTS: Plasma endotoxin levels increased progressively as liver function deteriorated. In short-term survival analysis, plasma endotoxin levels were significantly higher in non-survivors than those in survivors (10.6 +/- 2.2 pg/ml versus 5.8 +/- 0.5 pg/ml; P < 0.05). Both plasma endotoxin and serum bilirubin levels, but not the Child-Pugh score, were significant factors in predicting short-term survival in multivariate analysis. In long-term survival analysis, plasma endotoxin levels did not differ significantly between survivors and non-survivors (6.1 +/- 0.6 pg/ml versus 7.3 +/- 1.1 pg/ml; P > 0.05) and was not an independent predictor of long-term survival. In contrast, both Child-Pugh score and serum bilirubin levels were significant predictors of long-term survival in multivariate analysis. CONCLUSIONS: In patients with cirrhosis, plasma endotoxin levels progressively increase as liver function deteriorates and may be useful in predicting short-term survival.

Aged↗
PubMed1984

Endotoxin liberation and invasivity of Neisseria meningitidis.

The relationship between endotoxin liberation and invasiveness was studied in 50 strains of Neisseria meningitidis isolated from blood or cerebrospinal fluid (CSF) of 16 patients with invasive disease, from nasopharynx of 9 patients with upper respiratory tract symptoms, and from nasopharynx and rectum (1, serogroup W-135) in 25 persons examined for venereal disease. Meningococci varied in their ability to liberate endotoxin. Free endotoxin was partly a function of growth and seemed to be associated with certain properties of the individual strain. Strains isolated for patients with invasive disease liberated significantly more endotoxin than strains isolated from the venereal group (p less than 0.002). All 16 invasive strains were sulfonamide resistant, against 5/9 strains from patients with upper respiratory disease symptoms and only 4/25 strains from the venereal group. The difference between the invasive group and the venereal group was significant (p less than 0.002). Serogroup A, B, C meningococci liberated significantly more endotoxin than non-A, B, C strains (p = 0.01, and serogroup A, B, C strains isolated from nasopharynx tended to have a higher endotoxin release than non-A, B, C strains isolated from the same place (not significant). Serogroup B meningococci were most frequently isolated both from patients with invasive disease and from the nasopharynx of the persons examined for venereal disease. Serogroup B meningococci had significantly more free endotoxin when isolated from blood or CSF than when isolated from nasopharynx of presumably healthy persons (p = 0.002).

Bacteriological Techniques↗
PubMed1987

Endotoxin liberation from Neisseria meningitidis isolated from carriers and clinical cases.

Endotoxin liberation was studied in a blinded material of 121 Neisseria meningitidis isolates; from nasopharynx of 58 carriers and from cerebrospinal fluid or blood of 63 cases with meningococcal disease. Endotoxin activity in culture filtrates was determined by a Limulus lysate test. Meningococci isolated from clinical cases were significantly more frequently endotoxin-liberating (E+) (84.1%) than in carriers (25.9%); p less than 0.001. Serogroupable carrier isolates had a significantly higher frequency of E+ meningococci (61.9%) than non-groupable ones (5.4%); p less than 0.002. Serogroup B case isolates, which generally had a larger amount of capsular polysaccharide than B meningococci from carriers, had a significantly higher proportion of E+ meningococci than group B from carriers; p = 0.007. All 7 serogroup C isolates were E+ (5 cases and 2 carriers). No correlation was found between endotoxin liberation and the serotype: subtype 15:P1.16, tested by a selection of monoclonal antibodies, or between endotoxin liberation and sulfonamide resistance, when carrier and case isolates were studied separately. Meningococci isolated from cases had the following mean endotoxin titres: 320.5 in the meningitis group, 408.2 in the septicaemic group, 462.1 in the septicaemic and meningitis group, and 123.7 in the group with other systemic disease. E+ meningococci were isolated from 5/6 fatal cases. Thus, endotoxin liberation from meningococci is strongly, but not completely associated with establishment of meningococcal disease and with the presence of capsular polysaccharide.

Carrier State↗
PubMedDate not supplied

One-month exposure to inhaled endotoxin produces a dose-dependent increase in stored mucosubstances in rat intrapulmonary airways.

This study examined the production of stored mucosubtances in rats after repeated exposure to aerosolized endotoxin, a common contaminant of bioaerosols. Male Fischer 344 rats were exposed to aerosolized saline (sham control) or endotoxin (target concentrations of 0.05, 0.5, and 5.0 micrograms/m3) for 3 h/day, 5 days/week for 4 weeks. Following the final exposure, the left lung of each animal was lavaged and the right lung and nasal cavity were fixed with buffered formalin. Morphometric examination of Alcian blue/Periodic acid Schiffs-stained (AB/PAS) lung sections demonstrated dose-dependent increases in stored intraepithelial mucosubstances in the intrapulmonary airways of endotoxin-exposed rats. Threefold and eightfold increases in stored mucosubstances were observed in generation 5 airways of animals exposed to 0.5 or 5.0 microgram/m3 endotoxin, respectively (p < .05). This mucous cell metaplasia in the intrapulmonary airways was not accompanied by evidence of lung inflammation or increased AB/PAS-staining high molecular weight material in lavage fluid. Furthermore, despite significant deposition of endotoxin aerosols (mass median aerodynamic diameter of 1.9 microns) in the nasal cavity, no significant changes in stored mucosubstances were observed in the nasal septum. In animals repeatedly exposed to 5.0 micrograms/m3 endotoxin and allowed to recover for 1 month, stored mucosubstances in the intrapulmonary airway were still more than fivefold greater than control values. Thus, in rats, repeated exposure to inhaled endotoxin produced a persistent mucous cell metaplasia only in the intrapulmonary airways.

Administration, Inhalation↗
PubMed1986

Effects of endotoxin on mammary secretion of lactating goats.

The objectives were to describe the magnitude and time course of changes in milk pH, Na, K, lactose, and somatic cells and to determine if paracellular pathways were altered after infusion of Escherichia coli endotoxin (serotype #0128:AB12) to produce inflammation in one-half of the udder of the goat. Intramammary infusion of endotoxin increased pH, number of somatic cells, and Na and decreased K and lactose in milk. Sodium and number of somatic cells were increased by as little as .1 microgram of endotoxin; .25 microgram produced changes in most of the other parameters; maximal effect was elicited by 1 microgram of endotoxin. The gland response peaked from 5 to 7 h after infusion of endotoxin with an increase in milk cellularity as the only significant effect noted in the control gland. Infusion of [14C]lactose into the gland and [99mTc]albumin into the blood demonstrated that large molecules were more able to cross into and out of udder halves after endotoxin treatment. It is suggested that ion interchange rather than bulk flow across paracellular paths is responsible for changes. In addition, endotoxin appeared to reduce lactose secretion and synthesis.

Animals↗
PubMed1992

Antigenic homology of endotoxin with a coliform mastitis vaccine strain, Escherichia coli O111:B4 (J5).

This study examined recognition of heterologous Gram-negative endotoxin by antibodies recognizing common lipopolysaccharide core antigens. Gram-negative endotoxins from 11 heterologous bacterial strains were tested for recognition by antibodies against common lipopolysaccharide core antigens. Serum was harvested from a calf immunized with the Rc mutant, Escherichia coli O111:B4 (J5), and affinity purified against endotoxin derived from an Ra mutant, Salmonella typhimurium, producing an antibody reagent recognizing homologous Gram-negative core antigens present in the Rc mutant vaccinal antigen. This reagent demonstrated reactivity against 11 chemically purified Gram-negative endotoxins. Included were endotoxins derived from 3 smooth E. coli species, 2 Salmonella spp., Shigella flexneri, Klebsiella pneumoniae, Pseudomonas aeruginosa, Serratia marcescens, and lipid A. Endotoxin derived from K. pneumoniae had significantly higher ELISA reactivity with core antigen specific antibodies than did endotoxin derived from either E. coli O111:B4 (J5) or P. aeruginosa. These results suggest immunization with R mutant bacterins may have utility in the prevention of Gram-negative mastitis even when whole bacteria react poorly with antibodies recognizing common core antigens.

Animals↗
PubMed1999

Nitric oxide production during endotoxin-induced mastitis in the cow.

Nitric oxide production was measured during endotoxin-induced mastitis. One hour after morning milking, the right hind quarters of 15 cows were infused with saline containing Escherichia coli endotoxin. Left hind control quarters were infused with saline only. At varying intervals before and after infusion, diagnostic markers of mastitis were recorded and nitric oxide production was evaluated by measuring nitrite plus nitrate levels in milk. In endotoxin-infused quarters, a significant increase in nitrite plus nitrate concentrations was observed 3 h postinfusion; concentrations decreased to preinfusion levels within 48 h. This change indicates that significant amounts of nitric oxide are released during endotoxin-induced mastitis. At 3 different time points, somatic cells were harvested from milk samples, plated, and maintained in culture for 24 h. The concentration of nitrite plus nitrate in medium from cells harvested 12 h postinfusion was increased, suggesting that nitric oxide is released, at least in part, by milk somatic cells. In a second set of experiments, we evaluated nitric oxide production when animals were infused with endotoxin and aminoguanidine, a specific inhibitor of the inducible form of nitric oxide synthase. In cows treated with aminoguanidine, the increase in nitrite plus nitrate observed after endotoxin infusion was prevented. These results suggest that nitric oxide production during endotoxin-induced mastitis resulted from the activity of the inducible form of nitric oxide synthase. They also support a possible involvement for nitric oxide in the inflammatory reaction observed during mastitis.

Animals↗
PubMed1975

Failure to demonstrate circulating endotoxin in malaria (38572).

The possibility that endotoxin or an endotoxin-like substance plays a role in malaria has been suggested by the clinical similarity between human malaria and the febrile reaction to endotoxins, as well as the occurrence of endotoxin tolerance in humans infected with malaria. However, endotoxin or endotoxin-like activity was not demonstrable, using the Limulus test, in the plasma of humans or monkeys infected with plasmodia. The data indicate that the febrile paroxysm of malarial infection is not associated with detectable levels of endotoxin in the blood.

Animals↗
PubMed1975

Endotoxin binding by charged and uncharged resins.

Cholestyramine (Dowex 1-X2), a strongly basic anion-exchange resin, has previously been shown to bind bacterial endotoxin, preventing both its toxicity and intestinal absorption. Because hemoperfusion through charged and uncharged resins is practical, a study was undertaken to test the endotoxin-binding characteristics of a number of resins. The resin to be tested was washed and swelled overnight, and 1 mg/ml of 51Cr-labeled endotoxin was added and the mixture, agitated and incubated at 37 degrees for a specific time period. In the Dowex 1 series, the 1-X2 was superior to the 1-X4 and 1-X8 in its ability to bind E. coli endotoxin, removing about 90% from solution in 15 min. Increasing mesh size seemed to offer more binding sites for each Dowex 1 resin. Activated charcoal adsorbed about 90% of the endotoxin also, but Amberlite XAD-2 showed little binding capacity. Injection of filtrate from unlabeled E. coli and S. typhosa resin-treated solution into rats, demonstrated that both Dowex 1-X2 and activated charcoal prevented the transaminase rise noted in animals injected with solutions not so treated. It is concluded that Dowex 1-X2 resin and activated charcoal efficiently remove endotoxin in vitro, and may offer a unique method for removing circulating endotoxin in vivo.

Alanine Transaminase↗